WO2012020738A1 - Heterocyclic compound and use thereof - Google Patents

Heterocyclic compound and use thereof Download PDF

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Publication number
WO2012020738A1
WO2012020738A1 PCT/JP2011/068087 JP2011068087W WO2012020738A1 WO 2012020738 A1 WO2012020738 A1 WO 2012020738A1 JP 2011068087 W JP2011068087 W JP 2011068087W WO 2012020738 A1 WO2012020738 A1 WO 2012020738A1
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group
compound
substituent
methyl
optionally substituted
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PCT/JP2011/068087
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French (fr)
Japanese (ja)
Inventor
和義 麻生
和之 徳丸
崇 中畑
吉輝 伊藤
泉 野村
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武田薬品工業株式会社
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Priority to TW100148554A priority Critical patent/TW201307294A/en
Priority to ARP120100397A priority patent/AR085323A1/en
Publication of WO2012020738A1 publication Critical patent/WO2012020738A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—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

Definitions

  • the present invention relates to a novel heterocyclic compound, a process for producing the same, and a medicine containing the same. More specifically, the present invention relates to a compound having an agonist activity for GPR52 and effective as a medicament for the prevention / treatment of mental disorders such as schizophrenia.
  • Schizophrenia is a disease that develops from adolescence to adulthood and exhibits characteristic thought disorders, ego disorders, and behavioral abnormalities associated therewith. The incidence is said to be about 1% of the total population, but many are chronically progressed, and spontaneity and interpersonal contact are reduced, making social life extremely difficult.
  • the core symptoms of schizophrenia are (1) positive symptoms such as delusions and hallucinations, (2) dull sensation, withdrawal, negative symptoms such as decreased motivation and concentration, and (3) cognitive dysfunction. Often separated. In these core symptoms, hypersensitivity of the dopamine nervous system in the mesencephalic system is associated with positive symptoms, and neurological functions such as glutamate nervous system in the frontal cortex for negative symptoms and cognitive decline. The decline is said to be deeply involved.
  • typical antipsychotics having dopamine D2 receptor antagonist activity such as chlorpromazine have shown an improving effect.
  • multireceptor-acting drugs such as clozapine and olanzapine have a certain effect on negative symptoms and cognitive impairment, but are known to be less responsive to many patients .
  • typical antipsychotics have problems of extrapyramidal symptoms such as akathisia, dystonia, and Parkinsonian movement disorder, and hyperprolactinemia.
  • clozapine has granulocytopenia as a serious side effect, and side effects such as weight gain, abnormal lipid metabolism, hypersedation, and prolonged cardiac QT interval are also problems in atypical antipsychotics such as olanzapine.
  • Human GPR52 G Protein-Coupled Receptor 52
  • GPCR G Protein-Coupled Receptor
  • agonists and ligands for GPR52 increase the intracellular cAMP concentration of nerve cells expressing GPR52 and the like, and the mesencephalic dopamine pathway, which is one of the causes of positive symptoms of schizophrenia It is thought that the positive symptoms of schizophrenia can be improved by suppressing overactivity.
  • NMDA receptor functional decline it is possible to improve cerebral cortex NMDA receptor functional decline, one of the causes of schizophrenia negative symptoms and cognitive dysfunction, and to improve schizophrenia negative symptoms and cognitive dysfunction (Patent document 1).
  • the above-mentioned action to increase intracellular cAMP concentration in nerve cells is not only a dopamine system, but also regulation of functions of various neurotransmitters such as norepinephrine, serotonin, histamine, and acetylcholine, nerve survival, differentiation, and , May be involved in plastic changes. Therefore, agonists and ligands for GPR52 can be expected to exert useful effects on various systemic diseases caused by mental disorders, neurodegenerative diseases, or modulation of the nervous system.
  • GPR52 agonists are schizophrenia as GPR52 agonists (GPR52 agonists; GPR52 receptor agonists, GPR52 receptor agonists, GPR52 activators, sometimes referred to as GPR52 receptor activators) It is useful for the prevention and treatment of various diseases including psychiatric disorders such as infectious diseases.
  • Patent Documents 2 to 4 disclose compounds represented by the following general formulas (the meanings of the symbols in the general formulas of Patent Documents 2 to 4 are the same as those of each patent). See the literature description).
  • Patent Document 2 discloses a compound represented by the following general formula.
  • Patent Document 3 discloses a compound represented by the following general formula.
  • Patent Document 4 discloses a compound represented by the following general formula.
  • Patent Document 5 discloses the following two compounds. CAS registration number 473882-08-5
  • Patent Document 6 discloses the following compounds. CAS registration number 1186102-00-0
  • Patent Document 7 discloses the following compounds. CAS registration number RN848673-38-1
  • Patent Document 8 discloses the following compounds. CAS registration number RN847858-78-0
  • Patent Document 9 discloses the following compounds. CAS registration number RN280111-58-2
  • Patent Document 10 discloses the following compounds. CAS registration number RN795310-84-8
  • Patent Document 11 discloses the following compounds. CAS registration number RN442877-18-1
  • Non-Patent Document 2 discloses the following compounds. CAS registration number RN737766-67-5P
  • Non-Patent Document 3 discloses the following compounds. CAS registration number RN197717-25-2
  • Non-Patent Document 4 discloses the following compounds. CAS registration number RN301219-12-5
  • An object of the present invention is to provide a compound having an agonist activity for GPR52 and useful as a medicament for the prevention / treatment of mental disorders such as schizophrenia.
  • Ring A has an optionally substituted 6 to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered non-aromatic heterocyclic ring, or a substituent. May represent a 5- to 10-membered aromatic heterocycle; Ring B is (1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent, (2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring; Partial structural formula of formula (I):
  • R 1 has a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent.
  • a C 2-6 alkynyl group optionally having a C 3-6 cycloalkyl group, optionally having a C 6-14 aryl group, having a substituent
  • L 1 represents —O—, —CO—, an optionally substituted C 1-6 alkylene, or an optionally substituted C 3-6 cycloalkylene;
  • L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH—;
  • Y represents C 1-3 alkylene which may have a substituent;
  • L 3 represents — (CH 2 ) n — (n represents 0 or 1).
  • R 1 represents —CO—R xc (R xc represents a substituent) and L 1 represents —CH 2 —
  • L 1 represents —CH 2 —
  • the present invention also provides [1A] Formula (I ′):
  • Ring A has an optionally substituted 6 to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered non-aromatic heterocyclic ring, or a substituent. May represent a 5- to 10-membered aromatic heterocycle; Ring B is (1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent, (2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring; Partial structural formula of formula (I ′):
  • R 1 has a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent.
  • An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted amino group, a cyano group, or —S (O) m represents 0; 1 or 2;
  • Ra represents a hydrogen atom or a C 1-6 alkyl group);
  • R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent.
  • L 1 represents —O—, —CO—, an optionally substituted C 1-6 alkylene, or an optionally substituted C 3-6 cycloalkylene;
  • L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH—;
  • Y represents C 1-3 alkylene which may have a substituent.
  • R 1 represents —CO—R xc (R xc represents a substituent) and L 1 represents —CH 2 —
  • L 1 represents —CH 2 —
  • the present invention also provides [1B] Formula (I ′):
  • Ring A represents a 6 to 10-membered aromatic hydrocarbon ring which may have a substituent, or a 5 to 10-membered aromatic heterocycle which may have a substituent
  • Ring B is (1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent, (2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed.
  • R 1 has a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent.
  • An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted amino group, a cyano group, or —S (O) m represents 0; 1 or 2;
  • Ra represents a hydrogen atom or a C 1-6 alkyl group);
  • R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent.
  • L 1 represents —O—, —CO—, an optionally substituted C 1-6 alkylene, or an optionally substituted C 3-6 cycloalkylene;
  • L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH—;
  • Y represents C 1-3 alkylene which may have a substituent.
  • R 1 represents —CO—R xc (R xc represents a substituent) and L 1 represents —CH 2 —
  • L 1 represents —CH 2 —
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “C 1-6 alkyl group” and the “C 1-6 alkyl” in the substituent include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl.
  • C 1-6 alkoxy group and the “C 1-6 alkoxy” in the substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, Examples thereof include tert-butoxy, pentyloxy, hexyloxy and the like. Of these, “C 1-4 alkoxy (group)” is preferable.
  • examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, etc. . Of these, C 2-4 alkenyl (group) is preferable.
  • examples of the “C 2-6 alkenyloxy group” include ethenyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, -Butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3 -Hexenyloxy, 5-hexenyloxy and the like.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, -Pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • C 2-4 alkynyl (group) is preferable.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] Decyl, adamantyl and the like.
  • examples of the “C 3-6 cycloalkyl group” and the “C 3-6 cycloalkyl” in the substituent include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, bicyclo [2 2.1] heptyloxy, bicyclo [2.2.2] octyloxy, bicyclo [3.2.1] octyloxy, bicyclo [3.2.2] nonyloxy, bicyclo [3.3.1] nonyloxy, Bicyclo [4.2.1] nonyloxy, bicyclo [4.3.1] decyloxy, adamantyloxy and the like can be mentioned.
  • examples of the “C 6-14 aryl group” and the “C 6-14 aryl” in the substituent include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like.
  • examples of the “C 6-10 aryl group” and the “C 6-10 aryl” in the substituent include phenyl, naphthyl (1-naphthyl, 2-naphthyl) and the like.
  • examples of the “C 6-10 aryloxy group” include phenyloxy, naphthyloxy (1-naphthyloxy, 2-naphthyloxy) and the like.
  • C 7-13 aralkyl group and “C 7-13 aralkyl” in a substituent include benzyl, phenethyl, naphthylmethyl (1-naphthylmethyl, 2-naphthylmethyl), biphenylylmethyl, etc. Is mentioned.
  • examples of the “C 7-13 aralkyloxy group” include benzyloxy, phenethyloxy, naphthylmethyloxy (1-naphthylmethyloxy, 2-naphthylmethyloxy), biphenylylmethyloxy and the like.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, Examples thereof include tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl. 2,2-dimethylpropanoyl, hexanoyl, heptanoyl and the like.
  • examples of the “C 1-6 alkyl-carbonyloxy group” include acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy, pentanoyloxy, 3- Examples thereof include methylbutanoyloxy, 2-methylbutanoyloxy, 2,2-dimethylpropanoyloxy, hexanoyloxy, heptanoyloxy and the like.
  • examples of the “6- to 10-membered aromatic hydrocarbon ring” include benzene and naphthalene.
  • the “aromatic heterocyclic group” and the “aromatic heterocyclic ring” in the substituent include, for example, an oxygen atom, a sulfur atom (the sulfur atom other than a carbon atom) as a ring-constituting atom.
  • the atom may be oxidized) and a 4-7 membered (preferably 5 or 6 membered) monocyclic aromatic heterocyclic group and condensed aromatic containing 1 to 4 heteroatoms selected from nitrogen atoms
  • a heterocyclic group is mentioned.
  • condensed aromatic heterocyclic group examples include these 4 to 7-membered monocyclic aromatic heterocyclic groups and 5- or 6-membered aromatic heterocyclic rings containing 1 or 2 nitrogen atoms (eg, pyrrole). Imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing one sulfur atom (eg, thiophene), or a group in which one or two benzene rings are condensed.
  • Furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl
  • 5-pyrimidinyl pyridazinyl
  • pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl eg, 2-pyrazinyl
  • pyrrolyl eg, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl eg, 1 -Imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • thiazolyl eg, 2-thiazolyl, 4-thi
  • non-aromatic heterocyclic group examples include, for example, an oxygen atom, a sulfur atom ( The sulfur atom may be oxidized) and a 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atoms and A condensed non-aromatic heterocyclic group is mentioned.
  • condensed non-aromatic heterocyclic group examples include, for example, these 4- to 7-membered monocyclic non-aromatic heterocyclic groups and 5- or 6-membered aromatic or non-aromatic groups containing 1 or 2 nitrogen atoms.
  • Heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom eg, thiophene
  • a benzene ring examples include a group having two condensed groups.
  • Pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl
  • piperidinyl eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl
  • homopiperidinyl eg, homopiperidino, 2-homopiperidinyl, 3-homopiperidinyl, 4-homopiperidinyl
  • tetrahydropyridyl eg, 1,2,3,6-tetrahydropyridin-1-yl
  • dihydropyridyl eg, 2,3-dihydropyridin-4-yl
  • morpholinyl eg, morpholino, 2- Morpholinyl
  • thiomorpholinyl eg, thiomorpholino
  • 1,1-dioxothiomorpholinyl eg, 1,1-dioxothiomorpholinyl
  • examples of the “5- to 10-membered aromatic heterocyclic ring” include those exemplified as the above “aromatic heterocyclic group” and “aromatic heterocyclic ring” in the substituent. Examples thereof include a ring constituting a 5- to 10-membered aromatic heterocyclic group.
  • aromatic heterocyclic rings include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole (eg, 1, 2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (eg, 1,2,3-thiadiazole, 1,3,4-thiadiazole), triazole (eg, 1,2,4- Monocyclic aromatic heterocycles such as triazole, 1,2,3-triazole), tetrazole, triazine (eg, 1,2,4-triazine); Quinoline, isoquinoline, quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzimidazole, benzotriazine
  • examples of the “5- to 10-membered non-aromatic heterocyclic ring” include the above-mentioned “non-aromatic heterocyclic group” and “non-aromatic heterocyclic ring” in the substituent. Among them, a ring constituting a 5- to 10-membered non-aromatic heterocyclic group can be mentioned.
  • aromatic heterocycle examples include pyrrolidine, piperidine, homopiperidine, tetrahydropyridine (eg, 1,2,3,6-tetrahydropyridine), dihydropyridine (eg, 2,3-dihydropyridine), morpholine , Thiomorpholine, 1,1-dioxothiomorpholine, piperazine, 3-oxopiperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, 2-oxoimidazolidine, oxazoline, thiazoline, imidazoline, dioxol (eg, 1,3 -Dioxole), dioxolane (eg, 1,3-dioxolane), dihydrooxadiazole (eg, 4,5-dihydro-1,2,4-oxadiazole), pyran, tetrahydropyran, thiopyran, tetrahydrothio
  • examples of the “5- or 6-membered heterocycle” include a 5- or 6-membered aromatic heterocycle and a 5- or 6-membered non-aromatic heterocycle.
  • the 5- or 6-membered aromatic heterocycle includes, for example, 5- or 6-membered aromatic heterocycle among those exemplified as the above “aromatic heterocycle” and “aromatic heterocycle” in the substituent.
  • the ring which comprises a cyclic group is mentioned.
  • aromatic heterocycle examples include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole (eg, 1, 2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (eg, 1,2,3-thiadiazole, 1,3,4-thiadiazole), triazole (eg, 1,2,4- Triazole, 1,2,3-triazole), tetrazole, triazine (eg, 1,2,4-triazine) and the like.
  • oxadiazole eg, 1, 2,5-oxadiazole, 1,3,4-oxadiazole
  • thiadiazole eg, 1,2,3-thiadiazole, 1,3,4-thiadiazole
  • triazole eg, 1,2,4
  • examples of the 5- or 6-membered non-aromatic heterocyclic ring include 5- or 6-membered members out of those exemplified as the above-mentioned “non-aromatic heterocyclic group” and “non-aromatic heterocyclic ring” in the substituent.
  • the ring which comprises a non-aromatic heterocyclic group is mentioned.
  • non-aromatic heterocycles include pyrrolidine, piperidine, homopiperidine, tetrahydropyridine (eg, 1,2,3,6-tetrahydropyridine), dihydropyridine (eg, 1,2-dihydropyridine, 2 , 3-dihydropyridine), morpholine, thiomorpholine, 1,1-dioxothiomorpholine, piperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, 2-oxoimidazolidine, oxazoline, thiazoline, imidazoline, dioxol (eg, 1 , 3-dioxole), dioxolane (eg, 1,3-dioxolane), dihydrooxadiazole (eg, 4,5-dihydro-1,2,4-oxadiazole), pyran, tetrahydropyran, thiopyran, t
  • examples of the “5- or 6-membered ring” include benzene, the above-mentioned “5- or 6-membered aromatic heterocycle” and “5- or 6-membered non-aromatic heterocycle”.
  • examples of the “5- or 6-membered non-aromatic hydrocarbon rings” include benzene, the above-mentioned “5- or 6-membered aromatic heterocycle” and “5- or 6-membered non-aromatic heterocycle”.
  • examples of the “5- or 6-membered non-aromatic hydrocarbon rings” include benzene, the above-mentioned “5- or 6-membered aromatic heterocycle” and “5- or 6-membered non-aromatic heterocycle”.
  • examples of the “5- or 6-membered non-aromatic hydrocarbon rings” include benzene, the above-mentioned “5- or 6-membered aromatic heterocycle” and “5- or 6-membered non-aromatic heterocycle”.
  • C 1-6 alkylene examples include methylene, ethylene, trimethylene (— (CH 2 ) 3 —), —CH (CH 3 ) —CH 2 —, —CH 2 —CH (CH 3 ) —, —C (CH 3 ) 2 —, — (CH 2 ) 4 —, —CH (CH 3 ) — (CH 2 ) 2 —, —CH 2 —CH (CH 3 ) — CH 2 —, — (CH 2 ) 2 —CH (CH 3 ) —, —C (CH 3 ) 2 —CH 2 —, —CH 2 —C (CH 3 ) 2 —, —CH (CH 3 ) —CH (CH 3 ) —, —C (C 2 H 5 ) (CH 3 ) —, — (CH 2 ) 5 —, —CH (CH 3 ) 5 —, —CH (CH 3 ) 5 —, —CH (CH 3 ) 5 —,
  • C 1-4 alkylene is preferable.
  • examples of “C 1-3 alkylene” include methylene, ethylene, trimethylene (— (CH 2 ) 3 —), —CH (CH 3 ) —CH 2 —, —CH 2- CH (CH 3 ) —, —C (CH 3 ) 2 — and the like can be mentioned.
  • C 3-6 cycloalkylene examples include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like.
  • Ring A has a 6 to 10-membered aromatic hydrocarbon ring which may have a substituent, a 5 to 10-membered non-aromatic heterocyclic ring which may have a substituent, or a substituent. Or a 5- to 10-membered aromatic heterocycle.
  • Examples of the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A include benzene and naphthalene, preferably benzene It is.
  • the “6- to 10-membered aromatic hydrocarbon ring” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
  • a substituent for example, (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) a C 3-10 cycloalkyl group (eg, cyclopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom; (2) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, and (e) a C 6-14 aryl optionally substituted with 1 to 3 substituents selected from an amino group optionally mono- or di-substituted with a C 1-6 alkyl group Group; (3) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b)
  • the “5- to 10-membered non-aromatic heterocycle” of the “optionally substituted 5- to 10-membered non-aromatic heterocycle” represented by ring A includes 2-oxodihydroindole and 3-oxodihydro Examples include benzoxazine.
  • the “5- to 10-membered non-aromatic heterocyclic ring” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
  • the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” in the “6-to 10-membered aromatic hydrocarbon ring” described above may be substituted.
  • the group illustrated as a group is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • Examples of the “5- to 10-membered aromatic heterocycle” of the “optionally substituted 5- to 10-membered aromatic heterocycle” represented by ring A include indazole.
  • the “5- to 10-membered aromatic heterocyclic ring” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
  • the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” in the “6-to 10-membered aromatic hydrocarbon ring” described above may be substituted.
  • the group illustrated as a group is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • Ring A is preferably a 6- to 10-membered aromatic hydrocarbon ring which may have a substituent, more preferably benzene which may have a substituent, and more preferably (i) a halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom), (ii) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl) or 1 to 3 halogen atoms (preferably a fluorine atom) C 1-6 alkyl group (preferably methyl) optionally substituted with an atom), (iii) C 3-10 cycloalkyl group (preferably cyclopropyl), (iv) nitro group, (v) amino group, (vi) C 1-6 alkylsulfanyl groups (preferably methylsulfanyl), (vii) C 1-6 alkylsulfinyl group (preferably, methylsulfinyl) and (viii) C 1-6 Arukirusu Benzene which
  • ring A is preferably a 5- to 10-membered non-aromatic heterocyclic ring which may have a substituent, and more preferably, may have a substituent.
  • 2-oxodihydroindole or optionally substituted 3-oxodihydrobenzoxazine more preferably (i) a halogen atom (preferably a fluorine atom) and (ii) a C 1-6 alkyl group 2-oxodihydroindole or 3-oxodihydrobenzoxazine optionally substituted with 1 to 3 substituents selected from (preferably methyl).
  • ring A is preferably a 5- to 10-membered aromatic heterocyclic ring which may have a substituent, and more preferably has a substituent. More preferably, it is substituted with 1 to 3 substituents selected from (i) a halogen atom (preferably a fluorine atom) and (ii) a C 1-6 alkyl group (preferably methyl). Indazole which may have been used.
  • Ring B is (1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent, (2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring.
  • Examples of the “6- to 10-membered aromatic hydrocarbon ring” of the “6- to 10-membered aromatic hydrocarbon ring optionally having substituents” represented by ring B include benzene and naphthalene, preferably Benzene.
  • the “6- to 10-membered aromatic hydrocarbon ring” is a group other than the group represented by —L 2 —R 2 (wherein each symbol is as defined above), It may have 5 (preferably 1 to 3, more preferably 1 or 2) substituents.
  • the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “5- or 6-membered heterocycle” of the “optionally substituted 5- or 6-membered heterocycle” represented by ring B is a 5- or 6-membered aromatic heterocycle (preferably pyridine, thiazole , Pyrimidine) and 5- or 6-membered non-aromatic heterocycles (preferably piperidine, tetrahydropyridine).
  • the “5- or 6-membered heterocycle” contains a nitrogen atom as a ring atom, the nitrogen atom is preferably not quaternized.
  • the “5- or 6-membered aromatic heterocyclic ring” is 1 to 5 at a substitutable position other than the group represented by —L 2 —R 2 (wherein each symbol is as defined above).
  • the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “5- or 6-membered non-aromatic heterocycle” is a group other than the group represented by —L 2 —R 2 (wherein each symbol is as defined above), It may have 5 (preferably 1 to 3, more preferably 1 or 2) substituents.
  • substituents include: (1) Substitution that the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally-substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A may have Examples include groups exemplified as groups, and (2) oxo groups. When there are two or more substituents, each substituent may be the same or different.
  • the “5- or 6-membered heterocyclic ring optionally having substituent (s)” represented by ring B is preferably a 5- or 6-membered aromatic optionally further having substituent (s). Family heterocycle.
  • a benzene ring and a bicyclic condensed ring in which a 5- or 6-membered aromatic heterocyclic ring is condensed a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed, a benzene ring and And bicyclic condensed rings in which 5- or 6-membered non-aromatic hydrocarbon rings are condensed.
  • the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered aromatic heterocycle are condensed” includes indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, indazole, quinazoline, cinnoline, quinoxaline, phthalazine Benzofuran is preferable.
  • the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed” includes dihydroindole, dihydroisoindole, dihydrobenzofuran, dihydrobenzothiophene, chromene, dihydrochromene, dihydroquinoline, Tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydroindazole, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, dihydroquinoxaline, tetrahydroquinoxaline, dihydrophthalazine, tetrahydrophthalazine, etc., preferably dihydrobenzofuran (2 , 3-dihydrobenzofuran).
  • the “bicyclic fused ring in which a benzene ring and a 5- or 6-membered aromatic heterocycle are condensed” is a group represented by —L 2 —R 2 (wherein each symbol is as defined above). In addition, it may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
  • the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed” and the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic hydrocarbon ring are condensed” are: In addition to the group represented by L 2 -R 2 (wherein each symbol is as defined above), 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents may be present.
  • substituents examples include “5 or 6 membered” exemplified as “5 or 6 membered heterocyclic ring” of “an optionally substituted 5 or 6 membered heterocyclic ring” represented by ring B above.
  • the group illustrated as the substituent which the "non-aromatic heterocyclic ring” may have is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • ring B preferably (1) a 6 to 10-membered aromatic hydrocarbon ring (preferably benzene) which may further have a substituent, (2) a 5- or 6-membered aromatic heterocyclic ring (preferably pyridine, thiazole, pyrimidine) which may further have a substituent, (3) a 5- or 6-membered non-aromatic heterocyclic ring (preferably piperidine, tetrahydropyridine) which may further have a substituent, (4) A bicyclic condensed ring (preferably benzofuran) in which a benzene ring and a 5- or 6-membered aromatic heterocycle are condensed, or (5) an additional substituent.
  • a 6 to 10-membered aromatic hydrocarbon ring preferably benzene
  • a 5- or 6-membered aromatic heterocyclic ring preferably pyridine, thiazole, pyrimidine
  • a 5- or 6-membered non-aromatic heterocyclic ring preferably piperidine, tetrahydr
  • a bicyclic condensed ring (preferably 2,3-dihydrobenzofuran) in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed, more preferably, (1) a C 3-10 cycloalkyl group (preferably cyclopropyl); (2) a C 1-6 alkoxy group (preferably methoxy, isopropoxy); (3) a halogen atom (preferably a fluorine atom or a chlorine atom); (4) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) a cyano group, and (d) a tri (C 1-6 alkyl) silyloxy group (preferably tert-butyldimethylsilyloxy) A C 1-6 alkyl group (preferably methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from: (5) hydroxy group; (6)
  • a condensed condensed ring (preferably 2,3-dihydrobenzofuran), particularly preferably (1) C 3-10 cycloalkyl group (particularly cyclopropyl), halogen atom (especially chlorine atom), 1 to 3 halogen atoms (especially, fluorine atom) optionally substituted by C 1-6 An alkyl group (particularly methyl), a hydroxy group, a C 1-6 alkylsulfonyloxy group (particularly methylsulfonyloxy) substituted with 1 to 3 halogen atoms (particularly a fluorine atom), and C 1-6 alkyl Benzene optionally further substituted with 1 to 3 substituents selected from amino groups mono- or di-substituted with groups (particularly methyl), (2) From pyridine optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups (especially methyl), or (3) C 1-6 alkyl groups (especially methyl) It is a pyrimidine which may be further substituted with 1 to
  • R 1 may be a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent.
  • m represents 0, 1 or 2;
  • Ra represents a hydrogen atom or a C 1-6 alkyl group;
  • R 3 represents a hydrogen atom or C A 1-6 alkyl group;
  • R 1 may be a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent.
  • the “C 1-6 alkyl group” of the “C 1-6 alkyl group optionally having substituent (s)” represented by R 1 is preferably methyl or ethyl.
  • the “C 1-6 alkyl group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
  • a substituent for example, (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) a C 3-10 cycloalkyl group (eg, cyclopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom; (2) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, and (e) a C 6-14 aryl optionally substituted with 1 to 3 substituents selected from an amino group optionally mono- or di-substituted with a C 1-6 alkyl group Group; (3) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b)
  • R 1 Represented by R 1 in the "optionally substituted C 2-6 alkenyl group", “C 2-6 alkenyl group", 1 to 5 at substitutable positions (preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
  • substituents the groups exemplified as the "C 1-6 alkyl group” optionally has substituent of the "optionally substituted C 1-6 alkyl group” described above Can be mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “C 2-6 alkynyl group” of the “ optionally substituted C 2-6 alkynyl group” represented by R 1 has 1 to 5 (preferably 1 to 3, preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
  • substituents the groups exemplified as the "C 1-6 alkyl group” optionally has substituent of the "optionally substituted C 1-6 alkyl group” described above Can be mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “C 3-6 cycloalkyl group” of the “ optionally substituted C 3-6 cycloalkyl group” represented by R 1 is preferably cyclopropyl.
  • the “C 3-6 cycloalkyl group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions. Examples of such a substituent include “5 or 6 membered” exemplified as “5 or 6 membered heterocyclic ring” of “an optionally substituted 5 or 6 membered heterocyclic ring” represented by ring B above.
  • the group illustrated as the substituent which the "non-aromatic heterocyclic ring” may have is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “C 6-14 aryl group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions. Examples of such a substituent include “5 or 6 membered” exemplified as “5 or 6 membered heterocyclic ring” of “an optionally substituted 5 or 6 membered heterocyclic ring” represented by ring B above.
  • the group illustrated as a substituent which the "aromatic heterocyclic ring” may have is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “amino group” of the “optionally substituted amino group” represented by R 1 may have 1 or 2 substituents.
  • the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two substituents, each substituent may be the same or different.
  • acyl group represented by R 1 , for example, (1) formyl group, (2) a C 1-6 alkyl-carbonyl group, (3) a C 2-6 alkenyl-carbonyl group, (4) a C 2-6 alkynyl-carbonyl group, (5) a C 3-6 cycloalkyl-carbonyl group, (6) a C 3-6 cycloalkenyl-carbonyl group, (7) a C 6-10 aryl-carbonyl group, (8) Heterocycle-carbonyl group, (9) carboxyl group, (10) a C 1-6 alkoxy-carbonyl group, (11) C 2-6 alkenyloxy-carbonyl group, (12) C 2-6 alkynyloxy-carbonyl group, (13) a C 3-6 cycloalkyloxy-carbonyl group, (14) a C 3-6 cycloalkenyloxy-carbonyl group, (15) a C 6-10 aryloxy-carbonyl group, (16) He
  • the “C 2-6 alkenyl-carbonyl group” includes, for example, ethenylcarbonyl, 1-propenylcarbonyl, 2-propenylcarbonyl, 2-methyl-1-propenylcarbonyl, 1-butenylcarbonyl, 2-butenylcarbonyl, Tenenylcarbonyl, 3-butenylcarbonyl, 3-methyl-2-butenylcarbonyl, 1-pentenylcarbonyl, 2-pentenylcarbonyl, 3-pentenylcarbonyl, 4-pentenylcarbonyl, 4-methyl-3-pentenylcarbonyl, 1- Hexenylcarbonyl, 2-hexenylcarbonyl, 3-hexenylcarbonyl, 4-hexenylcarbonyl, 5-hexenylcarbonyl and the like can be mentioned.
  • C 2-6 alkynyl-carbonyl group examples include ethynylcarbonyl, 1-propynylcarbonyl, 2-propynylcarbonyl, 1-butynylcarbonyl, 2-butynylcarbonyl, 3-butynylcarbonyl and 1-pentynyl.
  • Examples of the “C 3-6 cycloalkyl-carbonyl group” include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.
  • Examples of the “C 3-6 cycloalkenyl-carbonyl group” include 2-cyclopropen-1-ylcarbonyl, 2-cyclobuten-1-ylcarbonyl, 2-cyclopenten-1-ylcarbonyl, 3-cyclopentene-1- And ylcarbonyl, 2-cyclohexen-1-ylcarbonyl, 3-cyclohexen-1-ylcarbonyl and the like.
  • C 6-10 aryl-carbonyl group examples include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
  • Heterocycle-carbonyl group means, for example, (1) a 5- or 6-membered monocyclic aromatic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridine, Pyrazole, etc.)-Carbonyl, (2) 8- to 12-membered condensed aromatic heterocycle (eg, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, etc.) -Carbonyl, (3) 3-6 membered non-aromatic heterocycle (eg, oxirane, azet
  • C 2-6 alkenyloxy-carbonyl group examples include ethenyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, Tenenyloxycarbonyl, 3-methyl-2-butenyloxycarbonyl, 1-pentenyloxycarbonyl, 2-pentenyloxycarbonyl, 3-pentenyloxycarbonyl, 4-pentenyloxycarbonyl, 1-hexenyloxycarbonyl, 2-hexenyloxycarbonyl , 3-hexenyloxycarbonyl, 4-hexenyloxycarbonyl, 5-hexenyloxycarbonyl and the like.
  • C 2-6 alkynyloxy-carbonyl group examples include, for example, ethynyloxycarbonyl, 1-propynyloxycarbonyl, 2-propynyloxycarbonyl, 1-butynyloxycarbonyl, 2-butynyloxycarbonyl, 3-butynyl Oxycarbonyl, 1-pentynyloxycarbonyl, 2-pentynyloxycarbonyl, 3-pentynyloxycarbonyl, 4-pentynyloxycarbonyl, 1-hexynyloxycarbonyl, 2-hexynyloxycarbonyl, 3-hexynyloxy Examples include carbonyl, 4-hexynyloxycarbonyl, 5-hexynyloxycarbonyl and the like.
  • Examples of the “C 3-6 cycloalkyloxy-carbonyl group” include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like.
  • Examples of the “C 3-6 cycloalkenyloxy-carbonyl group” include 2-cyclopropen-1-yloxycarbonyl, 2-cyclobuten-1-yloxycarbonyl, 2-cyclopenten-1-yloxycarbonyl, 3- Examples include cyclopenten-1-yloxycarbonyl, 2-cyclohexen-1-yloxycarbonyl, 3-cyclohexen-1-yloxycarbonyl, and the like.
  • Examples of the “C 6-10 aryloxy-carbonyl group” include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
  • Examples of the “heterocycle-oxycarbonyl group” include (1) a 5- or 6-membered monocyclic aromatic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridine).
  • the “acyl group” represented by R 1 is preferably a formyl group or a carboxyl group.
  • R 1 is preferably a C 1-6 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a substituent.
  • R 1 is preferably a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a substituted group.
  • An amino group, a cyano group, or —S (O) m Ra which may have; m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group; R 3 represents a hydrogen atom or a C 1-6 alkyl group.
  • R 1 is preferably a halogen atom, an acyl group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2.
  • a -6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6- 14 represents an aryl group, an optionally substituted amino group, or —S (O) m Ra;
  • m represents 0, 1 or 2;
  • Ra represents a hydrogen atom or a C 1-6 alkyl group
  • R 3 represents a hydrogen atom or a C 1-6 alkyl group.
  • R 1 is preferably a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, or a C which may have a substituent.
  • 2-6 alkenyl group, C 2-6 alkynyl group which may have a substituent, C 3-6 cycloalkyl group which may have a substituent, C 6 which may have a substituent -14 represents an aryl group, a cyano group, or -S (O) m Ra;
  • m represents 0, 1 or 2;
  • Ra represents a hydrogen atom or a C 1-6 alkyl group;
  • R 3 represents a hydrogen atom Or a C 1-6 alkyl group.
  • R 3 is preferably a hydrogen atom or methyl.
  • R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent.
  • 6 represents an alkyl group, a non-aromatic heterocyclic group which may have a substituent, or a C 3-6 cycloalkyl group which may have a substituent.
  • the “C 1-6 alkoxy group” of the “optionally substituted C 1-6 alkoxy group” represented by R 2 has 1 to 5 (preferably 1 to 3, preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
  • Such substituents, "C 1-6 alkyl group” optionally has substituent of the "optionally substituted C 1-6 alkyl group” represented by the R 1 And the groups exemplified as above.
  • each substituent may be the same or different.
  • the “optionally substituted C 1-6 alkoxy group” for R 2 is preferably a “C 1-3 alkoxy group”.
  • the “non-aromatic heterocyclic group” of the “non-aromatic heterocyclic group optionally having substituent (s)” represented by R 2 has 1 to 5 (preferably 1 to 3, preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
  • substituents such as a substituent, the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” in the “6-to 10-membered aromatic hydrocarbon ring” described above may be substituted.
  • the group illustrated as a group is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • R 2 is preferably a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group (preferably methoxy, ethoxy), or an optionally substituted group.
  • a C 1-6 alkyl group preferably methyl, ethyl
  • an optionally substituted non-aromatic heterocyclic group preferably piperazinyl, 3-oxopiperazinyl
  • C 3-6 cyclo An alkyl group (preferably cyclopropyl), more preferably (i) a hydrogen atom; (ii) a hydroxy group; (iii) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group; (iv) a C 1-6 alkoxy group (preferably methoxy, ethoxy); (v) (1) an amino group (preferably, mono- or di-substituted with a C 1-6 alkyl group (preferably methyl) or a C 1-6 alkyl-carbony
  • R 2 is particularly preferably (i) a hydroxy group, (ii) an amino group, (iii) a C 1-6 alkoxy group (particularly methoxy, ethoxy), (iv) (1) an amino group mono- or di-substituted with a C 1-6 alkyl group (especially methyl) or a C 1-6 alkyl-carbonyl group (especially methylcarbonyl) (especially dimethylamino, acetylamino) , (2) a carbamoyl group (particularly carbamoyl, methylcarbamoyl, dimethylcarbamoyl) optionally mono- or disubstituted with a C 1-6 alkyl group (particularly methyl), (3) a hydroxy group, (4) a C 1-6 alkylsulfanyl group (particularly methylsulfanyl), (5) a C 1-6 alkylsulfinyl group (particularly methylsulfinyl), (6) C 1-6 alkylsulf
  • a non-aromatic heterocyclic group (especially piperazinyl, 3-oxopiperazinyl) optionally substituted with 1 to 3 substituents selected from (vi) a C 3-6 cycloalkyl group (particularly cyclopropyl).
  • R 2 is preferably a hydrogen atom, a hydroxy group, an amino group which may have a substituent, or a C 1-6 alkyl group which may have a substituent.
  • L 1 represents —O—, —CO—, C 1-6 alkylene which may have a substituent, or C 3-6 cycloalkylene which may have a substituent.
  • C 1-6 alkylene Represented by L 1 in the "optionally substituted C 1-6 alkylene” as the “C 1-6 alkylene", methylene is preferable.
  • the “C 1-6 alkylene” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
  • substituents "C 1-6 alkyl group” optionally has substituent of the "optionally substituted C 1-6 alkyl group” represented by the R 1 And the groups exemplified as above. When there are two or more substituents, each substituent may be the same or different.
  • L 1 is preferably —CO— or an optionally substituted C 1-6 alkylene (preferably methylene), more preferably —CO— or a hydroxy group. Or a C 1-6 alkylene (preferably methylene), particularly preferably methylene.
  • L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH— (wherein Y represents an optionally substituted C 1-3 alkylene).
  • Y represents an optionally substituted C 1-3 alkylene.
  • a C 1-6 alkylene optionally having substituent represented by Y, those similar to the "optionally substituted C 1-6 alkylene” represented by L 1 described above Is mentioned.
  • L 2 is preferably —CO—, —COY—, —NHCO—, —YCO—, —CONH— (wherein Y represents C 1-3 alkylene), and more preferably —CO—, —COY—, —NHCO—, —CONH— (wherein Y represents C 1-3 alkylene), and more preferably —CO—, —CO—CH 2 —, — NHCO— and —CONH— are particularly preferred, —CO— and —NHCO—.
  • L 3 represents — (CH 2 ) n — (n represents 0 or 1). That is, L 3 represents a bond or a methylene group.
  • Ring A is an optionally substituted 6 to 10 membered aromatic hydrocarbon ring
  • Ring B is (1) a 6 to 10-membered aromatic hydrocarbon ring (preferably benzene) which may further have a substituent
  • a 5- or 6-membered aromatic heterocyclic ring preferably pyridine, thiazole, pyrimidine
  • a 5- or 6-membered non-aromatic heterocyclic ring preferably piperidine, tetrahydropyridine
  • a bicyclic condensed ring preferably benzofuran in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring may be further condensed
  • a bicyclic condensed ring preferably 2,3-dihydrobenzofuran fused with a benzene ring and a 5- or 6-membered non-aromatic
  • R 2 has a hydrogen atom, a hydroxy group, an optionally substituted amino group, a C 1-6 alkoxy group, an optionally substituted C 1-6 alkyl group, or a substituent.
  • R 3 is a hydrogen atom or a C 1-6 alkyl group
  • L 1 is —CO— or an optionally substituted C 1-6 alkylene (preferably methylene)
  • L 2 is —CO—, —COY—, —NHCO—, —YCO—, or —CONH— (wherein Y represents C 1-3 alkylene);
  • Ring A is an optionally substituted benzene
  • Ring B is (1) a C 3-10 cycloalkyl group (preferably cyclopropyl), (2) a C 1-6 alkoxy group (preferably methoxy, isopropoxy), (3) a halogen atom (preferably a fluorine atom, a chlorine atom), and (4) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) a cyano group, and (d) a tri (C 1-6 alkyl) silyloxy group (preferably tert-butyldimethylsilyloxy)
  • a C 1-6 alkyl group preferably methyl, ethyl, isopropyl
  • substituents selected from: (5) a hydroxy group, (6) a C 1-6 alkylsulfonyloxy group (preferably methylsulfonyloxy) optionally substituted with 1 to 3 halogens selected from: (5) a
  • R 1 may have a C 1-6 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a C 6-14 which may have a substituent.
  • R 2 is a hydrogen atom, a hydroxy group, an optionally substituted amino group, a C 1-6 alkoxy group (preferably methoxy, ethoxy), an optionally substituted C 1-6
  • An alkyl group preferably methyl, ethyl
  • an optionally substituted non-aromatic heterocyclic group preferably piperazinyl, 3-oxopiperazinyl
  • R 3 is a hydrogen atom or a C 1-6 alkyl group
  • L 1 is —CO— or C 1-6 alkylene (preferably methylene) optionally substituted with a hydroxy group
  • L 2 is —CO—, —COY—, —NHCO—, or —CONH— (wherein Y represents C 1-3 alkylene);
  • Ring A is (i) a halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom), (ii) C 1-6 alkoxy - carbonyl group (preferably, methoxycarbonyl) or 1 to 3 halogen atoms (preferably, fluorine atoms) are also C 1-6 alkyl group (preferably optionally substituted by, Methyl), (iii) a C 3-10 cycloalkyl group (preferably cyclopropyl), (iv) a nitro group, (v) an amino group, (vi) a C 1-6 alkylsulfanyl group (preferably, methylsulfanyl), (vii) a C 1-6 alkylsulfinyl group (preferably methylsulfinyl), and (viii) C 1-6 alkylsulfonyl group (preferably methylsulfonyl) Benzene optionally substituted with 1 to 3 substituents selected from:
  • benzene (2) a 5- or 6-membered aromatic heterocycle (preferably pyridine, thiazole, pyrimidine), (3) a 5- or 6-membered non-aromatic heterocyclic ring (preferably piperidine, tetrahydropyridine), (4) a bicyclic condensed ring (preferably benzofuran) in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring are condensed, or (5) a bicyclic ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed.
  • a 5- or 6-membered aromatic heterocycle preferably pyridine, thiazole, pyrimidine
  • a 5- or 6-membered non-aromatic heterocyclic ring preferably piperidine, tetrahydropyridine
  • bicyclic condensed ring preferably benzofuran in which a benzene ring and a 5- or 6-member
  • R 1 is (i) (1) an amino group (preferably dimethylamino) optionally mono- or disubstituted with a C 1-6 alkyl group (preferably methyl), (2) hydroxy group, (3) C 1-6 alkoxy group (preferably methoxy), and (4) C 3-10 cycloalkyl group (preferably cyclopropyl)
  • a C 1-6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 substituents selected from: (ii) a C 3-6 cycloalkyl group (preferably cyclopropyl), (iii) a C 6-14 aryl group (preferably phenyl), (iv) (1) C 1-6 alkoxy-carbonyl group (preferably tert-butoxycarbonyl), and (2) C 1-6 alkyl group (preferably methyl)
  • An amino group optionally substituted by 1 or 2 substituents selected from: (v) formyl group, or (vi) is
  • the compound represented by formula (I) includes: Ring A is (1) (i) a halogen atom, (ii) C 1-6 alkoxy - carbonyl group or one to three optionally substituted C 1-6 alkyl group by a halogen atom, (iii) C 3-10 cycloalkyl Selected from alkyl group, (iv) nitro group, (v) amino group, (vi) C 1-6 alkylsulfanyl group, (vii) C 1-6 alkylsulfinyl group and (viii) C 1-6 alkylsulfonyl group Benzene optionally substituted with 1 to 3 substituents; (2) 2-oxodihydroindole or 3-oxodihydrobenzoxazine optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C 1-6 alkyl group; or (3) (i) an indazole optionally substituted
  • the compound represented by formula (I) includes: Ring A is (1) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (ii) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) or 1 to 3 halogen atoms (eg, fluorine) C 1-6 alkyl group (eg, methyl) optionally substituted with (atom), (iii) C 3-10 cycloalkyl group (eg, cyclopropyl), (iv) nitro group, (v) amino group, 1-3 selected from (vi) a C 1-6 alkylsulfanyl group (eg, methylsulfanyl), (vii) a C 1-6 alkylsulfinyl group and (viii) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) Benzene optionally substituted with one substituent
  • R 1 is (i) (1) a hydroxy group, and (2) a C 3-10 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted by 1 to 3 substituents selected from: (ii) a C 3-6 cycloalkyl group (eg, cyclopropyl); or (iii) a C 6-14 aryl group (eg, phenyl); Is; R 2 is (i) a hydrogen atom; (ii) a hydroxy group; (iii) an amino group; (iv) a C 1-6 alkoxy group (eg, methoxy, ethoxy); (v) (1) an amino group mono- or di-substituted with a C 1-6 alkyl group (eg, methyl) or a C 1-6 alkyl-carbonyl group (eg, methylcarbonyl), (2) a carbamoyl group optionally mono
  • the compound represented by formula (I) includes: Ring A is (1) (i) a halogen atom (eg, fluorine atom, chlorine atom), (ii) a C 1-6 alkyl group (eg, methyl) substituted with 1 to 3 halogen atoms (eg, fluorine atom), benzene substituted with 1 to 3 substituents selected from (iii) a C 3-10 cycloalkyl group (eg, cyclopropyl) and (iv) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl); (2) 2-oxodihydroindole or 3-oxodihydrobenzoxazine; or (3) 1 selected from (i) a halogen atom (eg, fluorine atom) and (ii) a C 1-6 alkyl group (eg, methyl) Indazole substituted with ⁇ 3 substituents; Ring B
  • R 1 is (i) (1) a hydroxy group, and (2) a C 3-10 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from: or (ii) C 3-6 cycloalkyl group (eg, cyclopropyl) Is;
  • R 2 is (i) a hydrogen atom; (ii) an amino group; (iii) (1) an amino group mono- or di-substituted with a C 1-6 alkyl group (eg, methyl) or a C 1-6 alkyl-carbonyl group (eg, methylcarbonyl), (2) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group (eg, methyl), (3) a hydroxy group, (4) a C 1-6 alkylsulfinyl group (eg, methylsul
  • R 1 is a C 1-6 alkyl group (eg, methyl);
  • R 2 is (i) an amino group; or (ii) (1) a carbamoyl group monosubstituted with a C 1-6 alkyl group (eg, methyl), (2) a hydroxy group, and (3) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 1,2,4-triazol-1-yl group (eg, methyl, ethyl); Is;
  • R 3 is a hydrogen atom;
  • L 1 is methylene;
  • L 2 is —CO— or —NHCO—;
  • L 3 is a bond, Compounds are more preferred.
  • Ring A in which ring A is substituted with 1 to 3 substituents selected from fluorine atom, chlorine atom, bromine atom, trifluoromethyl, cyclopropyl, amino, nitro, methylsulfanyl, methylsulfinyl, methylsulfonyl and methoxycarbonyl Is;
  • Ring B may be substituted with (1) a C 3-10 cycloalkyl group (particularly cyclopropyl), a halogen atom (particularly a chlorine atom), or one to three halogen atoms (particularly a fluorine atom).
  • R 1 is a C 3-10 cycloalkyl group (especially cyclopropyl) or a C 1-6 alkyl group (especially methyl, ethyl) optionally substituted with a hydroxy group, a C 3-6
  • a non-aromatic heterocyclic group (especially piperazinyl, 3-oxopiperazinyl) optionally substituted with 1 to 3 substituents selected from (vi) is a C 3-6 cycloalkyl group (especially cyclopropyl); R 3 is a hydrogen atom or a C 1-6 alkyl group (particularly methyl); L 1 is methylene; L 2 is —CO— or —NHCO—; A compound in which L 3 is a bond or a methylene group.
  • Ring A is (i) a halogen atom (preferably a fluorine atom), and (ii) a C 1-6 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom)
  • Ring B is benzene optionally further substituted with 1 to 3 substituents selected from C 1-6 alkyl groups (preferably methyl);
  • R 1 is a C 1-6 alkyl group (preferably methyl);
  • R 2 is an amino group;
  • L 1 is C 1-6 alkylene (preferably methylene); L 2 is —CO—;
  • a compound in which L 3 is — (CH 2 ) n — (n represents 0), that is, a bond; and (ii) a partial structural formula:
  • Ring A is (i) a halogen atom (preferably a fluorine atom, a chlorine atom), and (ii) a C 1-6 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom) Benzene optionally substituted with 1 to 3 substituents selected from:
  • Ring B is (i) a halogen atom (preferably a chlorine atom), (ii) a C 1-6 alkyl group (preferably methyl), and (iii) C 3-6 cycloalkyl group (preferably cyclopropyl) Benzene optionally further substituted with 1 to 3 substituents selected from:
  • R 1 is (i) a C 1-6 alkyl group (preferably methyl), or (ii) a C 3-6 cycloalkyl group (preferably cyclopropyl);
  • R 2 is (i) a hydroxy group, (ii) a C 1-6 alkoxy group (preferably e
  • Examples 1 to 179 Specific examples of the compound represented by the formula (I) include the compounds of Examples 1 to 179. Among them, 4- ⁇ 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl ⁇ -2-methylbenzamide or a salt thereof (Example 31); 6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylnicotinamide or a salt thereof (Example 73); 4- ⁇ 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl ⁇ -2-methylbenzamide or a salt thereof (Example 141) And 4- ⁇ 2- [3-fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids.
  • metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. It is done. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
  • a compound labeled or substituted with an isotope eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.
  • the prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds wherein the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds,
  • the compound of the present invention has excellent GPR52 agonist activity, and is useful as a prophylactic / therapeutic agent for the diseases and symptoms described in (1) to (10) below.
  • Psychiatric disorders eg, depression, major depression, bipolar depression, mood disorders, emotional disorders (seasonal emotional disorders, etc.), recurrent depression, postpartum depression, stress disorder, depressive symptoms, Gonorrhea, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, taurette syndrome, autism , Adaptation disorder, bipolar disorder, neurosis, schizophrenia (schizophrenia), neurosis, chronic fatigue syndrome, anxiety, obsessive-compulsive disorder, phobic disorder, epilepsy, anxiety symptoms, uncomfortable mental state, emotional abnormalities , Emotional temperament, nervousness, fainting, weakness, decreased libido, attention deficit hyperactivity disorder (ADHD), psychotic major depression,
  • the compounds of the present invention are particularly useful for mental disorders (eg, schizophrenia, depression, anxiety, bipolar disorder or PTSD, anxiety, obsessive compulsive disorder etc.), neurodegenerative diseases (eg, Alzheimer's disease, mild Useful as a prophylactic / therapeutic agent for diseases such as cognitive impairment (MCI), Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, spinocerebellar degeneration, multiple sclerosis (MS), Pick's disease, etc.
  • MCI cognitive impairment
  • Parkinson's disease amyotrophic lateral sclerosis
  • MS spinocerebellar degeneration
  • MS multiple sclerosis
  • Pick's disease etc.
  • positive symptoms such as delusions and hallucinations in schizophrenia
  • negative symptoms such as sensory dullness, withdrawal, decreased motivation and concentration
  • prophylactic and therapeutic drugs for cognitive dysfunction Useful e.g, schizophrenia, depression, anxiety, bipolar disorder or PTSD, anxiety, obsessive compulsive disorder etc.
  • the compound of the present invention is excellent in metabolic stability, it can be expected to have an excellent therapeutic effect at a low dose against the above diseases.
  • the compound of the present invention has low toxicity (for example, it is excellent as a pharmaceutical from the viewpoint of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), and as it is as a pharmaceutical.
  • a medicine mixed with a pharmaceutically acceptable carrier or the like to a mammal eg, human, monkey, cow, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, goat, etc.
  • a mammal eg, human, monkey, cow, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, goat, etc.
  • a mammal eg, human, monkey, cow, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, goat, etc.
  • it can be safely administered orally or parenterally.
  • the medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier.
  • examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.
  • lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
  • the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethyl
  • Preferable examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
  • Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like.
  • Preferable examples of the soothing agent include benzyl alcohol.
  • Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferable examples of the antioxidant include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (E.g., aluminum salts of the above water-soluble edible tar dyes), natural dyes (e.g., ⁇ -carotene, chlorophyll, bengara) and the like.
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes E.g., aluminum salts of the above water-soluble edible tar dyes
  • natural dyes e.g., ⁇ -carotene, chlorophyll, bengara
  • the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., for example, about 0.01 to 100% by weight, preferably about the total amount of the composition 0.1 to 95% by weight.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc., but for example, when administered orally to a patient with schizophrenia (adult, body weight of about 60 kg) About 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight, and this amount is once to several times a day It is desirable to administer (eg, 3 times).
  • the compounds of the present invention may be used in combination with other active ingredients.
  • an active ingredient for example, (1) Atypical antipsychotic drugs (eg, clozapine, olanzapine, risperidone, aripiprazole, iloperidone, asenapine, ziprasidone, quetiapine, zotepine, paroperidone, lurasidone, etc.), (2) Typical antipsychotic drugs (eg, haloperidol, chlorpromazine, etc.) (3) selective serotonin reuptake inhibitors (eg, paroxetine, sertraline, fluvoxamine, fluoxetine, etc.), selective serotonin / noradrenaline reuptake inhibitors (eg, milnacipran, venlafaxine, etc.), (4) selective noradrenaline / dopamine reuptake inhibitors (eg, bupropion, etc.
  • Atypical antipsychotic drugs eg, cloza
  • Parkinson's disease eg, dopamine receptor agonists (L-dopa, bromocriptene, pergolide, taripexole, pripepexol, cabergoline, adamantazine, etc.), monoamine oxidase (MAO) inhibitors (deprenyl, sergiline ( Selegiline), remacemide, riluzole, etc.), anticholinergic agents (eg, trihexyphenidyl, biperidene, etc.), COMT inhibitors (eg, entacapone, etc.)], (30) Amyotrophic lateral sclerosis drug (eg, riluzole, etc., neurotrophic factor, etc.), (31) Antihyperlipidemic drugs such as cholesterol-lowering drugs [statins (eg, pravastatin sodium,
  • various central nervous system agonists or therapeutic drugs for diseases that are likely to accompany schizophrenia are preferable.
  • the compound of the present invention can be used in combination with a concomitant drug that does not act on GPR52.
  • the administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • dosage forms include: (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference, (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention ⁇ the concomitant drug)
  • the concomitant drug and the compound of the present invention may be administered at the same time, but after administering the concomitant drug, the compound of the present invention may be administered.
  • a concomitant drug may be administered after administration of the compound of the invention.
  • the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method.
  • the concomitant drug when administered first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. The method of doing is mentioned.
  • the daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when administered orally to a schizophrenic patient (adult, body weight about 60 kg), it is usually a single dose. About 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once (eg, 3 times). When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a tablet (sugar-coated tablet, film coating) Tablets, sublingual tablets, orally disintegrating tablets, buckle tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, solutions, emulsions, suspensions Suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, orally disintegrating films, oral mucosal film), injections (eg , Subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), instillation, transdermal preparation, ointment, lotion, patch, suppository (eg, anal suppository, vaginal seat) Agent),
  • the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the dose of the concomitant drug can be appropriately selected on the basis of the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight, preferably about 0, based on the whole preparation.
  • the range is from 1 to 50% by weight, more preferably from about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight with respect to the whole preparation, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.
  • the content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by weight, preferably about 10 to about 90% relative to the whole preparation. It is in the range of wt%.
  • the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
  • X 1 , X 2 and X 3 each independently represent a leaving group; R 4 represents an optionally substituted C 1-6 alkyl group; R a represents each independently And may represent a hydrogen atom or a C 1-6 alkyl group, or two R a may combine to form a C 2-6 alkylene chain; other symbols are as defined above.
  • Examples of the “leaving group” represented by X 1 , X 2 or X 3 include a hydroxy group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom), and optionally halogenated C.
  • 1-6 alkoxy groups eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.
  • optionally halogenated C 1-5 alkylsulfonyloxy groups eg Methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • optionally halogenated C 1-6 acyloxy group eg, acetyloxy, trifluoroacetyloxy, etc.
  • optionally substituted C 6 -10 arylsulfonyloxy group e.g., 4-toluenesulfonyl Oki Group
  • an optionally substituted phenyl group e.g., and a good benzothiazol-2-ylthio group which may be substituted.
  • the C 2-6 alkylene chain in which two R a is formed for example, -CH 2 -CH 2 -, - C (CH 3) 2 -C (CH 3) 2 -, - CH 2 -CH 2 -CH 2 -, And -CH 2 -C (CH 3 ) 2 -CH 2- and the like.
  • Compound (III) can be produced by Claisen condensation of compound (II) or a similar reaction. This reaction is carried out, for example, by condensing compound (II) with Meldrum's acid in the presence of a “base” and a “condensing agent”, if desired, and then an alcohol solvent represented by a general formula: R 4 —OH such as methanol or ethanol Or solvolysis in a mixed solvent of alcohol solvent and other “solvents used in organic synthesis” (Journal of Organic Chemistry (J. Org. Chem.), 70, 5331-5334, ( 2005)).
  • an alcohol solvent represented by a general formula: R 4 —OH such as methanol or ethanol Or solvolysis in a mixed solvent of alcohol solvent and other “solvents used in organic synthesis”
  • basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate
  • aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine
  • 4-dimethyl Tertiary amines such as aminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.
  • metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.
  • the amount of the base to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (II).
  • the “condensation agent” include N, N-carbodiimides such as N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC); N, N-carbonyl Azolites such as imidazole; 2-halogenopyridinium salts such as 2-chloro-1-methylpyridinium iodide and 2-fluoro-1-methylpyridinium iodide; and other N-ethoxycarbonyl-2-ethoxy-1,2- Dihydroquinoline, 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), 1H-benzotriazol-1-yloxytris hexafluor
  • the amount of the condensing agent to be used is generally about 0.8 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (II).
  • a condensation accelerator such as 1-hydroxy-1H-benzotriazole (HOBt) monohydrate may coexist.
  • the amount of the base to be used is generally about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (II).
  • solvent used in organic synthesis examples include alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, Diisopropyl ether, 1,2-dimethoxyethane, etc.), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), halogenated hydrocarbons ( Eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (eg, n-hexane, benzene, etc.
  • compound (II) is converted to acylimidazolide, and then a malonic acid monoalkyl ester or a salt thereof is reacted in the presence of a base such as triethylamine and magnesium chloride (Journal of Medicinal Chemistry (J. Med Chem.), 42, 619-627, (1999)).
  • a base such as triethylamine and magnesium chloride
  • Compound (V) can be produced by reacting compound (III) and compound (IV) in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1. Among them, it is preferable to use an alcohol solvent such as methanol or ethanol.
  • the amount of compound (IV) to be used is about 0.5 to about 20 mol, preferably about 0.9 to about 5 mol, per 1 mol of compound (III).
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (VI) can be produced by halogenation or sulfonylation of compound (V).
  • Halogenation can be performed using, for example, thionyl chloride, phosphorus oxychloride, phenylphosphonic dichloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, and the like.
  • the amount of thionyl chloride, phosphorus oxychloride, phenylphosphonic acid dichloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide and the like to be used is about 0.5 to about 50 mol, preferably about 1 to 1 mol of compound (VI) About 0.9 to about 30 moles.
  • the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used.
  • the reaction temperature is usually ⁇ 30 ° C. to 250 ° C., preferably ⁇ 30 ° C. to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • the sulfonylation can be carried out, for example, using methanesulfonyl chloride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) or the like, if desired, in the presence of a base.
  • the amount of methanesulfonyl chloride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) and the like to be used is about 0.5 to about 10 mol, preferably about 0.9, per 1 mol of compound (VI). To about 3 moles.
  • the “base” for example, the “base” shown in Reaction Scheme 1 Step 1 is used.
  • the amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (VI).
  • the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used. Of these, pyridine and N, N-dimethylformamide (DMF) are preferable.
  • the reaction temperature is usually ⁇ 100 ° C. to 250 ° C., preferably ⁇ 78 ° C. to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • a method using phenylphosphonic acid dichloride and a method using trifluoromethanesulfonic anhydride are preferable.
  • Step 4 Compound (Ia) is produced by a Suzuki coupling reaction of compound (VI) and compound (VII).
  • Compound (VII) can be obtained as a commercial product, and can also be produced according to a method known per se or a method analogous thereto.
  • Compound (VI) and Compound (VII) are carried out in the “solvent used for organic synthesis” shown in Step 1 in the presence of the “base” shown in Reaction Formula 1 Step 1 and a transition metal catalyst.
  • the amount of compound (VII) to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (VI).
  • the amount of the “base” to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (VI).
  • the “transition metal catalyst” include palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) , Palladium catalysts such as dichlorobis (triphenylphosphine) palladium (II) and tris (dibenzylideneacetone) dipalladium (0).
  • the amount of the transition metal catalyst to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (VI).
  • a ligand such as dicyclohexyl [2 ′, 4 ′, 6′-tris (1-methylethyl) biphenyl-2-yl] phosphane may be used.
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.
  • Compound (VIII) is produced by a boronation reaction of compound (VI).
  • the boronation reaction may be carried out by reacting a Grignard reagent or organolithium reagent prepared from compound (VI) with a trialkylborate, and diboronate such as bispinacolatodiboron with dichloro [1 , 1′-bis (diphenylphosphino) ferrocene] palladium (II) and the like, and a base in the presence of a base such as potassium acetate, a method of reacting in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 Etc.
  • the Grignard reagent or organolithium reagent of compound (VI) can be produced according to a method known per se or a method analogous thereto.
  • the amount of the trialkyl borate to be used is about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (VI).
  • the amount of diboronic acid ester to be used is about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (VI).
  • the amount of the transition metal catalyst to be used is about 0.0001 to about 2 mol, preferably about 0.01 to about 0.3 mol, per 1 mol of compound (VI).
  • the amount of the base to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (VI).
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Step 6 Compound (Ia) is produced by a Suzuki coupling reaction of compound (VIII) and compound (IX).
  • Compound (IX) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • the Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
  • Compound (XII) can be produced by reacting compound (X) with compound (XI) in the presence of a base.
  • Compound (X) and compound (XI) are commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (XI) to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (X).
  • Examples of the “base” include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, lithium diisopropylamide, sodium bis Metal amides such as (trimethylsilylamide) and potassium bis (trimethylsilylamide) are used.
  • the amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (X).
  • the reaction temperature is usually ⁇ 100 to 150 ° C., preferably ⁇ 80 to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Step 2 Compound (XIII) can be produced by reacting compound (XII) with compound (IV). This reaction can be carried out in the same manner as in the method described in Reaction Scheme 1, Step 2.
  • Compound (XIV) can be produced by a reduction reaction of compound (XIII).
  • the reduction reaction can be carried out in a solvent using a reducing agent in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) relative to compound (XIII).
  • the “reducing agent” include lithium aluminum hydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, calcium borohydride, borane complex (borane-THF complex, etc.), and the like. Of these, sodium borohydride is preferred.
  • the “solvent” for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used.
  • ether solvents such as tetrahydrofuran and alcohol solvents such as methanol and ethanol are preferable.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Step 4 Compound (XV) can be produced by halogenation or sulfonylation of compound (XIV). This reaction can be carried out in the same manner as in the method described in Reaction Scheme 1, Step 3.
  • Step 5 Compound (Iaa) is produced by a Suzuki coupling reaction of compound (XV) and compound (XVI).
  • Compound (XVI) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • the Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
  • Step 1 Compound (XVIII) can be produced by reacting compound (XVII) and compound (IX) in a solvent in the presence of a base and optionally a transition metal catalyst.
  • Compound (XVII) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (IX) to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XVII).
  • the “base” the “base” shown in Reaction Scheme 1, Step 1 is used.
  • the amount of the base to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XVII).
  • the “transition metal catalyst” include palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) , Dichlorobis (triphenylphosphine) palladium (II), palladium catalyst such as tris (dibenzylideneacetone) dipalladium (0), copper chloride (I), copper chloride (II), copper bromide (I), bromoiodide Copper catalysts such as copper (I) and copper acetate are used.
  • the amount of the transition metal catalyst to be used is about 0.001 to about 5 mol, preferably about 0.02 to about 2 mol, per 1 mol of compound (XVII).
  • the “solvent” for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used.
  • the reaction temperature is usually ⁇ 50 to 250 ° C., preferably 0 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (Ib) can be produced by a Negishi cross-coupling reaction between compound (XVIII) and compound (XIX).
  • Compound (XIX) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • the Negishi cross-coupling reaction the compound (XVIII) and the compound (XIX) are carried out in the presence of a transition metal catalyst in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1.
  • the amount of compound (XIX) to be used is about 0.5 to about 20 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XVIII).
  • a nickel catalyst such as dichlorobis (triphenylphosphine) nickel or the like may be used in addition to the “transition metal catalyst” shown in Reaction Formula 1 Step 1.
  • the amount of the transition metal catalyst to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (XVIII).
  • the “solvent” for example, the “solvent used for organic synthesis” shown in Reaction Scheme 1 Step 1 is used, among which ether solvents such as tetrahydrofuran, DMF and the like are preferable.
  • a ligand such as dicyclohexyl [2 ′, 4 ′, 6′-tris (1-methylethyl) biphenyl-2-yl] phosphane may be used.
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.
  • Compound (XXII) can be produced by reacting compound (XX) and compound (XXI) in a solvent in the presence of an “acid” or “base” as desired.
  • Compound (XX) and compound (XXI) are commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (XXI) to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XX).
  • Acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, nitric acid such as nitric acid, carboxylic acids such as acetic acid and trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluene Sulfonic acids such as sulfonic acid are used, and among them, mineral acids such as sulfuric acid are preferable.
  • the amount of the acid to be used is preferably about 0.5 to about 10 molar equivalents relative to compound (XX).
  • Examples of the “base” include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, lithium diisopropylamide, sodium bis Metal amides such as (trimethylsilylamide) and potassium bis (trimethylsilylamide) are used.
  • the amount of the base used is approximately 0.5 to approximately 30 mol, preferably approximately 0.9 to approximately 10 mol, with respect to 1 mol of the compound (XX).
  • the “solvent” for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used, and among these, toluene and the like are preferable.
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (Ic) can be produced by reacting compound (XXII) and compound (XXIII) in a solvent in the presence of an “acid” or “base” as desired.
  • the amount of compound (XXIII) to be used is about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXII).
  • Step 1 is used as the “acid”, for example, the “acid” shown in Reaction Scheme 4, Step 1 is used.
  • the amount of the acid to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXII).
  • the “base” for example, the “base” shown in Reaction Scheme 1, Step 1 is used.
  • the amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXII).
  • the “solvent” for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used. Of these, the reaction in pyridine is preferred.
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • X 5 represents a C 1-7 alkoxy group or a C 1-6 alkylsulfanyl group; other symbols are as defined above.
  • the compound (B2) in which X 5 is a C 1-7 alkoxy group is obtained by reacting the compound (B1) with an alcohol represented by the general formula: X 5 -H in the presence of an “acid” or “base”.
  • an alcohol represented by the general formula: X 5 -H
  • the alcohol for example, methanol, ethanol, benzyl alcohol and the like are used, and methanol and ethanol are particularly preferable.
  • the amount of the alcohol to be used is about 0.5 to about 200 mol, preferably about 0.9 to about 20 mol, per 1 mol of compound (B1).
  • Examples of the “acid” include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, nitric acid such as nitric acid, carboxylic acids such as acetic acid and trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluene Sulfonic acids such as sulfonic acid are used, and among them, mineral acids such as hydrochloric acid are preferable.
  • the amount of the acid to be used is about 0.5 to about 100 mol, preferably about 0.9 to about 30 mol, per 1 mol of compound (B1).
  • Examples of the “base” include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, lithium diisopropylamide, sodium bis Metal amides such as (trimethylsilylamide) and potassium bis (trimethylsilylamide) are used, among which metal alkoxides and metal hydrides are preferable.
  • the amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B1).
  • the reaction temperature is usually ⁇ 100 to 250 ° C., preferably ⁇ 30 to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (B2) in which X 5 is a C 1-6 alkylsulfanyl group can be produced by thioamidating compound (B1) and then S-alkylating it.
  • a method of thioamidation for example, a method using hydrogen sulfide and sodium hydrosulfide in ethanol, for example, a “solvent used for organic synthesis” shown in Reaction Formula 1, Step 1, dithiophosphate O, O-dialkyl, etc.
  • Examples thereof include a method using dithiophosphate (O, O-diethyl). Among them, a method using dithiophosphoric acid O, O-diethyl is preferable.
  • the amount of dithiophosphate O, O-dialkyl to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B1).
  • the reaction temperature is usually ⁇ 80 to 100 ° C., preferably ⁇ 30 to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • the S-alkylation can be performed, for example, by using an alkyl halide in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1. Among them, a method using methyl iodide in acetone is preferable.
  • the amount of the alkyl halide to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B1).
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (B1) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • Compound (B3) can be produced by reacting compound (B2) with compound (XXIII) in a solvent.
  • the amount of compound (XXIII) to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B2).
  • the solvent for example, the “solvent used for organic synthesis” shown in Reaction Formula 1, Step 1 is used. Among these, it is preferable to use alcohols such as ethanol and isopropyl alcohol, and acetic acid.
  • the reaction temperature is usually ⁇ 80 to 100 ° C., preferably ⁇ 30 to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (Ic) can be produced by reacting compound (B3) with compound (B4) or compound (B5), optionally in the presence of an “acid”, in a solvent or without a solvent.
  • the amount of compound (B4) or (B5) to be used is about 0.5 to about 200 mol, preferably about 0.9 to about 50 mol, per 1 mol of compound (B3).
  • Examples of the “acid” include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, nitric acid such as nitric acid, carboxylic acids such as acetic acid and trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluene Sulfonic acids such as sulfonic acid are used, among which acetic acid is preferred.
  • the amount of the acid to be used is about 0.5 to about 100 mol, preferably about 0.9 to about 30 mol, per 1 mol of compound (B3).
  • the solvent for example, the “solvent used for organic synthesis” shown in Reaction Formula 1, Step 1 is used. Of these, it is preferable to use acetic acid.
  • the reaction temperature is usually 0 to 200 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Step 1 Compound (XXVI) can be produced by reacting compound (XXIV) and compound (XXV) in a solvent, optionally in the presence of a “base”.
  • Compound (XXV) can be obtained as a commercial product, and can also be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (XXV) to be used is about 0.5 to about 20 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXIV).
  • the “base” for example, the “base” shown in Reaction Scheme 1, Step 1 is used. Of these, sodium hydride is preferably used.
  • the amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXIV).
  • the “solvent” for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used. Of these, ether solvents such as tetrahydrofuran, DMF and the like are preferable.
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Step 2 Compound (XXVII) can be produced by a Suzuki coupling reaction of compound (XXVI) and compound (VII).
  • the Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
  • Step 3 Compound (XXVIII) can be produced by a reduction reaction of compound (XXVII).
  • the reduction reaction can be performed in the same manner as the method described in Reaction Scheme 2, Step 3.
  • Step 4 Compound (XXIX) can be produced by halogenation or sulfonylation of compound (XXVIII). Halogenation or sulfonylation can be carried out in the same manner as described in Reaction Scheme 1, Step 3.
  • Step 5 Compound (Id) can be produced by a Suzuki coupling reaction of compound (XXIX) and compound (XVI).
  • the Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
  • Compound (XXXII) can be produced by a condensation reaction of compound (XXX) and compound (XXXI).
  • Compound (XXX) can be obtained as a commercially available product, and can also be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (XXXI) to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXX).
  • the condensation reaction is carried out in a solvent in the presence of a “condensing agent” or “base”, if desired.
  • the “condensation agent” shown in Reaction Formula 1 is used as the “condensation agent”, for example, the “condensation agent” shown in Reaction Formula 1, Step 1 is used.
  • the amount of the condensing agent to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXX).
  • the “base” shown in Reaction Scheme 1, Step 1 is used as the “base”.
  • the amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXX).
  • the “solvent” for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used.
  • the reaction temperature is usually ⁇ 50 ° C. to 250 ° C., preferably ⁇ 30 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (XXXIV) can be produced by reacting compound (XXXII) with compound (XXXIII) in a solvent.
  • Compound (XXXIII) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (XXXIII) to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXII).
  • the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used. Of these, ether solvents such as tetrahydrofuran are preferred.
  • the reaction temperature is usually ⁇ 100 ° C. to 250 ° C., preferably ⁇ 80 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (XXXV) can be produced by a halogenation reaction of compound (XXXIV).
  • the halogenation reaction can be carried out by a method using a halogenating agent such as fluorine, chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like. Of these, it is preferable to use bromine.
  • the amount of the halogenating agent to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XXXIV).
  • the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used.
  • the reaction temperature is usually ⁇ 100 ° C. to 150 ° C., preferably ⁇ 30 ° C. to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (XXXVI) can be produced by subjecting compound (XXXV) to an azidation reaction.
  • the azidation reaction can be performed, for example, by using an azidating agent such as sodium azide or trimethylsilyl azide. Of these, sodium azide is preferably used.
  • the amount of the azidating agent to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XXXV).
  • the “solvent used in organic synthesis” shown in Reaction Scheme 1, Step 1 is used. Of these, alcohol solvents such as methanol or ° C.
  • the reaction temperature is usually ⁇ 100 ° C. to 150 ° C., preferably ⁇ 30 ° C. to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (XXXVII) can be produced by a reduction reaction of compound (XXXVI).
  • the reduction reaction is performed, for example, by using a method using a metal such as iron or zinc, a method using a phosphine such as triphenylphosphine, or a method of hydrogenating in the presence of a transition metal catalyst such as palladium-carbon. be able to.
  • a metal such as iron or zinc
  • a method using a phosphine such as triphenylphosphine
  • a method of hydrogenating in the presence of a transition metal catalyst such as palladium-carbon be able to.
  • zinc is preferably used.
  • the amount of zinc to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXXVI).
  • the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used.
  • the reaction temperature is usually ⁇ 100 ° C. to 150 ° C., preferably ⁇ 30 ° C. to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Step 6 Compound (XXXVIII) can be produced by a condensation reaction of compound (XXXVII) and compound (II). The condensation reaction can be carried out in the same manner as in the method described in Reaction Scheme 6, Step 1.
  • Compound (Ie) can be produced by subjecting compound (XXXVIII) to dehydration cyclization in the presence of a “dehydrating agent” as desired.
  • a “dehydrating agent” include phosphorus oxychloride, diphosphorus pentoxide, concentrated sulfuric acid and the like. Of these, phosphorus oxychloride is preferably used.
  • the amount of the dehydrating agent to be used is about 0.5 to about 100 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXXVIII).
  • Step 1 Compound (If) can be produced by subjecting compound (XXXIX) to a carbonylation reaction.
  • the carbonylation reaction is carried out in the presence of a base and a transition metal catalyst in the “solvent used for organic synthesis” shown in Step 1 of Reaction Scheme 1, compound (XXXIX) and carbon monoxide or an equivalent thereof, and a general formula: R 4 — It can be produced by reacting with an alcohol represented by OH.
  • Examples of the “equivalent of carbon monoxide” include formic acid or a salt thereof, formic acid ester such as methyl formate and ethyl formate.
  • the alcohol represented by the general formula: R 4 —OH can be obtained as a commercial product, and can also be produced according to a method known per se or a method analogous thereto.
  • the amount of the alcohol to be used is about 0.5 to about 100 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXXIX).
  • the “base” shown in Reaction Scheme 1 Step 4 is used, and amines such as triethylamine are particularly preferable.
  • the amount of the “base” to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XXXIX).
  • the “transition metal catalyst” the “transition metal catalyst” shown in the reaction formula 1, step 4 is used.
  • tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) and the like are preferable.
  • the amount of the “transition metal catalyst” to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (XXXIX).
  • the reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • Compound (Ig) can be produced by hydrolysis of compound (If).
  • the hydrolysis can be performed by selecting from alkaline conditions and acidic conditions. Alkaline conditions are performed in the presence of a base in a solvent that does not affect the reaction.
  • bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (If).
  • the “solvent that does not affect the reaction” is selected from, for example, “solvents used in organic synthesis” shown in Step 1 of Reaction Scheme 1.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Acidic conditions are performed in the presence of an acid in a solvent that does not affect the reaction.
  • mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and nitric acid are preferable.
  • the amount of the acid used is preferably about 0.5 to about 10 molar equivalents relative to compound (If).
  • the “solvent that does not affect the reaction” is selected from, for example, the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Compound (Ig) can also be produced from a compound in which the ester group (—COOR 4 ) of compound (If) is another substituent that can be converted to a carboxyl group.
  • Examples of the “other substituent that can be converted into a carboxyl group” include, for example, a cyano group, a carbamoyl group, an oxazol-2-yl group, 4,4-dimethyl-4,5-dihydro-1,3-oxazole-2- Yl group and the like.
  • Step 3 Compound (Ii) can be produced by reacting compound (Ig) with compound (XXXXI) in the presence of a suitable condensing agent. This reaction can be carried out in the same manner as in the method described in Reaction Scheme 6, Step 1.
  • Compound (XXXX) can be produced by a cyanation reaction of compound (XXXIX). Cyanation can be performed, for example, by using sodium cyanide or potassium cyanide in the presence of a phase transfer catalyst (eg, benzyltributylammonium chloride), using trimethylsilyl cyanide and tetrabutylammonium fluoride (Journal of Organic Chemistry ( J. Org. Chem.), 64, 3171-3177, (1999)), in the presence of a transition metal catalyst, a method using zinc cyanide or the like.
  • a phase transfer catalyst eg, benzyltributylammonium chloride
  • trimethylsilyl cyanide and tetrabutylammonium fluoride Journal of Organic Chemistry ( J. Org. Chem.), 64, 3171-3177, (1999)
  • the amount of the phase transfer catalyst to be used is about 0.001 to about 10 mol, preferably about 0.01 to about 3 mol, per 1 mol of compound (XXXIX).
  • the amount of sodium cyanide, potassium cyanide and the like to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXIX).
  • the amount of trimethylsilylcyanide to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXIX).
  • the amount of tetrabutylammonium fluoride to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXIX).
  • the “transition metal catalyst” include palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Palladium catalysts such as dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), copper catalysts such as copper (I) bromide, copper (II) bromide, copper acetate, etc.
  • the amount of the transition metal catalyst to be used is about 0.001 to about 10 mol, preferably about 0.1 to about 3 mol, per 1 mol of compound (XXXIX).
  • the amount of zinc cyanide used is about 0.5 to about 30 moles, preferably about 0.9 to about 10 moles per mole of Compound (XXXIX).
  • the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used for cyanation. Of these, DMF and N-methylpyrrolidone are preferable.
  • the reaction temperature is usually 0 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • a method using zinc cyanide in the presence of tetrakis (triphenylphosphine) palladium (0) is preferable.
  • Step 5 Compound (Ih) is produced by hydrolysis of compound (XXXX).
  • hydrolysis may also be performed by a method using an oxidizing agent such as hydrogen peroxide in a solvent such as dimethyl sulfoxide in the presence of a base such as potassium carbonate.
  • an oxidative method using hydrogen peroxide in dimethyl sulfoxide in the presence of potassium carbonate is preferable.
  • the amount of the base such as potassium carbonate to be used is about 0.01 to about 10 mol, preferably about 0.2 to about 3 mol, per 1 mol of compound (XXXX).
  • the amount of the oxidizing agent such as hydrogen peroxide to be used is about 0.9 to about 30 mol, preferably about 0.9 to about 20 mol, per 1 mol of compound (XXXX).
  • the reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • a protective group generally used in peptide chemistry or the like may be introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • amino-protecting group examples include, for example, formyl, C 1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C 1-6 alkoxy-carbonyl (which may each have a substituent) For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), phenyloxycarbonyl, C 7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, etc. .
  • substituent for the “amino-protecting group” examples include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl). Etc.), the number of substituents is 1 to several (eg, 3).
  • Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 halogen atoms, C 1-6 alkoxy groups, nitro groups and the like.
  • Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuryl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like.
  • a C 1-6 alkyl group eg, phenyl group, a trityl group, a C 7-10 a
  • These groups may be substituted with 1 to 3 halogen atoms, a C 1-6 alkyl group, a C 1-6 alkoxy group, a nitro group and the like.
  • protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
  • the above-described method for removing protecting groups can be carried out in accordance with a known method, for example, the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980).
  • a known method for example, the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980).
  • a reduction method or the like is used.
  • the compound or salt thereof obtained in each of the above reactions can be isolated and purified by a known means such as solvent extraction, liquid conversion, phase transfer, concentration, crystallization, recrystallization, chromatography and the like.
  • the starting compound of each reaction or a salt thereof can be isolated and purified by the same known means as described above, but it is provided as a starting material for the next step as it is without isolation. Also good.
  • a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction may be carried out alone or in combination as desired.
  • a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (-Boc), a peak from which the tert-butoxycarbonyl group or tert-butyl group is eliminated should be observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
  • Ethyl 4- (4-iodo-2-methyl-1H-imidazol-1-yl) benzoate Sodium hydride (55%, 2.59 g) and 18-crown-6 (1.57 g) 1-methyl-2 4-Iodo-2-methyl-1H-imidazole (12.4 g) was added to a pyrrolidone (NMP) suspension (200 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes.
  • NMP pyrrolidone
  • Ethyl 4-fluorobenzoate (10.0 g) was added dropwise to the reaction mixture cooled to 0 ° C., and the mixture was heated and stirred at 110 ° C. overnight.
  • the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • the residue was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (7.03 g).
  • 1,2-dibromobutane (0.032 mL) was added to an anhydrous THF suspension (15 mL) of zinc powder (0.530 g), and the mixture was stirred at 70 ° C. for 30 minutes.
  • the reaction mixture was cooled to room temperature, chlorotrimethylsilane (0.047 mL) was added, and the mixture was stirred at room temperature for 15 minutes.
  • anhydrous THF solution (5 mL) of 1- (bromomethyl) -3-fluoro-5- (trifluoromethyl) benzene (2.083 g) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 5 hours.
  • Ethyl 2-cyclopropyl-4-fluorobenzoate (1.0 g) synthesized in Example 20-A), cyclopropylboronic acid (1.043 g), 2N aqueous sodium carbonate solution (6.07 mL) in 1,2-dimethoxyethane (DME) solution (20 mL) to dichloro [1,1'-bis (diphenylphosphino) -ferrocene] palladium (II) dichloromethane adduct (1: 1) (0.24 g) was added and stirred at 90 ° C. overnight under a nitrogen atmosphere.
  • DME 1,2-dimethoxyethane
  • E) Ethyl 4- [3- (Bromomethyl) -1-methyl-1H-pyrazol-5-yl] benzoate Ethyl 4- [3- (hydroxymethyl) -1-methyl-synthesized in Example 26-D) To a solution of [1H-pyrazol-5-yl] benzoate (14.0 g) in dichloromethane (150 mL) was added phosphorus tribromide (1M dichloromethane solution, 53.8 mL), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Ethyl 4- [3- (bromomethyl) synthesized in Example 26-E) ) -1-Methyl-1H-pyrazol-5-yl] benzoate (11.3 g), 3- (trifluoromethyl) phenylboronic acid (9.96 g), tetrakis (triphenylphosphine) palladium (0) (2.02 g) , A mixture of potassium phosphate (22.3 g) and 1,4-dioxane (120 mL) was stirred at 80 ° C. for 16 hours.
  • the reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (11.2 g).
  • the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and recrystallized from ethanol-ethyl acetate to give the title compound (193 mg).
  • Example 38 4- ⁇ 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl ⁇ -2-methyl-N- [2- (methylsulfanyl) ethyl] benzamide
  • Example 39 4- ⁇ 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl ⁇ -2-methyl-N- [2- (methylsulfinyl) ethyl] benzamide
  • Example 40 4- ⁇ 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl ⁇ -2-methyl-N- [2- (methylsulfonyl) ethyl] benzamide
  • the reaction mixture was stirred for 1 hour, diluted with ethyl acetate, and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (123 mg).
  • Example 70 4- ⁇ 1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl ⁇ -2-methyl-N- [2- (methylamino) -2-oxoethyl Benzamide
  • Methyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate Methyl propiolate (5.00 g) and methyl 3-aminobut-2-enoate (7.53 g) in methanol (50 mL) are heated overnight. Refluxed. The reaction mixture was cooled to 0 ° C., and the insoluble material was collected by filtration and washed with isopropanol. The solid was dried under reduced pressure to give the title compound (4.48 g).
  • the reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with water and saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate).
  • the obtained product was fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), a saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate.
  • the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (6.5 mg).
  • Methyl 5-bromo-1H-1,2,4-triazole-3-carboxylate Methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (15.0 g), concentrated sulfuric acid (6.0 mL ) And water (100 mL) were cooled to 0 ° C., and an aqueous solution of sodium nitrite (10.9 g) was slowly added dropwise. After stirring for 30 minutes, an aqueous solution of copper (I) bromide (7.6 g) and potassium bromide (25.1 g) was slowly added dropwise. The reaction mixture was warmed to room temperature and stirred overnight, and then filtered through celite. The filtrate was extracted with ethyl acetate.
  • Methyl 5- (4-cyanophenyl) -1-methyl-1H-1,2,4-triazole-3-carboxylate Methyl 5-bromo-1-methyl-1H- synthesized in Example 75-B) 1,2,4-triazole-3-carboxylate (55 mg), 4-cyanophenylboronic acid (44 mg), tris (dibenzylideneacetone) dipalladium (0) (11 mg), dicyclohexyl [2 ', 4 A mixture of ', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphane (X-Phos; 12 mg), cesium carbonate (122 mg) and 1,2-dimethoxyethane (DME; 1 mL) Heated at 150 ° C.
  • Example 80 4-[(4- ⁇ 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl ⁇ -2-methylphenyl) carbonyl] piperazin-2-one
  • Example 29-B Methyl 2- (dimethylamino) -4- ⁇ 3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl ⁇ benzoate
  • Example 29-B In the same manner as in Example 99-A), using methyl 4-bromo-2- (dimethylamino) benzoate, methyl 2- (dimethylamino) -4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) benzoate was synthesized.
  • Ethyl 4- (3- (Bromomethyl) -1-methyl -1H-pyrazol-5-yl) -2-methylbenzoate (0.280 g), 3-chloro-5-fluorophenylboronic acid (0.217 g), tripotassium phosphate (0.529 g), tetrakis (triphenylphosphine)
  • a DME solution (3 mL) of palladium (0) (0.096 g) was heated and stirred at 140 ° C. for 20 minutes under microwave irradiation.

Abstract

A compound that has agonist activity against GPR52 and that is useful as a preventive or therapeutic drug for mental disorders and the like such as schizophrenia is provided. The compound is a compound represented by general formula (I) [where each symbol is as defined in the Specification] or a salt thereof.

Description

複素環化合物およびその用途Heterocyclic compounds and uses thereof
　本発明は、新規複素環化合物、その製造法およびそれを含有する医薬に関する。さらに詳しくは、ＧＰＲ５２に対するアゴニスト活性を有し、統合失調症などの精神疾患等の予防・治療用の医薬として有効な化合物に関する。 The present invention relates to a novel heterocyclic compound, a process for producing the same, and a medicine containing the same. More specifically, the present invention relates to a compound having an agonist activity for GPR52 and effective as a medicament for the prevention / treatment of mental disorders such as schizophrenia.
（発明の背景）
　統合失調症は、思春期から成人期にかけて発病し、特徴的な思考障害、自我障害、およびそれに伴う行動異常を示す疾患である。発病率は全人口の１％程と言われているが、多くは慢性的に経過し、自発性や対人接触などが低下し、社会生活に著しく困難をきたす。統合失調症の中核症状は、（１）妄想、幻覚などの陽性症状、（２）感覚鈍麻、ひきこもり、意欲・集中力の低下などの陰性症状、および（３）認知機能障害の３つに大別されることが多い。これらの中核症状においては、陽性症状の発現には中脳辺縁系におけるドパミン神経系の過剰亢進が、陰性症状の発現や認知機能の低下には前頭葉皮質におけるグルタミン酸神経系などの神経系の機能低下が深く関わっているとされている。
　陽性症状に対しては、クロルプロマジンなどのドパミンＤ２受容体アンタゴニスト活性を有する定型抗精神病薬が改善効果を示している。一方で、陰性症状や認知機能の障害に対しては、クロザピンおよびオランザピンなどの多受容体作用型の薬剤が一定の効果を示しているが、多くの患者に反応しにくいことが知られている。また、副作用の面においても定型抗精神病薬はアカシジア、ジストニア、およびパーキンソン様運動障害などの錐体外路系症状の発現や、高プロラクチン血症が問題となっている。また、クロザピンは重篤な副作用として顆粒球減少症があり、オランザピンなどの非定型抗精神病薬においても体重増加、脂質代謝異常、過鎮静作用、および心臓ＱＴ間隔延長などの副作用が問題となっている。
　ヒトＧＰＲ５２（G Protein-Coupled Receptor 52）はＧＰＣＲ（G Protein-Coupled Receptor）の一つである（非特許文献１）。近年、ＧＰＲ５２に対するアゴニストおよびリガンドなどは、ＧＰＲ５２などを発現している神経細胞の細胞内ｃＡＭＰ濃度を上昇させるので、統合失調症の陽性症状の原因の一つとされている中脳辺縁系ドパミン経路の過活動を抑制して、統合失調症の陽性症状を改善できると考えられている。また、統合失調症の陰性症状や認知機能障害の原因の一つとされている大脳皮質のＮＭＤＡ型受容体の機能低下を改善し、統合失調症の陰性症状や認知機能障害を改善させることができることがわかってきた（特許文献１）。
　さらに、上述の神経細胞内の細胞内ｃＡＭＰ濃度を上昇させる作用は、ドパミン系のみならず、ノルエピネフリン、セロトニン、ヒスタミン、アセチルコリン等の種々の神経伝達物質の機能の調節、神経の生存、分化、および、可塑的変化に関与する可能性がある。このため、ＧＰＲ５２に対するアゴニストおよびリガンドなどは、精神疾患、神経変性疾患、あるいは神経系の変調に起因する種々の全身的な疾患に対して有用な作用を発揮することが期待できる。
　ＧＰＲ５２に対するアゴニスト活性を有する化合物は、ＧＰＲ５２作動薬（ＧＰＲ５２アゴニスト；ＧＰＲ５２受容体作動薬、ＧＰＲ５２受容体アゴニスト、ＧＰＲ５２活性化薬、ＧＰＲ５２受容体活性化薬と称される場合がある）として、統合失調症などの精神疾患をはじめとする種々の疾患の予防・治療のために有用である。 (Background of the Invention)
Schizophrenia is a disease that develops from adolescence to adulthood and exhibits characteristic thought disorders, ego disorders, and behavioral abnormalities associated therewith. The incidence is said to be about 1% of the total population, but many are chronically progressed, and spontaneity and interpersonal contact are reduced, making social life extremely difficult. The core symptoms of schizophrenia are (1) positive symptoms such as delusions and hallucinations, (2) dull sensation, withdrawal, negative symptoms such as decreased motivation and concentration, and (3) cognitive dysfunction. Often separated. In these core symptoms, hypersensitivity of the dopamine nervous system in the mesencephalic system is associated with positive symptoms, and neurological functions such as glutamate nervous system in the frontal cortex for negative symptoms and cognitive decline. The decline is said to be deeply involved.
For positive symptoms, typical antipsychotics having dopamine D2 receptor antagonist activity such as chlorpromazine have shown an improving effect. On the other hand, multireceptor-acting drugs such as clozapine and olanzapine have a certain effect on negative symptoms and cognitive impairment, but are known to be less responsive to many patients . Also, in terms of side effects, typical antipsychotics have problems of extrapyramidal symptoms such as akathisia, dystonia, and Parkinsonian movement disorder, and hyperprolactinemia. Also, clozapine has granulocytopenia as a serious side effect, and side effects such as weight gain, abnormal lipid metabolism, hypersedation, and prolonged cardiac QT interval are also problems in atypical antipsychotics such as olanzapine. Yes.
Human GPR52 (G Protein-Coupled Receptor 52) is one of GPCR (G Protein-Coupled Receptor) (Non-patent Document 1). In recent years, agonists and ligands for GPR52 increase the intracellular cAMP concentration of nerve cells expressing GPR52 and the like, and the mesencephalic dopamine pathway, which is one of the causes of positive symptoms of schizophrenia It is thought that the positive symptoms of schizophrenia can be improved by suppressing overactivity. In addition, it is possible to improve cerebral cortex NMDA receptor functional decline, one of the causes of schizophrenia negative symptoms and cognitive dysfunction, and to improve schizophrenia negative symptoms and cognitive dysfunction (Patent document 1).
Furthermore, the above-mentioned action to increase intracellular cAMP concentration in nerve cells is not only a dopamine system, but also regulation of functions of various neurotransmitters such as norepinephrine, serotonin, histamine, and acetylcholine, nerve survival, differentiation, and , May be involved in plastic changes. Therefore, agonists and ligands for GPR52 can be expected to exert useful effects on various systemic diseases caused by mental disorders, neurodegenerative diseases, or modulation of the nervous system.
Compounds having agonist activity for GPR52 are schizophrenia as GPR52 agonists (GPR52 agonists; GPR52 receptor agonists, GPR52 receptor agonists, GPR52 activators, sometimes referred to as GPR52 receptor activators) It is useful for the prevention and treatment of various diseases including psychiatric disorders such as infectious diseases.
　ＧＰＲ５２に対するアゴニスト活性を有する化合物として、例えば、特許文献２～４には、以下の一般式で表される化合物が開示されている(特許文献２～４の一般式における記号の意味は、各特許文献の明細書を参照のこと)。 As compounds having agonist activity for GPR52, for example, Patent Documents 2 to 4 disclose compounds represented by the following general formulas (the meanings of the symbols in the general formulas of Patent Documents 2 to 4 are the same as those of each patent). See the literature description).
　特許文献２には、以下の一般式で表される化合物が開示されている。 Patent Document 2 discloses a compound represented by the following general formula.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　特許文献３には、以下の一般式で表される化合物が開示されている。 Patent Document 3 discloses a compound represented by the following general formula.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　特許文献４には、以下の一般式で表される化合物が開示されている。 Patent Document 4 discloses a compound represented by the following general formula.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　特許文献５には、以下２個の化合物が開示されている。
　ＣＡＳ登録番号473882-08-5 Patent Document 5 discloses the following two compounds.
CAS registration number 473882-08-5
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　ＣＡＳ登録番号473882-17-6 CAS registration number 473882-17-6
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　特許文献６には、以下の化合物が開示されている。
　ＣＡＳ登録番号1186102-00-0 Patent Document 6 discloses the following compounds.
CAS registration number 1186102-00-0
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　特許文献７には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN848673-38-1 Patent Document 7 discloses the following compounds.
CAS registration number RN848673-38-1
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　特許文献８には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN847858-78-0 Patent Document 8 discloses the following compounds.
CAS registration number RN847858-78-0
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　特許文献９には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN280111-58-2 Patent Document 9 discloses the following compounds.
CAS registration number RN280111-58-2
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　特許文献１０には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN795310-84-8 Patent Document 10 discloses the following compounds.
CAS registration number RN795310-84-8
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　特許文献１１には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN442877-18-1 Patent Document 11 discloses the following compounds.
CAS registration number RN442877-18-1
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　非特許文献２には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN737766-67-5P Non-Patent Document 2 discloses the following compounds.
CAS registration number RN737766-67-5P
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　非特許文献３には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN197717-25-2 Non-Patent Document 3 discloses the following compounds.
CAS registration number RN197717-25-2
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　非特許文献４には、以下の化合物が開示されている。
　ＣＡＳ登録番号RN301219-12-5 Non-Patent Document 4 discloses the following compounds.
CAS registration number RN301219-12-5
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　ケミカルアブストラクトには、以下の化合物が開示されている。
　ＣＡＳ登録番号RN1054750-39-8 In the chemical abstract, the following compounds are disclosed.
CAS registration number RN1054750-39-8
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
国際公開第２００６／０９８５２０号パンフレットInternational Publication No. 2006/098520 Pamphlet 国際公開第２００９／１０７３９１号パンフレットInternational Publication No. 2009/107391 Pamphlet 国際公開第２００９／１５７１９６号パンフレットInternational Publication No. 2009/157196 Pamphlet 国際公開第２０１０／１８８７４号パンフレットInternational Publication No. 2010/18874 Pamphlet 国際公開第２００９／０９３２６４号パンフレットInternational Publication No. 2009/093264 Pamphlet 国際公開第２００９／１０８５５０号パンフレットInternational Publication No. 2009/108550 Pamphlet ＵＳ２００９／０１６３５４５US2009 / 0163545 ＵＳ２００９／０１６３５４５US2009 / 0163545 国際公開第２０００／０３９１２５号パンフレットInternational Publication No. 2000/039125 Pamphlet 国際公開第２００４／０９９１７８号パンフレットInternational Publication No. 2004/099178 Pamphlet ＵＳ２００２／００９４９８９US2002 / 0094989
　本発明は、ＧＰＲ５２に対するアゴニスト活性を有し、統合失調症などの精神疾患等の予防・治療用の医薬として有用な化合物を提供することを目的とする。 An object of the present invention is to provide a compound having an agonist activity for GPR52 and useful as a medicament for the prevention / treatment of mental disorders such as schizophrenia.
　本発明者らは、以下の式（Ｉ）で示される化合物またはその塩が、ＧＰＲ５２に対するアゴニスト活性を有することを見出し、さらなる研究により、本発明を完成するに至った。
　即ち本発明は、
［１］式（Ｉ）： The present inventors have found that a compound represented by the following formula (I) or a salt thereof has agonist activity for GPR52, and further studies have led to the completion of the present invention.
That is, the present invention
[1] Formula (I):
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
〔式中、
　環Ａは、置換基を有していてもよい６～１０員芳香族炭化水素環、置換基を有していてもよい５～１０員非芳香族複素環、または置換基を有していてもよい５～１０員芳香族複素環を示し；
　環Ｂは、
（１）さらに置換基を有していてもよい６～１０員芳香族炭化水素環、
（２）さらに置換基を有していてもよい５または６員複素環、または
（３）さらに置換基を有していてもよい、ベンゼン環及び５または６員環が縮合した二環性縮合環を示し；
　式（Ｉ）の部分構造式： [Where,
Ring A has an optionally substituted 6 to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered non-aromatic heterocyclic ring, or a substituent. May represent a 5- to 10-membered aromatic heterocycle;
Ring B is
(1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent,
(2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring;
Partial structural formula of formula (I):
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
は、 Is
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
（式中、Ｒ１は、ハロゲン原子、アシル基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、シアノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示し；Ｒ３は水素原子またはＣ１－６アルキル基を示す。）を示し；
　Ｒ２は、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよい非芳香族複素環基、または置換基を有していてもよいＣ３－６シクロアルキル基を示し；
　Ｌ１は、－Ｏ－、－ＣＯ－、置換基を有していてもよいＣ１－６アルキレン、または置換基を有していてもよいＣ３－６シクロアルキレンを示し；
　Ｌ２は、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＹＣＯ－または－ＣＯＮＨ－を示し；
　Ｙは、置換基を有していてもよいＣ１－３アルキレンを示し；
　Ｌ３は、－（ＣＨ２）ｎ－（ｎは０または１を示す。）を示す。〕
で表される化合物（但し、以下の化合物を除く：
（１）式： (In the formula, R 1 has a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. Optionally having a C 2-6 alkynyl group, optionally having a C 3-6 cycloalkyl group, optionally having a C 6-14 aryl group, having a substituent Optionally represents an amino group, a cyano group, or —S (O) m Ra; m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group; R 3 represents Represents a hydrogen atom or a C 1-6 alkyl group);
R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent. A 6 alkyl group, a non-aromatic heterocyclic group which may have a substituent, or a C 3-6 cycloalkyl group which may have a substituent;
L 1 represents —O—, —CO—, an optionally substituted C 1-6 alkylene, or an optionally substituted C 3-6 cycloalkylene;
L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH—;
Y represents C 1-3 alkylene which may have a substituent;
L 3 represents — (CH 2 ) n — (n represents 0 or 1). ]
A compound represented by (except the following compounds:
(1) Formula:
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
（式中、Ｒｘａは、メチル基、エチル基または２－フルオロエチル基を示し；Ｒｘｂは、水素原子、フッ素原子、エトキシ基またはｔｅｒｔ－ブトキシ基を示す。）で表される化合物、
（２）式（Ｉ）の部分構造式： (Wherein R xa represents a methyl group, an ethyl group or a 2-fluoroethyl group; R xb represents a hydrogen atom, a fluorine atom, an ethoxy group or a tert-butoxy group),
(2) Partial structural formula of formula (I):
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
が、 But,
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
を示し、Ｒ１が－ＣＯ－Ｒｘｃ（Ｒｘｃは置換基を示す）を示し、かつＬ１が－ＣＨ２－を示す化合物、並びに、
（３）以下の化合物：
3-(3-ベンジル-1-シクロヘキシル-1H-ピラゾール-5-イル)-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
3-{1-シクロヘキシル-3-[(3,5-ジメチル-1H-ピラゾール-1-イル)メチル]-1H-ピラゾール-5-イル}-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
(6R)-5-(アセチルアミノ)-4-アミノ-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノン酸、
tert-ブチル 4-{2-アミノ-4-[2-(4-ブロモフェニル)-1-(4-メトキシフェニル)エチル]-1H-イミダゾール-1-イル}ピペリジン-1-カルボキシラート、
1-[4-シアノ-2-(ナフタレン-1-イルメチル)-1,3-オキサゾール-5-イル]ピペリジン-4-カルボキサミド、
1-(2-ベンジル-4-シアノ-1,3-オキサゾール-5-イル)ピペリジン-4-カルボキサミド、
tert-ブチル 4-(2-ベンジル-4-エチル-1,3-オキサゾール-5-イル)ピペリジン-1-カルボキシラート、
ベンジル 4-(3-ベンジル-5-メチル-1H-1,2,4-トリアゾール-1-イル)ピペリジン-1-カルボキシラート、
ジフェニルメチル (6R)-5-(アセチルアミノ)-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-4-[(tert-ブトキシカルボニル)アミノ]-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノナート、および
ベンジル (1R,5S,6R)-6-(3-ベンジル-1-エチル-1H-ピラゾール-5-イル)-3-アザビシクロ[3.1.0]ヘキサン-3-カルボキシラート）
またはその塩（本明細書中、化合物（Ｉ）と称する場合がある）；
［２］環Ａが
（１）(i) ハロゲン原子、(ii) Ｃ１－６アルコキシ－カルボニル基または１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、(iii) Ｃ３－１０シクロアルキル基、(iv) ニトロ基、(v) アミノ基、(vi) Ｃ１－６アルキルスルファニル基、(vii) Ｃ１－６アルキルスルフィニル基および(viii) Ｃ１－６アルキルスルホニル基から選ばれる１～３個の置換基で置換されていてもよいベンゼン；
（２）(i) ハロゲン原子および(ii) Ｃ１－６アルキル基から選ばれる１～３個の置換基で置換されていてもよい、２－オキソジヒドロインドールまたは３－オキソジヒドロベンゾオキサジン；または
（３）(i) ハロゲン原子および(ii) Ｃ１－６アルキル基から選ばれる１～３個の置換基で置換されていてもよいインダゾール
である［１］記載の化合物またはその塩：
［３］環Ｂが、
（1）Ｃ３－１０シクロアルキル基；
（2）Ｃ１－６アルコキシ基；
（3）ハロゲン原子；
（4）(a) ハロゲン原子、
　　 (b) ヒドロキシ基、
　　 (c) シアノ基、および
　　 (d) トリ（Ｃ１－６アルキル）シリルオキシ基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
（5）ヒドロキシ基；
（6）１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキルスルホニルオキシ基；および
（7）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、
（２）５もしくは６員芳香族複素環、
（３）５もしくは６員非芳香族複素環、
（４）ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環、または
（５）ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環
である［１］記載の化合物またはその塩；
［４］Ｒ１が、
(i)（1）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
　 （2）ヒドロキシ基、
　 （3）Ｃ１－６アルコキシ基、および
　 （4）Ｃ３－１０シクロアルキル基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
(ii) Ｃ３－６シクロアルキル基；
(iii) Ｃ６－１４アリール基；
(iv)（1）Ｃ１－６アルコキシ－カルボニル基、および
　　（2）Ｃ１－６アルキル基
から選ばれる１または２個の置換基で置換されていてもよいアミノ基；
(v) ホルミル基；または
(vi) カルボキシル基
である［１］記載の化合物またはその塩；
［５］Ｒ２が、
(i) 水素原子；
(ii) ヒドロキシ基；
(iii) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基；
(iv) Ｃ１－６アルコキシ基；
(v)（1）Ｃ１－６アルキル基またはＣ１－６アルキル－カルボニル基でモノまたはジ置換されていてもよいアミノ基、
　 （2）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
　 （3）ヒドロキシ基、
　 （4）Ｃ１－６アルコキシ－カルボニル基、
　 （5）Ｃ１－６アルキルスルファニル基、
　 （6）Ｃ１－６アルキルスルフィニル基、
　 （7）Ｃ１－６アルキルスルホニル基、
　 （8）芳香族複素環基、および
　 （9）非芳香族複素環基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
(vi)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基、および
　　（2）Ｃ１－６アルキル－カルボニル基
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基；または
(vii) Ｃ３－６シクロアルキル基
である［１］記載の化合物またはその塩；
［６］Ｌ１がメチレンである［１］記載の化合物またはその塩；
［７］Ｌ２が－ＣＯ－または－ＮＨＣＯ－である［１］記載の化合物またはその塩；
［８］4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミドまたはその塩；
［９］6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルニコチンアミドまたはその塩；
［１０］4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンズアミドまたはその塩；
［１１］4-{2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール-5-イル}-2-メチルベンズアミドまたはその塩；
［１２］［１］記載の化合物またはその塩を含有する医薬；
［１３］ＧＰＲ５２作動薬である［１２］記載の医薬；
［１４］統合失調症の予防又は治療薬である［１２］記載の医薬；
［１５］［１］記載の化合物またはその塩の有効量を哺乳動物に投与することを特徴とする、統合失調症の予防又は治療方法；
［１６］統合失調症の予防または治療薬の製造のための、［１］記載の化合物またはその塩の使用；
［１７］統合失調症の予防または治療のための、［１］記載の化合物またはその塩；
等に関する。 A compound in which R 1 represents —CO—R xc (R xc represents a substituent) and L 1 represents —CH 2 —, and
(3) The following compounds:
3- (3-benzyl-1-cyclohexyl-1H-pyrazol-5-yl) -1- [2- (cyclopropylamino) -2-oxoethyl] pyridinium,
3- {1-cyclohexyl-3-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1H-pyrazol-5-yl} -1- [2- (cyclopropylamino) -2- Oxoethyl] pyridinium,
(6R) -5- (Acetylamino) -4-amino-2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -3,4 , 5-trideoxy-L-threo-hex-2-enoic acid,
tert-butyl 4- {2-amino-4- [2- (4-bromophenyl) -1- (4-methoxyphenyl) ethyl] -1H-imidazol-1-yl} piperidine-1-carboxylate,
1- [4-cyano-2- (naphthalen-1-ylmethyl) -1,3-oxazol-5-yl] piperidine-4-carboxamide,
1- (2-benzyl-4-cyano-1,3-oxazol-5-yl) piperidine-4-carboxamide,
tert-butyl 4- (2-benzyl-4-ethyl-1,3-oxazol-5-yl) piperidine-1-carboxylate,
Benzyl 4- (3-benzyl-5-methyl-1H-1,2,4-triazol-1-yl) piperidine-1-carboxylate,
Diphenylmethyl (6R) -5- (acetylamino) -2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -4-[(tert -Butoxycarbonyl) amino] -3,4,5-trideoxy-L-threo-hex-2-enoate and benzyl (1R, 5S, 6R) -6- (3-benzyl-1-ethyl-1H-pyrazole- 5-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate)
Or a salt thereof (sometimes referred to herein as compound (I));
[2] ring A is (1) (i) a halogen atom, (ii) C 1-6 alkoxy - carbonyl group or one to three optionally substituted C 1-6 alkyl group by a halogen atom, (iii ) C 3-10 cycloalkyl group, (iv) nitro group, (v) amino group, (vi) C 1-6 alkylsulfanyl group, (vii) C 1-6 alkylsulfinyl group and (viii) C 1-6 Benzene optionally substituted with 1 to 3 substituents selected from alkylsulfonyl groups;
(2) 2-oxodihydroindole or 3-oxodihydrobenzoxazine optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C 1-6 alkyl group; or (3) The compound or salt thereof according to [1], which is indazole optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C 1-6 alkyl group:
[3] Ring B is
(1) a C 3-10 cycloalkyl group;
(2) a C 1-6 alkoxy group;
(3) a halogen atom;
(4) (a) a halogen atom,
(b) a hydroxy group,
(c) cyano, and (d) tri (C 1-6 alkyl) 1-3 optionally substituted by a substituent a C 1-6 alkyl group selected from silyloxy groups;
(5) hydroxy group;
Selected from and (7) C 1-6 alkyl mono- or di-substituted by amino group which may be group; (6) 1-3 optionally substituted by a halogen atom C 1-6 alkylsulfonyloxy group Each of which may be further substituted with 1 to 3 substituents,
(1) benzene,
(2) 5- or 6-membered aromatic heterocycle,
(3) a 5- or 6-membered non-aromatic heterocycle,
(4) a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring are condensed, or (5) a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed [ 1] The compound or salt thereof according to
[4] R 1 is
(i) (1) an amino group which may be mono- or di-substituted with a C 1-6 alkyl group,
(2) hydroxy group,
(3) C 1-6 alkoxy group, and (4) C 3-10 optionally substituted with 1 to 3 substituents selected from cycloalkyl C 1-6 alkyl group;
(ii) a C 3-6 cycloalkyl group;
(iii) a C 6-14 aryl group;
(iv) an amino group optionally substituted with 1 or 2 substituents selected from (1) a C 1-6 alkoxy-carbonyl group, and (2) a C 1-6 alkyl group;
(v) a formyl group; or
(vi) The compound or a salt thereof according to [1], which is a carboxyl group;
[5] R 2 is
(i) a hydrogen atom;
(ii) a hydroxy group;
(iii) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group;
(iv) a C 1-6 alkoxy group;
(v) (1) an amino group which may be mono- or di-substituted with a C 1-6 alkyl group or a C 1-6 alkyl-carbonyl group,
(2) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group,
(3) a hydroxy group,
(4) a C 1-6 alkoxy-carbonyl group,
(5) a C 1-6 alkylsulfanyl group,
(6) a C 1-6 alkylsulfinyl group,
(7) a C 1-6 alkylsulfonyl group,
(8) an aromatic heterocyclic group, and (9) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from non-aromatic heterocyclic groups;
(vi) (1) a C 1-6 alkyl group optionally substituted with a hydroxy group, and (2) a substituent substituted with 1 to 3 substituents selected from a C 1-6 alkyl-carbonyl group A good non-aromatic heterocyclic group; or
(vii) The compound or a salt thereof according to [1], which is a C 3-6 cycloalkyl group;
[6] The compound or salt thereof according to [1], wherein L 1 is methylene;
[7] The compound or a salt thereof according to [1], wherein L 2 is —CO— or —NHCO—;
[8] 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide or a salt thereof;
[9] 6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylnicotinamide or a salt thereof;
[10] 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzamide or a salt thereof;
[11] 4- {2- [3-Fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl} -2-methylbenzamide or a salt thereof;
[12] A medicament containing the compound or salt thereof according to [1];
[13] The medicament according to [12], which is a GPR52 agonist;
[14] The medicament according to [12], which is a prophylactic or therapeutic drug for schizophrenia;
[15] A method for preventing or treating schizophrenia, comprising administering an effective amount of the compound or salt thereof according to [1] to a mammal;
[16] Use of the compound of [1] or a salt thereof for the manufacture of a preventive or therapeutic agent for schizophrenia;
[17] The compound according to [1] or a salt thereof for the prevention or treatment of schizophrenia;
Etc.
　本発明はまた、
［１Ａ］式（Ｉ’）： The present invention also provides
[1A] Formula (I ′):
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
〔式中、
　環Ａは、置換基を有していてもよい６～１０員芳香族炭化水素環、置換基を有していてもよい５～１０員非芳香族複素環、または置換基を有していてもよい５～１０員芳香族複素環を示し；
　環Ｂは、
（１）さらに置換基を有していてもよい６～１０員芳香族炭化水素環、
（２）さらに置換基を有していてもよい５または６員複素環、または
（３）さらに置換基を有していてもよい、ベンゼン環及び５または６員環が縮合した二環性縮合環を示し；
　式（Ｉ’）の部分構造式： [Where,
Ring A has an optionally substituted 6 to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered non-aromatic heterocyclic ring, or a substituent. May represent a 5- to 10-membered aromatic heterocycle;
Ring B is
(1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent,
(2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring;
Partial structural formula of formula (I ′):
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
は、 Is
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
（式中、Ｒ１は、ハロゲン原子、アシル基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいアミノ基、シアノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示す。）を示し；
　Ｒ２は、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよい非芳香族複素環基、または置換基を有していてもよいＣ３－６シクロアルキル基を示し；
　Ｌ１は、－Ｏ－、－ＣＯ－、置換基を有していてもよいＣ１－６アルキレン、または置換基を有していてもよいＣ３－６シクロアルキレンを示し；
　Ｌ２は、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＹＣＯ－または－ＣＯＮＨ－を示し；
　Ｙは、置換基を有していてもよいＣ１－３アルキレンを示す。〕
で表される化合物（但し、以下の化合物を除く：
（１）式： (In the formula, R 1 has a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted amino group, a cyano group, or —S (O) m represents 0; 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group);
R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent. A 6 alkyl group, a non-aromatic heterocyclic group which may have a substituent, or a C 3-6 cycloalkyl group which may have a substituent;
L 1 represents —O—, —CO—, an optionally substituted C 1-6 alkylene, or an optionally substituted C 3-6 cycloalkylene;
L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH—;
Y represents C 1-3 alkylene which may have a substituent. ]
A compound represented by (except the following compounds:
(1) Formula:
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式中、Ｒｘａは、メチル基、エチル基または２－フルオロエチル基を示し；Ｒｘｂは、水素原子、フッ素原子、エトキシ基またはｔｅｒｔ－ブトキシ基を示す。）で表される化合物、
（２）式（Ｉ’）の部分構造式： (Wherein R xa represents a methyl group, an ethyl group or a 2-fluoroethyl group; R xb represents a hydrogen atom, a fluorine atom, an ethoxy group or a tert-butoxy group),
(2) Partial structural formula of formula (I ′):
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
が、 But,
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
を示し、Ｒ１が－ＣＯ－Ｒｘｃ（Ｒｘｃは置換基を示す）を示し、かつＬ１が－ＣＨ２－を示す化合物、並びに、
（３）以下の化合物：
3-(3-ベンジル-1-シクロヘキシル-1H-ピラゾール-5-イル)-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
3-{1-シクロヘキシル-3-[(3,5-ジメチル-1H-ピラゾール-1-イル)メチル]-1H-ピラゾール-5-イル}-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
(6R)-5-(アセチルアミノ)-4-アミノ-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノン酸、
tert-ブチル 4-{2-アミノ-4-[2-(4-ブロモフェニル)-1-(4-メトキシフェニル)エチル]-1H-イミダゾール-1-イル}ピペリジン-1-カルボキシラート、
1-[4-シアノ-2-(ナフタレン-1-イルメチル)-1,3-オキサゾール-5-イル]ピペリジン-4-カルボキサミド、
1-(2-ベンジル-4-シアノ-1,3-オキサゾール-5-イル)ピペリジン-4-カルボキサミド、
tert-ブチル 4-(2-ベンジル-4-エチル-1,3-オキサゾール-5-イル)ピペリジン-1-カルボキシラート、
ベンジル 4-(3-ベンジル-5-メチル-1H-1,2,4-トリアゾール-1-イル)ピペリジン-1-カルボキシラート、
ジフェニルメチル (6R)-5-(アセチルアミノ)-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-4-[(tert-ブトキシカルボニル)アミノ]-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノナート、および
ベンジル (1R,5S,6R)-6-(3-ベンジル-1-エチル-1H-ピラゾール-5-イル)-3-アザビシクロ[3.1.0]ヘキサン-3-カルボキシラート）
またはその塩（本明細書中、化合物（Ｉ’）と称する場合がある）；
［２Ａ］上記［１Ａ］記載の化合物またはその塩のプロドラッグ；
［３Ａ］上記［１Ａ］記載の化合物もしくはその塩、またはそのプロドラッグを含有する医薬；
［４Ａ］ＧＰＲ５２作動薬である上記［３Ａ］記載の医薬；
［５Ａ］統合失調症の予防又は治療薬である上記［３Ａ］記載の医薬；
［６Ａ］上記［１Ａ］記載の化合物もしくはその塩、またはそのプロドラッグの有効量を哺乳動物に投与することを特徴とする、統合失調症の予防又は治療方法；
［７Ａ］統合失調症の予防または治療薬の製造のための、上記［１Ａ］記載の化合物もしくはその塩、またはそのプロドラッグの使用；
［８Ａ］統合失調症の予防または治療のための、上記［１Ａ］記載の化合物もしくはその塩、またはそのプロドラッグ；
等に関する。 A compound in which R 1 represents —CO—R xc (R xc represents a substituent) and L 1 represents —CH 2 —, and
(3) The following compounds:
3- (3-benzyl-1-cyclohexyl-1H-pyrazol-5-yl) -1- [2- (cyclopropylamino) -2-oxoethyl] pyridinium,
3- {1-cyclohexyl-3-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1H-pyrazol-5-yl} -1- [2- (cyclopropylamino) -2- Oxoethyl] pyridinium,
(6R) -5- (Acetylamino) -4-amino-2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -3,4 , 5-trideoxy-L-threo-hex-2-enoic acid,
tert-butyl 4- {2-amino-4- [2- (4-bromophenyl) -1- (4-methoxyphenyl) ethyl] -1H-imidazol-1-yl} piperidine-1-carboxylate,
1- [4-cyano-2- (naphthalen-1-ylmethyl) -1,3-oxazol-5-yl] piperidine-4-carboxamide,
1- (2-benzyl-4-cyano-1,3-oxazol-5-yl) piperidine-4-carboxamide,
tert-butyl 4- (2-benzyl-4-ethyl-1,3-oxazol-5-yl) piperidine-1-carboxylate,
Benzyl 4- (3-benzyl-5-methyl-1H-1,2,4-triazol-1-yl) piperidine-1-carboxylate,
Diphenylmethyl (6R) -5- (acetylamino) -2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -4-[(tert -Butoxycarbonyl) amino] -3,4,5-trideoxy-L-threo-hex-2-enoate and benzyl (1R, 5S, 6R) -6- (3-benzyl-1-ethyl-1H-pyrazole- 5-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate)
Or a salt thereof (sometimes referred to herein as compound (I ′));
[2A] A prodrug of the compound according to [1A] above or a salt thereof;
[3A] A medicament containing the compound of the above [1A] or a salt thereof, or a prodrug thereof;
[4A] The medicament according to [3A] above, which is a GPR52 agonist;
[5A] The medicament according to [3A] above, which is a prophylactic or therapeutic drug for schizophrenia;
[6A] A method for preventing or treating schizophrenia, comprising administering an effective amount of the compound or salt thereof, or a prodrug thereof according to [1A] above to a mammal;
[7A] Use of the compound of the above-mentioned [1A] or a salt thereof, or a prodrug thereof for the manufacture of a preventive or therapeutic agent for schizophrenia;
[8A] The compound of the above [1A] or a salt thereof, or a prodrug thereof for the prevention or treatment of schizophrenia;
Etc.
　本発明はまた、
［１Ｂ］　式（Ｉ’）： The present invention also provides
[1B] Formula (I ′):
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
〔式中、
　環Ａは、置換基を有していてもよい６～１０員芳香族炭化水素環、または置換基を有していてもよい５～１０員芳香族複素環を示し；
　環Ｂは、
（１）さらに置換基を有していてもよい６～１０員芳香族炭化水素環、
（２）さらに置換基を有していてもよい５または６員複素環、または
（３）さらに置換基を有していてもよい、ベンゼン環及び５または６員環が縮合した二環性縮合環を示し；
　式（Ｉ’）の部分構造式： [Where,
Ring A represents a 6 to 10-membered aromatic hydrocarbon ring which may have a substituent, or a 5 to 10-membered aromatic heterocycle which may have a substituent;
Ring B is
(1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent,
(2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring;
Partial structural formula of formula (I ′):
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
は、 Is
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（式中、Ｒ１は、ハロゲン原子、アシル基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいアミノ基、シアノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示す。）を示し；
　Ｒ２は、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ１－６アルキル基、または置換基を有していてもよいＣ３－６シクロアルキル基を示し；
　Ｌ１は、－Ｏ－、－ＣＯ－、置換基を有していてもよいＣ１－６アルキレン、または置換基を有していてもよいＣ３－６シクロアルキレンを示し；
　Ｌ２は、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＹＣＯ－または－ＣＯＮＨ－を示し；
　Ｙは、置換基を有していてもよいＣ１－３アルキレンを示す。〕
で表される化合物（但し、以下の化合物を除く：
（１）式： (In the formula, R 1 has a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted amino group, a cyano group, or —S (O) m represents 0; 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group);
R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent. A 6 alkyl group, or an optionally substituted C 3-6 cycloalkyl group;
L 1 represents —O—, —CO—, an optionally substituted C 1-6 alkylene, or an optionally substituted C 3-6 cycloalkylene;
L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH—;
Y represents C 1-3 alkylene which may have a substituent. ]
A compound represented by (except the following compounds:
(1) Formula:
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（式中、Ｒｘａは、メチル基、エチル基または２－フルオロエチル基を示し；Ｒｘｂは、水素原子、フッ素原子、エトキシ基またはｔｅｒｔ－ブトキシ基を示す。）で表される化合物、
（２）式（Ｉ’）の部分構造式： (Wherein R xa represents a methyl group, an ethyl group or a 2-fluoroethyl group; R xb represents a hydrogen atom, a fluorine atom, an ethoxy group or a tert-butoxy group),
(2) Partial structural formula of formula (I ′):
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
が、 But,
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
を示し、Ｒ１が－ＣＯ－Ｒｘｃ（Ｒｘｃは置換基を示す）を示し、かつＬ１が－ＣＨ２－を示す化合物、並びに、
（３）以下の化合物：
3-(3-ベンジル-1-シクロヘキシル-1H-ピラゾール-5-イル)-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
3-{1-シクロヘキシル-3-[(3,5-ジメチル-1H-ピラゾール-1-イル)メチル]-1H-ピラゾール-5-イル}-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
(6R)-5-(アセチルアミノ)-4-アミノ-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノン酸、
tert-ブチル 4-{2-アミノ-4-[2-(4-ブロモフェニル)-1-(4-メトキシフェニル)エチル]-1H-イミダゾール-1-イル}ピペリジン-1-カルボキシラート、
1-[4-シアノ-2-(ナフタレン-1-イルメチル)-1,3-オキサゾール-5-イル]ピペリジン-4-カルボキサミド、
1-(2-ベンジル-4-シアノ-1,3-オキサゾール-5-イル)ピペリジン-4-カルボキサミド、
tert-ブチル 4-(2-ベンジル-4-エチル-1,3-オキサゾール-5-イル)ピペリジン-1-カルボキシラート、
ベンジル 4-(3-ベンジル-5-メチル-1H-1,2,4-トリアゾール-1-イル)ピペリジン-1-カルボキシラート、
ジフェニルメチル (6R)-5-(アセチルアミノ)-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-4-[(tert-ブトキシカルボニル)アミノ]-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノナート、および
ベンジル (1R,5S,6R)-6-(3-ベンジル-1-エチル-1H-ピラゾール-5-イル)-3-アザビシクロ[3.1.0]ヘキサン-3-カルボキシラート）またはその塩；
[２Ｂ]　上記[１Ｂ]記載の化合物またはその塩のプロドラッグ；
[３Ｂ]　上記[１Ｂ]記載の化合物もしくはその塩、またはそのプロドラッグを含有する医薬；
[４Ｂ]　ＧＰＲ５２作動薬である上記[３Ｂ]記載の医薬；
[５Ｂ]　統合失調症の予防又は治療薬である上記[３Ｂ]記載の医薬；
[６Ｂ]　上記[１Ｂ]記載の化合物もしくはその塩、またはそのプロドラッグの有効量を哺乳動物に投与することを特徴とする、統合失調症の予防又は治療方法；
[７Ｂ]　統合失調症の予防または治療薬の製造のための、上記[１Ｂ]記載の化合物もしくはその塩、またはそのプロドラッグの使用；
[８Ｂ]　統合失調症の予防または治療のための、上記[１Ｂ]記載の化合物もしくはその塩、またはそのプロドラッグ；
等に関する。 A compound in which R 1 represents —CO—R xc (R xc represents a substituent) and L 1 represents —CH 2 —, and
(3) The following compounds:
3- (3-benzyl-1-cyclohexyl-1H-pyrazol-5-yl) -1- [2- (cyclopropylamino) -2-oxoethyl] pyridinium,
3- {1-cyclohexyl-3-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1H-pyrazol-5-yl} -1- [2- (cyclopropylamino) -2- Oxoethyl] pyridinium,
(6R) -5- (Acetylamino) -4-amino-2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -3,4 , 5-trideoxy-L-threo-hex-2-enoic acid,
tert-butyl 4- {2-amino-4- [2- (4-bromophenyl) -1- (4-methoxyphenyl) ethyl] -1H-imidazol-1-yl} piperidine-1-carboxylate,
1- [4-cyano-2- (naphthalen-1-ylmethyl) -1,3-oxazol-5-yl] piperidine-4-carboxamide,
1- (2-benzyl-4-cyano-1,3-oxazol-5-yl) piperidine-4-carboxamide,
tert-butyl 4- (2-benzyl-4-ethyl-1,3-oxazol-5-yl) piperidine-1-carboxylate,
Benzyl 4- (3-benzyl-5-methyl-1H-1,2,4-triazol-1-yl) piperidine-1-carboxylate,
Diphenylmethyl (6R) -5- (acetylamino) -2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -4-[(tert -Butoxycarbonyl) amino] -3,4,5-trideoxy-L-threo-hex-2-enoate and benzyl (1R, 5S, 6R) -6- (3-benzyl-1-ethyl-1H-pyrazole- 5-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate) or a salt thereof;
[2B] A prodrug of the compound according to [1B] above or a salt thereof;
[3B] A medicament containing the compound according to [1B] above or a salt thereof, or a prodrug thereof;
[4B] The medicament according to [3B] above, which is a GPR52 agonist;
[5B] The medicament according to [3B] above, which is a prophylactic or therapeutic drug for schizophrenia;
[6B] A method for preventing or treating schizophrenia, which comprises administering an effective amount of the compound or salt thereof, or a prodrug thereof according to [1B] above to a mammal;
[7B] Use of the compound according to [1B] above or a salt thereof, or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for schizophrenia;
[8B] The compound of the above-mentioned [1B] or a salt thereof, or a prodrug thereof for the prevention or treatment of schizophrenia;
Etc.
（発明の詳細な説明）
　以下に、本発明について詳細に説明する。
　本明細書中、特に限定しない限り、「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、およびヨウ素原子が挙げられる。
　本明細書中、特に限定しない限り、「Ｃ１－６アルキル基」および置換基中の「Ｃ１－６アルキル」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、１－エチルプロピル、１，１－ジメチルプロピル、ヘキシル、イソヘキシル、１，１－ジメチルブチル、２，２－ジメチルブチル、３，３－ジメチルブチル、２－エチルブチル等が挙げられる。なかでも、「Ｃ１－４アルキル（基）」が好ましい。 (Detailed description of the invention)
The present invention is described in detail below.
In the present specification, unless otherwise specified, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present specification, unless otherwise specified, the “C 1-6 alkyl group” and the “C 1-6 alkyl” in the substituent include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. Tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2- And ethyl butyl. Of these, “C 1-4 alkyl (group)” is preferable.
　本明細書中、特に限定しない限り、「Ｃ１－６アルコキシ基」および置換基中の「Ｃ１－６アルコキシ」としては、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等が挙げられる。なかでも、「Ｃ１－４アルコキシ（基）」が好ましい。 In the present specification, unless otherwise specified, the “C 1-6 alkoxy group” and the “C 1-6 alkoxy” in the substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, Examples thereof include tert-butoxy, pentyloxy, hexyloxy and the like. Of these, “C 1-4 alkoxy (group)” is preferable.
　本明細書中、特に限定しない限り、「Ｃ２－６アルケニル基」としては、例えば、エテニル、１－プロペニル、２－プロペニル、２－メチル－１－プロペニル、１－ブテニル、２－ブテニル、３－ブテニル、３－メチル－２－ブテニル、１－ペンテニル、２－ペンテニル、３－ペンテニル、４－ペンテニル、４－メチル－３－ペンテニル、１－ヘキセニル、３－ヘキセニル、５－ヘキセニル等が挙げられる。なかでも、Ｃ２－４アルケニル（基）が好ましい。
　本明細書中、特に限定しない限り、「Ｃ２－６アルケニルオキシ基」としては、例えば、エテニルオキシ、１－プロペニルオキシ、２－プロペニルオキシ、２－メチル－１－プロペニルオキシ、１－ブテニルオキシ、２－ブテニルオキシ、３－ブテニルオキシ、３－メチル－２－ブテニルオキシ、１－ペンテニルオキシ、２－ペンテニルオキシ、３－ペンテニルオキシ、４－ペンテニルオキシ、４－メチル－３－ペンテニルオキシ、１－ヘキセニルオキシ、３－ヘキセニルオキシ、５－ヘキセニルオキシ等が挙げられる。 In the present specification, unless otherwise specified, examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, etc. . Of these, C 2-4 alkenyl (group) is preferable.
In the present specification, unless otherwise specified, examples of the “C 2-6 alkenyloxy group” include ethenyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, -Butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3 -Hexenyloxy, 5-hexenyloxy and the like.
　本明細書中、特に限定しない限り、「Ｃ２－６アルキニル基」としては、例えば、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、２－ブチニル、３－ブチニル、１－ペンチニル、２－ペンチニル、３－ペンチニル、４－ペンチニル、１－ヘキシニル、２－ヘキシニル、３－ヘキシニル、４－ヘキシニル、５－ヘキシニル等が挙げられる。なかでも、Ｃ２－４アルキニル（基）が好ましい。 In the present specification, unless otherwise limited, examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, -Pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Of these, C 2-4 alkynyl (group) is preferable.
　本明細書中、特に限定しない限り、「Ｃ３－１０シクロアルキル基」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、ビシクロ［２．２．１］ヘプチル、ビシクロ［２．２．２］オクチル、ビシクロ［３．２．１］オクチル、ビシクロ［３．２．２］ノニル、ビシクロ［３．３．１］ノニル、ビシクロ［４．２．１］ノニル、ビシクロ［４．３．１］デシル、アダマンチル等が挙げられる。
　本明細書中、特に限定しない限り、「Ｃ３－６シクロアルキル基」および置換基中の「Ｃ３－６シクロアルキル」としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等が挙げられる。
　本明細書中、特に限定しない限り、「Ｃ３－１０シクロアルキルオキシ基」としては、例えば、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシ、ビシクロ［２．２．１］ヘプチルオキシ、ビシクロ［２．２．２］オクチルオキシ、ビシクロ［３．２．１］オクチルオキシ、ビシクロ［３．２．２］ノニルオキシ、ビシクロ［３．３．１］ノニルオキシ、ビシクロ［４．２．１］ノニルオキシ、ビシクロ［４．３．１］デシルオキシ、アダマンチルオキシ等が挙げられる。 In the present specification, unless otherwise specified, examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] Decyl, adamantyl and the like.
In the present specification, unless otherwise specified, examples of the “C 3-6 cycloalkyl group” and the “C 3-6 cycloalkyl” in the substituent include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
In this specification, unless otherwise specified, examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, bicyclo [2 2.1] heptyloxy, bicyclo [2.2.2] octyloxy, bicyclo [3.2.1] octyloxy, bicyclo [3.2.2] nonyloxy, bicyclo [3.3.1] nonyloxy, Bicyclo [4.2.1] nonyloxy, bicyclo [4.3.1] decyloxy, adamantyloxy and the like can be mentioned.
　本明細書中、特に限定しない限り、「Ｃ６－１４アリール基」および置換基中の「Ｃ６－１４アリール」としては、例えば、フェニル、ナフチル、アントリル、フェナントリル、アセナフチレニル、ビフェニリル等が挙げられる。
　本明細書中、「Ｃ６－１０アリール基」および置換基中の「Ｃ６－１０アリール」としては、フェニル、ナフチル（１－ナフチル、２－ナフチル）等が挙げられる。
　本明細書中、特に限定しない限り、「Ｃ６－１０アリールオキシ基」としては、例えば、フェニルオキシ、ナフチルオキシ（１－ナフチルオキシ、２－ナフチルオキシ）等が挙げられる。 In the present specification, unless otherwise specified, examples of the “C 6-14 aryl group” and the “C 6-14 aryl” in the substituent include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. .
In the present specification, examples of the “C 6-10 aryl group” and the “C 6-10 aryl” in the substituent include phenyl, naphthyl (1-naphthyl, 2-naphthyl) and the like.
In the present specification, unless otherwise specified, examples of the “C 6-10 aryloxy group” include phenyloxy, naphthyloxy (1-naphthyloxy, 2-naphthyloxy) and the like.
　本明細書中、「Ｃ７－１３アラルキル基」および置換基中の「Ｃ７－１３アラルキル」としては、ベンジル、フェネチル、ナフチルメチル（１－ナフチルメチル、２－ナフチルメチル）、ビフェニリルメチル等が挙げられる。
　本明細書中、「Ｃ７－１３アラルキルオキシ基」としては、ベンジルオキシ、フェネチルオキシ、ナフチルメチルオキシ（１－ナフチルメチルオキシ、２－ナフチルメチルオキシ）、ビフェニリルメチルオキシ等が挙げられる。 In the present specification, “C 7-13 aralkyl group” and “C 7-13 aralkyl” in a substituent include benzyl, phenethyl, naphthylmethyl (1-naphthylmethyl, 2-naphthylmethyl), biphenylylmethyl, etc. Is mentioned.
In the present specification, examples of the “C 7-13 aralkyloxy group” include benzyloxy, phenethyloxy, naphthylmethyloxy (1-naphthylmethyloxy, 2-naphthylmethyloxy), biphenylylmethyloxy and the like.
　本明細書中、特に限定しない限り、「Ｃ１－６アルコキシ－カルボニル基」としては、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、ペンチルオキシカルボニル、ヘキシルオキシカルボニル等が挙げられる。 In the present specification, unless otherwise specified, examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, Examples thereof include tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
　本明細書中、特に限定しない限り、「Ｃ１－６アルキル－カルボニル基」としては、例えば、アセチル、プロパノイル、ブタノイル、２－メチルプロパノイル、ペンタノイル、３－メチルブタノイル、２－メチルブタノイル、２，２－ジメチルプロパノイル、ヘキサノイル、ヘプタノイル等が挙げられる。
　本明細書中、特に限定しない限り、「Ｃ１－６アルキル－カルボニルオキシ基」としては、例えば、アセチルオキシ、プロパノイルオキシ、ブタノイルオキシ、２－メチルプロパノイルオキシ、ペンタノイルオキシ、３－メチルブタノイルオキシ、２－メチルブタノイルオキシ、２，２－ジメチルプロパノイルオキシ、ヘキサノイルオキシ、ヘプタノイルオキシ等が挙げられる。 In the present specification, unless otherwise specified, examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl. 2,2-dimethylpropanoyl, hexanoyl, heptanoyl and the like.
In this specification, unless otherwise specified, examples of the “C 1-6 alkyl-carbonyloxy group” include acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy, pentanoyloxy, 3- Examples thereof include methylbutanoyloxy, 2-methylbutanoyloxy, 2,2-dimethylpropanoyloxy, hexanoyloxy, heptanoyloxy and the like.
　本明細書中、特に限定しない限り、「６～１０員芳香族炭化水素環」としては、例えば、ベンゼン、ナフタレン等が挙げられる。 In this specification, unless otherwise specified, examples of the “6- to 10-membered aromatic hydrocarbon ring” include benzene and naphthalene.
　本明細書中、特に限定しない限り、「芳香族複素環基」および置換基中の「芳香族複素環－」としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子（該硫黄原子は、酸化されていてもよい）および窒素原子から選ばれるヘテロ原子を１～４個含有する４～７員（好ましくは５または６員）の単環式芳香族複素環基および縮合芳香族複素環基が挙げられる。該縮合芳香族複素環基としては、例えば、これら４～７員の単環式芳香族複素環基と、１または２個の窒素原子を含む５または６員の芳香族複素環（例、ピロール、イミダゾール、ピラゾール、ピラジン、ピリジン、ピリミジン）、１個の硫黄原子を含む５員の芳香族複素環（例、チオフェン）、あるいはベンゼン環等とが１または２個縮合した基等が挙げられる。
　芳香族複素環基の好適な例としては、
フリル（例、２－フリル、３－フリル）、チエニル（例、２－チエニル、３－チエニル）、ピリジル（例、２－ピリジル、３－ピリジル、４－ピリジル）、ピリミジニル（例、２－ピリミジニル、４－ピリミジニル、５－ピリミジニル）、ピリダジニル（例、３－ピリダジニル、４－ピリダジニル）、ピラジニル（例、２－ピラジニル）、ピロリル（例、２－ピロリル、３－ピロリル）、イミダゾリル（例、１－イミダゾリル、２－イミダゾリル、４－イミダゾリル）、ピラゾリル（例、１－ピラゾリル、３－ピラゾリル、４－ピラゾリル）、チアゾリル（例、２－チアゾリル、４－チアゾリル、５－チアゾリル）、イソチアゾリル（例、３－イソチアゾリル、４－イソチアゾリル、５－イソチアゾリル）、オキサゾリル（例、２－オキサゾリル、４－オキサゾリル、５－オキサゾリル）、イソオキサゾリル（例、３－イソオキサゾリル、４－イソオキサゾリル、５－イソオキサゾリル）、オキサジアゾリル（例、１，２，５－オキサジアゾール－３－イル、１，３，４－オキサジアゾール－２－イル）、チアジアゾリル（例、１，２，３－チアジアゾール－４－イル、１，３，４－チアジアゾール－２－イル）、トリアゾリル（例、１，２，４－トリアゾール－１－イル、１，２，４－トリアゾール－３－イル、１，２，３－トリアゾール－１－イル、１，２，３－トリアゾール－２－イル、１，２，３－トリアゾール－４－イル）、テトラゾリル（例、テトラゾール－１－イル、テトラゾール－５－イル）、トリアジニル（例、１，２，４－トリアジン－３－イル、１，２，４－トリアジン－５－イル、１，２，４－トリアジン－６－イル）等の単環式芳香族複素環基；
キノリル（例、２－キノリル、３－キノリル、４－キノリル、６－キノリル）、イソキノリル（例、３－イソキノリル）、キナゾリル（例、２－キナゾリル、４－キナゾリル）、キノキサリル（例、２－キノキサリル、６－キノキサリル）、ベンゾフラニル（例、２－ベンゾフラニル、３－ベンゾフラニル、４－ベンゾフラニル、５－ベンゾフラニル、６－ベンゾフラニル、７－ベンゾフラニル）、ベンゾチエニル（例、２－ベンゾチエニル、３－ベンゾチエニル）、ベンズオキサゾリル（例、２－ベンズオキサゾリル）、ベンズイソオキサゾリル（例、７－ベンズイソオキサゾリル）、ベンゾチアゾリル（例、２－ベンゾチアゾリル、６－ベンゾチアゾリル）、ベンゾイミダゾリル（例、ベンゾイミダゾール－１－イル、ベンゾイミダゾール－２－イル、ベンゾイミダゾール－５－イル）、ベンゾトリアゾリル（例、１Ｈ－１，２，３－ベンゾトリアゾール－１－イル、１Ｈ－１，２，３－ベンゾトリアゾール－５－イル）、インドリル（例、インドール－１－イル、インドール－２－イル、インドール－３－イル、インドール－５－イル）、インダゾリル（例、２Ｈ－インダゾール－３－イル）、ピロロピラジニル（例、１Ｈ－ピロロ［２，３－ｂ］ピラジン－２－イル、１Ｈ－ピロロ［２，３－ｂ］ピラジン－６－イル）、イミダゾピリジニル（例、１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル、１Ｈ－イミダゾ［４，５－ｃ］ピリジン－２－イル、２Ｈ－イミダゾ［１，２－ａ］ピリジン－３－イル）、イミダゾピラジニル（例、１Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－イル）、ピラゾロピリジニル（例、１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－３－イル）、チエノピラゾリル（例、１Ｈ－チエノ［２，３－ｃ］ピラゾール－５－イル）、ピラゾロトリアジニル（例、ピラゾロ［５，１－ｃ］［１，２，４］トリアジン－３－イル）、トリアゾロピリミジニル（例、［１，２，４］トリアゾロ［１，５－ａ］ピリミジン－２－イル）、フタラジニル等の縮合芳香族複素環基；
等が挙げられる。 In the present specification, unless otherwise specified, the “aromatic heterocyclic group” and the “aromatic heterocyclic ring” in the substituent include, for example, an oxygen atom, a sulfur atom (the sulfur atom other than a carbon atom) as a ring-constituting atom. The atom may be oxidized) and a 4-7 membered (preferably 5 or 6 membered) monocyclic aromatic heterocyclic group and condensed aromatic containing 1 to 4 heteroatoms selected from nitrogen atoms A heterocyclic group is mentioned. Examples of the condensed aromatic heterocyclic group include these 4 to 7-membered monocyclic aromatic heterocyclic groups and 5- or 6-membered aromatic heterocyclic rings containing 1 or 2 nitrogen atoms (eg, pyrrole). Imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing one sulfur atom (eg, thiophene), or a group in which one or two benzene rings are condensed.
As preferable examples of the aromatic heterocyclic group,
Furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl) 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1 -Imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (eg 2-oxazolyl) , 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg, 1,2,5-oxadiazol-3-yl, 1,3, 4-oxadiazol-2-yl), thiadiazolyl (eg, 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4- Triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazole- 4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), triazinyl (eg, 1,2,4-triazin-3-yl, 1,2,4) Triazin-5-yl, 1,2,4-triazin-6-yl) monocyclic aromatic heterocyclic group and the like;
Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl) , 6-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl) , Benzoxazolyl (eg, 2-benzoxazolyl), benzisoxazolyl (eg, 7-benzisoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl, 6-benzothiazolyl), benzoimidazolyl (eg, Benzimidazol-1-yl, benzimidazole -2-yl, benzimidazol-5-yl), benzotriazolyl (eg, 1H-1,2,3-benzotriazol-1-yl, 1H-1,2,3-benzotriazol-5-yl) , Indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (eg, 2H-indazol-3-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo) [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), imidazopyridinyl (eg, 1H-imidazo [4,5-b] pyridine-2 -Yl, 1H-imidazo [4,5-c] pyridin-2-yl, 2H-imidazo [1,2-a] pyridin-3-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5 -B] Pila 2-yl), pyrazolopyridinyl (eg, 1H-pyrazolo [4,3-c] pyridin-3-yl), thienopyrazolyl (eg, 1H-thieno [2,3-c] pyrazole-5) -Yl), pyrazolotriazinyl (eg, pyrazolo [5,1-c] [1,2,4] triazin-3-yl), triazolopyrimidinyl (eg, [1,2,4] triazolo [1 , 5-a] pyrimidin-2-yl), phthalazinyl and the like;
Etc.
　本明細書中、特に限定しない限り、「非芳香族複素環基」および置換基中の「非芳香族複素環－」としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子（該硫黄原子は、酸化されていてもよい）および窒素原子から選ばれるヘテロ原子を１～４個含有する４～７員（好ましくは５または６員）の単環式非芳香族複素環基および縮合非芳香族複素環基が挙げられる。該縮合非芳香族複素環基としては、例えば、これら４～７員の単環式非芳香族複素環基と、１または２個の窒素原子を含む５または６員の芳香族または非芳香族複素環（例、ピロール、イミダゾール、ピラゾール、ピラジン、ピリジン、ピリミジン）、１個の硫黄原子を含む５員の芳香族または非芳香族複素環（例、チオフェン）、あるいはベンゼン環等とが１または２個縮合した基等が挙げられる。
　非芳香族複素環基の好適な例としては、
ピロリジニル（例、１－ピロリジニル、２－ピロリジニル、３－ピロリジニル）、ピペリジニル（例、ピペリジノ、２－ピペリジニル、３－ピペリジニル、４－ピペリジニル）、ホモピペリジニル（例、ホモピペリジノ、２－ホモピペリジニル、３－ホモピペリジニル、４－ホモピペリジニル）、テトラヒドロピリジル（例、１，２，３，６－テトラヒドロピリジン－１－イル）、ジヒドロピリジル（例、２，３－ジヒドロピリジン－４－イル）、モルホリニル（例、モルホリノ、２－モルホリニル）、チオモルホリニル（例、チオモルホリノ）、１，１－ジオキソチオモルホリニル（例、１，１－ジオキソチオモルホリノ）、ピペラジニル（例、１－ピペラジニル、２－ピペラジニル）、３－オキソピペラジニル（例、３－オキソピペラジン－１－イル）、ヘキサメチレンイミニル（例、１－ヘキサメチレンイミニル）、オキサゾリジニル（例、２－オキサゾリジニル）、チアゾリジニル（例、３－チアゾリジニル、２－チアゾリジニル）、イミダゾリジニル（例、２－イミダゾリジニル、３－イミダゾリジニル）、２－オキソイミダゾリジニル（例、２－オキソイミダゾリジン－１－イル）、オキサゾリニル（例、２－オキサゾリニル）、チアゾリニル（例、２－チアゾリニル）、イミダゾリニル（例、２－イミダゾリニル、３－イミダゾリニル）、ジオキソリル（例、１，３－ジオキソール－４－イル）、ジオキソラニル（例、１，３－ジオキソラン－４－イル）、ジヒドロオキサジアゾリル（例、４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）、ピラニル（例、２－ピラニル、４－ピラニル）、テトラヒドロピラニル（例、２－テトラヒドロピラニル、３－テトラヒドロピラニル、４－テトラヒドロピラニル）、チオピラニル（例、４－チオピラニル）、テトラヒドロチオピラニル（例、２－テトラヒドロチオピラニル、３－テトラヒドロチオピラニル、４－テトラヒドロチオピラニル）、１－オキソテトラヒドロチオピラニル（例、１－オキソテトラヒドロチオピラン－４－イル）、１，１－ジオキソテトラヒドロチオピラニル（例、１，１－ジオキソテトラヒドロチオピラン－４－イル）、テトラヒドロフリル（例、テトラヒドロフラン－３－イル、テトラヒドロフラン－２－イル）、ピラゾリジニル（例、１－ピラゾリジニル、３－ピラゾリジニル）、ピラゾリニル（例、１－ピラゾリニル）、テトラヒドロピリミジニル（例、１－テトラヒドロピリミジニル）、ジヒドロトリアゾリル（例、２，３－ジヒドロ－１Ｈ－１，２，３－トリアゾール－１－イル）、テトラヒドロトリアゾリル（例、２，３，４，５－テトラヒドロ－１Ｈ－１，２，３－トリアゾール－１－イル）、ジヒドロオキサジアゾリル（例、４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）、チアジニル（例、１，４－チアジン－２－イル）、１，１－ジオキソチアジナニル（例、１，１－ジオキソ－１，２－チアジナン－２－イル）、ジヒドロピリダジニル（例、１，６－ジヒドロピリダジン－３－イル）、テトラヒドロピリダジニル（例、１，４，５，６－テトラヒドロピリダジン－３－イル）、ジヒドロチオキサジニル（例、２，３－ジヒドロ－１，４－チオキサジン－３－イル）、ジヒドロチアジニル（例、３，４－ジヒドロ－２Ｈ－１，４－チアジン－５－イル）等の単環式非芳香族複素環基；
ジヒドロインドリル（例、２，３－ジヒドロ－１Ｈ－インドール－１－イル）、２－オキソジヒドロインドリル（例、２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－６－イル）、ジヒドロイソインドリル（例、２，３－ジヒドロ－１Ｈ－イソインドール－１－イル、１，３－ジヒドロ－２Ｈ－イソインドール－２－イル）、ジヒドロベンゾフラニル（例、２，３－ジヒドロ－１－ベンゾフラン－５－イル）、ジヒドロベンゾジオキシニル（例、２，３－ジヒドロ－１，４－ベンゾジオキシニル）、３－オキソジヒドロベンゾジオキサジニル（例、３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾジオキサジン－６－イル）、ジヒドロベンゾジオキセピニル（例、３，４－ジヒドロ－２Ｈ－１，５－ベンゾジオキセピン－７－イル）、テトラヒドロベンゾフラニル（例、４，５，６，７－テトラヒドロ－１－ベンゾフラン－３－イル）、クロメニル（例、４Ｈ－クロメン－２－イル、２Ｈ－クロメン－３－イル、２Ｈ－クロメン－７－イル）、ジヒドロキノリニル（例、１，２－ジヒドロキノリン－４－イル、３，４－ジヒドロキノリン－１（２Ｈ）－イル）、テトラヒドロキノリニル（例、１，２，３，４－テトラヒドロキノリン－４－イル）、ジヒドロイソキノリニル（例、１，２－ジヒドロイソキノリン－４－イル）、テトラヒドロイソキノリニル（例、１，２，３，４－テトラヒドロイソキノリン－４－イル、１，２，３，４－テトラヒドロイソキノリン－２－イル）、ジヒドロフタラジニル（例、３，４－ジヒドロフタラジン－１－イル、１，４－ジヒドロフタラジン－４－イル）、テトラヒドロベンゾアゼピニル（例、２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｃ］アゼピン－１－イル）、ベンゾジオキソリル（例、１，３－ベンゾジオキソール－５－イル）、ベンゾチアジニル（例、３，４－ジヒドロ－２Ｈ－１，４－ベンゾチアジン－２－イル）等の縮合非芳香族複素環基；
等が挙げられる。 In the present specification, unless otherwise specified, examples of the “non-aromatic heterocyclic group” and the “non-aromatic heterocyclic ring” in the substituent include, for example, an oxygen atom, a sulfur atom ( The sulfur atom may be oxidized) and a 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atoms and A condensed non-aromatic heterocyclic group is mentioned. Examples of the condensed non-aromatic heterocyclic group include, for example, these 4- to 7-membered monocyclic non-aromatic heterocyclic groups and 5- or 6-membered aromatic or non-aromatic groups containing 1 or 2 nitrogen atoms. Heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom (eg, thiophene), or a benzene ring is 1 or Examples include a group having two condensed groups.
As a suitable example of a non-aromatic heterocyclic group,
Pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), homopiperidinyl (eg, homopiperidino, 2-homopiperidinyl, 3-homopiperidinyl, 4-homopiperidinyl), tetrahydropyridyl (eg, 1,2,3,6-tetrahydropyridin-1-yl), dihydropyridyl (eg, 2,3-dihydropyridin-4-yl), morpholinyl (eg, morpholino, 2- Morpholinyl), thiomorpholinyl (eg, thiomorpholino), 1,1-dioxothiomorpholinyl (eg, 1,1-dioxothiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl), 3-oxo Piperazinyl (eg, 3-oxopiperazi -1-yl), hexamethyleneiminyl (eg, 1-hexamethyleneiminyl), oxazolidinyl (eg, 2-oxazolidinyl), thiazolidinyl (eg, 3-thiazolidinyl, 2-thiazolidinyl), imidazolidinyl (eg, 2-imidazolidinyl) , 3-imidazolidinyl), 2-oxoimidazolidinyl (eg, 2-oxoimidazolidin-1-yl), oxazolinyl (eg, 2-oxazolinyl), thiazolinyl (eg, 2-thiazolinyl), imidazolinyl (eg, 2- Imidazolinyl, 3-imidazolinyl), dioxolyl (eg, 1,3-dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro- 1,2,4-oxadiazol-3-yl), pyranyl Examples, 2-pyranyl, 4-pyranyl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (eg, 4-thiopyranyl), tetrahydrothiopyranyl ( Examples, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxotetrahydrothiopyranyl (eg, 1-oxotetrahydrothiopyran-4-yl), 1,1- Dioxotetrahydrothiopyranyl (eg, 1,1-dioxotetrahydrothiopyran-4-yl), tetrahydrofuryl (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (eg, 1-pyrazolidinyl, 3-pyrazolidinyl), pyrazolinyl (eg, 1-pyrazolinyl) ), Tetrahydropyrimidinyl (eg, 1-tetrahydropyrimidinyl), dihydrotriazolyl (eg, 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2, 3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4-oxadiazol-3-yl) , Thiazinyl (eg, 1,4-thiazin-2-yl), 1,1-dioxothiadinanyl (eg, 1,1-dioxo-1,2-thiazin-2-yl), dihydropyridazinyl (Eg, 1,6-dihydropyridazin-3-yl), tetrahydropyridazinyl (eg, 1,4,5,6-tetrahydropyridazin-3-yl), dihydrothioxazinyl (eg, 2,3 -Jihi B 1,4 Chiokisajin 3-yl), dihydro-triazinyl (e.g., 3,4-dihydro-2H-1,4-thiazine-5-yl) monocyclic non-aromatic heterocyclic group and the like;
Dihydroindolyl (eg, 2,3-dihydro-1H-indol-1-yl), 2-oxodihydroindolyl (eg, 2-oxo-2,3-dihydro-1H-indol-6-yl), dihydro Isoindolyl (eg, 2,3-dihydro-1H-isoindol-1-yl, 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (eg, 2,3-dihydro- 1-benzofuran-5-yl), dihydrobenzodioxinyl (eg, 2,3-dihydro-1,4-benzodioxinyl), 3-oxodihydrobenzodioxazinyl (eg, 3-oxo-3) , 4-dihydro-2H-1,4-benzodioxazin-6-yl), dihydrobenzodioxepinyl (eg, 3,4-dihydro-2H-1,5-benzodioxepin-7-yl) Tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), chromenyl (eg, 4H-chromen-2-yl, 2H-chromen-3-yl, 2H-chromene) -7-yl), dihydroquinolinyl (eg, 1,2-dihydroquinolin-4-yl, 3,4-dihydroquinolin-1 (2H) -yl), tetrahydroquinolinyl (eg, 1,2, 3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydroisoquinoline) -4-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl), dihydrophthalazinyl (eg, 3,4-dihydrophthalazin-1-yl, 1,4-dihydroph Razin-4-yl), tetrahydrobenzoazepinyl (eg, 2,3,4,5-tetrahydro-1H-benzo [c] azepin-1-yl), benzodioxolyl (eg, 1,3-benzo Condensed non-aromatic heterocyclic groups such as dioxol-5-yl), benzothiazinyl (eg, 3,4-dihydro-2H-1,4-benzothiazin-2-yl);
Etc.
　本明細書中、特に限定しない限り、「５～１０員芳香族複素環」としては、例えば、上記「芳香族複素環基」および置換基中の「芳香族複素環－」として例示したもののうち５～１０員の芳香族複素環基を構成する環が挙げられる。
　このような芳香族複素環の好適な例としては、フラン、チオフェン、ピリジン、ピリミジン、ピリダジン、ピラジン、ピロール、イミダゾール、ピラゾール、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、オキサジアゾール（例、１，２，５－オキサジアゾール、１，３，４－オキサジアゾール）、チアジアゾール（例、１，２，３－チアジアゾール、１，３，４－チアジアゾール）、トリアゾール（例、１，２，４－トリアゾール、１，２，３－トリアゾール）、テトラゾール、トリアジン（例、１，２，４－トリアジン）等の単環式芳香族複素環；
キノリン、イソキノリン、キナゾリン、キノキサリン、ベンゾフラン、ベンゾチオフェン、ベンズオキサゾール、ベンズイソオキサゾール、ベンゾチアゾール、ベンゾイミダゾール、ベンゾトリアゾール（例、１Ｈ－１，２，３－ベンゾトリアゾール）、インドール、インダゾール、ピロロピラジン（例、１Ｈ－ピロロ［２，３－ｂ］ピラジン、イミダゾピリジン（例、１Ｈ－イミダゾ［４，５－ｂ］ピリジン、１Ｈ－イミダゾ［４，５－ｃ］ピリジン、２Ｈ－イミダゾ［１，２－ａ］ピリジン）、イミダゾピラジン（例、１Ｈ－イミダゾ［４，５－ｂ］ピラジン）、ピラゾロピリジン（例、１Ｈ－ピラゾロ［４，３－ｃ］ピリジン）、チエノピラゾール（例、１Ｈ－チエノ［２，３－ｃ］ピラゾール）、ピラゾロトリアジン（例、ピラゾロ［５，１－ｃ］［１，２，４］トリアジン）、トリアゾロピリミジン（例、［１，２，４］トリアゾロ［１，５－ａ］ピリミジン）、フタラジン等の縮合芳香族複素環；
等が挙げられる。 In the present specification, unless otherwise specified, examples of the “5- to 10-membered aromatic heterocyclic ring” include those exemplified as the above “aromatic heterocyclic group” and “aromatic heterocyclic ring” in the substituent. Examples thereof include a ring constituting a 5- to 10-membered aromatic heterocyclic group.
Suitable examples of such aromatic heterocyclic rings include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole (eg, 1, 2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (eg, 1,2,3-thiadiazole, 1,3,4-thiadiazole), triazole (eg, 1,2,4- Monocyclic aromatic heterocycles such as triazole, 1,2,3-triazole), tetrazole, triazine (eg, 1,2,4-triazine);
Quinoline, isoquinoline, quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzimidazole, benzotriazole (eg, 1H-1,2,3-benzotriazole), indole, indazole, pyrrolopyrazine ( Examples 1H-pyrrolo [2,3-b] pyrazine, imidazopyridine (eg, 1H-imidazo [4,5-b] pyridine, 1H-imidazo [4,5-c] pyridine, 2H-imidazo [1,2 -A] pyridine), imidazopyrazine (eg, 1H-imidazo [4,5-b] pyrazine), pyrazolopyridine (eg, 1H-pyrazolo [4,3-c] pyridine), thienopyrazole (eg, 1H- Thieno [2,3-c] pyrazole), pyrazolotriazines (eg, pyrazolo) 5,1-c] [1,2,4] triazine), triazolopyrimidine (e.g., [1,2,4] triazolo [1,5-a] pyrimidine), fused aromatic heterocyclic ring phthalazine like;
Etc.
　本明細書中、特に限定しない限り、「５～１０員非芳香族複素環」としては、例えば、上記「非芳香族複素環基」および置換基中の「非芳香族複素環－」として例示したもののうち５～１０員の非芳香族複素環基を構成する環が挙げられる。
　このような芳香族複素環の好適な例としては、ピロリジン、ピペリジン、ホモピペリジン、テトラヒドロピリジン（例、１，２，３，６－テトラヒドロピリジン）、ジヒドロピリジン（例、２，３－ジヒドロピリジン）、モルホリン、チオモルホリン、１，１－ジオキソチオモルホリン、ピペラジン、３－オキソピペラジン、ヘキサメチレンイミン、オキサゾリジン、チアゾリジン、イミダゾリジン、２－オキソイミダゾリジン、オキサゾリン、チアゾリン、イミダゾリン、ジオキソール（例、１，３－ジオキソール）、ジオキソラン（例、１，３－ジオキソラン）、ジヒドロオキサジアゾール（例、４，５－ジヒドロ－１，２，４－オキサジアゾール）、ピラン、テトラヒドロピラン、チオピラン、テトラヒドロチオピラン、１－オキソテトラヒドロチオピラン、１，１－ジオキソテトラヒドロチオピラン、テトラヒドロフラン、ピラゾリジン、ピラゾリン、テトラヒドロピリミジン、ジヒドロトリアゾール（例、２，３－ジヒドロ－１Ｈ－１，２，３－トリアゾール）、テトラヒドロトリアゾール（例、２，３，４，５－テトラヒドロ－１Ｈ－１，２，３－トリアゾール）、ジヒドロオキサジアゾール（例、４，５－ジヒドロ－１，２，４－オキサジアゾール）、チアジン（例、１，４－チアジン）、１，１－ジオキソチアジナン（例、１，１－ジオキソ－１，２－チアジナン）、ジヒドロピリダジン（例、１，６－ジヒドロピリダジン）、テトラヒドロピリダジン（例、１，４，５，６－テトラヒドロピリダジン）、ジヒドロチオキサジン（例、２，３－ジヒドロ－１，４－チオキサジン）、ジヒドロチアジン（例、３，４－ジヒドロ－２Ｈ－１，４－チアジン）等の単環式非芳香族複素環；
ジヒドロインドール（例、２，３－ジヒドロ－１Ｈ－インドール）、２－オキソジヒドロインドール（例、２－オキソ－２，３－ジヒドロ－１Ｈ－インドール）、ジヒドロイソインドール（例、２，３－ジヒドロ－１Ｈ－イソインドール、１，３－ジヒドロ－２Ｈ－イソインドール）、ジヒドロベンゾフラン（例、２，３－ジヒドロ－１－ベンゾフラン）、ジヒドロベンゾジオキシン（例、２，３－ジヒドロ－１，４－ベンゾジオキシン）、３－オキソジヒドロベンゾジオキサジン（例、３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾジオキサジン）、ジヒドロベンゾジオキセピン（例、３，４－ジヒドロ－２Ｈ－１，５－ベンゾジオキセピン）、テトラヒドロベンゾフラン（例、４，５，６，７－テトラヒドロ－１－ベンゾフラン）、クロメン（例、４Ｈ－クロメン、２Ｈ－クロメン）、ジヒドロキノリン（例、１，２－ジヒドロキノリン、３，４－ジヒドロキノリン）、テトラヒドロキノリン（例、１，２，３，４－テトラヒドロキノリン）、ジヒドロイソキノリン（例、１，２－ジヒドロイソキノリン）、テトラヒドロイソキノリン（例、１，２，３，４－テトラヒドロイソキノリン）、ジヒドロフタラジン（例、３，４－ジヒドロフタラジン、１，４－ジヒドロフタラジン）、テトラヒドロベンゾアゼピン（例、２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｃ］アゼピン）、ベンゾジオキソール（例、１，３－ベンゾジオキソール）、ベンゾチアジン（例、３，４－ジヒドロ－２Ｈ－１，４－ベンゾチアジン）等の縮合非芳香族複素環；
等が挙げられる。 In the present specification, unless otherwise specified, examples of the “5- to 10-membered non-aromatic heterocyclic ring” include the above-mentioned “non-aromatic heterocyclic group” and “non-aromatic heterocyclic ring” in the substituent. Among them, a ring constituting a 5- to 10-membered non-aromatic heterocyclic group can be mentioned.
Preferable examples of such aromatic heterocycle include pyrrolidine, piperidine, homopiperidine, tetrahydropyridine (eg, 1,2,3,6-tetrahydropyridine), dihydropyridine (eg, 2,3-dihydropyridine), morpholine , Thiomorpholine, 1,1-dioxothiomorpholine, piperazine, 3-oxopiperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, 2-oxoimidazolidine, oxazoline, thiazoline, imidazoline, dioxol (eg, 1,3 -Dioxole), dioxolane (eg, 1,3-dioxolane), dihydrooxadiazole (eg, 4,5-dihydro-1,2,4-oxadiazole), pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, 1-oxote Lahydrothiopyran, 1,1-dioxotetrahydrothiopyran, tetrahydrofuran, pyrazolidine, pyrazoline, tetrahydropyrimidine, dihydrotriazole (eg 2,3-dihydro-1H-1,2,3-triazole), tetrahydrotriazole (eg 2,3,4,5-tetrahydro-1H-1,2,3-triazole), dihydrooxadiazole (eg, 4,5-dihydro-1,2,4-oxadiazole), thiazine (eg, 1,4-thiazine), 1,1-dioxothiazinane (eg, 1,1-dioxo-1,2-thiazinane), dihydropyridazine (eg, 1,6-dihydropyridazine), tetrahydropyridazine (eg, 1 , 4,5,6-tetrahydropyridazine), dihydrothioxazine (eg 2,3-dihydro-1,4- Oxazine), dihydrothiazine (e.g., 3,4-dihydro-2H-1,4-thiazine) monocyclic non-aromatic heterocycle and the like;
Dihydroindole (eg, 2,3-dihydro-1H-indole), 2-oxodihydroindole (eg, 2-oxo-2,3-dihydro-1H-indole), dihydroisoindole (eg, 2,3-dihydro) -1H-isoindole, 1,3-dihydro-2H-isoindole), dihydrobenzofuran (eg, 2,3-dihydro-1-benzofuran), dihydrobenzodioxin (eg, 2,3-dihydro-1,4- Benzodioxin), 3-oxodihydrobenzodioxazine (eg, 3-oxo-3,4-dihydro-2H-1,4-benzodioxazine), dihydrobenzodioxepin (eg, 3,4-dihydro-2H) -1,5-benzodioxepin), tetrahydrobenzofuran (eg, 4,5,6,7-tetrahydro-1-benzofuran) , Chromene (eg, 4H-chromene, 2H-chromene), dihydroquinoline (eg, 1,2-dihydroquinoline, 3,4-dihydroquinoline), tetrahydroquinoline (eg, 1,2,3,4-tetrahydroquinoline) , Dihydroisoquinoline (eg, 1,2-dihydroisoquinoline), tetrahydroisoquinoline (eg, 1,2,3,4-tetrahydroisoquinoline), dihydrophthalazine (eg, 3,4-dihydrophthalazine, 1,4-dihydro) Phthalazine), tetrahydrobenzoazepine (eg, 2,3,4,5-tetrahydro-1H-benzo [c] azepine), benzodioxole (eg, 1,3-benzodioxole), benzothiazine (eg, 3,4-dihydro-2H-1,4-benzothiazine) and other non-aromatic heterocycles;
Etc.
　本明細書中、特に限定しない限り、「５または６員複素環」としては、例えば、５または６員の芳香族複素環、および５または６員の非芳香族複素環が挙げられる。
　ここで、５または６員の芳香族複素環としては、例えば、上記「芳香族複素環基」および置換基中の「芳香族複素環－」として例示したもののうち５または６員の芳香族複素環基を構成する環が挙げられる。
　このような芳香族複素環の好適な例としては、フラン、チオフェン、ピリジン、ピリミジン、ピリダジン、ピラジン、ピロール、イミダゾール、ピラゾール、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、オキサジアゾール（例、１，２，５－オキサジアゾール、１，３，４－オキサジアゾール）、チアジアゾール（例、１，２，３－チアジアゾール、１，３，４－チアジアゾール）、トリアゾール（例、１，２，４－トリアゾール、１，２，３－トリアゾール）、テトラゾール、トリアジン（例、１，２，４－トリアジン）等が挙げられる。 In the present specification, unless otherwise specified, examples of the “5- or 6-membered heterocycle” include a 5- or 6-membered aromatic heterocycle and a 5- or 6-membered non-aromatic heterocycle.
Here, the 5- or 6-membered aromatic heterocycle includes, for example, 5- or 6-membered aromatic heterocycle among those exemplified as the above “aromatic heterocycle” and “aromatic heterocycle” in the substituent. The ring which comprises a cyclic group is mentioned.
Suitable examples of such aromatic heterocycle include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole (eg, 1, 2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (eg, 1,2,3-thiadiazole, 1,3,4-thiadiazole), triazole (eg, 1,2,4- Triazole, 1,2,3-triazole), tetrazole, triazine (eg, 1,2,4-triazine) and the like.
　ここで、５または６員の非芳香族複素環としては、例えば、上記「非芳香族複素環基」および置換基中の「非芳香族複素環－」として例示したもののうち５または６員の非芳香族複素環基を構成する環が挙げられる。
　このような非芳香族複素環の好適な例としては、ピロリジン、ピペリジン、ホモピペリジン、テトラヒドロピリジン（例、１，２，３，６－テトラヒドロピリジン）、ジヒドロピリジン（例、１，２－ジヒドロピリジン、２，３－ジヒドロピリジン）、モルホリン、チオモルホリン、１，１－ジオキソチオモルホリン、ピペラジン、ヘキサメチレンイミン、オキサゾリジン、チアゾリジン、イミダゾリジン、２－オキソイミダゾリジン、オキサゾリン、チアゾリン、イミダゾリン、ジオキソール（例、１，３－ジオキソール）、ジオキソラン（例、１，３－ジオキソラン）、ジヒドロオキサジアゾール（例、４，５－ジヒドロ－１，２，４－オキサジアゾール）、ピラン、テトラヒドロピラン、チオピラン、テトラヒドロチオピラン、テトラヒドロフラン、ピラゾリジン、ピラゾリン、テトラヒドロピリミジン、ジヒドロトリアゾール（例、２，３－ジヒドロ－１Ｈ－１，２，３－トリアゾール）、テトラヒドロトリアゾール（例、２，３，４，５－テトラヒドロ－１Ｈ－１，２，３－トリアゾール）、ジヒドロオキサジアゾール（例、４，５－ジヒドロ－１，２，４－オキサジアゾール）、チアジン（例、１，４－チアジン）、ジヒドロピリダジン（例、１，６－ジヒドロピリダジン）、テトラヒドロピリダジン（例、１，４，５，６－テトラヒドロピリダジン）、ジヒドロチオキサジン（例、２，３－ジヒドロ－１，４－チオキサジン）、ジヒドロチアジン（例、３，４－ジヒドロ－２Ｈ－１，４－チアジン）等が挙げられる。 Here, examples of the 5- or 6-membered non-aromatic heterocyclic ring include 5- or 6-membered members out of those exemplified as the above-mentioned “non-aromatic heterocyclic group” and “non-aromatic heterocyclic ring” in the substituent. The ring which comprises a non-aromatic heterocyclic group is mentioned.
Suitable examples of such non-aromatic heterocycles include pyrrolidine, piperidine, homopiperidine, tetrahydropyridine (eg, 1,2,3,6-tetrahydropyridine), dihydropyridine (eg, 1,2-dihydropyridine, 2 , 3-dihydropyridine), morpholine, thiomorpholine, 1,1-dioxothiomorpholine, piperazine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, 2-oxoimidazolidine, oxazoline, thiazoline, imidazoline, dioxol (eg, 1 , 3-dioxole), dioxolane (eg, 1,3-dioxolane), dihydrooxadiazole (eg, 4,5-dihydro-1,2,4-oxadiazole), pyran, tetrahydropyran, thiopyran, tetrahydrothio Piran, Tetra Drofuran, pyrazolidine, pyrazoline, tetrahydropyrimidine, dihydrotriazole (eg, 2,3-dihydro-1H-1,2,3-triazole), tetrahydrotriazole (eg, 2,3,4,5-tetrahydro-1H-1, 2,3-triazole), dihydrooxadiazole (eg, 4,5-dihydro-1,2,4-oxadiazole), thiazine (eg, 1,4-thiazine), dihydropyridazine (eg, 1,6 -Dihydropyridazine), tetrahydropyridazine (eg, 1,4,5,6-tetrahydropyridazine), dihydrothioxazine (eg, 2,3-dihydro-1,4-thioxazine), dihydrothiazine (eg, 3,4) -Dihydro-2H-1,4-thiazine) and the like.
　本明細書中、特に限定しない限り、「５または６員環」としては、例えば、ベンゼン、上記の「５または６員の芳香族複素環」および「５または６員の非芳香族複素環」、並びに「５または６員の非芳香族炭化水素環」が挙げられる。
　ここで、「５または６員の非芳香族炭化水素環」としては、シクロペンタン、シクロヘキサン、シクロペンテン、シクロへキセン、１，３－シクロペンタジエン、１，３－シクロヘキサジエン、１，４－シクロヘキサジエン、シクロペンチン、シクロへキシン等が挙げられる。 In the present specification, unless otherwise specified, examples of the “5- or 6-membered ring” include benzene, the above-mentioned “5- or 6-membered aromatic heterocycle” and “5- or 6-membered non-aromatic heterocycle”. As well as “5- or 6-membered non-aromatic hydrocarbon rings”.
Here, as the “5- or 6-membered non-aromatic hydrocarbon ring”, cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1,3-cyclopentadiene, 1,3-cyclohexadiene, 1,4-cyclohexadiene , Cyclopentine, cyclohexyne and the like.
　本明細書中、特に限定しない限り、「Ｃ１－６アルキレン」としては、例えば、メチレン、エチレン、トリメチレン（－（ＣＨ２）３－）、－ＣＨ（ＣＨ３）－ＣＨ２－、－ＣＨ２－ＣＨ（ＣＨ３）－、－Ｃ（ＣＨ３）２－、－（ＣＨ２）４－、－ＣＨ（ＣＨ３）－（ＣＨ２）２－、－ＣＨ２－ＣＨ（ＣＨ３）－ＣＨ２－、－（ＣＨ２）２－ＣＨ（ＣＨ３）－、－Ｃ（ＣＨ３）２－ＣＨ２－、－ＣＨ２－Ｃ（ＣＨ３）２－、－ＣＨ（ＣＨ３）－ＣＨ（ＣＨ３）－、－Ｃ（Ｃ２Ｈ５）（ＣＨ３）－、－（ＣＨ２）５－、－ＣＨ（ＣＨ３）－（ＣＨ２）３－、－ＣＨ２－ＣＨ（ＣＨ３）－（ＣＨ２）２－、－（ＣＨ２）２－ＣＨ（ＣＨ３）－ＣＨ２－、－（ＣＨ２）３－ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ３）－（ＣＨ２）３－、－ＣＨ２－ＣＨ（ＣＨ３）－（ＣＨ２）２－、－（ＣＨ２）２－ＣＨ（ＣＨ３）－ＣＨ２－、－（ＣＨ２）３－ＣＨ（ＣＨ３）－、－Ｃ（ＣＨ３）２－（ＣＨ２）２－、－ＣＨ（ＣＨ３）－ＣＨ（ＣＨ３）－ＣＨ２－、－ＣＨ（ＣＨ３）－ＣＨ２－ＣＨ（ＣＨ３）－、－ＣＨ２－Ｃ（ＣＨ３）２－ＣＨ２－、－ＣＨ２－ＣＨ（ＣＨ３）－ＣＨ（ＣＨ３）－、－（ＣＨ２）２－Ｃ（ＣＨ３）２－、－Ｃ（ＣＨ３）２－ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ３）－Ｃ（ＣＨ３）２－、－Ｃ（Ｃ２Ｈ５）（ＣＨ３）－ＣＨ２－、－ＣＨ（Ｃ２Ｈ５）－ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ３）－ＣＨ（Ｃ２Ｈ５）－、－ＣＨ２－Ｃ（Ｃ２Ｈ５）（ＣＨ３）－、－ＣＨ（Ｃ３Ｈ７）－ＣＨ２－、－ＣＨ２－ＣＨ（Ｃ３Ｈ７）－、－ＣＨ（Ｃ４Ｈ９）－、－（ＣＨ２）６－等が挙げられる。なかでも、「Ｃ１－４アルキレン」が好ましい。
　本明細書中、特に限定しない限り、「Ｃ１－３アルキレン」としては、例えば、メチレン、エチレン、トリメチレン（－（ＣＨ２）３－）、－ＣＨ（ＣＨ３）－ＣＨ２－、－ＣＨ２－ＣＨ（ＣＨ３）－、－Ｃ（ＣＨ３）２－等が挙げられる。 In this specification, unless otherwise specified, examples of “C 1-6 alkylene” include methylene, ethylene, trimethylene (— (CH 2 ) 3 —), —CH (CH 3 ) —CH 2 —, —CH 2 —CH (CH 3 ) —, —C (CH 3 ) 2 —, — (CH 2 ) 4 —, —CH (CH 3 ) — (CH 2 ) 2 —, —CH 2 —CH (CH 3 ) — CH 2 —, — (CH 2 ) 2 —CH (CH 3 ) —, —C (CH 3 ) 2 —CH 2 —, —CH 2 —C (CH 3 ) 2 —, —CH (CH 3 ) —CH (CH 3 ) —, —C (C 2 H 5 ) (CH 3 ) —, — (CH 2 ) 5 —, —CH (CH 3 ) — (CH 2 ) 3 —, —CH 2 —CH (CH 3 ) — (CH 2 ) 2 —, — (CH 2 ) 2 —CH (CH 3 ) —CH 2 —, — (CH 2 ) 3 —CH (C H 3 ) —, —CH (CH 3 ) — (CH 2 ) 3 —, —CH 2 —CH (CH 3 ) — (CH 2 ) 2 —, — (CH 2 ) 2 —CH (CH 3 ) —CH 2 -, - (CH 2) 3 -CH (CH 3) -, - C (CH 3) 2 - (CH 2) 2 -, - CH (CH 3) -CH (CH 3) -CH 2 -, - CH (CH 3 ) —CH 2 —CH (CH 3 ) —, —CH 2 —C (CH 3 ) 2 —CH 2 —, —CH 2 —CH (CH 3 ) —CH (CH 3 ) —, — ( CH 2 ) 2 —C (CH 3 ) 2 —, —C (CH 3 ) 2 —CH (CH 3 ) —, —CH (CH 3 ) —C (CH 3 ) 2 —, —C (C 2 H 5 ) (CH 3 ) —CH 2 —, —CH (C 2 H 5 ) —CH (CH 3 ) —, —CH (CH 3 ) —CH (C 2 H 5 ) —, —CH 2 —C (C 2 H 5 ) (CH 3 ) —, —CH (C 3 H 7 ) —CH 2 —, —CH 2 —CH (C 3 H 7 ) —, —CH (C 4 H 9 ) —, — ( CH 2 ) 6- and the like. Of these, “C 1-4 alkylene” is preferable.
In the present specification, unless otherwise specified, examples of “C 1-3 alkylene” include methylene, ethylene, trimethylene (— (CH 2 ) 3 —), —CH (CH 3 ) —CH 2 —, —CH 2- CH (CH 3 ) —, —C (CH 3 ) 2 — and the like can be mentioned.
　本明細書中、特に限定しない限り、「Ｃ３－６シクロアルキレン」としては、例えば、シクロプロピレン、シクロブチレン、シクロペンチレン、シクロへキシレン等が挙げられる。 In the present specification, unless otherwise specified, examples of “C 3-6 cycloalkylene” include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like.
　以下、式（Ｉ）中の各記号の定義について詳述する。
　環Ａは、置換基を有していてもよい６～１０員芳香族炭化水素環、置換基を有していてもよい５～１０員非芳香族複素環、または置換基を有していてもよい５～１０員芳香族複素環を示す。
　環Ａで示される「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」としては、ベンゼン、ナフタレンが挙げられ、好ましくはベンゼンである。
　該「６～１０員芳香族炭化水素環」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。 Hereinafter, the definition of each symbol in formula (I) will be described in detail.
Ring A has a 6 to 10-membered aromatic hydrocarbon ring which may have a substituent, a 5 to 10-membered non-aromatic heterocyclic ring which may have a substituent, or a substituent. Or a 5- to 10-membered aromatic heterocycle.
Examples of the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A include benzene and naphthalene, preferably benzene It is.
The “6- to 10-membered aromatic hydrocarbon ring” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
　このような置換基としては、例えば、
（1）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、および
　　 (d) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよいＣ３－１０シクロアルキル基（例、シクロプロピル）；
（2）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、
　　 (d) ハロゲン原子、および
　　 (e) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基で置換されていてもよいＣ６－１４アリール基；
（3）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、および
　　 (d) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよい芳香族複素環基；
（4）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、
　　 (d) ハロゲン原子、および
　　 (e) オキソ基
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基；
（5）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基（例、メチル）、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、および
　　 (d) ハロゲン原子
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基（例、ジメチルアミノ）；
（6）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、および
　　 (d) ハロゲン原子
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；
（7）ヒドロキシ基；
（8）(a) ヒドロキシ基、
　　 (b) Ｃ１－６アルコキシ基、および
　　 (c) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ、イソプロポキシ）；
（9）(a) ヒドロキシ基、
　　 (b) Ｃ１－６アルコキシ基、および
　　 (c) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよいＣ２－６アルケニルオキシ基；
（10）Ｃ３－１０シクロアルキルオキシ基（例、シクロヘキシルオキシ）；
（11）Ｃ７－１３アラルキルオキシ基（例、ベンジルオキシ）；
（12）１～３個のハロゲン原子で置換されていてもよいＣ６－１０アリールオキシ基（例、フェノキシ、ナフチルオキシ）；
（13）Ｃ１－６アルキル－カルボニルオキシ基（例、アセチルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ）；
（14）スルファニル基；
（15）１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキルスルファニル基（例、メチルスルファニル、エチルスルファニル）；
（16）Ｃ７－１３アラルキルスルファニル基（例、ベンジルスルファニル）；
（17）Ｃ６－１４アリールスルファニル基（例、フェニルスルファニル、ナフチルスルファニル）；
（18）スルホン酸基；
（19）シアノ基；
（20）アジド基；
（21）ニトロ基；
（22）ニトロソ基；
（23）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）；
（24）Ｃ３－１０シクロアルキル－Ｃ１－６アルキルオキシ基（例、シクロプロピルメチルオキシ）；
（25）Ｃ１－３アルキレンジオキシ基（例、メチレンジオキシ、エチレンジオキシ）；
（26）モノまたはジＣ１－６アルキルホスホリル基（例、ジエチルホスホリル）；
（27）Ｃ１－６アルコキシ－カルボニル基（例、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル）；
（28）Ｃ１－６アルキル－カルボニル基；
（29）(a) ハロゲン原子（例、フッ素原子）、
　　　(b) カルボキシル基、
　　　(c) ヒドロキシ基、
　　　(d) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
　　　(e) Ｃ６－１０アリールオキシ基（例、フェノキシ）、
　　　(f) Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル）、
　　　(g) Ｃ１－６アルキル－カルボニルオキシ基、
　　　(h) カルバモイル基、
　　　(i) 芳香族複素環基、
　　　(j) 非芳香族複素環基、
　　　(k) シアノ基、および
　　　(l) トリ（Ｃ１－６アルキル）シリルオキシ基（例、ｔｅｒｔ－ブチルジメチルシリルオキシ）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、イソプロピル）；
（30）(a) ハロゲン原子、
　　　(b) カルボキシル基、
　　　(c) Ｃ１－６アルコキシ－カルボニル基、および
　　　(d) カルバモイル基
から選ばれる１～３個の置換基で置換されていてもよいＣ２－６アルケニル基；
（31）(a) ハロゲン原子、
　　　(b) カルボキシル基、
　　　(c) Ｃ１－６アルコキシ－カルボニル基、および
　　　(d) カルバモイル基
から選ばれる１～３個の置換基で置換されていてもよいＣ２－６アルキニル基；
（32）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　　(b) ヒドロキシ基、
　　　(c) Ｃ１－６アルコキシ基、および
　　　(d) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよいＣ７－１３アラルキル基；
（33）１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキルスルホニルオキシ基（例、メチルスルホニルオキシ）；
（34）Ｃ１－６アルキルスルフィニル基（例、メチルスルフィニル）；
（35）Ｃ１－６アルキルスルホニル基（例、メチルスルホニル）；
等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 As such a substituent, for example,
(1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a C 3-10 cycloalkyl group (eg, cyclopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom;
(2) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a C 6-14 aryl optionally substituted with 1 to 3 substituents selected from an amino group optionally mono- or di-substituted with a C 1-6 alkyl group Group;
(3) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom;
(4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom, and (e) an oxo group;
(5) (a) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an amino group (eg, dimethylamino) optionally mono- or di-substituted with a substituent selected from a halogen atom;
(6) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a carbamoyl group which may be mono- or di-substituted with a substituent selected from a halogen atom;
(7) hydroxy group;
(8) (a) a hydroxy group,
(b) a C 1-6 alkoxy group, and (c) a C 1-6 alkoxy group (eg, methoxy, isopropoxy) optionally substituted by 1 to 3 substituents selected from halogen atoms;
(9) (a) a hydroxy group,
(b) a C 1-6 alkoxy group, and (c) a C 2-6 alkenyloxy group optionally substituted by 1 to 3 substituents selected from a halogen atom;
(10) a C 3-10 cycloalkyloxy group (eg, cyclohexyloxy);
(11) C 7-13 aralkyloxy group (eg, benzyloxy);
(12) a C 6-10 aryloxy group (eg, phenoxy, naphthyloxy) optionally substituted by 1 to 3 halogen atoms;
(13) C 1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(14) a sulfanyl group;
(15) a C 1-6 alkylsulfanyl group (eg, methylsulfanyl, ethylsulfanyl) optionally substituted by 1 to 3 halogen atoms;
(16) C 7-13 aralkylsulfanyl group (eg, benzylsulfanyl);
(17) C 6-14 arylsulfanyl group (eg, phenylsulfanyl, naphthylsulfanyl);
(18) sulfonic acid group;
(19) cyano group;
(20) an azido group;
(21) Nitro group;
(22) Nitroso group;
(23) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(24) C 3-10 cycloalkyl-C 1-6 alkyloxy group (eg, cyclopropylmethyloxy);
(25) C 1-3 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy);
(26) mono- or di-C 1-6 alkylphosphoryl group (eg, diethylphosphoryl);
(27) C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, tert-butoxycarbonyl);
(28) a C 1-6 alkyl-carbonyl group;
(29) (a) a halogen atom (eg, fluorine atom),
(b) a carboxyl group,
(c) a hydroxy group,
(d) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(e) a C 6-10 aryloxy group (eg, phenoxy),
(f) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl),
(g) a C 1-6 alkyl-carbonyloxy group,
(h) a carbamoyl group,
(i) an aromatic heterocyclic group,
(j) a non-aromatic heterocyclic group,
(k) a cyano group, and (l) a tri (C 1-6 alkyl) silyloxy group (eg, tert-butyldimethylsilyloxy)
A C 1-6 alkyl group (eg, methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from:
(30) (a) a halogen atom,
(b) a carboxyl group,
(c) a C 1-6 alkoxy-carbonyl group, and (d) a C 2-6 alkenyl group optionally substituted with 1 to 3 substituents selected from a carbamoyl group;
(31) (a) a halogen atom,
(b) a carboxyl group,
(c) a C 1-6 alkoxy-carbonyl group, and (d) a C 2-6 alkynyl group optionally substituted by 1 to 3 substituents selected from a carbamoyl group;
(32) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a C 7-13 aralkyl group optionally substituted with 1 to 3 substituents selected from a halogen atom;
(33) a C 1-6 alkylsulfonyloxy group which may be substituted with 1 to 3 halogen atoms (eg, methylsulfonyloxy);
(34) a C 1-6 alkylsulfinyl group (eg, methylsulfinyl);
(35) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl);
Etc. When there are two or more substituents, each substituent may be the same or different.
　環Ａで示される「置換基を有していてもよい５～１０員非芳香族複素環」の「５～１０員非芳香族複素環」としては、２－オキソジヒドロインドールおよび３－オキソジヒドロベンゾオキサジンが挙げられる。該「５～１０員非芳香族複素環」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “5- to 10-membered non-aromatic heterocycle” of the “optionally substituted 5- to 10-membered non-aromatic heterocycle” represented by ring A includes 2-oxodihydroindole and 3-oxodihydro Examples include benzoxazine. The “5- to 10-membered non-aromatic heterocyclic ring” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
As such a substituent, the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” in the “6-to 10-membered aromatic hydrocarbon ring” described above may be substituted. The group illustrated as a group is mentioned. When there are two or more substituents, each substituent may be the same or different.
　環Ａで示される「置換基を有していてもよい５～１０員芳香族複素環」の「５～１０員芳香族複素環」としては、インダゾールが挙げられる。該「５～１０員芳香族複素環」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 Examples of the “5- to 10-membered aromatic heterocycle” of the “optionally substituted 5- to 10-membered aromatic heterocycle” represented by ring A include indazole. The “5- to 10-membered aromatic heterocyclic ring” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
As such a substituent, the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” in the “6-to 10-membered aromatic hydrocarbon ring” described above may be substituted. The group illustrated as a group is mentioned. When there are two or more substituents, each substituent may be the same or different.
　環Ａとしては、好ましくは、置換基を有していてもよい６～１０員芳香族炭化水素環であり、より好ましくは、置換基を有していてもよいベンゼンであり、さらに好ましくは、(i) ハロゲン原子（好ましくは、フッ素原子、塩素原子、臭素原子）、(ii) Ｃ１－６アルコキシ－カルボニル基（好ましくは、メトキシカルボニル）または１～３個のハロゲン原子（好ましくは、フッ素原子）で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル）、(iii) Ｃ３－１０シクロアルキル基（好ましくは、シクロプロピル）、(iv) ニトロ基、(v) アミノ基、(vi) Ｃ１－６アルキルスルファニル基（好ましくは、メチルスルファニル）、(vii) Ｃ１－６アルキルスルフィニル基（好ましくは、メチルスルフィニル）および(viii) Ｃ１－６アルキルスルホニル基（好ましくは、メチルスルホニル）から選ばれる１～３個の置換基で置換されていてもよいベンゼンであり、特に好ましくは、フッ素原子、塩素原子、臭素原子、トリフルオロメチル、シクロプロピル、アミノ、ニトロ、メチルスルファニル、メチルスルフィニル、メチルスルホニルおよびメトキシカルボニルから選ばれる１～３個の置換基で置換されたベンゼンである。 Ring A is preferably a 6- to 10-membered aromatic hydrocarbon ring which may have a substituent, more preferably benzene which may have a substituent, and more preferably (i) a halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom), (ii) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl) or 1 to 3 halogen atoms (preferably a fluorine atom) C 1-6 alkyl group (preferably methyl) optionally substituted with an atom), (iii) C 3-10 cycloalkyl group (preferably cyclopropyl), (iv) nitro group, (v) amino group, (vi) C 1-6 alkylsulfanyl groups (preferably methylsulfanyl), (vii) C 1-6 alkylsulfinyl group (preferably, methylsulfinyl) and (viii) C 1-6 Arukirusu Benzene which may be substituted with 1 to 3 substituents selected from a phonyl group (preferably methylsulfonyl), particularly preferably a fluorine atom, a chlorine atom, a bromine atom, trifluoromethyl, cyclopropyl, Benzene substituted with 1 to 3 substituents selected from amino, nitro, methylsulfanyl, methylsulfinyl, methylsulfonyl and methoxycarbonyl.
　本発明の別の態様では、環Ａとしては、好ましくは、置換基を有していてもよい５～１０員非芳香族複素環であり、より好ましくは、置換基を有していてもよい２－オキソジヒドロインドールまたは置換基を有していてもよい３－オキソジヒドロベンゾオキサジンであり、さらに好ましくは、(i) ハロゲン原子（好ましくは、フッ素原子）および(ii)Ｃ１－６アルキル基（好ましくは、メチル）から選ばれる１～３個の置換基で置換されていてもよい、２－オキソジヒドロインドールまたは３－オキソジヒドロベンゾオキサジンである。 In another embodiment of the present invention, ring A is preferably a 5- to 10-membered non-aromatic heterocyclic ring which may have a substituent, and more preferably, may have a substituent. 2-oxodihydroindole or optionally substituted 3-oxodihydrobenzoxazine, more preferably (i) a halogen atom (preferably a fluorine atom) and (ii) a C 1-6 alkyl group 2-oxodihydroindole or 3-oxodihydrobenzoxazine optionally substituted with 1 to 3 substituents selected from (preferably methyl).
　また、本発明のさらに別の態様では、環Ａとしては、好ましくは、置換基を有していてもよい５～１０員芳香族複素環であり、より好ましくは、置換基を有していてもよいインダゾールであり、さらに好ましくは、(i) ハロゲン原子（好ましくは、フッ素原子）および(ii) Ｃ１－６アルキル基（好ましくは、メチル）から選ばれる１～３個の置換基で置換されていてもよいインダゾールである。 In still another embodiment of the present invention, ring A is preferably a 5- to 10-membered aromatic heterocyclic ring which may have a substituent, and more preferably has a substituent. More preferably, it is substituted with 1 to 3 substituents selected from (i) a halogen atom (preferably a fluorine atom) and (ii) a C 1-6 alkyl group (preferably methyl). Indazole which may have been used.
　環Ｂは、
（１）さらに置換基を有していてもよい６～１０員芳香族炭化水素環、
（２）さらに置換基を有していてもよい５または６員複素環、または
（３）さらに置換基を有していてもよい、ベンゼン環及び５または６員環が縮合した二環性縮合環を示す。 Ring B is
(1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent,
(2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring.
　環Ｂで示される「さらに置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」としては、ベンゼン、ナフタレンが挙げられ、好ましくはベンゼンである。
　該「６～１０員芳香族炭化水素環」は、－Ｌ２－Ｒ２（式中、各記号は前記と同意義を示す。）で表される基以外に、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した環Ａで示される「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 Examples of the “6- to 10-membered aromatic hydrocarbon ring” of the “6- to 10-membered aromatic hydrocarbon ring optionally having substituents” represented by ring B include benzene and naphthalene, preferably Benzene.
The “6- to 10-membered aromatic hydrocarbon ring” is a group other than the group represented by —L 2 —R 2 (wherein each symbol is as defined above), It may have 5 (preferably 1 to 3, more preferably 1 or 2) substituents.
As such a substituent, the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two or more substituents, each substituent may be the same or different.
　環Ｂで示される「さらに置換基を有していてもよい５または６員複素環」の「５または６員複素環」としては、５または６員芳香族複素環（好ましくは、ピリジン、チアゾール、ピリミジン）および５または６員非芳香族複素環（好ましくは、ピペリジン、テトラヒドロピリジン）が挙げられる。
　該「５または６員複素環」が環原子として窒素原子を含む場合、該窒素原子は、好ましくは四級塩化されていない。
　該「５または６員芳香族複素環」は、－Ｌ２－Ｒ２（式中、各記号は前記と同意義を示す。）で表される基以外に、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した環Ａで示される「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “5- or 6-membered heterocycle” of the “optionally substituted 5- or 6-membered heterocycle” represented by ring B is a 5- or 6-membered aromatic heterocycle (preferably pyridine, thiazole , Pyrimidine) and 5- or 6-membered non-aromatic heterocycles (preferably piperidine, tetrahydropyridine).
When the “5- or 6-membered heterocycle” contains a nitrogen atom as a ring atom, the nitrogen atom is preferably not quaternized.
The “5- or 6-membered aromatic heterocyclic ring” is 1 to 5 at a substitutable position other than the group represented by —L 2 —R 2 (wherein each symbol is as defined above). May be substituted (preferably 1 to 3, more preferably 1 or 2).
As such a substituent, the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two or more substituents, each substituent may be the same or different.
　該「５または６員非芳香族複素環」は、－Ｌ２－Ｒ２（式中、各記号は前記と同意義を示す。）で表される基以外に、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、
(1) 前記した環Ａで示される「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基、および(2) オキソ基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “5- or 6-membered non-aromatic heterocycle” is a group other than the group represented by —L 2 —R 2 (wherein each symbol is as defined above), It may have 5 (preferably 1 to 3, more preferably 1 or 2) substituents.
Such substituents include:
(1) Substitution that the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally-substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A may have Examples include groups exemplified as groups, and (2) oxo groups. When there are two or more substituents, each substituent may be the same or different.
　本発明の１態様では、環Ｂで示される「さらに置換基を有していてもよい５または６員複素環」は、好ましくは、さらに置換基を有していてもよい５または６員芳香族複素環である。 In one embodiment of the present invention, the “5- or 6-membered heterocyclic ring optionally having substituent (s)” represented by ring B is preferably a 5- or 6-membered aromatic optionally further having substituent (s). Family heterocycle.
　環Ｂで示される「さらに置換基を有していてもよい、ベンゼン環及び５または６員環が縮合した二環性縮合環」の「ベンゼン環及び５または６員環が縮合した二環性縮合環」としては、ベンゼン環及び５または６員芳香族複素環が縮合した二環性縮合環、ベンゼン環及び５または６員非芳香族複素環が縮合した二環性縮合環、ベンゼン環および５または６員非芳香族炭化水素環が縮合した二環性縮合環等挙げられる。
　ここで、「ベンゼン環及び５または６員芳香族複素環が縮合した二環性縮合環」としては、インドール、イソインドール、ベンゾフラン、ベンゾチオフェン、キノリン、イソキノリン、インダゾール、キナゾリン、シンノリン、キノキサリン、フタラジン等が挙げられ、好ましくはベンゾフランである。
　ここで、「ベンゼン環及び５または６員非芳香族複素環が縮合した二環性縮合環」としては、ジヒドロインドール、ジヒドロイソインドール、ジヒドロベンゾフラン、ジヒドロベンゾチオフェン、クロメン、ジヒドロクロメン、ジヒドロキノリン、テトラヒドロキノリン、ジヒドロイソキノリン、テトラヒドロイソキノリン、ジヒドロインダゾール、ジヒドロキナゾリン、テトラヒドロキナゾリン、ジヒドロシンノリン、テトラヒドロシンノリン、ジヒドロキノキサリン、テトラヒドロキノキサリン、ジヒドロフタラジン、テトラヒドロフタラジン等が挙げられ、好ましくはジヒドロベンゾフラン（２，３－ジヒドロベンゾフラン）である。
　ここで、「ベンゼン環及び５または６員非芳香族炭化水素環が縮合した二環性縮合環」としては、インデン、インダン、１，２－ジヒドロナフタレン、１，４－ジヒドロナフタレン、１，２，３，４－テトラヒドロナフタレン等が挙げられる。 “Bicyclic condensed with benzene ring and 5- or 6-membered ring” of “Bicyclic condensed ring with condensed benzene ring and 5- or 6-membered ring optionally having substituent” represented by ring B As the “fused ring”, a benzene ring and a bicyclic condensed ring in which a 5- or 6-membered aromatic heterocyclic ring is condensed, a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed, a benzene ring and And bicyclic condensed rings in which 5- or 6-membered non-aromatic hydrocarbon rings are condensed.
Here, the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered aromatic heterocycle are condensed” includes indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, indazole, quinazoline, cinnoline, quinoxaline, phthalazine Benzofuran is preferable.
Here, the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed” includes dihydroindole, dihydroisoindole, dihydrobenzofuran, dihydrobenzothiophene, chromene, dihydrochromene, dihydroquinoline, Tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydroindazole, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, dihydroquinoxaline, tetrahydroquinoxaline, dihydrophthalazine, tetrahydrophthalazine, etc., preferably dihydrobenzofuran (2 , 3-dihydrobenzofuran).
Here, as the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic hydrocarbon ring are condensed”, indene, indane, 1,2-dihydronaphthalene, 1,4-dihydronaphthalene, 1,2 3,4-tetrahydronaphthalene and the like.
　該「ベンゼン環及び５または６員芳香族複素環が縮合した二環性縮合環」は、－Ｌ２－Ｒ２（式中、各記号は前記と同意義を示す。）で表される基以外に、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した環Ａで示される「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　該「ベンゼン環及び５または６員非芳香族複素環が縮合した二環性縮合環」および「ベンゼン環及び５または６員非芳香族炭化水素環が縮合した二環性縮合環」は、－Ｌ２－Ｒ２（式中、各記号は前記と同意義を示す。）で表される基以外に、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した環Ｂで示される「さらに置換基を有していてもよい５または６員複素環」の「５または６員複素環」として例示した「５または６員非芳香族複素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “bicyclic fused ring in which a benzene ring and a 5- or 6-membered aromatic heterocycle are condensed” is a group represented by —L 2 —R 2 (wherein each symbol is as defined above). In addition, it may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
As such a substituent, the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two or more substituents, each substituent may be the same or different.
The “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed” and the “bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic hydrocarbon ring are condensed” are: In addition to the group represented by L 2 -R 2 (wherein each symbol is as defined above), 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents may be present.
Examples of such a substituent include “5 or 6 membered” exemplified as “5 or 6 membered heterocyclic ring” of “an optionally substituted 5 or 6 membered heterocyclic ring” represented by ring B above. The group illustrated as the substituent which the "non-aromatic heterocyclic ring" may have is mentioned. When there are two or more substituents, each substituent may be the same or different.
　環Ｂとしては、好ましくは、
（１）さらに置換基を有していてもよい６～１０員芳香族炭化水素環（好ましくは、ベンゼン）、
（２）さらに置換基を有していてもよい５もしくは６員芳香族複素環（好ましくは、ピリジン、チアゾール、ピリミジン）、
（３）さらに置換基を有していてもよい５もしくは６員非芳香族複素環（好ましくは、ピペリジン、テトラヒドロピリジン）、
（４）さらに置換基を有していてもよい、ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環（好ましくは、ベンゾフラン）、または
（５）さらに置換基を有していてもよい、ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環（好ましくは、２，３－ジヒドロベンゾフラン）であり、より好ましくは、
（1）Ｃ３－１０シクロアルキル基（好ましくは、シクロプロピル）；
（2）Ｃ１－６アルコキシ基（好ましくは、メトキシ、イソプロポキシ）；
（3）ハロゲン原子（好ましくは、フッ素原子、塩素原子）；
（4）(a) ハロゲン原子（好ましくは、フッ素原子）、
　　 (b) ヒドロキシ基、
　　 (c) シアノ基、および
　　 (d) トリ（Ｃ１－６アルキル）シリルオキシ基（好ましくは、ｔｅｒｔ－ブチルジメチルシリルオキシ）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル、イソプロピル）；
（5）ヒドロキシ基；
（6）１～３個のハロゲン原子（好ましくは、フッ素原子）で置換されていてもよいＣ１－６アルキルスルホニルオキシ基（好ましくは、メチルスルホニルオキシ）；および
（7）Ｃ１－６アルキル基（好ましくは、メチル）でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、
（２）５もしくは６員芳香族複素環（好ましくは、ピリジン、チアゾール、ピリミジン）、
（３）５もしくは６員非芳香族複素環（好ましくは、ピペリジン、テトラヒドロピリジン）、
（４）ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環（好ましくは、ベンゾフラン）、または
（５）ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環（好ましくは、２，３－ジヒドロベンゾフラン）であり、特に好ましくは、
　（１）Ｃ３－１０シクロアルキル基（特に、シクロプロピル）、ハロゲン原子（特に、塩素原子）、１～３個のハロゲン原子（特に、フッ素原子）で置換されていてもよいＣ１－６アルキル基（特に、メチル）、ヒドロキシ基、１～３個のハロゲン原子（特に、フッ素原子）で置換されたＣ１－６アルキルスルホニルオキシ基（特に、メチルスルホニルオキシ）、およびＣ１－６アルキル基（特に、メチル）でモノまたはジ置換されたアミノ基から選ばれる１～３個の置換基でさらに置換されていてもよいベンゼン、
　（２）Ｃ１－６アルキル基（特に、メチル）から選ばれる１～３個の置換基でさらに置換されていてもよいピリジン、または
　（３）Ｃ１－６アルキル基（特に、メチル）から選ばれる１～３個の置換基でさらに置換されていてもよいピリミジンである。 As ring B, preferably
(1) a 6 to 10-membered aromatic hydrocarbon ring (preferably benzene) which may further have a substituent,
(2) a 5- or 6-membered aromatic heterocyclic ring (preferably pyridine, thiazole, pyrimidine) which may further have a substituent,
(3) a 5- or 6-membered non-aromatic heterocyclic ring (preferably piperidine, tetrahydropyridine) which may further have a substituent,
(4) A bicyclic condensed ring (preferably benzofuran) in which a benzene ring and a 5- or 6-membered aromatic heterocycle are condensed, or (5) an additional substituent. A bicyclic condensed ring (preferably 2,3-dihydrobenzofuran) in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed, more preferably,
(1) a C 3-10 cycloalkyl group (preferably cyclopropyl);
(2) a C 1-6 alkoxy group (preferably methoxy, isopropoxy);
(3) a halogen atom (preferably a fluorine atom or a chlorine atom);
(4) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) a cyano group, and (d) a tri (C 1-6 alkyl) silyloxy group (preferably tert-butyldimethylsilyloxy)
A C 1-6 alkyl group (preferably methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from:
(5) hydroxy group;
(6) a C 1-6 alkylsulfonyloxy group (preferably methylsulfonyloxy) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom); and (7) C 1-6 alkyl Each of which may be further substituted with 1 to 3 substituents selected from amino groups which may be mono- or di-substituted with a group (preferably methyl),
(1) benzene,
(2) a 5- or 6-membered aromatic heterocycle (preferably pyridine, thiazole, pyrimidine),
(3) a 5- or 6-membered non-aromatic heterocyclic ring (preferably piperidine, tetrahydropyridine),
(4) a bicyclic condensed ring (preferably benzofuran) in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring are condensed, or (5) a bicyclic ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed. A condensed condensed ring (preferably 2,3-dihydrobenzofuran), particularly preferably
(1) C 3-10 cycloalkyl group (particularly cyclopropyl), halogen atom (especially chlorine atom), 1 to 3 halogen atoms (especially, fluorine atom) optionally substituted by C 1-6 An alkyl group (particularly methyl), a hydroxy group, a C 1-6 alkylsulfonyloxy group (particularly methylsulfonyloxy) substituted with 1 to 3 halogen atoms (particularly a fluorine atom), and C 1-6 alkyl Benzene optionally further substituted with 1 to 3 substituents selected from amino groups mono- or di-substituted with groups (particularly methyl),
(2) From pyridine optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups (especially methyl), or (3) C 1-6 alkyl groups (especially methyl) It is a pyrimidine which may be further substituted with 1 to 3 selected substituents.
　式（Ｉ）の部分構造式： Partial structural formula of formula (I):
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
は、以下の構造を示す。 Shows the following structure.
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　上記部分構造式としては、好ましくは、 As the partial structural formula, preferably
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
である。
　Ｒ１は、ハロゲン原子、アシル基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、シアノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示し；Ｒ３は水素原子またはＣ１－６アルキル基を示す。 It is.
R 1 may be a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. A good C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-14 aryl group, an optionally substituted group An amino group, a cyano group, or —S (O) m Ra; m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group; R 3 represents a hydrogen atom or C A 1-6 alkyl group;
　また、式（Ｉ’）の部分構造式： Also, the partial structural formula of formula (I ′):
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
は、以下の構造を示す。 Shows the following structure.
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　上記部分構造式としては、好ましくは、 As the partial structural formula, preferably
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
である。 It is.
　Ｒ１は、水素原子、ハロゲン原子、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいアミノ基、シアノ基、アシル基または－Ｓ（Ｏ）ｍＲａ（式中、ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示す。）を示す。 R 1 may be a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. A good C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted amino group, a cyano group, an acyl group, or —S (O) m Ra (Wherein m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group).
　Ｒ１で示される「置換基を有していてもよいＣ１－６アルキル基」の「Ｃ１－６アルキル基」としては、メチル、エチルが好ましい。
　該「Ｃ１－６アルキル基」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、例えば、
（1）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、および
　　 (d) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよいＣ３－１０シクロアルキル基（例、シクロプロピル）；
（2）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、
　　 (d) ハロゲン原子、および
　　 (e) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基で置換されていてもよいＣ６－１４アリール基；
（3）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、および
　　 (d) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよい芳香族複素環基；
（4）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、
　　 (d) ハロゲン原子、および
　　 (e) オキソ基
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基；
（5）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基（例、メチル）、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、
　　 (d) ハロゲン原子、および
　　 (e) Ｃ１－６アルキル－カルボニル基（例、メチルカルボニル）
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基（例、ジメチルアミノ、アセチルアミノ）；
（6）(a) １～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基（例、メチル）、
　　 (b) ヒドロキシ基、
　　 (c) Ｃ１－６アルコキシ基、および
　　 (d) ハロゲン原子
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基（例、カルバモイル、メチルカルバモイル、ジメチルカルバモイル）；
（7）ヒドロキシ基；
（8）(a) ヒドロキシ基、
　　 (b) Ｃ１－６アルコキシ基、および
　　 (c) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ、イソプロポキシ）；
（9）(a) ヒドロキシ基、
　　 (b) Ｃ１－６アルコキシ基、および
　　 (c) ハロゲン原子
から選ばれる１～３個の置換基で置換されていてもよいＣ２－６アルケニルオキシ基；
（10）Ｃ３－１０シクロアルキルオキシ基（例、シクロヘキシルオキシ）；
（11）Ｃ７－１３アラルキルオキシ基（例、ベンジルオキシ）；
（12）１～３個のハロゲン原子で置換されていてもよいＣ６－１０アリールオキシ基（例、フェノキシ、ナフチルオキシ）；
（13）Ｃ１－６アルキル－カルボニルオキシ基（例、アセチルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ）；
（14）スルファニル基；
（15）１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキルスルファニル基（例、メチルスルファニル、エチルスルファニル）；
（16）Ｃ７－１３アラルキルスルファニル基（例、ベンジルスルファニル）；
（17）Ｃ６－１４アリールスルファニル基（例、フェニルスルファニル、ナフチルスルファニル）；
（18）スルホン酸基；
（19）シアノ基；
（20）アジド基；
（21）ニトロ基；
（22）ニトロソ基；
（23）ハロゲン原子（例、フッ素原子、塩素原子）；
（24）Ｃ３－１０シクロアルキル－Ｃ１－６アルキルオキシ基（例、シクロプロピルメチルオキシ）；
（25）Ｃ１－３アルキレンジオキシ基（例、メチレンジオキシ、エチレンジオキシ）；
（26）モノまたはジＣ１－６アルキルホスホリル基（例、ジエチルホスホリル）；
（27）Ｃ１－６アルコキシ－カルボニル基（例、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル）；
（28）Ｃ１－６アルキル－カルボニル基；
（29）Ｃ１－６アルキルスルフィニル基（例、メチルスルフィニル）；
（30）Ｃ１－６アルキルスルホニル基（例、メチルスルホニル）
等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “C 1-6 alkyl group” of the “C 1-6 alkyl group optionally having substituent (s)” represented by R 1 is preferably methyl or ethyl.
The “C 1-6 alkyl group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
As such a substituent, for example,
(1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a C 3-10 cycloalkyl group (eg, cyclopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom;
(2) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a C 6-14 aryl optionally substituted with 1 to 3 substituents selected from an amino group optionally mono- or di-substituted with a C 1-6 alkyl group Group;
(3) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom;
(4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom, and (e) an oxo group;
(5) (a) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a C 1-6 alkyl-carbonyl group (eg, methylcarbonyl)
An amino group (eg, dimethylamino, acetylamino) optionally mono- or di-substituted with a substituent selected from:
(6) (a) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a carbamoyl group (eg, carbamoyl, methylcarbamoyl, dimethylcarbamoyl) optionally mono- or di-substituted with a substituent selected from a halogen atom;
(7) hydroxy group;
(8) (a) a hydroxy group,
(b) a C 1-6 alkoxy group, and (c) a C 1-6 alkoxy group (eg, methoxy, isopropoxy) optionally substituted by 1 to 3 substituents selected from halogen atoms;
(9) (a) a hydroxy group,
(b) a C 1-6 alkoxy group, and (c) a C 2-6 alkenyloxy group optionally substituted by 1 to 3 substituents selected from a halogen atom;
(10) a C 3-10 cycloalkyloxy group (eg, cyclohexyloxy);
(11) C 7-13 aralkyloxy group (eg, benzyloxy);
(12) a C 6-10 aryloxy group (eg, phenoxy, naphthyloxy) optionally substituted by 1 to 3 halogen atoms;
(13) C 1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(14) a sulfanyl group;
(15) a C 1-6 alkylsulfanyl group (eg, methylsulfanyl, ethylsulfanyl) optionally substituted by 1 to 3 halogen atoms;
(16) C 7-13 aralkylsulfanyl group (eg, benzylsulfanyl);
(17) C 6-14 arylsulfanyl group (eg, phenylsulfanyl, naphthylsulfanyl);
(18) sulfonic acid group;
(19) cyano group;
(20) an azido group;
(21) Nitro group;
(22) Nitroso group;
(23) Halogen atoms (eg, fluorine atoms, chlorine atoms);
(24) C 3-10 cycloalkyl-C 1-6 alkyloxy group (eg, cyclopropylmethyloxy);
(25) C 1-3 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy);
(26) mono- or di-C 1-6 alkylphosphoryl group (eg, diethylphosphoryl);
(27) C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, tert-butoxycarbonyl);
(28) a C 1-6 alkyl-carbonyl group;
(29) a C 1-6 alkylsulfinyl group (eg, methylsulfinyl);
(30) C 1-6 alkylsulfonyl group (eg, methylsulfonyl)
Etc. When there are two or more substituents, each substituent may be the same or different.
　Ｒ１で示される「置換基を有していてもよいＣ２－６アルケニル基」の「Ｃ２－６アルケニル基」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した「置換基を有していてもよいＣ１－６アルキル基」の「Ｃ１－６アルキル基」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 Represented by R 1 in the "optionally substituted C 2-6 alkenyl group", "C 2-6 alkenyl group", 1 to 5 at substitutable positions (preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
As such substituents, the groups exemplified as the "C 1-6 alkyl group" optionally has substituent of the "optionally substituted C 1-6 alkyl group" described above Can be mentioned. When there are two or more substituents, each substituent may be the same or different.
　Ｒ１で示される「置換基を有していてもよいＣ２－６アルキニル基」の「Ｃ２－６アルキニル基」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した「置換基を有していてもよいＣ１－６アルキル基」の「Ｃ１－６アルキル基」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “C 2-6 alkynyl group” of the “ optionally substituted C 2-6 alkynyl group” represented by R 1 has 1 to 5 (preferably 1 to 3, preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
As such substituents, the groups exemplified as the "C 1-6 alkyl group" optionally has substituent of the "optionally substituted C 1-6 alkyl group" described above Can be mentioned. When there are two or more substituents, each substituent may be the same or different.
　Ｒ１で示される「置換基を有していてもよいＣ３－６シクロアルキル基」の「Ｃ３－６シクロアルキル基」としては、シクロプロピルが好ましい。
　該「Ｃ３－６シクロアルキル基」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した環Ｂで示される「さらに置換基を有していてもよい５または６員複素環」の「５または６員複素環」として例示した「５または６員非芳香族複素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “C 3-6 cycloalkyl group” of the “ optionally substituted C 3-6 cycloalkyl group” represented by R 1 is preferably cyclopropyl.
The “C 3-6 cycloalkyl group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
Examples of such a substituent include “5 or 6 membered” exemplified as “5 or 6 membered heterocyclic ring” of “an optionally substituted 5 or 6 membered heterocyclic ring” represented by ring B above. The group illustrated as the substituent which the "non-aromatic heterocyclic ring" may have is mentioned. When there are two or more substituents, each substituent may be the same or different.
　Ｒ１で示される「置換基を有していてもよいＣ６－１４アリール基」の「Ｃ６－１４アリール基」としては、フェニルが好ましい。
　該「Ｃ６－１４アリール基」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した環Ｂで示される「さらに置換基を有していてもよい５または６員複素環」の「５または６員複素環」として例示した「５または６員芳香族複素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 Represented by R 1 in the "optionally substituted C 6-14 aryl group" as the "C 6-14 aryl group", preferably phenyl.
The “C 6-14 aryl group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
Examples of such a substituent include “5 or 6 membered” exemplified as “5 or 6 membered heterocyclic ring” of “an optionally substituted 5 or 6 membered heterocyclic ring” represented by ring B above. The group illustrated as a substituent which the "aromatic heterocyclic ring" may have is mentioned. When there are two or more substituents, each substituent may be the same or different.
　Ｒ１で示される「置換基を有していてもよいアミノ基」の「アミノ基」は、１または２個の置換基を有していてもよい。
　このような置換基としては、前記した環Ａで示される「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個である場合、各置換基は同一でも異なっていてもよい。 The “amino group” of the “optionally substituted amino group” represented by R 1 may have 1 or 2 substituents.
As such a substituent, the “6- to 10-membered aromatic hydrocarbon ring” of the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” represented by ring A described above has The group illustrated as an example of the substituent which may be included is mentioned. When there are two substituents, each substituent may be the same or different.
　Ｒ１で示される「アシル基」としては、例えば、
（１）ホルミル基、
（２）Ｃ１－６アルキル－カルボニル基、
（３）Ｃ２－６アルケニル－カルボニル基、
（４）Ｃ２－６アルキニル－カルボニル基、
（５）Ｃ３－６シクロアルキル－カルボニル基、
（６）Ｃ３－６シクロアルケニル－カルボニル基、
（７）Ｃ６－１０アリール－カルボニル基、
（８）複素環－カルボニル基、
（９）カルボキシル基、
（１０）Ｃ１－６アルコキシ－カルボニル基、
（１１）Ｃ２－６アルケニルオキシ－カルボニル基、
（１２）Ｃ２－６アルキニルオキシ－カルボニル基、
（１３）Ｃ３－６シクロアルキルオキシ－カルボニル基、
（１４）Ｃ３－６シクロアルケニルオキシ－カルボニル基、
（１５）Ｃ６－１０アリールオキシ－カルボニル基、
（１６）複素環－オキシカルボニル基
等が挙げられる。 As the “acyl group” represented by R 1 , for example,
(1) formyl group,
(2) a C 1-6 alkyl-carbonyl group,
(3) a C 2-6 alkenyl-carbonyl group,
(4) a C 2-6 alkynyl-carbonyl group,
(5) a C 3-6 cycloalkyl-carbonyl group,
(6) a C 3-6 cycloalkenyl-carbonyl group,
(7) a C 6-10 aryl-carbonyl group,
(8) Heterocycle-carbonyl group,
(9) carboxyl group,
(10) a C 1-6 alkoxy-carbonyl group,
(11) C 2-6 alkenyloxy-carbonyl group,
(12) C 2-6 alkynyloxy-carbonyl group,
(13) a C 3-6 cycloalkyloxy-carbonyl group,
(14) a C 3-6 cycloalkenyloxy-carbonyl group,
(15) a C 6-10 aryloxy-carbonyl group,
(16) Heterocycle-oxycarbonyl group and the like.
　ここで、「Ｃ２－６アルケニル－カルボニル基」としては、例えば、エテニルカルボニル、１－プロペニルカルボニル、２－プロペニルカルボニル、２－メチル－１－プロペニルカルボニル、１－ブテニルカルボニル、２－ブテニルカルボニル、３－ブテニルカルボニル、３－メチル－２－ブテニルカルボニル、１－ペンテニルカルボニル、２－ペンテニルカルボニル、３－ペンテニルカルボニル、４－ペンテニルカルボニル、４－メチル－３－ペンテニルカルボニル、１－ヘキセニルカルボニル、２－ヘキセニルカルボニル、３－ヘキセニルカルボニル、４－ヘキセニルカルボニル、５－ヘキセニルカルボニル等が挙げられる。
　「Ｃ２－６アルキニル－カルボニル基」としては、例えば、エチニルカルボニル、１－プロピニルカルボニル、２－プロピニルカルボニル、１－ブチニルカルボニル、２－ブチニルカルボニル、３－ブチニルカルボニル、１－ペンチニルカルボニル、２－ペンチニルカルボニル、３－ペンチニルカルボニル、４－ペンチニルカルボニル、１－ヘキシニルカルボニル、２－ヘキシニルカルボニル、３－ヘキシニルカルボニル、４－ヘキシニルカルボニル、５－ヘキシニルカルボニル等が挙げられる。 Here, the “C 2-6 alkenyl-carbonyl group” includes, for example, ethenylcarbonyl, 1-propenylcarbonyl, 2-propenylcarbonyl, 2-methyl-1-propenylcarbonyl, 1-butenylcarbonyl, 2-butenylcarbonyl, Tenenylcarbonyl, 3-butenylcarbonyl, 3-methyl-2-butenylcarbonyl, 1-pentenylcarbonyl, 2-pentenylcarbonyl, 3-pentenylcarbonyl, 4-pentenylcarbonyl, 4-methyl-3-pentenylcarbonyl, 1- Hexenylcarbonyl, 2-hexenylcarbonyl, 3-hexenylcarbonyl, 4-hexenylcarbonyl, 5-hexenylcarbonyl and the like can be mentioned.
Examples of the “C 2-6 alkynyl-carbonyl group” include ethynylcarbonyl, 1-propynylcarbonyl, 2-propynylcarbonyl, 1-butynylcarbonyl, 2-butynylcarbonyl, 3-butynylcarbonyl and 1-pentynyl. Carbonyl, 2-pentynylcarbonyl, 3-pentynylcarbonyl, 4-pentynylcarbonyl, 1-hexynylcarbonyl, 2-hexynylcarbonyl, 3-hexynylcarbonyl, 4-hexynylcarbonyl, 5-hexynylcarbonyl, etc. Is mentioned.
　「Ｃ３－６シクロアルキル－カルボニル基」としては、例えば、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル等が挙げられる。
　「Ｃ３－６シクロアルケニル－カルボニル基」としては、例えば、２－シクロプロペン－１－イルカルボニル、２－シクロブテン－１－イルカルボニル、２－シクロペンテン－１－イルカルボニル、３－シクロペンテン－１－イルカルボニル、２－シクロヘキセン－１－イルカルボニル、３－シクロヘキセン－１－イルカルボニル等が挙げられる。 Examples of the “C 3-6 cycloalkyl-carbonyl group” include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.
Examples of the “C 3-6 cycloalkenyl-carbonyl group” include 2-cyclopropen-1-ylcarbonyl, 2-cyclobuten-1-ylcarbonyl, 2-cyclopenten-1-ylcarbonyl, 3-cyclopentene-1- And ylcarbonyl, 2-cyclohexen-1-ylcarbonyl, 3-cyclohexen-1-ylcarbonyl and the like.
　「Ｃ６－１０アリール－カルボニル基」としては、例えば、ベンゾイル、１－ナフトイル、２－ナフトイル等が挙げられる。
　「複素環－カルボニル基」とは、例えば、(1)５または６員の単環式芳香族複素環（例、フラン、チオフェン、ピロール、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、イミダゾール、ピリジン、ピラゾール等）－カルボニル、(2)８～１２員の縮合芳香族複素環（例、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、イソベンゾチオフェン、インドール、イソインドール、１Ｈ－インダゾール、ベンゾイミダゾール、ベンズオキサゾール等）－カルボニル、(3)３～６員の非芳香族複素環（例、オキシラン、アゼチジン、オキセタン、ピロリジン、テトラヒドロフラン、チオラン、ピペリジン等）－カルボニル等が挙げられる。 Examples of the “C 6-10 aryl-carbonyl group” include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
“Heterocycle-carbonyl group” means, for example, (1) a 5- or 6-membered monocyclic aromatic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridine, Pyrazole, etc.)-Carbonyl, (2) 8- to 12-membered condensed aromatic heterocycle (eg, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, etc.) -Carbonyl, (3) 3-6 membered non-aromatic heterocycle (eg, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, thiolane, piperidine, etc.)-Carbonyl and the like.
　「Ｃ２－６アルケニルオキシ－カルボニル基」としては、例えば、エテニルオキシカルボニル、１－プロペニルオキシカルボニル、２－プロペニルオキシカルボニル、１－ブテニルオキシカルボニル、２－ブテニルオキシカルボニル、３－ブテニルオキシカルボニル、３－メチル－２－ブテニルオキシカルボニル、１－ペンテニルオキシカルボニル、２－ペンテニルオキシカルボニル、３－ペンテニルオキシカルボニル、４－ペンテニルオキシカルボニル、１－ヘキセニルオキシカルボニル、２－ヘキセニルオキシカルボニル、３－ヘキセニルオキシカルボニル、４－ヘキセニルオキシカルボニル、５－ヘキセニルオキシカルボニル等が挙げられる。
　「Ｃ２－６アルキニルオキシ－カルボニル基」としては、例えば、エチニルオキシカルボニル、１－プロピニルオキシカルボニル、２－プロピニルオキシカルボニル、１－ブチニルオキシカルボニル、２－ブチニルオキシカルボニル、３－ブチニルオキシカルボニル、１－ペンチニルオキシカルボニル、２－ペンチニルオキシカルボニル、３－ペンチニルオキシカルボニル、４－ペンチニルオキシカルボニル、１－ヘキシニルオキシカルボニル、２－ヘキシニルオキシカルボニル、３－ヘキシニルオキシカルボニル、４－ヘキシニルオキシカルボニル、５－ヘキシニルオキシカルボニル等が挙げられる。 Examples of the “C 2-6 alkenyloxy-carbonyl group” include ethenyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, Tenenyloxycarbonyl, 3-methyl-2-butenyloxycarbonyl, 1-pentenyloxycarbonyl, 2-pentenyloxycarbonyl, 3-pentenyloxycarbonyl, 4-pentenyloxycarbonyl, 1-hexenyloxycarbonyl, 2-hexenyloxycarbonyl , 3-hexenyloxycarbonyl, 4-hexenyloxycarbonyl, 5-hexenyloxycarbonyl and the like.
Examples of the “C 2-6 alkynyloxy-carbonyl group” include, for example, ethynyloxycarbonyl, 1-propynyloxycarbonyl, 2-propynyloxycarbonyl, 1-butynyloxycarbonyl, 2-butynyloxycarbonyl, 3-butynyl Oxycarbonyl, 1-pentynyloxycarbonyl, 2-pentynyloxycarbonyl, 3-pentynyloxycarbonyl, 4-pentynyloxycarbonyl, 1-hexynyloxycarbonyl, 2-hexynyloxycarbonyl, 3-hexynyloxy Examples include carbonyl, 4-hexynyloxycarbonyl, 5-hexynyloxycarbonyl and the like.
　「Ｃ３－６シクロアルキルオキシ－カルボニル基」としては、例えば、シクロプロピルオキシカルボニル、シクロブチルオキシカルボニル、シクロペンチルオキシカルボニル、シクロヘキシルオキシカルボニル等が挙げられる。
　「Ｃ３－６シクロアルケニルオキシ－カルボニル基」としては、例えば、２－シクロプロペン－１－イルオキシカルボニル、２－シクロブテン－１－イルオキシカルボニル、２－シクロペンテン－１－イルオキシカルボニル、３－シクロペンテン－１－イルオキシカルボニル、２－シクロヘキセン－１－イルオキシカルボニル、３－シクロヘキセン－１－イルオキシカルボニル等が挙げられる。 Examples of the “C 3-6 cycloalkyloxy-carbonyl group” include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like.
Examples of the “C 3-6 cycloalkenyloxy-carbonyl group” include 2-cyclopropen-1-yloxycarbonyl, 2-cyclobuten-1-yloxycarbonyl, 2-cyclopenten-1-yloxycarbonyl, 3- Examples include cyclopenten-1-yloxycarbonyl, 2-cyclohexen-1-yloxycarbonyl, 3-cyclohexen-1-yloxycarbonyl, and the like.
　「Ｃ６－１０アリールオキシ－カルボニル基」としては、例えば、フェノキシカルボニル、１－ナフチルオキシカルボニル、２－ナフチルオキシカルボニル等が挙げられる。
　「複素環－オキシカルボニル基」としては、例えば、(1)５または６員の単環式芳香族複素環（例、フラン、チオフェン、ピロール、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、イミダゾール、ピリジン、ピラゾール等）－オキシカルボニル、(2)８～１２員の縮合芳香族複素環（例、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、イソベンゾチオフェン、インドール、イソインドール、１Ｈ－インダゾール、ベンゾイミダゾール、ベンズオキサゾール等）－オキシカルボニル、(3)３～６員の非芳香族複素環（例、オキシラン、アゼチジン、オキセタン、ピロリジン、テトラヒドロフラン、チオラン、ピペリジン等）－オキシカルボニル等が挙げられる。 Examples of the “C 6-10 aryloxy-carbonyl group” include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
Examples of the “heterocycle-oxycarbonyl group” include (1) a 5- or 6-membered monocyclic aromatic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyridine). , Pyrazole, etc.)-Oxycarbonyl, (2) 8- to 12-membered condensed aromatic heterocycle (eg, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole) Etc.)-Oxycarbonyl, (3) 3-6 membered non-aromatic heterocycle (eg, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, thiolane, piperidine, etc.)-Oxycarbonyl and the like.
　Ｒ１で示される「アシル基」としては、好ましくは、ホルミル基、カルボキシル基である。 The “acyl group” represented by R 1 is preferably a formyl group or a carboxyl group.
　Ｒ１としては、好ましくは、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、アシル基であり、より好ましくは、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、ホルミル基、カルボキシル基であり、さらに好ましくは、
(i)（1）Ｃ１－６アルキル基（好ましくは、メチル）でモノまたはジ置換されていてもよいアミノ基（好ましくは、ジメチルアミノ）、
　 （2）ヒドロキシ基、
　 （3）Ｃ１－６アルコキシ基（好ましくは、メトキシ）、および
　 （4）Ｃ３－１０シクロアルキル基（好ましくは、シクロプロピル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル）；
(ii) Ｃ３－６シクロアルキル基（好ましくは、シクロプロピル）；
(iii) Ｃ６－１４アリール基（好ましくは、フェニル）；
(iv)（1）Ｃ１－６アルコキシ－カルボニル基（好ましくは、ｔｅｒｔ－ブトキシカルボニル）、および
　　（2）Ｃ１－６アルキル基（好ましくは、メチル）
から選ばれる１または２個の置換基で置換されていてもよいアミノ基；
(v) ホルミル基；または
(vi) カルボキシル基であり、特に好ましくは、Ｃ３－１０シクロアルキル基（特に、シクロプロピル）またはヒドロキシ基で置換されていてもよいＣ１－６アルキル基（特に、メチル、エチル）、Ｃ３－６シクロアルキル基（特に、シクロプロピル）、またはＣ６－１４アリール基（特に、フェニル）である。 R 1 is preferably a C 1-6 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a substituent. A C 6-14 aryl group, an amino group which may have a substituent, and an acyl group, more preferably a C 1-6 alkyl group which may have a substituent, and a substituent. An optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-14 aryl group, an optionally substituted amino group, a formyl group, and a carboxyl group, and more preferably ,
(i) (1) an amino group (preferably dimethylamino) optionally mono- or disubstituted with a C 1-6 alkyl group (preferably methyl),
(2) hydroxy group,
(3) C 1-6 alkoxy group (preferably methoxy), and (4) C 3-10 cycloalkyl group (preferably cyclopropyl)
A C 1-6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 substituents selected from:
(ii) a C 3-6 cycloalkyl group (preferably cyclopropyl);
(iii) a C 6-14 aryl group (preferably phenyl);
(iv) (1) C 1-6 alkoxy-carbonyl group (preferably tert-butoxycarbonyl), and (2) C 1-6 alkyl group (preferably methyl)
An amino group optionally substituted by 1 or 2 substituents selected from:
(v) a formyl group; or
(vi) a carboxyl group, particularly preferably a C 3-10 cycloalkyl group (particularly cyclopropyl) or a C 1-6 alkyl group (particularly methyl, ethyl) optionally substituted by a hydroxy group, C A 3-6 cycloalkyl group (especially cyclopropyl) or a C 6-14 aryl group (especially phenyl).
　本発明の１態様では、Ｒ１は、好ましくは、ハロゲン原子、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、シアノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示し；Ｒ３は水素原子またはＣ１－６アルキル基を示す。 In one embodiment of the present invention, R 1 is preferably a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, a substituted group. An optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-14 aryl group, a substituent An amino group, a cyano group, or —S (O) m Ra, which may have; m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group; R 3 represents a hydrogen atom or a C 1-6 alkyl group.
　あるいは、本発明の別の態様では、Ｒ１は、好ましくは、ハロゲン原子、アシル基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示し；Ｒ３は水素原子またはＣ１－６アルキル基を示す。 Alternatively, in another aspect of the present invention, R 1 is preferably a halogen atom, an acyl group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2. A -6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6- 14 represents an aryl group, an optionally substituted amino group, or —S (O) m Ra; m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group R 3 represents a hydrogen atom or a C 1-6 alkyl group.
　あるいは、本発明のさらに別の態様では、Ｒ１は、好ましくは、ハロゲン原子、アシル基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、シアノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示し；Ｒ３は水素原子またはＣ１－６アルキル基を示す。 Alternatively, in still another aspect of the present invention, R 1 is preferably a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, or a C which may have a substituent. 2-6 alkenyl group, C 2-6 alkynyl group which may have a substituent, C 3-6 cycloalkyl group which may have a substituent, C 6 which may have a substituent -14 represents an aryl group, a cyano group, or -S (O) m Ra; m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group; R 3 represents a hydrogen atom Or a C 1-6 alkyl group.
　Ｒ３で示される「Ｃ１－６アルキル基」としては、メチルが好ましい。
　Ｒ３としては、好ましくは、水素原子またはメチルである。 As the “C 1-6 alkyl group” for R 3 , methyl is preferable.
R 3 is preferably a hydrogen atom or methyl.
　Ｒ２は、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよい非芳香族複素環基、または置換基を有していてもよいＣ３－６シクロアルキル基を示す。 R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent. 6 represents an alkyl group, a non-aromatic heterocyclic group which may have a substituent, or a C 3-6 cycloalkyl group which may have a substituent.
　Ｒ２で示される「置換基を有していてもよいアミノ基」、「置換基を有していてもよいＣ１－６アルキル基」および「置換基を有していてもよいＣ３－６シクロアルキル基」としては、前記したＲ１で示される「置換基を有していてもよいアミノ基」、「置換基を有していてもよいＣ１－６アルキル基」および「置換基を有していてもよいＣ３－６シクロアルキル基」と同様のものが挙げられる。 “An amino group optionally having substituent (s)” represented by R 2 , “C 1-6 alkyl group optionally having substituent (s)” and “C 3− optionally having substituent (s)” As the “6 cycloalkyl group”, the “optionally substituted amino group”, “optionally substituted C 1-6 alkyl group” and “substituent” represented by R 1 described above And the same as the “C 3-6 cycloalkyl group optionally having”.
　Ｒ２で示される「置換基を有していてもよいＣ１－６アルコキシ基」の「Ｃ１－６アルコキシ基」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記したＲ１で示される「置換基を有していてもよいＣ１－６アルキル基」の「Ｃ１－６アルキル基」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本発明の１態様では、Ｒ２で示される「置換基を有していてもよいＣ１－６アルコキシ基」は、好ましくは「Ｃ１－３アルコキシ基」である。 The “C 1-6 alkoxy group” of the “optionally substituted C 1-6 alkoxy group” represented by R 2 has 1 to 5 (preferably 1 to 3, preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
Such substituents, "C 1-6 alkyl group" optionally has substituent of the "optionally substituted C 1-6 alkyl group" represented by the R 1 And the groups exemplified as above. When there are two or more substituents, each substituent may be the same or different.
In one embodiment of the present invention, the “optionally substituted C 1-6 alkoxy group” for R 2 is preferably a “C 1-3 alkoxy group”.
　Ｒ２で示される「置換基を有していてもよい非芳香族複素環基」の「非芳香族複素環基」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記した「置換基を有していてもよい６～１０員芳香族炭化水素環」の「６～１０員芳香族炭化水素環」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 The “non-aromatic heterocyclic group” of the “non-aromatic heterocyclic group optionally having substituent (s)” represented by R 2 has 1 to 5 (preferably 1 to 3, preferably 1 to 3, More preferably, it may have 1 or 2 substituents.
As such a substituent, the “optionally substituted 6- to 10-membered aromatic hydrocarbon ring” in the “6-to 10-membered aromatic hydrocarbon ring” described above may be substituted. The group illustrated as a group is mentioned. When there are two or more substituents, each substituent may be the same or different.
　Ｒ２としては、好ましくは、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、Ｃ１－６アルコキシ基（好ましくは、メトキシ、エトキシ）、置換基を有していてもよいＣ１－６アルキル基（好ましくは、メチル、エチル）、置換基を有していてもよい非芳香族複素環基（好ましくは、ピペラジニル、３－オキソピペラジニル）、またはＣ３－６シクロアルキル基（好ましくは、シクロプロピル）であり、より好ましくは、
(i) 水素原子；
(ii) ヒドロキシ基；
(iii) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基；
(iv) Ｃ１－６アルコキシ基（好ましくは、メトキシ、エトキシ）；
(v)（1）Ｃ１－６アルキル基（好ましくは、メチル）またはＣ１－６アルキル－カルボニル基（好ましくは、メチルカルボニル）でモノまたはジ置換されていてもよいアミノ基（好ましくは、ジメチルアミノ、アセチルアミノ）、
　 （2）Ｃ１－６アルキル基（好ましくは、メチル）でモノまたはジ置換されていてもよいカルバモイル基（好ましくは、カルバモイル、メチルカルバモイル、ジメチルカルバモイル）、
　 （3）ヒドロキシ基、
　 （4）Ｃ１－６アルコキシ－カルボニル基（好ましくは、エトキシカルボニル）、
　 （5）Ｃ１－６アルキルスルファニル基（好ましくは、メチルスルファニル）、
　 （6）Ｃ１－６アルキルスルフィニル基（好ましくは、メチルスルフィニル）、
　 （7）Ｃ１－６アルキルスルホニル基（好ましくは、メチルスルホニル）、
　 （8）芳香族複素環基（好ましくは、１，２，４－トリアゾール－１－イル）、および
　 （9）非芳香族複素環基（好ましくは、２－オキソイミダゾリジニル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル、プロピル、ブチル、イソブチル）；
(vi)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル）、および
　　（2）Ｃ１－６アルキル－カルボニル基（好ましくは、メチルカルボニル）
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基（好ましくは、ピペラジニル、３－オキソピペラジニル）；または
(vii) Ｃ３－６シクロアルキル基（好ましくは、シクロプロピル）
である。 R 2 is preferably a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group (preferably methoxy, ethoxy), or an optionally substituted group. A C 1-6 alkyl group (preferably methyl, ethyl), an optionally substituted non-aromatic heterocyclic group (preferably piperazinyl, 3-oxopiperazinyl), or C 3-6 cyclo An alkyl group (preferably cyclopropyl), more preferably
(i) a hydrogen atom;
(ii) a hydroxy group;
(iii) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group;
(iv) a C 1-6 alkoxy group (preferably methoxy, ethoxy);
(v) (1) an amino group (preferably, mono- or di-substituted with a C 1-6 alkyl group (preferably methyl) or a C 1-6 alkyl-carbonyl group (preferably methylcarbonyl) Dimethylamino, acetylamino),
(2) a carbamoyl group (preferably carbamoyl, methylcarbamoyl, dimethylcarbamoyl) optionally mono- or disubstituted with a C 1-6 alkyl group (preferably methyl),
(3) a hydroxy group,
(4) a C 1-6 alkoxy-carbonyl group (preferably ethoxycarbonyl),
(5) a C 1-6 alkylsulfanyl group (preferably methylsulfanyl),
(6) a C 1-6 alkylsulfinyl group (preferably methylsulfinyl),
(7) a C 1-6 alkylsulfonyl group (preferably methylsulfonyl),
(8) an aromatic heterocyclic group (preferably 1,2,4-triazol-1-yl), and (9) a non-aromatic heterocyclic group (preferably 2-oxoimidazolidinyl)
A C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (preferably methyl, ethyl, propyl, butyl, isobutyl);
(vi) (1) a C 1-6 alkyl group optionally substituted with a hydroxy group (preferably methyl, ethyl), and (2) a C 1-6 alkyl-carbonyl group (preferably methylcarbonyl)
A non-aromatic heterocyclic group (preferably piperazinyl, 3-oxopiperazinyl) optionally substituted by 1 to 3 substituents selected from
(vii) C 3-6 cycloalkyl group (preferably cyclopropyl)
It is.
　Ｒ２として、特に好ましくは、
(i)ヒドロキシ基、
(ii)アミノ基、
(iii)Ｃ１－６アルコキシ基（特に、メトキシ、エトキシ）、
(iv)（1）Ｃ１－６アルキル基（特に、メチル）またはＣ１－６アルキル－カルボニル基（特に、メチルカルボニル）でモノまたはジ置換されたアミノ基（特に、ジメチルアミノ、アセチルアミノ）、
　　（2）Ｃ１－６アルキル基（特に、メチル）でモノまたはジ置換されていてもよいカルバモイル基（特に、カルバモイル、メチルカルバモイル、ジメチルカルバモイル）、
　　（3）ヒドロキシ基、
　　（4）Ｃ１－６アルキルスルファニル基（特に、メチルスルファニル）、
　　（5）Ｃ１－６アルキルスルフィニル基（特に、メチルスルフィニル）、
　　（6）Ｃ１－６アルキルスルホニル基（特に、メチルスルホニル）、
　　（7）芳香族複素環基（特に、１，２，４－トリアゾール－１－イル）、および
　　（8）非芳香族複素環基（特に、２－オキソイミダゾリジニル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（特に、メチル、エチル、プロピル、ブチル、イソブチル）、
(v)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基（特に、メチル、エチル）、および
　 （2）Ｃ１－６アルキル－カルボニル基（特に、メチルカルボニル）
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基（特に、ピペラジニル、３－オキソピペラジニル）、または
(vi)Ｃ３－６シクロアルキル基（特に、シクロプロピル）である。 R 2 is particularly preferably
(i) a hydroxy group,
(ii) an amino group,
(iii) a C 1-6 alkoxy group (particularly methoxy, ethoxy),
(iv) (1) an amino group mono- or di-substituted with a C 1-6 alkyl group (especially methyl) or a C 1-6 alkyl-carbonyl group (especially methylcarbonyl) (especially dimethylamino, acetylamino) ,
(2) a carbamoyl group (particularly carbamoyl, methylcarbamoyl, dimethylcarbamoyl) optionally mono- or disubstituted with a C 1-6 alkyl group (particularly methyl),
(3) a hydroxy group,
(4) a C 1-6 alkylsulfanyl group (particularly methylsulfanyl),
(5) a C 1-6 alkylsulfinyl group (particularly methylsulfinyl),
(6) C 1-6 alkylsulfonyl group (particularly methylsulfonyl),
(7) aromatic heterocyclic group (especially 1,2,4-triazol-1-yl), and (8) non-aromatic heterocyclic group (especially 2-oxoimidazolidinyl)
A C 1-6 alkyl group (particularly methyl, ethyl, propyl, butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from
(v) (1) a C 1-6 alkyl group (especially methyl, ethyl) optionally substituted with a hydroxy group, and (2) a C 1-6 alkyl-carbonyl group (especially methylcarbonyl).
A non-aromatic heterocyclic group (especially piperazinyl, 3-oxopiperazinyl) optionally substituted with 1 to 3 substituents selected from
(vi) a C 3-6 cycloalkyl group (particularly cyclopropyl).
　また、本発明の別の態様では、Ｒ２は、好ましくは、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよい非芳香族複素環基、または置換基を有していてもよいＣ３－６シクロアルキル基を示す。 In another embodiment of the present invention, R 2 is preferably a hydrogen atom, a hydroxy group, an amino group which may have a substituent, or a C 1-6 alkyl group which may have a substituent. Represents a non-aromatic heterocyclic group which may have a substituent, or a C 3-6 cycloalkyl group which may have a substituent.
　Ｌ１は、－Ｏ－、－ＣＯ－、置換基を有していてもよいＣ１－６アルキレン、または置換基を有していてもよいＣ３－６シクロアルキレンを示す。 L 1 represents —O—, —CO—, C 1-6 alkylene which may have a substituent, or C 3-6 cycloalkylene which may have a substituent.
　Ｌ１で示される「置換基を有していてもよいＣ１－６アルキレン」の「Ｃ１－６アルキレン」としては、メチレンが好ましい。
　該「Ｃ１－６アルキレン」は、置換可能な位置に１～５個（好ましくは１～３個、より好ましくは１または２個）の置換基を有していてもよい。
　このような置換基としては、前記したＲ１で示される「置換基を有していてもよいＣ１－６アルキル基」の「Ｃ１－６アルキル基」が有していてもよい置換基として例示した基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 Represented by L 1 in the "optionally substituted C 1-6 alkylene" as the "C 1-6 alkylene", methylene is preferable.
The “C 1-6 alkylene” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) substituents at substitutable positions.
Such substituents, "C 1-6 alkyl group" optionally has substituent of the "optionally substituted C 1-6 alkyl group" represented by the R 1 And the groups exemplified as above. When there are two or more substituents, each substituent may be the same or different.
　Ｌ１としては、好ましくは、－ＣＯ－、置換基を有していてもよいＣ１－６アルキレン（好ましくは、メチレン）であり、より好ましくは、－ＣＯ－、ヒドロキシ基で置換されていてもよいＣ１－６アルキレン（好ましくは、メチレン）であり、特に好ましくは、メチレンである。 L 1 is preferably —CO— or an optionally substituted C 1-6 alkylene (preferably methylene), more preferably —CO— or a hydroxy group. Or a C 1-6 alkylene (preferably methylene), particularly preferably methylene.
　Ｌ２は、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＹＣＯ－または－ＣＯＮＨ－（式中、Ｙは、置換基を有していてもよいＣ１－３アルキレンを示す。）を示す。
　Ｙで示される「置換基を有していてもよいＣ１－６アルキレン」としては、前記したＬ１で示される「置換基を有していてもよいＣ１－６アルキレン」と同様のものが挙げられる。 L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH— (wherein Y represents an optionally substituted C 1-3 alkylene). .
As "a C 1-6 alkylene optionally having substituent" represented by Y, those similar to the "optionally substituted C 1-6 alkylene" represented by L 1 described above Is mentioned.
　Ｌ２としては、好ましくは、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＹＣＯ－、－ＣＯＮＨ－（式中、Ｙは、Ｃ１－３アルキレンを示す。）であり、より好ましくは、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＣＯＮＨ－（式中、Ｙは、Ｃ１－３アルキレンを示す。）であり、さらに好ましくは、－ＣＯ－、－ＣＯ－ＣＨ２－、－ＮＨＣＯ－、－ＣＯＮＨ－であり、特に好ましくは、－ＣＯ－または－ＮＨＣＯ－である。 L 2 is preferably —CO—, —COY—, —NHCO—, —YCO—, —CONH— (wherein Y represents C 1-3 alkylene), and more preferably —CO—, —COY—, —NHCO—, —CONH— (wherein Y represents C 1-3 alkylene), and more preferably —CO—, —CO—CH 2 —, — NHCO— and —CONH— are particularly preferred, —CO— and —NHCO—.
　Ｌ３は、－（ＣＨ２）ｎ－（ｎは０または１を示す。）を示す。
　すなわち、Ｌ３は、結合手またはメチレン基を示す。 L 3 represents — (CH 2 ) n — (n represents 0 or 1).
That is, L 3 represents a bond or a methylene group.
　式（Ｉ）で表される化合物としては、好ましくは、
　環Ａが、置換基を有していてもよい６～１０員芳香族炭化水素環であり；
　環Ｂが、
（１）さらに置換基を有していてもよい６～１０員芳香族炭化水素環（好ましくは、ベンゼン）、
（２）さらに置換基を有していてもよい５もしくは６員芳香族複素環（好ましくは、ピリジン、チアゾール、ピリミジン）、
（３）さらに置換基を有していてもよい５もしくは６員非芳香族複素環（好ましくは、ピペリジン、テトラヒドロピリジン）、
（４）さらに置換基を有していてもよい、ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環（好ましくは、ベンゾフラン）、または
（５）さらに置換基を有していてもよい、ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環（好ましくは、２，３－ジヒドロベンゾフラン）であり；
　Ｒ１が、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、またはアシル基であり；
　Ｒ２が、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、Ｃ１－６アルコキシ基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよい非芳香族複素環基、またはＣ３－６シクロアルキル基であり；
　Ｒ３が、水素原子またはＣ１－６アルキル基であり；
　Ｌ１が、－ＣＯ－、または置換基を有していてもよいＣ１－６アルキレン（好ましくは、メチレン）であり；
　Ｌ２が、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＹＣＯ－、または－ＣＯＮＨ－（式中、Ｙは、Ｃ１－３アルキレンを示す。）であり；
　Ｌ３が、－（ＣＨ２）ｎ－（ｎは０または１を示す。）である化合物である。 As the compound represented by the formula (I), preferably,
Ring A is an optionally substituted 6 to 10 membered aromatic hydrocarbon ring;
Ring B is
(1) a 6 to 10-membered aromatic hydrocarbon ring (preferably benzene) which may further have a substituent,
(2) a 5- or 6-membered aromatic heterocyclic ring (preferably pyridine, thiazole, pyrimidine) which may further have a substituent,
(3) a 5- or 6-membered non-aromatic heterocyclic ring (preferably piperidine, tetrahydropyridine) which may further have a substituent,
(4) A bicyclic condensed ring (preferably benzofuran) in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring may be further condensed, or (5) a substituent further A bicyclic condensed ring (preferably 2,3-dihydrobenzofuran) fused with a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring;
R 1 may have a C 1-6 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a C 6-14 which may have a substituent. An aryl group, an amino group which may have a substituent, or an acyl group;
R 2 has a hydrogen atom, a hydroxy group, an optionally substituted amino group, a C 1-6 alkoxy group, an optionally substituted C 1-6 alkyl group, or a substituent. An optionally non-aromatic heterocyclic group, or a C 3-6 cycloalkyl group;
R 3 is a hydrogen atom or a C 1-6 alkyl group;
L 1 is —CO— or an optionally substituted C 1-6 alkylene (preferably methylene);
L 2 is —CO—, —COY—, —NHCO—, —YCO—, or —CONH— (wherein Y represents C 1-3 alkylene);
A compound in which L 3 is — (CH 2 ) n — (n represents 0 or 1).
　より好ましくは、
　環Ａが、置換基を有していてもよいベンゼンであり；
　環Ｂが、
（1）Ｃ３－１０シクロアルキル基（好ましくは、シクロプロピル）、
（2）Ｃ１－６アルコキシ基（好ましくは、メトキシ、イソプロポキシ）、
（3）ハロゲン原子（好ましくは、フッ素原子、塩素原子）、および
（4） (a) ハロゲン原子（好ましくは、フッ素原子）、
　　　(b) ヒドロキシ基、
　　　(c) シアノ基、および
　　　(d) トリ（Ｃ１－６アルキル）シリルオキシ基（好ましくは、ｔｅｒｔ－ブチルジメチルシリルオキシ）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル、イソプロピル）、
（5）ヒドロキシ基、
（6）１～３個のハロゲン原子（好ましくは、フッ素原子）で置換されていてもよいＣ１－６アルキルスルホニルオキシ基（好ましくは、メチルスルホニルオキシ）、および
（7）Ｃ１－６アルキル基（好ましくは、メチル）でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、
（２）５もしくは６員芳香族複素環（好ましくは、ピリジン、チアゾール、ピリミジン）、
（３）５もしくは６員非芳香族複素環（好ましくは、ピペリジン、テトラヒドロピリジン）、
（４）ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環（好ましくは、ベンゾフラン）、または
（５）ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環（好ましくは、２，３－ジヒドロベンゾフラン）であり；
　Ｒ１が、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、ホルミル基、またはカルボキシル基であり；
　Ｒ２が、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、Ｃ１－６アルコキシ基（好ましくは、メトキシ、エトキシ）、置換基を有していてもよいＣ１－６アルキル基（好ましくは、メチル、エチル）、置換基を有していてもよい非芳香族複素環基（好ましくは、ピペラジニル、３－オキソピペラジニル）、またはＣ３－６シクロアルキル基（好ましくは、シクロプロピル）であり；
　Ｒ３が、水素原子またはＣ１－６アルキル基であり；
　Ｌ１が、－ＣＯ－、またはヒドロキシ基で置換されていてもよいＣ１－６アルキレン（好ましくは、メチレン）であり；
　Ｌ２が、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、または－ＣＯＮＨ－（式中、Ｙは、Ｃ１－３アルキレンを示す。）であり；
　Ｌ３が、－（ＣＨ２）ｎ－（ｎは０または１を示す。）である化合物である。 More preferably,
Ring A is an optionally substituted benzene;
Ring B is
(1) a C 3-10 cycloalkyl group (preferably cyclopropyl),
(2) a C 1-6 alkoxy group (preferably methoxy, isopropoxy),
(3) a halogen atom (preferably a fluorine atom, a chlorine atom), and (4) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) a cyano group, and (d) a tri (C 1-6 alkyl) silyloxy group (preferably tert-butyldimethylsilyloxy)
A C 1-6 alkyl group (preferably methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from:
(5) a hydroxy group,
(6) a C 1-6 alkylsulfonyloxy group (preferably methylsulfonyloxy) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom), and (7) C 1-6 alkyl Each of which may be further substituted with 1 to 3 substituents selected from an amino group which may be mono- or di-substituted with a group (preferably methyl),
(1) benzene,
(2) a 5- or 6-membered aromatic heterocycle (preferably pyridine, thiazole, pyrimidine),
(3) a 5- or 6-membered non-aromatic heterocyclic ring (preferably piperidine, tetrahydropyridine),
(4) a bicyclic condensed ring (preferably benzofuran) in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring are condensed, or (5) a bicyclic ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed. A fused ring (preferably 2,3-dihydrobenzofuran);
R 1 may have a C 1-6 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a C 6-14 which may have a substituent. An aryl group, an amino group optionally having a substituent, a formyl group, or a carboxyl group;
R 2 is a hydrogen atom, a hydroxy group, an optionally substituted amino group, a C 1-6 alkoxy group (preferably methoxy, ethoxy), an optionally substituted C 1-6 An alkyl group (preferably methyl, ethyl), an optionally substituted non-aromatic heterocyclic group (preferably piperazinyl, 3-oxopiperazinyl), or a C 3-6 cycloalkyl group (preferably Is cyclopropyl);
R 3 is a hydrogen atom or a C 1-6 alkyl group;
L 1 is —CO— or C 1-6 alkylene (preferably methylene) optionally substituted with a hydroxy group;
L 2 is —CO—, —COY—, —NHCO—, or —CONH— (wherein Y represents C 1-3 alkylene);
A compound in which L 3 is — (CH 2 ) n — (n represents 0 or 1).
　さらに好ましくは、
　環Ａが、
(i) ハロゲン原子（好ましくは、フッ素原子、塩素原子、臭素原子）、
(ii) Ｃ１－６アルコキシ－カルボニル基（好ましくは、メトキシカルボニル）または１～３個のハロゲン原子（好ましくは、フッ素原子）で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル）、
(iii) Ｃ３－１０シクロアルキル基（好ましくは、シクロプロピル）、
(iv) ニトロ基、
(v) アミノ基、
(vi) Ｃ１－６アルキルスルファニル基（好ましくは、、メチルスルファニル）、
(vii) Ｃ１－６アルキルスルフィニル基（好ましくは、メチルスルフィニル）、および
(viii) Ｃ１－６アルキルスルホニル基（好ましくは、メチルスルホニル）
から選ばれる１～３個の置換基で置換されていてもよいベンゼンであり；
　環Ｂが、
（1）Ｃ３－１０シクロアルキル基（好ましくは、シクロプロピル）；
（2）Ｃ１－６アルコキシ基（好ましくは、メトキシ、イソプロポキシ）；
（3）ハロゲン原子（好ましくは、フッ素原子、塩素原子）；および
（4） (a) ハロゲン原子（好ましくは、フッ素原子）、
　　　(b) ヒドロキシ基、
　　　(c) シアノ基、および
　　　(d) トリ（Ｃ１－６アルキル）シリルオキシ基（好ましくは、ｔｅｒｔ－ブチルジメチルシリルオキシ）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル、イソプロピル）、および
（5）Ｃ１－６アルキル基（好ましくは、メチル）でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、
（２）５もしくは６員芳香族複素環（好ましくは、ピリジン、チアゾール、ピリミジン）、
（３）５もしくは６員非芳香族複素環（好ましくは、ピペリジン、テトラヒドロピリジン）、
（４）ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環（好ましくは、ベンゾフラン）、または
（５）ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環（好ましくは、２，３－ジヒドロベンゾフラン）であり；
　Ｒ１が、
(i)（1）Ｃ１－６アルキル基（好ましくは、メチル）でモノまたはジ置換されていてもよいアミノ基（好ましくは、ジメチルアミノ）、
　 （2）ヒドロキシ基、
　 （3）Ｃ１－６アルコキシ基（好ましくは、メトキシ）、および
　 （4）Ｃ３－１０シクロアルキル基（好ましくは、シクロプロピル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル）、
(ii) Ｃ３－６シクロアルキル基（好ましくは、シクロプロピル）、
(iii) Ｃ６－１４アリール基（好ましくは、フェニル）、
(iv)（1）Ｃ１－６アルコキシ－カルボニル基（好ましくは、ｔｅｒｔ－ブトキシカルボニル）、および
　　 （2）Ｃ１－６アルキル基（好ましくは、メチル）
から選ばれる１または２個の置換基で置換されていてもよいアミノ基、
(v) ホルミル基、または
(vi) カルボキシル基であり；
　Ｒ２が、
(i) 水素原子、
(ii) ヒドロキシ基、
(iii) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
(iv) Ｃ１－６アルコキシ基（好ましくは、メトキシ、エトキシ）、
(v)（1）Ｃ１－６アルキル基（好ましくは、メチル）またはＣ１－６アルキル－カルボニル基（好ましくは、メチルカルボニル）でモノまたはジ置換されていてもよいアミノ基（好ましくは、ジメチルアミノ、アセチルアミノ）、
　 （2）Ｃ１－６アルキル基（好ましくは、メチル）でモノまたはジ置換されていてもよいカルバモイル基（好ましくは、カルバモイル、メチルカルバモイル、ジメチルカルバモイル）、
　 （3）ヒドロキシ基、
　 （4）Ｃ１－６アルコキシ－カルボニル基（好ましくは、エトキシカルボニル）、
　 （5）Ｃ１－６アルキルスルファニル基（好ましくは、メチルスルファニル）、
　 （6）Ｃ１－６アルキルスルフィニル基（好ましくは、メチルスルフィニル）、
　 （7）Ｃ１－６アルキルスルホニル基（好ましくは、メチルスルホニル）、
　 （8）芳香族複素環基（好ましくは、１，２，４－トリアゾール－１－イル）、および
　 （9）非芳香族複素環基（好ましくは、２－オキソイミダゾリジニル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル、プロピル、ブチル、イソブチル）、
(vi)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル、エチル）、および
　 （2）Ｃ１－６アルキル－カルボニル基（好ましくは、メチルカルボニル）
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基（好ましくは、ピペラジニル、３－オキソピペラジニル）、または
(vii) Ｃ３－６シクロアルキル基（好ましくは、シクロプロピル）であり；
　Ｒ３が、水素原子またはＣ１－６アルキル基（好ましくは、メチル）であり；
　Ｌ１が、－ＣＯ－、またはヒドロキシ基で置換されていてもよいＣ１－６アルキレン（好ましくは、メチレン）であり；
　Ｌ２が、－ＣＯ－、－ＣＯ－ＣＨ２－、－ＮＨＣＯ－、または－ＣＯＮＨ－であり；
　Ｌ３が、結合手またはメチレン基である化合物である。 More preferably,
Ring A is
(i) a halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom),
(ii) C 1-6 alkoxy - carbonyl group (preferably, methoxycarbonyl) or 1 to 3 halogen atoms (preferably, fluorine atoms) are also C 1-6 alkyl group (preferably optionally substituted by, Methyl),
(iii) a C 3-10 cycloalkyl group (preferably cyclopropyl),
(iv) a nitro group,
(v) an amino group,
(vi) a C 1-6 alkylsulfanyl group (preferably, methylsulfanyl),
(vii) a C 1-6 alkylsulfinyl group (preferably methylsulfinyl), and
(viii) C 1-6 alkylsulfonyl group (preferably methylsulfonyl)
Benzene optionally substituted with 1 to 3 substituents selected from:
Ring B is
(1) a C 3-10 cycloalkyl group (preferably cyclopropyl);
(2) a C 1-6 alkoxy group (preferably methoxy, isopropoxy);
(3) a halogen atom (preferably a fluorine atom, a chlorine atom); and (4) (a) a halogen atom (preferably a fluorine atom),
(b) a hydroxy group,
(c) a cyano group, and (d) a tri (C 1-6 alkyl) silyloxy group (preferably tert-butyldimethylsilyloxy)
A C 1-6 alkyl group (preferably methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from: (5) a C 1-6 alkyl group (preferably methyl) Each of which may be further substituted with 1 to 3 substituents selected from amino groups that may be mono- or di-substituted.
(1) benzene,
(2) a 5- or 6-membered aromatic heterocycle (preferably pyridine, thiazole, pyrimidine),
(3) a 5- or 6-membered non-aromatic heterocyclic ring (preferably piperidine, tetrahydropyridine),
(4) a bicyclic condensed ring (preferably benzofuran) in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring are condensed, or (5) a bicyclic ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed. A fused ring (preferably 2,3-dihydrobenzofuran);
R 1 is
(i) (1) an amino group (preferably dimethylamino) optionally mono- or disubstituted with a C 1-6 alkyl group (preferably methyl),
(2) hydroxy group,
(3) C 1-6 alkoxy group (preferably methoxy), and (4) C 3-10 cycloalkyl group (preferably cyclopropyl)
A C 1-6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 substituents selected from:
(ii) a C 3-6 cycloalkyl group (preferably cyclopropyl),
(iii) a C 6-14 aryl group (preferably phenyl),
(iv) (1) C 1-6 alkoxy-carbonyl group (preferably tert-butoxycarbonyl), and (2) C 1-6 alkyl group (preferably methyl)
An amino group optionally substituted by 1 or 2 substituents selected from:
(v) formyl group, or
(vi) is a carboxyl group;
R 2 is
(i) a hydrogen atom,
(ii) a hydroxy group,
(iii) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group,
(iv) a C 1-6 alkoxy group (preferably methoxy, ethoxy),
(v) (1) an amino group (preferably, mono- or di-substituted with a C 1-6 alkyl group (preferably methyl) or a C 1-6 alkyl-carbonyl group (preferably methylcarbonyl) Dimethylamino, acetylamino),
(2) a carbamoyl group (preferably carbamoyl, methylcarbamoyl, dimethylcarbamoyl) optionally mono- or disubstituted with a C 1-6 alkyl group (preferably methyl),
(3) a hydroxy group,
(4) a C 1-6 alkoxy-carbonyl group (preferably ethoxycarbonyl),
(5) a C 1-6 alkylsulfanyl group (preferably methylsulfanyl),
(6) a C 1-6 alkylsulfinyl group (preferably methylsulfinyl),
(7) a C 1-6 alkylsulfonyl group (preferably methylsulfonyl),
(8) an aromatic heterocyclic group (preferably 1,2,4-triazol-1-yl), and (9) a non-aromatic heterocyclic group (preferably 2-oxoimidazolidinyl)
A C 1-6 alkyl group (preferably methyl, ethyl, propyl, butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from:
(vi) (1) a C 1-6 alkyl group optionally substituted with a hydroxy group (preferably methyl, ethyl), and (2) a C 1-6 alkyl-carbonyl group (preferably methylcarbonyl)
A non-aromatic heterocyclic group (preferably piperazinyl, 3-oxopiperazinyl) optionally substituted by 1 to 3 substituents selected from
(vii) a C 3-6 cycloalkyl group (preferably cyclopropyl);
R 3 is a hydrogen atom or a C 1-6 alkyl group (preferably methyl);
L 1 is —CO— or C 1-6 alkylene (preferably methylene) optionally substituted with a hydroxy group;
L 2 is —CO—, —CO—CH 2 —, —NHCO—, or —CONH—;
A compound in which L 3 is a bond or a methylene group.
　本発明の別の態様において、式（Ｉ）で表される化合物としては、
　環Ａが、
（１）(i) ハロゲン原子、(ii) Ｃ１－６アルコキシ－カルボニル基または１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、(iii) Ｃ３－１０シクロアルキル基、(iv) ニトロ基、(v) アミノ基、(vi) Ｃ１－６アルキルスルファニル基、(vii) Ｃ１－６アルキルスルフィニル基および(viii) Ｃ１－６アルキルスルホニル基から選ばれる１～３個の置換基で置換されていてもよいベンゼン；
（２）(i) ハロゲン原子および(ii) Ｃ１－６アルキル基から選ばれる１～３個の置換基で置換されていてもよい、２－オキソジヒドロインドールまたは３－オキソジヒドロベンゾオキサジン；または
（３）(i) ハロゲン原子および(ii) Ｃ１－６アルキル基から選ばれる１～３個の置換基で置換されていてもよいインダゾール
であり；
　環Ｂが、
（1）Ｃ３－１０シクロアルキル基；
（2）Ｃ１－６アルコキシ基；
（3）ハロゲン原子；
（4）(a) ハロゲン原子、
　　 (b) ヒドロキシ基、
　　 (c) シアノ基、および
　　 (d) トリ（Ｃ１－６アルキル）シリルオキシ基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
（5）ヒドロキシ基；
（6）１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキルスルホニルオキシ基；および
（7）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、
（２）５もしくは６員芳香族複素環、
（３）５もしくは６員非芳香族複素環、
（４）ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環、または
（５）ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環
であり；
　Ｒ１が、
(i)（1）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
　 （2）ヒドロキシ基、
　 （3）Ｃ１－６アルコキシ基、および
　 （4）Ｃ３－１０シクロアルキル基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
(ii) Ｃ３－６シクロアルキル基；
(iii) Ｃ６－１４アリール基；
(iv)（1）Ｃ１－６アルコキシ－カルボニル基、および
　　（2）Ｃ１－６アルキル基
から選ばれる１または２個の置換基で置換されていてもよいアミノ基；
(v) ホルミル基；または
(vi) カルボキシル基
であり；
　Ｒ２が、
(i) 水素原子；
(ii) ヒドロキシ基；
(iii) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基；
(iv) Ｃ１－６アルコキシ基；
(v)（1）Ｃ１－６アルキル基またはＣ１－６アルキル－カルボニル基でモノまたはジ置換されていてもよいアミノ基、
　 （2）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
　 （3）ヒドロキシ基、
　 （4）Ｃ１－６アルコキシ－カルボニル基、
　 （5）Ｃ１－６アルキルスルファニル基、
　 （6）Ｃ１－６アルキルスルフィニル基、
　 （7）Ｃ１－６アルキルスルホニル基、
　 （8）芳香族複素環基、および
　 （9）非芳香族複素環基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
(vi)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基、および
　　（2）Ｃ１－６アルキル－カルボニル基
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基；または
(vii) Ｃ３－６シクロアルキル基
であり；
　Ｒ３が、水素原子またはＣ１－６アルキル基であり；
　Ｌ１がメチレンであり；
　Ｌ２が－ＣＯ－または－ＮＨＣＯ－であり；
　Ｌ３が、－（ＣＨ２）ｎ－（ｎは０または１を示す。）である、
化合物が好ましい。 In another embodiment of the present invention, the compound represented by formula (I) includes:
Ring A is
(1) (i) a halogen atom, (ii) C 1-6 alkoxy - carbonyl group or one to three optionally substituted C 1-6 alkyl group by a halogen atom, (iii) C 3-10 cycloalkyl Selected from alkyl group, (iv) nitro group, (v) amino group, (vi) C 1-6 alkylsulfanyl group, (vii) C 1-6 alkylsulfinyl group and (viii) C 1-6 alkylsulfonyl group Benzene optionally substituted with 1 to 3 substituents;
(2) 2-oxodihydroindole or 3-oxodihydrobenzoxazine optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C 1-6 alkyl group; or (3) (i) an indazole optionally substituted with 1 to 3 substituents selected from a halogen atom and (ii) a C 1-6 alkyl group;
Ring B is
(1) a C 3-10 cycloalkyl group;
(2) a C 1-6 alkoxy group;
(3) a halogen atom;
(4) (a) a halogen atom,
(b) a hydroxy group,
(c) cyano, and (d) tri (C 1-6 alkyl) 1-3 optionally substituted by a substituent a C 1-6 alkyl group selected from silyloxy groups;
(5) hydroxy group;
Selected from and (7) C 1-6 alkyl mono- or di-substituted by amino group which may be group; (6) 1-3 optionally substituted by a halogen atom C 1-6 alkylsulfonyloxy group Each of which may be further substituted with 1 to 3 substituents,
(1) benzene,
(2) 5- or 6-membered aromatic heterocycle,
(3) a 5- or 6-membered non-aromatic heterocycle,
(4) a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring are condensed, or (5) a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed;
R 1 is
(i) (1) an amino group which may be mono- or di-substituted with a C 1-6 alkyl group,
(2) hydroxy group,
(3) C 1-6 alkoxy group, and (4) C 3-10 optionally substituted with 1 to 3 substituents selected from cycloalkyl C 1-6 alkyl group;
(ii) a C 3-6 cycloalkyl group;
(iii) a C 6-14 aryl group;
(iv) an amino group optionally substituted with 1 or 2 substituents selected from (1) a C 1-6 alkoxy-carbonyl group, and (2) a C 1-6 alkyl group;
(v) a formyl group; or
(vi) is a carboxyl group;
R 2 is
(i) a hydrogen atom;
(ii) a hydroxy group;
(iii) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group;
(iv) a C 1-6 alkoxy group;
(v) (1) an amino group which may be mono- or di-substituted with a C 1-6 alkyl group or a C 1-6 alkyl-carbonyl group,
(2) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group,
(3) a hydroxy group,
(4) a C 1-6 alkoxy-carbonyl group,
(5) a C 1-6 alkylsulfanyl group,
(6) a C 1-6 alkylsulfinyl group,
(7) a C 1-6 alkylsulfonyl group,
(8) an aromatic heterocyclic group, and (9) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from non-aromatic heterocyclic groups;
(vi) (1) a C 1-6 alkyl group optionally substituted with a hydroxy group, and (2) a substituent substituted with 1 to 3 substituents selected from a C 1-6 alkyl-carbonyl group A good non-aromatic heterocyclic group; or
(vii) a C 3-6 cycloalkyl group;
R 3 is a hydrogen atom or a C 1-6 alkyl group;
L 1 is methylene;
L 2 is —CO— or —NHCO—;
L 3 is — (CH 2 ) n — (n represents 0 or 1);
Compounds are preferred.
　本発明の別の態様において、式（Ｉ）で表される化合物としては、
　環Ａが、
（１）(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、(ii) Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル）または１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよいＣ１－６アルキル基（例、メチル）、(iii) Ｃ３－１０シクロアルキル基（例、シクロプロピル）、(iv) ニトロ基、(v) アミノ基、(vi) Ｃ１－６アルキルスルファニル基（例、メチルスルファニル）、(vii) Ｃ１－６アルキルスルフィニル基および(viii) Ｃ１－６アルキルスルホニル基（例、メチルスルホニル）から選ばれる１～３個の置換基で置換されていてもよいベンゼン；
（２）Ｃ１－６アルキル基（例、メチル）で置換されていてもよい、２－オキソジヒドロインドールまたは３－オキソジヒドロベンゾオキサジン；または
（３）(i) ハロゲン原子（例、フッ素原子）および(ii) Ｃ１－６アルキル基（例、メチル）から選ばれる１～３個の置換基で置換されていてもよいインダゾール
であり；
　環Ｂが、
（1）Ｃ３－１０シクロアルキル基（例、シクロプロピル）；
（2）ハロゲン原子（例、塩素原子）；
（3）１～３個のハロゲン原子（例、フッ素原子）で置換されていてもよいＣ１－６アルキル基（例、メチル）；
（4）ヒドロキシ基；
（5）１～３個のハロゲン原子（例、フッ素原子）で置換されたＣ１－６アルキルスルホニルオキシ基（例、メチルスルホニルオキシ）；および
（6）Ｃ１－６アルキル基（例、メチル）でモノまたはジ置換されたアミノ基
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、
（２）ピリジン、または
（３）ピリミジン
であり；
　部分構造式： In another embodiment of the present invention, the compound represented by formula (I) includes:
Ring A is
(1) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (ii) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) or 1 to 3 halogen atoms (eg, fluorine) C 1-6 alkyl group (eg, methyl) optionally substituted with (atom), (iii) C 3-10 cycloalkyl group (eg, cyclopropyl), (iv) nitro group, (v) amino group, 1-3 selected from (vi) a C 1-6 alkylsulfanyl group (eg, methylsulfanyl), (vii) a C 1-6 alkylsulfinyl group and (viii) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) Benzene optionally substituted with one substituent;
(2) 2-oxodihydroindole or 3-oxodihydrobenzoxazine optionally substituted with a C 1-6 alkyl group (eg, methyl); or (3) (i) a halogen atom (eg, a fluorine atom) And (ii) indazole optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups (eg, methyl);
Ring B is
(1) a C 3-10 cycloalkyl group (eg, cyclopropyl);
(2) halogen atoms (eg, chlorine atoms);
(3) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom);
(4) hydroxy group;
(5) a C 1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy) substituted with 1 to 3 halogen atoms (eg, fluorine atom); and (6) a C 1-6 alkyl group (eg, methyl). ) May be further substituted with 1 to 3 substituents selected from mono- or di-substituted amino groups,
(1) benzene,
(2) pyridine, or (3) pyrimidine;
Partial structural formula:
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
が、以下の構造を示し； Shows the structure:
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　Ｒ１が、
(i)（1）ヒドロキシ基、および
　 （2）Ｃ３－１０シクロアルキル基（例、シクロプロピル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル）；
(ii) Ｃ３－６シクロアルキル基（例、シクロプロピル）；または
(iii) Ｃ６－１４アリール基（例、フェニル）；
であり；
　Ｒ２が、
(i) 水素原子；
(ii) ヒドロキシ基；
(iii) アミノ基；
(iv) Ｃ１－６アルコキシ基（例、メトキシ、エトキシ）；
(v)（1）Ｃ１－６アルキル基（例、メチル）またはＣ１－６アルキル－カルボニル基（例、メチルカルボニル）でモノまたはジ置換されたアミノ基、
　 （2）Ｃ１－６アルキル基（例、メチル）でモノまたはジ置換されていてもよいカルバモイル基、
　 （3）ヒドロキシ基、
　 （4）Ｃ１－６アルキルスルファニル基（例、メチルスルファニル）、
　 （5）Ｃ１－６アルキルスルフィニル基（例、メチルスルフィニル）、
　 （6）Ｃ１－６アルキルスルホニル基（例、メチルスルホニル）、
　 （7）１，２，４－トリアゾール－１－イル基、および
　 （8）２－オキソイミダゾリジニル基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、ブチル、イソブチル）；
(vi)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル）、および
　　（2）Ｃ１－６アルキル－カルボニル基（例、メチルカルボニル）
から選ばれる１～３個の置換基で置換されていてもよい、ピペラジニル基または３－オキソピペラジニル基；または
(vii) Ｃ３－６シクロアルキル基（例、シクロプロピル）
であり；
　Ｒ３が水素原子またはメチル基であり；
　Ｌ１がメチレンであり；
　Ｌ２が－ＣＯ－または－ＮＨＣＯ－であり；
　Ｌ３が結合またはメチレン基である、
化合物が好ましい。 R 1 is
(i) (1) a hydroxy group, and (2) a C 3-10 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted by 1 to 3 substituents selected from:
(ii) a C 3-6 cycloalkyl group (eg, cyclopropyl); or
(iii) a C 6-14 aryl group (eg, phenyl);
Is;
R 2 is
(i) a hydrogen atom;
(ii) a hydroxy group;
(iii) an amino group;
(iv) a C 1-6 alkoxy group (eg, methoxy, ethoxy);
(v) (1) an amino group mono- or di-substituted with a C 1-6 alkyl group (eg, methyl) or a C 1-6 alkyl-carbonyl group (eg, methylcarbonyl),
(2) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group (eg, methyl),
(3) a hydroxy group,
(4) C 1-6 alkylsulfanyl group (eg, methylsulfanyl),
(5) a C 1-6 alkylsulfinyl group (eg, methylsulfinyl),
(6) C 1-6 alkylsulfonyl group (eg, methylsulfonyl),
(7) a 1,2,4-triazol-1-yl group, and (8) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 2-oxoimidazolidinyl group (Eg, methyl, ethyl, propyl, butyl, isobutyl);
(vi) (1) a C 1-6 alkyl group optionally substituted with a hydroxy group (eg, methyl, ethyl), and (2) a C 1-6 alkyl-carbonyl group (eg, methylcarbonyl)
A piperazinyl group or a 3-oxopiperazinyl group optionally substituted by 1 to 3 substituents selected from:
(vii) C 3-6 cycloalkyl group (eg, cyclopropyl)
Is;
R 3 is a hydrogen atom or a methyl group;
L 1 is methylene;
L 2 is —CO— or —NHCO—;
L 3 is a bond or a methylene group,
Compounds are preferred.
　本発明の別の態様において、式（Ｉ）で表される化合物としては、
　環Ａが、
（１）(i) ハロゲン原子（例、フッ素原子、塩素原子）、(ii) １～３個のハロゲン原子（例、フッ素原子）で置換されたＣ１－６アルキル基（例、メチル）、(iii) Ｃ３－１０シクロアルキル基（例、シクロプロピル）および(iv) Ｃ１－６アルキルスルホニル基（例、メチルスルホニル）から選ばれる１～３個の置換基で置換されたベンゼン；
（２）２－オキソジヒドロインドールまたは３－オキソジヒドロベンゾオキサジン；または
（３）(i) ハロゲン原子（例、フッ素原子）および(ii) Ｃ１－６アルキル基（例、メチル）から選ばれる１～３個の置換基で置換されたインダゾール
であり；
　環Ｂが、
（1）Ｃ３－１０シクロアルキル基（例、シクロプロピル）；
（2）ハロゲン原子（例、塩素原子）；
（3）１～３個のハロゲン原子（例、フッ素原子）、で置換されていてもよいＣ１－６アルキル基（例、メチル）；および
（4）Ｃ１－６アルキル基（例、メチル）でモノまたはジ置換されていてもよいアミノ基
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、
（２）ピリジン、または
（３）ピリミジン
であり；
　部分構造式： In another embodiment of the present invention, the compound represented by formula (I) includes:
Ring A is
(1) (i) a halogen atom (eg, fluorine atom, chlorine atom), (ii) a C 1-6 alkyl group (eg, methyl) substituted with 1 to 3 halogen atoms (eg, fluorine atom), benzene substituted with 1 to 3 substituents selected from (iii) a C 3-10 cycloalkyl group (eg, cyclopropyl) and (iv) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl);
(2) 2-oxodihydroindole or 3-oxodihydrobenzoxazine; or (3) 1 selected from (i) a halogen atom (eg, fluorine atom) and (ii) a C 1-6 alkyl group (eg, methyl) Indazole substituted with ~ 3 substituents;
Ring B is
(1) a C 3-10 cycloalkyl group (eg, cyclopropyl);
(2) halogen atoms (eg, chlorine atoms);
(3) C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom); and (4) C 1-6 alkyl group (eg, methyl) ) May be further substituted with 1 to 3 substituents selected from amino groups that may be mono- or di-substituted,
(1) benzene,
(2) pyridine, or (3) pyrimidine;
Partial structural formula:
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
が、以下の構造を示し； Shows the structure:
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　Ｒ１が、
(i)（1）ヒドロキシ基、および
　 （2）Ｃ３－１０シクロアルキル基（例、シクロプロピル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル）；または
(ii) Ｃ３－６シクロアルキル基（例、シクロプロピル）
であり；
　Ｒ２が、
(i) 水素原子；
(ii) アミノ基；
(iii)（1）Ｃ１－６アルキル基（例、メチル）またはＣ１－６アルキル－カルボニル基（例、メチルカルボニル）でモノまたはジ置換されたアミノ基、
　 　（2）Ｃ１－６アルキル基（例、メチル）でモノまたはジ置換されていてもよいカルバモイル基、
　 　（3）ヒドロキシ基、
　 　（4）Ｃ１－６アルキルスルフィニル基（例、メチルスルフィニル）、
　 　（5）Ｃ１－６アルキルスルホニル基（例、メチルスルホニル）、
　 　（6）１，２，４－トリアゾール－１－イル基、および
　 　（7）２－オキソイミダゾリジニル基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、ブチル）；
(iv) ヒドロキシ基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル）から選ばれる１～３個の置換基で置換されていてもよいピペラジニル基；または
(v) Ｃ３－６シクロアルキル基（例、シクロプロピル）
であり；
　Ｒ３が水素原子であり；
　Ｌ１がメチレンであり；
　Ｌ２が－ＣＯ－または－ＮＨＣＯ－であり；
　Ｌ３が結合またはメチレン基である、
化合物が好ましく、
　環Ａが、(i) ハロゲン原子（例、フッ素原子、塩素原子）および(ii) １～３個のハロゲン原子（例、フッ素原子）で置換されたＣ１－６アルキル基（例、メチル）から選ばれる１～３個の置換基で置換されたベンゼンであり；
　環Ｂが、
（1）Ｃ３－１０シクロアルキル基（例、シクロプロピル）；
（2）ハロゲン原子（例、塩素原子）；および
（3）１～３個のハロゲン原子（例、フッ素原子）、で置換されていてもよいＣ１－６アルキル基（例、メチル）
から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
（１）ベンゼン、または
（２）ピリジン
であり；
　部分構造式： R 1 is
(i) (1) a hydroxy group, and (2) a C 3-10 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from: or
(ii) C 3-6 cycloalkyl group (eg, cyclopropyl)
Is;
R 2 is
(i) a hydrogen atom;
(ii) an amino group;
(iii) (1) an amino group mono- or di-substituted with a C 1-6 alkyl group (eg, methyl) or a C 1-6 alkyl-carbonyl group (eg, methylcarbonyl),
(2) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group (eg, methyl),
(3) a hydroxy group,
(4) a C 1-6 alkylsulfinyl group (eg, methylsulfinyl),
(5) C 1-6 alkylsulfonyl group (eg, methylsulfonyl),
(6) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 1,2,4-triazol-1-yl group and (7) 2-oxoimidazolidinyl group (Eg, methyl, ethyl, propyl, butyl);
(iv) a piperazinyl group optionally substituted with 1 to 3 substituents selected from a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with a hydroxy group; or
(v) C 3-6 cycloalkyl group (eg, cyclopropyl)
Is;
R 3 is a hydrogen atom;
L 1 is methylene;
L 2 is —CO— or —NHCO—;
L 3 is a bond or a methylene group,
Compounds are preferred,
Ring 1 is a C 1-6 alkyl group (eg, methyl) substituted with (i) a halogen atom (eg, fluorine atom, chlorine atom) and (ii) 1 to 3 halogen atoms (eg, fluorine atom) Benzene substituted with 1 to 3 substituents selected from:
Ring B is
(1) a C 3-10 cycloalkyl group (eg, cyclopropyl);
(2) a halogen atom (eg, chlorine atom); and (3) a C 1-6 alkyl group (eg, methyl) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)
Each of which may be further substituted with 1 to 3 substituents selected from:
(1) benzene or (2) pyridine;
Partial structural formula:
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
が、以下の構造を示し； Shows the structure:
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　Ｒ１がＣ１－６アルキル基（例、メチル）であり；
　Ｒ２が、
(i) アミノ基；または
(ii)（1）Ｃ１－６アルキル基（例、メチル）でモノ置換されたカルバモイル基、
　  （2）ヒドロキシ基、および
　  （3）１，２，４－トリアゾール－１－イル基
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル）；
であり；
　Ｒ３が水素原子であり；
　Ｌ１がメチレンであり；
　Ｌ２が－ＣＯ－または－ＮＨＣＯ－であり；
　Ｌ３が結合である、
化合物がより好ましい。 R 1 is a C 1-6 alkyl group (eg, methyl);
R 2 is
(i) an amino group; or
(ii) (1) a carbamoyl group monosubstituted with a C 1-6 alkyl group (eg, methyl),
(2) a hydroxy group, and (3) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 1,2,4-triazol-1-yl group (eg, methyl, ethyl);
Is;
R 3 is a hydrogen atom;
L 1 is methylene;
L 2 is —CO— or —NHCO—;
L 3 is a bond,
Compounds are more preferred.
　式（Ｉ）で表される化合物として、特に好ましくは、
　部分構造式： As the compound represented by the formula (I), particularly preferably
Partial structural formula:
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
が、以下の構造を示し； Shows the structure:
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　環Ａが、フッ素原子、塩素原子、臭素原子、トリフルオロメチル、シクロプロピル、アミノ、ニトロ、メチルスルファニル、メチルスルフィニル、メチルスルホニルおよびメトキシカルボニルから選ばれる１～３個の置換基で置換されたベンゼンであり；
　環Ｂが、（１）Ｃ３－１０シクロアルキル基（特に、シクロプロピル）、ハロゲン原子（特に、塩素原子）、１～３個のハロゲン原子（特に、フッ素原子）で置換されていてもよいＣ１－６アルキル基（特に、メチル）、ヒドロキシ基、１～３個のハロゲン原子（特に、フッ素原子）で置換されたＣ１－６アルキルスルホニルオキシ基（特に、メチルスルホニルオキシ）およびＣ１－６アルキル基（特に、メチル）でモノまたはジ置換されたアミノ基から選ばれる１～３個の置換基でさらに置換されていてもよいベンゼン、（２）Ｃ１－６アルキル基（特に、メチル）から選ばれる１～３個の置換基でさらに置換されていてもよいピリジン、または（３）Ｃ１－６アルキル基（特に、メチル）から選ばれる１～３個の置換基でさらに置換されていてもよいピリミジンであり；
　Ｒ１が、Ｃ３－１０シクロアルキル基（特に、シクロプロピル）またはヒドロキシ基で置換されていてもよいＣ１－６アルキル基（特に、メチル、エチル）、Ｃ３－６シクロアルキル基（特に、シクロプロピル）、またはＣ６－１４アリール基（特に、フェニル）であり；
　Ｒ２が、
(i)ヒドロキシ基、
(ii)アミノ基、
(iii)Ｃ１－６アルコキシ基（特に、メトキシ、エトキシ）、または
(iv)（1）Ｃ１－６アルキル基（特に、メチル）またはＣ１－６アルキル－カルボニル基（特に、メチルカルボニル）でモノまたはジ置換されたアミノ基（特に、ジメチルアミノ、アセチルアミノ）、
　　（2）Ｃ１－６アルキル基（特に、メチル）でモノまたはジ置換されていてもよいカルバモイル基（特に、カルバモイル、メチルカルバモイル、ジメチルカルバモイル）、
　　（3）ヒドロキシ基、
　　（4）Ｃ１－６アルキルスルファニル基（特に、メチルスルファニル）、
　　（5）Ｃ１－６アルキルスルフィニル基（特に、メチルスルフィニル）、
　　（6）Ｃ１－６アルキルスルホニル基（特に、メチルスルホニル）、
　　（7）芳香族複素環基（特に、１，２，４－トリアゾール－１－イル）、および
　　（8）非芳香族複素環基（特に、２－オキソイミダゾリジニル）
から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基（特に、メチル、エチル、プロピル、ブチル、イソブチル）、
(v)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基（特に、メチル、エチル）、および
　 （2）Ｃ１－６アルキル－カルボニル基（特に、メチルカルボニル）
から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基（特に、ピペラジニル、３－オキソピペラジニル）、または
(vi)Ｃ３－６シクロアルキル基（特に、シクロプロピル）であり；
　Ｒ３が、水素原子またはＣ１－６アルキル基（特に、メチル）であり；
　Ｌ１が、メチレンであり；
　Ｌ２が、－ＣＯ－または－ＮＨＣＯ－であり；
　Ｌ３が、結合手またはメチレン基である化合物である。 Benzene in which ring A is substituted with 1 to 3 substituents selected from fluorine atom, chlorine atom, bromine atom, trifluoromethyl, cyclopropyl, amino, nitro, methylsulfanyl, methylsulfinyl, methylsulfonyl and methoxycarbonyl Is;
Ring B may be substituted with (1) a C 3-10 cycloalkyl group (particularly cyclopropyl), a halogen atom (particularly a chlorine atom), or one to three halogen atoms (particularly a fluorine atom). A C 1-6 alkyl group (particularly methyl), a hydroxy group, a C 1-6 alkylsulfonyloxy group (particularly methylsulfonyloxy) substituted with 1 to 3 halogen atoms (particularly a fluorine atom) and C 1 Benzene, which may be further substituted with 1 to 3 substituents selected from amino groups mono- or di-substituted with a -6 alkyl group (particularly methyl), (2) a C 1-6 alkyl group (particularly, 1-3 further optionally substituted pyridine with a substituent selected from methyl) or (3) C 1-6 alkyl group, (especially, further substituted with one to three substituents selected from methyl) Is there a good pyrimidin also be;
R 1 is a C 3-10 cycloalkyl group (especially cyclopropyl) or a C 1-6 alkyl group (especially methyl, ethyl) optionally substituted with a hydroxy group, a C 3-6 cycloalkyl group (especially , Cyclopropyl), or a C 6-14 aryl group (especially phenyl);
R 2 is
(i) a hydroxy group,
(ii) an amino group,
(iii) a C 1-6 alkoxy group (especially methoxy, ethoxy), or
(iv) (1) an amino group mono- or di-substituted with a C 1-6 alkyl group (especially methyl) or a C 1-6 alkyl-carbonyl group (especially methylcarbonyl) (especially dimethylamino, acetylamino) ,
(2) a carbamoyl group (particularly carbamoyl, methylcarbamoyl, dimethylcarbamoyl) optionally mono- or disubstituted with a C 1-6 alkyl group (particularly methyl),
(3) a hydroxy group,
(4) a C 1-6 alkylsulfanyl group (particularly methylsulfanyl),
(5) a C 1-6 alkylsulfinyl group (particularly methylsulfinyl),
(6) C 1-6 alkylsulfonyl group (particularly methylsulfonyl),
(7) aromatic heterocyclic group (especially 1,2,4-triazol-1-yl), and (8) non-aromatic heterocyclic group (especially 2-oxoimidazolidinyl)
A C 1-6 alkyl group (particularly methyl, ethyl, propyl, butyl, isobutyl) optionally substituted by 1 to 3 substituents selected from
(v) (1) a C 1-6 alkyl group (especially methyl, ethyl) optionally substituted with a hydroxy group, and (2) a C 1-6 alkyl-carbonyl group (especially methylcarbonyl).
A non-aromatic heterocyclic group (especially piperazinyl, 3-oxopiperazinyl) optionally substituted with 1 to 3 substituents selected from
(vi) is a C 3-6 cycloalkyl group (especially cyclopropyl);
R 3 is a hydrogen atom or a C 1-6 alkyl group (particularly methyl);
L 1 is methylene;
L 2 is —CO— or —NHCO—;
A compound in which L 3 is a bond or a methylene group.
　また、本発明の別の態様において、
（ｉ）部分構造式： In another embodiment of the present invention,
(I) Partial structural formula:
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
が、以下の構造を示し； Shows the structure:
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　環Ａが、
(i) ハロゲン原子（好ましくは、フッ素原子）、および
(ii) １～３個のハロゲン原子（好ましくは、フッ素原子）で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル）
から選ばれる１～３個の置換基で置換されていてもよいベンゼンであり；
　環Ｂが、Ｃ１－６アルキル基（好ましくは、メチル）から選ばれる１～３個の置換基でさらに置換されていてもよいベンゼンであり；
　Ｒ１が、Ｃ１－６アルキル基（好ましくは、メチル）であり；
　Ｒ２が、アミノ基であり；
　Ｌ１が、Ｃ１－６アルキレン（好ましくは、メチレン）であり；
　Ｌ２が、－ＣＯ－であり；
　Ｌ３が、－（ＣＨ２）ｎ－（ｎは０を示す。）、すなわち結合手である化合物；および
（ｉｉ）部分構造式： Ring A is
(i) a halogen atom (preferably a fluorine atom), and
(ii) a C 1-6 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom)
Benzene optionally substituted with 1 to 3 substituents selected from:
Ring B is benzene optionally further substituted with 1 to 3 substituents selected from C 1-6 alkyl groups (preferably methyl);
R 1 is a C 1-6 alkyl group (preferably methyl);
R 2 is an amino group;
L 1 is C 1-6 alkylene (preferably methylene);
L 2 is —CO—;
A compound in which L 3 is — (CH 2 ) n — (n represents 0), that is, a bond; and (ii) a partial structural formula:
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
が、以下の構造を示し； Shows the structure:
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　環Ａが、
(i) ハロゲン原子（好ましくは、フッ素原子、塩素原子）、および
(ii) １～３個のハロゲン原子（好ましくは、フッ素原子）で置換されていてもよいＣ１－６アルキル基（好ましくは、メチル）
から選ばれる１～３個の置換基で置換されていてもよいベンゼンであり；
　環Ｂが、
(i) ハロゲン原子（好ましくは、塩素原子）、
(ii) Ｃ１－６アルキル基（好ましくは、メチル）、および
(iii) Ｃ３－６シクロアルキル基（好ましくは、シクロプロピル）
から選ばれる１～３個の置換基でさらに置換されていてもよいベンゼンであり；
　Ｒ１が、
(i) Ｃ１－６アルキル基（好ましくは、メチル）、または
(ii) Ｃ３－６シクロアルキル基（好ましくは、シクロプロピル）であり；
　Ｒ２が、
(i) ヒドロキシ基、
(ii) Ｃ１－６アルコキシ基（好ましくは、エトキシ）、または
(iii) アミノ基であり；
　Ｌ１が、Ｃ１－６アルキレン（好ましくは、メチレン）であり；
　Ｌ２が、－ＣＯ－であり；
　Ｌ３が、－（ＣＨ２）ｎ－（ｎは０を示す。）、すなわち結合手である化合物；
が特に好ましい。 Ring A is
(i) a halogen atom (preferably a fluorine atom, a chlorine atom), and
(ii) a C 1-6 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably a fluorine atom)
Benzene optionally substituted with 1 to 3 substituents selected from:
Ring B is
(i) a halogen atom (preferably a chlorine atom),
(ii) a C 1-6 alkyl group (preferably methyl), and
(iii) C 3-6 cycloalkyl group (preferably cyclopropyl)
Benzene optionally further substituted with 1 to 3 substituents selected from:
R 1 is
(i) a C 1-6 alkyl group (preferably methyl), or
(ii) a C 3-6 cycloalkyl group (preferably cyclopropyl);
R 2 is
(i) a hydroxy group,
(ii) a C 1-6 alkoxy group (preferably ethoxy), or
(iii) is an amino group;
L 1 is C 1-6 alkylene (preferably methylene);
L 2 is —CO—;
A compound in which L 3 is — (CH 2 ) n — (n represents 0), that is, a bond;
Is particularly preferred.
　式（Ｉ）で表される化合物として、具体的には、実施例１～１７９の化合物が挙げられ、中でも、
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミドまたはその塩（実施例３１）；
　6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルニコチンアミドまたはその塩（実施例７３）；
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンズアミドまたはその塩（実施例１４１）；および
　4-{2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール-5-イル}-2-メチルベンズアミドまたはその塩（実施例１４７）
が好ましい。 Specific examples of the compound represented by the formula (I) include the compounds of Examples 1 to 179. Among them,
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide or a salt thereof (Example 31);
6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylnicotinamide or a salt thereof (Example 73);
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzamide or a salt thereof (Example 141) And 4- {2- [3-fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl} -2-methylbenzamide or a salt thereof (Example 147)
Is preferred.
　化合物（Ｉ）が塩である場合、このような塩としては、例えば金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩などが挙げられる。金属塩の好適な例としては、例えばナトリウム塩、カリウム塩などのアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩；アルミニウム塩などが挙げられる。有機塩基との塩の好適な例としては、例えばトリメチルアミン、トリエチルアミン、ピリジン、ピコリン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ'－ジベンジルエチレンジアミンなどとの塩が挙げられる。無機酸との塩の好適な例としては、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。有機酸との塩の好適な例としては、例えばギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸などとの塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えばアルギニン、リジン、オルニチンなどとの塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えばアスパラギン酸、グルタミン酸などとの塩が挙げられる。このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合にはアルカリ金属塩（例、ナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩など）などの無機塩、アンモニウム塩など、また、化合物内に塩基性官能基を有する場合には、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸などの無機酸との塩、または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸などの有機酸との塩が挙げられる。 When compound (I) is a salt, examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids. Etc. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. It is done. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), When the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
　化合物（Ｉ）が、互変異性体、光学異性体、立体異性体、位置異性体、回転異性体などの異性体を有する場合には、いずれか一方の異性体も混合物も本発明の化合物に包含される。さらに、化合物（Ｉ）に光学異性体が存在する場合には、ラセミ体から分割された光学異性体も化合物（Ｉ）に包含される。 When compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
　化合物（Ｉ）は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても化合物（Ｉ）に包含される。
　化合物（Ｉ）は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。
　化合物（Ｉ）は、溶媒和物（例えば、水和物など）であっても、無溶媒和物であってもよく、いずれも化合物（Ｉ）に包含される。
　同位元素（例、２Ｈ、３Ｈ、１1Ｃ、１４Ｃ、１8Ｆ、３５Ｓ、１２５Ｉなど）などで標識または置換された化合物も、化合物（Ｉ）に包含される。
　化合物（Ｉ）のプロドラッグとは、生体内における生理条件下で酵素や胃酸などによる反応により化合物（Ｉ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解などを起こして化合物（Ｉ）に変化する化合物、胃酸などにより加水分解などを起こして化合物（Ｉ）に変化する化合物をいう。 Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
A compound labeled or substituted with an isotope (eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.) is also encompassed in compound (I).
The prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).
　化合物（Ｉ）のプロドラッグとしては、化合物（Ｉ）のアミノ基がアシル化、アルキル化、りん酸化された化合物（例えば、化合物（Ｉ）のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ－ブチル化された化合物など）；化合物（Ｉ）のヒドロキシル基がアシル化、アルキル化、りん酸化、ホウ酸化された化合物（例えば、化合物（Ｉ）のヒドロキシル基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、スクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物など）；化合物（Ｉ）のカルボキシ基がエステル化、アミド化された化合物（例えば、化合物（Ｉ）のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物など）；などが挙げられる。これらの化合物は公知の方法によって化合物（Ｉ）から製造することができる。また、化合物（Ｉ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような生理的条件で化合物（Ｉ）に変化するものであってもよい。 Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds wherein the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds, etc.); Compound (I) Compound in which carboxy group is esterified or amidated (for example, carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxy Carbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.); Is mentioned. These compounds can be produced from compound (I) by a known method. The prodrug of compound (I) is changed to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Pharmaceutical Development”, Volume 7, Molecular Design, pages 163 to 198. There may be.
　本発明の化合物は、優れたＧＰＲ５２アゴニスト活性を有し、例えば以下（１）～（１０）記載の疾患や症状に対して予防・治療薬として有用である。
（１）精神疾患［例、うつ病、大うつ病、双極性うつ病、気分変調障害、情動障害（季節性情動障害など）、再発性うつ病、産後うつ病、ストレス性障害、うつ症状、躁病、不安、全般性不安障害、不安症候群、パニック障害、恐怖症、社会性恐怖症、社会性不安障害、強迫性障害、心的外傷後ストレス症候群、外傷後ストレス障害、タウレット症候群、自閉症、適応障害、双極性障害、神経症、統合失調症（精神分裂症）、神経症、慢性疲労症候群、不安神経症、強迫神経症、恐怖性障害、てんかん、不安症状、不快精神状態、情緒異常、感情循環気質、神経過敏症、失神、耽弱、性欲低下、注意欠陥多動性障害（ＡＤＨＤ）、精神病性大うつ病、難治性大うつ病、治療抵抗性うつ病］、
（２）神経変性疾患［例、アルツハイマー病、アルツハイマー型老人性認知症、パーキンソン病、ハンチントン舞踏病、脊髄小脳変性症、多発脳梗塞性認知症、前頭側頭認知症、パーキンソン型前頭側頭認知症、進行性核上麻痺、ピック症候群、ニーマン－ピック症候群、大脳皮質基底核変成症、ダウン症、血管性認知症、脳炎後のパーキンソン病、レヴィー小体認知症、ＨＩＶ性認知症、筋萎縮性脊髄側索硬化症（ＡＬＳ）、運動神経原性疾患（ＭＮＤ）、クロイツフェルト・ヤコブ病又はプリオン病、脳性麻痺、進行性核上麻痺、多発性硬化症］、
（３）加齢に伴う認知・記憶障害［例、加齢性記憶障害、老人性認知症］、
（４）睡眠障害［例、内在因性睡眠障害（例、精神生理性不眠など）、外在因性睡眠障害、概日リズム障害（例、時間帯域変化症候群（時差ボケ）、交代勤務睡眠障害、不規則型睡眠覚醒パターン、睡眠相後退症候群、睡眠相前進症候群、非２４時間睡眠覚醒など）、睡眠時随伴症、内科又は精神科障害（例、慢性閉塞性肺疾患、アルツハイマー病、パーキンソン病、脳血管性痴呆、統合失調症、うつ病、不安神経症）に伴う睡眠障害、ストレス性不眠症、不眠症、不眠性神経症、睡眠時無呼吸症候群］、
（５）麻酔薬（例、モルヒネ）、外傷性疾患、又は神経変性疾患などに起因する呼吸抑制、
（６）外傷性脳損傷、脳卒中、並びにそれらに伴う、抑うつ症、排尿障害、疼痛等の合併症、
（７）その他の神経疾患として、神経性食欲不振、摂食障害、神経性無食欲症、過食症、その他の摂食障害、アルコール依存症、アルコール乱用、アルコール性健忘症、アルコール妄想症、アルコール嗜好性、アルコール離脱、アルコール性精神病、アルコール中毒、アルコール性嫉妬、アルコール性躁病、アルコール依存性精神障害、アルコール精神病、ニコチン中毒、薬物嗜好、薬物恐怖症、薬物狂、薬物離脱、メニエール病、自律神経失調症、
（８）神経因性疼痛、術後疼痛、癌性疼痛、炎症性疼痛、偏頭痛、ストレス性頭痛、緊張性頭痛、感覚鈍磨等の感覚異常、
（９）ストレス等に起因する、糖尿病性ニューロパシー、肥満、糖尿病、筋肉痙攣、脱毛症、緑内障、高血圧、心臓病、頻脈、うっ血性心不全、過呼吸、気管支喘息、無呼吸、炎症性疾患、アレルギー疾患、インポテンス、不妊症、免疫不全症候群、末端肥大症、失禁、メタボリック・シンドローム、骨粗しょう症、胃腸障害、消化性潰瘍、過敏性腸症候群、炎症性腸疾患、潰瘍性大腸炎、クローン病、嘔吐、下痢、便秘、術後イレウス、
（１０）その他、更年期障害、乳幼児突然死症候群、脳腫瘍等の悪性腫瘍、ＨＩＶ感染による免疫不全症候群、脳脊髄膜炎。
　本発明の化合物は、特に、精神疾患（例、統合失調症、うつ病、不安症、双極性障害またはＰＴＳＤ、不安神経症、強迫性神経症等）、神経変性疾患（例、アルツハイマー病、軽度認知障害（ＭＣＩ）、パーキンソン病、筋萎縮性側索硬化症（ＡＬＳ）、ハンチントン病、脊髄小脳変性症、多発性硬化症（ＭＳ）、Ｐｉｃｋ病等）等の疾患の予防・治療薬として有用であり、中でも統合失調症の（１）妄想および幻覚などの陽性症状、（２）感覚鈍麻、ひきこもり、意欲・集中力の低下などの陰性症状、（３）認知機能障害の予防・治療薬として有用である。 The compound of the present invention has excellent GPR52 agonist activity, and is useful as a prophylactic / therapeutic agent for the diseases and symptoms described in (1) to (10) below.
(1) Psychiatric disorders [eg, depression, major depression, bipolar depression, mood disorders, emotional disorders (seasonal emotional disorders, etc.), recurrent depression, postpartum depression, stress disorder, depressive symptoms, Gonorrhea, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, taurette syndrome, autism , Adaptation disorder, bipolar disorder, neurosis, schizophrenia (schizophrenia), neurosis, chronic fatigue syndrome, anxiety, obsessive-compulsive disorder, phobic disorder, epilepsy, anxiety symptoms, uncomfortable mental state, emotional abnormalities , Emotional temperament, nervousness, fainting, weakness, decreased libido, attention deficit hyperactivity disorder (ADHD), psychotic major depression, refractory major depression, treatment-resistant depression],
(2) Neurodegenerative diseases [eg, Alzheimer's disease, Alzheimer type senile dementia, Parkinson's disease, Huntington's chorea, spinocerebellar degeneration, multiple cerebral infarction dementia, frontotemporal dementia, Parkinson's frontotemporal cognition Disease, progressive supranuclear palsy, Pick syndrome, Niemann-Pick syndrome, corticobasal degeneration, Down syndrome, vascular dementia, Parkinson's disease after encephalitis, Lewy body dementia, HIV dementia, muscle atrophy Spinal cord sclerosis (ALS), motor neurogenic disease (MND), Creutzfeldt-Jakob disease or prion disease, cerebral palsy, progressive supranuclear palsy, multiple sclerosis],
(3) Cognitive / memory impairment associated with aging [eg, age-related memory impairment, senile dementia],
(4) Sleep disorders [eg, intrinsic sleep disorders (eg, psychophysiological insomnia, etc.), extrinsic sleep disorders, circadian rhythm disorders (eg, time-zone change syndrome (time difference blur), shift work sleep disorders) , Irregular sleep-wake patterns, sleep phase regression syndrome, sleep phase advance syndrome, non-24-hour sleep awakening, etc.), parasomnia, internal or psychiatric disorders (eg, chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease) , Cerebrovascular dementia, schizophrenia, depression, anxiety), sleep disorders associated with stress insomnia, insomnia, insomnia, sleep apnea syndrome]
(5) respiratory depression due to anesthetics (eg, morphine), traumatic disease, or neurodegenerative disease,
(6) traumatic brain injury, stroke, and associated complications such as depression, dysuria, pain,
(7) Other neurological disorders include anorexia nervosa, eating disorders, anorexia nervosa, bulimia, other eating disorders, alcoholism, alcohol abuse, alcoholic amnesia, alcohol delusions, alcohol Palatability, alcohol withdrawal, alcoholic psychosis, alcoholism, alcoholic manic, alcoholic manic, alcohol-dependent mental disorder, alcohol psychosis, nicotine addiction, drug preference, drug phobia, drug madness, drug withdrawal, Meniere's disease, autonomous Schizophrenia,
(8) neuropathic pain, postoperative pain, cancer pain, inflammatory pain, migraine, stress headache, tension headache, sensory abnormalities such as sensory dullness,
(9) Diabetic neuropathy caused by stress, obesity, diabetes, muscle spasm, alopecia, glaucoma, hypertension, heart disease, tachycardia, congestive heart failure, hyperventilation, bronchial asthma, apnea, inflammatory disease, Allergic disease, impotence, infertility, immunodeficiency syndrome, acromegaly, incontinence, metabolic syndrome, osteoporosis, gastrointestinal disorders, peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease Vomiting, diarrhea, constipation, postoperative ileus,
(10) Others include menopause, sudden infant death syndrome, malignant tumors such as brain tumor, immunodeficiency syndrome due to HIV infection, encephalomyelitis.
The compounds of the present invention are particularly useful for mental disorders (eg, schizophrenia, depression, anxiety, bipolar disorder or PTSD, anxiety, obsessive compulsive disorder etc.), neurodegenerative diseases (eg, Alzheimer's disease, mild Useful as a prophylactic / therapeutic agent for diseases such as cognitive impairment (MCI), Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, spinocerebellar degeneration, multiple sclerosis (MS), Pick's disease, etc. Among them, (1) positive symptoms such as delusions and hallucinations in schizophrenia, (2) negative symptoms such as sensory dullness, withdrawal, decreased motivation and concentration, and (3) prophylactic and therapeutic drugs for cognitive dysfunction Useful.
　本発明の化合物は、代謝安定性に優れるので、上記疾患に対して低用量でかつ優れた治療効果が期待できる。 Since the compound of the present invention is excellent in metabolic stability, it can be expected to have an excellent therapeutic effect at a low dose against the above diseases.
　また、本発明の化合物は、毒性が低く（例えば、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、薬物相互作用、癌原性等の点から医薬として優れている）、そのまま医薬として、または薬学的に許容される担体等と混合された医薬として、哺乳動物（例えば、ヒト、サル、ウシ、ウマ、ブタ、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ヒツジ、ヤギ等）に対して、経口的または非経口的に安全に投与することができる。 In addition, the compound of the present invention has low toxicity (for example, it is excellent as a pharmaceutical from the viewpoint of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), and as it is as a pharmaceutical. Or as a medicine mixed with a pharmaceutically acceptable carrier or the like to a mammal (eg, human, monkey, cow, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, goat, etc.) On the other hand, it can be safely administered orally or parenterally.
　本発明の化合物を含有する医薬は、医薬製剤の製造法として自体公知の方法（例、日本薬局方記載の方法等）に従って、本発明化合物を単独で、または本発明化合物と薬理学的に許容される担体とを混合した医薬組成物として使用することができる。本発明の化合物を含有する医薬は、例えば錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤等として、経口的または非経口的（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位、病巣等）に安全に投与することができる。
　ここで、薬理学的に許容される担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤；液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等として配合される。また必要に応じて、防腐剤、抗酸化剤、着色剤、甘味剤等の製剤添加物を用いることもできる。 The medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier. Examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules). Capsules), lozenges, syrups, solutions, emulsions, suspensions, controlled release formulations (eg, immediate release formulations, sustained release formulations, sustained release microcapsules), aerosols, films ( E.g., orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, Lotions, patches, suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc., orally or parenterally (eg, intravenously) , Intramuscular, subcutaneous, intraorgan, intranasal, intradermal, eye drop, Among them, rectally, intravaginally, intraperitoneally, tumor interior, proximal tumors, can be safely administered into a lesion, etc.).
Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
　賦形剤の好適な例としては、乳糖、白糖、Ｄ－マンニトール、Ｄ－ソルビトール、デンプン、α化デンプン、デキストリン、結晶セルロース、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、アラビアゴム、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム等が挙げられる。
　滑沢剤の好適な例としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられる。 Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
　結合剤の好適な例としては、α化デンプン、ショ糖、ゼラチン、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、白糖、Ｄ－マンニトール、トレハロース、デキストリン、プルラン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン等が挙げられる。 Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
　崩壊剤の好適な例としては、乳糖、白糖、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロース等が挙げられる。 Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
　溶剤の好適な例としては、注射用水、生理的食塩水、リンゲル液、アルコール、プロピレングリコール、ポリエチレングリコール、ゴマ油、トウモロコシ油、オリーブ油、綿実油等が挙げられる。 Favorable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
　溶解補助剤の好適な例としては、ポリエチレングリコール、プロピレングリコール、Ｄ－マンニトール、トレハロース、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム、酢酸ナトリウム等が挙げられる。 Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
　懸濁化剤の好適な例としては、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤；ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子；ポリソルベート類、ポリオキシエチレン硬化ヒマシ油等が挙げられる。 Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
　等張化剤の好適な例としては、塩化ナトリウム、グリセリン、Ｄ－マンニトール、Ｄ－ソルビトール、ブドウ糖等が挙げられる。
　緩衝剤の好適な例としては、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液等が挙げられる。
　無痛化剤の好適な例としては、ベンジルアルコール等が挙げられる。
　防腐剤の好適な例としては、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。
　抗酸化剤の好適な例としては、亜硫酸塩、アスコルビン酸塩等が挙げられる。 Preferable examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like.
Preferable examples of the soothing agent include benzyl alcohol.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
　着色剤の好適な例としては、水溶性食用タール色素（例、食用赤色２号および３号、食用黄色４号および５号、食用青色１号および２号等の食用色素）、水不溶性レーキ色素（例、上記水溶性食用タール色素のアルミニウム塩）、天然色素（例、β－カロチン、クロロフィル、ベンガラ）等が挙げられる。
　甘味剤の好適な例としては、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテーム、ステビア等が挙げられる。 Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (E.g., aluminum salts of the above water-soluble edible tar dyes), natural dyes (e.g., β-carotene, chlorophyll, bengara) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
　なお、医薬組成物中の本発明の化合物の含量は、剤形、本発明の化合物の投与量等により異なるが、例えば、組成物全量に対して、約０．０１～１００重量％、好ましくは０．１～９５重量％である。 The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., for example, about 0.01 to 100% by weight, preferably about the total amount of the composition 0.1 to 95% by weight.
　本発明の化合物の投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、例えば、統合失調症の患者（成人、体重約６０ｋｇ）に経口投与する場合、通常１回量として約０．１～約２０ｍｇ／ｋｇ体重、好ましくは約０．２～約１０ｍｇ／ｋｇ体重、さらに好ましくは約０．５～約１０ｍｇ／ｋｇ体重であり、この量を１日１回～数回（例、３回）投与するのが望ましい。 The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc., but for example, when administered orally to a patient with schizophrenia (adult, body weight of about 60 kg) About 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight, and this amount is once to several times a day It is desirable to administer (eg, 3 times).
　本発明の化合物は、他の活性成分と組み合わせて用いてもよい。このような活性成分（以下「併用薬物」と称する。）としては、例えば、
（１）非定型抗精神病薬（例、クロザピン、オランザピン、リスペリドン、アリピプラゾール、イロペリドン、アセナピン、ジプラシドン、クエチアピン、ゾテピン、パロペリドン、ルラシドン等）、
（２）定型抗精神病薬（例、ハロペリドール、クロルプロマジン等）、
（３）選択的セロトニン再取り込み阻害薬（例、パロキセチン、セルトラリン、フルボキサミン、フルオキセチン等）、選択的セロトニン・ノルアドレナリン再取り込み阻害薬（例、ミルナシプラン、ベンラファキシン等）、
（４）選択的ノルアドレナリン・ドパミン再取り込み阻害薬（例、ｂｕｐｒｏｐｉｏｎ等）、
（５）四環系抗うつ薬（例、アモキサピン、クロミプラミン等）、
（６）三環系抗うつ薬（例、イミプラミン、アミトリプチリン等）、
（７）その他抗うつ薬（例、ＮＳ－２３５９、Ｌｕ　ＡＡ２１００４、ＤＯＶ２１９４７等）、
（８）ニコチン性アセチルコリン受容体調節薬（例、バニクレリン、ＳＳＲ－１８０７１１、ＰＮＵ－１２０５９６等）、
（９）ムスカリン性アセチルコリン受容体調節薬（例、サブコメリン等）、
（１０）イオンチャネル型グルタミン酸受容体調節薬（例、Ｄ－セリン，ＬＹ－４５１３９５等）、
（１１）代謝性グルタミン酸受容体調節薬（例、ＣＤＰＰＢ、ＭＰＥＰ、ＬＹ－２１４００２３等）、
（１２）ＧＡＢＡ受容体調節薬（例、バルプロ酸、ＭＫ-０７７７等）、
（１３）ヒスタミン受容体調節薬（例、ＧＳＫ－２３９５１２等）、
（１４）ドパミン受容体調節薬（例、カリプラジン等）、
（１５）セロトニン受容体調節薬（例、ピマバンセリン、ＧＳＫ－７４２４５７等）、
（１６）ノルアドレナリン受容体拮抗薬（例、イダゾキサン等）、
（１７）ＣＲＦ受容体調節薬（例、ペキサセルフォント等）、
（１８）サブスタンスＰ受容体調節薬（例、アプレピタント、オルベピタント等）、
（１９）オレキシン受容体調節薬（例、アルモレキサント、ＭＫ-４３０５等）、
（２０）フォスフォジエステラーゼ阻害薬（例、ＭＰ－１０、ＷＥＢ－３、ロリプラム等）、
（２１）グリシントランスポーター１阻害薬（例、ＲＧ１６７８、ＡＬＸ５４０７、ＳＳＲ５０４７３４等）、
（２２）抗不安薬［ベンゾジアゼピン系（例、ジアゼパム、エチゾラム等）、セロトニン５－ＨＴ１Ａ作動薬（例、タンドスピロン等）］、
（２３）睡眠導入剤［ベンゾジアゼピン系（例、エスタゾラム、トリアゾラム等）］、
（２４）非ベンゾジアゼピン系（例、ゾルピデム等）、
（２５）メラトニン受容体作動薬（例、ラメルテオン等）、
（２６）βアミロイドワクチン、βアミロイド抗体、
（２７）βアミロイド分解酵素等、
（２８）脳機能賦活薬（例、イデベノン、メマンチン、ビンポセチン等）、
（２９）パーキンソン病治療薬［例、ドーパミン受容体作動薬（Ｌ－ドーパ、ブロモクリプテン、パーゴライド、タリペキソール、プラシペキソール、カベルゴリン、アダマンタジン等）、モノアミン酸化酵素（ＭＡＯ）阻害薬（デプレニル、セルジリン（セレギリン）、レマセミド（ｒｅｍａｃｅｍｉｄｅ）、リルゾール（ｒｉｌｕｚｏｌｅ）等）、抗コリン剤（例、トリヘキシフェニジル、ビペリデン等）、ＣＯＭＴ阻害剤（例、エンタカポン等）］、
（３０）筋萎縮性側索硬化症治療薬（例、リルゾール等、神経栄養因子等）、
（３１）コレステロール低下薬等の高脂血症治療薬［スタチン系（例、プラバスタチンナトリウム、アトロバスタチン、シンバスタチン、ロスバスタチン等）、フィブラート（例、クロフィブラート等）、スクワレン合成酵素阻害剤］、
（３２）痴呆の進行に伴う異常行動・徘徊等の治療薬（例、鎮静剤、抗不安剤等）、
（３３）アポトーシス阻害薬（例、ＣＰＩ－１１８９、ＩＤＮ－６５５６、ＣＥＰ－１３４７等）、
（３４）神経分化・再生促進剤（例、レテプリニム（Ｌｅｔｅｐｒｉｎｉｍ）、キサリプローデン（Ｘａｌｉｐｒｏｄｅｎ；ＳＲ－５７７４６－Ａ）、ＳＢ－２１６７６３等）、
（３５）血圧降下薬（例、カプトプリル、テラプリル、エナラプリル、ニフェジピン、ニカルジピン、アムロジピン、アルプレノロール、プロプラノロール、メトプロロール、ロサルタン、バルサルタン、カンデサルタン等）、
（３６）糖尿病治療薬（例、ピオグリダゾン、ロシグリダゾン、メトフォルミン、グリベンクラミド、ナテグリニド、ボグリボース等）、
（３７）非ステロイド性抗炎症薬（例、メロキシカム、テオキシカム、インドメタシン、イブプロフェン、セレコキシブ、ロフェコキシブ、アスピリン、インドメタシン等）、
（３８）疾患修飾性抗リウマチ薬（ＤＭＡＲＤｓ）、
（３９）抗サイトカイン薬（例、ＴＮＦ阻害薬、ＭＡＰキナーゼ阻害薬等）、
（４０）ステロイド薬（例、デキサメサゾン、ヘキセストロール、酢酸コルチゾン等）、性ホルモンまたはその誘導体（例、プロゲステロン、エストラジオール、安息香酸エストラジオール等）、
（４１）副甲状腺ホルモン（ＰＴＨ）、
（４２）カルシウム受容体拮抗薬、
（４３）抗てんかん薬（例、フェニトイン、プレガバリン、カルバマゼピン等）、
（４４）双極性障害治療薬（リチウム、バルブロ酸等）、
（４５）コリンエステラーゼ阻害薬（ドネペジル、ガランタミン等）、
（４６）脳循環代謝改善薬（例、ニセルゴリン、イブジラスト、イフェンプロジル等）、
（４７）抗血小板薬（例、チクロピジン、ヘパリン、ウロキナーゼ、アルテプラーゼ、チソキナーゼ、ナサルプラーゼ、シロスタゾール等）、
（４８）抗酸化薬（例、リノレン酸、アスコルビン酸、イコサペンタエン酸、ドコサヘキサエン酸、トコフェロール等）、
（４９）ビタミン類（例、トコフェロール、アスコルビン酸等）、
（５０）性ホルモン（例、エストロゲン、エストロン、エストラジオール等）、
（５１）ＣＯＸ－２阻害薬（例、セレコキシブ、ロフェコキシブ等）
が挙げられる。
　併用薬物としては、各種中枢神経系作用薬、または統合失調症と併発し易い疾患の治療薬（糖尿病治療薬等）が好ましい。
　本発明の化合物は、特に、ＧＰＲ５２に対して作用しない併用薬物と組み合わせて用いることができる。 The compounds of the present invention may be used in combination with other active ingredients. As such an active ingredient (hereinafter referred to as “concomitant drug”), for example,
(1) Atypical antipsychotic drugs (eg, clozapine, olanzapine, risperidone, aripiprazole, iloperidone, asenapine, ziprasidone, quetiapine, zotepine, paroperidone, lurasidone, etc.),
(2) Typical antipsychotic drugs (eg, haloperidol, chlorpromazine, etc.)
(3) selective serotonin reuptake inhibitors (eg, paroxetine, sertraline, fluvoxamine, fluoxetine, etc.), selective serotonin / noradrenaline reuptake inhibitors (eg, milnacipran, venlafaxine, etc.),
(4) selective noradrenaline / dopamine reuptake inhibitors (eg, bupropion, etc.),
(5) tetracyclic antidepressants (eg, amoxapine, clomipramine, etc.),
(6) Tricyclic antidepressants (eg, imipramine, amitriptyline, etc.)
(7) Other antidepressants (eg, NS-2359, Lu AA21004, DOV21947, etc.),
(8) nicotinic acetylcholine receptor modulators (eg, vanicillin, SSR-180711, PNU-120596, etc.)
(9) Muscarinic acetylcholine receptor modulators (eg, subcomerin, etc.)
(10) an ion channel glutamate receptor modulator (eg, D-serine, LY-451395, etc.)
(11) Metabotropic glutamate receptor modulators (eg, CDPPB, MPEP, LY-2140023, etc.)
(12) GABA receptor modulator (eg, valproic acid, MK-0777, etc.),
(13) Histamine receptor modulator (eg, GSK-239512 etc.),
(14) dopamine receptor modulators (eg, caliprazine, etc.)
(15) Serotonin receptor modulators (eg, pimavanserin, GSK-742457, etc.)
(16) Noradrenaline receptor antagonist (eg, idazoxan, etc.),
(17) CRF receptor modulator (eg, pexacel font, etc.)
(18) substance P receptor modulator (eg, aprepitant, orbepitant, etc.),
(19) orexin receptor modulators (eg, almorexant, MK-4305, etc.)
(20) Phosphodiesterase inhibitors (eg, MP-10, WEB-3, rolipram, etc.)
(21) Glycine transporter 1 inhibitor (eg, RG1678, ALX5407, SSR504734, etc.),
(22) Anti-anxiety drugs [benzodiazepines (eg, diazepam, etizolam, etc.), serotonin 5-HT 1A agonists (eg, tandospirone, etc.)]
(23) Sleep inducers [benzodiazepines (eg, estazolam, triazolam, etc.)]
(24) Non-benzodiazepines (eg, zolpidem, etc.)
(25) Melatonin receptor agonist (eg, ramelteon),
(26) β-amyloid vaccine, β-amyloid antibody,
(27) β-amyloid degrading enzyme, etc.
(28) cerebral function activator (eg, idebenone, memantine, vinpocetine, etc.),
(29) Drugs for treating Parkinson's disease [eg, dopamine receptor agonists (L-dopa, bromocriptene, pergolide, taripexole, pripepexol, cabergoline, adamantazine, etc.), monoamine oxidase (MAO) inhibitors (deprenyl, sergiline ( Selegiline), remacemide, riluzole, etc.), anticholinergic agents (eg, trihexyphenidyl, biperidene, etc.), COMT inhibitors (eg, entacapone, etc.)],
(30) Amyotrophic lateral sclerosis drug (eg, riluzole, etc., neurotrophic factor, etc.),
(31) Antihyperlipidemic drugs such as cholesterol-lowering drugs [statins (eg, pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (eg, clofibrate, etc.), squalene synthase inhibitors],
(32) Drugs for the treatment of abnormal behavior and epilepsy associated with the progression of dementia (eg sedatives, anxiolytics,
(33) apoptosis inhibitor (eg, CPI-1189, IDN-6556, CEP-1347, etc.),
(34) Nerve differentiation / regeneration promoter (eg, Leteprimim, Xaliproden (SR-57746-A), SB-216763, etc.),
(35) Antihypertensive drugs (eg, captopril, telapril, enalapril, nifedipine, nicardipine, amlodipine, alprenolol, propranolol, metoprolol, losartan, valsartan, candesartan, etc.)
(36) Antidiabetic drugs (eg, pioglidazone, rosiglitazone, metformin, glibenclamide, nateglinide, voglibose, etc.),
(37) Non-steroidal anti-inflammatory drugs (eg, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.),
(38) Disease-modifying anti-rheumatic drugs (DMARDs),
(39) anti-cytokine drugs (eg, TNF inhibitors, MAP kinase inhibitors, etc.),
(40) Steroid drugs (eg, dexamethasone, hexestrol, cortisone acetate, etc.), sex hormones or derivatives thereof (eg, progesterone, estradiol, estradiol benzoate, etc.),
(41) Parathyroid hormone (PTH),
(42) calcium receptor antagonist,
(43) antiepileptic drugs (eg, phenytoin, pregabalin, carbamazepine, etc.),
(44) Bipolar disorder therapeutic agent (lithium, valuroic acid, etc.),
(45) cholinesterase inhibitors (donepezil, galantamine, etc.),
(46) cerebral circulation metabolism improving drug (eg, nicergoline, ibudilast, ifenprodil etc.),
(47) antiplatelet drugs (eg, ticlopidine, heparin, urokinase, alteplase, thisokinase, nasalplase, cilostazol, etc.),
(48) antioxidants (eg, linolenic acid, ascorbic acid, icosapentaenoic acid, docosahexaenoic acid, tocopherol, etc.),
(49) Vitamins (eg, tocopherol, ascorbic acid, etc.),
(50) sex hormones (eg, estrogen, estrone, estradiol, etc.),
(51) COX-2 inhibitor (eg, celecoxib, rofecoxib, etc.)
Is mentioned.
As the concomitant drug, various central nervous system agonists or therapeutic drugs (such as diabetes therapeutic drugs) for diseases that are likely to accompany schizophrenia are preferable.
The compound of the present invention can be used in combination with a concomitant drug that does not act on GPR52.
　本発明の化合物と併用薬物の投与形態は、特に限定されず、投与時に、本発明の化合物と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、
（１）本発明の化合物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、
（２）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、
（３）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、
（４）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、
（５）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例えば、本発明の化合物→併用薬物の順序での投与、あるいは逆の順序での投与）などが用いられる。以下、これらの投与形態をまとめて、本発明の併用剤と略記する。 The administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such dosage forms include:
(1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug,
(3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention → the concomitant drug) Or administration in the reverse order). Hereinafter, these administration forms are collectively abbreviated as the combination agent of the present invention.
　本発明の併用剤を投与するに際しては、併用薬物と本発明の化合物とを同時期に投与してもよいが、併用薬物の投与の後、本発明の化合物を投与してもよいし、本発明の化合物の投与後、併用薬物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形および投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後１分～３日以内、好ましくは１０分～１日以内、より好ましくは１５分～１時間以内に本発明の化合物を投与する方法が挙げられる。本発明の化合物を先に投与する場合、本発明の化合物を投与した後、１分～１日以内、好ましくは１０分～６時間以内、より好ましくは１５分～１時間以内に併用薬物を投与する方法が挙げられる。 When administering the concomitant drug of the present invention, the concomitant drug and the compound of the present invention may be administered at the same time, but after administering the concomitant drug, the compound of the present invention may be administered. A concomitant drug may be administered after administration of the compound of the invention. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when administering a concomitant drug first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. The method of doing is mentioned.
　併用薬物は、副作用が問題とならなければ、どのような量を設定することも可能である。併用薬物としての一日投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、例えば、統合失調症の患者（成人、体重約６０ｋｇ）に経口投与する場合、通常１回量として約０．１～約２０ｍｇ／ｋｇ体重、好ましくは約０．２～約１０ｍｇ／ｋｇ体重、さらに好ましくは約０．５～約１０ｍｇ／ｋｇ体重であり、この量を１日１回～数回（例、３回）投与するのが望ましい。
　本発明の化合物が併用薬物と組み合せて使用される場合には、お互いの剤の量は、それらの剤の反対効果を考えて安全な範囲内で低減できる。 Any amount of the concomitant drug can be set as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when administered orally to a schizophrenic patient (adult, body weight about 60 kg), it is usually a single dose. About 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once (eg, 3 times).
When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
　本発明の併用剤は、毒性が低く、例えば、本発明の化合物または（および）上記併用薬物を公知の方法に従って、薬理学的に許容される担体と混合して、例えば錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バックル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤等の剤形とし、経口的または非経口的（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、内皮、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位、病巣等）に安全に投与することができる。 The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a tablet (sugar-coated tablet, film coating) Tablets, sublingual tablets, orally disintegrating tablets, buckle tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, solutions, emulsions, suspensions Suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, orally disintegrating films, oral mucosal film), injections (eg , Subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), instillation, transdermal preparation, ointment, lotion, patch, suppository (eg, anal suppository, vaginal seat) Agent), pellet, nasal agent, trans The dosage form is an agent (inhalant), eye drops, etc., orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, endothelium, ophthalmic, intracerebral, rectal, intravaginal, Intraperitoneal, intratumoral, proximal to tumor, lesion, etc.).
　本発明の併用剤の製造に用いられてもよい薬理学的に許容される担体としては、上記した本発明の医薬組成物に使用されるものと同様のものを使用することができる。 As the pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention, the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
　本発明の併用剤における本発明の化合物と併用薬物との配合比は、投与対象、投与ルート、疾患などにより適宜選択することができる。
　上記併用薬物は、２種以上を適宜の割合で組み合せて用いてもよい。
　併用薬物の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明の化合物と併用薬物の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明の化合物１重量部に対し、併用薬物を０．０１～１００重量部用いればよい。 The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
The dose of the concomitant drug can be appropriately selected on the basis of the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
　例えば、本発明の併用剤における本発明の化合物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１～９９．９重量％の範囲であり、好ましくは約０．１～５０重量％の範囲であり、さらに好ましくは約０．５～２０重量％程度の範囲である。 For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight, preferably about 0, based on the whole preparation. The range is from 1 to 50% by weight, more preferably from about 0.5 to 20% by weight.
　本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１～９９．９重量％の範囲であり、好ましくは約０．１～約５０重量％の範囲であり、さらに好ましくは約０．５～約２０重量％の範囲である。 The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight with respect to the whole preparation, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.
　本発明の併用剤における担体などの添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約１～９９．９９重量％の範囲であり、好ましくは約１０～約９０重量％の範囲である。 The content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by weight, preferably about 10 to about 90% relative to the whole preparation. It is in the range of wt%.
　本発明の化合物および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。 The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
　上記したように投与量は種々の条件で変動するので、上記投与量より少ない量で十分な場合もあり、また範囲を超えて投与する必要がある場合もある。 As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
［製造方法］
　本発明の化合物の製造法を、以下に説明する。
　化合物（Ｉ）、および化合物（Ｉ）に包含される化合物（Ｉａ）、（Ｉａａ）、（Ｉｂ）、（Ｉｃ）、（Ｉｄ）、（Ｉｅ）、（Ｉｆ）、（Ｉｇ）、（Ｉｈ）および（Ｉｉ）は、例えば以下の反応式で示される方法またはこれに準じた方法により得られる。なお、式中の化合物は、塩を形成している場合も含み、このような塩としては、例えば前述の化合物（Ｉ）の塩と同様のものが挙げられる。また、各工程で得られた化合物は反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、それ自体が公知の手段、例えば、抽出、濃縮、中和、濾過、蒸留、再結晶、クロマトグラフィーなどの分離手段により容易に精製することができる。あるいは、式中の化合物が市販されている場合には市販品をそのまま用いることもできる。
　化合物（Ｉａ）は、次の反応式１に記載の方法によって製造することができる。
反応式１ [Production method]
A method for producing the compound of the present invention will be described below.
Compound (I) and compounds (Ia), (Iaa), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) included in compound (I) And (Ii) can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto. In addition, the compound in a formula also includes the case where it forms the salt, As such a salt, the thing similar to the salt of the above-mentioned compound (I) is mentioned, for example. In addition, the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method. It can be easily purified by separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization and chromatography. Or when the compound in a formula is marketed, a commercial item can also be used as it is.
Compound (Ia) can be produced by the method described in Reaction Scheme 1 below.
Reaction formula 1
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
（式中、Ｘ１、Ｘ２およびＸ３は、それぞれ独立して脱離基を示し；Ｒ４は置換基を有していてもよいＣ１－６アルキル基を示し；Ｒａはそれぞれ独立して、水素原子またはＣ１－６アルキル基を示すか、あるいは２つのＲａが結合してＣ２－６アルキレン鎖を形成してもよく；その他の記号は前記と同意義を示す。）
　Ｘ１、Ｘ２またはＸ３で示される「脱離基」としては、例えば、ヒドロキシ基、ハロゲン原子（例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、ハロゲン化されていてもよいＣ１－６アルコキシ基（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）、ハロゲン化されていてもよいＣ１－５アルキルスルホニルオキシ基（例、メタンスルホニルオキシ、エタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）、ハロゲン化されていてもよいＣ１－６アシルオキシ基（例、アセチルオキシ、トリフルオロアセチルオキシ等）、置換されていてもよいＣ６－１０アリールスルホニルオキシ基（例、４－トルエンスルホニルオキシ基）、置換されていてもよいフェニルオキシ基、置換されていてもよいベンゾチアゾール－２－イルチオ基等が挙げられる。
　２つのＲａが形成するＣ２－６アルキレン鎖としては例えば、－ＣＨ２－ＣＨ２－、－Ｃ（ＣＨ３）２－Ｃ（ＣＨ３）２－、－ＣＨ２－ＣＨ２－ＣＨ２－、および－ＣＨ２－Ｃ（ＣＨ３）２－ＣＨ２－等が挙げられる。 (Wherein X 1 , X 2 and X 3 each independently represent a leaving group; R 4 represents an optionally substituted C 1-6 alkyl group; R a represents each independently And may represent a hydrogen atom or a C 1-6 alkyl group, or two R a may combine to form a C 2-6 alkylene chain; other symbols are as defined above.)
Examples of the “leaving group” represented by X 1 , X 2 or X 3 include a hydroxy group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom), and optionally halogenated C. 1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), optionally halogenated C 1-5 alkylsulfonyloxy groups (eg Methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), optionally halogenated C 1-6 acyloxy group (eg, acetyloxy, trifluoroacetyloxy, etc.), optionally substituted C 6 -10 arylsulfonyloxy group (e.g., 4-toluenesulfonyl Oki Group), an optionally substituted phenyl group, and a good benzothiazol-2-ylthio group which may be substituted.
The C 2-6 alkylene chain in which two R a is formed, for example, -CH 2 -CH 2 -, - C (CH 3) 2 -C (CH 3) 2 -, - CH 2 -CH 2 -CH 2 -, And -CH 2 -C (CH 3 ) 2 -CH 2- and the like.
［工程１］
　化合物（ＩＩＩ）は化合物（ＩＩ）のクライゼン縮合あるいは類似の反応によって製造することができる。
　本反応は、例えば所望により「塩基」および「縮合剤」の存在下、化合物（ＩＩ）とメルドラム酸を縮合させた後、メタノールまたはエタノールなどの一般式：Ｒ４－ＯＨで表されるアルコール溶媒中あるいはアルコール溶媒と他の「有機合成に用いられる溶媒」との混合溶媒中での加溶媒分解により合成する方法（ジャーナル　オブ　オーガニック　ケミストリー (J. Org. Chem.), 70, 5331-5334, (2005)）が挙げられる。
　「塩基」としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム等の塩基性塩類、ピリジン、ルチジン等の芳香族アミン類、トリエチルアミン、トリプロピルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、Ｎ－メチルモルホリン等の第３級アミン類、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム第三ブトキシド、カリウム第三ブトキシド等の金属アルコキシド類等が挙げられる。塩基の使用量は、化合物（ＩＩ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「縮合剤」としては、例えば、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、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（ＷＳＣ）等のＮ，Ｎ－カルボジイミド類；Ｎ，Ｎ－カルボニルイミダゾール等のアゾライト類；２－クロロ－１－メチルピリジニウムヨージド、２－フルオロ－１－メチルピリジニウムヨージド等の２－ハロゲノピリジニウム塩；その他、Ｎ－エトキシカルボニル－２－エトキシ－１，２－ジヒドロキノリン、ヘキサフルオロりん酸２－（７－アザ－１Ｈ－ベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウム（ＨＡＴＵ）、１Ｈ－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）、ブロモトリピロリジノホスホニウムヘキサフルオロホスフェート（ＰｙＢｒｏｐ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリドｎ水和物（ＤＭＴＭＭ）、シアノリン酸ジエチル（ＤＥＰＣ）、ジフェニルホスホリルアジド（ジフェニルリン酸アジド；ＤＰＰＡ）、オキシ塩化リン、無水酢酸等が挙げられる。縮合剤の使用量は、化合物（ＩＩ）１モルに対し、通常約０．８～約５モル、好ましくは約１～約３モルである。
　当該反応は、所望により、１－ヒドロキシ－１Ｈ－ベンゾトリアゾール（ＨＯＢｔ）一水和物等の縮合促進剤を共存させてもよい。塩基の使用量は、化合物（ＩＩ）１モルに対し、通常約０．５～約５モル、好ましくは約１～約３モルである。
　「有機合成に用いられる溶媒」としては、アルコール類（例、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ｔｅｒｔ－ブタノール等）、エーテル類（例、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル、１，２－ジメトキシエタン等）、エステル類（例、ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル等）、カルボン酸類（例、ギ酸、酢酸、プロピオン酸等）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、四塩化炭素、トリクロロエチレン、１，２－ジクロロエタン、クロロベンゼン等）、炭化水素類（例、ｎ－ヘキサン、ベンゼン、トルエン等）、アミド類（例、ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド等）、ケトン類（例、アセトン、メチルエチルケトン、メチルイソブチルケトン等）、ニトリル類（例、アセトニトリル、プロピオニトリル等）、スルホキシド類（例、ジメチルスルホキシド等）、含窒素芳香族炭化水素類（例、ピリジン、ルチジン、キノリン等）等の溶媒等のほか、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
　他の例として、化合物（ＩＩ）をアシルイミダゾリドへと変換した後、トリエチルアミンなどの塩基および塩化マグネシウム存在下、マロン酸モノアルキルエステルあるいはその塩を反応させる方法（ジャーナル　オブ　メディシナル　ケミストリー (J. Med. Chem.), 42, 619-627, (1999)）などが挙げられる。 [Step 1]
Compound (III) can be produced by Claisen condensation of compound (II) or a similar reaction.
This reaction is carried out, for example, by condensing compound (II) with Meldrum's acid in the presence of a “base” and a “condensing agent”, if desired, and then an alcohol solvent represented by a general formula: R 4 —OH such as methanol or ethanol Or solvolysis in a mixed solvent of alcohol solvent and other “solvents used in organic synthesis” (Journal of Organic Chemistry (J. Org. Chem.), 70, 5331-5334, ( 2005)).
As the “base”, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethyl Tertiary amines such as aminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc. And metal alkoxides. The amount of the base to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (II).
Examples of the “condensation agent” include N, N-carbodiimides such as N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC); N, N-carbonyl Azolites such as imidazole; 2-halogenopyridinium salts such as 2-chloro-1-methylpyridinium iodide and 2-fluoro-1-methylpyridinium iodide; and other N-ethoxycarbonyl-2-ethoxy-1,2- Dihydroquinoline, 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), 1H-benzotriazol-1-yloxytris hexafluorophosphate (Dimethylamino) phosphonium hexafluorophosphate (BOP), bromotripi Loridinophosphonium hexafluorophosphate (PyBrop), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate (DMTMM), diethyl cyanophosphate (DEPC), diphenylphosphoryl azide (diphenylphosphoric acid azide; DPPA), phosphorus oxychloride, acetic anhydride and the like. The amount of the condensing agent to be used is generally about 0.8 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (II).
In the reaction, if desired, a condensation accelerator such as 1-hydroxy-1H-benzotriazole (HOBt) monohydrate may coexist. The amount of the base to be used is generally about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (II).
Examples of the “solvent used in organic synthesis” include alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, Diisopropyl ether, 1,2-dimethoxyethane, etc.), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), halogenated hydrocarbons ( Eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (eg, n-hexane, benzene, toluene, etc.), amides (eg, formamide, N, N-dimethyl) Formamide, N, N-dimethyl Luaceamide, etc.), ketones (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), nitrogen-containing aromatic hydrocarbons In addition to solvents such as pyridine, lutidine, quinoline and the like, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
As another example, compound (II) is converted to acylimidazolide, and then a malonic acid monoalkyl ester or a salt thereof is reacted in the presence of a base such as triethylamine and magnesium chloride (Journal of Medicinal Chemistry (J. Med Chem.), 42, 619-627, (1999)).
［工程２］
　化合物（Ｖ）は化合物（ＩＩＩ）と化合物（ＩＶ）を、反応式１工程１で示した「有機合成に用いられる溶媒」中反応させることによって製造することができる。中でもメタノールあるいはエタノールなどのアルコール溶媒を用いるのが好ましい。
　化合物（ＩＶ）の使用量は、化合物（ＩＩＩ）１モルに対し約０．５～約２０モル、好ましくは約０．９～約５モルである。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 2]
Compound (V) can be produced by reacting compound (III) and compound (IV) in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1. Among them, it is preferable to use an alcohol solvent such as methanol or ethanol.
The amount of compound (IV) to be used is about 0.5 to about 20 mol, preferably about 0.9 to about 5 mol, per 1 mol of compound (III).
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程３］
　化合物（ＶＩ）は化合物（Ｖ）のハロゲン化あるいはスルホニル化によって製造することができる。
　ハロゲン化は例えば、塩化チオニル、オキシ塩化リン、フェニルホスホン酸ジクロリド、オキシ臭化リン、三塩化リン、三臭化リンなどを用いて行うことができる。
　塩化チオニル、オキシ塩化リン、フェニルホスホン酸ジクロリド、オキシ臭化リン、三塩化リン、三臭化リンなどの使用量は、化合物（ＶＩ）１モルに対し約０．５～約５０モル、好ましくは約０．９～約３０モルである。
　ハロゲン化には反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。
　反応温度は通常－３０℃～２５０℃、好ましくは－３０℃～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。
　スルホニル化は例えば、所望により塩基の存在下、塩化メタンスルホニル、トリフルオロメタンスルホン酸無水物、Ｎ－フェニルビス（トリフルオロメタンスルホンイミド）などを用いて行うことができる。
　塩化メタンスルホニル、トリフルオロメタンスルホン酸無水物、Ｎ－フェニルビス（トリフルオロメタンスルホンイミド）などの使用量は、化合物（ＶＩ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「塩基」としては、例えば、例えば反応式１工程１で示した「塩基」が用いられる。塩基の使用量は、化合物（ＶＩ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　スルホニル化には反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でも、ピリジン、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）が望ましい。
　反応温度は通常－１００℃～２５０℃、好ましくは－７８℃～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。
　中でも、フェニルホスホン酸ジクロリドを用いる方法、トリフルオロメタンスルホン酸無水物を用いる方法が好ましい。 [Step 3]
Compound (VI) can be produced by halogenation or sulfonylation of compound (V).
Halogenation can be performed using, for example, thionyl chloride, phosphorus oxychloride, phenylphosphonic dichloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, and the like.
The amount of thionyl chloride, phosphorus oxychloride, phenylphosphonic acid dichloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide and the like to be used is about 0.5 to about 50 mol, preferably about 1 to 1 mol of compound (VI) About 0.9 to about 30 moles.
For the halogenation, the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used.
The reaction temperature is usually −30 ° C. to 250 ° C., preferably −30 ° C. to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
The sulfonylation can be carried out, for example, using methanesulfonyl chloride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) or the like, if desired, in the presence of a base.
The amount of methanesulfonyl chloride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) and the like to be used is about 0.5 to about 10 mol, preferably about 0.9, per 1 mol of compound (VI). To about 3 moles.
As the “base”, for example, the “base” shown in Reaction Scheme 1 Step 1 is used. The amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (VI).
For the sulfonylation, the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used. Of these, pyridine and N, N-dimethylformamide (DMF) are preferable.
The reaction temperature is usually −100 ° C. to 250 ° C., preferably −78 ° C. to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
Among these, a method using phenylphosphonic acid dichloride and a method using trifluoromethanesulfonic anhydride are preferable.
［工程４］
　化合物（Ｉａ）は、化合物（ＶＩ）と化合物（ＶＩＩ）の鈴木カップリング反応により製造される。
　化合物（ＶＩＩ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　反応は、化合物（ＶＩ）と化合物（ＶＩＩ）を、工程１で示した「有機合成に用いられる溶媒」中、反応式１工程１で示した「塩基」および遷移金属触媒の存在下で行う。
　化合物（ＶＩＩ）の使用量は、化合物（ＶＩ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「塩基」の使用量は、化合物（ＶＩ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「遷移金属触媒」としては、酢酸パラジウム（ＩＩ）、塩化パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）、ジクロロ［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）等のパラジウム触媒などが用いられる。遷移金属触媒の使用量は、化合物（ＶＩ）１モルに対し約０．００１～約３モル、好ましくは約０．０２～約０．２モルである。
　本反応には、ジシクロヘキシル［２’，４’，６’－トリス（１－メチルエチル）ビフェニル－２－イル］ホスファン等の配位子を用いてもよい。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。
　本反応は、マイクロウェーブ反応装置などを用いることにより反応時間の短縮を図ることができる。 [Step 4]
Compound (Ia) is produced by a Suzuki coupling reaction of compound (VI) and compound (VII).
Compound (VII) can be obtained as a commercial product, and can also be produced according to a method known per se or a method analogous thereto.
In the reaction, Compound (VI) and Compound (VII) are carried out in the “solvent used for organic synthesis” shown in Step 1 in the presence of the “base” shown in Reaction Formula 1 Step 1 and a transition metal catalyst.
The amount of compound (VII) to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (VI).
The amount of the “base” to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (VI).
Examples of the “transition metal catalyst” include palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) , Palladium catalysts such as dichlorobis (triphenylphosphine) palladium (II) and tris (dibenzylideneacetone) dipalladium (0). The amount of the transition metal catalyst to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (VI).
In this reaction, a ligand such as dicyclohexyl [2 ′, 4 ′, 6′-tris (1-methylethyl) biphenyl-2-yl] phosphane may be used.
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.
［工程５］
　化合物（ＶＩＩＩ）は、化合物（ＶＩ）のホウ素化反応により製造される。ホウ素化反応は、例えば、化合物（ＶＩ）から調製したグリニャール試薬あるいは有機リチウム試薬とトリアルキルボラートを反応させる方法、化合物（ＶＩ）とビスピナコラートジボロンなどのジボロン酸エステルを、ジクロロ［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）などの遷移金属触媒および酢酸カリウムなどの塩基存在下、反応式１工程１で示した「有機合成に用いられる溶媒」中反応させる方法などが挙げられる。
　化合物（ＶＩ）のグリニャール試薬あるいは有機リチウム試薬は、自体公知の方法またはこれらに準じた方法に従って製造することができる。
　トリアルキルボラートの使用量は、化合物（ＶＩ）１モルに対し約０．５～約５モル、好ましくは約１～約３モルである。
　ジボロン酸エステルの使用量は、化合物（ＶＩ）１モルに対し約０．５～約５モル、好ましくは約１～約３モルである。
　遷移金属触媒の使用量は、化合物（ＶＩ）１モルに対し約０．０００１～約２モル、好ましくは約０．０１～約０．３モルである。
　塩基の使用量は、化合物（ＶＩ）１モルに対し約０．５～約１０モル、好ましくは約１～約３モルである。
　中でも、化合物（ＶＩ）とビスピナコラートジボロンを、ジクロロ［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）および酢酸カリウム存在下、ＤＭＦ中で反応させるのが好ましい。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 5]
Compound (VIII) is produced by a boronation reaction of compound (VI). For example, the boronation reaction may be carried out by reacting a Grignard reagent or organolithium reagent prepared from compound (VI) with a trialkylborate, and diboronate such as bispinacolatodiboron with dichloro [1 , 1′-bis (diphenylphosphino) ferrocene] palladium (II) and the like, and a base in the presence of a base such as potassium acetate, a method of reacting in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 Etc.
The Grignard reagent or organolithium reagent of compound (VI) can be produced according to a method known per se or a method analogous thereto.
The amount of the trialkyl borate to be used is about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (VI).
The amount of diboronic acid ester to be used is about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (VI).
The amount of the transition metal catalyst to be used is about 0.0001 to about 2 mol, preferably about 0.01 to about 0.3 mol, per 1 mol of compound (VI).
The amount of the base to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (VI).
Among them, it is preferable to react the compound (VI) and bispinacolatodiboron in DMF in the presence of dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) and potassium acetate.
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程６］
　化合物（Ｉａ）は、化合物（ＶＩＩＩ）と化合物（ＩＸ）の鈴木カップリング反応により製造される。
　化合物（ＩＸ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　鈴木カップリング反応は、反応式１工程４に記載の方法と同様にして行うことができる。 [Step 6]
Compound (Ia) is produced by a Suzuki coupling reaction of compound (VIII) and compound (IX).
Compound (IX) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
The Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
　化合物（Ｉａａ）は、次の反応式２に記載の方法によって製造することができる。
反応式２ Compound (Iaa) can be produced by the method described in Reaction Scheme 2 below.
Reaction formula 2
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
（式中、各記号は前記と同意義を示す。）
［工程１］
　化合物（ＸＩＩ）は化合物（Ｘ）と化合物（ＸＩ）を塩基の存在下反応させることにより製造することができる。
　化合物（Ｘ）および化合物（ＸＩ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　化合物（ＸＩ）の使用量は、化合物（Ｘ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「塩基」としては、例えば、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム第三ブトキシド、カリウム第三ブトキシド等の金属アルコキシド類、水素化ナトリウム、水素化カリウムなどの金属ヒドリド類、リチウムジイソプロピルアミド、ナトリウムビス（トリメチルシリルアミド）、カリウムビス（トリメチルシリルアミド）などの金属アミド類等が用いられる。塩基の使用量は、化合物（Ｘ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　反応温度は通常－１００～１５０℃、好ましくは－８０～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 (In the formula, each symbol is as defined above.)
[Step 1]
Compound (XII) can be produced by reacting compound (X) with compound (XI) in the presence of a base.
Compound (X) and compound (XI) are commercially available, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (XI) to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (X).
Examples of the “base” include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, lithium diisopropylamide, sodium bis Metal amides such as (trimethylsilylamide) and potassium bis (trimethylsilylamide) are used. The amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (X).
The reaction temperature is usually −100 to 150 ° C., preferably −80 to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程２］
　化合物（ＸＩＩＩ）は化合物（ＸＩＩ）と化合物（ＩＶ）を反応させることにより製造することができる。本反応は反応式１工程２に記載の方法と同様にして行うことができる。 [Step 2]
Compound (XIII) can be produced by reacting compound (XII) with compound (IV). This reaction can be carried out in the same manner as in the method described in Reaction Scheme 1, Step 2.
［工程３］
　化合物（ＸＩＶ）は化合物（ＸＩＩＩ）の還元反応により製造することができる。還元反応は、溶媒中、化合物（ＸＩＩＩ）に対して還元剤を０．１モル当量～大過剰（好ましくは０．３～１０モル当量）使用して行うことができる。
　「還元剤」としては、例えば、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化ジイソブチルアルミニウム、水素化ホウ素カルシウム、ボラン錯体（ボラン－ＴＨＦ錯体など）などが挙げられる。中でも水素化ホウ素ナトリウムが好ましい。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられるが、中でもテトラヒドロフラン等のエーテル系溶媒、メタノール、エタノールなどのアルコール系溶媒が好ましい。
　反応時間は、通常、約０．１～約７２時間、好ましくは約０．３～約２４時間である。反応温度は、通常、約－８０℃～約１５０℃、好ましくは約－３０℃～約１００℃である。 [Step 3]
Compound (XIV) can be produced by a reduction reaction of compound (XIII). The reduction reaction can be carried out in a solvent using a reducing agent in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) relative to compound (XIII).
Examples of the “reducing agent” include lithium aluminum hydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, calcium borohydride, borane complex (borane-THF complex, etc.), and the like. Of these, sodium borohydride is preferred.
As the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used. Among them, ether solvents such as tetrahydrofuran and alcohol solvents such as methanol and ethanol are preferable.
The reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours. The reaction temperature is usually about −80 ° C. to about 150 ° C., preferably about −30 ° C. to about 100 ° C.
［工程４］
　化合物（ＸＶ）は化合物（ＸＩＶ）のハロゲン化あるいはスルホニル化によって製造することができる。該反応は反応式１工程３に記載の方法と同様にして行うことができる。 [Step 4]
Compound (XV) can be produced by halogenation or sulfonylation of compound (XIV). This reaction can be carried out in the same manner as in the method described in Reaction Scheme 1, Step 3.
［工程５］
　化合物（Ｉａａ）は化合物（ＸＶ）と化合物（ＸＶＩ）の鈴木カップリング反応により製造される。
　化合物（ＸＶＩ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　鈴木カップリング反応は、反応式１工程４に記載の方法と同様にして行うことができる。 [Step 5]
Compound (Iaa) is produced by a Suzuki coupling reaction of compound (XV) and compound (XVI).
Compound (XVI) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
The Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
　反応式２中にある化合物（ＸＩＶ）は、次の反応式Ａ２に記載の方法によっても製造することができる。
反応式Ａ２ Compound (XIV) in Reaction Scheme 2 can also be produced by the method described in the following Reaction Formula A2.
Reaction formula A2
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
（式中の記号は前記と同意義を示す。）
［工程１］
　化合物（Ｃ２）は、化合物（Ｃ１）と化合物（ＩＶ）から、反応式２工程２と同様の方法により製造することができる。
［工程２］
　化合物（Ｃ３）は、化合物（Ｃ２）から、反応式１工程３と同様の方法により製造することができる。
［工程３］
　化合物（ＸＩＶ）は、化合物（Ｃ３）と化合物（ＶＩＩ）から、反応式１工程４と同様の方法により製造することができる。 (The symbols in the formula are as defined above.)
[Step 1]
Compound (C2) can be produced from compound (C1) and compound (IV) by the same method as in Reaction Scheme 2, Step 2.
[Step 2]
Compound (C3) can be produced from compound (C2) by the same method as in Reaction Scheme 1, Step 3.
[Step 3]
Compound (XIV) can be produced from compound (C3) and compound (VII) by the same method as in Reaction Scheme 1, Step 4.
　化合物（Ｉｂ）は、次の反応式３に記載の方法によって製造することができる。
反応式３ Compound (Ib) can be produced by the method described in Reaction Scheme 3 below.
Reaction formula 3
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
（式中、Ｘ４はハロゲン原子を示し；その他の記号は前記と同意義を示す。）
［工程１］
　化合物（ＸＶＩＩＩ）は化合物（ＸＶＩＩ）と化合物（ＩＸ）を塩基および所望により遷移金属触媒の存在下、溶媒中反応させることにより製造することができる。
　化合物（ＸＶＩＩ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　化合物（ＩＸ）の使用量は、化合物（ＸＶＩＩ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「塩基」としては、反応式１工程１で示した「塩基」が用いられる。塩基の使用量は、化合物（ＸＶＩＩ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「遷移金属触媒」としては、酢酸パラジウム（ＩＩ）、塩化パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）、ジクロロ［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）等のパラジウム触媒、塩化銅（Ｉ）、塩化銅（ＩＩ）、臭化銅（Ｉ）、臭ヨウ化銅（Ｉ）、酢酸銅などの銅触媒などが用いられる。遷移金属触媒の使用量は、化合物（ＸＶＩＩ）１モルに対し約０．００１～約５モル、好ましくは約０．０２～約２モルである。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。
　反応温度は通常－５０～２５０℃、好ましくは０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 (In the formula, X 4 represents a halogen atom; other symbols have the same meaning as described above.)
[Step 1]
Compound (XVIII) can be produced by reacting compound (XVII) and compound (IX) in a solvent in the presence of a base and optionally a transition metal catalyst.
Compound (XVII) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (IX) to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XVII).
As the “base”, the “base” shown in Reaction Scheme 1, Step 1 is used. The amount of the base to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XVII).
Examples of the “transition metal catalyst” include palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) , Dichlorobis (triphenylphosphine) palladium (II), palladium catalyst such as tris (dibenzylideneacetone) dipalladium (0), copper chloride (I), copper chloride (II), copper bromide (I), bromoiodide Copper catalysts such as copper (I) and copper acetate are used. The amount of the transition metal catalyst to be used is about 0.001 to about 5 mol, preferably about 0.02 to about 2 mol, per 1 mol of compound (XVII).
As the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used.
The reaction temperature is usually −50 to 250 ° C., preferably 0 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程２］
　化合物（Ｉｂ）は化合物（ＸＶＩＩＩ）と化合物（ＸＩＸ）との根岸クロスカップリング反応により製造することができる。
　化合物（ＸＩＸ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　根岸クロスカップリング反応は、化合物（ＸＶＩＩＩ）と化合物（ＸＩＸ）を、反応式１工程１で示した「有機合成に用いられる溶媒」中、遷移金属触媒存在下で行う。
　化合物（ＸＩＸ）の使用量は、化合物（ＸＶＩＩＩ）１モルに対し約０．５～約２０モル、好ましくは約０．９～約１０モルである。
　「遷移金属触媒」としては、反応式１工程１で示した「遷移金属触媒」の他、ジクロロビス（トリフェニルホスフィン）ニッケルなどのニッケル触媒なども用いられる。遷移金属触媒の使用量は、化合物（ＸＶＩＩＩ）１モルに対し約０．００１～約３モル、好ましくは約０．０２～約０．２モルである。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられるが、中でもテトラヒドロフラン等のエーテル系溶媒、ＤＭＦなどが好ましい。
　本反応には、ジシクロヘキシル［２’，４’，６’－トリス（１－メチルエチル）ビフェニル－２－イル］ホスファン等の配位子を用いてもよい。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。
　本反応は、マイクロウェーブ反応装置などを用いることにより反応時間の短縮を図ることができる。 [Step 2]
Compound (Ib) can be produced by a Negishi cross-coupling reaction between compound (XVIII) and compound (XIX).
Compound (XIX) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
In the Negishi cross-coupling reaction, the compound (XVIII) and the compound (XIX) are carried out in the presence of a transition metal catalyst in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1.
The amount of compound (XIX) to be used is about 0.5 to about 20 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XVIII).
As the “transition metal catalyst”, a nickel catalyst such as dichlorobis (triphenylphosphine) nickel or the like may be used in addition to the “transition metal catalyst” shown in Reaction Formula 1 Step 1. The amount of the transition metal catalyst to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (XVIII).
As the “solvent”, for example, the “solvent used for organic synthesis” shown in Reaction Scheme 1 Step 1 is used, among which ether solvents such as tetrahydrofuran, DMF and the like are preferable.
In this reaction, a ligand such as dicyclohexyl [2 ′, 4 ′, 6′-tris (1-methylethyl) biphenyl-2-yl] phosphane may be used.
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.
　化合物（Ｉｃ）は、次の反応式４に記載の方法によって製造することができる。
反応式４ Compound (Ic) can be produced by the method described in Reaction Scheme 4 below.
Reaction formula 4
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
（式中、各記号は前記と同意義を示す。）
［工程１］
　化合物（ＸＸＩＩ）は化合物（ＸＸ）と化合物（ＸＸＩ）を所望により「酸」あるいは「塩基」の存在下、溶媒中反応させることにより製造することができる。
　化合物（ＸＸ）および化合物（ＸＸＩ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　化合物（ＸＸＩ）の使用量は、化合物（ＸＸ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　「酸」としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸、硝酸等の鉱酸類、酢酸、トリフルオロ酢酸等のカルボン酸類、メタンスルホン酸、トリフルオロメタンスルホン酸、ｐ-トルエンスルホン酸などのスルホン酸類などが用いられ、中でも硫酸などの鉱酸類が好ましい。酸の使用量は、化合物（ＸＸ）に対して好ましくは、約０．５～約１０モル当量である。
　「塩基」としては、例えば、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム第三ブトキシド、カリウム第三ブトキシド等の金属アルコキシド類、水素化ナトリウム、水素化カリウムなどの金属ヒドリド類、リチウムジイソプロピルアミド、ナトリウムビス（トリメチルシリルアミド）、カリウムビス（トリメチルシリルアミド）などの金属アミド類等が用いられる。塩基の使用量は、化合物（ＸＸ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられるが、中でもトルエンなどが好ましい。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 (In the formula, each symbol is as defined above.)
[Step 1]
Compound (XXII) can be produced by reacting compound (XX) and compound (XXI) in a solvent in the presence of an “acid” or “base” as desired.
Compound (XX) and compound (XXI) are commercially available, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (XXI) to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XX).
"Acids" include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, nitric acid such as nitric acid, carboxylic acids such as acetic acid and trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluene Sulfonic acids such as sulfonic acid are used, and among them, mineral acids such as sulfuric acid are preferable. The amount of the acid to be used is preferably about 0.5 to about 10 molar equivalents relative to compound (XX).
Examples of the “base” include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, lithium diisopropylamide, sodium bis Metal amides such as (trimethylsilylamide) and potassium bis (trimethylsilylamide) are used. The amount of the base used is approximately 0.5 to approximately 30 mol, preferably approximately 0.9 to approximately 10 mol, with respect to 1 mol of the compound (XX).
As the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used, and among these, toluene and the like are preferable.
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程２］
　化合物（Ｉｃ）は化合物（ＸＸＩＩ）と化合物（ＸＸＩＩＩ）を所望により「酸」あるいは「塩基」の存在下、溶媒中反応させることにより製造することができる。
　化合物（ＸＸＩＩＩ）の使用量は、化合物（ＸＸＩＩ）１モルに対し約０．５～約５モル、好ましくは約１～約３モルである。
　「酸」としては、例えば反応式４工程１で示した「酸」が用いられる。酸の使用量は、化合物（ＸＸＩＩ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　「塩基」としては、例えば反応式１工程１で示した「塩基」が用いられる。塩基の使用量は、化合物（ＸＸＩＩ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。
　中でも、ピリジン中反応させるのが好ましい。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 2]
Compound (Ic) can be produced by reacting compound (XXII) and compound (XXIII) in a solvent in the presence of an “acid” or “base” as desired.
The amount of compound (XXIII) to be used is about 0.5 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXII).
As the “acid”, for example, the “acid” shown in Reaction Scheme 4, Step 1 is used. The amount of the acid to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXII).
As the “base”, for example, the “base” shown in Reaction Scheme 1, Step 1 is used. The amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXII).
As the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used.
Of these, the reaction in pyridine is preferred.
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
　化合物（Ｉｃ）は、次の反応式Ａ１に記載の方法によっても製造することができる。
反応式Ａ１ Compound (Ic) can also be produced by the method described in the following reaction scheme A1.
Reaction formula A1
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
（式中、Ｘ５はＣ１－７アルコキシ基あるいはＣ１－６アルキルスルファニル基を示し；他の記号は前記と同意義を示す。）
［工程１］
　Ｘ５がＣ１－７アルコキシ基である化合物（Ｂ２）は、化合物（Ｂ１）と、一般式：Ｘ５－Ｈで表されるアルコール類とを、「酸」あるいは「塩基」の存在下反応させることにより製造することができる。
　アルコール類としては、例えばメタノール、エタノール、ベンジルアルコールなどが用いられ、中でもメタノール、エタノールが好ましい。アルコール類の使用量は、化合物（Ｂ１）１モルに対し約０．５～約２００モル、好ましくは約０．９～約２０モルである。
　「酸」としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸、硝酸等の鉱酸類、酢酸、トリフルオロ酢酸等のカルボン酸類、メタンスルホン酸、トリフルオロメタンスルホン酸、ｐ－トルエンスルホン酸などのスルホン酸類などが用いられ、中でも塩酸などの鉱酸類が好ましい。酸の使用量は、化合物（Ｂ１）１モルに対して約０．５～約１００モル、好ましくは、約０．９～約３０モルである。
　「塩基」としては、例えば、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム第三ブトキシド、カリウム第三ブトキシド等の金属アルコキシド類、水素化ナトリウム、水素化カリウムなどの金属ヒドリド類、リチウムジイソプロピルアミド、ナトリウムビス（トリメチルシリルアミド）、カリウムビス（トリメチルシリルアミド）などの金属アミド類等が用いられ、中でも金属アルコキシド類、金属ヒドリド類が好ましい。塩基の使用量は、化合物（Ｂ１）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　反応温度は通常－１００～２５０℃、好ましくは－３０～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 (In the formula, X 5 represents a C 1-7 alkoxy group or a C 1-6 alkylsulfanyl group; other symbols are as defined above.)
[Step 1]
The compound (B2) in which X 5 is a C 1-7 alkoxy group is obtained by reacting the compound (B1) with an alcohol represented by the general formula: X 5 -H in the presence of an “acid” or “base”. Can be manufactured.
As the alcohol, for example, methanol, ethanol, benzyl alcohol and the like are used, and methanol and ethanol are particularly preferable. The amount of the alcohol to be used is about 0.5 to about 200 mol, preferably about 0.9 to about 20 mol, per 1 mol of compound (B1).
Examples of the “acid” include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, nitric acid such as nitric acid, carboxylic acids such as acetic acid and trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluene Sulfonic acids such as sulfonic acid are used, and among them, mineral acids such as hydrochloric acid are preferable. The amount of the acid to be used is about 0.5 to about 100 mol, preferably about 0.9 to about 30 mol, per 1 mol of compound (B1).
Examples of the “base” include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, lithium diisopropylamide, sodium bis Metal amides such as (trimethylsilylamide) and potassium bis (trimethylsilylamide) are used, among which metal alkoxides and metal hydrides are preferable. The amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B1).
The reaction temperature is usually −100 to 250 ° C., preferably −30 to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
　Ｘ５がＣ１－６アルキルスルファニル基である化合物（Ｂ２）は、化合物（Ｂ１）をチオアミド化した後、Ｓ－アルキル化することにより製造することができる。
　チオアミド化の方法としては、例えばエタノール中、硫化水素と水硫化ナトリウムなどを用いる方法、例えば反応式１工程１で示した「有機合成に用いられる溶媒」中、ジチオリン酸　Ｏ，Ｏ－ジアルキルなど（例、ジチオリン酸Ｏ，Ｏ－ジエチル）を用いる方法が挙げられる。中でも、ジチオリン酸　Ｏ，Ｏ－ジエチルを用いる方法が好ましい。ジチオリン酸　Ｏ，Ｏ－ジアルキルの使用量は、化合物（Ｂ１）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　反応温度は通常－８０～１００℃、好ましくは－３０～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。
　Ｓ－アルキル化は、例えば、反応式１工程１で示した「有機合成に用いられる溶媒」中、ハロゲン化アルキルを用いることにより行うことができる。中でもアセトン中、ヨウ化メチルを用いる方法が好ましい。ハロゲン化アルキルの使用量は、化合物（Ｂ１）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。
　化合物（Ｂ１）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。 Compound (B2) in which X 5 is a C 1-6 alkylsulfanyl group can be produced by thioamidating compound (B1) and then S-alkylating it.
As a method of thioamidation, for example, a method using hydrogen sulfide and sodium hydrosulfide in ethanol, for example, a “solvent used for organic synthesis” shown in Reaction Formula 1, Step 1, dithiophosphate O, O-dialkyl, etc. Examples thereof include a method using dithiophosphate (O, O-diethyl). Among them, a method using dithiophosphoric acid O, O-diethyl is preferable. The amount of dithiophosphate O, O-dialkyl to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B1).
The reaction temperature is usually −80 to 100 ° C., preferably −30 to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
The S-alkylation can be performed, for example, by using an alkyl halide in the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1. Among them, a method using methyl iodide in acetone is preferable. The amount of the alkyl halide to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B1).
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
Compound (B1) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
［工程２］
　化合物（Ｂ３）は、化合物（Ｂ２）と化合物（ＸＸＩＩＩ）を溶媒中で反応させることにより製造することができる。
　化合物（ＸＸＩＩＩ）の使用量は、化合物（Ｂ２）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　溶媒は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でも、エタノール、イソプロピルアルコールなどのアルコール類や、酢酸などを用いるのが好ましい。
　反応温度は通常－８０～１００℃、好ましくは－３０～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 2]
Compound (B3) can be produced by reacting compound (B2) with compound (XXIII) in a solvent.
The amount of compound (XXIII) to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (B2).
As the solvent, for example, the “solvent used for organic synthesis” shown in Reaction Formula 1, Step 1 is used. Among these, it is preferable to use alcohols such as ethanol and isopropyl alcohol, and acetic acid.
The reaction temperature is usually −80 to 100 ° C., preferably −30 to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程３］
　化合物（Ｉｃ）は、化合物（Ｂ３）と化合物（Ｂ４）または化合物（Ｂ５）を所望により「酸」の存在下、溶媒中あるいは無溶媒で反応させることにより製造することができる。
　化合物（Ｂ４）または（Ｂ５）の使用量は、化合物（Ｂ３）１モルに対し約０．５～約２００モル、好ましくは約０．９～約５０モルである。
　「酸」としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸、硝酸等の鉱酸類、酢酸、トリフルオロ酢酸等のカルボン酸類、メタンスルホン酸、トリフルオロメタンスルホン酸、ｐ－トルエンスルホン酸などのスルホン酸類などが用いられ、中でも酢酸などが好ましい。酸の使用量は、化合物（Ｂ３）１モルに対して約０．５～約１００モル、好ましくは、約０．９～約３０モルである。
　溶媒は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でも酢酸などを用いるのが好ましい。
　反応温度は通常０～２００℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 3]
Compound (Ic) can be produced by reacting compound (B3) with compound (B4) or compound (B5), optionally in the presence of an “acid”, in a solvent or without a solvent.
The amount of compound (B4) or (B5) to be used is about 0.5 to about 200 mol, preferably about 0.9 to about 50 mol, per 1 mol of compound (B3).
Examples of the “acid” include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, nitric acid such as nitric acid, carboxylic acids such as acetic acid and trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluene Sulfonic acids such as sulfonic acid are used, among which acetic acid is preferred. The amount of the acid to be used is about 0.5 to about 100 mol, preferably about 0.9 to about 30 mol, per 1 mol of compound (B3).
As the solvent, for example, the “solvent used for organic synthesis” shown in Reaction Formula 1, Step 1 is used. Of these, it is preferable to use acetic acid.
The reaction temperature is usually 0 to 200 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
　化合物（Ｉｄ）は、次の反応式５に記載の方法によって製造することができる。
反応式５ Compound (Id) can be produced by the method described in Reaction Scheme 5 below.
Reaction formula 5
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
（式中、各記号は前記と同意義を示す。）
［工程１］
　化合物（ＸＸＶＩ）は化合物（ＸＸＩＶ）と化合物（ＸＸＶ）を所望により「塩基」の存在下、溶媒中反応させることにより製造することができる。
　化合物（ＸＸＶ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　化合物（ＸＸＶ）の使用量は、化合物（ＸＸＩＶ）１モルに対し約０．５～約２０モル、好ましくは約１～約１０モルである。
　「塩基」としては、例えば反応式１工程１で示した「塩基」が用いられる。中でも水素化ナトリウムを用いるのが好ましい。塩基の使用量は、化合物（ＸＸＩＶ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でもテトラヒドロフランなどのエーテル系溶媒、ＤＭＦなどが好ましい。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 (In the formula, each symbol is as defined above.)
[Step 1]
Compound (XXVI) can be produced by reacting compound (XXIV) and compound (XXV) in a solvent, optionally in the presence of a “base”.
Compound (XXV) can be obtained as a commercial product, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (XXV) to be used is about 0.5 to about 20 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXIV).
As the “base”, for example, the “base” shown in Reaction Scheme 1, Step 1 is used. Of these, sodium hydride is preferably used. The amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXIV).
As the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used. Of these, ether solvents such as tetrahydrofuran, DMF and the like are preferable.
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程２］
　化合物（ＸＸＶＩＩ）は化合物（ＸＸＶＩ）と化合物（ＶＩＩ）との鈴木カップリング反応により製造することができる。
　鈴木カップリング反応は、反応式１工程４に記載の方法と同様にして行うことができる。 [Step 2]
Compound (XXVII) can be produced by a Suzuki coupling reaction of compound (XXVI) and compound (VII).
The Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
［工程３］
　化合物（ＸＸＶＩＩＩ）は化合物（ＸＸＶＩＩ）の還元反応により製造することができる。
　還元反応は、反応式２工程３に記載の方法と同様にして行うことができる。 [Step 3]
Compound (XXVIII) can be produced by a reduction reaction of compound (XXVII).
The reduction reaction can be performed in the same manner as the method described in Reaction Scheme 2, Step 3.
［工程４］
　化合物（ＸＸＩＸ）は化合物（ＸＸＶＩＩＩ）のハロゲン化あるいはスルホニル化によって製造することができる。
　ハロゲン化あるいはスルホニル化は、反応式１工程３に記載の方法と同様にして行うことができる。 [Step 4]
Compound (XXIX) can be produced by halogenation or sulfonylation of compound (XXVIII).
Halogenation or sulfonylation can be carried out in the same manner as described in Reaction Scheme 1, Step 3.
［工程５］
　化合物（Ｉｄ）は化合物（ＸＸＩＸ）と化合物（ＸＶＩ）との鈴木カップリング反応により製造することができる。
　鈴木カップリング反応は、反応式１工程４に記載の方法と同様にして行うことができる。 [Step 5]
Compound (Id) can be produced by a Suzuki coupling reaction of compound (XXIX) and compound (XVI).
The Suzuki coupling reaction can be performed in the same manner as the method described in Reaction Scheme 1, Step 4.
　化合物（Ｉｅ）は、次の反応式６に記載の方法によって製造することができる。
反応式６ Compound (Ie) can be produced by the method described in Reaction Scheme 6 below.
Reaction formula 6
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
（式中、ＭはＬｉあるいはＭｇＸ４を示し；各記号は前記と同意義を示す。）
［工程１］
　化合物（ＸＸＸＩＩ）は化合物（ＸＸＸ）と化合物（ＸＸＸＩ）との縮合反応により製造することができる。
　化合物（ＸＸＸ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　化合物（ＸＸＸＩ）の使用量は、化合物（ＸＸＸ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　縮合反応は、所望により「縮合剤」あるいは「塩基」の存在下溶媒中で行う。
　「縮合剤」としては、例えば、反応式１工程１で示した「縮合剤」が用いられる。縮合剤の使用量は、化合物（ＸＸＸ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　「塩基」としては、例えば、反応式１工程１で示した「塩基」が用いられる。塩基の使用量は、化合物（ＸＸＸ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でもテトラヒドロフランなどのエーテル系溶媒、ＤＭＦなどが好ましい。
　反応温度は通常－５０℃～２５０℃、好ましくは－３０℃～１００℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 (In the formula, M represents Li or MgX 4 ; each symbol has the same meaning as described above.)
[Step 1]
Compound (XXXII) can be produced by a condensation reaction of compound (XXX) and compound (XXXI).
Compound (XXX) can be obtained as a commercially available product, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (XXXI) to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXX).
The condensation reaction is carried out in a solvent in the presence of a “condensing agent” or “base”, if desired.
As the “condensation agent”, for example, the “condensation agent” shown in Reaction Formula 1, Step 1 is used. The amount of the condensing agent to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXX).
As the “base”, for example, the “base” shown in Reaction Scheme 1, Step 1 is used. The amount of the base to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXX).
As the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used. Of these, ether solvents such as tetrahydrofuran, DMF and the like are preferable.
The reaction temperature is usually −50 ° C. to 250 ° C., preferably −30 ° C. to 100 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程２］
　化合物（ＸＸＸＩＶ）は化合物（ＸＸＸＩＩ）と化合物（ＸＸＸＩＩＩ）とを溶媒中反応させることにより製造することができる。
　化合物（ＸＸＸＩＩＩ）は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。
　化合物（ＸＸＸＩＩＩ）の使用量は、化合物（ＸＸＸＩＩ）１モルに対し約０．５～約１０モル、好ましくは約１～約３モルである。
　「溶媒」は、例えば反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でもテトラヒドロフランなどのエーテル系溶媒が好ましい。
　反応温度は通常－１００℃～２５０℃、好ましくは－８０℃～１００℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 2]
Compound (XXXIV) can be produced by reacting compound (XXXII) with compound (XXXIII) in a solvent.
Compound (XXXIII) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
The amount of compound (XXXIII) to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXII).
As the “solvent”, for example, the “solvent used in organic synthesis” shown in Reaction Scheme 1 Step 1 is used. Of these, ether solvents such as tetrahydrofuran are preferred.
The reaction temperature is usually −100 ° C. to 250 ° C., preferably −80 ° C. to 100 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程３］
　化合物（ＸＸＸＶ）は化合物（ＸＸＸＩＶ）のハロゲン化反応により製造することができる。
　ハロゲン化反応は、例えば、フッ素、塩素、臭素、ヨウ素、Ｎ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド、Ｎ－ヨードスクシンイミドなどのハロゲン化剤を用いる方法により行うことができる。中でも臭素を用いるのが好ましい。
　ハロゲン化剤の使用量は、化合物（ＸＸＸＩＶ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　ハロゲン化には反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でも酢酸などが好ましい。
　反応温度は通常－１００℃～１５０℃、好ましくは－３０℃～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 3]
Compound (XXXV) can be produced by a halogenation reaction of compound (XXXIV).
The halogenation reaction can be carried out by a method using a halogenating agent such as fluorine, chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like. Of these, it is preferable to use bromine.
The amount of the halogenating agent to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XXXIV).
For the halogenation, the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used. Of these, acetic acid is preferred.
The reaction temperature is usually −100 ° C. to 150 ° C., preferably −30 ° C. to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程４］
　化合物（ＸＸＸＶＩ）は化合物（ＸＸＸＶ）のアジド化反応により製造することができる。
　アジド化反応は、例えば、アジ化ナトリウム、トリメチルシリルアジドなどのアジド化剤を用いることにより行うことができる。中でもアジ化ナトリウムを用いるのが好ましい。
　アジド化剤の使用量は、化合物（ＸＸＸＶ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　アジド化には反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でもメタノールあるいはエタノールなどのアルコール溶媒が好ましい。
　反応温度は通常－１００℃～１５０℃、好ましくは－３０℃～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 4]
Compound (XXXVI) can be produced by subjecting compound (XXXV) to an azidation reaction.
The azidation reaction can be performed, for example, by using an azidating agent such as sodium azide or trimethylsilyl azide. Of these, sodium azide is preferably used.
The amount of the azidating agent to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XXXV).
For the azidation, the “solvent used in organic synthesis” shown in Reaction Scheme 1, Step 1 is used. Of these, alcohol solvents such as methanol or ethanol are preferred.
The reaction temperature is usually −100 ° C. to 150 ° C., preferably −30 ° C. to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程５］
　化合物（ＸＸＸＶＩＩ）は化合物（ＸＸＸＶＩ）の還元反応により製造することができる。
　還元反応は、例えば、鉄、亜鉛などの金属類を用いる方法、あるいはトリフェニルホスフィンなどのホスフィン類を用いる方法、あるいはパラジウム－炭素などの遷移金属触媒存在下水素化する方法などを用いることにより行うことができる。中でも亜鉛を用いるのが好ましい。
　亜鉛の使用量は、化合物（ＸＸＸＶＩ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　還元反応には反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でもメタノールあるいはエタノールなどのアルコール溶媒が好ましい。
　反応温度は通常－１００℃～１５０℃、好ましくは－３０℃～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 5]
Compound (XXXVII) can be produced by a reduction reaction of compound (XXXVI).
The reduction reaction is performed, for example, by using a method using a metal such as iron or zinc, a method using a phosphine such as triphenylphosphine, or a method of hydrogenating in the presence of a transition metal catalyst such as palladium-carbon. be able to. Of these, zinc is preferably used.
The amount of zinc to be used is about 0.5 to about 30 mol, preferably about 0.9 to about 10 mol, per 1 mol of compound (XXXVI).
For the reduction reaction, the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used. Of these, alcohol solvents such as methanol or ethanol are preferred.
The reaction temperature is usually −100 ° C. to 150 ° C., preferably −30 ° C. to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程６］
　化合物（ＸＸＸＶＩＩＩ）は化合物（ＸＸＸＶＩＩ）と化合物（ＩＩ）との縮合反応により製造することができる。
　縮合反応は、反応式６工程１に記載の方法と同様にして行うことができる。 [Step 6]
Compound (XXXVIII) can be produced by a condensation reaction of compound (XXXVII) and compound (II).
The condensation reaction can be carried out in the same manner as in the method described in Reaction Scheme 6, Step 1.
［工程７］
　化合物（Ｉｅ）は化合物（ＸＸＸＶＩＩＩ）を所望により「脱水剤」の存在下、脱水環化させることより製造することができる。
　「脱水剤」としては、例えば、オキシ塩化リン、五酸化二リン、濃硫酸などが挙げられる。中でもオキシ塩化リンを用いるのが好ましい。脱水剤の使用量は、化合物（ＸＸＸＶＩＩＩ）１モルに対し約０．５～約１００モル、好ましくは約１～約１０モルである。 [Step 7]
Compound (Ie) can be produced by subjecting compound (XXXVIII) to dehydration cyclization in the presence of a “dehydrating agent” as desired.
Examples of the “dehydrating agent” include phosphorus oxychloride, diphosphorus pentoxide, concentrated sulfuric acid and the like. Of these, phosphorus oxychloride is preferably used. The amount of the dehydrating agent to be used is about 0.5 to about 100 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXXVIII).
　化合物（Ｉｆ）、（Ｉｇ）、（Ｉｈ）、（Ｉｉ）は、次の反応式７に記載の方法によっても製造することができる。
反応式７ Compounds (If), (Ig), (Ih), and (Ii) can also be produced by the method described in Reaction Scheme 7.
Reaction formula 7
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
（式中、各記号は前記と同意義を示す。）
　化合物（ＸＸＸＩＸ）および化合物（ＸＸＸＸ）は、反応式１工程４、反応式１工程６、反応式２工程１、反応式３工程１、反応式４工程２、反応式５工程２、反応式６工程１において用いられる化合物（ＶＩＩ）、（ＩＸ）、（Ｘ）、（ＸＸＩＩＩ）、（ＸＸＸ）の置換基（Ｒ２－Ｌ２－）を、Ｘ１あるいはシアノ基へと変換した化合物を用いることにより製造することができる。
　化合物（ＶＩＩ）、（ＩＸ）、（Ｘ）、（ＸＸＩＩＩ）、（ＸＸＸ）の置換基（Ｒ２－Ｌ２－）を、Ｘ１あるいはシアノ基へと変換した化合物は市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。 (In the formula, each symbol is as defined above.)
Compound (XXXIX) and Compound (XXXX) are represented by Reaction Formula 1 Step 4, Reaction Formula 1 Step 6, Reaction Formula 2 Step 1, Reaction Formula 3 Step 1, Reaction Formula 4 Step 2, Reaction Formula 5 Step 2, and Reaction Formula 6. using a compound, which was converted into X 1 or a cyano group - compound used in step 1 (VII), (IX) , the substituents (X), (XXIII), (XXX) (R 2 -L 2) Can be manufactured.
Available at the compound was converted to X 1 or a cyano group of the commercially available product - the compound (VII), (IX), (X), (XXIII), (XXX) substituents (R 2 -L 2) Also, it can be produced according to a method known per se or a method analogous thereto.
［工程１］
　化合物（Ｉｆ）は化合物（ＸＸＸＩＸ）のカルボニル化反応により製造することができる。
　カルボニル化反応は、反応式１工程１で示した「有機合成に用いられる溶媒」中、塩基および遷移金属触媒存在下、化合物（ＸＸＸＩＸ）と一酸化炭素あるいはその等価体および一般式：Ｒ４－ＯＨで表されるアルコールとを反応させることにより製造することができる。
　「一酸化炭素の等価体」としては、例えば、ギ酸またはその塩、ギ酸メチル、ギ酸エチルなどのギ酸エステルなどが挙げられる。
　一般式：Ｒ４－ＯＨで表されるアルコールは市販品にて入手でき、また、自体公知の方法またはこれらに準じた方法に従って製造することもできる。該アルコールの使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．５～約１００モル、好ましくは約１～約１０モルである。
　「塩基」としては、反応式１工程４で示した「塩基」が用いられ、中でもトリエチルアミンなどのアミン類が好ましい。
　「塩基」の使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．５～約１０モル、好ましくは約０．９～約３モルである。
　「遷移金属触媒」としては、反応式１工程４で示した「遷移金属触媒」が用いられ、中でもテトラキス（トリフェニルホスフィン）パラジウム（０）、ジクロロ［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）等が好ましい。
　「遷移金属触媒」の使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．００１～約３モル、好ましくは約０．０２～約０．２モルである。
　反応温度は通常０～２５０℃、好ましくは５０～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 1]
Compound (If) can be produced by subjecting compound (XXXIX) to a carbonylation reaction.
The carbonylation reaction is carried out in the presence of a base and a transition metal catalyst in the “solvent used for organic synthesis” shown in Step 1 of Reaction Scheme 1, compound (XXXIX) and carbon monoxide or an equivalent thereof, and a general formula: R 4 — It can be produced by reacting with an alcohol represented by OH.
Examples of the “equivalent of carbon monoxide” include formic acid or a salt thereof, formic acid ester such as methyl formate and ethyl formate.
The alcohol represented by the general formula: R 4 —OH can be obtained as a commercial product, and can also be produced according to a method known per se or a method analogous thereto. The amount of the alcohol to be used is about 0.5 to about 100 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXXIX).
As the “base”, the “base” shown in Reaction Scheme 1 Step 4 is used, and amines such as triethylamine are particularly preferable.
The amount of the “base” to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XXXIX).
As the “transition metal catalyst”, the “transition metal catalyst” shown in the reaction formula 1, step 4 is used. Among them, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) and the like are preferable.
The amount of the “transition metal catalyst” to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (XXXIX).
The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
［工程２］
　化合物（Ｉｇ）は化合物（Ｉｆ）の加水分解により製造することができる。
　該加水分解は、アルカリ性条件と酸性条件から選択して行うことができる。
　アルカリ性条件は、塩基の存在下、反応に影響を及ぼさない溶媒中で行われる。
　「塩基」としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸カリウム、炭酸ナトリウム、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシドなどが挙げられる。塩基の使用量は、化合物（Ｉｆ）に対して好ましくは、約１～約５モル当量である。
　「反応に影響を及ぼさない溶媒」としては、例えば反応式１工程１で示した「有機合成に用いられる溶媒」から選択して用いられるが、例えば、エタノールなどのアルコール類、テトラヒドロフランなどのエーテル類、水などが好ましく、これらを単独あるいは混合溶媒として用いることができる。
　反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃である。反応時間は、通常、約０．１～約４８時間である。
　酸性条件は、酸の存在下、反応に影響を及ぼさない溶媒中で行われる。
　「酸」としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸、硝酸等の鉱酸類が好ましい。酸の使用量は、化合物（Ｉｆ）に対して好ましくは、約０．５～約１０モル当量である。
　「反応に影響を及ぼさない溶媒」としては、例えば反応式１工程１で示した「有機合成に用いられる溶媒」から選択されるが、例えばエタノールなどのアルコール類または水が好ましい。
　反応温度は、通常、約－１００℃～約２５０℃、好ましくは約０℃～約１５０℃である。反応時間は、通常、約０．１～約４８時間である。
　なお、化合物（Ｉｇ）は、化合物（Ｉｆ）のエステル基（－ＣＯＯＲ４）がカルボキシル基に変換可能な他の置換基である化合物からも製造できる。「カルボキシル基に変換可能な他の置換基」としては、例えば、シアノ基、カルバモイル基、オキサゾール－２－イル基、４，４－ジメチル－４，５－ジヒドロ－１，３－オキサゾール－２－イル基などが挙げられる。 [Step 2]
Compound (Ig) can be produced by hydrolysis of compound (If).
The hydrolysis can be performed by selecting from alkaline conditions and acidic conditions.
Alkaline conditions are performed in the presence of a base in a solvent that does not affect the reaction.
Examples of the “base” include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like. The amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (If).
The “solvent that does not affect the reaction” is selected from, for example, “solvents used in organic synthesis” shown in Step 1 of Reaction Scheme 1. For example, alcohols such as ethanol and ethers such as tetrahydrofuran are used. Water is preferable, and these can be used alone or as a mixed solvent.
The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C. The reaction time is usually about 0.1 to about 48 hours.
Acidic conditions are performed in the presence of an acid in a solvent that does not affect the reaction.
As the “acid”, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and nitric acid are preferable. The amount of the acid used is preferably about 0.5 to about 10 molar equivalents relative to compound (If).
The “solvent that does not affect the reaction” is selected from, for example, the “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1. For example, alcohols such as ethanol or water are preferable.
The reaction temperature is usually about −100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C. The reaction time is usually about 0.1 to about 48 hours.
Compound (Ig) can also be produced from a compound in which the ester group (—COOR 4 ) of compound (If) is another substituent that can be converted to a carboxyl group. Examples of the “other substituent that can be converted into a carboxyl group” include, for example, a cyano group, a carbamoyl group, an oxazol-2-yl group, 4,4-dimethyl-4,5-dihydro-1,3-oxazole-2- Yl group and the like.
［工程３］
　化合物（Ｉｉ）は化合物（Ｉｇ）と化合物（ＸＸＸＸＩ）を、適当な縮合剤の存在下で反応させることにより製造できる。
　該反応は、反応式６工程１に記載の方法と同様にして行うことができる。 [Step 3]
Compound (Ii) can be produced by reacting compound (Ig) with compound (XXXXI) in the presence of a suitable condensing agent.
This reaction can be carried out in the same manner as in the method described in Reaction Scheme 6, Step 1.
［工程４］
　化合物（ＸＸＸＸ）は化合物（ＸＸＸＩＸ）のシアノ化反応により製造できる。
　シアノ化は例えば、所望により相間移動触媒（例、塩化ベンジルトリブチルアンモニウム）の存在下、シアン化ナトリウム、シアン化カリウムなどを用いる方法、トリメチルシリルシアニドおよびテトラブチルアンモニウムフルオリドを用いる方法（ジャーナル　オブ　オーガニック　ケミストリー (J. Org. Chem.), 64, 3171-3177, (1999)）、遷移金属触媒存在下、シアン化亜鉛などを用いる方法によって行うことができる。
　相間移動触媒の使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．００１～約１０モル、好ましくは約０．０１～約３モルである。
　シアン化ナトリウム、シアン化カリウムなどの使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．５～約１０モル、好ましくは約１～約３モルである。
　トリメチルシリルシアニドの使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．５～約１０モル、好ましくは約１～約３モルである。
　テトラブチルアンモニウムフルオリドの使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．５～約１０モル、好ましくは約１～約３モルである。
　「遷移金属触媒」としては、酢酸パラジウム（ＩＩ）、塩化パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）、ジクロロ［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）等のパラジウム触媒、臭化銅（Ｉ）、臭化銅（ＩＩ）、酢酸銅等の銅触媒などが用いられる。遷移金属触媒の使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．００１～約１０モル、好ましくは約０．１～約３モルである。
　シアン化亜鉛などの使用量は、化合物（ＸＸＸＩＸ）１モルに対し約０．５～約３０モル、好ましくは約０．９～約１０モルである。
　シアノ化には反応式１工程１で示した「有機合成に用いられる溶媒」が用いられる。中でも、ＤＭＦ、Ｎ－メチルピロリドンが好ましい。
　反応温度は通常０℃～３００℃、好ましくは０℃～１５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。
　中でも、テトラキス（トリフェニルホスフィン）パラジウム（０）存在下、シアン化亜鉛を用いる方法が好ましい。 [Step 4]
Compound (XXXX) can be produced by a cyanation reaction of compound (XXXIX).
Cyanation can be performed, for example, by using sodium cyanide or potassium cyanide in the presence of a phase transfer catalyst (eg, benzyltributylammonium chloride), using trimethylsilyl cyanide and tetrabutylammonium fluoride (Journal of Organic Chemistry ( J. Org. Chem.), 64, 3171-3177, (1999)), in the presence of a transition metal catalyst, a method using zinc cyanide or the like.
The amount of the phase transfer catalyst to be used is about 0.001 to about 10 mol, preferably about 0.01 to about 3 mol, per 1 mol of compound (XXXIX).
The amount of sodium cyanide, potassium cyanide and the like to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXIX).
The amount of trimethylsilylcyanide to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXIX).
The amount of tetrabutylammonium fluoride to be used is about 0.5 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (XXXIX).
Examples of the “transition metal catalyst” include palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Palladium catalysts such as dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), copper catalysts such as copper (I) bromide, copper (II) bromide, copper acetate, etc. Used. The amount of the transition metal catalyst to be used is about 0.001 to about 10 mol, preferably about 0.1 to about 3 mol, per 1 mol of compound (XXXIX).
The amount of zinc cyanide used is about 0.5 to about 30 moles, preferably about 0.9 to about 10 moles per mole of Compound (XXXIX).
The “solvent used for organic synthesis” shown in Reaction Scheme 1, Step 1 is used for cyanation. Of these, DMF and N-methylpyrrolidone are preferable.
The reaction temperature is usually 0 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
Among them, a method using zinc cyanide in the presence of tetrakis (triphenylphosphine) palladium (0) is preferable.
［工程５］
　化合物（Ｉｈ）は、化合物（ＸＸＸＸ）の加水分解により製造される。加水分解は、反応式７工程２に記載した加水分解の方法の他、炭酸カリウムなどの塩基の存在下、ジメチルスルホキシドなどの溶媒中、過酸化水素などの酸化剤を用いる方法などによっても行うことができる。中でも、ジメチルスルホキシド中、炭酸カリウム存在下、過酸化水素を用いる酸化的方法が好ましい。
　炭酸カリウムなどの塩基の使用量は、化合物（ＸＸＸＸ）１モルに対し約０．０１～約１０モル、好ましくは約０．２～約３モルである。
　過酸化水素などの酸化剤の使用量は、化合物（ＸＸＸＸ）１モルに対し約０．９～約３０モル、好ましくは約０．９～約２０モルである。
　反応温度は通常－２０℃～１５０℃、好ましくは０℃～５０℃である。反応時間は通常約５分～約４８時間、好ましくは約３０分～約２４時間である。 [Step 5]
Compound (Ih) is produced by hydrolysis of compound (XXXX). In addition to the hydrolysis method described in Reaction Scheme 7, Step 2, hydrolysis may also be performed by a method using an oxidizing agent such as hydrogen peroxide in a solvent such as dimethyl sulfoxide in the presence of a base such as potassium carbonate. Can do. Among them, an oxidative method using hydrogen peroxide in dimethyl sulfoxide in the presence of potassium carbonate is preferable.
The amount of the base such as potassium carbonate to be used is about 0.01 to about 10 mol, preferably about 0.2 to about 3 mol, per 1 mol of compound (XXXX).
The amount of the oxidizing agent such as hydrogen peroxide to be used is about 0.9 to about 30 mol, preferably about 0.9 to about 20 mol, per 1 mol of compound (XXXX).
The reaction temperature is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
　前記の各反応において、所望により、公知の脱保護反応、アシル化反応、アルキル化反応、水素添加反応、酸化反応、還元反応、炭素鎖延長反応または置換基交換反応を、単独あるいはその二つ以上を組み合わせて行うことにより、環Ａ上の置換基、環Ｂ上の置換基、置換基Ｒ１を変換することができる。 In each of the above reactions, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction may be performed alone or in combination thereof, as desired. In combination, the substituent on the ring A, the substituent on the ring B, and the substituent R 1 can be converted.
　前記の各反応において、原料化合物が置換基としてアミノ基、カルボキシル基、ヒドロキシ基またはカルボニル基を有する場合、これらの基にペプチド化学等で一般的に用いられるような保護基が導入されていてもよく、反応後に必要に応じて、保護基を除去することにより目的化合物を得ることができる。
　アミノ基の保護基としては、例えば、ホルミル、それぞれ置換基を有していてもよい、Ｃ１－６アルキルカルボニル（例えば、アセチル、エチルカルボニル等）、フェニルカルボニル、Ｃ１－６アルコキシ－カルボニル（例えば、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等）、フェニルオキシカルボニル、Ｃ７－１０アラルキル－カルボニル（例えば、ベンジルカルボニル等）、トリチル、フタロイル、およびＮ，Ｎ－ジメチルアミノメチレン等が挙げられる。該「アミノ基の保護基」の置換基としては、ハロゲン原子（例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、Ｃ１－６アルキル－カルボニル（例えば、メチルカルボニル、エチルカルボニル、ブチルカルボニル等）、ニトロ基等が挙げられる、置換基の数は１～数個（例、３個）である。
　カルボキシル基の保護基としては、例えば、Ｃ１－６アルキル基、Ｃ７－１１アラルキル基（例、ベンジル）、フェニル基、トリチル基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）等が挙げられる。これらの基は、１～３個のハロゲン原子、Ｃ１－６アルコキシ基、ニトロ基等で置換されていてもよい。
　ヒドロキシ基の保護基としては、例えば、Ｃ１－６アルキル基、フェニル基、トリチル基、Ｃ７－１０アラルキル基（例、ベンジル）、ホルミル基、Ｃ１－６アルキル－カルボニル基、ベンゾイル基、Ｃ７－１０アラルキル－カルボニル基（例、ベンジルカルボニル）、２－テトラヒドロピラニル基、２－テトラヒドロフリル基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）等が挙げられる。これらの基は、１～３個のハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、ニトロ基等で置換されていてもよい。
　カルボニル基の保護基としては、例えば、環状アセタール（例、１，３－ジオキサン）、非環状アセタール（例、ジ－Ｃ１－６アルキルアセタール）等が挙げられる。 In each of the above reactions, when the raw material compound has an amino group, a carboxyl group, a hydroxy group or a carbonyl group as a substituent, a protective group generally used in peptide chemistry or the like may be introduced into these groups. Well, the target compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of the amino-protecting group include, for example, formyl, C 1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C 1-6 alkoxy-carbonyl (which may each have a substituent) For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), phenyloxycarbonyl, C 7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, etc. . Examples of the substituent for the “amino-protecting group” include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl). Etc.), the number of substituents is 1 to several (eg, 3).
Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 halogen atoms, C 1-6 alkoxy groups, nitro groups and the like.
Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuryl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 halogen atoms, a C 1-6 alkyl group, a C 1-6 alkoxy group, a nitro group and the like.
Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
　上記した保護基の除去方法は、公知の方法、例えば、プロテクティブ　グループス　イン　オーガニック　シンセシス (Protective Groups in Organic Synthesis)、John Wiley and Sons 刊 (1980)に記載の方法等に準じて行うことができる。例えば、酸、塩基、紫外光、ヒドラジン、フェニルヒドラジン、Ｎ－メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウム (II)、トリアルキルシリルハライド（例えば、トリメチルシリルヨージド、トリメチルシリルブロミド）等を使用する方法、還元法等が用いられる。 The above-described method for removing protecting groups can be carried out in accordance with a known method, for example, the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980). For example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium (II) acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. Or a reduction method or the like is used.
　前記の各反応で得られる化合物またはその塩は、公知の手段、例えば、溶媒抽出、液性変換、転溶、濃縮、晶出、再結晶、クロマトグラフィー等によって単離精製することができる。また、前記の各反応の原料化合物またはその塩は、前記と同様の公知の手段等によって単離精製することができるが、単離することなくそのまま反応混合物として次の工程の原料として供されてもよい。
　いずれの場合にも、さらに所望により、公知の脱保護反応、アシル化反応、アルキル化反応、水素添加反応、酸化反応、還元反応、炭素鎖延長反応または置換基交換反応を、単独あるいはその二つ以上を組み合わせることにより、化合物（Ｉ）を合成することができる。 The compound or salt thereof obtained in each of the above reactions can be isolated and purified by a known means such as solvent extraction, liquid conversion, phase transfer, concentration, crystallization, recrystallization, chromatography and the like. In addition, the starting compound of each reaction or a salt thereof can be isolated and purified by the same known means as described above, but it is provided as a starting material for the next step as it is without isolation. Also good.
In any case, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction may be carried out alone or in combination as desired. By combining the above, compound (I) can be synthesized.
　本発明は、更に以下の実施例、試験例および製剤例によって詳しく説明されるが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
　以下の実施例中の「室温」は通常約 10 ℃ないし約 35 ℃を示す。混合溶媒において示した比は、特に断らない限り容量比を示す。％は、特に断らない限り重量％を示す。
　シリカゲルカラムクロマトグラフィーにおいて、NHと記載した場合は、アミノプロピルシラン結合シリカゲルを用いた。HPLC (高速液体クロマトグラフィー) において、C18と記載した場合は、オクタデシル結合シリカゲルを用いた。溶出溶媒の比は、特に断らない限り容量比を示す。
　以下の実施例においては下記の略号を使用する。
　THF:テトラヒドロフラン、1H NMR (プロトン核磁気共鳴スペクトル) はフーリエ変換型NMRで測定した。解析にはACD/SpecManager (商品名) などを用いた。水酸基やアミノ基などのプロトンが非常に緩やかなピークについては記載していない。
　MS (マススペクトル) は、LC/MS (液体クロマトグラフ質量分析計) により測定した。イオン化法としては、ESI (ElectroSpray Ionization、エレクトロスプレーイオン化) 法、または、APCI (Atomospheric Pressure Cheimcal Ionization、大気圧化学イオン化) 法を用いた。データは実測値 (found) を記載した。通常、分子イオンピークが観測されるが、tert-ブトキシカルボニル基 (-Boc) を有する化合物の場合、フラグメントイオンとして、tert-ブトキシカルボニル基あるいはtert-ブチル基が脱離したピークが観測されることもある。また、水酸基 (-OH) を有する化合物の場合、フラグメントイオンとして、H2Oが脱離したピークが観測されることもある。塩の場合は、通常、フリー体の分子イオンピークもしくはフラグメントイオンピークが観測される。 The present invention is further explained in detail by the following examples, test examples and formulation examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
“Room temperature” in the following examples usually indicates about 10 ° C. to about 35 ° C. The ratio shown in the mixed solvent is a volume ratio unless otherwise specified. Unless otherwise indicated, “%” indicates “% by weight”.
In the silica gel column chromatography, when described as NH, aminopropylsilane-bonded silica gel was used. In HPLC (high performance liquid chromatography), when it was described as C18, octadecyl-bonded silica gel was used. The ratio of elution solvent indicates a volume ratio unless otherwise specified.
The following abbreviations are used in the following examples.
THF: tetrahydrofuran, 1 H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR. ACD / SpecManager (trade name) etc. was used for the analysis. Peaks with very gentle protons such as hydroxyl groups and amino groups are not described.
MS (mass spectrum) was measured by LC / MS (liquid chromatograph mass spectrometer). As the ionization method, ESI (ElectroSpray Ionization) method or APCI (Atomospheric Pressure Cheimcal Ionization) method was used. The data shows the measured value (found). Usually, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (-Boc), a peak from which the tert-butoxycarbonyl group or tert-butyl group is eliminated should be observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
実施例１
エチル 4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンゾアート Example 1
Ethyl 4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoate
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　Ａ）エチル 4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)ベンゾアート
　水素化ナトリウム（55%、2.59 g）と18-crown-6（1.57 g）の1-メチル-2-ピロリドン(NMP) 懸濁液（200 mL）に0 ℃において4-ヨード-2-メチル-1H-イミダゾール（12.4 g）を加え、室温で30分間撹拌した。0 ℃に冷却した反応混合物にエチル 4-フルオロベンゾアート（10.0 g）を滴下し、110 ℃で終夜加熱撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー（酢酸エチル/ヘキサン）により精製して標題化合物（15.0 g）を得た。
1H NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 4.40 (2H, q, J = 7.2 Hz), 7.11 (1H, s), 7.33 (2H, d, J = 4.4 Hz), 8.16 (2H, d, J = 4.4 Hz). A) Ethyl 4- (4-iodo-2-methyl-1H-imidazol-1-yl) benzoate Sodium hydride (55%, 2.59 g) and 18-crown-6 (1.57 g) 1-methyl-2 4-Iodo-2-methyl-1H-imidazole (12.4 g) was added to a pyrrolidone (NMP) suspension (200 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Ethyl 4-fluorobenzoate (10.0 g) was added dropwise to the reaction mixture cooled to 0 ° C., and the mixture was heated and stirred at 110 ° C. overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (15.0 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 4.40 (2H, q, J = 7.2 Hz), 7.11 (1H, s), 7.33 (2H, d, J = 4.4 Hz), 8.16 (2H, d, J = 4.4 Hz).
　Ｂ）エチル 4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンゾアート
　窒素雰囲気下室温で、亜鉛粉末（2.76 g）の無水テトラヒドロフラン (THF) 懸濁液（100 mL）に1,2-ジブロモブタン（0.102 mL）を加えた。30分間加熱還流した後に、室温に戻した。反応混合物へクロロトリメチルシラン（0.054 mL）を加え、室温で10分間撹拌した。反応混合物に1-(ブロモメチル)-3-フルオロ-5-(トリフルオロメチル)ベンゼン（7.71 mL）を加え、室温で2時間撹拌した。反応混合物に実施例１－Ａ）で合成したエチル 4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)ベンゾアート（15.0 g）、酢酸パラジウム（II）（0.189 g）、2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル(BINAP; 0.526 g）の無水THF（100 mL）溶液を加え、15時間加熱還流した。反応混合物をセライトろ過し、ろ液を減圧濃縮した。残渣を酢酸エチルで希釈し飽和塩化アンモニウム水溶液、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（7.03 g）を得た。
1H NMR (400 MHz, CDCl3) δ 1.42 (3H, t, J = 7.6 Hz), 2.39 (3H, s), 3.99 (2H, s), 4.42 (2H, q, J = 7.6 Hz), 6.68 (1H, s), 7.34 (2H, d, J = 8.4 Hz), 7.42 (1H, t, J = 7.6 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.14 (2H, d, J = 8.4 Hz).
MS (ESI+): [M+H]+389.2. B) Ethyl 4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoate Zinc powder (2.76 g) in anhydrous tetrahydrofuran (THF) at room temperature under nitrogen atmosphere ) 1,2-Dibromobutane (0.102 mL) was added to the suspension (100 mL). After heating to reflux for 30 minutes, the temperature was returned to room temperature. Chlorotrimethylsilane (0.054 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. 1- (Bromomethyl) -3-fluoro-5- (trifluoromethyl) benzene (7.71 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Ethyl 4- (4-iodo-2-methyl-1H-imidazol-1-yl) benzoate (15.0 g), palladium (II) acetate (0.189 g), 2 synthesized in Example 1-A) into the reaction mixture 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP; 0.526 g) in anhydrous THF (100 mL) was added, and the mixture was heated to reflux for 15 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (7.03 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.6 Hz), 2.39 (3H, s), 3.99 (2H, s), 4.42 (2H, q, J = 7.6 Hz), 6.68 (1H, s), 7.34 (2H, d, J = 8.4 Hz), 7.42 (1H, t, J = 7.6 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.58 (1H, s), 8.14 (2H, d, J = 8.4 Hz).
MS (ESI +): [M + H] + 389.2.
実施例２
4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}安息香酸 Example 2
4- {2-Methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoic acid
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　実施例１で合成したエチル 4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンゾアート（6.50 g）のエタノール溶液（80 mL）に6N　水酸化ナトリウム水溶液（3.35 mL）を0 ℃で加えた。反応混合物を室温で6時間撹拌した。反応混合物を減圧濃縮し、残渣を水で希釈し酢酸エチルで洗浄した。水層に6 N塩酸を加えた後に、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣を酢酸エチル－ヘキサン混合液に懸濁させ、固体をろ取した。固体をヘキサンで洗浄し、標題化合物（5.29 g）を得た。
1H NMR (400 MHz, DMSO-d6) δ 2.43 (3H, s), 4.06 (2H, s), 7.50 (1H, s), 7.56-7.63 (2H, m), 7.67-7.69 (3H, m) 7.75 (1H, s), 8.11 (2H, d, J = 8.0 Hz) (COOHピークは観測されなかった).
MS (ESI+): [M+H]+361.3. 6N was added to an ethanol solution (80 mL) of ethyl 4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoate (6.50 g) synthesized in Example 1. Aqueous sodium hydroxide (3.35 mL) was added at 0 ° C. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and washed with ethyl acetate. 6N Hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in an ethyl acetate-hexane mixture, and the solid was collected by filtration. The solid was washed with hexane to obtain the title compound (5.29 g).
1 H NMR (400 MHz, DMSO-d 6 ) δ 2.43 (3H, s), 4.06 (2H, s), 7.50 (1H, s), 7.56-7.63 (2H, m), 7.67-7.69 (3H, m ) 7.75 (1H, s), 8.11 (2H, d, J = 8.0 Hz) (COOH peak was not observed).
MS (ESI +): [M + H] + 361.3.
実施例３
4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンズアミド Example 3
4- {2-Methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzamide
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　実施例２で合成した4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}安息香酸 (360 mg)、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 (WSC塩酸塩; 230 mg)、1-ヒドロキシベンゾトリアゾールアンモニア和物(HOBtアンモニア和物; 182 mg) および N,N-ジメチルホルムアミド (DMF; 3 mL) の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣を再結晶(ヘプタン－酢酸エチル)して標題化合物(290 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.38 (3H, s), 3.99 (2H, s), 5.85 (1H, brs), 6.09 (1H, brs), 6.68 (1H, s), 7.32-7.61 (6H, m), 7.87-7.97 (2H, m).
MS (ESI+): [M+H]+ 360.1. 4- {2-Methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoic acid (360 mg) synthesized in Example 2, 1-ethyl-3- (3- A mixture of (dimethylaminopropyl) carbodiimide hydrochloride (WSC hydrochloride; 230 mg), 1-hydroxybenzotriazole ammonia hydrate (HOBt ammonia hydrate; 182 mg) and N, N-dimethylformamide (DMF; 3 mL) at room temperature Stir overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized (heptane-ethyl acetate) to give the title compound (290 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.38 (3H, s), 3.99 (2H, s), 5.85 (1H, brs), 6.09 (1H, brs), 6.68 (1H, s), 7.32-7.61 ( 6H, m), 7.87-7.97 (2H, m).
MS (ESI +): [M + H] + 360.1.
実施例４
エチル 2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンゾアート Example 4
Ethyl 2-methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoate
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　Ａ）エチル 4-フルオロ-2-メチルベンゾアート
　4-フルオロ-2-メチル安息香酸 （10 mL）に塩化チオニル（10 mL）を0 ℃で加え、80 ℃で2時間撹拌した。反応混合物を減圧濃縮し、残渣にエタノール（20 mL）を加え、室温で終夜撹拌した。反応混合物を減圧濃縮し、残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル）により精製して標題化合物 (11.0 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.39 (3H, t, J = 7.0 Hz), 2.61 (3H, s), 4.35 (2H, q, J = 7.1 Hz), 6.86-6.98 (2H, m), 7.90-8.00 (1H, m). A) Ethyl 4-fluoro-2-methylbenzoate To 4-fluoro-2-methylbenzoic acid (10 mL) was added thionyl chloride (10 mL) at 0 ° C., and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, ethanol (20 mL) was added to the residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (11.0 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.39 (3H, t, J = 7.0 Hz), 2.61 (3H, s), 4.35 (2H, q, J = 7.1 Hz), 6.86-6.98 (2H, m) , 7.90-8.00 (1H, m).
　Ｂ）エチル 4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンゾアート
　水素化ナトリウム（60%、1.098 g）と18-crown-6（0.691 g）のNMP懸濁液（85 mL）に0℃で4-ヨード-2-メチル-1H-イミダゾール（5.44 g）を加え、窒素雰囲気下室温において20分間撹拌した。0 ℃に冷却した反応混合物に実施例４－Ａ）で合成したエチル 4-フルオロ-2-メチルベンゾアート（5.00 g）のNMP溶液（15 mL）を滴下し、窒素雰囲気下110 ℃で終夜加熱撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（5.57 g）を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 2.66 (3H, s), 4.40 (2H, q, J = 7.2 Hz), 7.10 (1H, s), 7.12-7.19 (2H, m), 8.00-8.07 (1H, m).
MS (ESI+): [M+H]+371.2. B) Ethyl 4- (4-Iodo-2-methyl-1H-imidazol-1-yl) -2-methylbenzoate Sodium hydride (60%, 1.098 g) and 18-crown-6 (0.691 g) NMP 4-iodo-2-methyl-1H-imidazole (5.44 g) was added to the suspension (85 mL) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes under a nitrogen atmosphere. To the reaction mixture cooled to 0 ° C., an NMP solution (15 mL) of ethyl 4-fluoro-2-methylbenzoate (5.00 g) synthesized in Example 4-A) was added dropwise and heated at 110 ° C. overnight under a nitrogen atmosphere. Stir. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (5.57 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 2.66 (3H, s), 4.40 (2H, q, J = 7.2 Hz), 7.10 (1H, s), 7.12-7.19 (2H, m), 8.00-8.07 (1H, m).
MS (ESI +): [M + H] + 371.2.
　Ｃ）エチル 2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンゾアート
　アルゴン雰囲気下室温において、亜鉛粉末（87 mg）の無水THF懸濁液（5 mL）に1,2-ジブロモブタン（3 μL）を加え、70 ℃で30分間撹拌した。反応混合物を室温に冷却しクロロトリメチルシラン（2 μL）を加え、室温で15分間撹拌した。続いて反応混合液に1-(ブロモメチル)-3-(トリフルオロメチル)ベンゼン（0.38 g）を滴下し、室温で2時間撹拌後、反応混合物に実施例４－Ｂ）で合成したエチル 4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンゾアート（0.50 g）、酢酸パラジウム（II）（7 mg）、BINAP（19 mg）を加え、80 ℃で終夜撹拌した。反応混合物をセライトろ過後、ろ液を減圧濃縮した。残渣を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥後、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(ヘキサン/酢酸エチル)により精製して標題化合物（0.18 g）を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 2.64 (3H, s), 3.98 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.65 (1H, s), 7.06-7.20 (2H, m), 7.37-7.63 (4H, m), 8.00 (1H, d, J = 9.0 Hz).
MS (ESI+): [M+H]+403.5. C) Ethyl 2-methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoate Zinc powder (87 mg) at room temperature under argon atmosphere 1,2-Dibromobutane (3 μL) was added to anhydrous THF suspension (5 mL), and the mixture was stirred at 70 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, chlorotrimethylsilane (2 μL) was added, and the mixture was stirred at room temperature for 15 minutes. Subsequently, 1- (bromomethyl) -3- (trifluoromethyl) benzene (0.38 g) was added dropwise to the reaction mixture, stirred at room temperature for 2 hours, and then ethyl 4-synthesized in Example 4-B) into the reaction mixture. (4-Iodo-2-methyl-1H-imidazol-1-yl) -2-methylbenzoate (0.50 g), palladium (II) acetate (7 mg), BINAP (19 mg) were added, and the mixture was kept at 80 ° C overnight. Stir. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (0.18 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 2.64 (3H, s), 3.98 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.65 (1H, s), 7.06-7.20 (2H, m), 7.37-7.63 (4H, m), 8.00 (1H, d, J = 9.0 Hz).
MS (ESI +): [M + H] + 403.5.
実施例５
2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}安息香酸 Example 5
2-Methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoic acid
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　実施例４で合成したエチル 2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンゾアート（0.18 g）のエタノール溶液（4 mL）に8 N水酸化ナトリウム水溶液(67 μL)を加え、70 ℃で終夜撹拌した。反応混合物を6 N塩酸で中和した後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物(0.15 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.71 (3H, s), 2.72 (3H, s), 4.27 (2H, s), 6.69 (1H, s), 7.18-7.28 (2H, m), 7.46-7.65 (3H, m), 7.70-7.81 (1H, m), 8.19 (1H, d, J = 9.1 Hz), (COOHピークは観測されなかった).
MS (ESI+): [M+H]+375.1. Ethyl 2-methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoate (0.18 g) synthesized in Example 4 in ethanol solution (4 8N aqueous sodium hydroxide solution (67 μL) was added to the reaction mixture, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was neutralized with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (0.15 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.71 (3H, s), 2.72 (3H, s), 4.27 (2H, s), 6.69 (1H, s), 7.18-7.28 (2H, m), 7.46- 7.65 (3H, m), 7.70-7.81 (1H, m), 8.19 (1H, d, J = 9.1 Hz), (COOH peak not observed).
MS (ESI +): [M + H] + 375.1.
実施例６
2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンズアミド Example 6
2-Methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzamide
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　実施例５で合成した2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}安息香酸（75 mg）のDMF（3 mL）溶液にWSC（115 mg）、HOBt（92 mg）を加え、室温で5分間攪拌後、アンモニア水（1 mL）を加え、終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。残渣をアミノシリカゲルカラムクロマトグラフィー (メタノール/酢酸エチル)で精製後、エタノール－酢酸エチルから再結晶して標題化合物 (14 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.26 (3H, s), 2.41 (3H, s), 3.89 (2H, s), 7.08 (1H, s), 7.23-7.34 (2H, m), 7.40-7.70 (6H, m), 7.80 (1H, brs).
MS (ESI+): [M+H]+374.3. DMF (3 mL) of 2-methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoic acid (75 mg) synthesized in Example 5 WSC (115 mg) and HOBt (92 mg) were added to the solution, and after stirring at room temperature for 5 minutes, aqueous ammonia (1 mL) was added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (methanol / ethyl acetate) and recrystallized from ethanol-ethyl acetate to give the title compound (14 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.26 (3H, s), 2.41 (3H, s), 3.89 (2H, s), 7.08 (1H, s), 7.23-7.34 (2H, m), 7.40-7.70 (6H, m), 7.80 (1H, brs).
MS (ESI +): [M + H] + 374.3.
実施例７
N-(2-ヒドロキシエチル)-2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}ベンズアミド Example 7
N- (2-hydroxyethyl) -2-methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzamide
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　実施例５で合成した2-メチル-4-{2-メチル-4-[3-(トリフルオロメチル)ベンジル]-1H-イミダゾール-1-イル}安息香酸（75 mg）のDMF（3 mL）溶液にWSC（115 mg）、HOBt（92 mg）を加え、室温で5分間攪拌後、2-アミノエタノール（37 mg）を加え、終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、メタノール/酢酸エチル)で精製後、エタノール－酢酸エチルから再結晶して標題化合物 (18 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.26 (3H, s), 2.37 (3H, s), 3.25-3.36 (2H, m), 3.45-3.57 (2H, m), 3.90 (2H, s), 4.69 (1H, t, J = 5.7 Hz), 7.08 (1H, s), 7.24-7.35 (2H, m), 7.40-7.72 (5H, m), 8.22-8.31 (1H, m).
MS (ESI+): [M+H]+418.3. DMF (3 mL) of 2-methyl-4- {2-methyl-4- [3- (trifluoromethyl) benzyl] -1H-imidazol-1-yl} benzoic acid (75 mg) synthesized in Example 5 WSC (115 mg) and HOBt (92 mg) were added to the solution, and after stirring at room temperature for 5 minutes, 2-aminoethanol (37 mg) was added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate), and recrystallized from ethanol-ethyl acetate to give the title compound (18 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.26 (3H, s), 2.37 (3H, s), 3.25-3.36 (2H, m), 3.45-3.57 (2H, m), 3.90 (2H, s ), 4.69 (1H, t, J = 5.7 Hz), 7.08 (1H, s), 7.24-7.35 (2H, m), 7.40-7.72 (5H, m), 8.22-8.31 (1H, m).
MS (ESI +): [M + H] + 418.3.
実施例８
エチル 4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンゾアート Example 8
Ethyl 4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　アルゴン雰囲気下室温において、亜鉛粉末（0.530 g）の無水THF懸濁液（15 mL）に1,2-ジブロモブタン（0.032 mL）を加え、70 ℃で30分間撹拌した。反応混合物を室温に冷却しクロロトリメチルシラン（0.047 mL）を加え、室温において15分間撹拌した。窒素雰囲気下において反応混合液に1-(ブロモメチル)-3-フルオロ-5-(トリフルオロメチル)ベンゼン（2.083 g）の無水THF溶液（5 mL）を滴下し、室温5時間撹拌した。
　反応混合物に実施例４－Ｂ）で合成したエチル 4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンゾアート（2.00 g）、酢酸パラジウム（II）（0.121 g）、BINAP（0.336 g）を加え、80 ℃で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（1.83 g）を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 2.65 (3H, s), 3.97 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 6.73 (1H, s), 7.13-7.26 (4H, m), 7.38 (1H, s), 7.98-8.06 (1H, m).
MS (ESI+): [M+H]+421.4. At room temperature under an argon atmosphere, 1,2-dibromobutane (0.032 mL) was added to an anhydrous THF suspension (15 mL) of zinc powder (0.530 g), and the mixture was stirred at 70 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, chlorotrimethylsilane (0.047 mL) was added, and the mixture was stirred at room temperature for 15 minutes. Under a nitrogen atmosphere, anhydrous THF solution (5 mL) of 1- (bromomethyl) -3-fluoro-5- (trifluoromethyl) benzene (2.083 g) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 5 hours.
Ethyl 4- (4-iodo-2-methyl-1H-imidazol-1-yl) -2-methylbenzoate (2.00 g), palladium acetate (II) (0.121) synthesized in Example 4-B) was added to the reaction mixture. g) and BINAP (0.336 g) were added and stirred at 80 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (1.83 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 2.65 (3H, s), 3.97 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 6.73 (1H, s), 7.13-7.26 (4H, m), 7.38 (1H, s), 7.98-8.06 (1H, m).
MS (ESI +): [M + H] + 421.4.
実施例９
4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチル安息香酸 Example 9
4- (4- (3-Fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　実施例８で合成したエチル 4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンゾアート（1.83 g）のエタノール溶液（18 mL）に1 N水酸化ナトリウム水溶液(6.53 mL)を加え、室温で終夜撹拌した。反応混合物を1 N塩酸で中和した後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物(1.40 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.30 (3H, s), 2.57 (3H, s), 3.93 (2H, s), 7.18 (1H, s), 7.32-7.58 (5H, m), 7.93 (1H, d, J = 7.9 Hz), (COOHピークは観測されなかった).
MS (ESI+): [M+H]+393.4. Of ethyl 4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzoate (1.83 g) synthesized in Example 8 To an ethanol solution (18 mL) was added 1 N aqueous sodium hydroxide solution (6.53 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (1.40 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.30 (3H, s), 2.57 (3H, s), 3.93 (2H, s), 7.18 (1H, s), 7.32-7.58 (5H, m), 7.93 (1H, d, J = 7.9 Hz), (COOH peak not observed).
MS (ESI +): [M + H] + 393.4.
実施例１０
4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンズアミド Example 10
4- (4- (3-Fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　実施例９で合成した4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチル安息香酸(300 mg)、WSC (220 mg)、HOBtアンモニア和物 (175 mg)およびDMF (3 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して、標題化合物 (220 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.27 (3H, s), 2.41 (3H, s), 3.92 (2H, s), 7.12 (1H, s), 7.25-7.36 (2H, m), 7.41-7.60 (5H, m), 7.82 (1H, brs).
MS (ESI+): [M+H]+392.3. 4- (4- (3-Fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzoic acid (300 mg), WSC synthesized in Example 9 A mixture of (220 mg), HOBt ammonia solvate (175 mg) and DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (220 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.27 (3H, s), 2.41 (3H, s), 3.92 (2H, s), 7.12 (1H, s), 7.25-7.36 (2H, m), 7.41-7.60 (5H, m), 7.82 (1H, brs).
MS (ESI +): [M + H] + 392.3.
実施例１１
4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-N-(2-ヒドロキシエチル)-2-メチルベンズアミド Example 11
4- (4- (3-Fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -N- (2-hydroxyethyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　実施例９で合成した4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチル安息香酸(300 mg)、2－アミノエタノール(0.092 mL)、WSC (293 mg)、HOBt (207 mg)およびDMF (2 mL)の混合物を室温で4時間撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して、標題化合物 (244 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.27 (3H, s), 2.38 (3H, s), 3.24-3.39 (2H, m), 3.51 (2H, q, J = 5.8 Hz), 3.92 (2H, s), 4.71 (1H, t, J = 5.5 Hz), 7.12 (1H, s), 7.25-7.37 (2H, m), 7.40-7.60 (4H, m), 8.29 (1H, t, J = 5.5 Hz).
MS (ESI+): [M+H]+436.3. 4- (4- (3-Fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzoic acid (300 mg) synthesized in Example 9, 2 A mixture of aminoethanol (0.092 mL), WSC (293 mg), HOBt (207 mg) and DMF (2 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (244 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.27 (3H, s), 2.38 (3H, s), 3.24-3.39 (2H, m), 3.51 (2H, q, J = 5.8 Hz), 3.92 ( 2H, s), 4.71 (1H, t, J = 5.5 Hz), 7.12 (1H, s), 7.25-7.37 (2H, m), 7.40-7.60 (4H, m), 8.29 (1H, t, J = 5.5 Hz).
MS (ESI +): [M + H] + 436.3.
実施例１２
N-(2-アミノ-2-オキソエチル)-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンズアミド Example 12
N- (2-amino-2-oxoethyl) -4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　実施例９で合成した4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチル安息香酸(300 mg)、グリシンアミド塩酸塩 (169 mg)、N-エチルジイソプロピルアミン (0.267 mL)、WSC (293 mg)、HOBt (207 mg)およびDMF (2 mL)の混合物を室温で4時間撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して、標題化合物 (216 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.28 (3H, s), 2.41 (3H, s), 3.80 (2H, d, J = 6.0 Hz), 3.93 (2H, s), 7.05 (1H, brs), 7.14 (1H, s), 7.26-7.41 (3H, m), 7.44-7.62 (4H, m), 8.47 (1H, t, J = 6.0 Hz).
MS (ESI+): [M+H]+449.3. 4- (4- (3-Fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzoic acid (300 mg), glycine synthesized in Example 9 A mixture of amide hydrochloride (169 mg), N-ethyldiisopropylamine (0.267 mL), WSC (293 mg), HOBt (207 mg) and DMF (2 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (216 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.28 (3H, s), 2.41 (3H, s), 3.80 (2H, d, J = 6.0 Hz), 3.93 (2H, s), 7.05 (1H, brs), 7.14 (1H, s), 7.26-7.41 (3H, m), 7.44-7.62 (4H, m), 8.47 (1H, t, J = 6.0 Hz).
MS (ESI +): [M + H] + 449.3.
実施例１３
N-(2-(ジメチルアミノ)エチル)-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチルベンズアミド ジヒドロクロリド Example 13
N- (2- (dimethylamino) ethyl) -4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzamide dihydro Chloride
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　実施例９で合成した4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-2-メチル安息香酸(300 mg)、N,N-ジメチルエタン-1,2-ジアミン(119 μL) 、HOBt (172 mg) およびWSC (244 mg)のDMF溶液(3 mL) を室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣に4 N塩化水素-酢酸エチル溶液を加え、溶媒を減圧下留去した。得られた残渣をジイソプロピルエーテルで洗浄し、固体をろ取することにより標題化合物(205 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.44 (3H, s), 2.53 (3H, s), 2.81 (6H, d, J = 3.8 Hz), 3.27 (2H, d, J = 5.3 Hz), 3.65 (2H, q, J = 5.7 Hz), 4.21 (2H, s), 7.44-7.84 (7H, m), 8.84 (1H, t, J = 5.5 Hz), 10.88 (1H, brs), 15.55 (1H, brs).
MS (ESI+): [M+H-2HCl]+463.32. 4- (4- (3-Fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -2-methylbenzoic acid (300 mg), N, synthesized in Example 9 , N-dimethylethane-1,2-diamine (119 μL), HOBt (172 mg) and WSC (244 mg) in DMF (3 mL) were stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added 4N hydrogen chloride-ethyl acetate solution, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether, and the solid was collected by filtration to give the title compound (205 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.44 (3H, s), 2.53 (3H, s), 2.81 (6H, d, J = 3.8 Hz), 3.27 (2H, d, J = 5.3 Hz) , 3.65 (2H, q, J = 5.7 Hz), 4.21 (2H, s), 7.44-7.84 (7H, m), 8.84 (1H, t, J = 5.5 Hz), 10.88 (1H, brs), 15.55 ( 1H, brs).
MS (ESI +): [M + H-2HCl] + 463.32.
実施例１４
エチル 2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンゾアート Example 14
Ethyl 2-chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoate
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　Ａ）エチル 2-クロロ-4-フルオロベンゾアート
　2-クロロ-4-フルオロ安息香酸 （26.71 g）に塩化チオニル（26 mL）を0 ℃で加え、2時間加熱還流した。反応混合物にエタノール（50 mL）を加え、80 ℃で終夜撹拌した。反応混合物を減圧濃縮し、残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル）により精製して標題化合物 (26.32 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 6.98-7.09 (1H, m), 7.19 (1H, dd, J = 8.5, 2.5 Hz), 7.89 (1H, dd, J = 8.7, 6.1 Hz). A) Ethyl 2-chloro-4-fluorobenzoate To 2-chloro-4-fluorobenzoic acid (26.71 g) was added thionyl chloride (26 mL) at 0 ° C., and the mixture was heated to reflux for 2 hours. Ethanol (50 mL) was added to the reaction mixture, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (26.32 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 6.98-7.09 (1H, m), 7.19 (1H, dd, J = 8.5, 2.5 Hz), 7.89 (1H, dd, J = 8.7, 6.1 Hz).
　Ｂ）エチル 2-クロロ-4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)ベンゾアート
　水素化ナトリウム（60%、0.423 g）と18-crown-6（0.254 g）のNMP懸濁液（30 mL）に0℃で4-ヨード-2-メチル-1H-イミダゾール（2.00 g）のNMP溶液（10 mL）を加え、窒素雰囲気下室温で30分間撹拌した。0 ℃に冷却した反応混合物に実施例１４－Ａ）で合成したエチル 2-クロロ-4-フルオロベンゾアート（2.05 g）のNMP溶液（10 mL）を滴下し、窒素雰囲気下110 ℃で5時間加熱撹拌した。反応混合物に1.0N水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をヘキサンで洗浄して標題化合物（2.76 g）を得た。
1H NMR (300 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 4.44 (2H, q, J = 7.2 Hz), 7.11 (1H, s), 7.22-7.27 (1H, m), 7.41 (1H, d, J = 1.9 Hz), 7.97 (1H, d, J = 8.7 Hz).
MS (ESI+): [M+H]+391.1. B) Ethyl 2-chloro-4- (4-iodo-2-methyl-1H-imidazol-1-yl) benzoate NMP of sodium hydride (60%, 0.423 g) and 18-crown-6 (0.254 g) To the suspension (30 mL), an NMP solution (10 mL) of 4-iodo-2-methyl-1H-imidazole (2.00 g) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the reaction mixture cooled to 0 ° C., an NMP solution (10 mL) of ethyl 2-chloro-4-fluorobenzoate (2.05 g) synthesized in Example 14-A) was added dropwise, and the mixture was stirred at 110 ° C. for 5 hours under a nitrogen atmosphere. Stir with heating. To the reaction mixture was added 1.0N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain the title compound (2.76 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 4.44 (2H, q, J = 7.2 Hz), 7.11 (1H, s), 7.22 -7.27 (1H, m), 7.41 (1H, d, J = 1.9 Hz), 7.97 (1H, d, J = 8.7 Hz).
MS (ESI +): [M + H] + 391.1.
　Ｃ）エチル 2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンゾアート
　アルゴン雰囲気下室温において、亜鉛粉末（0.628 g）の無水THF懸濁液（11 mL）に1,2-ジブロモブタン（0.038 mL）を加え、80 ℃で30分間撹拌した。反応混合物を室温に冷却しクロロトリメチルシラン（0.055 mL）を加え、室温で20分間撹拌した。窒素雰囲気下において反応混合液に1-(ブロモメチル)-3-フルオロ-5-(トリフルオロメチル)ベンゼン（2.468 g）の無水THF溶液（11 mL）を滴下し、室温で3時間撹拌した。反応混合物に実施例１４－Ｂ）で合成したエチル 2-クロロ-4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)ベンゾアート（2.50 g）、酢酸パラジウム（II）（0.144 g）、BINAP（0.399 g）、無水THF（11 mL）を加え、80 ℃で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（1.52 g）を得た。
1H NMR (300 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.97 (2H, s), 4.44 (2H, q, J = 7.2 Hz), 6.74 (1H, s), 7.12-7.32 (3H, m), 7.34-7.45 (2H, m), 7.95 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+441.2. C) Ethyl 2-chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoate zinc powder (at room temperature under argon atmosphere) 1,2-Dibromobutane (0.038 mL) was added to an anhydrous THF suspension (11 mL) of 0.628 g), and the mixture was stirred at 80 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, chlorotrimethylsilane (0.055 mL) was added, and the mixture was stirred at room temperature for 20 minutes. Under a nitrogen atmosphere, 1- (bromomethyl) -3-fluoro-5- (trifluoromethyl) benzene (2.468 g) in anhydrous THF (11 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Ethyl 2-chloro-4- (4-iodo-2-methyl-1H-imidazol-1-yl) benzoate (2.50 g), palladium (II) acetate (0.144) synthesized in Example 14-B) was added to the reaction mixture. g), BINAP (0.399 g) and anhydrous THF (11 mL) were added, and the mixture was stirred at 80 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (1.52 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.97 (2H, s), 4.44 (2H, q, J = 7.2 Hz), 6.74 (1H, s), 7.12-7.32 (3H, m), 7.34-7.45 (2H, m), 7.95 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 441.2.
実施例１５
2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 Example 15
2-Chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　実施例１４で合成したエチル 2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンゾアート（1.56 ｇ）のエタノール溶液（16 mL）に1 N水酸化ナトリウム水溶液 (7.08 mL) を加え、室温で終夜撹拌した。反応混合物を1N塩酸で中和した後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物(1.13 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.37 (3H, s), 4.00 (2H, s), 7.36 (1H, s), 7.44-7.63 (4H, m), 7.77 (1H, d, J = 2.3 Hz), 7.94 (1H, d, J = 8.7 Hz), (COOHピークは観測されなかった).
MS (ESI+): [M+H]+413.0. Of ethyl 2-chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoate (1.56 g) synthesized in Example 14 To an ethanol solution (16 mL) was added 1 N aqueous sodium hydroxide solution (7.08 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (1.13 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.37 (3H, s), 4.00 (2H, s), 7.36 (1H, s), 7.44-7.63 (4H, m), 7.77 (1H, d, J = 2.3 Hz), 7.94 (1H, d, J = 8.7 Hz), (COOH peak not observed).
MS (ESI +): [M + H] + 413.0.
実施例１６
2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンズアミド Example 16
2-Chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzamide
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　実施例１５で合成した2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (250 mg)、WSC (232 mg)、HOBtアンモニア和物 (184 mg)およびDMF (1.5 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘキサン)して標題化合物 (167 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.39 (3H, s), 3.97 (2H, s), 5.99-6.50 (2H, m), 6.73 (1H, s), 7.11-7.46 (5H, m), 7.94 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 412.3. 2-Chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (250 mg), WSC synthesized in Example 15 A mixture of (232 mg), HOBt ammonia hydrate (184 mg) and DMF (1.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / hexane) to give the title compound (167 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.39 (3H, s), 3.97 (2H, s), 5.99-6.50 (2H, m), 6.73 (1H, s), 7.11-7.46 (5H, m), 7.94 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 412.3.
実施例１７
N-(2-アミノ-2-オキソエチル)-2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンズアミド Example 17
N- (2-amino-2-oxoethyl) -2-chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzamide
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　実施例１５で合成した2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (250 mg)、グリシンアミド塩酸塩 (134 mg)、N-エチルジイソプロピルアミン (0.212 mL)、WSC (232 mg)、HOBt (164 mg)およびDMF (1 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して標題化合物 (193 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.39 (3H, s), 3.96 (2H, s), 4.22 (2H, d, J = 4.9 Hz), 5.46-6.14 (2H, m), 6.73 (1H, s), 7.05-7.42 (6H, m), 7.82 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+469.3. 2-Chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (250 mg) synthesized in Example 15 and glycine A mixture of amide hydrochloride (134 mg), N-ethyldiisopropylamine (0.212 mL), WSC (232 mg), HOBt (164 mg) and DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (193 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.39 (3H, s), 3.96 (2H, s), 4.22 (2H, d, J = 4.9 Hz), 5.46-6.14 (2H, m), 6.73 (1H, s), 7.05-7.42 (6H, m), 7.82 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 469.3.
実施例１８
2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-N-(2-ヒドロキシエチル)ベンズアミド Example 18
2-Chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -N- (2-hydroxyethyl) benzamide
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　実施例１５で合成した2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (250 mg)、2－アミノエタノール (0.073 mL)、WSC (232 mg)、HOBt (164 mg)およびDMF (1.5 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して標題化合物 (158 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.28 (1H, brs), 2.38 (3H, s), 3.68 (2H, q, J = 5.0 Hz), 3.83-3.93 (2H, m), 3.96 (2H, s), 6.72 (2H, s), 7.13-7.42 (5H, m), 7.82 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+456.4. 2-Chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (250 mg) synthesized in Example 15, 2 A mixture of aminoethanol (0.073 mL), WSC (232 mg), HOBt (164 mg) and DMF (1.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (158 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.28 (1H, brs), 2.38 (3H, s), 3.68 (2H, q, J = 5.0 Hz), 3.83-3.93 (2H, m), 3.96 (2H, s), 6.72 (2H, s), 7.13-7.42 (5H, m), 7.82 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 456.4.
実施例１９
2-クロロ-N-(2-(ジメチルアミノ)エチル)-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンズアミド ジヒドロクロリド Example 19
2-Chloro-N- (2- (dimethylamino) ethyl) -4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzamide dihydro Chloride
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　実施例１５で合成した2-クロロ-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (250 mg)、N,N-ジメチルエタン-1,2-ジアミン(113 μL) 、HOBt (164 mg) およびWSC (232 mg)のDMF溶液(3 mL) を室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣に4 mol/L塩化水素-酢酸エチル溶液を加え、溶媒を減圧下留去した。得られた残渣をジイソプロピルエーテルで洗浄し、固体をろ取することにより標題化合物(179 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.52 (3H, brs), 2.82 (6H, d, J = 4.5 Hz), 3.18-3.33 (2H, m), 3.65 (2H, q, J = 6.0 Hz), 4.20 (2H, s), 7.53-7.77 (5H, m), 7.85-7.97 (2H, m), 8.98 (1H, t, J = 5.5 Hz), 10.79 (1H, brs), 15.43 (1H, brs).
MS (ESI+): [M+H-2HCl]+483.23. 2-Chloro-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (250 mg) synthesized in Example 15, N , N-dimethylethane-1,2-diamine (113 μL), HOBt (164 mg) and WSC (232 mg) in DMF (3 mL) were stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added 4 mol / L hydrogen chloride-ethyl acetate solution, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether, and the solid was collected by filtration to give the title compound (179 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.52 (3H, brs), 2.82 (6H, d, J = 4.5 Hz), 3.18-3.33 (2H, m), 3.65 (2H, q, J = 6.0 Hz), 4.20 (2H, s), 7.53-7.77 (5H, m), 7.85-7.97 (2H, m), 8.98 (1H, t, J = 5.5 Hz), 10.79 (1H, brs), 15.43 (1H , brs).
MS (ESI +): [M + H-2HCl] + 483.23.
実施例２０
エチル 2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンゾアート Example 20
Ethyl 2-cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoate
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　Ａ）エチル 2-ブロモ-4-フルオロベンゾアート
　2-ブロモ-4-フルオロ安息香酸 （15 g）に塩化チオニル（10 mL）を室温で加え、80 ℃で5時間撹拌した。反応混合物を減圧濃縮し、残渣にエタノール（10 mL）を0 ℃で加えた。反応混合物を室温で終夜撹拌した。反応混合物を減圧濃縮し、残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル）により精製して標題化合物 (16.63 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.0 Hz), 4.39 (2H, q, J = 6.9 Hz), 7.03-7.13 (1H, m), 7.41(1H, dd, J = 8.3, 2.7 Hz), 7.86 (1H, dd, J = 8.7, 6.1 Hz). A) Ethyl 2-bromo-4-fluorobenzoate To 2-bromo-4-fluorobenzoic acid (15 g) was added thionyl chloride (10 mL) at room temperature, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (10 mL) was added to the residue at 0 ° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (16.63 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.0 Hz), 4.39 (2H, q, J = 6.9 Hz), 7.03-7.13 (1H, m), 7.41 (1H, dd, J = 8.3, 2.7 Hz), 7.86 (1H, dd, J = 8.7, 6.1 Hz).
　Ｂ）2-シクロプロピル-4-フルオロ安息香酸エチル
　実施例２０－Ａ）で合成したエチル 2-ブロモ-4-フルオロベンゾアート（1.0 g）、シクロプロピルボロン酸（1.043 g）、2N炭酸ナトリウム水溶液（6.07 mL）の1,2-ジメトキシエタン (DME) 溶液（20 mL）にジクロロ[1,1'-ビス(ジフェニルホスフィノ)-フェロセン]パラジウム(II) ジクロロメタン付加物 (1:1)（0.24 g）を加え、窒素雰囲気下90℃において終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（0.86 g）を得た。
1H NMR (300 MHz, CDCl3) δ 0.65-0.73 (2H, m), 0.99-1.08 (2H, m), 1.39 (3H, t, J = 7.2 Hz), 2.65-2.85 (1H, m), 4.37 (2H, q, J = 6.9 Hz), 6.66 (1H, dd, J = 10.6, 2.6 Hz), 6.87 (1H, td, J = 8.3, 2.6 Hz), 7.85 (1H, dd, J = 8.7, 6.0 Hz). B) Ethyl 2-cyclopropyl-4-fluorobenzoate Ethyl 2-bromo-4-fluorobenzoate (1.0 g) synthesized in Example 20-A), cyclopropylboronic acid (1.043 g), 2N aqueous sodium carbonate solution (6.07 mL) in 1,2-dimethoxyethane (DME) solution (20 mL) to dichloro [1,1'-bis (diphenylphosphino) -ferrocene] palladium (II) dichloromethane adduct (1: 1) (0.24 g) was added and stirred at 90 ° C. overnight under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (0.86 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.65-0.73 (2H, m), 0.99-1.08 (2H, m), 1.39 (3H, t, J = 7.2 Hz), 2.65-2.85 (1H, m), 4.37 (2H, q, J = 6.9 Hz), 6.66 (1H, dd, J = 10.6, 2.6 Hz), 6.87 (1H, td, J = 8.3, 2.6 Hz), 7.85 (1H, dd, J = 8.7, 6.0 Hz).
　Ｃ）エチル 2-シクロプロピル-4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)ベンゾアート
　水素化ナトリウム（60%、0.182 g）と18-crown-6（0.109 g）のNMP懸濁液（10 mL）に0℃で4-ヨード-2-メチル-1H-イミダゾール（0.86 g）のNMP溶液（5 mL）を加え、窒素雰囲気下室温で30分間撹拌した。0 ℃に冷却した反応混合物に実施例２０－Ｂ）で合成した2-シクロプロピル-4-フルオロ安息香酸エチル（0.904 g）のNMP溶液（5 mL）を滴下し、窒素雰囲気下110 ℃で終夜加熱撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（0.504 ｇ）を得た。
1H NMR (300 MHz, CDCl3) δ 0.66-0.74 (2H, m), 1.04-1.13 (2H, m), 1.43 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 2.71 (1H, tt, J = 8.5, 5.4 Hz), 4.42 (2H, q, J = 7.2 Hz), 6.88 (1H, d, J = 2.3 Hz), 7.10 (1H, dd, J = 8.1, 2.1 Hz), 7.27 (1H, s), 7.91 (1H, d, J = 8.3 Hz). C) Ethyl 2-cyclopropyl-4- (4-iodo-2-methyl-1H-imidazol-1-yl) benzoate Sodium hydride (60%, 0.182 g) and 18-crown-6 (0.109 g) To an NMP suspension (10 mL), an NMP solution (5 mL) of 4-iodo-2-methyl-1H-imidazole (0.86 g) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the reaction mixture cooled to 0 ° C., an NMP solution (5 mL) of ethyl 2-cyclopropyl-4-fluorobenzoate (0.904 g) synthesized in Example 20-B) was added dropwise, and the mixture was overnight at 110 ° C. under a nitrogen atmosphere. Stir with heating. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (0.504 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.66-0.74 (2H, m), 1.04-1.13 (2H, m), 1.43 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 2.71 ( 1H, tt, J = 8.5, 5.4 Hz), 4.42 (2H, q, J = 7.2 Hz), 6.88 (1H, d, J = 2.3 Hz), 7.10 (1H, dd, J = 8.1, 2.1 Hz), 7.27 (1H, s), 7.91 (1H, d, J = 8.3 Hz).
　Ｄ）エチル 2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンゾアート
　アルゴン雰囲気下室温で、亜鉛粉末（0.726 g）の無水THF懸濁液（12 mL）に1,2-ジブロモブタン（0.044 mL）を加え、80 ℃で30分間撹拌した。反応混合物を室温に冷却しクロロトリメチルシラン（0.064 mL）を加え、室温で20分間撹拌した。窒素雰囲気下で反応混合液に1-(ブロモメチル)-3-フルオロ-5-(トリフルオロメチル)ベンゼン（2.85 g）の無水THF溶液（12 mL）を滴下し、室温で3時間撹拌した。反応混合物に実施例２０－Ｃ）で合成したエチル 2-シクロプロピル-4-(4-ヨード-2-メチル-1H-イミダゾール-1-イル)ベンゾアート（2.93 g）、酢酸パラジウム（II）（0.166 g）、BINAP（0.460 g）、無水THF（12 mL）を加え、80 ℃で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（2.39 g）を得た。
1H NMR (300 MHz, CDCl3) δ 0.70 (2H, q, J = 5.2 Hz), 1.01-1.12 (2H, m), 1.42 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 2.65-2.78 (1H, m), 3.97 (2H, s), 4.42 (2H, q, J = 7.2 Hz), 6.71 (1H, s), 6.89 (1H, d, J = 2.3 Hz), 7.08-7.29 (3H, m), 7.38 (1H, s), 7.90 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+447.2. D) Ethyl 2-cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoate zinc powder at room temperature under argon atmosphere 1,2-Dibromobutane (0.044 mL) was added to an anhydrous THF suspension (12 mL) of (0.726 g), and the mixture was stirred at 80 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, chlorotrimethylsilane (0.064 mL) was added, and the mixture was stirred at room temperature for 20 minutes. An anhydrous THF solution (12 mL) of 1- (bromomethyl) -3-fluoro-5- (trifluoromethyl) benzene (2.85 g) was added dropwise to the reaction mixture under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, ethyl 2-cyclopropyl-4- (4-iodo-2-methyl-1H-imidazol-1-yl) benzoate (2.93 g) synthesized in Example 20-C), palladium (II) acetate ( 0.166 g), BINAP (0.460 g), and anhydrous THF (12 mL) were added, and the mixture was stirred at 80 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (2.39 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.70 (2H, q, J = 5.2 Hz), 1.01-1.12 (2H, m), 1.42 (3H, t, J = 7.2 Hz), 2.35 (3H, s) , 2.65-2.78 (1H, m), 3.97 (2H, s), 4.42 (2H, q, J = 7.2 Hz), 6.71 (1H, s), 6.89 (1H, d, J = 2.3 Hz), 7.08- 7.29 (3H, m), 7.38 (1H, s), 7.90 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 447.2.
実施例２１
2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 Example 21
2-Cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　実施例２０で合成したエチル 2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンゾアート（0.16 g）のエタノール溶液（3 mL）に1 N水酸化ナトリウム水溶液(1.5 mL)を加え、50 ℃で3時間撹拌した。反応混合物を1 N塩酸で中和し、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物(110 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 0.73-0.89 (2H, m), 0.97-1.11 (2H, m), 2.47 (3H, s), 2.64-2.79 (1H, m), 4.19 (2H, s), 7.17 (1H, d, J = 1.9 Hz), 7.45 (1H, dd, J = 8.1, 2.1 Hz), 7.55-7.73 (4H, m), 7.88 (1H, d, J = 8.3 Hz), (COOHピークは観測されなかった).
MS (ESI+): [M+H]+419.2. Ethyl 2-cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoate (0.16 g) synthesized in Example 20 1N aqueous sodium hydroxide solution (1.5 mL) was added to an ethanol solution (3 mL), and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (110 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.73-0.89 (2H, m), 0.97-1.11 (2H, m), 2.47 (3H, s), 2.64-2.79 (1H, m), 4.19 (2H , s), 7.17 (1H, d, J = 1.9 Hz), 7.45 (1H, dd, J = 8.1, 2.1 Hz), 7.55-7.73 (4H, m), 7.88 (1H, d, J = 8.3 Hz) , (No COOH peak was observed).
MS (ESI +): [M + H] + 419.2.
実施例２２
2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンズアミド Example 22
2-Cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzamide
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　実施例２１で合成した2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (110 mg)、WSC (101 mg)、HOBtアンモニア和物 (80 mg)およびDMF (1 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘキサン)して標題化合物 (105 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.74-0.84 (2H, m), 1.06-1.16 (2H, m), 2.27-2.44 (4H, m), 3.96 (2H, s), 5.96 (2H, brs), 6.68 (1H, s), 6.86 (1H, d, J = 1.9 Hz), 7.08-7.30 (3H, m), 7.38 (1H, s), 7.62 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+418.3. 2-Cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (110 mg) synthesized in Example 21 A mixture of WSC (101 mg), HOBt ammonia solvate (80 mg) and DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / hexane) to give the title compound (105 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.74-0.84 (2H, m), 1.06-1.16 (2H, m), 2.27-2.44 (4H, m), 3.96 (2H, s), 5.96 (2H, brs ), 6.68 (1H, s), 6.86 (1H, d, J = 1.9 Hz), 7.08-7.30 (3H, m), 7.38 (1H, s), 7.62 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 418.3.
実施例２３
N-(2-アミノ-2-オキソエチル)-2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンズアミド Example 23
N- (2-amino-2-oxoethyl) -2-cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzamide
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　実施例２１で合成した2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (250 mg)、グリシンアミド塩酸塩 (132 mg)、N-エチルジイソプロピルアミン (0.209 mL)、WSC (229 mg)、HOBt (161 mg)およびDMF (2 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘキサン)して標題化合物 (151 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.72-0.81 (2H, m), 1.04-1.16 (2H, m), 2.25-2.38 (4H, m), 3.96 (2H, s), 4.23 (2H, d, J = 4.9 Hz), 5.59 (1H, brs), 6.18 (1H, brs), 6.69 (1H, s), 6.87 (1H, d, J = 1.9 Hz), 6.92 (1H, t, J = 4.5 Hz), 7.09-7.29 (3H, m), 7.38 (1H, s), 7.59 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+475.1. 2-cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (250 mg) synthesized in Example 21, A mixture of glycinamide hydrochloride (132 mg), N-ethyldiisopropylamine (0.209 mL), WSC (229 mg), HOBt (161 mg) and DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / hexane) to give the title compound (151 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.72-0.81 (2H, m), 1.04-1.16 (2H, m), 2.25-2.38 (4H, m), 3.96 (2H, s), 4.23 (2H, d , J = 4.9 Hz), 5.59 (1H, brs), 6.18 (1H, brs), 6.69 (1H, s), 6.87 (1H, d, J = 1.9 Hz), 6.92 (1H, t, J = 4.5 Hz ), 7.09-7.29 (3H, m), 7.38 (1H, s), 7.59 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 475.1.
実施例２４
2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)-N-(2-ヒドロキシエチル)ベンズアミド Example 24
2-Cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) -N- (2-hydroxyethyl) benzamide
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　実施例２１で合成した2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (250 mg)、2－アミノエタノール(0.072 mL)、WSC (229 mg)、HOBt (161 mg)およびDMF (2 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘキサン)させ、標題化合物 (105 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.68-0.82 (2H, m), 1.02-1.16 (2H, m), 2.22-2.40 (4H, m), 2.53 (1H, brs), 3.67 (2H, q, J = 5.3 Hz), 3.83-3.91 (2H, m), 3.96 (2H, s), 6.46-6.55 (1H, m), 6.68 (1H, s), 6.84 (1H, d, J = 1.9 Hz), 7.07-7.29 (3H, m), 7.38 (1H, s), 7.54 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+462.1. 2-cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (250 mg) synthesized in Example 21, A mixture of 2-aminoethanol (0.072 mL), WSC (229 mg), HOBt (161 mg) and DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / hexane) to give the title compound (105 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.68-0.82 (2H, m), 1.02-1.16 (2H, m), 2.22-2.40 (4H, m), 2.53 (1H, brs), 3.67 (2H, q , J = 5.3 Hz), 3.83-3.91 (2H, m), 3.96 (2H, s), 6.46-6.55 (1H, m), 6.68 (1H, s), 6.84 (1H, d, J = 1.9 Hz) , 7.07-7.29 (3H, m), 7.38 (1H, s), 7.54 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 462.1.
実施例２５
2-シクロプロピル-N-(2-(ジメチルアミノ)エチル)-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)ベンズアミド ジヒドロクロリド Example 25
2-Cyclopropyl-N- (2- (dimethylamino) ethyl) -4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzamide Dihydrochloride
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　実施例２１で合成した2-シクロプロピル-4-(4-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-1H-イミダゾール-1-イル)安息香酸 (250 mg)、N,N-ジメチルエタン-1,2-ジアミン(112 μL) 、HOBt (161 mg) およびWSC (229 mg)のDMF溶液(3 mL) を室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣に4 N塩化水素-酢酸エチル溶液を加え、溶媒を減圧下留去した。得られた残渣をジイソプロピルエーテルで洗浄し、固体をろ取することにより標題化合物(227 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 0.70-0.82 (2H, m), 0.93-1.04 (2H, m), 2.21-2.34 (1H, m), 2.48 (3H, s), 2.82 (6H, d, J = 4.1 Hz), 3.27 (2H, d, J = 4.9 Hz), 3.66 (2H, q, J = 5.9 Hz), 4.20 (2H, s), 7.15 (1H, s), 7.44 (1H, d, J = 8.3 Hz), 7.56-7.75 (5H, m), 8.84 (1H, t, J = 5.5 Hz), 10.82 (1H, brs), 15.37 (1H, brs).
MS (ESI+): [M+H-2HCl]+489.32. 2-cyclopropyl-4- (4- (3-fluoro-5- (trifluoromethyl) benzyl) -2-methyl-1H-imidazol-1-yl) benzoic acid (250 mg) synthesized in Example 21, A DMF solution (3 mL) of N, N-dimethylethane-1,2-diamine (112 μL), HOBt (161 mg) and WSC (229 mg) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added 4N hydrogen chloride-ethyl acetate solution, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether, and the solid was collected by filtration to give the title compound (227 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.70-0.82 (2H, m), 0.93-1.04 (2H, m), 2.21-2.34 (1H, m), 2.48 (3H, s), 2.82 (6H , d, J = 4.1 Hz), 3.27 (2H, d, J = 4.9 Hz), 3.66 (2H, q, J = 5.9 Hz), 4.20 (2H, s), 7.15 (1H, s), 7.44 (1H , d, J = 8.3 Hz), 7.56-7.75 (5H, m), 8.84 (1H, t, J = 5.5 Hz), 10.82 (1H, brs), 15.37 (1H, brs).
MS (ESI +): [M + H-2HCl] + 489.32.
実施例２６
エチル 4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}ベンゾアート Example 26
Ethyl 4- {1-methyl-3- [3- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} benzoate
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　Ａ）エチル 4-(4-ブロモフェニル)-4-ヒドロキシ-2-オキソブタ-3-エノアート
　エタノール(1.5 L)中に金属ナトリウム(16.6 g)を加えることにより調製したナトリウムエトキシド溶液中に、1-(4-ブロモフェニル)エタノン(120 g)を加え室温で30分間撹拌した。反応混合物を0℃に冷却した後、シュウ酸ジエチル(90.0 mL)を加えた。反応混合物を室温で18時間撹拌した後、エーテルで希釈し、水を加えた。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後減圧濃縮することにより、標題化合物(170 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 4.41 (2H, q, 7.2 Hz), 7.04 (1H, s), 7.64-7.67 (2H, m), 7.85-7.88 (2H, m), OHピークは観測されなかった. A) Ethyl 4- (4-bromophenyl) -4-hydroxy-2-oxobut-3-enoate In a sodium ethoxide solution prepared by adding metallic sodium (16.6 g) in ethanol (1.5 L), 1 -(4-Bromophenyl) ethanone (120 g) was added and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 ° C., and diethyl oxalate (90.0 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with ether and water was added. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (170 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 4.41 (2H, q, 7.2 Hz), 7.04 (1H, s), 7.64-7.67 (2H, m), 7.85 -7.88 (2H, m), no OH peak was observed.
　Ｂ）エチル 5-(4-ブロモフェニル)-1-メチル-1H-ピラゾール-3-カルボキシラート
　実施例２６－Ａ）で合成したエチル 4-(4-ブロモフェニル)-4-ヒドロキシ-2-オキソブタ-3-エノアート(170 g)のエタノール(2.0 L)溶液にメチルヒドラジン(40%水溶液、98 g)を室温で加えた。反応混合物を16時間加熱還流した後、減圧下濃縮した。得られた残渣を酢酸エチルで希釈し、水、1N 塩酸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、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(45.1 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 3.95 (3H, s), 4.43 (2H, q, J = 6.8 Hz), 6.85 (1H, s), 7.28-7.31 (2H, m), 7.61-7.63 (2H, m). B) Ethyl 5- (4-bromophenyl) -1-methyl-1H-pyrazole-3-carboxylate Ethyl 4- (4-bromophenyl) -4-hydroxy-2-oxobutane synthesized in Example 26-A) Methylhydrazine (40% aqueous solution, 98 g) was added to a solution of -3-enoate (170 g) in ethanol (2.0 L) at room temperature. The reaction mixture was heated to reflux for 16 hours and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with water, 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (45.1 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 3.95 (3H, s), 4.43 (2H, q, J = 6.8 Hz), 6.85 (1H, s), 7.28 -7.31 (2H, m), 7.61-7.63 (2H, m).
　Ｃ） [5-(4-ブロモフェニル)-1-メチル-1H-ピラゾール-3-イル]メタノール
　実施例２６－Ｂ）で合成したエチル 5-(4-ブロモフェニル)-1-メチル-1H-ピラゾール-3-カルボキシラート(55.0 g)のエタノール(600 mL)溶液を0℃に冷却し、水素化ホウ素ナトリウム(40.4 g)をゆっくり加えた。反応混合物を48時間加熱還流した後室温に冷却し、水を加えてから減圧下濃縮した。残渣をジクロロメタンで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(35.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.92 (1H, s), 3.84 (3H, s), 4.71 (2H, d, J = 5.2 Hz), 6.30 (1H, s), 7.28 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz). C) [5- (4-Bromophenyl) -1-methyl-1H-pyrazol-3-yl] methanol Ethyl 5- (4-bromophenyl) -1-methyl-1H- synthesized in Example 26-B) A solution of pyrazole-3-carboxylate (55.0 g) in ethanol (600 mL) was cooled to 0 ° C. and sodium borohydride (40.4 g) was added slowly. The reaction mixture was heated to reflux for 48 hours, cooled to room temperature, water was added, and the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (35.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.92 (1H, s), 3.84 (3H, s), 4.71 (2H, d, J = 5.2 Hz), 6.30 (1H, s), 7.28 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz).
　Ｄ）エチル 4-[3-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-5-イル]ベンゾアート
　実施例２６－Ｃ）で合成した[5-(4-ブロモフェニル)-1-メチル-1H-ピラゾール-3-イル]メタノール(35.5 g)、酢酸パラジウム（II）(14.9 g)、1,1’-ビス(ジフェニルホスフィノ)フェロセン(dppf; 36.8 g)、トリエチルアミン(55.6 mL)およびエタノール(440 mL)の混合物を、一酸化炭素雰囲気下60℃で18時間撹拌した。反応混合物をジクロロメタンで希釈し、セライトろ過した。ろ液を水および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、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/メタノール)で精製して標題化合物(19.0 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 2.31 (1H, t, J = 6.0 Hz), 3.88 (3H, s), 4.41 (2H, q, J = 7.2 Hz), 4.72 (2H, d, J = 6.0 Hz), 6.38 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 8.13 (2H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+ 261.0. D) Ethyl 4- [3- (hydroxymethyl) -1-methyl-1H-pyrazol-5-yl] benzoate [5- (4-bromophenyl) -1-methyl-synthesized in Example 26-C) 1H-pyrazol-3-yl] methanol (35.5 g), palladium (II) acetate (14.9 g), 1,1′-bis (diphenylphosphino) ferrocene (dppf; 36.8 g), triethylamine (55.6 mL) and ethanol (440 mL) was stirred at 60 ° C. for 18 hours under a carbon monoxide atmosphere. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (19.0 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 2.31 (1H, t, J = 6.0 Hz), 3.88 (3H, s), 4.41 (2H, q, J = 7.2 Hz), 4.72 (2H, d, J = 6.0 Hz), 6.38 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 8.13 (2H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 261.0.
　Ｅ）エチル 4-[3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル]ベンゾアート
　実施例２６－Ｄ）で合成したエチル 4-[3-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-5-イル]ベンゾアート(14.0 g)のジクロロメタン(150 mL)溶液に三臭化リン(1Mジクロロメタン溶液、53.8 mL)を加え、室温で12時間撹拌した。反応混合物に水を加え、ジクロロメタンで抽出した。有機層を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、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(12.2 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 3.89 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 4.52 (2H, s), 6.43 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 8.13 (2H, d, J = 8.4 Hz). E) Ethyl 4- [3- (Bromomethyl) -1-methyl-1H-pyrazol-5-yl] benzoate Ethyl 4- [3- (hydroxymethyl) -1-methyl-synthesized in Example 26-D) To a solution of [1H-pyrazol-5-yl] benzoate (14.0 g) in dichloromethane (150 mL) was added phosphorus tribromide (1M dichloromethane solution, 53.8 mL), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (12.2 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 3.89 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 4.52 (2H, s), 6.43 (1H, s), 7.49 (2H, d, J = 8.4 Hz), 8.13 (2H, d, J = 8.4 Hz).
　Ｆ）エチル 4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}ベンゾアート
　実施例２６－Ｅ）で合成したエチル 4-[3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル]ベンゾアート(11.3 g)、3-(トリフルオロメチル)フェニルボロン酸(9.96 g)、テトラキス（トリフェニルホスフィン）パラジウム（0）(2.02 g)、リン酸カリウム(22.3 g)および1,4-ジオキサン(120 mL)の混合物を80℃で16時間撹拌した。反応混合物をジクロロメタンで希釈し、セライトろ過した。ろ液を水および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、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(11.2 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 3.88 (3H, s), 4.05 (2H, s), 4.41 (2H, q, J = 7.2 Hz), 6.11 (1H, s), 7.40-7.51 (5H, m), 7.57 (1H, s), 8.11 (2H, d, J = 8.4 Hz).
MS (ESI+): [M+H]+ 389.3. F) Ethyl 4- {1-methyl-3- [3- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} benzoate Ethyl 4- [3- (bromomethyl) synthesized in Example 26-E) ) -1-Methyl-1H-pyrazol-5-yl] benzoate (11.3 g), 3- (trifluoromethyl) phenylboronic acid (9.96 g), tetrakis (triphenylphosphine) palladium (0) (2.02 g) , A mixture of potassium phosphate (22.3 g) and 1,4-dioxane (120 mL) was stirred at 80 ° C. for 16 hours. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (11.2 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 3.88 (3H, s), 4.05 (2H, s), 4.41 (2H, q, J = 7.2 Hz), 6.11 (1H, s), 7.40-7.51 (5H, m), 7.57 (1H, s), 8.11 (2H, d, J = 8.4 Hz).
MS (ESI +): [M + H] + 389.3.
実施例２７
4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}安息香酸 Example 27
4- {1-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} benzoic acid
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　実施例２６で合成したエチル 4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}ベンゾアート(8.85 g)のエタノール(114 mL)溶液に6N水酸化ナトリウム水溶液(19.0 mL)を加え、室温で3時間撹拌した。反応混合物に2N塩酸を加えて中和した後、酢酸エチルで抽出した。有機層を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、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製して標題化合物(3.96 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.85 (3H, s), 4.02 (2H, s), 6.36 (1H, s), 7.52-7.59 (2H, m), 7.61-7.66 (4H, m), 8.02 (2H, d, J = 8.4 Hz), 13.1 (1H, s).
MS (ESI+): [M+H]+ 361.2. To a solution of ethyl 4- {1-methyl-3- [3- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} benzoate (8.85 g) synthesized in Example 26 in ethanol (114 mL) was added 6N. Aqueous sodium hydroxide (19.0 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (3.96 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.85 (3H, s), 4.02 (2H, s), 6.36 (1H, s), 7.52-7.59 (2H, m), 7.61-7.66 (4H, m), 8.02 (2H, d, J = 8.4 Hz), 13.1 (1H, s).
MS (ESI +): [M + H] + 361.2.
実施例２８
4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}ベンズアミド Example 28
4- {1-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　実施例２７で合成した4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}安息香酸(360 mg)、WSC塩酸塩(230 mg)、HOBtアンモニア和物(182 mg)およびDMF(3 mL)の混合物を室温で5時間撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣を再結晶(ヘプタン/酢酸エチル)して標題化合物(310 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 3.88 (3H, s), 4.05 (2H, s), 5.52-6.28 (3H, m), 7.36-7.62 (6H, m), 7.83-7.94 (2H, m).
MS (ESI+): [M+H]+ 360.4. 4- {1-methyl-3- [3- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} benzoic acid (360 mg), WSC hydrochloride (230 mg), HOBt synthesized in Example 27 A mixture of ammonia hydrate (182 mg) and DMF (3 mL) was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized (heptane / ethyl acetate) to give the title compound (310 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 3.88 (3H, s), 4.05 (2H, s), 5.52-6.28 (3H, m), 7.36-7.62 (6H, m), 7.83-7.94 (2H, m ).
MS (ESI +): [M + H] + 360.4.
実施例２９
エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート Example 29
Ethyl 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　Ａ）エチル 4-ブロモ-2-メチルベンゾアート
　エタノール(200 mL)中に塩化チオニル(20 mL)を加え、室温で30分間撹拌した後、4-ブロモ-2-メチル安息香酸(15 g)を加えた。反応混合物を室温で一晩撹拌した後、減圧下濃縮した。残渣を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去して標題化合物(16.9 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.39 (3H, t, J = 7.0 Hz), 2.58 (3H, s), 4.35 (2H, q, J = 7.2 Hz), 7.34-7.46 (2H, m), 7.78 (1H, d, J = 8.3 Hz). A) Ethyl 4-bromo-2-methylbenzoate Add thionyl chloride (20 mL) to ethanol (200 mL) and stir at room temperature for 30 minutes, and then add 4-bromo-2-methylbenzoic acid (15 g). added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (16.9 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.39 (3H, t, J = 7.0 Hz), 2.58 (3H, s), 4.35 (2H, q, J = 7.2 Hz), 7.34-7.46 (2H, m) , 7.78 (1H, d, J = 8.3 Hz).
　Ｂ）エチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート
　実施例２９－Ａ）で合成したエチル 4-ブロモ-2-メチルベンゾアート(12.1 g)、ビス(ピナコラート)ジボロン(15.2 g)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(817 mg)、酢酸カリウム(9.8 g)およびDMF(50 mL)の混合物を80℃で6時間撹拌した。反応混合物を酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製し、標題化合物(14.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.35 (12H, s), 1.39 (3H, t, J = 7.2 Hz), 2.59 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 7.62-7.70 (2H, m), 7.87 (1H, d, J = 7.5 Hz). B) Ethyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate Ethyl 4-bromo-2 synthesized in Example 29-A) -Methylbenzoate (12.1 g), bis (pinacolato) diboron (15.2 g), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (817 mg), potassium acetate (9.8 mg) A mixture of g) and DMF (50 mL) was stirred at 80 ° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (14.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.35 (12H, s), 1.39 (3H, t, J = 7.2 Hz), 2.59 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 7.62 -7.70 (2H, m), 7.87 (1H, d, J = 7.5 Hz).
　Ｃ）メチル 4-[3-フルオロ-5-(トリフルオロメチル)フェニル]-3-オキソブタノアート
　[3-フルオロ-5-(トリフルオロメチル)フェニル]酢酸（9.96 g）のDMF（30 mL）溶液にWSC（11.2 g）、2,2-ジメチル-1,3-ジオキサン-4,6-ジオン（8.4 g）を加え、室温で5分間撹拌後、N,N-ジメチルピリジン-4-アミン（8.76 g）を加え、4時間撹拌した。反応混合物に1N塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣にメタノール（50 mL）を加え、加熱還流下、終夜撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して、標題化合物 （7.7 g）を得た。
1H NMR (300 MHz, CDCl3) δ 3.53 (2H, s), 3.76 (3H, s), 3.93 (2H, s), 7.08-7.38 (3H, m). C) Methyl 4- [3-Fluoro-5- (trifluoromethyl) phenyl] -3-oxobutanoate [3-Fluoro-5- (trifluoromethyl) phenyl] acetic acid (9.96 g) in DMF (30 mL ) Add WSC (11.2 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (8.4 g) to the solution and stir at room temperature for 5 minutes, then N, N-dimethylpyridin-4-amine (8.76 g) was added and stirred for 4 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Methanol (50 mL) was added to the residue, and the mixture was stirred overnight with heating under reflux. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (7.7 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.53 (2H, s), 3.76 (3H, s), 3.93 (2H, s), 7.08-7.38 (3H, m).
　Ｄ）5-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-2-メチル-2,4-ジヒドロ-3H-ピラゾール-3-オン
　実施例２９－Ｃ）で合成したメチル 4-[3-フルオロ-5-(トリフルオロメチル)フェニル]-3-オキソブタノアート（5.0 g）のメタノール溶液（30 mL）にメチルヒドラジン(1.24 g)を加え、室温で4時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して、標題化合物 （3.4 g）を得た。
1H NMR (300 MHz, CDCl3) δ 3.12 (2H, s), 3.31 (3H, s), 3.77 (2H, s), 7.14 (1H, d, J = 8.3 Hz), 7.23-7.31 (2H, m).
MS (ESI+): [M+H]+275.1. D) 5- [3-Fluoro-5- (trifluoromethyl) benzyl] -2-methyl-2,4-dihydro-3H-pyrazol-3-one Methyl 4- [3 synthesized in Example 29-C) Methylhydrazine (1.24 g) was added to a methanol solution (30 mL) of -fluoro-5- (trifluoromethyl) phenyl] -3-oxobutanoate (5.0 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.4 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.12 (2H, s), 3.31 (3H, s), 3.77 (2H, s), 7.14 (1H, d, J = 8.3 Hz), 7.23-7.31 (2H, m).
MS (ESI +): [M + H] + 275.1.
　Ｅ）3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例２９－Ｄ）で合成した5-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-2-メチル-2,4-ジヒドロ-3H-ピラゾール-3-オン（3.39 g）のピリジン溶液（50 mL）にトリフルオロメタンスルホン酸無水物（4.19 g）を-20 ℃でゆっくり加え、室温で1時間撹拌した。反応混合物にトルエンを加え、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（NH、ヘキサン/酢酸エチル）により精製することで、標題化合物 (2.42 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.79 (3H, s), 3.96 (2H, s), 5.92 (1H, s), 7.07-7.35 (3H, m).
MS (ESI+): [M+H]+407.1. E) 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate Example 29-D) 5- [3-Fluoro- Trifluoromethanesulfonic anhydride (4.19 g) was added to a pyridine solution (50 mL) of 5- (trifluoromethyl) benzyl] -2-methyl-2,4-dihydro-3H-pyrazol-3-one (3.39 g). Slowly added at −20 ° C. and stirred at room temperature for 1 hour. Toluene was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (NH, hexane / ethyl acetate) to give the title compound (2.42 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.79 (3H, s), 3.96 (2H, s), 5.92 (1H, s), 7.07-7.35 (3H, m).
MS (ESI +): [M + H] + 407.1.
　Ｆ）エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート
　実施例２９－Ｅ）で合成した3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート（2.42 g）のDME(30 mL)溶液に、実施例２９－Ｂ）で合成したエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート（2.59 g）、テトラキストリフェニルホスフィンパラジウム（0.69 g）、2 N炭酸ナトリウム水溶液（6 mL）を加え、90℃で終夜攪拌した。反応混合物に水を注ぎ、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/へキサン）で精製し、標題化合物（2.16 g）を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.87 (3H, s), 4.04 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.11 (1H, s), 7.14-7.24 (2H, m), 7.24-7.32 (2H, m), 7.37 (1H, s), 7.98 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+421.3. F) Ethyl 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoate synthesized in Example 29-E) To a solution of 3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2.42 g) in DME (30 mL), Example 29-B 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (2.59 g), tetrakistriphenylphosphine palladium (0.69 g) ), 2N aqueous sodium carbonate solution (6 mL) was added, and the mixture was stirred at 90 ° C. overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.16 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.87 (3H, s), 4.04 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.11 (1H, s), 7.14-7.24 (2H, m), 7.24-7.32 (2H, m), 7.37 (1H, s), 7.98 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 421.3.
実施例３０
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸 Example 30
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　実施例２９で合成したエチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート（2.16 g）のエタノール溶液（30 mL）に8 N水酸化ナトリウム水溶液(1.93 mL)を加え、80℃で3時間撹拌した。反応混合物を6N塩酸で中和した後、残渣をろ過し、水、ヘキサンで洗浄後、減圧下乾燥し、標題化合物(1.61 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.56 (3H, s), 3.83 (3H, s), 4.03 (2H, s), 6.36 (1H, s), 7.32-7.58 (5H, m), 7.89 (1H, d, J = 8.0 Hz), 12.93 (1H, brs).
MS (ESI+): [M+H]+393.3. Of ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoate (2.16 g) synthesized in Example 29 To the ethanol solution (30 mL) was added 8 N aqueous sodium hydroxide solution (1.93 mL), and the mixture was stirred at 80 ° C. for 3 hr. The reaction mixture was neutralized with 6N hydrochloric acid, the residue was filtered, washed with water and hexane, and dried under reduced pressure to give the title compound (1.61 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.56 (3H, s), 3.83 (3H, s), 4.03 (2H, s), 6.36 (1H, s), 7.32-7.58 (5H, m), 7.89 (1H, d, J = 8.0 Hz), 12.93 (1H, brs).
MS (ESI +): [M + H] + 393.3.
実施例３１
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 31
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸（200 mg）のDMF（3 mL）溶液にWSC（293 mg）、HOBt（234 mg）を加え、室温で5分間攪拌後、アンモニア水（3 mL）を加え、終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。粗結晶をエタノール－酢酸エチルから再結晶し標題化合物 (79 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.41 (3H, s), 3.81 (3H, s), 4.03 (2H, s), 6.30 (1H, s), 7.30-7.58 (7H, m), 7.77 (1H, brs).
MS (ESI+): [M+H]+392.3. DMF of 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg) synthesized in Example 30 WSC (293 mg) and HOBt (234 mg) were added to the (3 mL) solution, and after stirring at room temperature for 5 minutes, aqueous ammonia (3 mL) was added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude crystals were recrystallized from ethanol-ethyl acetate to obtain the title compound (79 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.41 (3H, s), 3.81 (3H, s), 4.03 (2H, s), 6.30 (1H, s), 7.30-7.58 (7H, m), 7.77 (1H, brs).
MS (ESI +): [M + H] + 392.3.
実施例３２
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-(2-ヒドロキシエチル)-2-メチルベンズアミド Example 32
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- (2-hydroxyethyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸（155 mg）のDMF（5 mL）溶液にWSC（227 mg）、HOBt（181 mg）を加え、室温で5分間攪拌後、2-アミノエタノール（72 mg）を加え、終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。残渣をアミノシリカゲルカラムクロマトグラフィー (メタノール/酢酸エチル)で精製後、酢酸エチル－ヘキサンから再結晶し標題化合物(86 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.37 (3H, s), 3.25-3.36 (2H, m), 3.45-3.56 (2H, m), 4.03 (3H, s), 4.64-4.74 (2H, m), 6.30 (1H, s), 7.17-7.66 (6H, m), 8.24 (1H, s), (OHピークは観測されなかった).
MS (ESI+): [M+H]+436.3. DMF of 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (155 mg) synthesized in Example 30 (5 mL) To the solution, WSC (227 mg) and HOBt (181 mg) were added, and after stirring at room temperature for 5 minutes, 2-aminoethanol (72 mg) was added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (methanol / ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (86 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.37 (3H, s), 3.25-3.36 (2H, m), 3.45-3.56 (2H, m), 4.03 (3H, s), 4.64-4.74 (2H , m), 6.30 (1H, s), 7.17-7.66 (6H, m), 8.24 (1H, s), (OH peak not observed).
MS (ESI +): [M + H] + 436.3.
実施例３３
N-(2-アミノ-2-オキソエチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 33
N- (2-amino-2-oxoethyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg)のDMF(3 mL)溶液にWSC(293 mg)、HOBt（234 mg）を加え、室温で5分間攪拌後、グリシンアミド塩酸塩（68 mg）およびジイソプロピルエチルアミン（200 mg, 0.68 mmol）を加え、終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、メタノール/酢酸エチル)で精製後、エタノール－酢酸エチルから再結晶し標題化合物 (193 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.41 (3H, s), 3.75-3.87 (5H, m), 4.03 (2H, s), 6.31 (1H, s), 7.03 (1H, brs), 7.30-7.43 (3H, m), 7.43-7.63 (4H, m), 8.33-8.48 (1H, m).MS (ESI+): [M+H]+ 449.4. DMF of 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg) synthesized in Example 30 (3 mL) Add WSC (293 mg) and HOBt (234 mg) to the solution, stir at room temperature for 5 min, add glycinamide hydrochloride (68 mg) and diisopropylethylamine (200 mg, 0.68 mmol), and stir overnight did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and recrystallized from ethanol-ethyl acetate to give the title compound (193 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.41 (3H, s), 3.75-3.87 (5H, m), 4.03 (2H, s), 6.31 (1H, s), 7.03 (1H, brs), 7.30- 7.43 (3H, m), 7.43-7.63 (4H, m), 8.33-8.48 (1H, m) .MS (ESI +): [M + H] + 449.4.
実施例３４
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(メチルアミノ)-2-オキソエチル]ベンズアミド Example 34
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (methylamino) -2-oxoethyl Benzamide
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、N-メチルグリシンアミド塩酸塩 (76 mg) 、HOBt (83 mg) 、WSC (117 mg) およびトリエチルアミン (85 μL)のDMF溶液 (3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (219 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 2.89 (3H, d, J = 4.9 Hz), 3.86 (3H, s), 4.03 (2H, s), 4.12 (2H, d, J = 4.9 Hz), 5.99-6.15 (2H, m), 6.61-6.75 (1H, m), 7.12-7.32 (4H, m), 7.34-7.41 (1H, m), 7.51 (1H, d, J = 7.6 Hz).
MS (ESI+): [M+H]+463.24. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg) synthesized in Example 30, N -A DMF solution (3.4 mL) of methylglycinamide hydrochloride (76 mg), HOBt (83 mg), WSC (117 mg) and triethylamine (85 μL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (219 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.50 (3H, s), 2.89 (3H, d, J = 4.9 Hz), 3.86 (3H, s), 4.03 (2H, s), 4.12 (2H, d, J = 4.9 Hz), 5.99-6.15 (2H, m), 6.61-6.75 (1H, m), 7.12-7.32 (4H, m), 7.34-7.41 (1H, m), 7.51 (1H, d, J = (7.6 Hz).
MS (ESI +): [M + H] + 463.24.
実施例３５
N-[2-(アセチルアミノ)エチル]-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 35
N- [2- (acetylamino) ethyl] -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(250 mg) 、N-(2-アミノエチル)アセトアミド (78 mg) 、HOBt (103 mg) およびWSC (147 mg)のDMF溶液(4.2 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (245.9 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.01 (3H, s), 2.49 (3H, s), 3.45-3.56 (2H, m), 3.56-3.67 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.07 (1H, s), 6.12-6.30 (1H, m), 6.60-6.75 (1H, m), 7.12-7.30 (4H, m), 7.33-7.39 (1H, m), 7.41-7.49 (1H, m).
MS (ESI+): [M+H]+477.26. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (250 mg) synthesized in Example 30, N A DMF solution (4.2 mL) of-(2-aminoethyl) acetamide (78 mg), HOBt (103 mg) and WSC (147 mg) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (245.9 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.01 (3H, s), 2.49 (3H, s), 3.45-3.56 (2H, m), 3.56-3.67 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.07 (1H, s), 6.12-6.30 (1H, m), 6.60-6.75 (1H, m), 7.12-7.30 (4H, m), 7.33-7.39 (1H, m), 7.41-7.49 (1H, m).
MS (ESI +): [M + H] + 477.26.
実施例３６
N-[2-(ジメチルアミノ)-2-オキソエチル]-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 36
N- [2- (Dimethylamino) -2-oxoethyl] -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2- Methylbenzamide
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、N,N-ジメチルグリシンアミド塩酸塩(85 mg) 、HOBt (83 mg) 、WSC (117 mg) およびトリエチルアミン (85 μL)のDMF溶液 (3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (232.1 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.51 (3H, s), 3.04 (3H, s), 3.05 (3H, s), 3.85 (3H, s), 4.04 (2H, s), 4.26 (2H, d, J = 4.1 Hz), 6.08 (1H, s), 6.92-7.04 (1H, m), 7.12-7.31 (4H, m), 7.34-7.41 (1H, m), 7.53 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+447.20. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg) synthesized in Example 30, N , N-dimethylglycinamide hydrochloride (85 mg), HOBt (83 mg), WSC (117 mg) and triethylamine (85 μL) in DMF (3.4 mL) were stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (232.1 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.51 (3H, s), 3.04 (3H, s), 3.05 (3H, s), 3.85 (3H, s), 4.04 (2H, s), 4.26 (2H, d, J = 4.1 Hz), 6.08 (1H, s), 6.92-7.04 (1H, m), 7.12-7.31 (4H, m), 7.34-7.41 (1H, m), 7.53 (1H, d, J = (7.9 Hz).
MS (ESI +): [M + H] + 447.20.
実施例３７
N-[2-(ジメチルアミノ)エチル]-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 37
N- [2- (Dimethylamino) ethyl] -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(250 mg) 、N,N-ジメチルエタン-1,2-ジアミン(71 μL) 、HOBt (103 mg) およびWSC (147 mg)のDMF溶液(4.2 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、ヘキサン/酢酸エチル) で精製して標題化合物 (262.4 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.26 (6H, s), 2.44-2.56 (5H, m), 3.47-3.59 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.06 (1H, s), 6.32-6.58 (1H, m), 7.13-7.30 (4H, m), 7.33-7.41 (1H, m), 7.46 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+463.24. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (250 mg) synthesized in Example 30, N , N-dimethylethane-1,2-diamine (71 μL), HOBt (103 mg) and WSC (147 mg) in DMF (4.2 mL) were stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate) to give the title compound (262.4 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.26 (6H, s), 2.44-2.56 (5H, m), 3.47-3.59 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.06 (1H, s), 6.32-6.58 (1H, m), 7.13-7.30 (4H, m), 7.33-7.41 (1H, m), 7.46 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 463.24.
実施例３８
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(メチルスルファニル)エチル]ベンズアミド Example 38
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (methylsulfanyl) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　実施例３０で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(800.0 mg) 、2-(メチルスルファニル)エタンアミン (228 μL) 、HOBt (331 mg) およびWSC (469 mg)のDMF溶液(13.6 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (784.8 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.15 (3H, s), 2.51 (3H, s), 2.70-2.86 (2H, m), 3.61-3.76 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.07 (1H, s), 6.13-6.31 (1H, m), 7.13-7.31 (4H, m), 7.33-7.40 (1H, m), 7.47 (1H, d, J = 7.6 Hz).
MS (ESI+): [M+H]+466.15. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (800.0 mg) synthesized in Example 30, 2 A DMF solution (13.6 mL) of-(methylsulfanyl) ethanamine (228 μL), HOBt (331 mg) and WSC (469 mg) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (784.8 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.15 (3H, s), 2.51 (3H, s), 2.70-2.86 (2H, m), 3.61-3.76 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.07 (1H, s), 6.13-6.31 (1H, m), 7.13-7.31 (4H, m), 7.33-7.40 (1H, m), 7.47 (1H, d, J = 7.6 Hz).
MS (ESI +): [M + H] + 466.15.
実施例３９
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(メチルスルフィニル)エチル]ベンズアミド Example 39
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (methylsulfinyl) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　実施例３８で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(メチルスルファニル)エチル]ベンズアミド (331.3 mg) の酢酸エチル溶液 (6.5 mL) に3-クロロベンゼンカルボペルオキソ酸(mCPBA; 178 mg) を0℃で加え、そのまま30分間撹拌した。反応混合物に0℃で飽和チオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して、標題化合物(260.7 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 2.69 (3H, s), 2.83-2.98 (1H, m), 3.09-3.26 (1H, m), 3.84 (3H, s), 3.90-4.15 (4H, m), 6.07 (1H, s), 6.82-6.96 (1H, m), 7.12-7.31 (4H, m), 7.33-7.41 (1H, m), 7.47 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+482.18. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (methyl) synthesized in Example 38 To a solution of sulfanyl) ethyl] benzamide (331.3 mg) in ethyl acetate (6.5 mL) was added 3-chlorobenzenecarboperoxoacid (mCPBA; 178 mg) at 0 ° C., and the mixture was stirred as it was for 30 minutes. To the reaction mixture was added saturated aqueous sodium thiosulfate solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (260.7 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.50 (3H, s), 2.69 (3H, s), 2.83-2.98 (1H, m), 3.09-3.26 (1H, m), 3.84 (3H, s), 3.90-4.15 (4H, m), 6.07 (1H, s), 6.82-6.96 (1H, m), 7.12-7.31 (4H, m), 7.33-7.41 (1H, m), 7.47 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 482.18.
実施例４０
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(メチルスルホニル)エチル]ベンズアミド Example 40
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (methylsulfonyl) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　実施例３８で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(メチルスルファニル)エチル]ベンズアミド (318.0 mg) の酢酸エチル溶液 (6 mL) にmCPBA (112 mg) を0℃で加えた。そのまま30分間撹拌した後、さらにmCPBA (134 mg) を加え、0℃で30分間撹拌した。反応混合物に0℃で飽和チオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (319.4 mg) を得た。1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 3.02 (3H, s), 3.31-3.44 (2H, m), 3.85 (3H, s), 3.95-4.10 (4H, m), 6.08 (1H, s), 6.55-6.68 (1H, m), 7.12-7.31 (4H, m), 7.34-7.40 (1H, m), 7.48 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+498.20. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (methyl) synthesized in Example 38 MCPBA (112 mg) was added to an ethyl acetate solution (6 mL) of sulfanyl) ethyl] benzamide (318.0 mg) at 0 ° C. After stirring for 30 minutes as it was, mCPBA (134 mg) was further added, and the mixture was stirred at 0 ° C. for 30 minutes. To the reaction mixture was added saturated aqueous sodium thiosulfate solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (319.4 mg). 1 H NMR (300 MHz, CDCl 3 ) δ 2.50 (3H, s), 3.02 (3H, s), 3.31-3.44 (2H, m), 3.85 (3H, s), 3.95-4.10 (4H, m), 6.08 (1H, s), 6.55-6.68 (1H, m), 7.12-7.31 (4H, m), 7.34-7.40 (1H, m), 7.48 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 498.20.
実施例４１
エチル 2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾアート Example 41
Ethyl 2-chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoate
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　エチル 4-ブロモ-2-クロロベンゾアート(2.40 g) 、4,4,4',4',5,5,5',5'-オクタメチル-2,2'-ビ-1,3,2-ジオキサボロラン (2.31 g) 、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) (333 mg) 、酢酸カリウム (2.06 g) のDMF溶液 (30 mL) をアルゴン気流下、85℃で16時間撹拌した。反応混合物に水を加えセライトろ過した後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた粗生成物、実施例２９－Ｅ）で合成した3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート (2.84 g) 、ジクロロビス（トリフェニルホスフィン）パラジウム(II) (491 mg) 、および炭酸カリウム (2.90 g) の1,2-ジメトキシエタン－水混合溶液 (3：1、40 mL) をアルゴン気流下、85℃で5時間撹拌した後、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (2.48 g) を得た。
1H NMR (300 MHz, CDCl3) δ1.42 (3H, t, J = 7.2 Hz), 3.88 (3H, s), 4.03 (2H, s), 4.43 (2H, q, J = 7.2 Hz), 6.14 (1H, s), 7.14-7.23 (2H, m), 7.32-7.39 (2H, m), 7.50 (1H, d, J = 1.9 Hz), 7.90 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+441.1. Ethyl 4-bromo-2-chlorobenzoate (2.40 g), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2- DMF solution (30 mL) of dioxaborolane (2.31 g), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (333 mg) and potassium acetate (2.06 g) in an argon stream at 85 ° C For 16 hours. Water was added to the reaction mixture, the mixture was filtered through celite, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product, 3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate synthesized in Example 29-E) (2.84 g) 1,2-dimethoxyethane-water mixed solution (3: 1, 40 mL) of dichlorobis (triphenylphosphine) palladium (II) (491 mg) and potassium carbonate (2.90 g) under an argon stream After stirring at 5 ° C. for 5 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.48 g).
1 H NMR (300 MHz, CDCl 3 ) δ1.42 (3H, t, J = 7.2 Hz), 3.88 (3H, s), 4.03 (2H, s), 4.43 (2H, q, J = 7.2 Hz), 6.14 (1H, s), 7.14-7.23 (2H, m), 7.32-7.39 (2H, m), 7.50 (1H, d, J = 1.9 Hz), 7.90 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 441.1.
実施例４２
2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 Example 42
2-Chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　実施例４１で合成したエチル 2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾアート (2.48 g) のエタノール溶液 (120 mL) に1N水酸化ナトリウム水溶液 (10.0 mL) を加えた。反応混合物を70℃で1時間半撹拌した後、1N塩酸 (10.0 mL) を加えて中和し、溶媒を留去した後に酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (2.16 g) を得た。
1H NMR (300 MHz, DMSO-d6) δ 3.85 (3H, s), 4.04 (2H, s), 6.46 (1H, s), 7.43 - 7.63 (4H, m), 7.71 (1H, d, J = 1.5 Hz), 7.87 (1H, d, J = 7.9 Hz), 13.54 (1H, br. s.)
MS (ESI+): [M+H]+413.1. Of ethyl 2-chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoate (2.48 g) synthesized in Example 41 A 1N aqueous sodium hydroxide solution (10.0 mL) was added to an ethanol solution (120 mL). The reaction mixture was stirred at 70 ° C. for 1.5 hours, neutralized by adding 1N hydrochloric acid (10.0 mL), the solvent was distilled off, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (2.16 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 3.85 (3H, s), 4.04 (2H, s), 6.46 (1H, s), 7.43-7.63 (4H, m), 7.71 (1H, d, J = 1.5 Hz), 7.87 (1H, d, J = 7.9 Hz), 13.54 (1H, br.s.)
MS (ESI +): [M + H] + 413.1.
実施例４３
2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 43
2-Chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　実施例４２で合成した2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (350 mg) 、HOBtアンモニウム和物 (155 mg) 、WSC (195 mg) のDMF溶液(5 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (316 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 3.88 (3H, s), 4.04 (2H, s), 6.05 (1H, brs), 6.13 (1H, s), 6.41 (1H, brs), 7.15-7.23 (2H, m), 7.33-7.42 (2H, m), 7.48 (1H, d, J = 1.5 Hz), 7.90 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+412.2. 2-chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (350 mg) synthesized in Example 42, HOBt A solution of ammonium hydrate (155 mg) and WSC (195 mg) in DMF (5 mL) was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (316 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 3.88 (3H, s), 4.04 (2H, s), 6.05 (1H, brs), 6.13 (1H, s), 6.41 (1H, brs), 7.15-7.23 ( 2H, m), 7.33-7.42 (2H, m), 7.48 (1H, d, J = 1.5 Hz), 7.90 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 412.2.
実施例４４
2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-(2-ヒドロキシエチル)ベンズアミド Example 44
2-Chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- (2-hydroxyethyl) benzamide
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　実施例４２で合成した2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (350 mg) 、2－アミノエタノール (61 μL) 、HOBt (156 mg) 、WSC (195 mg) のDMF溶液 (5 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (352 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.30 (1H, t, J = 5.1 Hz), 3.63-3.72 (2H, m), 3.83-3.92 (5H, m), 4.03 (2H, s), 6.12 (1H, s), 6.68-6.77 (1H, m), 7.15-7.22 (2H, m), 7.33-7.40 (2H, m), 7.46 (1H, d, J = 1.5 Hz), 7.78 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+456.2. 2-Chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (350 mg) synthesized in Example 42, 2 -A DMF solution (5 mL) of aminoethanol (61 μL), HOBt (156 mg) and WSC (195 mg) was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (352 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.30 (1H, t, J = 5.1 Hz), 3.63-3.72 (2H, m), 3.83-3.92 (5H, m), 4.03 (2H, s), 6.12 ( 1H, s), 6.68-6.77 (1H, m), 7.15-7.22 (2H, m), 7.33-7.40 (2H, m), 7.46 (1H, d, J = 1.5 Hz), 7.78 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 456.2.
実施例４５
N-(2-アミノ-2-オキソエチル)-2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 45
N- (2-amino-2-oxoethyl) -2-chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　実施例４２で合成した2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (350 mg) 、グリシンアミド塩酸塩 (112 mg) 、HOBt (156 mg) 、WSC (195 mg) およびトリエチルアミン (142 μL)のDMF溶液 (5 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (366 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 3.88 (3H, s), 4.03 (2H, s), 4.23 (2H, d, J = 4.9 Hz), 5.57 (1H, brs), 6.08 (1H, brs), 6.13 (1H, s), 7.09 (1H, t, J = 4.7 Hz), 7.15-7.23 (2H, m), 7.34-7.41 (2H, m), 7.48 (1H, d, J = 1.5 Hz), 7.78 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+469.2. 2-chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (350 mg) synthesized in Example 42, glycine A DMF solution (5 mL) of amide hydrochloride (112 mg), HOBt (156 mg), WSC (195 mg) and triethylamine (142 μL) was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (366 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 3.88 (3H, s), 4.03 (2H, s), 4.23 (2H, d, J = 4.9 Hz), 5.57 (1H, brs), 6.08 (1H, brs) , 6.13 (1H, s), 7.09 (1H, t, J = 4.7 Hz), 7.15-7.23 (2H, m), 7.34-7.41 (2H, m), 7.48 (1H, d, J = 1.5 Hz), 7.78 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 469.2.
実施例４６
2-クロロ-N-[2-(ジメチルアミノ)エチル]-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 46
2-Chloro-N- [2- (dimethylamino) ethyl] -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　実施例４２で合成した2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (350 mg) 、N,N-ジメチルエタン-1,2-ジアミン(112 μL) 、HOBt (156 mg) およびWSC (195 mg)のDMF溶液(5 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、ヘキサン/酢酸エチル) で精製して標題化合物 (345 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.26 (6H, s), 2.49-2.56 (2H, m), 3.51-3.59 (2H, m), 3.86 (3H, s), 4.03 (2H, s), 6.10 (1H, s), 6.82-6.90 (1H, m), 7.13-7.23 (2H, m), 7.30-7.38 (2H, m), 7.44 (1H, d, J = 1.5 Hz), 7.73 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+483.30. 2-Chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (350 mg) synthesized in Example 42, N , N-dimethylethane-1,2-diamine (112 μL), HOBt (156 mg) and WSC (195 mg) in DMF (5 mL) were stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate) to give the title compound (345 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.26 (6H, s), 2.49-2.56 (2H, m), 3.51-3.59 (2H, m), 3.86 (3H, s), 4.03 (2H, s), 6.10 (1H, s), 6.82-6.90 (1H, m), 7.13-7.23 (2H, m), 7.30-7.38 (2H, m), 7.44 (1H, d, J = 1.5 Hz), 7.73 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 483.30.
実施例４７
2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-[2-(メチルアミノ)-2-オキソエチル]ベンズアミド Example 47
2-Chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- [2- (methylamino) -2-oxoethyl Benzamide
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　実施例４２で合成した2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (350 mg) 、N-メチルグリシンアミド塩酸塩 (127 mg) 、HOBt (137 mg) 、WSC (195 mg) およびトリエチルアミン (142 μL)のDMF溶液 (6 mL) を室温で2時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (372 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.89 (3H, d, J = 4.9 Hz), 3.88 (3H, s), 4.03 (2H, s), 4.16 (2H, d, J = 5.3 Hz), 5.86-6.07 (1H, m), 6.13 (1H, s), 7.02-7.14 (1H, m), 7.14-7.24 (2H, m), 7.33-7.43 (2H, m), 7.48 (1H, d, J = 1.5 Hz), 7.79 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+483.29. 2-Chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (350 mg) synthesized in Example 42, N -A DMF solution (6 mL) of methylglycinamide hydrochloride (127 mg), HOBt (137 mg), WSC (195 mg) and triethylamine (142 μL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (372 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.89 (3H, d, J = 4.9 Hz), 3.88 (3H, s), 4.03 (2H, s), 4.16 (2H, d, J = 5.3 Hz), 5.86 -6.07 (1H, m), 6.13 (1H, s), 7.02-7.14 (1H, m), 7.14-7.24 (2H, m), 7.33-7.43 (2H, m), 7.48 (1H, d, J = 1.5 Hz), 7.79 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 483.29.
実施例４８
2-クロロ-N-[2-(ジメチルアミノ)-2-オキソエチル]-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 48
2-Chloro-N- [2- (dimethylamino) -2-oxoethyl] -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl } Benzamide
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　実施例４２で合成した2-クロロ-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (394.4 mg) 、N,N-ジメチルグリシンアミド塩酸塩 (159 mg) 、HOBt (155 mg) 、WSC (220 mg) およびトリエチルアミン (160 μL)のDMF溶液 (6.5 mL) を室温で2時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (450.5 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 3.04 (3H, s), 3.05 (3H, s), 3.87 (3H, s), 4.03 (2H, s), 4.29 (2H, d, J = 3.8 Hz), 6.12 (1H, s), 7.14-7.24 (2H, m), 7.32-7.41 (2H, m), 7.44-7.55 (2H, m), 7.78 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+497.15. 2-chloro-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid synthesized in Example 42 (394.4 mg), N , N-dimethylglycinamide hydrochloride (159 mg), HOBt (155 mg), WSC (220 mg) and triethylamine (160 μL) in DMF (6.5 mL) were stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (450.5 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 3.04 (3H, s), 3.05 (3H, s), 3.87 (3H, s), 4.03 (2H, s), 4.29 (2H, d, J = 3.8 Hz) , 6.12 (1H, s), 7.14-7.24 (2H, m), 7.32-7.41 (2H, m), 7.44-7.55 (2H, m), 7.78 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 497.15.
実施例４９
エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-ヒドロキシベンゾアート Example 49
Ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-hydroxybenzoate
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　Ａ）エチル 4-ブロモ-2-ヒドロキシベンゾアート
　4-ブロモ-2-ヒドロキシ安息香酸(6.51 g), DMF (0.2 mL) のTHF溶液(150 mL) に塩化オキザリル (5.25 mL) を滴下し、45分間撹拌した。エタノール (50 mL) を反応混合物に加え、さらに1時間撹拌した。溶媒を減圧下留去し、残渣を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (5.05 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 7.02 (1H, dd, J = 8.7, 1.9 Hz), 7.18 (1H, d, J = 1.9 Hz), 7.70 (1H, d, J = 8.7 Hz), 10.92 (1H, s). A) Ethyl 4-bromo-2-hydroxybenzoate Oxalyl chloride (5.25 mL) was added dropwise to a THF solution (150 mL) of 4-bromo-2-hydroxybenzoic acid (6.51 g) and DMF (0.2 mL). Stir for minutes. Ethanol (50 mL) was added to the reaction mixture and stirred for an additional hour. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (5.05 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 7.02 (1H, dd, J = 8.7, 1.9 Hz), 7.18 (1H, d, J = 1.9 Hz), 7.70 (1H, d, J = 8.7 Hz), 10.92 (1H, s).
　Ｂ）エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-ヒドロキシベンゾアート
　実施例４９－Ａ）で合成したエチル 4-ブロモ-2-ヒドロキシベンゾアート(2.23 g) 、4,4,4',4',5,5,5',5'-オクタメチル-2,2'-ビ-1,3,2-ジオキサボロラン (2.31 g) 、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) (333 mg) 、酢酸カリウム (2.06 g) のDMF溶液 (50 mL) をアルゴン気流下、85℃で15時間撹拌した。反応混合物に水を加えセライトろ過した後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた粗生成物、実施例２９－Ｅ）で合成した3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート (2.84 g) 、ジクロロビス（トリフェニルホスフィン）パラジウム(II) (491 mg) 、および炭酸カリウム (2.90 g) の1,2-ジメトキシエタン－水混合溶液 (3：1、30 mL) をアルゴン気流下、85℃で4時間半撹拌した後、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (2.21 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz), 3.90 (3H, s), 4.03 (2H, s), 4.44 (2H, q, J = 7.2 Hz), 6.13 (1H, s), 6.92 (1H, dd, J = 8.1, 1.7 Hz), 7.02 (1H, d, J = 1.5 Hz), 7.14-7.23 (2H, m), 7.36 (1H, brs), 7.90 (1H, d, J = 8.3 Hz), 10.94 (1H, s).
MS (ESI+): [M+H]+423.2. B) Ethyl 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-hydroxybenzoate Example 49-A) Ethyl 4-bromo-2-hydroxybenzoate (2.23 g), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2- DMF solution (50 mL) of dioxaborolane (2.31 g), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (333 mg) and potassium acetate (2.06 g) in an argon stream at 85 ° C For 15 hours. Water was added to the reaction mixture, the mixture was filtered through celite, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product, 3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate synthesized in Example 29-E) (2.84 g) 1,2-dimethoxyethane-water mixed solution of dichlorobis (triphenylphosphine) palladium (II) (491 mg) and potassium carbonate (2.90 g) (3: 1, 30 mL) under argon flow After stirring for 4 and a half hours at ° C, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.21 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.43 (3H, t, J = 7.2 Hz), 3.90 (3H, s), 4.03 (2H, s), 4.44 (2H, q, J = 7.2 Hz), 6.13 (1H, s), 6.92 (1H, dd, J = 8.1, 1.7 Hz), 7.02 (1H, d, J = 1.5 Hz), 7.14-7.23 (2H, m), 7.36 (1H, brs), 7.90 ( 1H, d, J = 8.3 Hz), 10.94 (1H, s).
MS (ESI +): [M + H] + 423.2.
実施例５０
エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-{[(トリフルオロメチル)スルホニル]オキシ}ベンゾアート Example 50
Ethyl 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-{[(trifluoromethyl) sulfonyl] oxy} benzoate
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
　実施例４９で合成したエチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-ヒドロキシベンゾアート(2.21 g) 、N-フェニルビス（トリフルオロメタンスルホンイミド） (2.24 g) 、炭酸セシウム (2.05 mg) のDMF溶液 (35 mL) を室温で2時間撹拌した。反応混合物に水を加え、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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (2.69 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz), 3.90 (3H, s), 4.04 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 6.18 (1H, s), 7.15-7.23 (2H, m), 7.31-7.38 (2H, m), 7.48-7.54 (1H, m), 8.16 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+555.2. Ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-hydroxybenzoate (2.21 g) synthesized in Example 49 A DMF solution (35 mL) of N-phenylbis (trifluoromethanesulfonimide) (2.24 g) and cesium carbonate (2.05 mg) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.69 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.43 (3H, t, J = 7.2 Hz), 3.90 (3H, s), 4.04 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 6.18 (1H, s), 7.15-7.23 (2H, m), 7.31-7.38 (2H, m), 7.48-7.54 (1H, m), 8.16 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 555.2.
実施例５１
エチル 2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾアート Example 51
Ethyl 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoate
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
　実施例５０で合成したエチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-{[(トリフルオロメチル)スルホニル]オキシ}ベンゾアート (2.69 g) 、シクロプロピルボロン酸 (500 mg) 、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)(355 mg) 、炭酸カリウム (1.34 g) の1,2-ジメトキシエタン－水混合溶液 (4：1、50 mL) を窒素気流下、85℃で5時間撹拌した後、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (1.69 g) を得た。
1H NMR (300 MHz, CDCl3) δ 0.66-0.75 (2H, m), 0.98-1.09 (2H, m), 1.42 (3H, t, J = 7.0 Hz), 2.62-2.74 (1H, m), 3.84 (3H, s), 4.03 (2H, s), 4.41 (2H, q, J = 7.2 Hz), 6.08 (1H, s), 7.02 (1H, d, J = 1.5 Hz), 7.14-7.25 (3H, m), 7.35-7.39 (1H, m), 7.85 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+447.2. Ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-{[(trifluoromethyl) sulfonyl synthesized in Example 50 ] Oxy} benzoate (2.69 g), cyclopropylboronic acid (500 mg), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (355 mg), potassium carbonate (1.34 g) The 1,2-dimethoxyethane-water mixed solution (4: 1, 50 mL) was stirred at 85 ° C. for 5 hours under a nitrogen stream, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.69 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.66-0.75 (2H, m), 0.98-1.09 (2H, m), 1.42 (3H, t, J = 7.0 Hz), 2.62-2.74 (1H, m), 3.84 (3H, s), 4.03 (2H, s), 4.41 (2H, q, J = 7.2 Hz), 6.08 (1H, s), 7.02 (1H, d, J = 1.5 Hz), 7.14-7.25 (3H , m), 7.35-7.39 (1H, m), 7.85 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 447.2.
実施例５２
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 Example 52
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
　実施例５１で合成したエチル 2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾアート (1.69 g) のエタノール溶液 (100 mL) に1N水酸化ナトリウム水溶液 (8.0 mL) を加えた。反応混合物を80℃で2時間半撹拌した後、1N塩酸 (8.0 mL) を加えて中和し、溶媒を留去した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (1.47 g) を得た。
1H NMR (300 MHz, CDCl3) δ 0.70-0.80 (2H, m), 1.03-1.14 (2H, m), 2.78-2.90 (1H, m), 3.88 (3H, s), 4.05 (2H, s), 6.11 (1H, s), 7.05 (1H, d, J = 1.5 Hz), 7.14-7.30 (3H, m), 7.36-7.39 (1H, m), 8.04 (1H, d, J = 8.3 Hz), (CO2Hピークは観測されなかった).
MS (ESI+): [M+H]+419.2. Ethyl 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoate synthesized in Example 51 (1.69 g) 1N aqueous sodium hydroxide solution (8.0 mL) was added to an ethanol solution (100 mL). The reaction mixture was stirred at 80 ° C. for 2.5 hours, neutralized with 1N hydrochloric acid (8.0 mL), the solvent was distilled off, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (1.47 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.70-0.80 (2H, m), 1.03-1.14 (2H, m), 2.78-2.90 (1H, m), 3.88 (3H, s), 4.05 (2H, s ), 6.11 (1H, s), 7.05 (1H, d, J = 1.5 Hz), 7.14-7.30 (3H, m), 7.36-7.39 (1H, m), 8.04 (1H, d, J = 8.3 Hz) , (CO 2 H peak was not observed).
MS (ESI +): [M + H] + 419.2.
実施例５３
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 53
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
　実施例５２で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (300 mg) 、HOBtアンモニウム和物 (131 mg) 、WSC (165 mg) のDMF溶液(5 mL) を室温で16時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (273 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.75-0.82 (2H, m), 1.03-1.12 (2H, m), 2.29-2.43 (1H, m), 3.83 (3H, s), 4.03 (2H, s), 5.91-6.11 (3H, m), 6.98 (1H, d, J = 1.5 Hz), 7.14-7.28 (3H, m), 7.35-7.39 (1H, m), 7.60 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+418.2. 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (300 mg) synthesized in Example 52, A DMF solution (5 mL) of HOBt ammonium solvate (131 mg) and WSC (165 mg) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (273 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.75-0.82 (2H, m), 1.03-1.12 (2H, m), 2.29-2.43 (1H, m), 3.83 (3H, s), 4.03 (2H, s ), 5.91-6.11 (3H, m), 6.98 (1H, d, J = 1.5 Hz), 7.14-7.28 (3H, m), 7.35-7.39 (1H, m), 7.60 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 418.2.
実施例５４
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-(2-ヒドロキシエチル)ベンズアミド Example 54
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- (2-hydroxyethyl) benzamide
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
　実施例５２で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (300 mg) 、2－アミノエタノール (52 μL) 、HOBt (132 mg) 、WSC (165 mg) のDMF溶液(5 mL) を室温で16時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (309 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.70-0.81 (2H, m), 0.99-1.11 (2H, m), 2.22-2.34 (1H, m), 2.41 (1H, t, J = 4.9 Hz), 3.63-3.71 (2H, m), 3.82 (3H, s), 3.84-3.91 (2H, m), 4.03 (2H, s), 6.05 (1H, s), 6.45-6.54 (1H, m), 6.97 (1H, d, J = 1.5 Hz), 7.13-7.25 (3H, m), 7.34-7.39 (1H, m), 7.52 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+462.3. 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (300 mg) synthesized in Example 52, A DMF solution (5 mL) of 2-aminoethanol (52 μL), HOBt (132 mg), and WSC (165 mg) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (309 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.70-0.81 (2H, m), 0.99-1.11 (2H, m), 2.22-2.34 (1H, m), 2.41 (1H, t, J = 4.9 Hz), 3.63-3.71 (2H, m), 3.82 (3H, s), 3.84-3.91 (2H, m), 4.03 (2H, s), 6.05 (1H, s), 6.45-6.54 (1H, m), 6.97 ( 1H, d, J = 1.5 Hz), 7.13-7.25 (3H, m), 7.34-7.39 (1H, m), 7.52 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 462.3.
実施例５５
N-(2-アミノ-2-オキソエチル)-2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 55
N- (2-Amino-2-oxoethyl) -2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
　実施例５２で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (300 mg) 、グリシンアミド塩酸塩 (95 mg) 、HOBt (132 mg) 、WSC (165 mg) およびトリエチルアミン (120 μL)のDMF溶液 (5 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (313 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.71-0.82 (2H, m), 1.01-1.12 (2H, m), 2.22-2.36 (1H, m), 3.83 (3H, s), 4.03 (2H, s), 4.23 (2H, d, J = 4.9 Hz), 5.52 (1H, brs), 5.99-6.16 (2H, m), 6.83-6.92 (1H, m), 6.99 (1H, d, J = 1.5 Hz), 7.13-7.29 (3H, m), 7.35-7.39 (1H, m), 7.57 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+475.3. 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (300 mg) synthesized in Example 52, A DMF solution (5 mL) of glycinamide hydrochloride (95 mg), HOBt (132 mg), WSC (165 mg) and triethylamine (120 μL) was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (313 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.71-0.82 (2H, m), 1.01-1.12 (2H, m), 2.22-2.36 (1H, m), 3.83 (3H, s), 4.03 (2H, s ), 4.23 (2H, d, J = 4.9 Hz), 5.52 (1H, brs), 5.99-6.16 (2H, m), 6.83-6.92 (1H, m), 6.99 (1H, d, J = 1.5 Hz) , 7.13-7.29 (3H, m), 7.35-7.39 (1H, m), 7.57 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 475.3.
実施例５６
2-シクロプロピル-N-[2-(ジメチルアミノ)エチル]-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 56
2-Cyclopropyl-N- [2- (dimethylamino) ethyl] -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
　実施例５２で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (300 mg) 、N,N-ジメチルエタン-1,2-ジアミン(95 μL) 、無水HOBt (116 mg) およびWSC (165 mg) のDMF溶液(5 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、ヘキサン/酢酸エチル) で精製して標題化合物 (265 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.71-0.80 (2H, m), 0.98-1.08 (2H, m), 2.21-2.38 (7H, m), 2.52 (2H, t, J = 5.9 Hz), 3.51-3.60 (2H, m), 3.82 (3H, s), 4.03 (2H, s), 6.04 (1H, s), 6.59-6.67 (1H, m), 6.95 (1H, d, J = 1.5 Hz), 7.13-7.24 (3H, m), 7.35-7.39 (1H, m), 7.51 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+489.4. 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (300 mg) synthesized in Example 52, A DMF solution (5 mL) of N, N-dimethylethane-1,2-diamine (95 μL), anhydrous HOBt (116 mg) and WSC (165 mg) was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate) to give the title compound (265 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.71-0.80 (2H, m), 0.98-1.08 (2H, m), 2.21-2.38 (7H, m), 2.52 (2H, t, J = 5.9 Hz), 3.51-3.60 (2H, m), 3.82 (3H, s), 4.03 (2H, s), 6.04 (1H, s), 6.59-6.67 (1H, m), 6.95 (1H, d, J = 1.5 Hz) , 7.13-7.24 (3H, m), 7.35-7.39 (1H, m), 7.51 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 489.4.
実施例５７
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-[2-(メチルアミノ)-2-オキソエチル]ベンズアミド Example 57
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- [2- (methylamino) -2- Oxoethyl] benzamide
Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123
　実施例５２で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (200 mg) 、N-メチルグリシンアミド塩酸塩 (71.5 mg) 、HOBt (78 mg) 、WSC (110 mg) およびトリエチルアミン (80 μL)のDMF溶液 (3.2 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (212.8 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.70-0.82 (2H, m), 1.00-1.13 (2H, m), 2.20-2.37 (1H, m), 2.88 (3H, d, J = 4.9 Hz), 3.83 (3H, s), 4.03 (2H, s), 4.16 (2H, d, J = 4.9 Hz), 6.06 (1H, s), 6.09-6.24 (1H, m), 6.89-7.03 (2H, m), 7.12-7.30 (3H, m), 7.32-7.40 (1H, m), 7.57 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+489.24. 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (200 mg) synthesized in Example 52, A DMF solution (3.2 mL) of N-methylglycinamide hydrochloride (71.5 mg), HOBt (78 mg), WSC (110 mg) and triethylamine (80 μL) was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (212.8 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.70-0.82 (2H, m), 1.00-1.13 (2H, m), 2.20-2.37 (1H, m), 2.88 (3H, d, J = 4.9 Hz), 3.83 (3H, s), 4.03 (2H, s), 4.16 (2H, d, J = 4.9 Hz), 6.06 (1H, s), 6.09-6.24 (1H, m), 6.89-7.03 (2H, m) , 7.12-7.30 (3H, m), 7.32-7.40 (1H, m), 7.57 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 489.24.
実施例５８
2-シクロプロピル-N-[2-(ジメチルアミノ)-2-オキソエチル]-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 58
2-Cyclopropyl-N- [2- (dimethylamino) -2-oxoethyl] -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazole-5- Il} benzamide
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124
　実施例５２で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (200 mg) 、N,N-ジメチルグリシンアミド塩酸塩 (80 mg) 、HOBt (78 mg) 、WSC (110 mg) およびトリエチルアミン (80 μL)のDMF溶液 (3.2 mL) を室温で5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (231.0 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.69-0.82 (2H, m), 0.99-1.15 (2H, m), 2.24-2.37 (1H, m), 3.04 (3H, s), 3.06 (3H, s), 3.83 (3H, s), 4.03 (2H, s), 4.30 (2H, d, J = 3.8 Hz), 6.06 (1H, s), 6.95-7.01 (1H, m), 7.13-7.31 (4H, m), 7.34-7.41 (1H, m), 7.59 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+503.31. 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (200 mg) synthesized in Example 52, N, N-dimethylglycinamide hydrochloride (80 mg), HOBt (78 mg), WSC (110 mg) and triethylamine (80 μL) in DMF (3.2 mL) were stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (231.0 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.69-0.82 (2H, m), 0.99-1.15 (2H, m), 2.24-2.37 (1H, m), 3.04 (3H, s), 3.06 (3H, s ), 3.83 (3H, s), 4.03 (2H, s), 4.30 (2H, d, J = 3.8 Hz), 6.06 (1H, s), 6.95-7.01 (1H, m), 7.13-7.31 (4H, m), 7.34-7.41 (1H, m), 7.59 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 503.31.
実施例５９
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-[2-(メチルスルファニル)エチル]ベンズアミド Example 59
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- [2- (methylsulfanyl) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125
　実施例５２で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 (789.0 mg) 、2-(メチルスルファニル)エタンアミン (211 μL) 、HOBt (306 mg) およびWSC (434 mg)のDMF溶液 (12.6 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (779.4 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.70-0.81 (2H, m), 0.99-1.11 (2H, m), 2.15 (3H, s), 2.23-2.37 (1H, m), 2.79 (2H, t), 3.71 (2H, q, J = 5.9 Hz), 3.82 (3H, s), 4.03 (2H, s), 6.05 (1H, s), 6.32-6.52 (1H, m), 6.97 (1H, d, J = 1.5 Hz), 7.12-7.25 (3H, m), 7.33-7.41 (1H, m), 7.52 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+492.25. 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (789.0 mg) synthesized in Example 52, A solution of 2- (methylsulfanyl) ethanamine (211 μL), HOBt (306 mg) and WSC (434 mg) in DMF (12.6 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (779.4 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.70-0.81 (2H, m), 0.99-1.11 (2H, m), 2.15 (3H, s), 2.23-2.37 (1H, m), 2.79 (2H, t ), 3.71 (2H, q, J = 5.9 Hz), 3.82 (3H, s), 4.03 (2H, s), 6.05 (1H, s), 6.32-6.52 (1H, m), 6.97 (1H, d, J = 1.5 Hz), 7.12-7.25 (3H, m), 7.33-7.41 (1H, m), 7.52 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 492.25.
実施例６０
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-[2-(メチルスルフィニル)エチル]ベンズアミド Example 60
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- [2- (methylsulfinyl) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126
　実施例５９で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-[2-(メチルスルファニル)エチル]ベンズアミド (220 mg) の酢酸エチル溶液 (4 mL) にmCPBA (112 mg) を0℃で加え、そのまま30分間撹拌した。反応混合物に0℃で飽和チオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して、標題化合物(179.9 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.64-0.85 (2H, m), 0.93-1.13 (2H, m), 2.21-2.39 (1H, m), 2.68 (3H, s), 2.83-3.00 (1H, m), 3.10-3.29 (1H, m), 3.82 (3H, s), 3.92-4.16 (4H, m), 6.05 (1H, s), 6.88-7.05 (2H, m), 7.13-7.31 (3H, m), 7.33-7.41 (1H, m), 7.50 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+508.22. 2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- [2- (synthesized in Example 59 MCPBA (112 mg) was added to an ethyl acetate solution (4 mL) of methylsulfanyl) ethyl] benzamide (220 mg) at 0 ° C., and the mixture was stirred as it was for 30 minutes. To the reaction mixture was added saturated aqueous sodium thiosulfate solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (179.9 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.64-0.85 (2H, m), 0.93-1.13 (2H, m), 2.21-2.39 (1H, m), 2.68 (3H, s), 2.83-3.00 (1H , m), 3.10-3.29 (1H, m), 3.82 (3H, s), 3.92-4.16 (4H, m), 6.05 (1H, s), 6.88-7.05 (2H, m), 7.13-7.31 (3H , m), 7.33-7.41 (1H, m), 7.50 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 508.22.
実施例６１
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-[2-(メチルスルホニル)エチル]ベンズアミド Example 61
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- [2- (methylsulfonyl) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127
　実施例５９で合成した2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-[2-(メチルスルファニル)エチル]ベンズアミド (254.9 mg) の酢酸エチル溶液 (4 mL) にmCPBA (285 mg) を0℃で加え、そのまま30分間撹拌した。反応混合物に0℃で飽和チオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (255.3 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.69-0.83 (2H, m), 0.98-1.13 (2H, m), 2.21-2.39 (1H, m), 3.01 (3H, s), 3.29-3.48 (2H, m), 3.82 (3H, s), 3.92-4.14 (4H, m), 6.05 (1H, s), 6.72-6.89 (1H, m), 6.98 (1H, d, J = 1.5 Hz), 7.10-7.32 (3H, m), 7.33-7.44 (1H, m), 7.53 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+524.45. 2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- [2- (synthesized in Example 59 To a solution of methylsulfanyl) ethyl] benzamide (254.9 mg) in ethyl acetate (4 mL) was added mCPBA (285 mg) at 0 ° C., and the mixture was stirred for 30 min. To the reaction mixture was added saturated aqueous sodium thiosulfate solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (255.3 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.69-0.83 (2H, m), 0.98-1.13 (2H, m), 2.21-2.39 (1H, m), 3.01 (3H, s), 3.29-3.48 (2H , m), 3.82 (3H, s), 3.92-4.14 (4H, m), 6.05 (1H, s), 6.72-6.89 (1H, m), 6.98 (1H, d, J = 1.5 Hz), 7.10- 7.32 (3H, m), 7.33-7.44 (1H, m), 7.53 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 524.45.
実施例６２
エチル 4-{1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート Example 62
Ethyl 4- {1-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128
　Ａ）1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例２９－Ｃ）で合成したメチル 4-[3-フルオロ-5-(トリフルオロメチル)フェニル]-3-オキソブタノアート(3.0 g)、シクロプロピルヒドラジン塩酸塩(US2007/225280)(0.63 Mエタノール溶液, 25.7 mL)およびエタノール(30 mL)の混合物を80℃で一晩撹拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して2-シクロプロピル-5-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-2,4-ジヒドロ-3H-ピラゾール-3-オンを含む混合物(600 mg)を得た。得られた混合物(590 mg)をピリジン(5 mL)に溶解させて0℃に冷却し、トリフルオロメタンスルホン酸無水物(0.40 mL)をゆっくり滴下した。反応混合物を1時間撹拌した後、酢酸エチルで希釈し、1N塩酸、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して標題化合物(123 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.06-1.25 (4H, m), 3.34-3.44 (1H, m), 3.95 (2H, s), 5.87 (1H, s), 7.07-7.23 (2H, m), 7.27-7.31 (1H, m). A) 1-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl trifluoromethanesulfonate Example 29-C) Methyl 4- [3- Fluoro-5- (trifluoromethyl) phenyl] -3-oxobutanoate (3.0 g), cyclopropylhydrazine hydrochloride (US2007 / 225280) (0.63 M ethanol solution, 25.7 mL) and ethanol (30 mL) Was stirred at 80 ° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 2-cyclopropyl-5- [3-fluoro-5- (trifluoromethyl) benzyl] -2,4-dihydro-3H-pyrazole-3- A mixture (600 mg) containing ON was obtained. The obtained mixture (590 mg) was dissolved in pyridine (5 mL), cooled to 0 ° C., and trifluoromethanesulfonic anhydride (0.40 mL) was slowly added dropwise. The reaction mixture was stirred for 1 hour, diluted with ethyl acetate, and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (123 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.06-1.25 (4H, m), 3.34-3.44 (1H, m), 3.95 (2H, s), 5.87 (1H, s), 7.07-7.23 (2H, m ), 7.27-7.31 (1H, m).
　Ｂ）エチル 4-{1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート
　実施例６２－Ａ）で合成した1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル トリフルオロメタンスルホナート(120 mg)、実施例２９－Ｂ）で合成したエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート(89 mg)、ジクロロビス(トリフェニルホスフィン)パラジウム(9.7 mg)、炭酸カリウム(115 mg)、DME(2 mL)および水(0.50 mL)の混合物を80℃で4時間撹拌した。反応混合物を無水硫酸ナトリウムで乾燥した後、セライトろ過した。ろ液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して標題化合物(99 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.93-1.13 (4H, m), 1.41 (3H, t, J = 7.1 Hz), 2.64 (3H, s), 3.55-3.65 (1H, m), 4.02 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 6.09 (1H, s), 7.14-7.21 (2H, m), 7.34-7.47 (3H, m), 7.97 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 447.1. B) Ethyl 4- {1-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate synthesized in Example 62-A) 1-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl trifluoromethanesulfonate (120 mg), ethyl synthesized in Example 29-B) 2 -Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (89 mg), dichlorobis (triphenylphosphine) palladium (9.7 mg), potassium carbonate A mixture of (115 mg), DME (2 mL) and water (0.50 mL) was stirred at 80 ° C. for 4 hours. The reaction mixture was dried over anhydrous sodium sulfate and filtered through celite. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (99 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.93-1.13 (4H, m), 1.41 (3H, t, J = 7.1 Hz), 2.64 (3H, s), 3.55-3.65 (1H, m), 4.02 ( 2H, s), 4.38 (2H, q, J = 7.1 Hz), 6.09 (1H, s), 7.14-7.21 (2H, m), 7.34-7.47 (3H, m), 7.97 (1H, d, J = (7.9 Hz).
MS (ESI +): [M + H] + 447.1.
実施例６３
4-{1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸 Example 63
4- {1-Cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129
　実施例６２で合成したエチル 4-{1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート(99 mg)、1N水酸化ナトリウム水溶液(0.67 mL)およびエタノール(1.5 mL)の混合物を80℃で4時間撹拌した。反応混合物に1N塩酸を加えて中和した後、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、無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去して標題化合物(90 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.95-1.15 (4H, m), 2.71 (3H, s), 3.58-3.69 (1H, m), 4.05 (2H, s), 6.13 (1H, s), 7.15-7.23 (2H, m), 7.35-7.39 (1H, m), 7.44-7.52 (2H, m), 8.13 (1H, d, J = 7.9 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 419.2. Ethyl 4- {1-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate (99 mg) synthesized in Example 62 , A mixture of 1N aqueous sodium hydroxide solution (0.67 mL) and ethanol (1.5 mL) was stirred at 80 ° C. for 4 hours. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (90 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.95-1.15 (4H, m), 2.71 (3H, s), 3.58-3.69 (1H, m), 4.05 (2H, s), 6.13 (1H, s), 7.15-7.23 (2H, m), 7.35-7.39 (1H, m), 7.44-7.52 (2H, m), 8.13 (1H, d, J = 7.9 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 419.2.
実施例６４
4-{1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 64
4- {1-Cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130
　実施例６３で合成した4-{1-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸(90 mg)、WSC塩酸塩(36 mg)、HOBtアンモニア和物(45 mg)およびDMF(1 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣を再結晶(ヘプタン－酢酸エチル)して標題化合物(56 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.92-1.13 (4H, m), 2.55 (3H, s), 3.53-3.64 (1H, m), 4.02 (2H, s), 5.74 (2H, brs), 6.06 (1H, s), 7.12-7.22 (2H, m), 7.33-7.44 (3H, m), 7.50-7.55 (1H, m).
MS (ESI+): [M+H]+ 418.1. 4- {1-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid (90 mg) synthesized in Example 63, A mixture of WSC hydrochloride (36 mg), HOBt ammonia solvate (45 mg) and DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized (heptane-ethyl acetate) to give the title compound (56 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.92-1.13 (4H, m), 2.55 (3H, s), 3.53-3.64 (1H, m), 4.02 (2H, s), 5.74 (2H, brs), 6.06 (1H, s), 7.12-7.22 (2H, m), 7.33-7.44 (3H, m), 7.50-7.55 (1H, m).
MS (ESI +): [M + H] + 418.1.
実施例６５
エチル 4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート Example 65
Ethyl 4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
　Ａ）2-エチル-5-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-2,4-ジヒドロ-3H-ピラゾール-3-オン
　実施例２９－Ｃ）で合成したメチル 4-[3-フルオロ-5-(トリフルオロメチル)フェニル]-3-オキソブタノアート(1.38 g) のエタノール溶液 (20 mL) にエチルヒドラジン (447 mg) を加え、2時間加熱還流した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (1.43 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.28 (3H, t, J = 7.2 Hz), 3.12 (2H, s), 3.72 (2H, q, J = 7.2 Hz), 3.78 (2H, s), 7.11-7.18 (1H, m), 7.23-7.31 (2H, m).
MS (ESI+): [M+H]+289.2. A) 2-ethyl-5- [3-fluoro-5- (trifluoromethyl) benzyl] -2,4-dihydro-3H-pyrazol-3-one methyl 4- [3 synthesized in Example 29-C) Ethylhydrazine (447 mg) was added to an ethanol solution (20 mL) of -fluoro-5- (trifluoromethyl) phenyl] -3-oxobutanoate (1.38 g), and the mixture was heated to reflux for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.43 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.28 (3H, t, J = 7.2 Hz), 3.12 (2H, s), 3.72 (2H, q, J = 7.2 Hz), 3.78 (2H, s), 7.11 -7.18 (1H, m), 7.23-7.31 (2H, m).
MS (ESI +): [M + H] + 289.2.
　Ｂ）1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例６５－Ａ）で合成した2-エチル-5-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-2,4-ジヒドロ-3H-ピラゾール-3-オン (1.04 g) のピリジン溶液 (10 mL) にトリフルオロメタンスルホン酸無水物 (0.73 mL) を0℃で滴下し、１時間撹拌した。溶媒を留去した後、酢酸エチルで抽出した。有機層を、1N塩酸および飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (1.17 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.47 (3H, t, J = 7.4 Hz), 3.97 (2H, s), 4.09 (2H, q, J = 7.2 Hz), 5.89 (1H, s), 7.09-7.22 (2H, m), 7.28-7.31 (1H, m).
MS (ESI+): [M+H]+421.2. B) 1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl trifluoromethanesulfonate 2-ethyl-5- [synthesized in Example 65-A) Trifluoromethanesulfonic anhydride (0.73 mL) was added to a pyridine solution (10 mL) of 3-fluoro-5- (trifluoromethyl) benzyl] -2,4-dihydro-3H-pyrazol-3-one (1.04 g). The solution was added dropwise at 0 ° C. and stirred for 1 hour. After the solvent was distilled off, the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.17 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.47 (3H, t, J = 7.4 Hz), 3.97 (2H, s), 4.09 (2H, q, J = 7.2 Hz), 5.89 (1H, s), 7.09 -7.22 (2H, m), 7.28-7.31 (1H, m).
MS (ESI +): [M + H] + 421.2.
　Ｃ）エチル 4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート
　実施例６５－Ｂ）で合成した1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル トリフルオロメタンスルホナート (1.17 g) 、実施例２９－Ｂ）で合成したエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート (889 mg) 、ジクロロビス（トリフェニルホスフィン）パラジウム(II) (195 mg) 、および炭酸カリウム (1.15 g) の1,2-ジメトキシエタン－水混合溶液 (3：1、20 mL) を窒素気流下、85℃で16時間撹拌した後、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (1.07 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (6H, t, J = 7.2 Hz), 2.64 (3H, s), 4.05 (2H, s), 4.15 (2H, q, J = 7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 6.05 (1H, s), 7.13-7.30 (4H, m), 7.35-7.40 (1H, m), 7.94-8.00 (1H, m).
MS (ESI+): [M+H]+435.3. C) Ethyl 4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate synthesized in Example 65-B) 1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl trifluoromethanesulfonate (1.17 g), ethyl 2-methyl synthesized in Example 29-B) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (889 mg), dichlorobis (triphenylphosphine) palladium (II) (195 mg), and A 1,2-dimethoxyethane-water mixed solution of potassium carbonate (1.15 g) (3: 1, 20 mL) was stirred at 85 ° C. for 16 hours under a nitrogen stream, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.07 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (6H, t, J = 7.2 Hz), 2.64 (3H, s), 4.05 (2H, s), 4.15 (2H, q, J = 7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 6.05 (1H, s), 7.13-7.30 (4H, m), 7.35-7.40 (1H, m), 7.94-8.00 (1H, m).
MS (ESI +): [M + H] + 435.3.
実施例６６
4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸 Example 66
4- {1-Ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132
　実施例６５で合成したエチル 4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート (1.07 g) のエタノール溶液 (25 mL) に1N水酸化ナトリウム水溶液 (5.0 mL) を加えた。反応混合物を70℃で1時間半撹拌した後、1N塩酸 (5.0 mL) を加えて中和し、溶媒を留去した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (926 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz), 2.70 (3H, s), 4.07 (2H, s), 4.18 (2H, q, J = 7.2 Hz), 6.08 (1H, s), 7.14-7.33 (4H, m), 7.36-7.40 (1H, m), 8.09-8.15 (1H, m). CO2Hピークは観測されなかった.
MS (ESI+): [M+H]+407.3. Of ethyl 4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate (1.07 g) synthesized in Example 65 To an ethanol solution (25 mL) was added 1N aqueous sodium hydroxide solution (5.0 mL). The reaction mixture was stirred at 70 ° C. for 1.5 hours, neutralized with 1N hydrochloric acid (5.0 mL), the solvent was distilled off, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (926 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.43 (3H, t, J = 7.2 Hz), 2.70 (3H, s), 4.07 (2H, s), 4.18 (2H, q, J = 7.2 Hz), 6.08 (1H, s), 7.14-7.33 (4H, m), 7.36-7.40 (1H, m), 8.09-8.15 (1H, m) .No CO 2 H peak was observed.
MS (ESI +): [M + H] + 407.3.
実施例６７
4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 67
4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
　実施例６６で合成した4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸 (230 mg) 、HOBtアンモニウム和物 (103 mg) 、WSC (130 mg) のDMF溶液(5 mL) を室温で16時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (214 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 2.54 (3H, s), 4.05 (2H, s), 4.13 (2H, q, J = 7.3 Hz), 5.76 (2H, brs), 6.02 (1H, s), 7.14-7.28 (4H, m), 7.36-7.39 (1H, m), 7.53 (1H, d, J = 7.5 Hz).
MS (ESI+): [M+H]+406.3. 4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid (230 mg) synthesized in Example 66, HOBt A solution of ammonium solvate (103 mg) and WSC (130 mg) in DMF (5 mL) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (214 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 2.54 (3H, s), 4.05 (2H, s), 4.13 (2H, q, J = 7.3 Hz), 5.76 (2H, brs), 6.02 (1H, s), 7.14-7.28 (4H, m), 7.36-7.39 (1H, m), 7.53 (1H, d, J = 7.5 Hz).
MS (ESI +): [M + H] + 406.3.
実施例６８
4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-N-(2-ヒドロキシエチル)-2-メチルベンズアミド Example 68
4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -N- (2-hydroxyethyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134
　実施例６６で合成した4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸 (230 mg) 、2－アミノエタノール (41 μL) 、HOBt (92 mg) 、WSC (130 mg) のDMF溶液 (5 mL) を室温で16時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (239 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 1.39 (3H, t, J = 7.2 Hz), 2.32 (1H, t, J = 5.1 Hz), 2.50 (3H, s), 3.60-3.70 (2H, m), 3.82-3.91 (2H, m), 4.05 (2H, s), 4.12 (2H, q, J = 7.2 Hz), 6.02 (1H, s), 6.21-6.30 (1H, m), 7.14-7.28 (4H, m), 7.36-7.39 (1H, m), 7.46 (1H, d, J = 7.5 Hz).
MS (ESI+): [M+H]+450.4. 4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid (230 mg) synthesized in Example 66, 2 -A DMF solution (5 mL) of aminoethanol (41 μL), HOBt (92 mg), and WSC (130 mg) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (239 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.39 (3H, t, J = 7.2 Hz), 2.32 (1H, t, J = 5.1 Hz), 2.50 (3H, s), 3.60-3.70 (2H, m) , 3.82-3.91 (2H, m), 4.05 (2H, s), 4.12 (2H, q, J = 7.2 Hz), 6.02 (1H, s), 6.21-6.30 (1H, m), 7.14-7.28 (4H , m), 7.36-7.39 (1H, m), 7.46 (1H, d, J = 7.5 Hz).
MS (ESI +): [M + H] + 450.4.
実施例６９
N-(2-アミノ-2-オキソエチル)-4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 69
N- (2-Amino-2-oxoethyl) -4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
　実施例６６で合成した4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸 (230 mg) 、グリシンアミド塩酸塩 (75 mg) 、HOBt (92 mg) 、WSC (130 mg) およびトリエチルアミン (95 μL)のDMF溶液 (5 mL) を室温で16時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (239 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.4 Hz), 2.50 (3H, s), 4.05 (2H, s), 4.13 (2H, q, J = 7.3 Hz), 4.19 (2H, d, J = 4.9 Hz), 5.53 (1H, brs), 5.98-6.11 (2H, m), 6.63 (1H, t, J = 4.9 Hz), 7.14-7.29 (4H, m), 7.36-7.39 (1H, m), 7.51 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+463.4. 4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid (230 mg) synthesized in Example 66, glycine Amide hydrochloride (75 mg), HOBt (92 mg), WSC (130 mg) and triethylamine (95 μL) in DMF (5 mL) were stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (239 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.4 Hz), 2.50 (3H, s), 4.05 (2H, s), 4.13 (2H, q, J = 7.3 Hz), 4.19 (2H, d, J = 4.9 Hz), 5.53 (1H, brs), 5.98-6.11 (2H, m), 6.63 (1H, t, J = 4.9 Hz), 7.14-7.29 (4H, m), 7.36- 7.39 (1H, m), 7.51 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 463.4.
実施例７０
4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル-N-[2-(メチルアミノ)-2-オキソエチル]ベンズアミド Example 70
4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methyl-N- [2- (methylamino) -2-oxoethyl Benzamide
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
　実施例６６で合成した4-{1-エチル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸 (230 mg) 、N-メチルグリシンアミド塩酸塩 (85 mg) 、HOBt (92 mg) 、WSC (130 mg) およびトリエチルアミン (95 μL)のDMF溶液 (5 mL) を室温で16時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (254 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 2.50 (3H, s), 2.89 (3H, d, J = 4.9 Hz), 4.05 (2H, s), 4.08-4.18 (4H, m), 6.03 (1H, s), 6.08 (1H, brs), 6.68 (1H, t, J = 4.7 Hz), 7.13-7.28 (4H, m), 7.36-7.39 (1H, m), 7.50 (1H, d, J = 7.6 Hz).
MS (ESI+): [M+H]+477.4. 4- {1-ethyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid synthesized in Example 66 (230 mg), N -A DMF solution (5 mL) of methylglycinamide hydrochloride (85 mg), HOBt (92 mg), WSC (130 mg) and triethylamine (95 μL) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (254 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 2.50 (3H, s), 2.89 (3H, d, J = 4.9 Hz), 4.05 (2H, s), 4.08 -4.18 (4H, m), 6.03 (1H, s), 6.08 (1H, brs), 6.68 (1H, t, J = 4.7 Hz), 7.13-7.28 (4H, m), 7.36-7.39 (1H, m ), 7.50 (1H, d, J = 7.6 Hz).
MS (ESI +): [M + H] + 477.4.
実施例７１
メチル 6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルピリジン-3-カルボキシラート Example 71
Methyl 6- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylpyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
　Ａ）メチル 2-メチル-6-オキソ-1,6-ジヒドロピリジン-3-カルボキシラート
　メチル プロピオラート（5.00 g）とメチル 3-アミノブタ-2-エノアート（7.53 g）のメタノール溶液（50 mL）を終夜加熱還流させた。反応混合物を0 ℃に冷却し、不溶物をろ取してイソプロパノールで洗浄した。固体を減圧乾燥させ、標題化合物（4.48 g）を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.52 (3H, s), 3.74 (3H, s), 6.20 (1H, d, J = 9.8 Hz), 7.81 (1H, d, J = 9.5 Hz), 12.05 (1H, brs).
MS (ESI+): [M+H]+167.9. A) Methyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate Methyl propiolate (5.00 g) and methyl 3-aminobut-2-enoate (7.53 g) in methanol (50 mL) are heated overnight. Refluxed. The reaction mixture was cooled to 0 ° C., and the insoluble material was collected by filtration and washed with isopropanol. The solid was dried under reduced pressure to give the title compound (4.48 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.52 (3H, s), 3.74 (3H, s), 6.20 (1H, d, J = 9.8 Hz), 7.81 (1H, d, J = 9.5 Hz) , 12.05 (1H, brs).
MS (ESI +): [M + H] + 167.9.
　Ｂ）メチル 2-メチル-6-(((トリフルオロメチル)スルホニル)オキシ)ピリジン-3-カルボキシラート
　実施例７１－Ａ）で合成したメチル 2-メチル-6-オキソ-1,6-ジヒドロピリジン-3-カルボキシラート（4.00 g）のピリジン溶液（20 mL）に無水トリフルオロメタンスルホン酸（4.85 mL）を0 ℃で加え、室温で終夜撹拌した。反応混合物を減圧濃縮し、残渣に水を加え、酢酸エチルで抽出した。抽出液を0.1 N 塩酸、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（4.72 ｇ）を得た。
1H NMR (300 MHz, CDCl3) δ 2.83 (3H, s), 3.95 (3H, s), 7.06 (1H, d, J = 8.3 Hz), 8.39 (1H, d, J = 8.3 Hz). B) Methyl 2-methyl-6-(((trifluoromethyl) sulfonyl) oxy) pyridine-3-carboxylate Methyl 2-methyl-6-oxo-1,6-dihydropyridine- synthesized in Example 71-A) To a pyridine solution (20 mL) of 3-carboxylate (4.00 g) was added trifluoromethanesulfonic anhydride (4.85 mL) at 0 ° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 0.1 N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (4.72 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.83 (3H, s), 3.95 (3H, s), 7.06 (1H, d, J = 8.3 Hz), 8.39 (1H, d, J = 8.3 Hz).
　Ｃ）メチル 6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルピリジン-3-カルボキシラート
　実施例２９－Ｅ）で得た3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート（150 mg）、酢酸カリウム（54.4 mg）、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物（30.2 mg）、ビスピナコラトジボロン（103 mg）のDME溶液（1.5 mL）を窒素雰囲気中マイクロウェーブ照射下140 ℃において15分間撹拌した。反応混合物を減圧濃縮し、残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製した。残渣に実施例７１－Ｂ）で合成したメチル 2-メチル-6-(トリフルオロメチルスルホニルオキシ)ニコチナート（166 mg）、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物（37.7 mg）、リン酸三カリウム（294 mg）、NMP（1 mL）を加え、窒素雰囲気下80 ℃において3時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥させ減圧濃縮した。残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)により精製して標題化合物（107 mg）を得た。
1H NMR (300 MHz, CDCl3) δ 2.88 (3H, s), 3.93 (3H, s), 4.05 (2H, s), 4.26 (3H, s), 6.41 (1H, s), 7.18 (2H, d, J = 9.1 Hz), 7.36 (1H, s), 7.42 (1H, d, J = 7.9 Hz), 8.23 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+408.1. C) Methyl 6- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylpyridine-3-carboxylate Example 29-E 3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate (150 mg), potassium acetate (54.4 mg), [1 , 1'-Bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane adduct (30.2 mg) and bispinacolatodiboron (103 mg) in DME solution (1.5 mL) in a nitrogen atmosphere under microwave irradiation Stir at 15 ° C. for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate). Methyl 2-methyl-6- (trifluoromethylsulfonyloxy) nicotinate (166 mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride synthesized in Example 71-B) Dichloromethane adduct (37.7 mg), tripotassium phosphate (294 mg) and NMP (1 mL) were added, and the mixture was stirred at 80 ° C. for 3 hours under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (107 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.88 (3H, s), 3.93 (3H, s), 4.05 (2H, s), 4.26 (3H, s), 6.41 (1H, s), 7.18 (2H, d, J = 9.1 Hz), 7.36 (1H, s), 7.42 (1H, d, J = 7.9 Hz), 8.23 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 408.1.
実施例７２
6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルピリジン-3-カルボン酸 Example 72
6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylpyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138
　実施例７１で合成したメチル 6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルニコチナート（100 mg）のメタノール‐THF溶液（2:1、3 mL）に1 N水酸化ナトリウム水溶液(0.49 mL)を加え、50 ℃で2時間撹拌した。反応混合物を0.1 N塩酸で中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物(41 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.92 (3H, s), 4.06 (2H, s), 4.27 (3H, s), 6.43 (1H, s), 7.14-7.22 (2H, m), 7.36 (1H, s), 7.46 (1H, d, J = 8.3 Hz), 8.31 (1H, d, J = 8.3 Hz), (COOHピークは観測されなかった).
MS (ESI+): [M+H]+394.1. Of methyl 6- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylnicotinate (100 mg) synthesized in Example 71 To a methanol-THF solution (2: 1, 3 mL) was added 1 N aqueous sodium hydroxide solution (0.49 mL), and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was neutralized with 0.1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (41 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.92 (3H, s), 4.06 (2H, s), 4.27 (3H, s), 6.43 (1H, s), 7.14-7.22 (2H, m), 7.36 ( 1H, s), 7.46 (1H, d, J = 8.3 Hz), 8.31 (1H, d, J = 8.3 Hz), (COOH peak not observed).
MS (ESI +): [M + H] + 394.1.
実施例７３
6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルピリジン-3-カルボキサミド Example 73
6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylpyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
　実施例７２で合成した6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルニコチン酸 (41 mg)、WSC (40 mg)、HOBtアンモニア和物 (31.7 mg)およびDMF (1 mL)の混合物を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル/ヘキサン）により精製し、標題化合物 (167 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.78 (3H, s), 4.05 (2H, s), 4.22 (3H, s), 5.79 (2H, brs), 6.36 (1H, s), 7.14-7.22 (2H, m), 7.34-7.43 (2H, m), 7.80 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+393.1. 6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylnicotinic acid (41 mg), WSC synthesized in Example 72 A mixture of (40 mg), HOBt ammonia hydrate (31.7 mg) and DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (167 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.78 (3H, s), 4.05 (2H, s), 4.22 (3H, s), 5.79 (2H, brs), 6.36 (1H, s), 7.14-7.22 ( 2H, m), 7.34-7.43 (2H, m), 7.80 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 393.1.
実施例７４
4-{5-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}ベンズアミド Example 74
4- {5-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} benzamide
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
　Ａ）2-[3-(トリフルオロメチル)フェニル]アセトアミド
　[3-(トリフルオロメチル)フェニル]酢酸(25 g)、塩化アンモニウム(19.9 g)、WSC塩酸塩(28.2 g)、HOBt(19.8 g)、N-エチルジイソプロピルアミン(64 mL)およびDMF(250 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣を再結晶(ヘプタン/酢酸エチル)して標題化合物(14.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.63 (2H, s), 5.50 (1H, brs), 5.91 (1H, brs), 7.43-7.61 (4H, m). A) 2- [3- (Trifluoromethyl) phenyl] acetamide [3- (Trifluoromethyl) phenyl] acetic acid (25 g), ammonium chloride (19.9 g), WSC hydrochloride (28.2 g), HOBt (19.8 g ), N-ethyldiisopropylamine (64 mL) and DMF (250 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized (heptane / ethyl acetate) to give the title compound (14.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.63 (2H, s), 5.50 (1H, brs), 5.91 (1H, brs), 7.43-7.61 (4H, m).
　Ｂ）N-アセチル-2-[3-(トリフルオロメチル)フェニル]アセトアミド
　実施例７４－Ａ）で合成した2-[3-(トリフルオロメチル)フェニル]アセトアミド(200 mg)、無水酢酸(0.5 mL)、濃硫酸(0.010 mL)およびトルエン(2 mL)の混合物を2時間加熱還流した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去して標題化合物(240 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.36 (3H, s), 3.93 (2H, s), 7.43-7.61 (4H, m), 8.74 (1H, brs). B) N-acetyl-2- [3- (trifluoromethyl) phenyl] acetamide 2- [3- (trifluoromethyl) phenyl] acetamide (200 mg) synthesized in Example 74-A), acetic anhydride (0.5 mL), concentrated sulfuric acid (0.010 mL) and toluene (2 mL) were heated to reflux for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (240 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.36 (3H, s), 3.93 (2H, s), 7.43-7.61 (4H, m), 8.74 (1H, brs).
　Ｃ）4-{5-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}ベンゾニトリル
　実施例７４－Ｂ）で合成したN-アセチル-2-[3-(トリフルオロメチル)フェニル]アセトアミド(100 mg)、4-シアノフェニルヒドラジン(69 mg)およびピリジン(1 mL)の混合物を100℃で5時間撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して標題化合物(13 mg)を得た。
1H NMR (300 MHz, CDCl3) δ2.58 (3H, s), 4.14 (2H, s), 7.34-7.68 (6H, m), 7.79-7.85 (2H, m).
MS (ESI+): [M+H]+ 343.0. C) 4- {5-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} benzonitrile N-acetyl synthesized in Example 74-B) A mixture of -2- [3- (trifluoromethyl) phenyl] acetamide (100 mg), 4-cyanophenylhydrazine (69 mg) and pyridine (1 mL) was stirred at 100 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (13 mg).
1 H NMR (300 MHz, CDCl 3 ) δ2.58 (3H, s), 4.14 (2H, s), 7.34-7.68 (6H, m), 7.79-7.85 (2H, m).
MS (ESI +): [M + H] + 343.0.
　Ｄ）4-{5-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}ベンズアミド
　実施例７４－Ｃ）で合成した4-{5-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}ベンゾニトリル(13 mg)、炭酸カリウム(2.6 mg)およびジメチルスルホキシド (DMSO) (0.50 mL)の混合物を０℃に冷却し、35%過酸化水素水(0.050 mL)をゆっくり滴下した。反応混合物を室温で１時間撹拌した後酢酸エチルで希釈し、水、および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール/酢酸エチル)で精製した。得られた生成物をHPLC (C18、移動相：水/アセトニトリル (0.1% TFA含有系)) にて分取し、得られた画分に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後、減圧下濃縮して標題化合物(6.5 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.55 (3H, s), 4.14 (2H, s), 5.86 (1H, brs), 6.05 (1H, brs), 7.39-7.68 (6H, m), 7.93-7.99 (2H, m).
MS (ESI+): [M+H]+ 361.0. D) 4- {5-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} benzamide 4- {5 synthesized in Example 74-C) -Methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} benzonitrile (13 mg), potassium carbonate (2.6 mg) and dimethyl sulfoxide (DMSO) ( 0.50 mL) was cooled to 0 ° C., and 35% aqueous hydrogen peroxide (0.050 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained product was fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), a saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (6.5 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.55 (3H, s), 4.14 (2H, s), 5.86 (1H, brs), 6.05 (1H, brs), 7.39-7.68 (6H, m), 7.93- 7.99 (2H, m).
MS (ESI +): [M + H] + 361.0.
実施例７５
4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-5-イル}ベンズアミド Example 75
4- {1-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
　Ａ）メチル 5-ブロモ-1H-1,2,4-トリアゾール-3-カルボキシラート
　メチル 5-アミノ-1H-1,2,4-トリアゾール-3-カルボキシラート(15.0 g)、濃硫酸(6.0 mL)および水(100 mL)の混合物を0℃に冷却し、亜硝酸ナトリウム(10.9 g)水溶液をゆっくり滴下した。30分間撹拌した後、臭化銅(I)(7.6 g)および臭化カリウム(25.1 g)水溶液をゆっくり滴下した。反応混合物を室温まで昇温し一晩撹拌した後、セライトろ過した。ろ液を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製して標題化合物(8.9 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 3.90 (3H, s), 15.70 (1H, brs).
MS (ESI+): [M+H]+ 206.0. A) Methyl 5-bromo-1H-1,2,4-triazole-3-carboxylate Methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (15.0 g), concentrated sulfuric acid (6.0 mL ) And water (100 mL) were cooled to 0 ° C., and an aqueous solution of sodium nitrite (10.9 g) was slowly added dropwise. After stirring for 30 minutes, an aqueous solution of copper (I) bromide (7.6 g) and potassium bromide (25.1 g) was slowly added dropwise. The reaction mixture was warmed to room temperature and stirred overnight, and then filtered through celite. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (8.9 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 3.90 (3H, s), 15.70 (1H, brs).
MS (ESI +): [M + H] + 206.0.
　Ｂ）メチル 5-ブロモ-1-メチル-1H-1,2,4-トリアゾール-3-カルボキシラート
　実施例７５－Ａ）で合成したメチル 5-ブロモ-1H-1,2,4-トリアゾール-3-カルボキシラート(5.0 g)およびTHF(200 mL)の混合物を0℃に冷却し、水素化ナトリウム(60%, 1.2 g)をゆっくり加えた。反応混合物を30分間撹拌した後、ヨウ化メチル(1.8 mL)を加えた。反応混合物を80℃で4時間撹拌した後、溶媒を減圧下留去した。残渣を酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して標題化合物(2.0 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.99 (3H, s), 4.00 (3H, s).
MS (ESI+): [M+H]+ 220.3. B) Methyl 5-bromo-1H-1,2,4-triazole-3 synthesized in Example 75-A) -A mixture of carboxylate (5.0 g) and THF (200 mL) was cooled to 0 ° C and sodium hydride (60%, 1.2 g) was added slowly. The reaction mixture was stirred for 30 minutes and then methyl iodide (1.8 mL) was added. The reaction mixture was stirred at 80 ° C. for 4 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.0 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.99 (3H, s), 4.00 (3H, s).
MS (ESI +): [M + H] + 220.3.
　Ｃ）メチル 5-(4-シアノフェニル)-1-メチル-1H-1,2,4-トリアゾール-3-カルボキシラート
　実施例７５－Ｂ）で合成したメチル 5-ブロモ-1-メチル-1H-1,2,4-トリアゾール-3-カルボキシラート(55 mg)、4-シアノフェニルボロン酸(44 mg)、トリス(ジベンジリデンアセトン)ジパラジウム (0) (11 mg)、ジシクロヘキシル[2',4',6'-トリス(1-メチルエチル)ビフェニル-2-イル]ホスファン(X-Phos; 12 mg)、炭酸セシウム(122 mg)および1,2-ジメトキシエタン(DME;1 mL) の混合物を、マイクロウェーブ照射下150℃で15分間加熱した。反応混合物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して標題化合物(24 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 4.04 (3H, s), 4.12 (3H, s), 7.80-7.94 (4H, m). C) Methyl 5- (4-cyanophenyl) -1-methyl-1H-1,2,4-triazole-3-carboxylate Methyl 5-bromo-1-methyl-1H- synthesized in Example 75-B) 1,2,4-triazole-3-carboxylate (55 mg), 4-cyanophenylboronic acid (44 mg), tris (dibenzylideneacetone) dipalladium (0) (11 mg), dicyclohexyl [2 ', 4 A mixture of ', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphane (X-Phos; 12 mg), cesium carbonate (122 mg) and 1,2-dimethoxyethane (DME; 1 mL) Heated at 150 ° C. for 15 minutes under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (24 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 4.04 (3H, s), 4.12 (3H, s), 7.80-7.94 (4H, m).
　Ｄ）4-[3-(ヒドロキシメチル)-1-メチル-1H-1,2,4-トリアゾール-5-イル]ベンゾニトリル
　実施例７５－Ｃ）で合成したメチル 5-(4-シアノフェニル)-1-メチル-1H-1,2,4-トリアゾール-3-カルボキシラート(100 mg)のTHF(10 mL)溶液に、水素化ホウ素リチウム(45 mg)を加え、室温で30分間撹拌した。反応混合物に水および無水硫酸ナトリウムを加えてろ過した。ろ液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール/酢酸エチル)で精製して標題化合物(41 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.99 (1H, brs), 4.00 (3H, s), 4.78 (2H, s), 7.82 (4H, s).
MS (ESI+): [M+H]+ 215.0. D) 4- [3- (Hydroxymethyl) -1-methyl-1H-1,2,4-triazol-5-yl] benzonitrile Methyl 5- (4-cyanophenyl) synthesized in Example 75-C) To a solution of 1-methyl-1H-1,2,4-triazole-3-carboxylate (100 mg) in THF (10 mL) was added lithium borohydride (45 mg), and the mixture was stirred at room temperature for 30 minutes. Water and anhydrous sodium sulfate were added to the reaction mixture and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (41 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.99 (1H, brs), 4.00 (3H, s), 4.78 (2H, s), 7.82 (4H, s).
MS (ESI +): [M + H] + 215.0.
　Ｅ）4-[3-(ブロモメチル)-1-メチル-1H-1,2,4-トリアゾール-5-イル]ベンゾニトリル
　実施例７５－Ｄ）で合成した4-[3-(ヒドロキシメチル)-1-メチル-1H-1,2,4-トリアゾール-5-イル]ベンゾニトリル(40 mg)のTHF(10 mL)溶液に、三臭化リン(0.021 mL)を加え、室温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウムおよび無水硫酸ナトリウムを加えてろ過した。ろ液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール/酢酸エチル)で精製して標題化合物(28 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 4.01 (3H, s), 4.51 (2H, s), 7.80-7.87 (4H, m).
MS (ESI+): [M+H]+ 276.8. E) 4- [3- (Bromomethyl) -1-methyl-1H-1,2,4-triazol-5-yl] benzonitrile 4- [3- (hydroxymethyl)-synthesized in Example 75-D) To a solution of 1-methyl-1H-1,2,4-triazol-5-yl] benzonitrile (40 mg) in THF (10 mL) was added phosphorus tribromide (0.021 mL), and the mixture was stirred at room temperature for 1 hour. . Saturated sodium hydrogen carbonate and anhydrous sodium sulfate were added to the reaction mixture and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (28 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 4.01 (3H, s), 4.51 (2H, s), 7.80-7.87 (4H, m).
MS (ESI +): [M + H] + 276.8.
　Ｆ）4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-5-イル}ベンゾニトリル
　実施例７５－Ｅ）で合成した4-[3-(ブロモメチル)-1-メチル-1H-1,2,4-トリアゾール-5-イル]ベンゾニトリル(28 mg)、3-(トリフルオロメチル)フェニルボロン酸(23 mg)、テトラキス（トリフェニルホスフィン）パラジウム（0）(12 mg)、リン酸カリウム(32 mg)およびDME(1 mL)の混合物をマイクロウェーブ照射下150℃で15分間加熱した。反応混合物を酢酸エチルで希釈してセライトろ過した。ろ液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製して標題化合物(22 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 3.98 (3H, s), 4.15 (2H, s), 7.36-7.66 (4H, m), 7.76-7.85 (4H, m).
MS (ESI+): [M+H]+ 343.0. F) 4- {1-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-5-yl} benzonitrile 4- [synthesized in Example 75-E) 3- (Bromomethyl) -1-methyl-1H-1,2,4-triazol-5-yl] benzonitrile (28 mg), 3- (trifluoromethyl) phenylboronic acid (23 mg), tetrakis (triphenyl A mixture of phosphine) palladium (0) (12 mg), potassium phosphate (32 mg) and DME (1 mL) was heated at 150 ° C. for 15 minutes under microwave irradiation. The reaction mixture was diluted with ethyl acetate and filtered through celite. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (22 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 3.98 (3H, s), 4.15 (2H, s), 7.36-7.66 (4H, m), 7.76-7.85 (4H, m).
MS (ESI +): [M + H] + 343.0.
　Ｇ）4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-5-イル}ベンズアミド
　実施例７４－Ｄ）と同様の方法により、実施例７５－Ｆ）で合成した4-{1-メチル-3-[3-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-5-イル}ベンゾニトリルを用いて標題化合物を得た。
1H NMR (300 MHz, CDCl3) δ 3.97 (3H, s), 4.16 (2H, s), 5.67 (1H, brs), 6.10 (1H, brs), 7.36-7.69 (4H, m), 7.74-7.80 (2H, m), 7.91-7.98 (2H, m).
MS (ESI+): [M+H]+ 361.1. G) 4- {1-Methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-5-yl} benzamide Performed in the same manner as in Example 74-D) The title compound was prepared using 4- {1-methyl-3- [3- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-5-yl} benzonitrile synthesized in Example 75-F). Obtained.
1 H NMR (300 MHz, CDCl 3 ) δ 3.97 (3H, s), 4.16 (2H, s), 5.67 (1H, brs), 6.10 (1H, brs), 7.36-7.69 (4H, m), 7.74- 7.80 (2H, m), 7.91-7.98 (2H, m).
MS (ESI +): [M + H] + 361.1.
実施例７６
4-{4-メチル-2-[3-(トリフルオロメチル)ベンジル]-1,3-オキサゾール-5-イル}ベンズアミド Example 76
4- {4-Methyl-2- [3- (trifluoromethyl) benzyl] -1,3-oxazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
　Ａ）4-ブロモ-N-メトキシ-N-メチルベンズアミド
　4-ブロモ安息香酸 (30.0 g) のDMF溶液(250 mL) に WSC (34.3 g) およびHOBt (24.2 g) を加え、室温で30分間撹拌した。N-メトキシメタンアミン塩酸塩 (16.0 g) およびトリエチルアミン (52.1 mL) を加え、室温で15時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (石油エーテル/酢酸エチル) で精製して標題化合物 (27.0 g) を得た。
1H NMR (400 MHz, CDCl3) δ 3.36 (3H, s), 3.53 (3H, s), 7.51-7.54 (2H, m), 7.55-7.58 (2H, m). A) 4-Bromo-N-methoxy-N-methylbenzamide To a DMF solution (250 mL) of 4-bromobenzoic acid (30.0 g), add WSC (34.3 g) and HOBt (24.2 g), and stir at room temperature for 30 minutes. did. N-methoxymethanamine hydrochloride (16.0 g) and triethylamine (52.1 mL) were added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (27.0 g).
1 H NMR (400 MHz, CDCl 3 ) δ 3.36 (3H, s), 3.53 (3H, s), 7.51-7.54 (2H, m), 7.55-7.58 (2H, m).
　Ｂ）1-(4-ブロモフェニル)プロパン-1-オン
　実施例７６-Ａ）で合成した4-ブロモ-N-メトキシ-N-メチルベンズアミド (20.0 g) のTHF溶液(200 mL) にクロロ(エチル)マグネシウムの2M THF溶液 (45 mL) を-78℃でゆっくりと加え、室温で2時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去して標題化合物 (16.8 g) を得た。
1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J = 7.2 Hz), 2.98 (2H, q, J = 7.2 Hz), 7.58-7.62 (2H, m), 7.81-7.85 (2H, m). B) 1- (4-Bromophenyl) propan-1-one 4-bromo-N-methoxy-N-methylbenzamide (20.0 g) synthesized in Example 76-A) was added to a THF solution (200 mL) with chloro ( Ethyl) magnesium in 2M THF (45 mL) was slowly added at −78 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (16.8 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.22 (3H, t, J = 7.2 Hz), 2.98 (2H, q, J = 7.2 Hz), 7.58-7.62 (2H, m), 7.81-7.85 (2H, m).
　Ｃ）2-ブロモ-1-(4-ブロモフェニル)プロパン-1-オン
　実施例７６-Ｂ）で合成した1-(4-ブロモフェニル)プロパン-1-オン (15.7 g) の酢酸溶液(150 mL) に臭素 (3.77 mL) を0℃で滴下し、室温で臭素の色が消えるまで4時間撹拌した。反応混合物を飽和炭酸ナトリウム水溶液により中和した後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去することで標題化合物 (15.4 g) を得た。
1H NMR (400 MHz, CDCl3) δ 1.90 (3H, d, J = 6.4 Hz), 5.22 (1H, q, J = 6.4 Hz), 7.62-7.65 (2H, m), 7.81-7.91 (2H, m). C) 2-Bromo-1- (4-bromophenyl) propan-1-one 1- (4-Bromophenyl) propan-1-one (15.7 g) synthesized in Example 76-B) in acetic acid solution (150 Bromine (3.77 mL) was added dropwise to mL) at 0 ° C., and the mixture was stirred at room temperature for 4 hours until the color of bromine disappeared. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (15.4 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.90 (3H, d, J = 6.4 Hz), 5.22 (1H, q, J = 6.4 Hz), 7.62-7.65 (2H, m), 7.81-7.91 (2H, m).
　Ｄ）2-アジド-1-(4-ブロモフェニル)プロパン-1-オン
　実施例７６-Ｃ）で合成した2-ブロモ-1-(4-ブロモフェニル)プロパン-1-オン (5.80 g)のメタノール溶液 (50 mL) にアジ化ナトリウム (1.36 g) を0℃で加え、室温で2時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去することで標題化合物 (4.15 g) を得た。
1H NMR (400 MHz, CDCl3) δ 1.56 (3H, d, J = 6.8 Hz), 4.64 (1H, q, J = 6.8 Hz), 7.63-7.66 (2H, m), 7.80-7.83 (2H, m). D) 2-azido-1- (4-bromophenyl) propan-1-one of 2-bromo-1- (4-bromophenyl) propan-1-one (5.80 g) synthesized in Example 76-C) Sodium azide (1.36 g) was added to a methanol solution (50 mL) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.15 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.56 (3H, d, J = 6.8 Hz), 4.64 (1H, q, J = 6.8 Hz), 7.63-7.66 (2H, m), 7.80-7.83 (2H, m).
　Ｅ）tert-ブチル [2-(4-ブロモフェニル)-1-メチル-2-オキソエチル]カルバマート
　粉末亜鉛 (1.54 g) およびトリクロロアルミニウム 6水和物(2.10 g) の水溶液(60 mL)に実施例７６-Ｄ）で合成した 2-アジド-1-(4-ブロモフェニル)プロパン-1-オン (3.00 g) のエタノール溶液 (10 mL) を室温で滴下し、3時間撹拌した。反応混合物をろ過し、ジ-tert-ブチル ジカルボナート (3.01 g) および炭酸カリウム (1.99 g) を加え、室温で15時間撹拌した。反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣を石油エーテル中に懸濁させ、固体をろ別することで標題化合物 (2.30 g) を得た。
1H NMR (400 MHz, CDCl3) δ 1.39 (3H, d, J = 7.2 Hz), 1.45 (9H, s), 5.19-5.25 (1H, m), 5.48 (1H, d, J = 6.4 Hz), 7.63-7.65 (2H, m), 7.83-7.85 (2H, m). E) Example of tert-butyl [2- (4-bromophenyl) -1-methyl-2-oxoethyl] carbamate powdered zinc (1.54 g) and trichloroaluminum hexahydrate (2.10 g) in aqueous solution (60 mL) 76-D) was added dropwise an ethanol solution (10 mL) of 2-azido-1- (4-bromophenyl) propan-1-one (3.00 g) synthesized at room temperature and stirred for 3 hours. The reaction mixture was filtered, di-tert-butyl dicarbonate (3.01 g) and potassium carbonate (1.99 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in petroleum ether and the solid was filtered off to obtain the title compound (2.30 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.39 (3H, d, J = 7.2 Hz), 1.45 (9H, s), 5.19-5.25 (1H, m), 5.48 (1H, d, J = 6.4 Hz) , 7.63-7.65 (2H, m), 7.83-7.85 (2H, m).
　Ｆ）N-[2-(4-ブロモフェニル)-1-メチル-2-オキソエチル]-2-[3-(トリフルオロメチル)フェニル]アセトアミド
　実施例７６-Ｅ）で合成したtert-ブチル[2-(4-ブロモフェニル)-1-メチル-2-オキソエチル]カルバマート(2.30 g) のジエチルエーテル溶液 (60 mL) に塩化水素ガスを1時間バブリングし、室温で10時間撹拌した。反応混合物をろ過し、2-アミノ-1-(4-ブロモフェニル)プロパン-1-オン塩酸塩を得た。[3-(トリフルオロメチル)フェニル]酢酸 (1.43 g) の塩化メチレン溶液 (35 mL)にWSC (1.47 g) およびHOBt (1.04 g) を加え、室温で30分間撹拌した。この反応混合物を先に得られた2-アミノ-1-(4-ブロモフェニル)プロパン-1-オン塩酸塩のエーテル懸濁液に加え、さらにトリエチルアミン (2.43 mL) を加えて室温で4時間撹拌した。反応混合物に水を加え、塩化メチレンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (石油エーテル/酢酸エチル) で精製して標題化合物 (2.30 g) を得た。
1H NMR (400 MHz, CDCl3) δ 1.40 (3H, d, J = 6.8 Hz), 3.67 (2H, s), 5.45-5.53 (1H, m), 6.56 (1H, d, J = 6.4 Hz), 7.46-7.51 (2H, m), 7.54-7.57 (2H, m), 7.63-7.65 (2H, m), 7.81-7.83 (2H, m). F) N- [2- (4-Bromophenyl) -1-methyl-2-oxoethyl] -2- [3- (trifluoromethyl) phenyl] acetamide tert-butyl [2] synthesized in Example 76-E) Hydrogen chloride gas was bubbled into a diethyl ether solution (60 mL) of-(4-bromophenyl) -1-methyl-2-oxoethyl] carbamate (2.30 g) for 1 hour and stirred at room temperature for 10 hours. The reaction mixture was filtered to give 2-amino-1- (4-bromophenyl) propan-1-one hydrochloride. WSC (1.47 g) and HOBt (1.04 g) were added to a solution of [3- (trifluoromethyl) phenyl] acetic acid (1.43 g) in methylene chloride (35 mL), and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was added to the ether suspension of 2-amino-1- (4-bromophenyl) propan-1-one hydrochloride obtained earlier, and further triethylamine (2.43 mL) was added and stirred at room temperature for 4 hours. did. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (2.30 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, d, J = 6.8 Hz), 3.67 (2H, s), 5.45-5.53 (1H, m), 6.56 (1H, d, J = 6.4 Hz) , 7.46-7.51 (2H, m), 7.54-7.57 (2H, m), 7.63-7.65 (2H, m), 7.81-7.83 (2H, m).
　Ｇ）5-(4-ブロモフェニル)-4-メチル-2-[3-(トリフルオロメチル)ベンジル]-1,3-オキサゾール
　実施例７６-Ｆ）で合成したN-[2-(4-ブロモフェニル)-1-メチル-2-オキソエチル]-2-[3-(トリフルオロメチル)フェニル]アセトアミド (2.30 g) のアセトニトリル溶液 (30 mL)にリン酸 トリクロリド (10.2 mL) を室温で加え、70℃で5時間撹拌した。反応混合物を飽和炭酸ナトリウム水溶液により中和した後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去して標題化合物 (1.80 g) を得た。
1H NMR (400 MHz, CDCl3) δ 2.40 (3H, s), 4.20 (2H, s), 7.42-7.50 (3H, m), 7.54-7.57 (4H, m), 7.63 (1H, s). G) 5- (4-Bromophenyl) -4-methyl-2- [3- (trifluoromethyl) benzyl] -1,3-oxazole Example 76-F) N- [2- (4- Bromophenyl) -1-methyl-2-oxoethyl] -2- [3- (trifluoromethyl) phenyl] acetamide (2.30 g) in acetonitrile (30 mL) was added phosphoric acid trichloride (10.2 mL) at room temperature, Stir at 70 ° C. for 5 hours. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.80 g).
1 H NMR (400 MHz, CDCl 3 ) δ 2.40 (3H, s), 4.20 (2H, s), 7.42-7.50 (3H, m), 7.54-7.57 (4H, m), 7.63 (1H, s).
　Ｈ）4-{4-メチル-2-[3-(トリフルオロメチル)ベンジル]-1,3-オキサゾール-5-イル}ベンゾニトリル
　実施例７６-Ｇ）で合成した5-(4-ブロモフェニル)-4-メチル-2-[3-(トリフルオロメチル)ベンジル]-1,3-オキサゾール(1.80 g) のDMF溶液 (30 mL) にシアン化亜鉛 (320 mg) およびテトラキストリフェニルホスフィンパラジウム (525 mg) を室温で加え、窒素雰囲気下170℃で2時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (石油エーテル/酢酸エチル) で精製して標題化合物 (1.05 g) を得た。
1H NMR (400 MHz, CDCl3) δ 2.46 (3H, s), 4.21 (2H, s), 7.48 (1H, t, J = 7.6 Hz), 7.54-7.59 (2H, m), 7.62 (1H, s), 7.64-7.66 (2H, m), 7.69-7.72 (2H, m).
MS (ESI+): [M+H]+343.15. H) 4- {4-Methyl-2- [3- (trifluoromethyl) benzyl] -1,3-oxazol-5-yl} benzonitrile 5- (4-Bromophenyl) synthesized in Example 76-G) ) -4-methyl-2- [3- (trifluoromethyl) benzyl] -1,3-oxazole (1.80 g) in DMF (30 mL) was added to zinc cyanide (320 mg) and tetrakistriphenylphosphine palladium ( 525 mg) was added at room temperature, and the mixture was stirred at 170 ° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (1.05 g).
1 H NMR (400 MHz, CDCl 3 ) δ 2.46 (3H, s), 4.21 (2H, s), 7.48 (1H, t, J = 7.6 Hz), 7.54-7.59 (2H, m), 7.62 (1H, s), 7.64-7.66 (2H, m), 7.69-7.72 (2H, m).
MS (ESI +): [M + H] + 343.15.
　Ｉ）4-{4-メチル-2-[3-(トリフルオロメチル)ベンジル]-1,3-オキサゾール-5-イル}ベンズアミド
　実施例７６-Ｈ）で合成した4-{4-メチル-2-[3-(トリフルオロメチル)ベンジル]-1,3-オキサゾール-5-イル}ベンゾニトリル (342 mg) のDMSO溶液 (10 mL) に炭酸カリウム (69.1 mg) を加え0℃で撹拌した。過酸化水素水 (0.5 mL) を加えた後、室温で30分間撹拌し、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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して、標題化合物 (156 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.45 (3H, s), 4.20 (2H, s), 5.27-6.47 (2H, m), 7.41-7.59 (3H, m), 7.59-7.68 (3H, m), 7.81-7.92 (2H, m).
MS (ESI+): [M+H]+361.22. I) 4- {4-Methyl-2- [3- (trifluoromethyl) benzyl] -1,3-oxazol-5-yl} benzamide 4- {4-methyl-2 synthesized in Example 76-H) To a DMSO solution (10 mL) of-[3- (trifluoromethyl) benzyl] -1,3-oxazol-5-yl} benzonitrile (342 mg) was added potassium carbonate (69.1 mg), and the mixture was stirred at 0 ° C. Aqueous hydrogen peroxide (0.5 mL) was added, and the mixture was stirred at room temperature for 30 min and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (156 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.45 (3H, s), 4.20 (2H, s), 5.27-6.47 (2H, m), 7.41-7.59 (3H, m), 7.59-7.68 (3H, m ), 7.81-7.92 (2H, m).
MS (ESI +): [M + H] + 361.22.
実施例77
(4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルフェニル)(4-メチルピペラジン-1-イル)メタノン塩酸塩 Example 77
(4- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylphenyl) (4-methylpiperazin-1-yl) methanone Hydrochloride
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、1-メチルピペラジン (51 mg) 、HOBt (94 mg) およびWSC (117 mg)のDMF溶液(5 mL) を室温で18時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (メタノール/酢酸エチル) で精製して(4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルフェニル)(4-メチルピペラジン-1-イル)メタノン (158 mg) を得た。得られた化合物の酢酸エチル (1 mL) 溶液に4N塩酸酢酸エチル溶液（2.50 mL）を加え、室温で30分攪拌した。溶媒を減圧下留去後、得られた固体を酢酸エチル－イソプロピルエーテルから再結晶して標題化合物 (143 mg) を得た。
MS (ESI+): [M-HCl+H]+ 475.5.
1H NMR (300 MHz, CDCl3) δ 2.29 (3H, s), 2.77 (3H, d, J = 4.5 Hz), 2.98-3.16 (2H, m), 3.25-3.38 (2H, m), 3.83 (3H, s), 4.04 (2H, s), 4.43 (4H, bs), 6.31 (1H, s), 7.27-7.59 (6H, m), 11.26-11.51 (1H, m). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 1-methylpiperazine (51 mg ), HOBt (94 mg) and WSC (117 mg) in DMF (5 mL) were stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give (4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl)- 2-Methylphenyl) (4-methylpiperazin-1-yl) methanone (158 mg) was obtained. To a solution of the obtained compound in ethyl acetate (1 mL) was added 4N hydrochloric acid ethyl acetate solution (2.50 mL), and the mixture was stirred at room temperature for 30 min. After evaporating the solvent under reduced pressure, the obtained solid was recrystallized from ethyl acetate-isopropyl ether to obtain the title compound (143 mg).
MS (ESI +): [M-HCl + H] + 475.5.
1 H NMR (300 MHz, CDCl 3 ) δ 2.29 (3H, s), 2.77 (3H, d, J = 4.5 Hz), 2.98-3.16 (2H, m), 3.25-3.38 (2H, m), 3.83 ( 3H, s), 4.04 (2H, s), 4.43 (4H, bs), 6.31 (1H, s), 7.27-7.59 (6H, m), 11.26-11.51 (1H, m).
実施例78
(4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルフェニル)(4-(2-ヒドロキシエチル)ピペラジン-1-イル)メタノン塩酸塩 Example 78
(4- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylphenyl) (4- (2-hydroxyethyl) piperazine- 1-yl) methanone hydrochloride
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、2-(ピペラジン-1-イル)エタノール (66 mg) 、HOBt (94 mg) およびWSC (117 mg)のDMF溶液 (5 mL) を室温で18時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (メタノール/酢酸エチル) で精製して((4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルフェニル)(4-(2-ヒドロキシエチル)ピペラジン-1-イル)メタノン (111 mg) を得た。得られた化合物の酢酸エチル (0.5 mL) 溶液に4N塩酸酢酸エチル溶液（1.65 mL）を加え、室温で30分攪拌した。溶媒を減圧下留去後、得られた固体を酢酸エチル－イソプロピルエーテルから再結晶して標題化合物 (47 mg) を得た。
MS (ESI+): [M-HCl+H]+ 505.5.
1H NMR (300 MHz, CDCl3) δ 2.29 (3H, s), 3.15-3.80 (13H, m), 3.83 (3H, s), 4.04 (2H, m), 6.31 (1H, s), 7.28-7.59 (6H, m), 10.52-10.75 (1H, m). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 2- (piperazine-1- Yl) A DMF solution (5 mL) of ethanol (66 mg), HOBt (94 mg) and WSC (117 mg) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) ((4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) 2-methylphenyl) (4- (2-hydroxyethyl) piperazin-1-yl) methanone (111 mg) was obtained, and 4N hydrochloric acid ethyl acetate solution (1.65) was added to the ethyl acetate (0.5 mL) solution of the obtained compound. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethyl acetate-isopropyl ether to obtain the title compound (47 mg).
MS (ESI +): [M-HCl + H] + 505.5.
1 H NMR (300 MHz, CDCl 3 ) δ 2.29 (3H, s), 3.15-3.80 (13H, m), 3.83 (3H, s), 4.04 (2H, m), 6.31 (1H, s), 7.28- 7.59 (6H, m), 10.52-10.75 (1H, m).
実施例79
1-アセチル-4-[(4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルフェニル)カルボニル]ピペラジン Example 79
1-acetyl-4-[(4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylphenyl) carbonyl] piperazine
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、1-アセチルピペラジン (78 mg) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液(3.4 mL) を室温で一晩、50℃で4.5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、メタノール/酢酸エチル) で精製して標題化合物 (197.7 mg) を得た。
MS (ESI+): [M+H]+ 503.27.
1H NMR (300 MHz, CDCl3) δ 2.06-2.20 (3H, m), 2.36 (3H, s), 3.17-3.46 (3H, m), 3.48-3.63 (2H, m), 3.66-3.92 (6H, m), 4.04 (2H, s), 6.07 (1H, s), 7.13-7.32 (5H, m), 7.33-7.42 (1H, m). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 1-acetylpiperazine (78 mg ), HOBt (83 mg) and WSC (117 mg) in DMF (3.4 mL) were stirred at room temperature overnight and at 50 ° C. for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (197.7 mg).
MS (ESI +): [M + H] + 503.27.
1 H NMR (300 MHz, CDCl 3 ) δ 2.06-2.20 (3H, m), 2.36 (3H, s), 3.17-3.46 (3H, m), 3.48-3.63 (2H, m), 3.66-3.92 (6H , m), 4.04 (2H, s), 6.07 (1H, s), 7.13-7.32 (5H, m), 7.33-7.42 (1H, m).
実施例80
4-[(4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルフェニル)カルボニル]ピペラジン-2-オン Example 80
4-[(4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylphenyl) carbonyl] piperazin-2-one
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、ピペラジン-2-オン (61.2 mg) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液(3.4 mL) を室温で一晩、50℃で4.5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、メタノール/酢酸エチル) で精製して標題化合物 (194.6 mg) を得た。
MS (ESI+): [M+H]+ 475.22.
1H NMR (300 MHz, CDCl3) δ 2.27-2.42 (3H, m), 3.28-3.61 (3H, m), 3.86 (3H, s), 3.90-3.98 (1H, m), 3.99-4.07 (3H, m), 4.30-4.64 (1H, m), 6.00-6.23 (2H, m), 7.12-7.33 (5H, m), 7.34-7.42 (1H, m). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), piperazin-2-one (61.2 mg), HOBt (83 mg) and WSC (117 mg) in DMF (3.4 mL) were stirred at room temperature overnight and at 50 ° C. for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (194.6 mg).
MS (ESI +): [M + H] + 475.22.
1 H NMR (300 MHz, CDCl 3 ) δ 2.27-2.42 (3H, m), 3.28-3.61 (3H, m), 3.86 (3H, s), 3.90-3.98 (1H, m), 3.99-4.07 (3H , m), 4.30-4.64 (1H, m), 6.00-6.23 (2H, m), 7.12-7.33 (5H, m), 7.34-7.42 (1H, m).
実施例81
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-(3-ヒドロキシプロピル)-2-メチルベンズアミド Example 81
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- (3-hydroxypropyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、3-アミノプロパン-1-オール (47 μL) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液(3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (211.5 mg) を得た。
MS (ESI+): [M+H]+ 450.42.
1H NMR (300 MHz, CDCl3) δ 1.74-1.89 (2H, m), 2.50 (3H, s), 2.95 (1H, t, J = 6.0 Hz), 3.59-3.69 (2H, m), 3.72-3.81 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.07 (1H, s), 6.15-6.34 (1H, m), 7.12-7.31 (4H, m), 7.34-7.39 (1H, m), 7.45 (1H, d, J = 7.9 Hz). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 3-aminopropane-1- A DMF solution (3.4 mL) of oar (47 μL), HOBt (83 mg) and WSC (117 mg) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (211.5 mg).
MS (ESI +): [M + H] + 450.42.
1 H NMR (300 MHz, CDCl 3 ) δ 1.74-1.89 (2H, m), 2.50 (3H, s), 2.95 (1H, t, J = 6.0 Hz), 3.59-3.69 (2H, m), 3.72- 3.81 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 6.07 (1H, s), 6.15-6.34 (1H, m), 7.12-7.31 (4H, m), 7.34-7.39 ( 1H, m), 7.45 (1H, d, J = 7.9 Hz).
実施例82
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N,2-ジメチルベンズアミド Example 82
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N, 2-dimethylbenzamide
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
A)1-{[(4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルフェニル)カルボニル]オキシ}-1H-ベンゾトリアゾール
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸 (210 mg) 、メタンアミンの2M THF溶液 (321 μL) 、HOBt (87 mg) およびWSC (123 mg)のDMF溶液(3.4 mL) を室温で一晩撹拌した。メタンアミンの2M THF溶液 (80 μL) を加え、室温で更に一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (180 mg) を得た。
MS (ESI+): [M+H]+ 510.25.
1H NMR (300 MHz, CDCl3) δ 2.73 (3H, s), 3.95 (3H, s), 4.07 (2H, s), 6.21 (1H, s), 7.15-7.31 (2H, m), 7.35-7.41 (1H, m), 7.42-7.53 (4H, m), 7.54-7.64 (1H, m), 8.13 (1H, d, J = 8.3 Hz), 8.44 (1H, d, J = 7.9 Hz). A) 1-{[(4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylphenyl) carbonyl] oxy}- 1H-benzotriazole 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (210 mg), 2M of methanamine A DMF solution (3.4 mL) of THF solution (321 μL), HOBt (87 mg) and WSC (123 mg) was stirred overnight at room temperature. Methanolamine in 2M THF (80 μL) was added, and the mixture was further stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (180 mg).
MS (ESI +): [M + H] + 510.25.
1 H NMR (300 MHz, CDCl 3 ) δ 2.73 (3H, s), 3.95 (3H, s), 4.07 (2H, s), 6.21 (1H, s), 7.15-7.31 (2H, m), 7.35- 7.41 (1H, m), 7.42-7.53 (4H, m), 7.54-7.64 (1H, m), 8.13 (1H, d, J = 8.3 Hz), 8.44 (1H, d, J = 7.9 Hz).
B)4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N,2-ジメチルベンズアミド
　1-{[(4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルフェニル)カルボニル]オキシ}-1H-ベンゾトリアゾール(177 mg) およびメタンアミンの2M THF溶液 (3 mL) を50℃で4.5時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製後、ヘキサン－酢酸エチルから再結晶して標題化合物 (118 mg) を得た。
MS (ESI+): [M+H]+ 406.42.
1H NMR (300 MHz, CDCl3) δ 2.49 (3H, s), 3.02 (3H, d, J = 4.5 Hz), 3.85 (3H, s), 4.03 (2H, s), 5.69-5.88 (1H, m), 6.06 (1H, s), 7.13-7.30 (4H, m), 7.34-7.39 (1H, m), 7.42 (1H, d, J = 8.0 Hz). B) 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N, 2-dimethylbenzamide 1-{[(4- {3 -[3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylphenyl) carbonyl] oxy} -1H-benzotriazole (177 mg) and methanamine 2M THF solution (3 mL) was stirred at 50 ° C. for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and recrystallized from hexane-ethyl acetate to give the title compound (118 mg).
MS (ESI +): [M + H] + 406.42.
1 H NMR (300 MHz, CDCl 3 ) δ 2.49 (3H, s), 3.02 (3H, d, J = 4.5 Hz), 3.85 (3H, s), 4.03 (2H, s), 5.69-5.88 (1H, m), 6.06 (1H, s), 7.13-7.30 (4H, m), 7.34-7.39 (1H, m), 7.42 (1H, d, J = 8.0 Hz).
実施例83
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-(4-ヒドロキシブチル)-2-メチルベンズアミド Example 83
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- (4-hydroxybutyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、4-アミノブタン-1-オール (56 μL) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液(3.4 mL) を室温で4日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (212.5 mg) を得た。
MS (ESI+): [M+H]+ 464.25.
1H NMR (300 MHz, CDCl3) δ 1.60-1.81 (5H, m), 2.49 (3H, s), 3.44-3.57 (2H, m), 3.68-3.79 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 5.94-6.15 (2H, m), 7.13-7.31 (4H, m), 7.33-7.39 (1H, m), 7.42 (1H, d, J = 7.9 Hz). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 4-aminobutan-1-ol (56 μL), HOBt (83 mg) and WSC (117 mg) in DMF (3.4 mL) were stirred at room temperature for 4 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (212.5 mg).
MS (ESI +): [M + H] + 464.25.
1 H NMR (300 MHz, CDCl 3 ) δ 1.60-1.81 (5H, m), 2.49 (3H, s), 3.44-3.57 (2H, m), 3.68-3.79 (2H, m), 3.85 (3H, s ), 4.03 (2H, s), 5.94-6.15 (2H, m), 7.13-7.31 (4H, m), 7.33-7.39 (1H, m), 7.42 (1H, d, J = 7.9 Hz).
実施例84
N-(2,3-ジヒドロキシプロピル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 84
N- (2,3-dihydroxypropyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、3-アミノプロパン-1,2-ジオール (47 μL) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液(3.4 mL) を室温で4日間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (212.1 mg) を得た。
MS (ESI+): [M+H]+ 466.22.
1H NMR (300 MHz, CDCl3) δ 1.60-1.81 (5H, m), 2.49 (3H, s), 3.44-3.57 (2H, m), 3.68-3.79 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 5.94-6.15 (2H, m), 7.13-7.31 (4H, m), 7.33-7.39 (1H, m), 7.42 (1H, d, J = 7.9 Hz). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 3-aminopropane-1, A solution of 2-diol (47 μL), HOBt (83 mg) and WSC (117 mg) in DMF (3.4 mL) was stirred at room temperature for 4 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (212.1 mg).
MS (ESI +): [M + H] + 466.22.
1 H NMR (300 MHz, CDCl 3 ) δ 1.60-1.81 (5H, m), 2.49 (3H, s), 3.44-3.57 (2H, m), 3.68-3.79 (2H, m), 3.85 (3H, s ), 4.03 (2H, s), 5.94-6.15 (2H, m), 7.13-7.31 (4H, m), 7.33-7.39 (1H, m), 7.42 (1H, d, J = 7.9 Hz).
実施例85
N-(3-アミノ-3-オキソプロピル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 85
N- (3-amino-3-oxopropyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、beta-アラニンアミド塩酸塩 (76 mg) 、HOBt (83 mg) 、WSC (117 mg) およびトリエチルアミン (85 μL)のDMF溶液 (3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (197.5 mg) を得た。
MS (ESI+): [M+H]+ 463.18.
1H NMR (300 MHz, CDCl3) δ 2.48 (3H, s), 2.56-2.67 (2H, m), 3.66-3.80 (2H, m), 3.84 (3H, s), 4.03 (2H, s), 5.28-5.54 (1H, m), 5.59-5.85 (1H, m), 6.07 (1H, s), 6.61-6.78 (1H, m), 7.13-7.31 (4H, m), 7.33-7.40 (1H, m), 7.43 (1H, d, J = 7.9 Hz). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), beta-alaninamide hydrochloride ( 76 mg), HOBt (83 mg), WSC (117 mg) and triethylamine (85 μL) in DMF (3.4 mL) were stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (197.5 mg).
MS (ESI +): [M + H] + 463.18.
1 H NMR (300 MHz, CDCl 3 ) δ 2.48 (3H, s), 2.56-2.67 (2H, m), 3.66-3.80 (2H, m), 3.84 (3H, s), 4.03 (2H, s), 5.28-5.54 (1H, m), 5.59-5.85 (1H, m), 6.07 (1H, s), 6.61-6.78 (1H, m), 7.13-7.31 (4H, m), 7.33-7.40 (1H, m ), 7.43 (1H, d, J = 7.9 Hz).
実施例86
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(1H-1,2,4-トリアゾール-1-イル)エチル]ベンズアミド Example 86
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (1H-1,2,4 -Triazol-1-yl) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、2-(1H-1,2,4-トリアゾール-1-イル)エタンアミン二塩酸塩(113 mg) 、HOBt (83 mg) 、WSC (117 mg) およびトリエチルアミン (171 μL)のDMF溶液 (3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (233.5 mg) を得た。
MS (ESI+): [M+H]+ 487.10.
1H NMR (300 MHz, CDCl3) δ 2.46 (3H, s), 3.85 (3H, s), 3.88-3.99 (2H, m), 4.03 (2H, s), 4.41-4.54 (2H, m), 6.07 (1H, s), 6.26-6.47 (1H, m), 7.12-7.32 (4H, m), 7.32-7.43 (2H, m), 7.98 (1H, s), 8.12 (1H, s). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 2- (1H-1, 2,4-triazol-1-yl) ethanamine dihydrochloride (113 mg), HOBt (83 mg), WSC (117 mg) and triethylamine (171 μL) in DMF (3.4 mL) were stirred at room temperature overnight. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (233.5 mg).
MS (ESI +): [M + H] + 487.10.
1 H NMR (300 MHz, CDCl 3 ) δ 2.46 (3H, s), 3.85 (3H, s), 3.88-3.99 (2H, m), 4.03 (2H, s), 4.41-4.54 (2H, m), 6.07 (1H, s), 6.26-6.47 (1H, m), 7.12-7.32 (4H, m), 7.32-7.43 (2H, m), 7.98 (1H, s), 8.12 (1H, s).
実施例87
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル-N-[2-(2-オキソイミダゾリジン-1-イル)エチル]ベンズアミド Example 87
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methyl-N- [2- (2-oxoimidazolidine-1 -Il) ethyl] benzamide
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、1-(2-アミノエチル)イミダゾリジン-2-オン (79 mg) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液 (3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (242.9 mg) を得た。
MS (ESI+): [M+H]+ 504.13.
1H NMR (300 MHz, CDCl3) δ 2.49 (3H, s), 3.38-3.53 (4H, m), 3.53-3.69 (4H, m), 3.84 (3H, s), 4.03 (2H, s), 4.28-4.42 (1H, m), 6.06 (1H, s), 6.61-6.80 (1H, m), 7.13-7.25 (4H, m), 7.34-7.40 (1H, m), 7.45-7.52 (1H, m). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 1- (2-aminoethyl ) A DMF solution (3.4 mL) of imidazolidin-2-one (79 mg), HOBt (83 mg) and WSC (117 mg) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (242.9 mg).
MS (ESI +): [M + H] + 504.13.
1 H NMR (300 MHz, CDCl 3 ) δ 2.49 (3H, s), 3.38-3.53 (4H, m), 3.53-3.69 (4H, m), 3.84 (3H, s), 4.03 (2H, s), 4.28-4.42 (1H, m), 6.06 (1H, s), 6.61-6.80 (1H, m), 7.13-7.25 (4H, m), 7.34-7.40 (1H, m), 7.45-7.52 (1H, m ).
実施例88
N-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 88
N-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、シクロプロパンアミン (43 μL) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液 (3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製後、ヘキサン－酢酸エチルから再結晶して標題化合物 (95.9 mg) を得た。
MS (ESI+): [M+H]+ 432.18.
1H NMR (300 MHz, CDCl3) δ 0.56-0.67 (2H, m), 0.83-0.96 (2H, m), 2.48 (3H, s), 2.86-2.98 (1H, m), 3.84 (3H, s), 4.03 (2H, s), 5.80-5.98 (1H, m), 6.06 (1H, s), 7.13-7.31 (4H, m), 7.33-7.43 (2H, m). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), cyclopropanamine (43 μL) , HOBt (83 mg) and WSC (117 mg) in DMF (3.4 mL) were stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate), and recrystallized from hexane-ethyl acetate to give the title compound (95.9 mg).
MS (ESI +): [M + H] + 432.18.
1 H NMR (300 MHz, CDCl 3 ) δ 0.56-0.67 (2H, m), 0.83-0.96 (2H, m), 2.48 (3H, s), 2.86-2.98 (1H, m), 3.84 (3H, s ), 4.03 (2H, s), 5.80-5.98 (1H, m), 6.06 (1H, s), 7.13-7.31 (4H, m), 7.33-7.43 (2H, m).
実施例89
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-N-(2-ヒドロキシ-2-メチルプロピル)-2-メチルベンズアミド Example 89
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -N- (2-hydroxy-2-methylpropyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155
　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg) 、1-アミノ-2-メチルプロパン-2-オール (54.5 mg) 、HOBt (83 mg) およびWSC (117 mg)のDMF溶液 (3.4 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (154.9 mg) を得た。
MS (ESI+): [M+H]+ 464.2.
1H NMR (300 MHz, CDCl3) δ 1.32 (6H, s), 2.01 (1H, brs), 2.51 (3H, s), 3.49 (2H, d, J = 6.0 Hz), 3.85 (3H, s), 4.04 (2H, s), 6.07 (1H, s), 6.17-6.31 (1H, m), 7.12-7.32 (4H, m), 7.34-7.40 (1H, m), 7.47 (1H, d, J = 7.6 Hz). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), 1-amino-2-methyl Propan-2-ol (54.5 mg), HOBt (83 mg) and WSC (117 mg) in DMF (3.4 mL) were stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (154.9 mg).
MS (ESI +): [M + H] + 464.2.
1 H NMR (300 MHz, CDCl 3 ) δ 1.32 (6H, s), 2.01 (1H, brs), 2.51 (3H, s), 3.49 (2H, d, J = 6.0 Hz), 3.85 (3H, s) , 4.04 (2H, s), 6.07 (1H, s), 6.17-6.31 (1H, m), 7.12-7.32 (4H, m), 7.34-7.40 (1H, m), 7.47 (1H, d, J = (7.6 Hz).
実施例90
N-エチル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 90
N-ethyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156
　実施例30で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg)、エチルアミン(2.0 M THF溶液、0.51 mL)、HOBt (83 mg)、WSC塩酸塩(117 mg)およびDMF(2 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製した後、酢酸エチル-ヘキサンから再結晶することにより、標題化合物(153 mg)を得た。
MS (ESI+): [M+H]+ 420.4.
1H NMR (300 MHz, CDCl3) δ 1.27 (3H, t, J = 7.2 Hz), 2.49 (3H, s), 3.45-3.56 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 5.67-5.82 (1H, m), 6.06 (1H, s), 7.14-7.28 (4H, m), 7.35-7.45 (2H, m). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (200 mg), ethylamine synthesized in Example 30 A mixture of (2.0 M THF solution, 0.51 mL), HOBt (83 mg), WSC hydrochloride (117 mg) and DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and recrystallized from ethyl acetate-hexane to give the title compound (153 mg).
MS (ESI +): [M + H] + 420.4.
1 H NMR (300 MHz, CDCl 3 ) δ 1.27 (3H, t, J = 7.2 Hz), 2.49 (3H, s), 3.45-3.56 (2H, m), 3.85 (3H, s), 4.03 (2H, s), 5.67-5.82 (1H, m), 6.06 (1H, s), 7.14-7.28 (4H, m), 7.35-7.45 (2H, m).
実施例91
メチル 2-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルピリミジン-5-カルボキシラート Example 91
Methyl 2- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylpyrimidine-5-carboxylate
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157
A) メチル 2-クロロ-4-メチルピリミジン-5-カルボキシラート
　2-クロロ-4-メチルピリミジン-5-カルボン酸(2.00 g)のトルエン/メタノール溶液(1/1、10 mL)へ2 Nトリメチルシリルジアゾメタン‐ジエチルエーテル溶液(12 mL)を0 ℃で加えた。室温で1時間撹拌した後に、反応混合物へ酢酸を0 ℃で加えた。室温へ戻した後、反応混合物へ水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し標題化合物(1.29 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.84 (3H, s), 3.97 (3H, s), 9.03 (1H, s).
MS (ESI+): [M+H]+ 187.0. A) Methyl 2-chloro-4-methylpyrimidine-5-carboxylate 2 N trimethylsilyl to 2-chloro-4-methylpyrimidine-5-carboxylic acid (2.00 g) in toluene / methanol solution (1/1, 10 mL) Diazomethane-diethyl ether solution (12 mL) was added at 0 ° C. After stirring at room temperature for 1 hour, acetic acid was added to the reaction mixture at 0 ° C. After returning to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.29 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.84 (3H, s), 3.97 (3H, s), 9.03 (1H, s).
MS (ESI +): [M + H] + 187.0.
B) メチル 2-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルピリミジン-5-カルボキシラート
　実施例71と同様の方法で合成した3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-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(1.42 g)、実施例91-A)で得られたメチル 2-クロロ-4-メチルピリミジン-5-カルボキシラート(0.689 g)、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) (0.151 g)、リン酸三カリウム (1.57 g)のNMP溶液 (10 mL)をアルゴン雰囲気下70 ℃で終夜加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (0.87 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.86 (3H, s), 3.96 (3H, s), 4.06 (2H, s), 4.35 (3H, s), 6.92 (1H, s), 7.10-7.24 (2H, m), 7.36 (1H, s), 9.16 (1H, s).
MS (ESI+): [M+H]+ 409.1. B) Methyl 2- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylpyrimidine-5-carboxylate as in Example 71 3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) -1H-pyrazole (1.42 g), methyl 2-chloro-4-methylpyrimidine-5-carboxylate (0.689 g) obtained in Example 91-A), dichloro [1,1′-bis (diphenyl) An NMP solution (10 mL) of (phosphino) ferrocene] palladium (II) (0.151 g) and tripotassium phosphate (1.57 g) was heated and stirred at 70 ° C. overnight under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.87 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.86 (3H, s), 3.96 (3H, s), 4.06 (2H, s), 4.35 (3H, s), 6.92 (1H, s), 7.10-7.24 ( 2H, m), 7.36 (1H, s), 9.16 (1H, s).
MS (ESI +): [M + H] + 409.1.
実施例92
2-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルピリミジン-5-カルボン酸 Example 92
2- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylpyrimidine-5-carboxylic acid
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158
　実施例91で得られたメチル 2-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルピリミジン-5-カルボキシラート(0.87 g)のメタノール/THF溶液(1/1、18 mL)へ1 N水酸化ナトリウム水溶液 (3.2 mL)を加え、室温で3時間撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をジイソプロピルエーテルで洗浄し、標題化合物 (0.80 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.90 (3H, s), 4.07 (2H, s), 4.37 (3H, s), 6.95 (1H, s), 7.11-7.23 (2H, m), 7.36 (1H, s), 9.25 (1H, s), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 395.1. Methyl 2- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylpyrimidine-5-carboxylate obtained in Example 91 To a 0.88 g methanol / THF solution (1/1, 18 mL) was added 1 N aqueous sodium hydroxide solution (3.2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (0.80 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.90 (3H, s), 4.07 (2H, s), 4.37 (3H, s), 6.95 (1H, s), 7.11-7.23 (2H, m), 7.36 ( 1H, s), 9.25 (1H, s), COOH peak was not observed.
MS (ESI +): [M + H] + 395.1.
実施例93
2-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルピリミジン-5-カルボキサミド Example 93
2- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylpyrimidine-5-carboxamide
Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159
　実施例92で得られた2-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルピリミジン-5-カルボン酸(300 mg)、WSC (292 mg)、HOBtアンモニア和物(232 mg)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して、標題化合物 (220 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.76 (3H, s), 4.06 (2H, s), 4.33 (3H, s), 5.84 (2H, brs), 6.88 (1H, s), 7.18 (2H, dd, J = 8.1, 6.2 Hz), 7.36 (1H, s), 8.80 (1H, s).
MS (ESI+): [M+H]+ 394.2. 2- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylpyrimidine-5-carboxylic acid obtained in Example 92 ( 300 mg), WSC (292 mg), and HOBt ammonia hydrate (232 mg) in DMF (3 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (220 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.76 (3H, s), 4.06 (2H, s), 4.33 (3H, s), 5.84 (2H, brs), 6.88 (1H, s), 7.18 (2H, dd, J = 8.1, 6.2 Hz), 7.36 (1H, s), 8.80 (1H, s).
MS (ESI +): [M + H] + 394.2.
実施例94
エチル 6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルニコチナート Example 94
Ethyl 6- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylnicotinate
Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160
A) エチル 6-クロロ-4-メチルニコチナート
　6-クロロ-4-メチルニコチン酸(6.30 g)のエタノール溶液(122 mL)へ塩化チオニル(5.36 mL)を0 ℃で加え、50 ℃で10時間加熱撹拌した。反応混合物を減圧濃縮し、残渣を酢酸エチルで希釈し、水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製して標題化合物(4.00 g)を得た。
1H NMR (400 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 2.62 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 7.24 (1H, s), 8.86 (1H, s).
MS (ESI+): [M+H]+ 200.1. A) Ethyl 6-chloro-4-methylnicotinate Addition of thionyl chloride (5.36 mL) to ethanol solution (122 mL) of 6-chloro-4-methylnicotinic acid (6.30 g) at 0 ° C and 10 hours at 50 ° C Stir with heating. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (4.00 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 2.62 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 7.24 (1H, s), 8.86 (1H, s).
MS (ESI +): [M + H] + 200.1.
B) エチル 6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルニコチナート
　実施例71と同様の方法で合成した3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-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(1.00 g)、実施例94-A)で得られたエチル 6-クロロ-4-メチルニコチナート(0.52 g)、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)(0.106 g)、リン酸三カリウム (1.11 g)のNMP溶液 (7 mL)を窒素雰囲気下80 ℃で終夜加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (0.44 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t), 2.65 (3H, s), 4.05 (2H, s), 4.22 (3H, s), 4.41 (2H, q, J = 7.2 Hz), 6.39 (1H, s), 7.19 (2H, d, J = 8.7 Hz), 7.33-7.44 (2H, m), 9.12 (1H, s).
MS (ESI+): [M+H]+ 422.2. B) Ethyl 6- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylnicotinate Synthesized in the same manner as in Example 71 3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -Pyrazole (1.00 g), ethyl 6-chloro-4-methylnicotinate (0.52 g) obtained in Example 94-A), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II ) (0.106 g) and tripotassium phosphate (1.11 g) in NMP (7 mL) were stirred with heating at 80 ° C. overnight under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.44 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t), 2.65 (3H, s), 4.05 (2H, s), 4.22 (3H, s), 4.41 (2H, q, J = 7.2 Hz) , 6.39 (1H, s), 7.19 (2H, d, J = 8.7 Hz), 7.33-7.44 (2H, m), 9.12 (1H, s).
MS (ESI +): [M + H] + 422.2.
実施例95
6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルニコチン酸 Example 95
6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylnicotinic acid
Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161
　実施例94で得られたエチル 6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルニコチナート(0.438 g)のエタノール/THF溶液 (5/2、7 mL)へ1 N水酸化ナトリウム水溶液(1.6 mL)を加え、室温で4時間撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (0.405 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.58 (3H, s), 4.06 (2H, s), 4.12 (3H, s), 6.75 (1H, s), 7.42-7.60 (3H, m), 7.74 (1H, s), 8.98 (1H, s), 13.31 (1H, brs).
MS (ESI+): [M+H]+ 394.2. Ethyl 6- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylnicotinate (0.438 g) obtained in Example 94 1N aqueous sodium hydroxide solution (1.6 mL) was added to an ethanol / THF solution (5/2, 7 mL) and stirred at room temperature for 4 hours. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.405 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.58 (3H, s), 4.06 (2H, s), 4.12 (3H, s), 6.75 (1H, s), 7.42-7.60 (3H, m), 7.74 (1H, s), 8.98 (1H, s), 13.31 (1H, brs).
MS (ESI +): [M + H] + 394.2.
実施例96
6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルニコチンアミド Example 96
6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylnicotinamide
Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162
　実施例95で得られた6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-4-メチルニコチン酸(405 mg)、WSC (296 mg)、HOBtアンモニア和物(235 mg)のDMF溶液 (9 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘキサン)して、標題化合物 (307 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.43 (3H, s), 4.05 (2H, s), 4.10 (3H, s), 6.68 (1H, s), 7.42-7.64 (4H, m), 7.67 (1H, s), 7.97 (1H, brs), 8.60 (1H, s).
MS (ESI+): [M+H]+ 393.2. 6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -4-methylnicotinic acid (405 mg) obtained in Example 95, A DMF solution (9 mL) of WSC (296 mg) and HOBt ammonia hydrate (235 mg) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / hexane) to give the title compound (307 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.43 (3H, s), 4.05 (2H, s), 4.10 (3H, s), 6.68 (1H, s), 7.42-7.64 (4H, m), 7.67 (1H, s), 7.97 (1H, brs), 8.60 (1H, s).
MS (ESI +): [M + H] + 393.2.
実施例97
4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-3,5-ジメチルベンズアミド Example 97
4- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -3,5-dimethylbenzamide
Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163
A) 4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-3,5-ジメチルベンゾニトリル
　実施例71と同様の方法で合成した3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-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（100 mg）、4-ブロモ-3,5-ジメチルベンゾニトリル（54.7 mg）、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) (10.6 mg)、リン酸三カリウム (111 mg)のNMP溶液 (2 mL)をマイクロウェーブ照射下140 ℃で30分間加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (32 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.09 (6H, s), 3.53 (3H, s), 4.08 (2H, s), 5.92 (1H, s), 7.18 (2H, d, J = 8.7 Hz), 7.32 (1H, s), 7.42 (2H, s).
MS (ESI+): [M+H]+ 388.2. A) 4- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -3,5-dimethylbenzonitrile In the same manner as in Example 71 Synthesized 3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (100 mg), 4-bromo-3,5-dimethylbenzonitrile (54.7 mg), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (10.6 mg), phosphoric acid An NMP solution (2 mL) of tripotassium (111 mg) was heated and stirred at 140 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (32 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.09 (6H, s), 3.53 (3H, s), 4.08 (2H, s), 5.92 (1H, s), 7.18 (2H, d, J = 8.7 Hz) , 7.32 (1H, s), 7.42 (2H, s).
MS (ESI +): [M + H] + 388.2.
B) 4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-3,5-ジメチルベンズアミド
　実施例97-A)で得られた4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-3,5-ジメチルベンゾニトリル（32 mg）のDMSO溶液（1 ml)へ炭酸カリウム（22.8 mg）、30%過酸化水素水（0.169 ml）を0 ℃で加え、室温で30分間撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (19 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.10 (6H, s), 3.52 (3H, s), 4.08 (2H, s), 5.61 (1H, brs), 5.92 (1H, s), 6.06 (1H, brs), 7.18 (2H, d, J = 9.1 Hz), 7.33 (1H, s), 7.56 (2H, s).
MS (ESI+): [M+H]+ 406.2. B) 4- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -3,5-dimethylbenzamide obtained in Example 97-A) 4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -3,5-dimethylbenzonitrile (32 mg) in DMSO solution (1 ml) was added potassium carbonate (22.8 mg) and 30% hydrogen peroxide (0.169 ml) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (19 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.10 (6H, s), 3.52 (3H, s), 4.08 (2H, s), 5.61 (1H, brs), 5.92 (1H, s), 6.06 (1H, brs), 7.18 (2H, d, J = 9.1 Hz), 7.33 (1H, s), 7.56 (2H, s).
MS (ESI +): [M + H] + 406.2.
実施例98
3-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-5-メチルベンズアミド Example 98
3- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -5-methylbenzamide
Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164
A) 3-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-5-メチルベンゾニトリル
　実施例71と同様の方法で合成した3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-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（1000 mg）、3-ブロモ-5-メチルベンゾニトリル（510 mg）、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) (106 mg)、リン酸三カリウム (1105 mg)のNMP溶液 (6 mL)をアルゴン雰囲気下80 ℃で終夜加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (507 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.45 (3H, s), 3.86 (3H, s), 4.03 (2H, s), 6.09 (1H, s), 7.19 (2H, d, J = 8.7 Hz), 7.36 (1H, s), 7.43 (1H, s), 7.50 (2H, s).
MS (ESI+): [M+H]+ 374.2. A) 3- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -5-methylbenzonitrile Synthesized in the same manner as in Example 71 3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- Pyrazole (1000 mg), 3-bromo-5-methylbenzonitrile (510 mg), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (106 mg), tripotassium phosphate (1105 mg) of NMP (6 mL) was stirred with heating at 80 ° C. overnight under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (507 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.45 (3H, s), 3.86 (3H, s), 4.03 (2H, s), 6.09 (1H, s), 7.19 (2H, d, J = 8.7 Hz) , 7.36 (1H, s), 7.43 (1H, s), 7.50 (2H, s).
MS (ESI +): [M + H] + 374.2.
B) 3-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-5-メチルベンズアミド
　実施例98-A)で得られた3-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-5-メチルベンゾニトリル（500 mg）のDMSO/水溶液（20/1、14.7 ml)へ炭酸カリウム（370 mg）、30%過酸化水素水（2.74 ml）を0 ℃で加え、室温で90分間撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (340 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.40 (3H, s), 3.81 (3H, s), 4.04 (2H, s), 6.31 (1H, s), 7.34-7.61 (5H, m), 7.70-7.84 (2H, m), 8.00 (1H, brs).
MS (ESI+): [M+H]+ 392.2. B) 3- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -5-methylbenzamide 3 obtained in Example 98-A) -(3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -5-methylbenzonitrile (500 mg) in DMSO / water solution (20/1, To 14.7 ml), potassium carbonate (370 mg) and 30% aqueous hydrogen peroxide (2.74 ml) were added at 0 ° C., followed by stirring at room temperature for 90 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (340 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.40 (3H, s), 3.81 (3H, s), 4.04 (2H, s), 6.31 (1H, s), 7.34-7.61 (5H, m), 7.70-7.84 (2H, m), 8.00 (1H, brs).
MS (ESI +): [M + H] + 392.2.
実施例99
メチル 2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾアート Example 99
Methyl 2- (dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoate
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165
A) メチル 4-ブロモ-2-(ジメチルアミノ)ベンゾアート
　メチル 2-アミノ-4-ブロモベンゾアート(5 g)、ヨウ化メチル(4.06 mL)、炭酸水素ナトリウム(9.13 g)およびメタノール(20 mL)の混合物を一晩加熱還流した。反応混合物を酢酸エチルで希釈し、不溶の固体をろ過して除去した。ろ液を減圧濃縮して得られた残渣をTHF(20 mL)に溶解させ0℃に冷却した後、水素化ナトリウム(60%, 1.30 g)をゆっくり加えた。反応混合物を室温まで昇温し、30分間撹拌した。ヨウ化メチル(4.06 mL)を加え、さらに一晩撹拌した。反応混合物を酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮することにより、標題化合物(4.80 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.86 (6H, s), 3.89 (3H, s), 6.94 (1H, dd, J = 8.3, 1.9 Hz), 7.06 (1H, d, J = 1.9 Hz), 7.52 (1H, d, J = 8.3 Hz). A) Methyl 4-bromo-2- (dimethylamino) benzoate Methyl 2-amino-4-bromobenzoate (5 g), methyl iodide (4.06 mL), sodium bicarbonate (9.13 g) and methanol (20 mL) ) Was heated to reflux overnight. The reaction mixture was diluted with ethyl acetate and the insoluble solid was removed by filtration. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in THF (20 mL) and cooled to 0 ° C., and then sodium hydride (60%, 1.30 g) was slowly added. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Methyl iodide (4.06 mL) was added and further stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (4.80 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.86 (6H, s), 3.89 (3H, s), 6.94 (1H, dd, J = 8.3, 1.9 Hz), 7.06 (1H, d, J = 1.9 Hz) , 7.52 (1H, d, J = 8.3 Hz).
B) メチル 2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾアート
　実施例29-B)と同様にして、実施例99-A)で合成したメチル 4-ブロモ-2-(ジメチルアミノ)ベンゾアートを用いてメチル 2-(ジメチルアミノ)-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアートを合成した。次に、実施例29-F)と同様にして、実施例29－E)で合成した3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナートおよびメチル 2-(ジメチルアミノ)-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアートを用いて標題化合物を合成した。
MS (ESI+): [M+H]+ 436.2.
1H NMR (300 MHz, CDCl3) δ 2.90 (6H, s), 3.87 (3H, s), 3.93 (3H, s), 4.04 (2H, s), 6.10 (1H, s), 6.84 (1H, dd, J = 7.9, 1.5 Hz), 6.90 (1H, d, J = 1.5 Hz), 7.14-7.24 (2H, m), 7.36-7.40 (1H, m), 7.72 (1H, d, J = 7.9 Hz). B) Methyl 2- (dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoate Example 29-B) In the same manner as in Example 99-A), using methyl 4-bromo-2- (dimethylamino) benzoate, methyl 2- (dimethylamino) -4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) benzoate was synthesized. Next, in the same manner as in Example 29-F), 3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazole-5- synthesized in Example 29-E) The title compound was synthesized using yl trifluoromethanesulfonate and methyl 2- (dimethylamino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate .
MS (ESI +): [M + H] + 436.2.
1 H NMR (300 MHz, CDCl 3 ) δ 2.90 (6H, s), 3.87 (3H, s), 3.93 (3H, s), 4.04 (2H, s), 6.10 (1H, s), 6.84 (1H, dd, J = 7.9, 1.5 Hz), 6.90 (1H, d, J = 1.5 Hz), 7.14-7.24 (2H, m), 7.36-7.40 (1H, m), 7.72 (1H, d, J = 7.9 Hz ).
実施例100
2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸 Example 100
2- (Dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid
Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166
　実施例30と同様にして、実施例99で合成したメチル 2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾアートを用いて標題化合物を合成した。
MS (ESI+): [M+H]+ 422.3.
1H NMR (300 MHz, CDCl3) δ 2.86 (6H, s), 3.90 (3H, s), 4.05 (2H, s), 6.15 (1H, s), 7.16-7.24 (2H, m), 7.35-7.40 (1H, m), 7.42-7.47 (2H, m), 8.37 (1H, d, J = 8.3 Hz), COOHピークは観測されなかった. Methyl 2- (dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazole- synthesized in Example 99 in the same manner as in Example 30 The title compound was synthesized using 5-yl} benzoate.
MS (ESI +): [M + H] + 422.3.
1 H NMR (300 MHz, CDCl 3 ) δ 2.86 (6H, s), 3.90 (3H, s), 4.05 (2H, s), 6.15 (1H, s), 7.16-7.24 (2H, m), 7.35- 7.40 (1H, m), 7.42-7.47 (2H, m), 8.37 (1H, d, J = 8.3 Hz), no COOH peak was observed.
実施例101
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-(メチルアミノ)ベンズアミド Example 101
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2- (methylamino) benzamide
Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167
実施例102
2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 102
2- (Dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168
　実施例100で合成した2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}安息香酸(200 mg)、HOBtアンモニア和物(79 mg)、WSC塩酸塩(100 mg)およびDMF(2 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製した後、酢酸エチル-ヘキサンから再結晶することにより、4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-(メチルアミノ)ベンズアミド(57 mg)および2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド(21 mg)を得た。
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-(メチルアミノ)ベンズアミド(実施例101)
MS (ESI+): [M+H]+ 407.3.
1H NMR (300 MHz, CDCl3) δ 2.89 (3H, d, J = 5.3 Hz), 3.89 (3H, s), 4.04 (2H, s), 5.68 (2H, brs), 6.11 (1H, s), 6.59 (1H, dd, J = 8.3, 1.5 Hz), 6.65 (1H, d, J = 1.5 Hz), 7.13-7.25 (2H, m), 7.36-7.45 (2H, m), 7.82-7.96 (1H, m).
2-(ジメチルアミノ)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド(実施例102)
MS (ESI+): [M+H]+ 421.4.
1H NMR (300 MHz, CDCl3) δ 2.80 (6H, s), 3.89 (3H, s), 4.04 (2H, s), 5.77 (1H, brs), 6.12 (1H, s), 7.15-7.24 (4H, m), 7.36-7.40 (1H, m), 8.18 (1H, d, J = 8.3 Hz), 9.16 (1H, brs). 2- (Dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzoic acid (200 mg) synthesized in Example 100 ), HOBt ammonia solvate (79 mg), WSC hydrochloride (100 mg) and DMF (2 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then recrystallized from ethyl acetate-hexane to give 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl]. -1-methyl-1H-pyrazol-5-yl} -2- (methylamino) benzamide (57 mg) and 2- (dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) [Benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide (21 mg) was obtained.
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2- (methylamino) benzamide (Example 101)
MS (ESI +): [M + H] + 407.3.
1 H NMR (300 MHz, CDCl 3 ) δ 2.89 (3H, d, J = 5.3 Hz), 3.89 (3H, s), 4.04 (2H, s), 5.68 (2H, brs), 6.11 (1H, s) , 6.59 (1H, dd, J = 8.3, 1.5 Hz), 6.65 (1H, d, J = 1.5 Hz), 7.13-7.25 (2H, m), 7.36-7.45 (2H, m), 7.82-7.96 (1H , m).
2- (Dimethylamino) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide (Example 102)
MS (ESI +): [M + H] + 421.4.
1 H NMR (300 MHz, CDCl 3 ) δ 2.80 (6H, s), 3.89 (3H, s), 4.04 (2H, s), 5.77 (1H, brs), 6.12 (1H, s), 7.15-7.24 ( 4H, m), 7.36-7.40 (1H, m), 8.18 (1H, d, J = 8.3 Hz), 9.16 (1H, brs).
実施例103
2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド Example 103
2- (Difluoromethyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169
A) 2-(ベンジルオキシ)-5-ブロモベンズアルデヒド
　5-ブロモ-2-ヒドロキシベンズアルデヒド (4.02 g)、炭酸カリウム (4.15g) のDMF懸濁液 (40 mL)に臭化ベンジル (2.85 mL) を加え、70℃で4時間撹拌した。反応混合物に水を加え、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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (5.80 g) を得た。
1H NMR (300 MHz, CDCl3) δ5.18 (2 H, s), 6.95 (1 H, d, J = 9.09 Hz), 7.31 - 7.46 (5 H, m), 7.60 (1 H, dd, J= 8.71, 2.65 Hz), 7.94 (1 H, d, J= 2.65 Hz), 10.46 (1 H, s). A) Add benzyl bromide (2.85 mL) to a DMF suspension (40 mL) of 2- (benzyloxy) -5-bromobenzaldehyde 5-bromo-2-hydroxybenzaldehyde (4.02 g) and potassium carbonate (4.15 g). In addition, the mixture was stirred at 70 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (5.80 g).
1 H NMR (300 MHz, CDCl 3 ) δ5.18 (2 H, s), 6.95 (1 H, d, J = 9.09 Hz), 7.31-7.46 (5 H, m), 7.60 (1 H, dd, J = 8.71, 2.65 Hz), 7.94 (1 H, d, J = 2.65 Hz), 10.46 (1 H, s).
B) 1-(ベンジルオキシ)-4-ブロモ-2-(ジフルオロメチル)ベンゼン
　2-(ベンジルオキシ)-5-ブロモベンズアルデヒド (4.24 g) のトルエン溶液 (100 mL) に三フッ化N,N-ジエチルアミノ硫黄 (3.46 mL) を加え、60 ℃で16時間撹拌した。室温に冷却した後、反応混合物に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (3.70 g) を得た。
1H NMR (300 MHz, CDCl3) δ 5.11 (2H, s), 6.74-7.15 (2H, m), 7.30-7.43 (5H, m), 7.46-7.52 (1H, m), 7.67-7.70 (1H, m). B) 1- (Benzyloxy) -4-bromo-2- (difluoromethyl) benzene 2- (benzyloxy) -5-bromobenzaldehyde (4.24 g) in toluene solution (100 mL) Diethylaminosulfur (3.46 mL) was added, and the mixture was stirred at 60 ° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.70 g).
1 H NMR (300 MHz, CDCl 3 ) δ 5.11 (2H, s), 6.74-7.15 (2H, m), 7.30-7.43 (5H, m), 7.46-7.52 (1H, m), 7.67-7.70 (1H , m).
C) 5-[4-(ベンジルオキシ)-3-(ジフルオロメチル)フェニル]-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール
　1-(ベンジルオキシ)-4-ブロモ-2-(ジフルオロメチル)ベンゼン (3.70 g) 、4,4,4',4',5,5,5',5'-オクタメチル-2,2'-ビ-1,3,2-ジオキサボロラン (3.00 g) 、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) (468 mg) 、酢酸カリウム (3.48 g) のDMF溶液 (50 mL) をアルゴン気流下、85℃で15時間撹拌した。反応混合物に水を加えセライトろ過した後、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた粗生成物、3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート (4.00 g) 、ジクロロビス(トリフェニルホスフィン)パラジウム(II) (691 mg) 、および炭酸カリウム (4.08 g) の1,2-ジメトキシエタン－水混合溶液 (3：1、40 mL) をアルゴン気流下、85℃で4時間半撹拌した後、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (4.32 g) を得た。
MS (ESI+): [M+H]+ 491.4
1H NMR (300 MHz, CDCl3) δ 3.84 (3H, s), 4.03 (2H, s), 5.18 (2H, s), 6.04 (1H, s), 6.83-7.23 (4H, m), 7.32-7.47 (7H, m), 7.59-7.63 (1H, m). C) 5- [4- (Benzyloxy) -3- (difluoromethyl) phenyl] -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazole 1- (benzyloxy ) -4-Bromo-2- (difluoromethyl) benzene (3.70 g), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3 , 2-dioxaborolane (3.00 g), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (468 mg), potassium acetate (3.48 g) in DMF (50 mL) under an argon stream And stirred at 85 ° C. for 15 hours. Water was added to the reaction mixture, the mixture was filtered through celite, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product, 3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate (4.00 g), dichlorobis (triphenylphosphine) A mixture of palladium (II) (691 mg) and potassium carbonate (4.08 g) in 1,2-dimethoxyethane-water (3: 1, 40 mL) was stirred at 85 ° C. for 4 and a half hours under an argon stream. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.32 g).
MS (ESI +): [M + H] + 491.4
1 H NMR (300 MHz, CDCl 3 ) δ 3.84 (3H, s), 4.03 (2H, s), 5.18 (2H, s), 6.04 (1H, s), 6.83-7.23 (4H, m), 7.32- 7.47 (7H, m), 7.59-7.63 (1H, m).
D) 2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}フェノール
　5-[4-(ベンジルオキシ)-3-(ジフルオロメチル)フェニル]-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール (1.19 g) のメタノール溶液 (30 mL) に10%パラジウム炭素(150 mg) を加え、水素気流下、室温で2時間撹拌した。反応混合物をろ過した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (856 mg) を得た。
MS (ESI+): [M+H]+ 401.2.
1H NMR (300 MHz, CDCl3) δ 3.84 (3H, s), 4.03 (2H, s), 6.06 (1H, s), 6.73-7.13 (3H, m), 7.11-7.23 (2H, m), 7.31-7.39 (2H, m), 7.48-7.52 (1H, m). D) 2- (Difluoromethyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} phenol 5- [4- (benzyloxy ) -3- (Difluoromethyl) phenyl] -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazole (1.19 g) in methanol (30 mL) in 10% palladium Carbon (150 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen stream. After filtering the reaction mixture, the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (856 mg).
MS (ESI +): [M + H] + 401.2.
1 H NMR (300 MHz, CDCl 3 ) δ 3.84 (3H, s), 4.03 (2H, s), 6.06 (1H, s), 6.73-7.13 (3H, m), 7.11-7.23 (2H, m), 7.31-7.39 (2H, m), 7.48-7.52 (1H, m).
E) 2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}フェニル トリフルオロメタンスルホナート
　2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}フェノール (850 mg) 、N-フェニルビス(トリフルオロメタンスルホンイミド) (910 mg) 、炭酸セシウム (899 mg) のDMF溶液 (30 mL) を室温で2時間撹拌した。反応混合物に水を加え、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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (1065 mg) を得た。
MS (ESI+): [M+H]+ 533.3.
1H NMR (300 MHz, CDCl3) δ 3.88 (3H, s), 4.04 (2H, s), 6.15 (1H, s), 6.71-7.11 (1H, m), 7.15-7.23 (2H, m), 7.34-7.39 (1H, m), 7.48-7.54 (1H, m), 7.58-7.65 (1H, m), 7.74-7.78 (1H, m). E) 2- (Difluoromethyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} phenyl trifluoromethanesulfonate 2- (difluoro Methyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} phenol (850 mg), N-phenylbis (trifluoromethanesulfonimide) ) (910 mg) and a DMF solution (30 mL) of cesium carbonate (899 mg) were stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1065 mg).
MS (ESI +): [M + H] + 533.3.
1 H NMR (300 MHz, CDCl 3 ) δ 3.88 (3H, s), 4.04 (2H, s), 6.15 (1H, s), 6.71-7.11 (1H, m), 7.15-7.23 (2H, m), 7.34-7.39 (1H, m), 7.48-7.54 (1H, m), 7.58-7.65 (1H, m), 7.74-7.78 (1H, m).
F) 2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾニトリル
　2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}フェニル トリフルオロメタンスルホナート (1060 mg)、シアン化亜鉛 (140 mg)、テトラキストリフェニルホスフィンパラジウム(0) (230 mg) のDMF溶液(20 mL) を、アルゴン気流下80℃で17時間半撹拌した。反応混合物に水を加え、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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (770 mg) を得た。
MS (ESI+): [M+H]+ 410.2.
1H NMR (300 MHz, CDCl3) δ 3.91 (3H, s), 4.04 (2H, s), 6.20 (1H, s), 6.77-7.23 (3H, m), 7.33-7.37 (1H, m), 7.62-7.69 (1H, m), 7.78-7.87 (2H, m). F) 2- (Difluoromethyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzonitrile 2- (difluoromethyl)- 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} phenyl trifluoromethanesulfonate (1060 mg), zinc cyanide (140 mg), A DMF solution (20 mL) of tetrakistriphenylphosphine palladium (0) (230 mg) was stirred at 80 ° C. for 17 and a half hours under an argon stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (770 mg).
MS (ESI +): [M + H] + 410.2.
1 H NMR (300 MHz, CDCl 3 ) δ 3.91 (3H, s), 4.04 (2H, s), 6.20 (1H, s), 6.77-7.23 (3H, m), 7.33-7.37 (1H, m), 7.62-7.69 (1H, m), 7.78-7.87 (2H, m).
G) 2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンズアミド
　2-(ジフルオロメチル)-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}ベンゾニトリル (770 mg) のDMSO溶液(15 mL) に炭酸カリウム (130 mg) を加え0℃で撹拌した。過酸化水素水 (1 mL) を加えた後、室温で30分間撹拌し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をヘキサン－酢酸エチルから再結晶して標題化合物 (667 mg) を得た。
MS (ESI+): [M+H]+ 428.2.
1H NMR (300 MHz, CDCl3) δ 3.89 (3H, s), 4.04 (2H, s), 5.75-6.06 (2H, m), 6.16 (1H, s), 7.13-7.59 (5H, m), 7.69 (1H, d, J = 7.9 Hz), 7.80-7.83 (1H, m). G) 2- (Difluoromethyl) -4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzamide 2- (difluoromethyl) -4 -{3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} benzonitrile (770 mg) in DMSO solution (15 mL) and potassium carbonate (130 mg ) Was added and stirred at 0 ° C. Aqueous hydrogen peroxide (1 mL) was added, and the mixture was stirred at room temperature for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain the title compound (667 mg).
MS (ESI +): [M + H] + 428.2.
1 H NMR (300 MHz, CDCl 3 ) δ 3.89 (3H, s), 4.04 (2H, s), 5.75-6.06 (2H, m), 6.16 (1H, s), 7.13-7.59 (5H, m), 7.69 (1H, d, J = 7.9 Hz), 7.80-7.83 (1H, m).
実施例104
エチル 4-{1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート Example 104
Ethyl 4- {1- (cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170
A) (シクロプロピルメチル)ヒドラジン
　ヒドラジン一水和物(18.0 mL)中に、(ブロモメチル)シクロプロパン(10 g)を室温で滴下した。反応混合物を室温で1時間撹拌した後、50℃に昇温しさらに1時間撹拌した。反応混合物に水を加え、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮することにより、標題化合物(2.29 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.12-0.22 (2H, m), 0.44-0.61 (2H, m), 0.87-1.04 (1H, m), 2.45 (1H, d, J = 6.8 Hz), 2.63 (1H, d, J = 6.8 Hz), 2.99 (2H, brs), NHピークは観測されなかった. A) (Cyclopropylmethyl) hydrazine (Bromomethyl) cyclopropane (10 g) was added dropwise at room temperature to hydrazine monohydrate (18.0 mL). The reaction mixture was stirred at room temperature for 1 hour, then warmed to 50 ° C. and further stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (2.29 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.12-0.22 (2H, m), 0.44-0.61 (2H, m), 0.87-1.04 (1H, m), 2.45 (1H, d, J = 6.8 Hz), 2.63 (1H, d, J = 6.8 Hz), 2.99 (2H, brs), NH peaks were not observed.
B) エチル 4-[3-フルオロ-5-(トリフルオロメチル)フェニル]-3-オキソブタノアート
　カリウム 3-エトキシ-3-オキソプロパノアート(3.37 g)とアセトニトリル(30 mL)の混合物中に、トリエチルアミン(4.14 mL)および塩化マグネシウム(2.36 g)を加えた。反応混合物を室温で2時間撹拌した後、別途[3-フルオロ-5-(トリフルオロメチル)フェニル]酢酸(2.2 g)と1,1'-カルボニルビス(1H-イミダゾール)(1.93 g)との反応により調製した1-{[3-フルオロ-5-(トリフルオロメチル)フェニル]アセチル}-1H-イミダゾールのアセトニトリル(15 mL)溶液を加えた。反応混合物を一晩撹拌した後、6N塩酸を加えさらに30分間撹拌した後、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(2.69 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.29 (3H, t, J = 7.2 Hz), 3.52 (2H, s), 3.94 (2H, s), 4.21 (2H, q, J = 7.2 Hz), 7.10-7.34 (3H, m). B) Ethyl 4- [3-fluoro-5- (trifluoromethyl) phenyl] -3-oxobutanoate potassium in a mixture of 3-ethoxy-3-oxopropanoate (3.37 g) and acetonitrile (30 mL) To was added triethylamine (4.14 mL) and magnesium chloride (2.36 g). After the reaction mixture was stirred at room temperature for 2 hours, separately with [3-fluoro-5- (trifluoromethyl) phenyl] acetic acid (2.2 g) and 1,1′-carbonylbis (1H-imidazole) (1.93 g). A solution of 1-{[3-fluoro-5- (trifluoromethyl) phenyl] acetyl} -1H-imidazole prepared by the reaction in acetonitrile (15 mL) was added. The reaction mixture was stirred overnight, 6N hydrochloric acid was added, the mixture was further stirred for 30 min, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.69 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.29 (3H, t, J = 7.2 Hz), 3.52 (2H, s), 3.94 (2H, s), 4.21 (2H, q, J = 7.2 Hz), 7.10 -7.34 (3H, m).
C) 2-(シクロプロピルメチル)-5-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-2,4-ジヒドロ-3H-ピラゾール-3-オン
　実施例104-B)で合成したエチル 4-[3-フルオロ-5-(トリフルオロメチル)フェニル]-3-オキソブタノアート(7.06 g)、実施例104-A)で合成した(シクロプロピルメチル)ヒドラジン(2.29 g)およびエタノール(50 mL)の混合物を80℃で5時間撹拌した。反応混合物を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製した。得られたアモルファスをヘキサン-酢酸エチル混合溶媒中に懸濁させ、生じた固体をろ取することにより、標題化合物(0.69 g)を得た。
MS (ESI+): [M+H]+ 315.1.
1H NMR (300 MHz, CDCl3) δ 0.30-0.37 (2H, m), 0.50-0.59 (2H, m), 1.11-1.22 (1H, m), 3.14 (2H, s), 3.53 (2H, d, J = 6.8 Hz), 3.79 (2H, s), 7.12-7.19 (1H, m), 7.23-7.33 (2H, m). C) 2- (Cyclopropylmethyl) -5- [3-fluoro-5- (trifluoromethyl) benzyl] -2,4-dihydro-3H-pyrazol-3-one Ethyl synthesized in Example 104-B) 4- [3-Fluoro-5- (trifluoromethyl) phenyl] -3-oxobutanoate (7.06 g), (cyclopropylmethyl) hydrazine (2.29 g) synthesized in Example 104-A) and ethanol ( (50 mL) was stirred at 80 ° C. for 5 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained amorphous was suspended in a mixed solvent of hexane-ethyl acetate, and the resulting solid was collected by filtration to give the title compound (0.69 g).
MS (ESI +): [M + H] + 315.1.
1 H NMR (300 MHz, CDCl 3 ) δ 0.30-0.37 (2H, m), 0.50-0.59 (2H, m), 1.11-1.22 (1H, m), 3.14 (2H, s), 3.53 (2H, d , J = 6.8 Hz), 3.79 (2H, s), 7.12-7.19 (1H, m), 7.23-7.33 (2H, m).
D) 1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例104-C)で合成した2-(シクロプロピルメチル)-5-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-2,4-ジヒドロ-3H-ピラゾール-3-オン(650 mg)とピリジン(5 mL)の混合物を0℃に冷却し、トリフルオロメタンスルホン酸無水物(0.52 mL)を滴下した。反応混合物を2時間撹拌した後、飽和炭酸水素ナトリウムを加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後減圧濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(648 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.37-0.44 (2H, m), 0.58-0.67 (2H, m), 1.20-1.36 (1H, m), 3.92 (2H, d, J = 7.2 Hz), 3.98 (2H, s), 5.91 (1H, s), 7.10-7.23 (2H, m), 7.28-7.32 (1H, m). D) 1- (Cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl trifluoromethanesulfonate Example 104-C) Cyclopropylmethyl) -5- [3-fluoro-5- (trifluoromethyl) benzyl] -2,4-dihydro-3H-pyrazol-3-one (650 mg) and pyridine (5 mL) And trifluoromethanesulfonic anhydride (0.52 mL) was added dropwise. The reaction mixture was stirred for 2 hours, saturated sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (648 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.37-0.44 (2H, m), 0.58-0.67 (2H, m), 1.20-1.36 (1H, m), 3.92 (2H, d, J = 7.2 Hz), 3.98 (2H, s), 5.91 (1H, s), 7.10-7.23 (2H, m), 7.28-7.32 (1H, m).
E) エチル4-{1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアート
　実施例29-F)と同様にして、実施例104-D)で合成した1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル トリフルオロメタンスルホナートおよび実施例29－B)で合成したエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアートを用いて標題化合物を合成した。
MS (ESI+): [M+H]+ 461.3.
1H NMR (300 MHz, CDCl3) δ 0.14-0.22 (2H, m), 0.44-0.52 (2H, m), 1.09-1.24 (1H, m), 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.99 (2H, d, J = 6.8 Hz), 4.06 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.07 (1H, s), 7.14-7.24 (2H, m), 7.25-7.29 (2H, m), 7.37-7.40 (1H, m), 7.95-8.00 (1H, m). E) Ethyl 4- {1- (cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoate Example 29-F ) 1- (cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl trifluoromethanesulfo synthesized in Example 104-D) The title compound was obtained using ethyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate synthesized in Example 29-B). Synthesized.
MS (ESI +): [M + H] + 461.3.
1 H NMR (300 MHz, CDCl 3 ) δ 0.14-0.22 (2H, m), 0.44-0.52 (2H, m), 1.09-1.24 (1H, m), 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.99 (2H, d, J = 6.8 Hz), 4.06 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.07 (1H, s), 7.14-7.24 (2H , m), 7.25-7.29 (2H, m), 7.37-7.40 (1H, m), 7.95-8.00 (1H, m).
実施例105
4-{1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸 Example 105
4- {1- (Cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171
　実施例30と同様にして、実施例104で合成したエチル 4-{1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンゾアートを用いて標題化合物を合成した。
MS (ESI+): [M+H]+ 433.1.
1H NMR (300 MHz, CDCl3) δ0.17-0.24 (2H, m), 0.46-0.54 (2H, m), 1.09-1.25 (1H, m), 2.70 (3H, s), 4.03 (2H, d, J = 6.8 Hz), 4.08 (2H, s), 6.10 (1H, s), 7.15-7.25 (2H, m), 7.28-7.42 (3H, m), 8.09-8.15 (1H, m), COOHピークは観測されなかった. Ethyl 4- {1- (cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl synthesized in Example 104 in the same manner as in Example 30 The title compound was synthesized using} -2-methylbenzoate.
MS (ESI +): [M + H] + 433.1.
1 H NMR (300 MHz, CDCl 3 ) δ0.17-0.24 (2H, m), 0.46-0.54 (2H, m), 1.09-1.25 (1H, m), 2.70 (3H, s), 4.03 (2H, d, J = 6.8 Hz), 4.08 (2H, s), 6.10 (1H, s), 7.15-7.25 (2H, m), 7.28-7.42 (3H, m), 8.09-8.15 (1H, m), COOH No peak was observed.
実施例106
4-{1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 106
4- {1- (Cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172
　実施例105で合成した4-{1-(シクロプロピルメチル)-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-ピラゾール-5-イル}-2-メチル安息香酸(200 mg)、HOBtアンモニア和物(84 mg)、WSC塩酸塩(106 mg)およびDMF(2 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製した後、酢酸エチル-ヘキサンから再結晶することにより、標題化合物(168 mg)を得た。
MS (ESI+): [M+H]+ 432.1.
1H NMR (300 MHz, CDCl3) δ 0.15-0.22 (2H, m), 0.44-0.53 (2H, m), 1.09-1.24 (1H, m), 2.54 (3H, s), 3.98 (2H, d, J = 7.2 Hz), 4.06 (2H, s), 5.75 (2H, brs), 6.04 (1H, s), 7.14-7.30 (4H, m), 7.36-7.40 (1H, m), 7.53 (1H, d, J = 7.6 Hz). 4- {1- (cyclopropylmethyl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-pyrazol-5-yl} -2-methylbenzoic acid synthesized in Example 105 (200 mg), HOBt ammonia hydrate (84 mg), WSC hydrochloride (106 mg) and DMF (2 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and recrystallized from ethyl acetate-hexane to give the title compound (168 mg).
MS (ESI +): [M + H] + 432.1.
1 H NMR (300 MHz, CDCl 3 ) δ 0.15-0.22 (2H, m), 0.44-0.53 (2H, m), 1.09-1.24 (1H, m), 2.54 (3H, s), 3.98 (2H, d , J = 7.2 Hz), 4.06 (2H, s), 5.75 (2H, brs), 6.04 (1H, s), 7.14-7.30 (4H, m), 7.36-7.40 (1H, m), 7.53 (1H, d, J = 7.6 Hz).
実施例107
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-(2-ヒドロキシエチル)-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 107
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1- (2-hydroxyethyl) -1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173
A) 4-ブロモ-N-メトキシ-N,3-ジメチルベンズアミド
　4-ブロモ-3-メチル安息香酸(16.2 g)、N,O-ジメチルヒドロキシルアミン　塩酸塩(8.82 g)、WSC塩酸塩(17.3 g)、HOBt(12.2 g)、トリエチルアミン(12.6 mL)およびDMF(100 mL)の混合物を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、無水硫酸ナトリウムで乾燥した後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(NH、酢酸エチル/ヘキサン)で精製することにより、標題化合物(14.1 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.43 (3H, s), 3.35 (3H, s), 3.55 (3H, s), 7.34-7.40 (1H, m), 7.54-7.58 (2H, m). A) 4-Bromo-N-methoxy-N, 3-dimethylbenzamide 4-Bromo-3-methylbenzoic acid (16.2 g), N, O-dimethylhydroxylamine hydrochloride (8.82 g), WSC hydrochloride (17.3 g ), HOBt (12.2 g), triethylamine (12.6 mL) and DMF (100 mL) were stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (14.1 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.43 (3H, s), 3.35 (3H, s), 3.55 (3H, s), 7.34-7.40 (1H, m), 7.54-7.58 (2H, m).
B) 1-(4-ブロモ-3-メチルフェニル)エタノン
　実施例107-A)で合成した4-ブロモ-N-メトキシ-N,3-ジメチルベンズアミド(14 g)のTHF(150 mL)溶液を0℃に冷却し、臭化メチルマグネシウム(1.4 Mトルエン/THF溶液、70 mL)を滴下した。反応混合物を室温まで昇温して2時間撹拌した後、再度0℃に冷却した。1N塩酸を滴下した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧濃縮することにより、標題化合物(11.6 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.46 (3H, s), 2.58 (3H, s), 7.60-7.63 (2H, m), 7.80-7.83 (1H, m). B) 1- (4-Bromo-3-methylphenyl) ethanone A solution of 4-bromo-N-methoxy-N, 3-dimethylbenzamide (14 g) synthesized in Example 107-A) in THF (150 mL) was used. After cooling to 0 ° C., methylmagnesium bromide (1.4 M toluene / THF solution, 70 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours, and then cooled again to 0 ° C. 1N Hydrochloric acid was added dropwise, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (11.6 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.46 (3H, s), 2.58 (3H, s), 7.60-7.63 (2H, m), 7.80-7.83 (1H, m).
C) エチル 4-(4-ブロモ-3-メチルフェニル)-4-ヒドロキシ-2-オキソブタ-3-エノアート
　ナトリウムエトキシド(20%エタノール溶液、27.7 mL)をエタノール(20 mL)で希釈した溶液中に、実施例107-B)で合成した1-(4-ブロモ-3-メチルフェニル)エタノン(14 g)を加え、室温で1時間撹拌した。反応混合物を0℃に冷却し、シュウ酸ジエチル(8.1 mL)を加えた。反応混合物を室温まで昇温して一晩撹拌した後、1N塩酸を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(15.2 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 2.48 (3H, s), 4.41 (2H, q, J = 7.2 Hz), 7.02 (1H, s), 7.64-7.67 (2H, m), 7.82-7.86 (1H, m), 15.17 (1H, brs). C) Ethyl 4- (4-bromo-3-methylphenyl) -4-hydroxy-2-oxobut-3-enoate Sodium ethoxide (20% ethanol solution, 27.7 mL) in a solution diluted with ethanol (20 mL) To the mixture was added 1- (4-bromo-3-methylphenyl) ethanone (14 g) synthesized in Example 107-B), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C. and diethyl oxalate (8.1 mL) was added. The reaction mixture was warmed to room temperature and stirred overnight, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (15.2 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 2.48 (3H, s), 4.41 (2H, q, J = 7.2 Hz), 7.02 (1H, s), 7.64 -7.67 (2H, m), 7.82-7.86 (1H, m), 15.17 (1H, brs).
D) エチル 5-(4-ブロモ-3-メチルフェニル)-1-(2-ヒドロキシエチル)-1H-ピラゾール-3-カルボキシラート
　実施例107-C)で合成したエチル 4-(4-ブロモ-3-メチルフェニル)-4-ヒドロキシ-2-オキソブタ-3-エノアート(12.4 g)、2-ヒドラジノエタノール(4.52 g)および酢酸(80 mL)の混合物を80℃で4時間撹拌した。反応混合物を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(8.0 g)を得た。
MS (ESI+): [M+H]+ 353.2.
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 2.70-2.81 (1H, m), 4.02-4.13 (2H, m), 4.24-4.30 (2H, m), 4.41 (2H, q, J = 7.2 Hz), 6.82 (1H, s), 7.14 (1H, dd, J = 8.3, 2.3 Hz), 7.32 (1H, d, J = 2.3 Hz), 7.63 (1H, d, J = 8.3 Hz). D) Ethyl 5- (4-Bromo-3-methylphenyl) -1- (2-hydroxyethyl) -1H-pyrazole-3-carboxylate Ethyl 4- (4-bromo-) synthesized in Example 107-C) A mixture of 3-methylphenyl) -4-hydroxy-2-oxobut-3-enoate (12.4 g), 2-hydrazinoethanol (4.52 g) and acetic acid (80 mL) was stirred at 80 ° C. for 4 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.0 g).
MS (ESI +): [M + H] + 353.2.
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 2.70-2.81 (1H, m), 4.02-4.13 (2H, m), 4.24- 4.30 (2H, m), 4.41 (2H, q, J = 7.2 Hz), 6.82 (1H, s), 7.14 (1H, dd, J = 8.3, 2.3 Hz), 7.32 (1H, d, J = 2.3 Hz ), 7.63 (1H, d, J = 8.3 Hz).
E) エチル 5-(4-ブロモ-3-メチルフェニル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-3-カルボキシラート
　実施例107-D)で合成したエチル 5-(4-ブロモ-3-メチルフェニル)-1-(2-ヒドロキシエチル)-1H-ピラゾール-3-カルボキシラート(7.5 g)、p-トルエンスルホン酸一水和物(0.81 g)、3,4-ジヒドロ-2H-ピラン(5.8 mL)およびTHF(50 mL)の混合物を室温で3時間撹拌した。反応混合物を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(9.2 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.37-1.74 (9H, m), 2.45 (3H, s), 3.39-3.48 (1H, m), 3.56-3.66 (1H, m), 3.85-3.96 (1H, m), 4.11-4.20 (1H, m), 4.31-4.53 (5H, m), 6.80 (1H, s), 7.23-7.27 (1H, m), 7.43 (1H, d, J = 1.9 Hz), 7.61 (1H, d, J = 8.3 Hz). E) Ethyl 5- (4-bromo-3-methylphenyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazole-3-carboxylate in Example 107-D) Synthesized ethyl 5- (4-bromo-3-methylphenyl) -1- (2-hydroxyethyl) -1H-pyrazole-3-carboxylate (7.5 g), p-toluenesulfonic acid monohydrate (0.81 g ), 3,4-dihydro-2H-pyran (5.8 mL) and THF (50 mL) were stirred at room temperature for 3 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (9.2 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.37-1.74 (9H, m), 2.45 (3H, s), 3.39-3.48 (1H, m), 3.56-3.66 (1H, m), 3.85-3.96 (1H , m), 4.11-4.20 (1H, m), 4.31-4.53 (5H, m), 6.80 (1H, s), 7.23-7.27 (1H, m), 7.43 (1H, d, J = 1.9 Hz), 7.61 (1H, d, J = 8.3 Hz).
F) {5-(4-ブロモ-3-メチルフェニル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-3-イル}メタノール
　実施例107-E)で合成したエチル 5-(4-ブロモ-3-メチルフェニル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-3-カルボキシラート(9.0 g)、THF(60 mL)およびメタノール(1 mL)の混合物を0℃に冷却し、水素化ホウ素リチウム(1.35 g)を加えた。反応混合物を室温まで昇温させて3時間撹拌した後、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(6.2 g)を得た。
MS (ESI+): [M+H]+ 395.2.
1H NMR (300 MHz, CDCl3) δ 1.38-1.80 (6H, m), 2.12 (1H, brs), 2.44 (3H, s), 3.38-3.48 (1H, m), 3.56-3.67 (1H, m), 3.81-3.90 (1H, m), 4.07-4.16 (1H, m), 4.21-4.29 (2H, m), 4.49-4.54 (1H, m), 4.71 (2H, d, J = 5.3 Hz), 6.25 (1H, s), 7.23 (1H, dd, J = 8.3, 2.3 Hz), 7.41 (1H, d, J = 2.3 Hz), 7.59 (1H, d, J = 8.3 Hz). F) {5- (4-Bromo-3-methylphenyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-3-yl} methanol Example 107-E) 5- (4-Bromo-3-methylphenyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazole-3-carboxylate (9.0 g), THF synthesized in A mixture of (60 mL) and methanol (1 mL) was cooled to 0 ° C. and lithium borohydride (1.35 g) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, after which water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.2 g).
MS (ESI +): [M + H] + 395.2.
1 H NMR (300 MHz, CDCl 3 ) δ 1.38-1.80 (6H, m), 2.12 (1H, brs), 2.44 (3H, s), 3.38-3.48 (1H, m), 3.56-3.67 (1H, m ), 3.81-3.90 (1H, m), 4.07-4.16 (1H, m), 4.21-4.29 (2H, m), 4.49-4.54 (1H, m), 4.71 (2H, d, J = 5.3 Hz), 6.25 (1H, s), 7.23 (1H, dd, J = 8.3, 2.3 Hz), 7.41 (1H, d, J = 2.3 Hz), 7.59 (1H, d, J = 8.3 Hz).
G) 4-{3-(ヒドロキシメチル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-5-イル}-2-メチルベンゾニトリル
　実施例107-F)で合成した{5-(4-ブロモ-3-メチルフェニル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-3-イル}メタノール(6.0 g)、シアン化亜鉛(2.67 g)、テトラキス(トリフェニルホフフィン)パラジウム(0.88 g)およびNMP(30 mL)の混合物を120℃で一晩撹拌した。反応混合物を酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(4.3 g)を得た。
MS (ESI+): [M+H]+ 342.2.
1H NMR (300 MHz, CDCl3) δ 1.37-1.76 (6H, m), 2.13 (1H, t, J = 5.7 Hz), 2.60 (3H, s), 3.39-3.49 (1H, m), 3.56-3.66 (1H, m), 3.83-3.92 (1H, m), 4.10-4.18 (1H, m), 4.23-4.30 (2H, m), 4.49-4.54 (1H, m), 4.72 (2H, d, J = 5.7 Hz), 6.32 (1H, s), 7.46-7.57 (2H, m), 7.67 (1H, d, J = 7.9 Hz). G) 4- {3- (hydroxymethyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-5-yl} -2-methylbenzonitrile Example 107-F )-Synthesized {5- (4-bromo-3-methylphenyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-3-yl} methanol (6.0 g) , A mixture of zinc cyanide (2.67 g), tetrakis (triphenylphosphine) palladium (0.88 g) and NMP (30 mL) was stirred at 120 ° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.3 g).
MS (ESI +): [M + H] + 342.2.
1 H NMR (300 MHz, CDCl 3 ) δ 1.37-1.76 (6H, m), 2.13 (1H, t, J = 5.7 Hz), 2.60 (3H, s), 3.39-3.49 (1H, m), 3.56- 3.66 (1H, m), 3.83-3.92 (1H, m), 4.10-4.18 (1H, m), 4.23-4.30 (2H, m), 4.49-4.54 (1H, m), 4.72 (2H, d, J = 5.7 Hz), 6.32 (1H, s), 7.46-7.57 (2H, m), 7.67 (1H, d, J = 7.9 Hz).
H) {5-(4-シアノ-3-メチルフェニル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-3-イル}メチル メタンスルホナート
　実施例107-G)で合成した4-{3-(ヒドロキシメチル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-5-イル}-2-メチルベンゾニトリル(3.0 g)、N-エチルジイソプロピルアミン(4.6 mL)およびTHF(30 mL)の混合物中に、塩化メタンスルホニル(0.75 mL)を加えた。反応混合物を室温で3時間撹拌した後、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後減圧濃縮することにより、標題化合物(3.7 g)を得た。
MS (ESI+): [M+H]+ 420.1.
1H NMR (300 MHz, CDCl3) δ 1.37-1.73 (6H, m), 2.61 (3H, s), 3.03 (3H, s), 3.39-3.49 (1H, m), 3.53-3.64 (1H, m), 3.82-3.92 (1H, m), 4.11-4.20 (1H, m), 4.25-4.32 (2H, m), 4.48-4.54 (1H, m), 5.28 (2H, s), 6.46 (1H, s), 7.47-7.57 (2H, m), 7.69 (1H, d, J = 7.9 Hz). H) {5- (4-Cyano-3-methylphenyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-3-yl} methyl methanesulfonate Example 107 -G) 4- {3- (hydroxymethyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-5-yl} -2-methylbenzonitrile ( To a mixture of 3.0 g), N-ethyldiisopropylamine (4.6 mL) and THF (30 mL) was added methanesulfonyl chloride (0.75 mL). The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (3.7 g).
MS (ESI +): [M + H] + 420.1.
1 H NMR (300 MHz, CDCl 3 ) δ 1.37-1.73 (6H, m), 2.61 (3H, s), 3.03 (3H, s), 3.39-3.49 (1H, m), 3.53-3.64 (1H, m ), 3.82-3.92 (1H, m), 4.11-4.20 (1H, m), 4.25-4.32 (2H, m), 4.48-4.54 (1H, m), 5.28 (2H, s), 6.46 (1H, s ), 7.47-7.57 (2H, m), 7.69 (1H, d, J = 7.9 Hz).
I) 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-(2-ヒドロキシエチル)-1H-ピラゾール-5-イル}-2-メチルベンゾニトリル
　実施例107-H)で合成した{5-(4-シアノ-3-メチルフェニル)-1-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エチル]-1H-ピラゾール-3-イル}メチル メタンスルホナート(3.5 g)、[3-フルオロ-5-(トリフルオロメチル)フェニル]ボロン酸(2.1 g)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(0.69 g)、炭酸セシウム(4.1 g)およびDME(15 mL)の混合物をマイクロウェーブ照射下140℃で1時間撹拌した。反応混合物を酢酸エチルで希釈してセライトろ過した。ろ液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(528 mg)を得た。
MS (ESI+): [M+H]+ 404.2.
1H NMR (300 MHz, CDCl3) δ 2.59 (3H, s), 3.32-3.45 (1H, m), 3.98-4.07 (4H, m), 4.16-4.21 (2H, m), 6.12 (1H, s), 7.15-7.23 (2H, m), 7.31-7.40 (3H, m), 7.67 (1H, d, J = 7.9 Hz). I) 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1- (2-hydroxyethyl) -1H-pyrazol-5-yl} -2-methylbenzonitrile Example 107-H ) Synthesized with {5- (4-cyano-3-methylphenyl) -1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-3-yl} methyl methanesulfonate ( 3.5 g), [3-fluoro-5- (trifluoromethyl) phenyl] boronic acid (2.1 g), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (0.69 g ), Cesium carbonate (4.1 g) and DME (15 mL) were stirred at 140 ° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with ethyl acetate and filtered through celite. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (528 mg).
MS (ESI +): [M + H] + 404.2.
1 H NMR (300 MHz, CDCl 3 ) δ 2.59 (3H, s), 3.32-3.45 (1H, m), 3.98-4.07 (4H, m), 4.16-4.21 (2H, m), 6.12 (1H, s ), 7.15-7.23 (2H, m), 7.31-7.40 (3H, m), 7.67 (1H, d, J = 7.9 Hz).
J) 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-(2-ヒドロキシエチル)-1H-ピラゾール-5-イル}-2-メチルベンズアミド
　実施例107-I)で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-(2-ヒドロキシエチル)-1H-ピラゾール-5-イル}-2-メチルベンゾニトリル(200 mg)、炭酸カリウム(34 mg)、DMSO(2.5 mL)および水(0.2 mL)の混合物を0℃に冷却し、30%過酸化水素水(0.25 mL)を加えた。反応混合物を室温まで昇温して2時間撹拌した後、酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後減圧濃縮した。得られた残渣を酢酸エチル-ヘキサン混合溶媒中に懸濁させ、生じた固体をろ取することにより、標題化合物(182 mg)を得た。
MS (ESI+): [M+H]+ 422.3.
1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 3.59 (1H, t, J = 6.2 Hz), 3.95-4.02 (2H, m), 4.05 (2H, s), 4.16-4.21 (2H, m), 5.74 (2H, brs), 6.09 (1H, s), 7.16-7.29 (4H, m), 7.35-7.38 (1H, m), 7.53 (1H, d, J = 7.6 Hz). J) 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1- (2-hydroxyethyl) -1H-pyrazol-5-yl} -2-methylbenzamide Example 107-I) 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1- (2-hydroxyethyl) -1H-pyrazol-5-yl} -2-methylbenzonitrile (200 mg) A mixture of potassium carbonate (34 mg), DMSO (2.5 mL) and water (0.2 mL) was cooled to 0 ° C., and 30% aqueous hydrogen peroxide (0.25 mL) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours, then diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was suspended in a mixed solvent of ethyl acetate-hexane, and the resulting solid was collected by filtration to give the title compound (182 mg).
MS (ESI +): [M + H] + 422.3.
1 H NMR (300 MHz, CDCl 3 ) δ 2.54 (3H, s), 3.59 (1H, t, J = 6.2 Hz), 3.95-4.02 (2H, m), 4.05 (2H, s), 4.16-4.21 ( 2H, m), 5.74 (2H, brs), 6.09 (1H, s), 7.16-7.29 (4H, m), 7.35-7.38 (1H, m), 7.53 (1H, d, J = 7.6 Hz).
実施例108
エチル 4-(3-(3-クロロ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート Example 108
Ethyl 4- (3- (3-chloro-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174
A) 3-(tert-ブトキシメチル)-1-メチル-1H-ピラゾール-5(4H)-オン
　水素化ナトリウム(16.06 g)の無水THF懸濁液(150 mL)へエチル 4-クロロ-3-オキソブタノアート(25.0 g)の無水THF溶液(150 mL)を-78 ℃で加えた。30分間撹拌後、反応混合物へナトリウム2-メチルプロパン-2-オラート(16.06 g)の無水THF懸濁液(150 mL)を徐々に加え、室温で終夜撹拌した。0 ℃で1 N塩酸を加え中和し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣のエタノール溶液(140 mL)へメチルヒドラジン(8.19 mL)を0 ℃で加え、室温で2時間撹拌した。溶媒を減圧下留去し、残渣をカラムクロマトグラフィー(メタノール/酢酸エチル)により精製して標題化合物(14.6 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.24 (9H, s), 3.29 (5H, s), 4.16 (2H, s).
MS (ESI+): [M+H]+ 185.1. A) 3- (tert-Butoxymethyl) -1-methyl-1H-pyrazol-5 (4H) -one To an anhydrous THF suspension (150 mL) of sodium hydride (16.06 g) in ethyl 4-chloro-3- An anhydrous THF solution (150 mL) of oxobutanoate (25.0 g) was added at −78 ° C. After stirring for 30 minutes, an anhydrous THF suspension (150 mL) of sodium 2-methylpropan-2-olate (16.06 g) was gradually added to the reaction mixture, and the mixture was stirred overnight at room temperature. The mixture was neutralized with 1N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Methylhydrazine (8.19 mL) was added to an ethanol solution (140 mL) of the obtained residue at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (methanol / ethyl acetate) to obtain the title compound (14.6 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.24 (9H, s), 3.29 (5H, s), 4.16 (2H, s).
MS (ESI +): [M + H] + 185.1.
B) エチル 4-(3-(tert-ブトキシメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート
　3-(tert-ブトキシメチル)-1-メチル-1H-ピラゾール-5(4H)-オン(20.0 g)と1,1,1-トリフルオロ-N-フェニル-N-(トリフルオロメチルスルホニル)メタンスルホンアミド(42.7 g)の無水THF懸濁液(400 mL)へトリエチルアミン(18 mL)を加え、室温で1時間撹拌した。溶媒を減圧下留去し、残渣に飽和塩化アンモニウム溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製した。得られた化合物のDME/水溶液(5/1、360 mL)へエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート(34.7 g)、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)(8.87 g)、炭酸カリウム(45.0 g)を加え、窒素雰囲気下90℃で3時間加熱撹拌した。溶媒を減圧下留去し、得られた残渣をセライトろ過し、酢酸エチルで希釈した。有機層を飽和塩化アンモニウム水溶液、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製して標題化合物(35.9 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.31 (9H, s), 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.85 (3H, s), 4.38 (2H, q, J = 6.9 Hz), 4.46 (2H, s), 6.36 (1H, s), 7.24-7.36 (2H, m), 7.98 (1H, d, J = 8.7 Hz).
MS (ESI+): [M+H]+ 331.2. B) Ethyl 4- (3- (tert-butoxymethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate 3- (tert-butoxymethyl) -1-methyl-1H-pyrazole- To an anhydrous THF suspension (400 mL) of 5 (4H) -one (20.0 g) and 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (42.7 g) Triethylamine (18 mL) was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, saturated ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane). Ethyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate into DME / water solution (5/1, 360 mL) of the obtained compound (34.7 g), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) (8.87 g) and potassium carbonate (45.0 g) were added, and the mixture was heated and stirred at 90 ° C. for 3 hours in a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and the resulting residue was filtered through celite and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (35.9 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.31 (9H, s), 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.85 (3H, s), 4.38 (2H, q, J = 6.9 Hz), 4.46 (2H, s), 6.36 (1H, s), 7.24-7.36 (2H, m), 7.98 (1H, d, J = 8.7 Hz).
MS (ESI +): [M + H] + 331.2.
C) エチル 4-(3-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート
　エチル 4-(3-(tert-ブトキシメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(1.75 g)のトルエン溶液(9 mL)へトリフルオロ酢酸(8 mL)を加え、室温で30分間撹拌した。溶媒を減圧下留去し、得られた残渣をカラムクロマトグラフィー(メタノール/酢酸エチル)により精製して標題化合物(0.706 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.0 Hz), 2.65 (3H, s), 3.88 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 6.35 (1H, s), 7.22-7.36 (2H, m), 8.00 (1H, d, J = 8.7 Hz), OHピークは観測されなかった.
MS (ESI+): [M+H]+ 275.1. C) Ethyl 4- (3- (hydroxymethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate Ethyl 4- (3- (tert-butoxymethyl) -1-methyl-1H- Trifluoroacetic acid (8 mL) was added to a toluene solution (9 mL) of pyrazol-5-yl) -2-methylbenzoate (1.75 g), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (methanol / ethyl acetate) to give the title compound (0.706 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.0 Hz), 2.65 (3H, s), 3.88 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 6.35 (1H, s), 7.22-7.36 (2H, m), 8.00 (1H, d, J = 8.7 Hz), no OH peak was observed.
MS (ESI +): [M + H] + 275.1.
D) エチル 4-(3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート
　エチル 4-(3-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(5.00 g)の無水THF溶液(50 mL)へトリブロモホスフィン(2.58 mL)を加え、60 ℃で２時間撹拌した。溶媒を減圧下留去し、水を加え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、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製して標題化合物(4.50 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 2.65 (3H, s), 3.87 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 4.51 (2H, s), 6.40 (1H, s), 7.22-7.37 (2H, m), 7.99 (1H, d, J = 8.3 Hz). D) Ethyl 4- (3- (bromomethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate ethyl 4- (3- (hydroxymethyl) -1-methyl-1H-pyrazole-5 Triylphosphine (2.58 mL) was added to an anhydrous THF solution (50 mL) of -yl) -2-methylbenzoate (5.00 g), and the mixture was stirred at 60 ° C for 2 hours. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (4.50 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 2.65 (3H, s), 3.87 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 4.51 (2H, s), 6.40 (1H, s), 7.22-7.37 (2H, m), 7.99 (1H, d, J = 8.3 Hz).
E) エチル 4-(3-(3-クロロ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート
　エチル 4-(3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(0.280 g)、3-クロロ-5-フルオロフェニルボロン酸(0.217 g)、リン酸三カリウム (0.529 g)、テトラキス（トリフェニルホスフィン）パラジウム（0） (0.096 g)のDME溶液 (3 mL)をマイクロウェーブ照射下140 ℃で20分間加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (0.160 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t), 2.64 (3H, s), 3.87 (3H, s), 3.95 (2H, s), 4.38 (2H, q, J = 6.9 Hz), 6.10 (1H, s), 6.93 (2H, t, J = 8.3 Hz), 7.09 (1H, s), 7.24-7.33 (2H, m), 7.98 (1H, d, J = 8.7 Hz).
MS (ESI+): [M+H]+ 387.1. E) Ethyl 4- (3- (3-Chloro-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate Ethyl 4- (3- (Bromomethyl) -1-methyl -1H-pyrazol-5-yl) -2-methylbenzoate (0.280 g), 3-chloro-5-fluorophenylboronic acid (0.217 g), tripotassium phosphate (0.529 g), tetrakis (triphenylphosphine) A DME solution (3 mL) of palladium (0) (0.096 g) was heated and stirred at 140 ° C. for 20 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.160 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t), 2.64 (3H, s), 3.87 (3H, s), 3.95 (2H, s), 4.38 (2H, q, J = 6.9 Hz) , 6.10 (1H, s), 6.93 (2H, t, J = 8.3 Hz), 7.09 (1H, s), 7.24-7.33 (2H, m), 7.98 (1H, d, J = 8.7 Hz).
MS (ESI +): [M + H] + 387.1.
実施例109
4-(3-(3-クロロ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸 Example 109
4- (3- (3-Chloro-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175
　実施例108で得られたエチル 4-(3-(3-クロロ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(0.160 g)のエタノール溶液 (3 mL)へ1 N水酸化ナトリウム水溶液 (1.1 mL)を加え、室温で終夜撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (0.141 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.69 (3H, s), 3.89 (3H, s), 3.96 (2H, s), 6.13 (1H, s), 6.88-6.98 (2H, m), 7.10 (1H, s), 7.31 (2H, d, J = 4.1 Hz), 8.10 (1H, d, J = 8.3 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 359.1. Ethanol 4- (3- (3-chloro-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (0.160 g) obtained in Example 108 in ethanol ( 3 mL) was added 1 N aqueous sodium hydroxide solution (1.1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.141 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.69 (3H, s), 3.89 (3H, s), 3.96 (2H, s), 6.13 (1H, s), 6.88-6.98 (2H, m), 7.10 ( 1H, s), 7.31 (2H, d, J = 4.1 Hz), 8.10 (1H, d, J = 8.3 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 359.1.
実施例110
4-(3-(3-クロロ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンズアミド Example 110
4- (3- (3-Chloro-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176
　実施例109で得られた4-(3-(3-クロロ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸(141 mg)、WSC (151 mg)、HOBtアンモニア和物(120 mg)のDMF溶液 (5 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して、標題化合物 (139 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.55 (3H, s), 3.85 (3H, s), 3.95 (2H, s), 5.77 (2H, brs), 6.08 (1H, s), 6.87-6.98 (2H, m), 7.09 (1H, s), 7.22-7.30 (2H, m), 7.53 (1H, d, J = 8.0 Hz).
MS (ESI+): [M+H]+ 358.3. 4- (3- (3-Chloro-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid (141 mg), WSC (151 mg) obtained in Example 109 ), A DMF solution (5 mL) of HOBt ammonia hydrate (120 mg) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (139 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.55 (3H, s), 3.85 (3H, s), 3.95 (2H, s), 5.77 (2H, brs), 6.08 (1H, s), 6.87-6.98 ( 2H, m), 7.09 (1H, s), 7.22-7.30 (2H, m), 7.53 (1H, d, J = 8.0 Hz).
MS (ESI +): [M + H] + 358.3.
実施例111
エチル 4-(3-(3,5-ジフルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート Example 111
Ethyl 4- (3- (3,5-difluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177
　実施例108-D)で得られたエチル 4-(3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(0.250 g)、3,5-ジフルオロフェニルボロン酸(0.176 g)、リン酸三カリウム (0.472 g)、テトラキス（トリフェニルホスフィン）パラジウム（0） (0.086 g)のDME溶液 (3 mL)をマイクロウェーブ照射下140 ℃で20分間加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (0.197 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.0 Hz), 2.64 (3H, s), 3.87 (3H, s), 3.96 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.11 (1H, s), 6.65 (1H, tt, J = 9.1, 2.3 Hz), 6.77-6.89 (2H, m), 7.22-7.33 (2H, m), 7.98 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 371.1. Ethyl 4- (3- (bromomethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (0.250 g), 3,5-difluorophenylboron obtained in Example 108-D) A DME solution (3 mL) of acid (0.176 g), tripotassium phosphate (0.472 g), and tetrakis (triphenylphosphine) palladium (0) (0.086 g) was heated and stirred at 140 ° C. for 20 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (0.197 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.0 Hz), 2.64 (3H, s), 3.87 (3H, s), 3.96 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.11 (1H, s), 6.65 (1H, tt, J = 9.1, 2.3 Hz), 6.77-6.89 (2H, m), 7.22-7.33 (2H, m), 7.98 (1H, d , J = 8.3 Hz).
MS (ESI +): [M + H] + 371.1.
実施例112
4-(3-(3,5-ジフルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸 Example 112
4- (3- (3,5-Difluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178
　実施例111で得られたエチル 4-(3-(3,5-ジフルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(197 mg)のエタノール溶液 (3 mL)へ1 N水酸化ナトリウム水溶液 (1.1 mL)を加え、室温で終夜撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (0.18 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.69 (3H, s), 3.90 (3H, s), 3.98 (2H, s), 6.13 (1H, s), 6.60-6.72 (1H, m), 6.83 (2H, d, J = 6.0 Hz), 7.31 (2H, d, J = 4.1 Hz), 8.11 (1H, d, J = 8.7 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 343.1. Ethyl 4- (3- (3,5-difluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (197 mg) obtained in Example 111 in ethanol (3 mL 1N aqueous sodium hydroxide solution (1.1 mL) was added to) and stirred at room temperature overnight. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.18 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.69 (3H, s), 3.90 (3H, s), 3.98 (2H, s), 6.13 (1H, s), 6.60-6.72 (1H, m), 6.83 ( 2H, d, J = 6.0 Hz), 7.31 (2H, d, J = 4.1 Hz), 8.11 (1H, d, J = 8.7 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 343.1.
実施例113
4-(3-(3,5-ジフルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンズアミド Example 113
4- (3- (3,5-Difluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179
　実施例112で得られた4-(3-(3,5-ジフルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸 (180 mg)、WSC (151 mg)、HOBtアンモニア和物(120 mg)のDMF溶液 (5 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘプタン)して、標題化合物 (108 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.55 (3H, s), 3.85 (3H, s), 3.96 (2H, s), 5.73 (2H, brs), 6.08 (1H, s), 6.66 (1H, td, J = 9.0, 1.9 Hz), 6.82 (2H, d, J = 6.4 Hz), 7.21-7.34 (2H, m), 7.53 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 342.2. 4- (3- (3,5-difluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid (180 mg), WSC (151 mg) obtained in Example 112, A DMF solution (5 mL) of HOBt ammonia hydrate (120 mg) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / heptane) to give the title compound (108 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.55 (3H, s), 3.85 (3H, s), 3.96 (2H, s), 5.73 (2H, brs), 6.08 (1H, s), 6.66 (1H, td, J = 9.0, 1.9 Hz), 6.82 (2H, d, J = 6.4 Hz), 7.21-7.34 (2H, m), 7.53 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 342.2.
実施例114
エチル 2-メチル-4-(1-メチル-3-(3-(メチルチオ)ベンジル)-1H-ピラゾール-5-イル)ベンゾアート Example 114
Ethyl 2-methyl-4- (1-methyl-3- (3- (methylthio) benzyl) -1H-pyrazol-5-yl) benzoate
Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180
　実施例108-D)で得られたエチル 4-(3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(1.00 g)、 3-(メチルチオ)フェニルボロン酸(0.598 g)、リン酸三カリウム (1.888 g)、テトラキス（トリフェニルホスフィン）パラジウム（0）(0.343 g)のDME溶液 (10 mL)をマイクロウェーブ照射下140 ℃で30分間加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)およびHPLC (C18、移動相：水/アセトニトリル (0.1% TFA含有系)) にて分取し、得られた画分に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後、減圧下濃縮し、標題化合物 (0.520 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.31-1.46 (3H, m), 2.48 (3H, s), 2.63 (3H, s), 3.86 (3H, s), 3.96 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.08 (1H, s), 7.10 (2H, t, J = 8.0 Hz), 7.16-7.32 (4H, m), 7.96 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 381.2. Ethyl 4- (3- (bromomethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (1.00 g), 3- (methylthio) phenylboron obtained in Example 108-D) A DME solution (10 mL) of acid (0.598 g), tripotassium phosphate (1.888 g), and tetrakis (triphenylphosphine) palladium (0) (0.343 g) was heated and stirred at 140 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was fractionated by column chromatography (ethyl acetate / hexane) and HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. And extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.520 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.31-1.46 (3H, m), 2.48 (3H, s), 2.63 (3H, s), 3.86 (3H, s), 3.96 (2H, s), 4.38 ( 2H, q, J = 7.2 Hz), 6.08 (1H, s), 7.10 (2H, t, J = 8.0 Hz), 7.16-7.32 (4H, m), 7.96 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 381.2.
実施例115
2-メチル-4-(1-メチル-3-(3-(メチルチオ)ベンジル)-1H-ピラゾール-5-イル)安息香酸 Example 115
2-Methyl-4- (1-methyl-3- (3- (methylthio) benzyl) -1H-pyrazol-5-yl) benzoic acid
Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181
　実施例114で得られたエチル 2-メチル-4-(1-メチル-3-(3-(メチルチオ)ベンジル)-1H-ピラゾール-5-イル)ベンゾアート(0.52 g)のTHF/エタノール溶液 (2/1、9 mL)へ1 N水酸化ナトリウム水溶液 (2.7 mL)を加え、室温で終夜撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (0.45 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.48 (3H, s), 2.69 (3H, s), 3.90 (3H, s), 3.97 (2H, s), 6.11 (1H, s), 7.03-7.16 (2H, m), 7.18-7.38 (4H, m), 8.11 (1H, d, J = 8.7 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 353.1. A THF / ethanol solution of ethyl 2-methyl-4- (1-methyl-3- (3- (methylthio) benzyl) -1H-pyrazol-5-yl) benzoate (0.52 g) obtained in Example 114 ( 2/1, 9 mL) was added 1 N aqueous sodium hydroxide solution (2.7 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.45 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.48 (3H, s), 2.69 (3H, s), 3.90 (3H, s), 3.97 (2H, s), 6.11 (1H, s), 7.03-7.16 ( 2H, m), 7.18-7.38 (4H, m), 8.11 (1H, d, J = 8.7 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 353.1.
実施例116
2-メチル-4-(1-メチル-3-(3-(メチルチオ)ベンジル)-1H-ピラゾール-5-イル)ベンズアミド Example 116
2-Methyl-4- (1-methyl-3- (3- (methylthio) benzyl) -1H-pyrazol-5-yl) benzamide
Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182
　実施例115で得られた2-メチル-4-(1-メチル-3-(3-(メチルチオ)ベンジル)-1H-ピラゾール-5-イル)安息香酸(0.45 g)、WSC (0.49 g)、HOBtアンモニア和物(0.389 g)のDMF溶液 (5 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し標題化合物 (0.418 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.48 (3H, s), 2.53 (3H, s), 3.85 (3H, s), 3.95 (2H, s), 5.80 (2H, brs), 6.06 (1H, s), 7.05-7.16 (2H, m), 7.18-7.30 (4H, m), 7.51 (1H, d, J = 7.6 Hz).
MS (ESI+): [M+H]+ 352.2. 2-methyl-4- (1-methyl-3- (3- (methylthio) benzyl) -1H-pyrazol-5-yl) benzoic acid obtained in Example 115 (0.45 g), WSC (0.49 g), A DMF solution (5 mL) of HOBt ammonia hydrate (0.389 g) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound (0.418 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.48 (3H, s), 2.53 (3H, s), 3.85 (3H, s), 3.95 (2H, s), 5.80 (2H, brs), 6.06 (1H, s), 7.05-7.16 (2H, m), 7.18-7.30 (4H, m), 7.51 (1H, d, J = 7.6 Hz).
MS (ESI +): [M + H] + 352.2.
実施例117
2-メチル-4-(1-メチル-3-(3-(メチルスルフィニル)ベンジル)-1H-ピラゾール-5-イル)ベンズアミド Example 117
2-Methyl-4- (1-methyl-3- (3- (methylsulfinyl) benzyl) -1H-pyrazol-5-yl) benzamide
Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183
　実施例116で得られた2-メチル-4-(1-メチル-3-(3-(メチルチオ)ベンジル)-1H-ピラゾール-5-イル)ベンズアミド(0.200 g)のDMF溶液(4 mL)へメタクロロ過安息香酸(100 mg)を0 ℃で加え、10分間撹拌した。反応混合物へチオ硫酸ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(メタノール/酢酸エチル)により精製し標題化合物 (0.120 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 2.73 (3H, s), 3.85 (3H, s), 4.06 (2H, s), 5.78 (2H, brs), 6.07 (1H, s), 7.19-7.33 (2H, m), 7.41-7.57 (4H, m), 7.61 (1H, s).
MS (ESI+): [M+H]+ 368.1. To a DMF solution (4 mL) of 2-methyl-4- (1-methyl-3- (3- (methylthio) benzyl) -1H-pyrazol-5-yl) benzamide (0.200 g) obtained in Example 116 Metachloroperbenzoic acid (100 mg) was added at 0 ° C. and stirred for 10 minutes. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (methanol / ethyl acetate) to give the title compound (0.120 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.54 (3H, s), 2.73 (3H, s), 3.85 (3H, s), 4.06 (2H, s), 5.78 (2H, brs), 6.07 (1H, s), 7.19-7.33 (2H, m), 7.41-7.57 (4H, m), 7.61 (1H, s).
MS (ESI +): [M + H] + 368.1.
実施例118
2-メチル-4-(1-メチル-3-(3-(メチルスルホニル)ベンジル)-1H-ピラゾール-5-イル)ベンズアミド Example 118
2-Methyl-4- (1-methyl-3- (3- (methylsulfonyl) benzyl) -1H-pyrazol-5-yl) benzamide
Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184
　実施例116で得られた2-メチル-4-(1-メチル-3-(3-(メチルチオ)ベンジル)-1H-ピラゾール-5-イル)ベンズアミド(0.200 g)のDMF溶液(5 mL)へメタクロロ過安息香酸(245 mg)を0 ℃で加え、30分間撹拌した。反応混合物へチオ硫酸ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(メタノール/酢酸エチル)により精製し標題化合物 (0.110 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 3.05 (3H, s), 3.85 (3H, s), 4.08 (2H, s), 5.78 (2H, brs), 6.07 (1H, s), 7.20-7.34 (2H, m), 7.46-7.67 (3H, m), 7.80 (1H, d, J = 7.5 Hz), 7.89 (1H, s).
MS (ESI+): [M+H]+ 384.2. To a DMF solution (5 mL) of 2-methyl-4- (1-methyl-3- (3- (methylthio) benzyl) -1H-pyrazol-5-yl) benzamide (0.200 g) obtained in Example 116 Metachloroperbenzoic acid (245 mg) was added at 0 ° C. and stirred for 30 minutes. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (methanol / ethyl acetate) to obtain the title compound (0.110 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.54 (3H, s), 3.05 (3H, s), 3.85 (3H, s), 4.08 (2H, s), 5.78 (2H, brs), 6.07 (1H, s), 7.20-7.34 (2H, m), 7.46-7.67 (3H, m), 7.80 (1H, d, J = 7.5 Hz), 7.89 (1H, s).
MS (ESI +): [M + H] + 384.2.
実施例119
エチル 4-(3-(3-ブロモ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート Example 119
Ethyl 4- (3- (3-bromo-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185
A) 3-ブロモ-5-フルオロフェニルボロン酸
　1,3-ジブロモ-5-フルオロベンゼン(2.80 g)のジエチルエーテル溶液(50 mL)へn-ブチルリチウムのヘキサン溶液(1.6 N、6.89 mL)を-78 ℃で加え、10分間撹拌した。反応混合物へトリイソプロピルボラート(2.8 mL)を加え、窒素雰囲気下室温で5時間撹拌した。反応混合物へ2N塩酸(20 mL)を加え、室温で1時間撹拌した。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させ、溶媒を減圧下留去した。得られた残渣をヘキサンで洗浄し標題化合物(0.71 g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.30-7.44 (1H, m), 7.46-8.15 (2H, m), OHピークは観測されなかった. A) 3-Bromo-5-fluorophenylboronic acid 1,3-dibromo-5-fluorobenzene (2.80 g) in diethyl ether (50 mL) and n-butyllithium in hexane (1.6 N, 6.89 mL) It added at -78 degreeC and stirred for 10 minutes. Triisopropyl borate (2.8 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with hexane to obtain the title compound (0.71 g).
1 H NMR (300 MHz, CDCl 3 ) δ 7.30-7.44 (1H, m), 7.46-8.15 (2H, m), no OH peak was observed.
B) エチル4-(3-(3-ブロモ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート
　実施例108-D)で得られたエチル 4-(3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(100 mg)、実施例119-A)で得られた 3-ブロモ-5-フルオロフェニルボロン酸(71.4 mg)、リン酸三カリウム (189 mg)、テトラキス（トリフェニルホスフィン）パラジウム（0） (34.3 mg)のDME溶液 (2 mL)をマイクロウェーブ照射下140 ℃で20分間加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (83.8 mg)を得た。
MS (ESI+): [M+H]+ 431.1. B) Ethyl 4- (3- (3-bromo-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate Ethyl 4-obtained in Example 108-D) 3-Bromo-5-fluorophenylboronic acid obtained in (3- (bromomethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (100 mg, Example 119-A) (71.4 mg), tripotassium phosphate (189 mg), tetrakis (triphenylphosphine) palladium (0) (34.3 mg) in DME (2 mL) were stirred with heating at 140 ° C. for 20 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (83.8 mg).
MS (ESI +): [M + H] + 431.1.
実施例120
エチル 4-(3-(3-フルオロ-5-(メチルスルホニル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート Example 120
Ethyl 4- (3- (3-fluoro-5- (methylsulfonyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186
　実施例119で得られたエチル 4-(3-(3-ブロモ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(22 mg)、ヨウ化銅 (146 mg)、(S)-ピロリジン-2-カルボン酸(23.49 mg)、水酸化ナトリウム(8.2 mg)、メタンスルホン酸ナトリウム(72.9 mg)のDMSO溶液 (1 mL)をマイクロウェーブ照射下160 ℃で1時間加熱撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (32 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.06 (3H, s), 3.88 (3H, s), 4.08 (2H, s), 4.39 (2H, q, J = 6.9 Hz), 6.13 (1H, s), 7.21-7.36 (3H, m), 7.50 (1H, d, J = 7.6 Hz), 7.70 (1H, s), 7.98 (1H, d, J = 8.3 Hz). Ethyl 4- (3- (3-bromo-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (22 mg) obtained in Example 119, copper iodide DMSO solution (1 mL) of (146 mg), (S) -pyrrolidine-2-carboxylic acid (23.49 mg), sodium hydroxide (8.2 mg), sodium methanesulfonate (72.9 mg) at 160 ° C under microwave irradiation And stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (32 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.06 (3H, s), 3.88 (3H, s), 4.08 (2H, s) , 4.39 (2H, q, J = 6.9 Hz), 6.13 (1H, s), 7.21-7.36 (3H, m), 7.50 (1H, d, J = 7.6 Hz), 7.70 (1H, s), 7.98 ( (1H, d, J = 8.3 Hz).
実施例121
4-(3-(3-フルオロ-5-(メチルスルホニル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸 Example 121
4- (3- (3-Fluoro-5- (methylsulfonyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187
　実施例120で得られたエチル 4-(3-(3-フルオロ-5-(メチルスルホニル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(32 mg)のTHF/エタノール溶液(1/1、2 mL)へ1 N水酸化ナトリウム水溶液(0.15 mL)を加え、室温で終夜撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (30 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.55 (3H, s), 3.06 (3H, s), 3.86 (3H, s), 4.08 (2H, s), 6.10 (1H, s), 7.18-7.38 (3H, m), 7.43-7.62 (2H, m), 7.70 (1H, s), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 403.2. Ethyl 4- (3- (3-fluoro-5- (methylsulfonyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (32 mg) obtained in Example 120 To a THF / ethanol solution (1/1, 2 mL) was added 1 N aqueous sodium hydroxide solution (0.15 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (30 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.55 (3H, s), 3.06 (3H, s), 3.86 (3H, s), 4.08 (2H, s), 6.10 (1H, s), 7.18-7.38 ( 3H, m), 7.43-7.62 (2H, m), 7.70 (1H, s), COOH peaks were not observed.
MS (ESI +): [M + H] + 403.2.
実施例122
4-(3-(3-フルオロ-5-(メチルスルホニル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンズアミド Example 122
4- (3- (3-Fluoro-5- (methylsulfonyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188
　実施例121で得られた4-(3-(3-フルオロ-5-(メチルスルホニル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸(29.8 mg)、WSC (71 mg)、HOBtアンモニア和物(34 mg)のDMF溶液 (1 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(NH、酢酸エチル/ヘキサン)およびHPLC (C18、移動相：水/アセトニトリル (0.1% 酢酸アンモニウム含有系)) にて分取し、得られた画分に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後、減圧下濃縮し、標題化合物 (12 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 2.55 (3H, s), 3.06 (3H, s), 3.86 (3H, s), 4.07 (2H, s), 5.88 (2H, d, J = 2.6 Hz), 6.10 (1H, s), 7.19-7.37 (3H, m), 7.45-7.58 (2H, m), 7.70 (1H, s).
MS (ESI+): [M+H]+ 402.2. 4- (3- (3-Fluoro-5- (methylsulfonyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid (29.8 mg), WSC obtained in Example 121 (71 mg), HOBt ammonia hydrate (34 mg) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was fractionated by column chromatography (NH, ethyl acetate / hexane) and HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% ammonium acetate)), and the obtained fraction was saturated with saturated carbonate. Aqueous sodium hydride was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (12 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.55 (3H, s), 3.06 (3H, s), 3.86 (3H, s), 4.07 (2H, s), 5.88 (2H, d, J = 2.6 Hz) , 6.10 (1H, s), 7.19-7.37 (3H, m), 7.45-7.58 (2H, m), 7.70 (1H, s).
MS (ESI +): [M + H] + 402.2.
実施例123
エチル 4-(3-(3-シクロプロピル-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート Example 123
Ethyl 4- (3- (3-cyclopropyl-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189
　実施例119で得られたエチル 4-(3-(3-ブロモ-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(500 mg)、シクロプロピルボロン酸(149 mg)、2 N 炭酸ナトリウム水溶液 (1.16 mL)、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) (95 mg)のDME溶液 (5 mL)をアルゴン雰囲気下90 ℃で終夜加熱撹拌した。反応混合物をセライトろ過し、溶媒を留去した。得られた残渣をシクロプロピルボロン酸(149 mg)、テトラキス（トリフェニルホスフィン）パラジウム（0）(134 mg)、リン酸三カリウム(738 mg)、臭素化ナトリウム(117 mg)のトルエン溶液(5 mL)へ加え、マイクロウェーブ照射下160 ℃で1時間加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (198 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.63-0.73 (2H, m), 0.89-1.02 (2H, m), 1.41 (3H, t, J = 7.0 Hz), 1.79-1.93 (1H, m), 2.63 (3H, s), 3.87 (3H, s), 3.93 (2H, s), 4.38 (2H, q, J = 6.9 Hz), 6.09 (1H, s), 6.56 (1H, d, J = 9.8 Hz), 6.77 (1H, d, J = 9.4 Hz), 6.84 (1H, s), 7.20-7.35 (2H, m), 7.97 (1H, d, J = 8.7 Hz).
MS (ESI+): [M+H]+ 393.3. Ethyl 4- (3- (3-bromo-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (500 mg), cyclopropylboron obtained in Example 119 Acid (149 mg), 2 N aqueous sodium carbonate solution (1.16 mL), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (95 mg) in DME (5 mL) under argon atmosphere The mixture was stirred at 90 ° C. overnight. The reaction mixture was filtered through celite, and the solvent was distilled off. The resulting residue was added to a toluene solution of cyclopropylboronic acid (149 mg), tetrakis (triphenylphosphine) palladium (0) (134 mg), tripotassium phosphate (738 mg), sodium bromide (117 mg) (5 mg and stirred under microwave irradiation at 160 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (198 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.63-0.73 (2H, m), 0.89-1.02 (2H, m), 1.41 (3H, t, J = 7.0 Hz), 1.79-1.93 (1H, m), 2.63 (3H, s), 3.87 (3H, s), 3.93 (2H, s), 4.38 (2H, q, J = 6.9 Hz), 6.09 (1H, s), 6.56 (1H, d, J = 9.8 Hz ), 6.77 (1H, d, J = 9.4 Hz), 6.84 (1H, s), 7.20-7.35 (2H, m), 7.97 (1H, d, J = 8.7 Hz).
MS (ESI +): [M + H] + 393.3.
実施例124
4-(3-(3-シクロプロピル-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸 Example 124
4- (3- (3-Cyclopropyl-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190
　実施例123で得られたエチル 4-(3-(3-シクロプロピル-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(0.200 g)のTHF/エタノール溶液 (1/1、4 mL)へ1 N水酸化ナトリウム水溶液(1.0 mL)を加え、室温で終夜撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (0.17 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.61-0.78 (2H, m), 0.87-1.07 (2H, m), 1.78-1.96 (1H, m), 2.70 (3H, s), 3.90 (3H, s), 3.95 (2H, s), 6.12 (1H, s), 6.57 (1H, d, J = 10.2 Hz), 6.78 (1H, d, J = 9.4 Hz), 6.85 (1H, s), 7.32(2H, d, J = 4.5 Hz), 8.12 (1H, d, J = 8.3 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 365.2. Ethyl 4- (3- (3-cyclopropyl-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (0.200 g) obtained in Example 123 in THF / A 1 N aqueous sodium hydroxide solution (1.0 mL) was added to the ethanol solution (1/1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.17 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.61-0.78 (2H, m), 0.87-1.07 (2H, m), 1.78-1.96 (1H, m), 2.70 (3H, s), 3.90 (3H, s ), 3.95 (2H, s), 6.12 (1H, s), 6.57 (1H, d, J = 10.2 Hz), 6.78 (1H, d, J = 9.4 Hz), 6.85 (1H, s), 7.32 (2H , d, J = 4.5 Hz), 8.12 (1H, d, J = 8.3 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 365.2.
実施例125
4-(3-(3-シクロプロピル-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンズアミド Example 125
4- (3- (3-Cyclopropyl-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000191
Figure JPOXMLDOC01-appb-C000191
　実施例124で得られた4-(3-(3-シクロプロピル-5-フルオロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチル安息香酸(0.180 g)、WSC (0.49 g)、HOBtアンモニア和物(0.389 g)のDMF溶液 (5 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(NH、酢酸エチル/ヘキサン)およびHPLC (C18、移動相：水/アセトニトリル (0.1% TFA含有系)) にて分取し、得られた画分に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後、減圧下濃縮し、標題化合物 (0.056 g) を得た。
1H NMR (300 MHz, CDCl3) δ 0.62-0.74 (2H, m), 0.89-1.02 (2H, m), 1.79-1.93 (1H, m), 2.54 (3H, s), 3.84 (3H, s), 3.92 (2H, s), 5.94 (2H, brs), 6.06 (1H, s), 6.56 (1H, d, J = 9.8 Hz), 6.77 (1H, d, J = 9.4 Hz), 6.84 (1H, s), 7.17-7.33 (2H, m), 7.52 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 364.2. 4- (3- (3-Cyclopropyl-5-fluorobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoic acid (0.180 g), WSC (0.49) obtained in Example 124. g) A DMF solution (5 mL) of HOBt ammonia hydrate (0.389 g) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was fractionated by column chromatography (NH, ethyl acetate / hexane) and HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), and the resulting fraction was saturated with hydrogen carbonate. An aqueous sodium solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.056 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.62-0.74 (2H, m), 0.89-1.02 (2H, m), 1.79-1.93 (1H, m), 2.54 (3H, s), 3.84 (3H, s ), 3.92 (2H, s), 5.94 (2H, brs), 6.06 (1H, s), 6.56 (1H, d, J = 9.8 Hz), 6.77 (1H, d, J = 9.4 Hz), 6.84 (1H , s), 7.17-7.33 (2H, m), 7.52 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 364.2.
実施例126
エチル 4-(3-(4-(2-メトキシ-2-オキソエチル)-3-ニトロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート Example 126
Ethyl 4- (3- (4- (2-methoxy-2-oxoethyl) -3-nitrobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000192
Figure JPOXMLDOC01-appb-C000192
A) メチル 2-(2-ニトロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)アセタート
　メチル 2-(4-ブロモ-2-ニトロフェニル)アセタート(1000 mg)、4,4,4',4',5,5,5',5'-オクタメチル-2,2'-ビ(1,3,2-ジオキサボロラン) (1112 mg)、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)(149 mg)、酢酸カリウム(1074 mg)の DME溶液(20 mL)を窒素雰囲気下80℃で終夜加熱撹拌した。反応混合物を水へ加え、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、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製して標題化合物を含む混合物(1420 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.36 (12H, s), 3.70 (3H, s), 4.04 (2H, s), 7.35 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7.5 Hz), 8.50 (1H, s). A) Methyl 2- (2-nitro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetate methyl 2- (4-bromo-2-nitro Phenyl) acetate (1000 mg), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (1112 mg), A DME solution (20 mL) of dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) (149 mg) and potassium acetate (1074 mg) was stirred with heating at 80 ° C. overnight under a nitrogen atmosphere. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give a mixture (1420 mg) containing the title compound.
1 H NMR (300 MHz, CDCl 3 ) δ 1.36 (12H, s), 3.70 (3H, s), 4.04 (2H, s), 7.35 (1H, d, J = 7.5 Hz), 7.98 (1H, d, J = 7.5 Hz), 8.50 (1H, s).
B) エチル4-(3-(4-(2-メトキシ-2-オキソエチル)-3-ニトロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート
　実施例108-D)で得られたエチル 4-(3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(1.376 g)、実施例126-A)で得られたメチル 2-(2-ニトロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)アセタート(1.17 g)、リン酸三カリウム (2.60 g)、テトラキス（トリフェニルホスフィン）パラジウム（0）(0.471 g)のDME溶液 (10 mL)をマイクロウェーブ照射下140 ℃で30分間加熱撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (1.05 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.71 (3H, s), 3.87 (3H, s), 3.99 (2H, s), 4.07 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.12 (1H, s), 7.23-7.33 (3H, m), 7.54 (1H, dd, J = 7.9, 1.5 Hz), 7.98 (1H, d, J = 8.7 Hz), 8.05 (1H, s).
MS (ESI+): [M+H]+ 452.2. B) Ethyl 4- (3- (4- (2-methoxy-2-oxoethyl) -3-nitrobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate Example 108-D Ethyl 4- (3- (bromomethyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate (1.376 g) obtained in Example 126-A) -(2-Nitro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetate (1.17 g), tripotassium phosphate (2.60 g), tetrakis A DME solution (10 mL) of (triphenylphosphine) palladium (0) (0.471 g) was heated and stirred at 140 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (1.05 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 2.64 (3H, s), 3.71 (3H, s), 3.87 (3H, s), 3.99 (2H, s) , 4.07 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.12 (1H, s), 7.23-7.33 (3H, m), 7.54 (1H, dd, J = 7.9, 1.5 Hz), 7.98 (1H, d, J = 8.7 Hz), 8.05 (1H, s).
MS (ESI +): [M + H] + 452.2.
実施例127
エチル 4-(3-(3-アミノ-4-(2-メトキシ-2-オキソエチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート Example 127
Ethyl 4- (3- (3-amino-4- (2-methoxy-2-oxoethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000193
Figure JPOXMLDOC01-appb-C000193
　実施例126で得られたエチル 4-(3-(4-(2-メトキシ-2-オキソエチル)-3-ニトロベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(1.05 g)のエタノール溶液(5 mL)へ10% パラジウム炭素(0.248 g)を加え、水素雰囲気下室温で終夜撹拌した。反応混合物をセライトろ過し、溶媒を減圧留去し標題化合物(0.700 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.0 Hz), 2.63 (3H, s), 3.53 (2H, s), 3.67 (3H, s), 3.86 (3H, s), 3.88 (2H, s), 4.03 (2H, brs), 4.38 (2H, q, J = 7.2 Hz), 6.10 (1H, s), 6.62-6.77 (2H, m), 7.02 (1H, d, J = 7.6 Hz), 7.21-7.32 (2H, m), 7.96 (1H, d, J = 8.7 Hz).
MS (ESI+): [M+H]+ 422.3. Ethyl 4- (3- (4- (2-methoxy-2-oxoethyl) -3-nitrobenzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate obtained in Example 126 10% Palladium carbon (0.248 g) was added to an ethanol solution (5 mL) of (1.05 g), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound (0.700 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.0 Hz), 2.63 (3H, s), 3.53 (2H, s), 3.67 (3H, s), 3.86 (3H, s) , 3.88 (2H, s), 4.03 (2H, brs), 4.38 (2H, q, J = 7.2 Hz), 6.10 (1H, s), 6.62-6.77 (2H, m), 7.02 (1H, d, J = 7.6 Hz), 7.21-7.32 (2H, m), 7.96 (1H, d, J = 8.7 Hz).
MS (ESI +): [M + H] + 422.3.
実施例128
2-メチル-4-(1-メチル-3-((2-オキソインドリン-6-イル)メチル)-1H-ピラゾール-5-イル)安息香酸 Example 128
2-Methyl-4- (1-methyl-3-((2-oxoindoline-6-yl) methyl) -1H-pyrazol-5-yl) benzoic acid
Figure JPOXMLDOC01-appb-C000194
Figure JPOXMLDOC01-appb-C000194
　実施例127で得られたエチル 4-(3-(3-アミノ-4-(2-メトキシ-2-オキソエチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルベンゾアート(20 mg)、28%アンモニア水溶液(0.5 mL)、シアン化ナトリウム(2.0 mg)のNMP溶液(0.5 mL)をマイクロウェーブ照射下150℃で30分間加熱撹拌した。反応混合物に水を加え、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後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去し標題化合物 (14 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.67 (3H, s), 3.50 (2H, s), 3.88 (3H, s), 3.97 (2H, s), 6.11 (1H, s), 6.85 (1H, s), 6.98 (1H, d, J = 7.2 Hz), 7.15 (1H, d, J = 7.6 Hz), 7.27 (2H, s), 8.00-8.13 (1H, m), 8.28 (1H, brs), COOHピークは観測されなかった. Ethyl 4- (3- (3-amino-4- (2-methoxy-2-oxoethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylbenzoate obtained in Example 127 (20 mg), 28% aqueous ammonia (0.5 mL), and sodium cyanide (2.0 mg) in NMP (0.5 mL) were heated and stirred at 150 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (14 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.67 (3H, s), 3.50 (2H, s), 3.88 (3H, s), 3.97 (2H, s), 6.11 (1H, s), 6.85 (1H, s), 6.98 (1H, d, J = 7.2 Hz), 7.15 (1H, d, J = 7.6 Hz), 7.27 (2H, s), 8.00-8.13 (1H, m), 8.28 (1H, brs), No COOH peak was observed.
実施例129
2-メチル-4-(1-メチル-3-((2-オキソインドリン-6-イル)メチル)-1H-ピラゾール-5-イル)ベンズアミド Example 129
2-Methyl-4- (1-methyl-3-((2-oxoindoline-6-yl) methyl) -1H-pyrazol-5-yl) benzamide
Figure JPOXMLDOC01-appb-C000195
Figure JPOXMLDOC01-appb-C000195
　実施例128で得られた2-メチル-4-(1-メチル-3-((2-オキソインドリン-6-イル)メチル)-1H-ピラゾール-5-イル)安息香酸(14 mg) 、WSC (15 mg)、HOBtアンモニア和物(12 mg)のDMF溶液 (1 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(NH、酢酸エチル/ヘキサン)およびHPLC (C18、移動相：水/アセトニトリル (0.1% 酢酸アンモニウム含有系)) にて分取し、得られた画分に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後、減圧下濃縮し、標題化合物 (10 mg) を得た。
1H NMR (300 MHz, CD3OD) δ 2.38 (3H, s), 3.38 (2H, s), 3.54 (1H, s), 3.72 (3H, s), 3.82 (2H, s), 4.47 (2H, brs), 6.05 (1H, s), 6.72 (1H, s), 6.84 (1H, d, J = 7.2 Hz), 7.06 (1H, d, J = 7.5 Hz), 7.17-7.31 (2H, m), 7.41 (1H, d, J = 7.5 Hz).
MS (ESI+): [M+H]+ 361.2. 2-methyl-4- (1-methyl-3-((2-oxoindoline-6-yl) methyl) -1H-pyrazol-5-yl) benzoic acid (14 mg) obtained in Example 128, WSC (15 mg), HOBt ammonia hydrate (12 mg) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was fractionated by column chromatography (NH, ethyl acetate / hexane) and HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% ammonium acetate)), and the obtained fraction was saturated with saturated carbonate. Aqueous sodium hydride was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (10 mg).
1 H NMR (300 MHz, CD 3 OD) δ 2.38 (3H, s), 3.38 (2H, s), 3.54 (1H, s), 3.72 (3H, s), 3.82 (2H, s), 4.47 (2H , brs), 6.05 (1H, s), 6.72 (1H, s), 6.84 (1H, d, J = 7.2 Hz), 7.06 (1H, d, J = 7.5 Hz), 7.17-7.31 (2H, m) , 7.41 (1H, d, J = 7.5 Hz).
MS (ESI +): [M + H] + 361.2.
実施例130
エチル 2-メチル-4-{1-メチル-3-[(3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}ベンゾアート Example 130
Ethyl 2-methyl-4- {1-methyl-3-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H-pyrazol-5-yl} Benzoart
Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196
　実施例108-D)で合成したエチル 4-[3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル]-2-メチルベンゾアート(2.0 g)、6-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-2H-1,4-ベンゾオキサジン-3(4H)-オン(3.26 g)、テトラキス（トリフェニルホスフィン）パラジウム（0）(343 mg)、リン酸カリウム(3.78 g)およびDME(15 mL)の混合物をマイクロウェーブ照射下、140℃で1時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(NH、酢酸エチル/ヘキサン)で精製することにより、標題化合物(210 mg)を得た。
MS (ESI+): [M+H]+ 406.3.
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 2.62 (3H, s), 3.85 (3H, s), 3.90 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 4.56 (2H, s), 6.08 (1H, s), 6.78 (1H, s), 6.85-6.95 (2H, m), 7.21-7.29 (2H, m), 7.96 (1H, d, J = 8.3 Hz), 9.10 (1H, brs). Ethyl 4- [3- (bromomethyl) -1-methyl-1H-pyrazol-5-yl] -2-methylbenzoate (2.0 g), 6- (4,4,5) synthesized in Example 108-D) , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-1,4-benzoxazin-3 (4H) -one (3.26 g), tetrakis (triphenylphosphine) palladium (0) ( 343 mg), potassium phosphate (3.78 g) and DME (15 mL) were stirred at 140 ° C. for 1 hour under microwave irradiation. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (210 mg).
MS (ESI +): [M + H] + 406.3.
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 2.62 (3H, s), 3.85 (3H, s), 3.90 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 4.56 (2H, s), 6.08 (1H, s), 6.78 (1H, s), 6.85-6.95 (2H, m), 7.21-7.29 (2H, m), 7.96 (1H, d , J = 8.3 Hz), 9.10 (1H, brs).
実施例131
2-メチル-4-{1-メチル-3-[(3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}安息香酸 Example 131
2-Methyl-4- {1-methyl-3-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H-pyrazol-5-yl} benzoate acid
Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197
　実施例30と同様にして、実施例130で合成したエチル 2-メチル-4-{1-メチル-3-[(3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}ベンゾアートを用いて標題化合物を合成した。
MS (ESI+): [M+H]+ 378.2.
1H NMR (300 MHz, DMSO-d6) δ 2.56 (3H, s), 3.79 (2H, s), 3.82 (3H, s), 4.51 (2H, s), 6.23 (1H, s), 6.77-6.91 (3H, m), 7.37-7.47 (2H, m), 7.89 (1H, d, J = 7.9 Hz), 10.61 (1H, s), 12.95 (1H, brs). In the same manner as in Example 30, ethyl 2-methyl-4- {1-methyl-3-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6) synthesized in Example 130 The title compound was synthesized using -yl) methyl] -1H-pyrazol-5-yl} benzoate.
MS (ESI +): [M + H] + 378.2.
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.56 (3H, s), 3.79 (2H, s), 3.82 (3H, s), 4.51 (2H, s), 6.23 (1H, s), 6.77- 6.91 (3H, m), 7.37-7.47 (2H, m), 7.89 (1H, d, J = 7.9 Hz), 10.61 (1H, s), 12.95 (1H, brs).
実施例132
2-メチル-4-{1-メチル-3-[(3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}ベンズアミド Example 132
2-Methyl-4- {1-methyl-3-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H-pyrazol-5-yl} benzamide
Figure JPOXMLDOC01-appb-C000198
Figure JPOXMLDOC01-appb-C000198
　実施例131で合成した2-メチル-4-{1-メチル-3-[(3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}安息香酸(23 mg)、HOBtアンモニア和物(9.3 mg)、WSC塩酸塩(12 mg)およびDMF(1 mL)の混合物を室温で4時間撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣を酢酸エチル-ヘキサン混合溶媒中に懸濁させ、生じた固体をろ取することにより、標題化合物(16 mg)を得た。
MS (ESI+): [M+H]+ 377.2.
1H NMR (300 MHz, DMSO-d6) δ 2.40 (3H, s), 3.78 (2H, s), 3.80 (3H, s), 4.51 (2H, s), 6.17 (1H, s), 6.79-6.89 (3H, m), 7.31-7.47 (4H, m), 7.78 (1H, brs), 10.62 (1H, s). 2-Methyl-4- {1-methyl-3-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H-pyrazole synthesized in Example 131 A mixture of -5-yl} benzoic acid (23 mg), HOBt ammonia solvate (9.3 mg), WSC hydrochloride (12 mg) and DMF (1 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was suspended in a mixed solvent of ethyl acetate-hexane, and the resulting solid was collected by filtration to give the title compound (16 mg).
MS (ESI +): [M + H] + 377.2.
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.40 (3H, s), 3.78 (2H, s), 3.80 (3H, s), 4.51 (2H, s), 6.17 (1H, s), 6.79- 6.89 (3H, m), 7.31-7.47 (4H, m), 7.78 (1H, brs), 10.62 (1H, s).
実施例133
エチル 2-メチル-4-{1-メチル-3-[(4-メチル-3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}ベンゾアート Example 133
Ethyl 2-methyl-4- {1-methyl-3-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H-pyrazole- 5-yl} benzoate
Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199
　実施例130で合成したエチル 2-メチル-4-{1-メチル-3-[(3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}ベンゾアート(60 mg)のDMF(1 mL)溶液を0℃に冷却し、水素化ナトリウム(60%, 7.1 mg)を加えた。反応混合物を1時間撹拌した後、ヨウ化メチル(0.014 mL)を加えた。反応混合物を室温まで昇温し、3時間撹拌した後、酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(NH、酢酸エチル/ヘキサン)で精製することにより、標題化合物(47 mg)を得た。
MS (ESI+): [M+H]+ 420.1.
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.1 Hz), 2.63 (3H, s), 3.34 (3H, s), 3.86 (3H, s), 3.96 (2H, s), 4.37 (2H, q, J = 7.1 Hz), 4.58 (2H, s), 6.09 (1H, s), 6.87-6.98 (3H, m), 7.22-7.29 (2H, m), 7.93-7.99 (1H, m). Ethyl 2-methyl-4- {1-methyl-3-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H- synthesized in Example 130 A solution of pyrazol-5-yl} benzoate (60 mg) in DMF (1 mL) was cooled to 0 ° C., and sodium hydride (60%, 7.1 mg) was added. The reaction mixture was stirred for 1 hour and then methyl iodide (0.014 mL) was added. The reaction mixture was warmed to room temperature, stirred for 3 hours, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (47 mg).
MS (ESI +): [M + H] + 420.1.
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.1 Hz), 2.63 (3H, s), 3.34 (3H, s), 3.86 (3H, s), 3.96 (2H, s) , 4.37 (2H, q, J = 7.1 Hz), 4.58 (2H, s), 6.09 (1H, s), 6.87-6.98 (3H, m), 7.22-7.29 (2H, m), 7.93-7.99 (1H , m).
実施例134
2-メチル-4-{1-メチル-3-[(4-メチル-3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}安息香酸 Example 134
2-Methyl-4- {1-methyl-3-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H-pyrazole-5 -Il} benzoic acid
Figure JPOXMLDOC01-appb-C000200
Figure JPOXMLDOC01-appb-C000200
　実施例30と同様にして、実施例133で合成したエチル 2-メチル-4-{1-メチル-3-[(4-メチル-3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}ベンゾアートを用いて標題化合物を合成した。
MS (ESI+): [M+H]+ 392.3.
1H NMR (300 MHz, CDCl3) δ 2.70 (3H, s), 3.35 (3H, s), 3.91 (3H, s), 3.99 (2H, s), 4.59 (2H, s), 6.13 (1H, s), 6.89-7.00 (3H, m), 7.28-7.35 (2H, m), 8.08-8.14 (1H, m), COOHピークは観測されなかった. In the same manner as in Example 30, ethyl 2-methyl-4- {1-methyl-3-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-) synthesized in Example 133 was used. The title compound was synthesized using benzooxazin-6-yl) methyl] -1H-pyrazol-5-yl} benzoate.
MS (ESI +): [M + H] + 392.3.
1 H NMR (300 MHz, CDCl 3 ) δ 2.70 (3H, s), 3.35 (3H, s), 3.91 (3H, s), 3.99 (2H, s), 4.59 (2H, s), 6.13 (1H, s), 6.89-7.00 (3H, m), 7.28-7.35 (2H, m), 8.08-8.14 (1H, m), no COOH peak was observed.
実施例135
2-メチル-4-{1-メチル-3-[(4-メチル-3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}ベンズアミド Example 135
2-Methyl-4- {1-methyl-3-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] -1H-pyrazole-5 -Il} benzamide
Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201
　実施例134で合成した2-メチル-4-{1-メチル-3-[(4-メチル-3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-6-イル)メチル]-1H-ピラゾール-5-イル}安息香酸(40 mg)、HOBtアンモニア和物(19 mg)、WSC塩酸塩(24 mg)およびDMF(1 mL)の混合物を室温で4時間撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣を酢酸エチル-THFから再結晶することにより、標題化合物(11 mg)を得た。
MS (ESI+): [M+H]+ 391.1.
1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 3.35 (3H, s), 3.85 (3H, s), 3.96 (2H, s), 4.59 (2H, s), 5.73 (2H, brs), 6.07 (1H, s), 6.89-6.98 (3H, m), 7.19-7.28 (2H, m), 7.52 (1H, d, J = 7.6 Hz). 2-Methyl-4- {1-methyl-3-[(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) methyl] synthesized in Example 134 A mixture of -1H-pyrazol-5-yl} benzoic acid (40 mg), HOBt ammonia solvate (19 mg), WSC hydrochloride (24 mg) and DMF (1 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-THF to give the title compound (11 mg).
MS (ESI +): [M + H] + 391.1.
1 H NMR (300 MHz, CDCl 3 ) δ 2.54 (3H, s), 3.35 (3H, s), 3.85 (3H, s), 3.96 (2H, s), 4.59 (2H, s), 5.73 (2H, brs), 6.07 (1H, s), 6.89-6.98 (3H, m), 7.19-7.28 (2H, m), 7.52 (1H, d, J = 7.6 Hz).
実施例136
エチル 4-{3-[(4-フルオロ-1-メチル-1H-インダゾール-6-イル)メチル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート Example 136
Ethyl 4- {3-[(4-Fluoro-1-methyl-1H-indazol-6-yl) methyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000202
Figure JPOXMLDOC01-appb-C000202
A) 6-ブロモ-4-フルオロ-1-メチル-1H-インダゾール
　6-ブロモ-4-フルオロ-1H-インダゾール(500 mg)のDMF(5 mL)溶液を0℃に冷却し、水素化ナトリウム(60%, 112 mg)を加えた。反応混合物を30分間撹拌した後、ヨウ化メチル(0.22 mL)を加え、さらに一晩撹拌した。反応混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(320 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 4.04 (3H, s), 6.95 (1H, dd, J = 9.3, 1.3 Hz), 7.37-7.39 (1H, m), 8.00 (1H, d, J = 0.8 Hz). A) 6-Bromo-4-fluoro-1-methyl-1H-indazole 6-Bromo-4-fluoro-1H-indazole (500 mg) in DMF (5 mL) was cooled to 0 ° C. and sodium hydride ( 60%, 112 mg) was added. The reaction mixture was stirred for 30 minutes, then methyl iodide (0.22 mL) was added and further stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (320 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 4.04 (3H, s), 6.95 (1H, dd, J = 9.3, 1.3 Hz), 7.37-7.39 (1H, m), 8.00 (1H, d, J = 0.8 Hz).
B) 4-フルオロ-1-メチル-6-(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-インダゾール
　実施例136-A)で合成した6-ブロモ-4-フルオロ-1-メチル-1H-インダゾール(300 mg)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(108 mg)、ビス(ピナコラート)ジボロン(399 mg)、酢酸カリウム(257 mg)およびDMF(3 mL)の混合物を80℃で3時間撹拌した。反応混合物を酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(309 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.38 (12H, s), 4.11 (3H, s), 7.17 (1H, d, J = 10.6 Hz), 7.68 (1H, s), 8.04 (1H, d, J = 0.8 Hz). B) 4-Fluoro-1-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole synthesized in Example 136-A) 6 -Bromo-4-fluoro-1-methyl-1H-indazole (300 mg), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (108 mg), bis (pinacolato) A mixture of diboron (399 mg), potassium acetate (257 mg) and DMF (3 mL) was stirred at 80 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (309 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.38 (12H, s), 4.11 (3H, s), 7.17 (1H, d, J = 10.6 Hz), 7.68 (1H, s), 8.04 (1H, d, J = 0.8 Hz).
C) エチル 4-{3-[(4-フルオロ-1-メチル-1H-インダゾール-6-イル)メチル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート
　実施例108-D)で合成したエチル 4-[3-(ブロモメチル)-1-メチル-1H-ピラゾール-5-イル]-2-メチルベンゾアート(354 mg)、実施例136-B)で合成した4-フルオロ-1-メチル-6-(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-インダゾール(290 mg)、テトラキス（トリフェニルホスフィン）パラジウム（0）(61 mg)、リン酸カリウム(669 mg)およびDME(3 mL)の混合物をマイクロウェーブ照射下、150℃で20分間撹拌した。反応混合物をセライトろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(227 mg)を得た。
MS (ESI+): [M+H]+ 407.2.
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 2.63 (3H, s), 3.88 (3H, s), 4.04 (3H, s), 4.10 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.13 (1H, s), 6.77 (1H, d, J = 10.9 Hz), 7.11 (1H, s), 7.24-7.30 (2H, m), 7.93-8.00 (2H, m). C) Ethyl 4- {3-[(4-Fluoro-1-methyl-1H-indazol-6-yl) methyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoate Example 108 -D) ethyl 4- [3- (bromomethyl) -1-methyl-1H-pyrazol-5-yl] -2-methylbenzoate (354 mg), synthesized in Example 136-B) Fluoro-1-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (290 mg), tetrakis (triphenylphosphine) palladium (0 ) (61 mg), potassium phosphate (669 mg) and DME (3 mL) were stirred at 150 ° C. for 20 minutes under microwave irradiation. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (227 mg).
MS (ESI +): [M + H] + 407.2.
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 2.63 (3H, s), 3.88 (3H, s), 4.04 (3H, s), 4.10 (2H, s) , 4.38 (2H, q, J = 7.2 Hz), 6.13 (1H, s), 6.77 (1H, d, J = 10.9 Hz), 7.11 (1H, s), 7.24-7.30 (2H, m), 7.93- 8.00 (2H, m).
実施例137
4-{3-[(4-フルオロ-1-メチル-1H-インダゾール-6-イル)メチル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸 Example 137
4- {3-[(4-Fluoro-1-methyl-1H-indazol-6-yl) methyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203
　実施例30と同様にして、実施例136で合成したエチル 4-{3-[(4-フルオロ-1-メチル-1H-インダゾール-6-イル)メチル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンゾアートを用いて標題化合物を合成した。
MS (ESI+): [M+H]+ 379.1.
1H NMR (300 MHz, CDCl3) δ2.69 (3H, s), 3.91 (3H, s), 4.05 (3H, s), 4.12 (2H, s), 6.15 (1H, s), 6.77 (1H, dd, J = 10.9, 0.8 Hz), 7.12 (1H, s), 7.29-7.34 (2H, m), 7.98 (1H, d, J = 0.8 Hz), 8.11 (1H, d, J = 8.7 Hz), COOHピークは観測されなかった. Ethyl 4- {3-[(4-fluoro-1-methyl-1H-indazol-6-yl) methyl] -1-methyl-1H-pyrazole-5 synthesized in Example 136 in the same manner as in Example 30 The title compound was synthesized using -yl} -2-methylbenzoate.
MS (ESI +): [M + H] + 379.1.
1 H NMR (300 MHz, CDCl 3 ) δ 2.69 (3H, s), 3.91 (3H, s), 4.05 (3H, s), 4.12 (2H, s), 6.15 (1H, s), 6.77 (1H , dd, J = 10.9, 0.8 Hz), 7.12 (1H, s), 7.29-7.34 (2H, m), 7.98 (1H, d, J = 0.8 Hz), 8.11 (1H, d, J = 8.7 Hz) , COOH peak was not observed.
実施例138
4-{3-[(4-フルオロ-1-メチル-1H-インダゾール-6-イル)メチル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 138
4- {3-[(4-Fluoro-1-methyl-1H-indazol-6-yl) methyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204
　実施例137で合成した4-{3-[(4-フルオロ-1-メチル-1H-インダゾール-6-イル)メチル]-1-メチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(150 mg)、HOBtアンモニア和物(72 mg)、WSC塩酸塩(91 mg)およびDMF(2 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製した後、酢酸エチル-ヘキサンから再結晶することにより、標題化合物(110 mg)を得た。
MS (ESI+): [M+H]+ 378.4.
1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 3.86 (3H, s), 4.04 (3H, s), 4.10 (2H, s), 5.75 (2H, brs), 6.10 (1H, s), 6.76 (1H, dd, J = 10.8, 0.8 Hz), 7.11 (1H, s), 7.22-7.29 (2H, m), 7.52 (1H, d, J = 7.6 Hz), 7.97 (1H, d, J = 0.8 Hz). 4- {3-[(4-Fluoro-1-methyl-1H-indazol-6-yl) methyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzoic acid synthesized in Example 137 A mixture of (150 mg), HOBt ammonia solvate (72 mg), WSC hydrochloride (91 mg) and DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and recrystallized from ethyl acetate-hexane to give the title compound (110 mg).
MS (ESI +): [M + H] + 378.4.
1 H NMR (300 MHz, CDCl 3 ) δ 2.54 (3H, s), 3.86 (3H, s), 4.04 (3H, s), 4.10 (2H, s), 5.75 (2H, brs), 6.10 (1H, s), 6.76 (1H, dd, J = 10.8, 0.8 Hz), 7.11 (1H, s), 7.22-7.29 (2H, m), 7.52 (1H, d, J = 7.6 Hz), 7.97 (1H, d , J = 0.8 Hz).
実施例139
エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンゾアート Example 139
Ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000205
Figure JPOXMLDOC01-appb-C000205
A) 2-[3-フルオロ-5-(トリフルオロメチル)フェニル]エタンチオアミド
　[3-フルオロ-5-(トリフルオロメチル)フェニル]アセトニトリル(25 g)、ジチオリン酸 O,O-ジエチル(26.6 mL)および4N塩化水素-酢酸エチル溶液(250 mL)の混合物を室温で一晩撹拌した。反応混合物をヘキサンで希釈し、水、1N水酸化ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残留物をヘキサン(500 mL)中に懸濁させ、生じた固体をろ取することにより、標題化合物(24.1 g)を得た。
MS (ESI+): [M+H]+ 238.0.
1H NMR (300 MHz, CDCl3) δ 4.10 (2H, s), 6.69 (1H, brs), 7.21-7.41 (3H, m), 7.56 (1H, brs). A) 2- [3-Fluoro-5- (trifluoromethyl) phenyl] ethanethioamide [3-Fluoro-5- (trifluoromethyl) phenyl] acetonitrile (25 g), dithiophosphate O, O-diethyl (26.6 mL) ) And 4N hydrogen chloride-ethyl acetate solution (250 mL) were stirred at room temperature overnight. The reaction mixture was diluted with hexane and washed with water, 1N aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was suspended in hexane (500 mL), and the resulting solid was collected by filtration to give the title compound (24.1 g).
MS (ESI +): [M + H] + 238.0.
1 H NMR (300 MHz, CDCl 3 ) δ 4.10 (2H, s), 6.69 (1H, brs), 7.21-7.41 (3H, m), 7.56 (1H, brs).
B) メチル 2-[3-フルオロ-5-(トリフルオロメチル)フェニル]エタンイミドチオアート　ヨウ化水素酸塩
　実施例139-A)で合成した 2-[3-フルオロ-5-(トリフルオロメチル)フェニル]エタンチオアミド(6.0 g)、ヨウ化メチル(2.37 mL)およびアセトン(30 mL)の混合物を室温で5時間撹拌した後、50℃でさらに2時間撹拌した。反応混合物を減圧濃縮して得られた残留物をイソプロピルエーテル中に懸濁させ、生じた固体をろ取することにより、標題化合物(9.2 g)を得た。
MS (ESI+): [M+H]+ 252.1.
1H NMR (300 MHz, DMSO-d6) δ 2.65 (3H, s), 4.35 (2H, s), 7.62-7.77 (3H, m), 11.67 (2H, brs). B) Methyl 2- [3-Fluoro-5- (trifluoromethyl) phenyl] ethaneimidethioate hydroiodide 2- [3-Fluoro-5- (trifluoromethyl) synthesized in Example 139-A) ) Phenyl] ethanethioamide (6.0 g), methyl iodide (2.37 mL) and acetone (30 mL) were stirred at room temperature for 5 hours and then at 50 ° C. for an additional 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was suspended in isopropyl ether, and the resulting solid was collected by filtration to give the title compound (9.2 g).
MS (ESI +): [M + H] + 252.1.
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.65 (3H, s), 4.35 (2H, s), 7.62-7.77 (3H, m), 11.67 (2H, brs).
C) エチル 4-フルオロ-2-メチルベンゾアート
　4-フルオロ-2-メチル安息香酸(25 g)、濃硫酸(3 mL)およびエタノール(500 mL)の混合物を2日間加熱還流した。反応混合物を減圧濃縮した後、残渣を酢酸エチルで希釈し、水、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後減圧濃縮することにより、標題化合物(26.3 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.39 (3H, t, J = 7.1 Hz), 2.61 (3H, s), 4.35 (2H, q, J = 7.1 Hz), 6.87-6.98 (2H, m), 7.90-7.99 (1H, m). C) Ethyl 4-fluoro-2-methylbenzoate A mixture of 4-fluoro-2-methylbenzoic acid (25 g), concentrated sulfuric acid (3 mL) and ethanol (500 mL) was heated to reflux for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (26.3 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.39 (3H, t, J = 7.1 Hz), 2.61 (3H, s), 4.35 (2H, q, J = 7.1 Hz), 6.87-6.98 (2H, m) , 7.90-7.99 (1H, m).
D) エチル 4-ヒドラジノ-2-メチルベンゾアート
　実施例139-C)で合成した エチル 4-フルオロ-2-メチルベンゾアート(20 g)、ヒドラジン一水和物(26.6 mL)およびDMSO(100 mL)の混合物を120℃で4時間撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥した後減圧濃縮することにより、標題化合物(18.3 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.36 (3H, t, J = 7.2 Hz), 2.58 (3H, s), 3.61 (2H, s), 4.30 (2H, q, J = 7.2 Hz), 5.44 (1H, brs), 6.59-6.64 (2H, m), 7.86-7.92 (1H, m). D) Ethyl 4-hydrazino-2-methylbenzoate Ethyl 4-fluoro-2-methylbenzoate (20 g), hydrazine monohydrate (26.6 mL) and DMSO (100 mL) synthesized in Example 139-C) ) Was stirred at 120 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (18.3 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.36 (3H, t, J = 7.2 Hz), 2.58 (3H, s), 3.61 (2H, s), 4.30 (2H, q, J = 7.2 Hz), 5.44 (1H, brs), 6.59-6.64 (2H, m), 7.86-7.92 (1H, m).
E) エチル 4-[2-{1-アミノ-2-[3-フルオロ-5-(トリフルオロメチル)フェニル]エチリデン}ヒドラジノ]-2-メチルベンゾアート　塩酸塩
　実施例139-B)で合成したメチル 2-[3-フルオロ-5-(トリフルオロメチル)フェニル]エタンイミドチオアート　ヨウ化水素酸塩(9.0 g)、実施例139-D)で合成したエチル 4-ヒドラジノ-2-メチルベンゾアート(4.61 g)およびエタノール(50 mL)の混合物を0℃で1時間撹拌した。反応混合物を減圧濃縮して得られた残渣を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。残渣をヘキサン-酢酸エチル混合溶媒で希釈し、生じた不溶の固体をろ過して除去した。ろ液を減圧濃縮して得られた残渣をヘキサン-酢酸エチル混合溶媒に溶解し、4N塩化水素-酢酸エチル溶液を加えた。生じた固体をろ取することにより、標題化合物(10.1 g)を得た。
MS (ESI+): [M+H]+ 398.2.
1H NMR (300 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.1 Hz), 2.42 (3H, s), 4.12 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.49 (1H, d, J = 2.1 Hz), 6.65 (1H, dd, J = 8.7, 2.1 Hz), 7.71-7.82 (2H, m), 7.87-7.99 (2H, m), 9.04 (1H, s), 9.35 (1H, brs), 10.05 (1H, brs), 12.10 (1H, brs). E) Ethyl 4- [2- {1-amino-2- [3-fluoro-5- (trifluoromethyl) phenyl] ethylidene} hydrazino] -2-methylbenzoate hydrochloride synthesized in Example 139-B) Methyl 2- [3-fluoro-5- (trifluoromethyl) phenyl] ethaneimidethioate Ethyl 4-hydrazino-2-methylbenzoate synthesized with hydroiodide (9.0 g), Example 139-D) A mixture of (4.61 g) and ethanol (50 mL) was stirred at 0 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was diluted with a hexane-ethyl acetate mixed solvent, and the resulting insoluble solid was removed by filtration. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in a hexane-ethyl acetate mixed solvent, and 4N hydrogen chloride-ethyl acetate solution was added. The resulting solid was collected by filtration to give the title compound (10.1 g).
MS (ESI +): [M + H] + 398.2.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.29 (3H, t, J = 7.1 Hz), 2.42 (3H, s), 4.12 (2H, s), 4.22 (2H, q, J = 7.1 Hz) , 6.49 (1H, d, J = 2.1 Hz), 6.65 (1H, dd, J = 8.7, 2.1 Hz), 7.71-7.82 (2H, m), 7.87-7.99 (2H, m), 9.04 (1H, s ), 9.35 (1H, brs), 10.05 (1H, brs), 12.10 (1H, brs).
F) エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンゾアート
　実施例139-E)で合成したエチル 4-[2-{1-アミノ-2-[3-フルオロ-5-(トリフルオロメチル)フェニル]エチリデン}ヒドラジノ]-2-メチルベンゾアート　塩酸塩(15 g)、オルト酢酸トリメチル(110 mL)および酢酸(0.99 mL)の混合物を100℃で2時間撹拌した。反応混合物を減圧濃縮して得られた残渣を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製し、得られた粗生成物をヘキサン中に懸濁させ、生じた固体をろ取することにより、標題化合物(11.9 g)を得た。
MS (ESI+): [M+H]+ 422.2.
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 2.54 (3H, s), 2.68 (3H, s), 4.13 (2H, s), 4.40 (2H, q, J = 7.2 Hz), 7.17-7.23 (1H, m), 7.27-7.46 (4H, m), 8.06 (1H, d, J = 8.3 Hz). F) Ethyl 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzoate Example 139 -E) ethyl 4- [2- {1-amino-2- [3-fluoro-5- (trifluoromethyl) phenyl] ethylidene} hydrazino] -2-methylbenzoate hydrochloride (15 g), A mixture of trimethyl orthoacetate (110 mL) and acetic acid (0.99 mL) was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), the obtained crude product was suspended in hexane, and the resulting solid was collected by filtration to give the title compound (11.9 g). Obtained.
MS (ESI +): [M + H] + 422.2.
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 2.54 (3H, s), 2.68 (3H, s), 4.13 (2H, s), 4.40 (2H, q, J = 7.2 Hz), 7.17-7.23 (1H, m), 7.27-7.46 (4H, m), 8.06 (1H, d, J = 8.3 Hz).
実施例140
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチル安息香酸 Example 140
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000206
Figure JPOXMLDOC01-appb-C000206
　実施例139で合成したエチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンゾアート(6.4 g)、4N水酸化ナトリウム水溶液(11.4 mL)およびエタノール(23 mL)の混合物を80℃で3時間撹拌した。反応混合物に1N塩酸を加えた後、酢酸エチル-THF混合溶媒で抽出した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をイソプロピルエーテル中に懸濁させ、生じた固体をろ取することにより、標題化合物(5.64 g)を得た。
MS (ESI+): [M+H]+ 394.2.
1H NMR (300 MHz, DMSO-d6) δ 2.49 (3H, s), 2.59 (3H, s), 4.17 (2H, s), 7.45-7.65 (5H, m), 7.95 (1H, d, J = 8.3 Hz), COOHピークは観測されなかった. Ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzo synthesized in Example 139 A mixture of Art (6.4 g), 4N aqueous sodium hydroxide solution (11.4 mL) and ethanol (23 mL) was stirred at 80 ° C. for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate-THF. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was suspended in isopropyl ether, and the resulting solid was collected by filtration to give the title compound (5.64 g).
MS (ESI +): [M + H] + 394.2.
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.49 (3H, s), 2.59 (3H, s), 4.17 (2H, s), 7.45-7.65 (5H, m), 7.95 (1H, d, J = 8.3 Hz), no COOH peak was observed.
実施例141
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンズアミド Example 141
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000207
Figure JPOXMLDOC01-appb-C000207
　実施例140で合成した4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチル安息香酸(5.4 g)、HOBtアンモニア和物(2.3 g)、WSC塩酸塩(2.9 g)およびDMF(50 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をエタノール-水から再結晶することにより、標題化合物(4.7 g)を得た。
MS (ESI+): [M+H]+ 393.2.
1H NMR (300 MHz, CDCl3) δ 2.52 (3H, s), 2.58 (3H, s), 4.13 (2H, s), 5.84 (1H, brs), 5.92 (1H, brs), 7.16-7.23 (1H, m), 7.27-7.47 (4H, m), 7.60 (1H, d, J = 8.2 Hz). 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzoic acid synthesized in Example 140 A mixture of (5.4 g), HOBt ammonia solvate (2.3 g), WSC hydrochloride (2.9 g) and DMF (50 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol-water to give the title compound (4.7 g).
MS (ESI +): [M + H] + 393.2.
1 H NMR (300 MHz, CDCl 3 ) δ 2.52 (3H, s), 2.58 (3H, s), 4.13 (2H, s), 5.84 (1H, brs), 5.92 (1H, brs), 7.16-7.23 ( 1H, m), 7.27-7.47 (4H, m), 7.60 (1H, d, J = 8.2 Hz).
実施例142
エチル 2-クロロ-4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル)ベンゾアート Example 142
Ethyl 2-chloro-4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -5-methyl-1H-1,2,4-triazol-1-yl) benzoate
Figure JPOXMLDOC01-appb-C000208
Figure JPOXMLDOC01-appb-C000208
A) エチル 2-クロロ-4-フルオロベンゾアート
　2-クロロ-4-フルオロ安息香酸(23.0 g)と濃硫酸(0.351 mL)のエタノール溶液(660 mL)を5日間加熱還流した。溶媒を減圧下留去した後、残渣を酢酸エチルで希釈し、1N 水酸化ナトリウム水溶液で中和した。水層を酢酸エチルで抽出し、合わせた有機層を水、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、溶媒を減圧下留去して標題化合物(22.9 g)を得た。
1H-NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 7.01-7.05 (1H, m), 7.20 (1H, dd, J = 8.4, 2.4 Hz), 7.89 (1H, dd, J = 8.8, 6.0 Hz). A) Ethyl 2-chloro-4-fluorobenzoate Ethanol solution (660 mL) of 2-chloro-4-fluorobenzoic acid (23.0 g) and concentrated sulfuric acid (0.351 mL) was heated to reflux for 5 days. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and neutralized with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (22.9 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 7.01-7.05 (1H, m), 7.20 (1H, dd , J = 8.4, 2.4 Hz), 7.89 (1H, dd, J = 8.8, 6.0 Hz).
B) エチル 2-クロロ-4-ヒドラジニルベンゾアート
　エチル 2-クロロ-4-フルオロベンゾアート(22.0 g)およびヒドラジン一水和物(7.25 mL)のエタノール溶液(68 mL)を22時間加熱還流した。反応混合物へ水を加え、析出した固体をろ取し、ヘキサンで洗浄して標題化合物(8.39 g)を得た。
1H-NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J = 7.2 Hz), 3.65 (2H, d, J = 2.0 Hz), 4.34 (2H, q, J = 7.2 Hz), 5.54 (1H, brs), 6.66 (1H, dd, J = 8.8, 2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 7.82 (1H, d, J = 8.8 Hz).
MS (ESI+): [M+H]+ 214.9. B) Ethyl 2-chloro-4-hydrazinylbenzoate Ethyl 2-chloro-4-fluorobenzoate (22.0 g) and hydrazine monohydrate (7.25 mL) in ethanol (68 mL) were heated to reflux for 22 hours. did. Water was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with hexane to obtain the title compound (8.39 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.38 (3H, t, J = 7.2 Hz), 3.65 (2H, d, J = 2.0 Hz), 4.34 (2H, q, J = 7.2 Hz), 5.54 ( 1H, brs), 6.66 (1H, dd, J = 8.8, 2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 7.82 (1H, d, J = 8.8 Hz).
MS (ESI +): [M + H] + 214.9.
C) エチル 2-クロロ-4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル)ベンゾアート
　実施例139-B)で合成したメチル 2-[3-フルオロ-5-(トリフルオロメチル)フェニル]エタンイミドチオアート　ヨウ化水素酸塩(1000 mg)のエタノール溶液(6 mL)へ実施例142-B)で得られたエチル 2-クロロ-4-ヒドラジニルベンゾアート(566 mg)を0 ℃で加え、2時間撹拌した。溶媒を減圧下留去し、得られた残渣へ1,1,1-トリメトキシエタン(9.94 ml)、酢酸(0.136 mL)を加え、100 ℃で終夜撹拌した。溶媒を減圧下留去し、得られた残渣を1 N塩酸に加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し標題化合物 (868 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz), 2.57 (3H, s), 4.13 (2H, s), 4.44 (2H, q, J = 7.2 Hz), 7.13-7.35 (2H, m), 7.39-7.52 (2H, m), 7.64 (1H, d, J = 1.9 Hz), 7.99 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 442.2. C) Ethyl 2-chloro-4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -5-methyl-1H-1,2,4-triazol-1-yl) benzoate Example 139 -B) methyl 2- [3-fluoro-5- (trifluoromethyl) phenyl] ethanimidothioate into a solution of hydroiodide (1000 mg) in ethanol (6 mL) Example 142-B) Ethyl 2-chloro-4-hydrazinylbenzoate (566 mg) obtained in 1 above was added at 0 ° C. and stirred for 2 hours. The solvent was evaporated under reduced pressure, and 1,1,1-trimethoxyethane (9.94 ml) and acetic acid (0.136 mL) were added to the resulting residue, followed by stirring at 100 ° C. overnight. The solvent was evaporated under reduced pressure, and the resulting residue was added to 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (868 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.43 (3H, t, J = 7.2 Hz), 2.57 (3H, s), 4.13 (2H, s), 4.44 (2H, q, J = 7.2 Hz), 7.13 -7.35 (2H, m), 7.39-7.52 (2H, m), 7.64 (1H, d, J = 1.9 Hz), 7.99 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 442.2.
実施例143
2-クロロ-4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル)安息香酸 Example 143
2-Chloro-4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -5-methyl-1H-1,2,4-triazol-1-yl) benzoic acid
Figure JPOXMLDOC01-appb-C000209
Figure JPOXMLDOC01-appb-C000209
　実施例142で得られたエチル 2-クロロ-4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル)ベンゾアート(868 mg)のTHF/エタノール溶液 (2/1、12 mL)へ1 N水酸化ナトリウム水溶液 (3.0 mL)を加え、室温で3時間終夜撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をジイソプロピルエーテルで洗浄し標題化合物 (783 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.52 (3H, s), 4.17 (2H, s), 7.49-7.59 (2H, m), 7.62 (1H, s), 7.68 (1H, dd, J = 8.3, 1.9 Hz), 7.83 (1H, d, J = 1.9 Hz), 7.96 (1H, d, J = 8.3 Hz), 13.64 (1H, brs).
MS (ESI+): [M+H]+ 414.1. Ethyl 2-chloro-4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -5-methyl-1H-1,2,4-triazol-1-yl) obtained in Example 142 To a THF / ethanol solution (2/1, 12 mL) of benzoate (868 mg) was added 1 N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 3 hours overnight. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (783 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.52 (3H, s), 4.17 (2H, s), 7.49-7.59 (2H, m), 7.62 (1H, s), 7.68 (1H, dd, J = 8.3, 1.9 Hz), 7.83 (1H, d, J = 1.9 Hz), 7.96 (1H, d, J = 8.3 Hz), 13.64 (1H, brs).
MS (ESI +): [M + H] + 414.1.
実施例144
2-クロロ-4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル)ベンズアミド Example 144
2-Chloro-4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -5-methyl-1H-1,2,4-triazol-1-yl) benzamide
Figure JPOXMLDOC01-appb-C000210
Figure JPOXMLDOC01-appb-C000210
　実施例143で得られた2-クロロ-4-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル)安息香酸(783 mg)、 WSC (544 mg)、HOBtアンモニア和物(432 mg)のDMF溶液 (8 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を再結晶 (酢酸エチル/ヘキサン)して、標題化合物 (580 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.57 (3H, s), 4.12 (2H, s), 5.80-6.55 (2H, m), 7.05-7.34 (2H, m), 7.34-7.52 (2H, m), 7.63 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 413.1. 2-Chloro-4- (3- (3-fluoro-5- (trifluoromethyl) benzyl) -5-methyl-1H-1,2,4-triazol-1-yl) benzoic acid obtained in Example 143 A DMF solution (8 mL) of acid (783 mg), WSC (544 mg), and HOBt ammonia hydrate (432 mg) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized (ethyl acetate / hexane) to give the title compound (580 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.57 (3H, s), 4.12 (2H, s), 5.80-6.55 (2H, m), 7.05-7.34 (2H, m), 7.34-7.52 (2H, m ), 7.63 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 413.1.
実施例145
4-{5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}-2-メチル安息香酸 Example 145
4- {5-Cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000211
Figure JPOXMLDOC01-appb-C000211
A) 2-[3-フルオロ-5-(トリフルオロメチル)フェニル]アセトアミド
　[3-フルオロ-5-(トリフルオロメチル)フェニル]アセトニトリル(10.0 g)、炭酸カリウム(1.36 g)、DMSO(50.0 mL)および水(0.50 mL)の混合物を0℃に冷却し、35%過酸化水素水(10.6 mL)をゆっくり滴下した。反応混合物を0℃で2時間撹拌した後、水を加えて希釈した。生じた固体をろ取することにより、標題化合物(10.8 g)を得た。
1H NMR (400 MHz, CDCl3) δ 3.63 (2H, s), 5.49-5.62 (2H, m), 7.23-7.28 (2H, m), 7.35 (1H, brs). A) 2- [3-Fluoro-5- (trifluoromethyl) phenyl] acetamide [3-Fluoro-5- (trifluoromethyl) phenyl] acetonitrile (10.0 g), potassium carbonate (1.36 g), DMSO (50.0 mL) ) And water (0.50 mL) were cooled to 0 ° C., and 35% aqueous hydrogen peroxide (10.6 mL) was slowly added dropwise. The reaction mixture was stirred at 0 ° C. for 2 hours and then diluted by adding water. The resulting solid was collected by filtration to give the title compound (10.8 g).
1 H NMR (400 MHz, CDCl 3 ) δ 3.63 (2H, s), 5.49-5.62 (2H, m), 7.23-7.28 (2H, m), 7.35 (1H, brs).
B) N-{2-[3-フルオロ-5-(トリフルオロメチル)フェニル]アセチル}シクロプロパンカルボキサミド
　実施例145-A)で合成した2-[3-フルオロ-5-(トリフルオロメチル)フェニル]アセトアミド(5.40 g)、シクロプロパンカルボニル クロリド(12.8 g)、濃硫酸(0.48 g)およびトルエン(100 mL)の混合物を100℃で2時間撹拌した。反応混合物を室温に冷却し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後減圧濃縮することにより、標題化合物(6.60 g)を得た。
1H NMR (400 MHz, CD3OD) δ 0.89-0.98 (4H, m), 1.95-1.99 (1H, m), 4.01 (2H, s), 7.28-7.33 (2H, m), 7.40-7.46 (1H, m), NHピークは観測されなかった. B) N- {2- [3-Fluoro-5- (trifluoromethyl) phenyl] acetyl} cyclopropanecarboxamide 2- [3-Fluoro-5- (trifluoromethyl) phenyl synthesized in Example 145-A) ] A mixture of acetamide (5.40 g), cyclopropanecarbonyl chloride (12.8 g), concentrated sulfuric acid (0.48 g) and toluene (100 mL) was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (6.60 g).
1 H NMR (400 MHz, CD 3 OD) δ 0.89-0.98 (4H, m), 1.95-1.99 (1H, m), 4.01 (2H, s), 7.28-7.33 (2H, m), 7.40-7.46 ( 1H, m), NH peak was not observed.
C) (4-ブロモ-3-メチルフェニル)ヒドラジン　塩酸塩
　4-ブロモ-3-メチルアニリン(10.0 g)と濃塩酸(50.0 mL)の混合物を0℃に冷却し、亜硝酸ナトリウム(4.45 g)の水(10.0 mL)溶液を滴下した。反応混合物を0℃で1時間撹拌した後、塩化スズ(II)(20.4 g)の濃塩酸(50.0 mL)溶液を滴下し、さらに2時間撹拌した。生じた固体をろ取しジエチルエーテルで洗浄することにより、標題化合物(11.1 g)を得た。
1H NMR (400 MHz, DMSO-d6) δ 2.50 (3H, s), 6.72-6.79 (1H, m), 6.92-7.00 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 8.34 (1H, brs), 10.2 (3H, brs). C) (4-Bromo-3-methylphenyl) hydrazine hydrochloride A mixture of 4-bromo-3-methylaniline (10.0 g) and concentrated hydrochloric acid (50.0 mL) was cooled to 0 ° C. and sodium nitrite (4.45 g) Of water (10.0 mL) was added dropwise. After the reaction mixture was stirred at 0 ° C. for 1 hour, a solution of tin (II) chloride (20.4 g) in concentrated hydrochloric acid (50.0 mL) was added dropwise, and the mixture was further stirred for 2 hours. The resulting solid was collected by filtration and washed with diethyl ether to give the title compound (11.1 g).
1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (3H, s), 6.72-6.79 (1H, m), 6.92-7.00 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 8.34 (1H, brs), 10.2 (3H, brs).
D) 1-(4-ブロモ-3-メチルフェニル)-5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール
　実施例145-B)で合成したN-{2-[3-フルオロ-5-(トリフルオロメチル)フェニル]アセチル}シクロプロパンカルボキサミド(4.08 g)、実施例145-C)で合成した(4-ブロモ-3-メチルフェニル)ヒドラジン　塩酸塩(4.97 g)およびピリジン(50.0 mL)の混合物を120℃で12時間撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(2.31 g)を得た。
1H NMR (400 MHz, CDCl3) δ 1.05-1.10 (2H, m), 1.17-1.21 (2H, m), 1.87-1.92 (1H, m), 2.47 (3H, s), 4.08 (2H, s), 7.16-7.19 (1H, m), 7.25-7.28 (2H, m), 7.42-7.43 (1H, m), 7.46 (1H, d, J = 2.8 Hz), 7.66 (1H, d, J = 8.4 Hz). D) 1- (4-Bromo-3-methylphenyl) -5-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4-triazole Example 145- B) synthesized with N- {2- [3-fluoro-5- (trifluoromethyl) phenyl] acetyl} cyclopropanecarboxamide (4.08 g), Example 145-C) (4-bromo-3- A mixture of methylphenyl) hydrazine hydrochloride (4.97 g) and pyridine (50.0 mL) was stirred at 120 ° C. for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.31 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.05-1.10 (2H, m), 1.17-1.21 (2H, m), 1.87-1.92 (1H, m), 2.47 (3H, s), 4.08 (2H, s ), 7.16-7.19 (1H, m), 7.25-7.28 (2H, m), 7.42-7.43 (1H, m), 7.46 (1H, d, J = 2.8 Hz), 7.66 (1H, d, J = 8.4 Hz).
E) メチル 4-{5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンゾアート
　実施例145-D)で合成した1-(4-ブロモ-3-メチルフェニル)-5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール(2.31 g)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン付加物(3.72 g)、N-エチルジイソプロピルアミン(15.4 g)およびメタノール(100 mL)の混合物を一酸化炭素雰囲気下、48時間加熱還流した。反応混合物を室温に冷却した後、不溶の固体をろ過して除去した。ろ液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(1.32 g)を得た。
1H NMR (400 MHz, CDCl3) δ 1.08-1.13 (2H, m), 1.20-1.25 (2H, m), 1.93-1.98 (1H, m), 1.98 (3H, s), 3.93 (3H, s), 4.09 (2H, s), 7.16-7.20 (1H, m), 7.24-7.30 (1H, m), 7.42-7.46 (1H, m), 7.47-7.51 (2H, m), 8.06 (1H, d, J = 8.4 Hz). E) Methyl 4- {5-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} -2-methylbenzoate Examples 1- (4-Bromo-3-methylphenyl) -5-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4- Mixture of triazole (2.31 g), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (3.72 g), N-ethyldiisopropylamine (15.4 g) and methanol (100 mL) Was heated to reflux for 48 hours under a carbon monoxide atmosphere. After the reaction mixture was cooled to room temperature, the insoluble solid was removed by filtration. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.32 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.08-1.13 (2H, m), 1.20-1.25 (2H, m), 1.93-1.98 (1H, m), 1.98 (3H, s), 3.93 (3H, s ), 4.09 (2H, s), 7.16-7.20 (1H, m), 7.24-7.30 (1H, m), 7.42-7.46 (1H, m), 7.47-7.51 (2H, m), 8.06 (1H, d , J = 8.4 Hz).
F) 4-{5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}-2-メチル安息香酸
　実施例145-E)で合成したメチル 4-{5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンゾアート(2.84 g)、水酸化ナトリウム(0.525 g)、メタノール(50.0 mL)および水(5.0 mL)の混合物を12時間加熱還流した。反応混合物に濃塩酸を加えた後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製することにより、標題化合物(1.94 g)を得た。
MS (ESI+): [M+H]+ 420.4.
1H NMR (400 MHz, CD3OD) δ 1.08-1.13 (4H, m), 2.00-2.05 (1H, m), 2.65 (3H, s), 4.09 (2H, s), 7.28-7.35 (2H, m), 7.43-7.48 (1H, brs), 7.51-7.54 (2H, m), 8.08 (1H, d, J = 8.4 Hz), COOHピークは観測されなかった. F) 4- {5-Cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} -2-methylbenzoic acid Example 145 -E) methyl 4- {5-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} -2-methyl A mixture of benzoate (2.84 g), sodium hydroxide (0.525 g), methanol (50.0 mL) and water (5.0 mL) was heated to reflux for 12 hours. Concentrated hydrochloric acid was added to the reaction mixture, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.94 g).
MS (ESI +): [M + H] + 420.4.
1 H NMR (400 MHz, CD 3 OD) δ 1.08-1.13 (4H, m), 2.00-2.05 (1H, m), 2.65 (3H, s), 4.09 (2H, s), 7.28-7.35 (2H, m), 7.43-7.48 (1H, brs), 7.51-7.54 (2H, m), 8.08 (1H, d, J = 8.4 Hz), no COOH peak was observed.
実施例146
4-{5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンズアミド Example 146
4- {5-Cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000212
Figure JPOXMLDOC01-appb-C000212
　実施例145で合成した4-{5-シクロプロピル-3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1H-1,2,4-トリアゾール-1-イル}-2-メチル安息香酸(200 mg)、HOBtアンモニア和物(87 mg)、WSC塩酸塩(110 mg)およびDMF(2 mL)の混合物を室温で一晩撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製した後、酢酸エチル-ヘキサンから再結晶することにより、標題化合物(105 mg)を得た。
MS (ESI+): [M+H]+ 419.0.
1H NMR (300 MHz, CDCl3) δ 1.05-1.25 (4H, m), 1.88-1.98 (1H, m), 2.58 (3H, s), 4.09 (2H, s), 5.78 (2H, brs), 7.15-7.21 (1H, m), 7.24-7.31 (1H, m), 7.42-7.51 (3H, m), 7.60 (1H, d, J = 8.3 Hz). 4- {5-cyclopropyl-3- [3-fluoro-5- (trifluoromethyl) benzyl] -1H-1,2,4-triazol-1-yl} -2-methylbenzoic acid synthesized in Example 145 A mixture of acid (200 mg), HOBt ammonia solvate (87 mg), WSC hydrochloride (110 mg) and DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and recrystallized from ethyl acetate-hexane to give the title compound (105 mg).
MS (ESI +): [M + H] + 419.0.
1 H NMR (300 MHz, CDCl 3 ) δ 1.05-1.25 (4H, m), 1.88-1.98 (1H, m), 2.58 (3H, s), 4.09 (2H, s), 5.78 (2H, brs), 7.15-7.21 (1H, m), 7.24-7.31 (1H, m), 7.42-7.51 (3H, m), 7.60 (1H, d, J = 8.3 Hz).
実施例147
4-{2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール-5-イル}-2-メチルベンズアミド Example 147
4- {2- [3-Fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000213
Figure JPOXMLDOC01-appb-C000213
A) 4-ブロモ-N-メトキシ-N,3-ジメチルベンズアミド
　4-ブロモ-3-メチル安息香酸(9.75 g) 、N-メトキシメタンアミン塩酸塩 (4.86 g) 、HOBt (7.35 g) 、WSC (10.43 g) およびトリエチルアミン (15.8 mL)のDMF溶液 (114 mL) を室温で3時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (8.75 g) を得た。
MS (ESI+): [M+H]+ 260.06.
1H NMR (300 MHz, CDCl3) δ 2.43 (3H, s), 3.35 (3H, s), 3.55 (3H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.51-7.60 (2H, m). A) 4-Bromo-N-methoxy-N, 3-dimethylbenzamide 4-Bromo-3-methylbenzoic acid (9.75 g), N-methoxymethanamine hydrochloride (4.86 g), HOBt (7.35 g), WSC ( 10.43 g) and triethylamine (15.8 mL) in DMF (114 mL) were stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (8.75 g).
MS (ESI +): [M + H] + 260.06.
1 H NMR (300 MHz, CDCl 3 ) δ 2.43 (3H, s), 3.35 (3H, s), 3.55 (3H, s), 7.37 (1H, dd, J = 8.3, 1.9 Hz), 7.51-7.60 ( 2H, m).
B) 2-ブロモ-1-(4-ブロモ-3-メチルフェニル)プロパン-1-オン
　4-ブロモ-N-メトキシ-N,3-ジメチルベンズアミド (7.75 g) のTHF溶液 (75 mL) にクロロ(エチル)マグネシウムの2 M THF溶液(16.51 mL) を-78℃でゆっくりと加え、アルゴン雰囲気下室温で2.5時間撹拌した。クロロ(エチル)マグネシウムの2 M THF溶液 (1.5 mL) を加え、室温で更に1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた1-(4-ブロモ-3-メチルフェニル)プロパン-1-オンの酢酸溶液 (40 mL) に臭素 (1.846 mL) の酢酸溶液 (20.2 mL) を0℃で滴下し、室温で2.5時間撹拌した。反応混合物に飽和チオ硫酸ナトリウム水溶液を加え、飽和炭酸ナトリウム水溶液により中和した後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (6.06 g) を得た。
MS (ESI+): [M+H]+ 307.00.
1H NMR (300 MHz, CDCl3) δ 1.89 (3H, d, J = 6.4 Hz), 2.47 (3H, s), 5.23 (1H, q, J = 6.8 Hz), 7.61-7.72 (2H, m), 7.84-7.92 (1H, m). B) 2-Bromo-1- (4-bromo-3-methylphenyl) propan-1-one 4-bromo-N-methoxy-N, 3-dimethylbenzamide (7.75 g) in THF (75 mL) A 2 M THF solution (16.51 mL) of (ethyl) magnesium was slowly added at −78 ° C., and the mixture was stirred at room temperature for 2.5 hours under an argon atmosphere. A 2 M THF solution (1.5 mL) of chloro (ethyl) magnesium was added, and the mixture was further stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained 1- (4-bromo-3-methylphenyl) propan-1-one in acetic acid solution (40 mL), bromine (1.846 mL) in acetic acid (20.2 mL) was added dropwise at 0 ° C. Stir for hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, neutralized with a saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (6.06 g).
MS (ESI +): [M + H] + 307.00.
1 H NMR (300 MHz, CDCl 3 ) δ 1.89 (3H, d, J = 6.4 Hz), 2.47 (3H, s), 5.23 (1H, q, J = 6.8 Hz), 7.61-7.72 (2H, m) , 7.84-7.92 (1H, m).
C) 2-アジド-1-(4-ブロモ-3-メチルフェニル)プロパン-1-オン
　2-ブロモ-1-(4-ブロモ-3-メチルフェニル)プロパン-1-オン (6.06 g) のメタノール溶液 (49.5 mL) にナトリウム アジド (1.352 g) を0℃で加え、室温で6時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (5.09 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.51-1.61 (3H, m), 2.47 (3H, s), 4.64 (1H, q, J = 6.8 Hz), 7.55-7.63 (1H, m), 7.63-7.72 (1H, m), 7.80 (1H, d, J = 2.3 Hz). C) 2-azido-1- (4-bromo-3-methylphenyl) propan-1-one 2-bromo-1- (4-bromo-3-methylphenyl) propan-1-one (6.06 g) in methanol Sodium azide (1.352 g) was added to the solution (49.5 mL) at 0 ° C., and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (5.09 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.51-1.61 (3H, m), 2.47 (3H, s), 4.64 (1H, q, J = 6.8 Hz), 7.55-7.63 (1H, m), 7.63- 7.72 (1H, m), 7.80 (1H, d, J = 2.3 Hz).
D) tert-ブチル [2-(4-ブロモ-3-メチルフェニル)-1-メチル-2-オキソエチル]カルバマート
　2-アジド-1-(4-ブロモ-3-メチルフェニル)プロパン-1-オン (4.51 g) のTHF-水(5:1) 溶液 (84 mL) にトリフェニルホスフィン(5.29 g) を室温で加え、3.5時間撹拌した。反応混合物にジ-tert-ブチル ジカルボナート (4.69 mL) を加え、室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (4.06 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.38 (3H, d, J = 7.2 Hz), 1.45 (9H, s), 2.46 (3H, s), 5.12-5.34 (1H, m), 5.35-5.62 (1H, m), 7.58-7.70 (2H, m), 7.78-7.87 (1H, m). D) tert-butyl [2- (4-bromo-3-methylphenyl) -1-methyl-2-oxoethyl] carbamate 2-azido-1- (4-bromo-3-methylphenyl) propan-1-one ( Triphenylphosphine (5.29 g) was added to a THF-water (5: 1) solution (84 mL) of 4.51 g) at room temperature, and the mixture was stirred for 3.5 hours. Di-tert-butyl dicarbonate (4.69 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.06 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.38 (3H, d, J = 7.2 Hz), 1.45 (9H, s), 2.46 (3H, s), 5.12-5.34 (1H, m), 5.35-5.62 ( 1H, m), 7.58-7.70 (2H, m), 7.78-7.87 (1H, m).
E) 2-アミノ-1-(4-ブロモ-3-メチルフェニル)プロパン-1-オン塩酸塩
　tert-ブチル [2-(4-ブロモ-3-メチルフェニル)-1-メチル-2-オキソエチル]カルバマート (4.06 g) の酢酸エチル溶液 (39.5 mL) に塩化水素の4 M酢酸エチル溶液 (50.4 mL) を加え、室温で6時間撹拌した。反応液中に生成した沈殿物をろ取することで標題化合物 (3.14 g) を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.42 (3H, d, J = 7.2 Hz), 2.45 (3H, s), 5.10 (1H, q, J = 7.2 Hz), 7.73-7.88 (2H, m), 8.01-8.13 (1H, m), 8.54 (3H, brs). E) 2-Amino-1- (4-bromo-3-methylphenyl) propan-1-one hydrochloride tert-butyl [2- (4-bromo-3-methylphenyl) -1-methyl-2-oxoethyl] To a solution of carbamate (4.06 g) in ethyl acetate (39.5 mL) was added 4 M ethyl acetate solution of hydrogen chloride (50.4 mL), and the mixture was stirred at room temperature for 6 hours. The precipitate formed in the reaction mixture was collected by filtration to obtain the title compound (3.14 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.42 (3H, d, J = 7.2 Hz), 2.45 (3H, s), 5.10 (1H, q, J = 7.2 Hz), 7.73-7.88 (2H, m), 8.01-8.13 (1H, m), 8.54 (3H, brs).
F) N-[2-(4-ブロモ-3-メチルフェニル)-1-メチル-2-オキソエチル]-2-[3-フルオロ-5-(トリフルオロメチル)フェニル]アセトアミド
　2-アミノ-1-(4-ブロモ-3-メチルフェニル)プロパン-1-オン塩酸塩 (3.13 g) 、[3-フルオロ-5-(トリフルオロメチル)フェニル]酢酸 (3.00 g) 、HOBt (1.67 g) 、WSC (2.369 g) およびトリエチルアミン (3.92 mL)のDMF溶液 (56 mL) を室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (4.18 g) を得た。
MS (ESI+): [M+H]+ 446.01.
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, d, J = 7.2 Hz), 2.46 (3H, s), 3.65 (2H, s), 5.49 (1H, quin, J = 7.1 Hz), 6.55-6.75 (1H, m), 7.20-7.30 (2H, m), 7.33-7.40 (1H, m), 7.58-7.71 (2H, m), 7.78-7.86 (1H, m). F) N- [2- (4-Bromo-3-methylphenyl) -1-methyl-2-oxoethyl] -2- [3-fluoro-5- (trifluoromethyl) phenyl] acetamide 2-amino-1- (4-Bromo-3-methylphenyl) propan-1-one hydrochloride (3.13 g), [3-fluoro-5- (trifluoromethyl) phenyl] acetic acid (3.00 g), HOBt (1.67 g), WSC ( 2.369 g) and triethylamine (3.92 mL) in DMF (56 mL) were stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (4.18 g).
MS (ESI +): [M + H] + 446.01.
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, d, J = 7.2 Hz), 2.46 (3H, s), 3.65 (2H, s), 5.49 (1H, quin, J = 7.1 Hz), 6.55 -6.75 (1H, m), 7.20-7.30 (2H, m), 7.33-7.40 (1H, m), 7.58-7.71 (2H, m), 7.78-7.86 (1H, m).
G) 5-(4-ブロモ-3-メチルフェニル)-2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール
　N-[2-(4-ブロモ-3-メチルフェニル)-1-メチル-2-オキソエチル]-2-[3-フルオロ-5-(トリフルオロメチル)フェニル]アセトアミド (4.18 g) のアセトニトリル溶液 (51.2 mL) にリン酸 トリクロリド (17.46 mL) を室温で加え、70℃で一晩撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液により中和した後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (3.75 g) を得た。
1H NMR (300 MHz, CDCl3) δ 2.38 (3H, s), 2.44 (3H, s), 4.17 (2H, s), 7.16-7.32 (3H, m), 7.36-7.47 (2H, m), 7.57 (1H, d, J = 8.3 Hz). G) 5- (4-Bromo-3-methylphenyl) -2- [3-fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazole N- [2- (4-Bromo -3-methylphenyl) -1-methyl-2-oxoethyl] -2- [3-fluoro-5- (trifluoromethyl) phenyl] acetamide (4.18 g) in acetonitrile (51.2 mL) and trichloride phosphate (17.46 mL) was added at room temperature and stirred at 70 ° C. overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.75 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.38 (3H, s), 2.44 (3H, s), 4.17 (2H, s), 7.16-7.32 (3H, m), 7.36-7.47 (2H, m), 7.57 (1H, d, J = 8.3 Hz).
H) 4-{2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール-5-イル}-2-メチルベンゾニトリル
　5-(4-ブロモ-3-メチルフェニル)-2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール (2.74 g) のDMF溶液(42.7 mL) にシアン化亜鉛 (526 mg) およびテトラキストリフェニルホスフィンパラジウム (739 mg) を室温で加え、窒素雰囲気下170℃で7時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製して標題化合物 (2.05 g) を得た。
MS (ESI+): [M+H]+ 375.13.
1H NMR (300 MHz, CDCl3) δ 2.44 (3H, s), 2.59 (3H, s), 4.19 (2H, s), 7.19-7.32 (2H, m), 7.39-7.54 (3H, m), 7.64 (1H, d, J = 8.0 Hz). H) 4- {2- [3-Fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl} -2-methylbenzonitrile 5- (4-bromo-3 -Methylphenyl) -2- [3-fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazole (2.74 g) in DMF solution (42.7 mL) with zinc cyanide (526 mg) Then, tetrakistriphenylphosphine palladium (739 mg) was added at room temperature, and the mixture was stirred at 170 ° C. for 7 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.05 g).
MS (ESI +): [M + H] + 375.13.
1 H NMR (300 MHz, CDCl 3 ) δ 2.44 (3H, s), 2.59 (3H, s), 4.19 (2H, s), 7.19-7.32 (2H, m), 7.39-7.54 (3H, m), 7.64 (1H, d, J = 8.0 Hz).
I) 4-{2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール-5-イル}-2-メチルベンズアミド
　4-{2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール-5-イル}-2-メチルベンゾニトリル(1830 mg) のDMSO/水溶液 (50:1、51 mL) に炭酸カリウム (1351 mg) を加え10℃で撹拌した。過酸化水素水 (9.99 mL) を滴下した後、室温で1時間撹拌した。反応混合物へ水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣へメタノール（40 mL)を加え、0 ℃で水素化ホウ素ナトリウム（111 mg）を加えた。反応混合物を室温で20分間撹拌した。反応混合物へ水を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル) で精製後、ヘキサン－酢酸エチルから再結晶して標題化合物 (1150 mg) を得た。
MS (ESI+): [M+H]+ 393.2.
1H NMR (300 MHz, DMSO-d6) δ 2.33 (3H, s), 2.42 (3H, s), 4.34 (2H, s), 7.29-7.52 (4H, m), 7.55-7.70 (3H, m), 7.75 (1H, brs). I) 4- {2- [3-Fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl} -2-methylbenzamide 4- {2- [3-Fluoro -5- (Trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl} -2-methylbenzonitrile (1830 mg) in DMSO / water solution (50: 1, 51 mL) in potassium carbonate (1351 mg) was added and stirred at 10 ° C. After dropwise addition of aqueous hydrogen peroxide (9.99 mL), the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Methanol (40 mL) was added to the residue, and sodium borohydride (111 mg) was added at 0 ° C. The reaction mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and recrystallized from hexane-ethyl acetate to give the title compound (1150 mg).
MS (ESI +): [M + H] + 393.2.
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.33 (3H, s), 2.42 (3H, s), 4.34 (2H, s), 7.29-7.52 (4H, m), 7.55-7.70 (3H, m ), 7.75 (1H, brs).
実施例148
エチル 2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}ベンゾアート Example 148
Ethyl 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} benzoate
Figure JPOXMLDOC01-appb-C000214
Figure JPOXMLDOC01-appb-C000214
A)エチル 2-ブロモ-4-フルオロベンゾアート
　2-ブロモ-4-フルオロ安息香酸(100 g)のエタノール溶液(2.3 L)へ濃硫酸(1.22 mL)を加え5日間加熱還流した。室温に冷却後、溶媒を減圧下留去した。残渣を酢酸エチル(1 L)で希釈し、1N水酸化ナトリウム水溶液を加えpH10に調整し、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後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、標題化合物 (85.0 g)を得た。
1H NMR (400 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 7.06-7.10 (1H, m), 7.41 (1H, dd, J = 8.0, 2.4 Hz), 7.87 (1H, dd, J = 8.8, 6.4 Hz). A) Ethyl 2-bromo-4-fluorobenzoate Concentrated sulfuric acid (1.22 mL) was added to an ethanol solution (2.3 L) of 2-bromo-4-fluorobenzoic acid (100 g), and the mixture was heated to reflux for 5 days. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate (1 L), adjusted to pH 10 with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (85.0 g).
1 H NMR (400 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 7.06-7.10 (1H, m), 7.41 (1H, dd, J = 8.0, 2.4 Hz), 7.87 (1H, dd, J = 8.8, 6.4 Hz).
B)エチル 2-シクロプロピル-4-フルオロベンゾアート
　実施例148-A)で得たエチル 2-ブロモ-4-フルオロベンゾアート(20.0 g)、シクロプロピルボロン酸(10.4 g)、ジクロロビス(ジフェニルホスフィノフェロセン)パラジウム(II)(1.19 g)、2M 炭酸ナトリウム水溶液(81.0 mL)のDME溶液(81 mL)を85℃で24時間加熱撹拌した。反応混合物をセライトろ過した。ろ液を酢酸エチルで希釈し、水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して、エチル 2-ブロモ-4-フルオロベンゾアートとエチル 2-シクロプロピル-4-フルオロベンゾアートの混合物 (16.4 g)を得た。混合物(16.4 g)、シクロプロピルボロン酸(5.67 g)、ジクロロビス(ジフェニルホスフィノフェロセン)パラジウム(II)(0.483 g)、2M 炭酸ナトリウム水溶液(66.0 mL)のDME溶液(66 mL)を85℃で4時間加熱撹拌した。反応混合物をセライトでろ過した。ろ液を酢酸エチルで希釈し、水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製し、標題化合物 (15.0 g)を得た。
1H NMR (400 MHz, CDCl3) δ 0.67-0.71 (2H, m), 1.01-1.06 (2H, m), 1.40 (3H, t, J = 7.2 Hz), 2.71-2.78 (1H, m), 4.37 (2H, q, J = 7.2 Hz), 6.67 (1H, dd, J = 10.4, 2.4 Hz), 6.87 (1H, td, J = 8.4, 2.4 Hz), 7.85 (1H, dd, J = 8.4, 6.0 Hz). B) Ethyl 2-cyclopropyl-4-fluorobenzoate Ethyl 2-bromo-4-fluorobenzoate (20.0 g) obtained in Example 148-A), cyclopropylboronic acid (10.4 g), dichlorobis (diphenylphosphine) Finoferrocene) palladium (II) (1.19 g) and 2M aqueous sodium carbonate solution (81.0 mL) in DME (81 mL) were stirred with heating at 85 ° C. for 24 hours. The reaction mixture was filtered through celite. The filtrate was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain a mixture (16.4 g) of ethyl 2-bromo-4-fluorobenzoate and ethyl 2-cyclopropyl-4-fluorobenzoate. Mixture (16.4 g), cyclopropylboronic acid (5.67 g), dichlorobis (diphenylphosphinoferrocene) palladium (II) (0.483 g), 2M aqueous sodium carbonate solution (66.0 mL) in DME (66 mL) at 85 ° C. The mixture was heated and stirred for 4 hours. The reaction mixture was filtered through celite. The filtrate was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (15.0 g).
1 H NMR (400 MHz, CDCl 3 ) δ 0.67-0.71 (2H, m), 1.01-1.06 (2H, m), 1.40 (3H, t, J = 7.2 Hz), 2.71-2.78 (1H, m), 4.37 (2H, q, J = 7.2 Hz), 6.67 (1H, dd, J = 10.4, 2.4 Hz), 6.87 (1H, td, J = 8.4, 2.4 Hz), 7.85 (1H, dd, J = 8.4, 6.0 Hz).
C)エチル 2-シクロプロピル-4-ヒドラジノベンゾアート
　実施例148-B)で得たエチル 2-シクロプロピル-4-フルオロベンゾアート(15.0 g)のDMSO溶液(45 mL)へヒドラジン一水和物(4.81 mL)を加え、120℃で15時間加熱撹拌した。反応混合物に水を加え、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後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、標題化合物 (11.3 g)を得た。
1H NMR (400 MHz, CDCl3) δ 0.65-0.69 (2H, m), 0.95-1.00 (2H, m), 1.38 (3H, t, J = 7.2 Hz), 2.77-2.84 (1H, m), 3.60 (2H, brs), 4.33 (2H, q, J = 7.2 Hz), 5.39 (1H, brs), 6.40 (1H, d, J = 2.4 Hz), 6.60 (1H, dd, J = 8.8, 2.4 Hz), 7.84 (1H, d, J = 8.4 Hz).
MS (ESI+): [M+H]+ 221.0. C) Ethyl 2-cyclopropyl-4-hydrazinobenzoate Hydrazine monohydrate in a DMSO solution (45 mL) of ethyl 2-cyclopropyl-4-fluorobenzoate (15.0 g) obtained in Example 148-B) (4.81 mL) was added, and the mixture was heated with stirring at 120 ° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (11.3 g).
1 H NMR (400 MHz, CDCl 3 ) δ 0.65-0.69 (2H, m), 0.95-1.00 (2H, m), 1.38 (3H, t, J = 7.2 Hz), 2.77-2.84 (1H, m), 3.60 (2H, brs), 4.33 (2H, q, J = 7.2 Hz), 5.39 (1H, brs), 6.40 (1H, d, J = 2.4 Hz), 6.60 (1H, dd, J = 8.8, 2.4 Hz) ), 7.84 (1H, d, J = 8.4 Hz).
MS (ESI +): [M + H] + 221.0.
D) エチル 2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}ベンゾアート
　実施例139-B)で得たメチル 2-(3-フルオロ-5-(トリフルオロメチル)フェニル)エタンイミドチオアート ヨウ化水素酸塩(1.02 g)のエタノール溶液(6 mL)へ実施例148-C)で得たエチル 2-シクロプロピル-4-ヒドラジニルベンゾアート(0.591 g)を加え、0 ℃で乾燥空気下2時間撹拌した。溶媒を減圧下留去し、残渣へ1,1,1-トリメトキシエタン(10.1 mL)、酢酸(0.138 mL)を加え100℃で終夜加熱撹拌した。溶媒を減圧下留去し、残渣へ1N塩酸を加え、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。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して、標題化合物 (1.05 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.74 (2H, q), 1.01-1.13 (2H, m), 1.43 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 2.72 (1H, tt, J = 8.5, 5.5 Hz), 4.13 (2H, s), 4.42 (2H, q, J = 7.2 Hz), 7.12 (1H, d, J = 1.9 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.24-7.34 (2H, m), 7.45 (1H, s), 7.94 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 448.2. D) Ethyl 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} benzoate Examples Methyl 2- (3-fluoro-5- (trifluoromethyl) phenyl) ethaneimidethioate obtained in 139-B) into an ethanol solution (6 mL) of hydroiodide (1.02 g) Example 148-C The ethyl 2-cyclopropyl-4-hydrazinylbenzoate (0.591 g) obtained in (1) was added and stirred at 0 ° C. under dry air for 2 hours. The solvent was evaporated under reduced pressure, 1,1,1-trimethoxyethane (10.1 mL) and acetic acid (0.138 mL) were added to the residue, and the mixture was stirred with heating at 100 ° C. overnight. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.05 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.74 (2H, q), 1.01-1.13 (2H, m), 1.43 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 2.72 (1H, tt, J = 8.5, 5.5 Hz), 4.13 (2H, s), 4.42 (2H, q, J = 7.2 Hz), 7.12 (1H, d, J = 1.9 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.24-7.34 (2H, m), 7.45 (1H, s), 7.94 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 448.2.
実施例149
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}安息香酸 Example 149
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} benzoic acid
Figure JPOXMLDOC01-appb-C000215
Figure JPOXMLDOC01-appb-C000215
　実施例148-D)で得たエチル 2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}ベンゾアート(1.05 g)のエタノール/THF溶液(6/3 mL)へ1N水酸化ナトリウム水溶液(3.52 ml)を加え、室温で5時間撹拌した。反応混合物へ0℃で1N塩酸を加え中和し、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、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物 (0.393 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 0.76 (2H, q), 0.96-1.08 (2H, m), 2.45 (3H, s), 2.69-2.83 (1H, m), 4.16 (2H, s), 7.13 (1H, d, J = 1.9 Hz), 7.43 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (2H, d, J = 9.5 Hz), 7.62 (1H, s), 7.86 (1H, d, J = 8.3 Hz), 13.17 (1H, brs).
MS (ESI+): [M+H]+ 420.1. Ethyl 2-cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazole-1 obtained in Example 148-D) To a solution of -yl} benzoate (1.05 g) in ethanol / THF (6/3 mL) was added 1N aqueous sodium hydroxide solution (3.52 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized with 1N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (0.393 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.76 (2H, q), 0.96-1.08 (2H, m), 2.45 (3H, s), 2.69-2.83 (1H, m), 4.16 (2H, s ), 7.13 (1H, d, J = 1.9 Hz), 7.43 (1H, dd, J = 8.3, 1.9 Hz), 7.54 (2H, d, J = 9.5 Hz), 7.62 (1H, s), 7.86 (1H , d, J = 8.3 Hz), 13.17 (1H, brs).
MS (ESI +): [M + H] + 420.1.
実施例150
2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}ベンズアミド Example 150
2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} benzamide
Figure JPOXMLDOC01-appb-C000216
Figure JPOXMLDOC01-appb-C000216
　実施例149で得た2-シクロプロピル-4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}安息香酸(0.300 g)、WSC (0.274 g)、HOBtアンモニア和物(0.218 g)のDMF溶液 (6 mL)を室温で終夜撹拌した。反応混合物を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。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣を再結晶 (酢酸エチル/ヘキサン)して、標題化合物 (0.224 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.78-0.87 (2H, m), 1.04-1.17 (2H, m), 2.34-2.43 (1H, m), 2.49 (3H, s), 4.12 (2H, s), 5.69-6.09 (2H, m), 7.07 (1H, d, J = 1.9 Hz), 7.14-7.35 (3H, m), 7.45 (1H, s), 7.66 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 419.2. 2-Cyclopropyl-4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} benzoate obtained in Example 149 A DMF solution (6 mL) of acid (0.300 g), WSC (0.274 g), and HOBt ammonia hydrate (0.218 g) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized (ethyl acetate / hexane) to give the title compound (0.224 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.78-0.87 (2H, m), 1.04-1.17 (2H, m), 2.34-2.43 (1H, m), 2.49 (3H, s), 4.12 (2H, s ), 5.69-6.09 (2H, m), 7.07 (1H, d, J = 1.9 Hz), 7.14-7.35 (3H, m), 7.45 (1H, s), 7.66 (1H, d, J = 8.3 Hz) .
MS (ESI +): [M + H] + 419.2.
実施例151
エチル 4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-シクロプロピルベンゾアート Example 151
Ethyl 4- [3- (4-chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-cyclopropylbenzoate
Figure JPOXMLDOC01-appb-C000217
Figure JPOXMLDOC01-appb-C000217
A)2-(4-クロロフェニル)エタンチオアミド
　2-(4-クロロフェニル)アセトニトリル(6.00 g)へ4N塩酸酢酸エチル溶液(100 mL)およびジチオリン酸 O,O-ジエチル エステル(6.25 mL)を加え、室温で終夜撹拌した。0℃で反応混合物へ水を加え、酢酸エチルで抽出した。有機層を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、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。0℃で残渣へヘキサンを加え、固体をろ取し、ヘキサンで洗浄して、標題化合物 (5.10 g)を得た。
1H NMR (300 MHz, CDCl3) δ 4.06 (2H, s), 6.64 (1H, brs), 7.17-7.26 (2H, m), 7.30-7.41 (2H, m), 7.51 (1H, brs). A) 2- (4-Chlorophenyl) ethanethioamide Add 4-N hydrochloric acid ethyl acetate solution (100 mL) and dithiophosphoric acid O, O-diethyl ester (6.25 mL) to 2- (4-chlorophenyl) acetonitrile (6.00 g) at room temperature. And stirred overnight. Water was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the residue at 0 ° C., and the solid was collected by filtration and washed with hexane to obtain the title compound (5.10 g).
1 H NMR (300 MHz, CDCl 3 ) δ 4.06 (2H, s), 6.64 (1H, brs), 7.17-7.26 (2H, m), 7.30-7.41 (2H, m), 7.51 (1H, brs).
B)メチル 2-(4-クロロフェニル)エタンイミドチオアート 塩酸塩
　実施例151-A)で得た2-(4-クロロフェニル)エタンチオアミド(2.00 g)のアセトン溶液(10 mL)へヨウ化メタン(2.29 g)を加え、50℃で1.5時間加熱撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄し、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、硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣へ4N塩酸酢酸エチル溶液を加え、溶媒を減圧下留去した。残渣をエタノール/ヘキサンから再結晶化して、標題化合物 (1.31 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ2.63 (3H, s), 4.27 (2H, s), 6.89-7.88 (4H, m), 11.41-13.35 (2H, m). B) Methyl 2- (4-chlorophenyl) ethanimidothioate hydrochloride Hydromethane iodide (10 mL) in 2- (4-chlorophenyl) ethanethioamide (2.00 g) obtained in Example 151-A) 2.29 g) was added and the mixture was stirred with heating at 50 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added 4N hydrochloric acid ethyl acetate solution, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol / hexane to give the title compound (1.31 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ2.63 (3H, s), 4.27 (2H, s), 6.89-7.88 (4H, m), 11.41-13.35 (2H, m).
C) エチル 4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-シクロプロピルベンゾアート
　実施例151-B)で得たメチル 2-(4-クロロフェニル)エタンイミドチオアート 塩酸塩(0.546 g)のエタノール溶液(5 mL)へ実施例148-C)で得たエチル 2-シクロプロピル-4-ヒドラジニルベンゾアート(0.509 g)を加え、0℃で乾燥空気下2時間撹拌した。溶媒を減圧下留去し、残渣へ1,1,1-トリメトキシエタン(5.6 mL)、酢酸(0.026 mL)を加え100℃で終夜加熱撹拌した。溶媒を減圧下留去し、残渣へ0.5N塩酸を加え、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。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して、標題化合物 (0.852 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.73 (2H, q, J = 5.5 Hz), 1.01-1.13 (2H, m), 1.42 (3H, t, J = 7.2 Hz), 2.48 (3H, s), 2.72 (1H, tt, J = 8.5, 5.4 Hz), 4.04 (2H, s), 4.41 (2H, q, J = 7.2 Hz), 7.10 (1H, d, J = 1.9 Hz), 7.21-7.38 (5H, m), 7.92 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 396.1. C) Ethyl 4- [3- (4-Chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-cyclopropylbenzoate Methyl obtained in Example 151-B) Ethyl 2-cyclopropyl-4-hydrazinylbenzoate (0.509 g) obtained in Example 148-C) into an ethanol solution (5 mL) of 2- (4-chlorophenyl) ethaneimidothioate hydrochloride (0.546 g) ) Was added and stirred at 0 ° C. under dry air for 2 hours. The solvent was evaporated under reduced pressure, 1,1,1-trimethoxyethane (5.6 mL) and acetic acid (0.026 mL) were added to the residue, and the mixture was heated with stirring at 100 ° C. overnight. The solvent was evaporated under reduced pressure, 0.5N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.852 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.73 (2H, q, J = 5.5 Hz), 1.01-1.13 (2H, m), 1.42 (3H, t, J = 7.2 Hz), 2.48 (3H, s) , 2.72 (1H, tt, J = 8.5, 5.4 Hz), 4.04 (2H, s), 4.41 (2H, q, J = 7.2 Hz), 7.10 (1H, d, J = 1.9 Hz), 7.21-7.38 ( 5H, m), 7.92 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 396.1.
実施例152
4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-シクロプロピル安息香酸 Example 152
4- [3- (4-Chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-cyclopropylbenzoic acid
Figure JPOXMLDOC01-appb-C000218
Figure JPOXMLDOC01-appb-C000218
　実施例151-C)で得たエチル4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-シクロプロピルベンゾアート(0.852 g)のエタノール溶液(10 mL)へ1N水酸化ナトリウム水溶液(3.23 ml)を加え、室温で終夜撹拌した。反応混合物へ1N塩酸を加え中和し、固体をろ取した。固体をジイソプロピルエーテルで洗浄し、標題化合物(0.604 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 0.70-0.81 (2H, m), 0.95-1.05 (2H, m), 2.44 (3H, s), 2.68-2.83 (1H, m), 3.99 (2H, s), 7.11 (1H, d, J = 1.9 Hz), 7.31-7.46 (5H, m), 7.84 (1H, d, J = 8.3 Hz), 13.14 (1H, brs).
MS (ESI+): [M+H]+ 368.0. Ethyl 4- [3- (4-chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-cyclopropylbenzoate (0.852 g) obtained in Example 151-C) 1N aqueous solution of sodium hydroxide (3.23 ml) was added to an ethanol solution (10 mL) and stirred overnight at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid, and the solid was collected by filtration. The solid was washed with diisopropyl ether to give the title compound (0.604 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.70-0.81 (2H, m), 0.95-1.05 (2H, m), 2.44 (3H, s), 2.68-2.83 (1H, m), 3.99 (2H , s), 7.11 (1H, d, J = 1.9 Hz), 7.31-7.46 (5H, m), 7.84 (1H, d, J = 8.3 Hz), 13.14 (1H, brs).
MS (ESI +): [M + H] + 368.0.
実施例153
4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-シクロプロピルベンズアミド Example 153
4- [3- (4-Chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-cyclopropylbenzamide
Figure JPOXMLDOC01-appb-C000219
Figure JPOXMLDOC01-appb-C000219
　実施例152で得た4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-シクロプロピル安息香酸(0.300 g)、WSC (0.313 g)、HOBtアンモニア和物(0.248 g)のDMF溶液 (6 mL)を室温で終夜撹拌した。反応混合物へ炭酸水素ナトリウム水溶液を加え、固体をろ取した。固体を再結晶 (エタノール/水)して、標題化合物 (0.254 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.77-0.86 (2H, m), 1.06-1.15 (2H, m), 2.33-2.42 (1H, m), 2.46 (3H, s), 4.04 (2H, s), 5.67-6.10 (2H, m), 7.06 (1H, d, J = 1.9 Hz), 7.21-7.38 (5H, m), 7.65 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 367.1. 4- [3- (4-Chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-cyclopropylbenzoic acid (0.300 g) obtained in Example 152, WSC ( 0.313 g), a DMF solution (6 mL) of HOBt ammonia hydrate (0.248 g) was stirred at room temperature overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solid was collected by filtration. The solid was recrystallized (ethanol / water) to give the title compound (0.254 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.77-0.86 (2H, m), 1.06-1.15 (2H, m), 2.33-2.42 (1H, m), 2.46 (3H, s), 4.04 (2H, s ), 5.67-6.10 (2H, m), 7.06 (1H, d, J = 1.9 Hz), 7.21-7.38 (5H, m), 7.65 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 367.1.
実施例154
エチル 4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-メチルベンゾアート Example 154
Ethyl 4- [3- (4-chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000220
Figure JPOXMLDOC01-appb-C000220
　実施例151-B)で得たメチル 2-(4-クロロフェニル)エタンイミドチオアート 塩酸塩(0.500 g)のエタノール溶液(5 mL)へ実施例135-D)で得たエチル 2-メチル-4-ヒドラジニルベンゾアート(0.411 g)を加え、0℃で乾燥空気下4時間撹拌した。溶媒を減圧下留去し、残渣へ1,1,1-トリメトキシエタン(5.6 mL)、酢酸(0.024 mL)を加え100℃で終夜加熱撹拌した。溶媒を減圧下留去し、残渣へ0.5N塩酸を加え、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。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル/ヘキサン) で精製して、標題化合物 (0.605 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 2.52 (3H, s), 2.67 (3H, s), 4.05 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 7.22-7.41 (6H, m), 8.04 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 370.1. Ethyl 2-methyl-4 obtained in Example 135-D) into an ethanol solution (5 mL) of methyl 2- (4-chlorophenyl) ethaneimidothioate hydrochloride (0.500 g) obtained in Example 151-B) -Hydrazinyl benzoate (0.411 g) was added, and the mixture was stirred at 0 ° C. under dry air for 4 hours. The solvent was evaporated under reduced pressure, 1,1,1-trimethoxyethane (5.6 mL) and acetic acid (0.024 mL) were added to the residue, and the mixture was heated with stirring at 100 ° C. overnight. The solvent was evaporated under reduced pressure, 0.5N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.605 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 2.52 (3H, s), 2.67 (3H, s), 4.05 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 7.22-7.41 (6H, m), 8.04 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 370.1.
実施例155
4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-メチル安息香酸 Example 155
4- [3- (4-Chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000221
Figure JPOXMLDOC01-appb-C000221
　実施例154で得たエチル 4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-メチルベンゾアート(0.605 g)のエタノール/THF溶液(6/6 mL)へ1N水酸化ナトリウム水溶液(2.45 ml)を加え、室温で終夜撹拌した。反応混合物へ1N塩酸を加え水で希釈し、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、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物 (0.480 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.48 (3H, brs), 2.59 (3H, s), 3.99 (2H, s), 7.36 (4H, s), 7.45-7.58 (2H, m), 7.96 (1H, d, J = 8.3 Hz), 13.07 (1H, brs).
MS (ESI+): [M+H]+ 342.1. Ethyl 4- [3- (4-chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-methylbenzoate (0.605 g) obtained in Example 154 in ethanol / To a THF solution (6/6 mL) was added 1N aqueous sodium hydroxide solution (2.45 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N hydrochloric acid, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (0.480 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.48 (3H, brs), 2.59 (3H, s), 3.99 (2H, s), 7.36 (4H, s), 7.45-7.58 (2H, m), 7.96 (1H, d, J = 8.3 Hz), 13.07 (1H, brs).
MS (ESI +): [M + H] + 342.1.
実施例156
4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-メチルベンズアミド Example 156
4- [3- (4-Chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000222
Figure JPOXMLDOC01-appb-C000222
　実施例155で得た4-[3-(4-クロロベンジル)-5-メチル-1H-1,2,4-トリアゾール-1-イル]-2-メチル安息香酸(0.480 g)、WSC (0.427 g)、HOBtアンモニア和物(0.538 g)のDMF溶液 (10 mL)を40℃で終夜撹拌した。反応混合物を酢酸エチルで希釈し、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、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣を酢酸エチル/ヘキサンから再結晶化して、標題化合物 (0.355 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 2.57 (3H, s), 4.04 (2H, s), 5.70 (2H, brs), 7.19-7.41 (6H, m), 7.59 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 341.2. 4- [3- (4-Chlorobenzyl) -5-methyl-1H-1,2,4-triazol-1-yl] -2-methylbenzoic acid (0.480 g) obtained in Example 155, WSC (0.427 g) A DMF solution (10 mL) of HOBt ammonia hydrate (0.538 g) was stirred at 40 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the title compound (0.355 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.50 (3H, s), 2.57 (3H, s), 4.04 (2H, s), 5.70 (2H, brs), 7.19-7.41 (6H, m), 7.59 ( (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 341.2.
実施例157
エチル 2-クロロ-4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]ベンゾアート Example 157
Ethyl 2-chloro-4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] benzoate
Figure JPOXMLDOC01-appb-C000223
Figure JPOXMLDOC01-appb-C000223
A)エチル 2-クロロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート
　エチル 4-ブロモ-2-クロロベンゾアート(3.0 g)、ビス(ピナコラート)ジボロン(3.18 g)、ジクロロビス(ジフェニルホスフィノフェロセン)パラジウム(II)塩化メチレン付加物(417 mg)、酢酸カリウム(3.35 g)およびDMF(30 mL)の混合物を85℃で終夜撹拌した。反応混合物を酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製し、標題化合物(3.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.35 (12H, s), 1.40 (3H, t, J = 7.2 Hz), 4.40 (2H, d, J = 7.2 Hz), 7.69 (1H, s), 7.73-7.81 (1H, m), 7.86 (1H, s). A) ethyl 2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate ethyl 4-bromo-2-chlorobenzoate (3.0 g), Stir a mixture of bis (pinacolato) diboron (3.18 g), dichlorobis (diphenylphosphinoferrocene) palladium (II) methylene chloride adduct (417 mg), potassium acetate (3.35 g) and DMF (30 mL) at 85 ° C. overnight. did. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.35 (12H, s), 1.40 (3H, t, J = 7.2 Hz), 4.40 (2H, d, J = 7.2 Hz), 7.69 (1H, s), 7.73 -7.81 (1H, m), 7.86 (1H, s).
B)エチル 4-(4-クロロフェニル)-3-オキソブタノアート
　カリウム 3-エトキシ-3-オキソプロパノアート(39.0 g)のアセトニトリル(100 mL)懸濁液にトリエチルアミン(48.0 g)、塩化マグネシウム(26.0 g)を加え、室温で2時間撹拌した。この混合物に4-クロロフェニル酢酸(18.6 g)と1,1'-カルボニルジイミダゾール(19.5 g)のアセトニトリル(100 mL)溶液を80℃で2時間撹拌した溶液を加え、室温で終夜撹拌した。反応混合物に6 mol/L塩酸を加え、30分間撹拌後、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (21.9 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.16-1.34 (3H, m), 3.38-3.52 (2H, m), 3.81 (2H, s), 4.12-4.26 (2H, m), 7.07-7.18 (2H, m), 7.28-7.41 (2H, m). B) Ethyl 4- (4-chlorophenyl) -3-oxobutanoate Potassium 3-Ethoxy-3-oxopropanoate (39.0 g) in acetonitrile (100 mL) suspension in triethylamine (48.0 g), magnesium chloride (26.0 g) was added and stirred at room temperature for 2 hours. A solution of 4-chlorophenylacetic acid (18.6 g) and 1,1′-carbonyldiimidazole (19.5 g) in acetonitrile (100 mL) stirred at 80 ° C. for 2 hours was added to this mixture, and the mixture was stirred at room temperature overnight. 6 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (21.9 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.16-1.34 (3H, m), 3.38-3.52 (2H, m), 3.81 (2H, s), 4.12-4.26 (2H, m), 7.07-7.18 (2H , m), 7.28-7.41 (2H, m).
C)5-(4-クロロベンジル)-2-メチル-2,4-ジヒドロ-3H-ピラゾール-3-オン
　実施例157-B)で得たエチル 4-(4-クロロフェニル)-3-オキソブタノアート(10g)のエタノール溶液(40 mL)にメチルヒドラジン (2.3 g)を加え、80℃で3時間撹拌した。反応混合物を減圧濃縮し、残渣をエタノール-ヘキサンから結晶化させ標題化合物 (8.0 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.07 (2H, s), 3.22-3.38 (3H, m), 3.68 (2H, s), 7.15 (2H, d, J = 8.3 Hz), 7.28-7.37 (2H, m).
MS (ESI+): [M+H]+ 223.1. C) 5- (4-Chlorobenzyl) -2-methyl-2,4-dihydro-3H-pyrazol-3-one Ethyl 4- (4-chlorophenyl) -3-oxobutane obtained in Example 157-B) Methylhydrazine (2.3 g) was added to an ethanol solution (40 mL) of Noate (10 g), and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol-hexane to give the title compound (8.0 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.07 (2H, s), 3.22-3.38 (3H, m), 3.68 (2H, s), 7.15 (2H, d, J = 8.3 Hz), 7.28-7.37 ( 2H, m).
MS (ESI +): [M + H] + 223.1.
D)3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例157-C)で得た5-(4-クロロベンジル)-2-メチル-2,4-ジヒドロ-3H-ピラゾール-3-オン(3 g)のピリジン溶液(15 mL)にトリフルオロメタンスルホン酸無水物(2.5 mL)を0℃で加え、室温で1時間撹拌した。減圧下溶媒を留去した。残渣を酢酸エチルで希釈し、1 mol/L塩酸および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (4.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ3.77 (3H, s), 3.87 (2H, s), 5.86 (1H, s), 7.12-7.22 (2H, m), 7.23-7.32 (2H, m). D) 3- (4-Chlorobenzyl) -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate 5- (4-chlorobenzyl) -2-methyl-2, obtained in Example 157-C) To a pyridine solution (15 mL) of 4-dihydro-3H-pyrazol-3-one (3 g) was added trifluoromethanesulfonic anhydride (2.5 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with 1 mol / L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (4.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ3.77 (3H, s), 3.87 (2H, s), 5.86 (1H, s), 7.12-7.22 (2H, m), 7.23-7.32 (2H, m) .
E)エチル 2-クロロ-4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]ベンゾアート
　実施例157-D)で得た3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート(600 mg)、実施例157-A)で得たエチル 2-クロロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート(578 mg)、 ジクロロビス(トリフェニルホスフィン)パラジウム(II)(59 mg)と炭酸カリウム(701mg)のDME(10 mL)-水(3 mL)溶液を80℃で終夜撹拌した。反応混合物に水を注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/へキサン)で精製し、標題化合物(322 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.0 Hz), 3.87 (3H, s), 3.95 (2H, s), 4.42 (2H, q, J = 7.2 Hz), 6.09 (1H, s), 7.17-7.30 (4H, m), 7.33 (1H, dd, J = 7.9, 1.5 Hz), 7.48 (1H, d, J = 1.5 Hz), 7.89 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 389.2. E) Ethyl 2-chloro-4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] benzoate 3- (4-Chlorobenzyl) obtained in Example 157-D) 1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate (600 mg), ethyl 2-chloro-4- (4,4,5,5-tetramethyl-1) obtained in Example 157-A) , 3,2-Dioxaborolan-2-yl) benzoate (578 mg), dichlorobis (triphenylphosphine) palladium (II) (59 mg) and potassium carbonate (701 mg) in DME (10 mL) -water (3 mL) The solution was stirred at 80 ° C. overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (322 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.0 Hz), 3.87 (3H, s), 3.95 (2H, s), 4.42 (2H, q, J = 7.2 Hz), 6.09 (1H, s), 7.17-7.30 (4H, m), 7.33 (1H, dd, J = 7.9, 1.5 Hz), 7.48 (1H, d, J = 1.5 Hz), 7.89 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 389.2.
実施例158
2-クロロ-4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]安息香酸 Example 158
2-Chloro-4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] benzoic acid
Figure JPOXMLDOC01-appb-C000224
Figure JPOXMLDOC01-appb-C000224
　実施例157-E)で得たエチル 2-クロロ-4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]ベンゾアート(322 mg)のメタノール/THF溶液 (1/4、15 mL)へ1 N水酸化ナトリウム水溶液 (2.0 mL)を加え、室温で1時間撹拌した。反応混合物へ1 N塩酸を0℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (233 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 3.84 (3H, s), 3.89 (2H, s), 6.37 (1H, s), 7.24-7.42 (4H, m), 7.49-7.63 (1H, m), 7.69 (1H, d, J = 1.5 Hz), 7.86 (1H, d, J = 7.9 Hz), 13.51 (1H, brs).
MS (ESI+): [M+H]+ 361.0. A solution of ethyl 2-chloro-4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] benzoate (322 mg) obtained in Example 157-E) in methanol / THF ( (1/4, 15 mL) was added 1 N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (233 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 3.84 (3H, s), 3.89 (2H, s), 6.37 (1H, s), 7.24-7.42 (4H, m), 7.49-7.63 (1H, m ), 7.69 (1H, d, J = 1.5 Hz), 7.86 (1H, d, J = 7.9 Hz), 13.51 (1H, brs).
MS (ESI +): [M + H] + 361.0.
実施例159
2-クロロ-4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]ベンズアミド Example 159
2-Chloro-4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] benzamide
Figure JPOXMLDOC01-appb-C000225
Figure JPOXMLDOC01-appb-C000225
　実施例158で得た2-クロロ-4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]安息香酸(233 mg)、WSC (136 mg)、HOBtアンモニア和物(108 mg)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣を酢酸エチル-ヘキサンより結晶化させ、標題化合物(180 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 3.86 (3H, s), 3.95 (2H, s), 5.99 (1H, brs), 6.08 (1H, s), 6.40 (1H, brs), 7.16-7.32 (4H, m), 7.37 (1H, dd, J = 8.1, 1.7 Hz), 7.46 (1H, d, J = 1.5 Hz), 7.89 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 359.9. 2-chloro-4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] benzoic acid (233 mg), WSC (136 mg), HOBt ammonia hydrate obtained in Example 158 (108 mg) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (180 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 3.86 (3H, s), 3.95 (2H, s), 5.99 (1H, brs), 6.08 (1H, s), 6.40 (1H, brs), 7.16-7.32 ( 4H, m), 7.37 (1H, dd, J = 8.1, 1.7 Hz), 7.46 (1H, d, J = 1.5 Hz), 7.89 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 359.9.
実施例160
エチル 4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]-2-メチルベンゾアート Example 160
Ethyl 4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000226
  
Figure JPOXMLDOC01-appb-C000226
  
　実施例157-D)で得た3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート(600 mg)、実施例29-B)で得たエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート(540 mg)、ジクロロビス(トリフェニルホスフィン)パラジウム(II)(59 mg)と炭酸カリウム(701mg)のDME(10 mL)-水(3 mL)溶液を80℃で終夜撹拌した。反応混合物に水を注ぎ、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/へキサン)で精製し、標題化合物(305 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.40 (3H, t, J = 7.2 Hz), 2.63 (3H, s), 3.86 (3H, s), 3.95 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.06 (1H, s), 7.14-7.36 (6H, m), 7.96 (1H, d, J = 8.7 Hz).
MS (ESI+): [M+H]+ 369.1. 3- (4-Chlorobenzyl) -1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate (600 mg) obtained in Example 157-D), ethyl 2- Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (540 mg), dichlorobis (triphenylphosphine) palladium (II) (59 mg) and A solution of potassium carbonate (701 mg) in DME (10 mL) -water (3 mL) was stirred at 80 ° C. overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (305 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.2 Hz), 2.63 (3H, s), 3.86 (3H, s), 3.95 (2H, s), 4.38 (2H, q, J = 7.2 Hz), 6.06 (1H, s), 7.14-7.36 (6H, m), 7.96 (1H, d, J = 8.7 Hz).
MS (ESI +): [M + H] + 369.1.
実施例161
4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]-2-メチル安息香酸 Example 161
4- [3- (4-Chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000227
Figure JPOXMLDOC01-appb-C000227
　実施例160で得たエチル4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]-2-メチルベンゾアート(305 mg)のメタノール/THF溶液 (1/4、15 mL)へ1 N水酸化ナトリウム水溶液 (2.0 mL)を加え、室温で1時間撹拌した。反応混合物へ1 N塩酸を0℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (186 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.69 (3H, s), 3.89 (3H, s), 3.97 (2H, s), 6.09 (1H, s), 7.12-7.39 (6H, m), 8.11 (1H, d, J = 8.3 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 341.2. A methanol / THF solution of ethyl 4- [3- (4-chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] -2-methylbenzoate (305 mg) obtained in Example 160 (1/4 1 N aqueous sodium hydroxide solution (2.0 mL) was added to 15 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (186 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.69 (3H, s), 3.89 (3H, s), 3.97 (2H, s), 6.09 (1H, s), 7.12-7.39 (6H, m), 8.11 ( 1H, d, J = 8.3 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 341.2.
実施例162
4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]-2-メチルベンズアミド Example 162
4- [3- (4-Chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000228
Figure JPOXMLDOC01-appb-C000228
　実施例161で得た4-[3-(4-クロロベンジル)-1-メチル-1H-ピラゾール-5-イル]-2-メチル安息香酸(186 mg)、WSC (115 mg)、HOBtアンモニア和物(91 mg)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、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(酢酸エチル/メタノール)により精製し、標題化合物(130 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 3.84 (3H, s), 3.95 (2H, s), 5.74 (2H, brs), 6.03 (1H, s), 7.16-7.36 (6H, m), 7.52 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 340.1. 4- [3- (4-Chlorobenzyl) -1-methyl-1H-pyrazol-5-yl] -2-methylbenzoic acid (186 mg), WSC (115 mg), HOBt ammonia sum obtained in Example 161 The product (91 mg) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate / methanol) to give the title compound (130 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.54 (3H, s), 3.84 (3H, s), 3.95 (2H, s), 5.74 (2H, brs), 6.03 (1H, s), 7.16-7.36 ( 6H, m), 7.52 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 340.1.
実施例163
エチル 4-[3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル]-2-メチルベンゾアート Example 163
Ethyl 4- [3- (4-chlorobenzyl) -1-phenyl-1H-pyrazol-5-yl] -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000229
Figure JPOXMLDOC01-appb-C000229
A)5-(4-クロロベンジル)-2-フェニル-2,4-ジヒドロ-3H-ピラゾール-3-オン
　実施例157-B)で合成したエチル 4-(4-クロロフェニル)-3-オキソブタノアート(2 g)のエタノール溶液(40 mL)にフェニルヒドラジン塩酸塩 (1.3 g)とトリエチルアミン(1.39 mL)を加え、80℃で3時間撹拌した。減圧下溶媒を留去し、水を加え、酢酸エチルで抽出した。1N塩酸および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製後、標題化合物 (700 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 3.32 (2H, s), 3.80 (2H, s), 7.12-7.25 (3H, m), 7.29-7.52 (4H, m), 7.78-8.01 (2H, m).
MS (ESI+): [M+H]+ 285.2. A) 5- (4-Chlorobenzyl) -2-phenyl-2,4-dihydro-3H-pyrazol-3-one Ethyl 4- (4-chlorophenyl) -3-oxobutane synthesized in Example 157-B) Phenylhydrazine hydrochloride (1.3 g) and triethylamine (1.39 mL) were added to an ethanol solution (40 mL) of Noate (2 g), and the mixture was stirred at 80 ° C. for 3 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (700 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 3.32 (2H, s), 3.80 (2H, s), 7.12-7.25 (3H, m), 7.29-7.52 (4H, m), 7.78-8.01 (2H, m ).
MS (ESI +): [M + H] + 285.2.
B)3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例163-A)で得た5-(4-クロロベンジル)-2-フェニル-2,4-ジヒドロ-3H-ピラゾール-3-オン(700 mg)のピリジン溶液(5 mL)にトリフルオロメタンスルホン酸無水物(0.46 mL)を0℃で加え、室温で1時間撹拌した。溶媒を減圧下留去し、残渣を酢酸エチルで希釈した。1N塩酸および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (676 mg)を得た。
1H NMR (300 MHz, CDCl3) δ3.98 (2H, s), 6.06 (1H, s), 7.20-7.60 (9H, m). B) 3- (4-Chlorobenzyl) -1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate 5- (4-chlorobenzyl) -2-phenyl-2, obtained in Example 163-A) To a pyridine solution (5 mL) of 4-dihydro-3H-pyrazol-3-one (700 mg) was added trifluoromethanesulfonic anhydride (0.46 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (676 mg).
1 H NMR (300 MHz, CDCl 3 ) δ3.98 (2H, s), 6.06 (1H, s), 7.20-7.60 (9H, m).
C)エチル4-[3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル]-2-メチルベンゾアート
　実施例163-B)で合成した3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート(676 mg)、実施例29-B)で合成したエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート(518 mg)、ジクロロビス(トリフェニルホスフィン)パラジウム(II)(57 mg)と炭酸カリウム(673 mg)のDME(10 mL)-水(3 mL)溶液を80℃で終夜撹拌した。反応混合物に水を注ぎ、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/へキサン)で精製し、標題化合物(252 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.37 (3H, t, J = 7.2 Hz), 2.50 (3H, s), 4.05 (2H, s), 4.33 (2H, d, J = 6.8 Hz), 6.26 (1H, s), 6.98 (1H, dd, J = 8.1, 1.3 Hz), 7.08-7.18 (1H, m), 7.20-7.45 (9H, m), 7.77 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 431.2. C) Ethyl 4- [3- (4-chlorobenzyl) -1-phenyl-1H-pyrazol-5-yl] -2-methylbenzoate 3- (4-chlorobenzyl) synthesized in Example 163-B) 1-phenyl-1H-pyrazol-5-yl trifluoromethanesulfonate (676 mg), ethyl 2-methyl-4- (4,4,5,5-tetramethyl-1) synthesized in Example 29-B) , 3,2-Dioxaborolan-2-yl) benzoate (518 mg), dichlorobis (triphenylphosphine) palladium (II) (57 mg) and potassium carbonate (673 mg) in DME (10 mL) -water (3 mL The solution was stirred at 80 ° C. overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (252 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.37 (3H, t, J = 7.2 Hz), 2.50 (3H, s), 4.05 (2H, s), 4.33 (2H, d, J = 6.8 Hz), 6.26 (1H, s), 6.98 (1H, dd, J = 8.1, 1.3 Hz), 7.08-7.18 (1H, m), 7.20-7.45 (9H, m), 7.77 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 431.2.
実施例164
4-[3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル]-2-メチル安息香酸 Example 164
4- [3- (4-Chlorobenzyl) -1-phenyl-1H-pyrazol-5-yl] -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000230
Figure JPOXMLDOC01-appb-C000230
　実施例163-C)で得たエチル 4-[3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル]-2-メチルベンゾアート(252 mg)のメタノール/THF溶液 (1/4、10 mL)へ1 N水酸化ナトリウム水溶液 (2.0 mL)を加え、室温で1時間撹拌した。反応混合物へ1 N塩酸を0 ℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (183 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 4.06 (2H, s), 6.28 (1H, s), 7.02 (1H, d, J = 9.8 Hz), 7.14 (1H, s), 7.20-7.47 (9H, m), 7.90 (1H, d, J = 7.9 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 403.1. A methanol / THF solution of ethyl 4- [3- (4-chlorobenzyl) -1-phenyl-1H-pyrazol-5-yl] -2-methylbenzoate (252 mg) obtained in Example 163-C) ( 1/4, 10 mL) was added 1 N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 1 N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (183 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 2.54 (3H, s), 4.06 (2H, s), 6.28 (1H, s), 7.02 (1H, d, J = 9.8 Hz), 7.14 (1H, s) , 7.20-7.47 (9H, m), 7.90 (1H, d, J = 7.9 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 403.1.
実施例165
4-[3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル]-2-メチルベンズアミド Example 165
4- [3- (4-Chlorobenzyl) -1-phenyl-1H-pyrazol-5-yl] -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000231
Figure JPOXMLDOC01-appb-C000231
　実施例164で得た4-[3-(4-クロロベンジル)-1-フェニル-1H-ピラゾール-5-イル]-2-メチル安息香酸(183 mg)、WSC (104 mg)、HOBtアンモニア和物(83 mg)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン)により精製し、標題化合物(110 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 2.28 (3H, s), 3.99 (2H, s), 6.48 (1H, s), 6.94 (1H, dd, J = 7.9, 1.1 Hz), 7.15 (1H, d, J = 1.1 Hz), 7.22-7.31 (3H, m), 7.32-7.50 (8H, m), 7.72 (1H, brs).
MS (ESI+): [M+H]+ 402.2. 4- [3- (4-Chlorobenzyl) -1-phenyl-1H-pyrazol-5-yl] -2-methylbenzoic acid (183 mg), WSC (104 mg), HOBt ammonia sum obtained in Example 164 The product (83 mg) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound (110 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 2.28 (3H, s), 3.99 (2H, s), 6.48 (1H, s), 6.94 (1H, dd, J = 7.9, 1.1 Hz), 7.15 ( 1H, d, J = 1.1 Hz), 7.22-7.31 (3H, m), 7.32-7.50 (8H, m), 7.72 (1H, brs).
MS (ESI +): [M + H] + 402.2.
実施例166
エチル 4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-2-メチルベンゾアート Example 166
Ethyl 4- [3- (4-chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000232
Figure JPOXMLDOC01-appb-C000232
A)エチル 4-(4-クロロフェニル)-2-メチル-3-オキソブタノアート
　実施例157-B)で得たエチル 4-(4-クロロフェニル)-3-オキソブタノアート(1.0 g)のアセトン(15 mL)溶液に炭酸カリウム(574 mg)を加え、室温で5分撹拌後、ヨードメタン(708 mg)を加え、終夜加熱還流した。不溶物をろ過で除き、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (970 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.26 (3H, t, J = 7.2 Hz), 1.33 (3H, d, J = 6.8 Hz), 3.60 (1H, q, J = 7.0 Hz), 3.75-3.90 (2H, m, J = 5.3 Hz), 4.17 (2H, q, J = 7.2Hz), 7.08-7.18 (2H, m), 7.27-7.34 (2H, m). A) Ethyl 4- (4-chlorophenyl) -2-methyl-3-oxobutanoate Ethyl 4- (4-chlorophenyl) -3-oxobutanoate (1.0 g) obtained in Example 157-B) Potassium carbonate (574 mg) was added to an acetone (15 mL) solution, and the mixture was stirred at room temperature for 5 minutes. Insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (970 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.26 (3H, t, J = 7.2 Hz), 1.33 (3H, d, J = 6.8 Hz), 3.60 (1H, q, J = 7.0 Hz), 3.75-3.90 (2H, m, J = 5.3 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.08-7.18 (2H, m), 7.27-7.34 (2H, m).
B)5-(4-クロロベンジル)-2,4-ジメチル-2,4-ジヒドロ-3H-ピラゾール-3-オン
　実施例166-A)で得たエチル 4-(4-クロロフェニル)-2-メチル-3-オキソブタノアート(970 mg)のエタノール溶液(10 mL)にメチルヒドラジン (211 mg)を加え、80℃で終夜撹拌した。溶媒を減圧下留去し、残渣をエタノール-ヘキサンで結晶化させ標題化合物 (550 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.26 (3H, d, J = 7.9 Hz), 2.92 (1H, q, J = 7.9 Hz), 3.30 (3H, s), 3.55-3.77 (2H, m), 7.17 (2H, d, J = 8.7 Hz), 7.29-7.36 (2H, m).
MS (ESI+): [M+H]+ 237.2. B) 5- (4-Chlorobenzyl) -2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one Ethyl 4- (4-chlorophenyl) -2-yl obtained in Example 166-A) Methylhydrazine (211 mg) was added to an ethanol solution (10 mL) of methyl-3-oxobutanoate (970 mg), and the mixture was stirred at 80 ° C. overnight. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-hexane to obtain the title compound (550 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.26 (3H, d, J = 7.9 Hz), 2.92 (1H, q, J = 7.9 Hz), 3.30 (3H, s), 3.55-3.77 (2H, m) , 7.17 (2H, d, J = 8.7 Hz), 7.29-7.36 (2H, m).
MS (ESI +): [M + H] + 237.2.
C)3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例166-B)で得た5-(4-クロロベンジル)-2,4-ジメチル-2,4-ジヒドロ-3H-ピラゾール-3-オン(550 mg)のピリジン溶液(10 mL)にトリフルオロメタンスルホン酸無水物(721 mg)を0℃で加え、室温で1時間撹拌した。溶媒を減圧下留去した。残渣を酢酸エチルで希釈し、1 mol/L塩酸を加え、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (616 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.85 (3H, s), 3.76 (3H, s), 3.86 (2H, s), 7.05-7.17 (2H, m), 7.21-7.31 (2H, m). C) 3- (4-Chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate 5- (4-chlorobenzyl) -2,4- obtained in Example 166-B) To a pyridine solution (10 mL) of dimethyl-2,4-dihydro-3H-pyrazol-3-one (550 mg) was added trifluoromethanesulfonic anhydride (721 mg) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, 1 mol / L hydrochloric acid was added, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (616 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.85 (3H, s), 3.76 (3H, s), 3.86 (2H, s), 7.05-7.17 (2H, m), 7.21-7.31 (2H, m).
D)エチル 4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-2-メチルベンゾアート
　実施例166-C)で合成した3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート(610 mg)、実施例29－B)で合成したエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート(528 mg)とテトラキス(トリフェニルホスフィン)パラジウム(0)(96 mg)のDME(20 mL)- 2 M炭酸ナトリウム水溶液(6 mL)溶液を80℃で3時間攪拌した。反応混合物に水を注ぎ、酢酸エチルで抽出した。抽出液を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/へキサン)で精製し、標題化合物(557 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41 (3H, t, J = 7.2 Hz), 1.84 (3H, s), 2.64 (3H, s), 3.74 (3H, s), 3.94 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 7.11-7.34 (6H, m), 7.99 (1H, d, J = 8.7 Hz).
MS (ESI+): [M+H]+ 383.2. D) Ethyl 4- [3- (4-chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -2-methylbenzoate 3- (4-chloro) synthesized in Example 166-C) (Benzyl) -1,4-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (610 mg), ethyl 2-methyl-4- (4,4,5,5- synthesized in Example 29-B) Tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (528 mg) and tetrakis (triphenylphosphine) palladium (0) (96 mg) in DME (20 mL)-2 M aqueous sodium carbonate solution (6 mL) The solution was stirred at 80 ° C. for 3 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (557 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.2 Hz), 1.84 (3H, s), 2.64 (3H, s), 3.74 (3H, s), 3.94 (2H, s) , 4.39 (2H, q, J = 7.2 Hz), 7.11-7.34 (6H, m), 7.99 (1H, d, J = 8.7 Hz).
MS (ESI +): [M + H] + 383.2.
実施例167
4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-2-メチル安息香酸 Example 167
4- [3- (4-Chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000233
Figure JPOXMLDOC01-appb-C000233
　実施例166-D)で得たエチル 4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-2-メチルベンゾアート(557 mg)のメタノール/THF溶液 (1/4、15 mL)へ2 N水酸化ナトリウム水溶液 (2.0 mL)を加え、室温で1時間撹拌した。反応混合物へ1 N塩酸を0℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (360 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.84 (3H, s), 2.57 (3H, s), 3.68 (3H, s), 3.89 (2H, s), 7.18-7.44 (6H, m), 7.91 (1H, d, J = 7.9 Hz), 12.92 (1H, brs).
MS (ESI+): [M+H]+ 355.1. Ethyl 4- [3- (4-chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -2-methylbenzoate (557 mg) methanol / THF obtained in Example 166-D) To the solution (1/4, 15 mL) was added 2N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (360 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.84 (3H, s), 2.57 (3H, s), 3.68 (3H, s), 3.89 (2H, s), 7.18-7.44 (6H, m), 7.91 (1H, d, J = 7.9 Hz), 12.92 (1H, brs).
MS (ESI +): [M + H] + 355.1.
実施例168
4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-2-メチルベンズアミド Example 168
4- [3- (4-Chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000234
Figure JPOXMLDOC01-appb-C000234
　実施例167で得た4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-2-メチル安息香酸(180 mg)、WSC (117 mg)、HOBtアンモニア和物(93 mg)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィー(メタノール/酢酸エチル)により精製して標題化合物(120 mg)を得た。
1H NMR (300 MHz, CDCl3) δ1.83 (3H, s), 2.55 (3H, s), 3.73 (3H, s), 3.94 (2H, s), 5.80 (2H, brs), 7.09-7.31 (6H, m), 7.55 (1H, d, J = 7.6 Hz).
MS (ESI+): [M+H]+ 354.1. 4- [3- (4-Chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -2-methylbenzoic acid (180 mg), WSC (117 mg), HOBt obtained in Example 167 A solution of ammonia hydrate (93 mg) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography (methanol / ethyl acetate) to give the title compound (120 mg).
1 H NMR (300 MHz, CDCl 3 ) δ1.83 (3H, s), 2.55 (3H, s), 3.73 (3H, s), 3.94 (2H, s), 5.80 (2H, brs), 7.09-7.31 (6H, m), 7.55 (1H, d, J = 7.6 Hz).
MS (ESI +): [M + H] + 354.1.
実施例169
4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-N-(2-ヒドロキシエチル)-2-メチルベンズアミド Example 169
4- [3- (4-Chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -N- (2-hydroxyethyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000235
Figure JPOXMLDOC01-appb-C000235
　実施例167で合成した4-[3-(4-クロロベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル]-2-メチル安息香酸(180 mg)、2－アミノエタノール (37 mg)、HOBt (82 mg)、WSC (117 mg) のDMF溶液(3 mL) を室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥し、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(メタノール/酢酸エチル)により精製し、標題化合物(144 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.82 (3H, s), 2.33 (1H, t, J = 5.1 Hz), 2.51 (3H, s), 3.60-3.69 (2H, m), 3.72 (3H, s), 3.87 (2H, q, J = 4.9 Hz), 3.94 (2H, s), 6.27(1H, brs), 7.08-7.34 (6H, m), 7.48 (1H, d, J = 7.9 Hz).
MS (ESI+): [M+H]+ 398.2. 4- [3- (4-Chlorobenzyl) -1,4-dimethyl-1H-pyrazol-5-yl] -2-methylbenzoic acid (180 mg), 2-aminoethanol (37 mg) synthesized in Example 167 ), HOBt (82 mg), WSC (117 mg) in DMF (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (methanol / ethyl acetate) to give the title compound (144 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.82 (3H, s), 2.33 (1H, t, J = 5.1 Hz), 2.51 (3H, s), 3.60-3.69 (2H, m), 3.72 (3H, s), 3.87 (2H, q, J = 4.9 Hz), 3.94 (2H, s), 6.27 (1H, brs), 7.08-7.34 (6H, m), 7.48 (1H, d, J = 7.9 Hz).
MS (ESI +): [M + H] + 398.2.
実施例170
エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート Example 170
Ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -2-methylbenzoate
Figure JPOXMLDOC01-appb-C000236
Figure JPOXMLDOC01-appb-C000236
A)エチル 4-(3-フルオロ-5-(トリフルオロメチル)フェニル)-3-オキソブタノアート A) Ethyl 4- (3-fluoro-5- (trifluoromethyl) phenyl) -3-oxobutanoate
　カリウム 3-エトキシ-3-オキソプロパノアート(32.2 g)のアセトニトリル(100 mL)懸濁液にトリエチルアミン(54.6 mL)、塩化マグネシウム(21.4 g)を加え、室温で2時間撹拌した。反応混合物に(3-フルオロ-5-(トリフルオロメチル)フェニル)酢酸(20.0 g)と1,1'-カルボニルジイミダゾール(16.1 g)のアセトニトリル(100 mL)溶液を80℃で2時間撹拌した溶液を加え、室温で終夜撹拌した。反応混合物に6 N塩酸を加え、30分間撹拌後、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (22.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ1.25-1.34 (3H, m), 3.40-3.59 (2H, m), 3.94 (2H, s), 4.16-4.27 (2H, m), 7.04-7.40 (3H, m). Triethylamine (54.6 mL) and magnesium chloride (21.4 g) were added to a suspension of potassium 3-ethoxy-3-oxopropanoate (32.2 g) in acetonitrile (100 mL), and the mixture was stirred at room temperature for 2 hours. A solution of (3-fluoro-5- (trifluoromethyl) phenyl) acetic acid (20.0 g) and 1,1′-carbonyldiimidazole (16.1 g) in acetonitrile (100 mL) was stirred at 80 ° C. for 2 hours. The solution was added and stirred at room temperature overnight. 6N hydrochloric acid was added to the reaction mixture, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (22.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ1.25-1.34 (3H, m), 3.40-3.59 (2H, m), 3.94 (2H, s), 4.16-4.27 (2H, m), 7.04-7.40 ( 3H, m).
B)エチル 4-(3-フルオロ-5-(トリフルオロメチル)フェニル)-2-メチル-3-オキソブタノアート
　実施例170-A)で合成したエチル 4-(3-フルオロ-5-(トリフルオロメチル)フェニル)-3-オキソブタノアート(8.0 g)のアセトン(50 mL)溶液に炭酸カリウム(3.97 g)を加え、室温で5分撹拌後、ヨードメタン(4.66 g)を加え、終夜加熱還流した。不溶物をろ過で除き、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (5.3 g)を得た。
1H NMR (300 MHz, CDCl3) δ1.24-1.31 (3H, m), 1.38 (3H, d, J = 7.2 Hz), 3.62 (1H, q, J = 7.2 Hz), 3.81-4.02 (2H, m), 4.20 (2H, q, J = 7.2 Hz), 7.13 (1H, d, J = 9.1 Hz), 7.17-7.36 (2H, m). B) Ethyl 4- (3-Fluoro-5- (trifluoromethyl) phenyl) -2-methyl-3-oxobutanoate Ethyl 4- (3-fluoro-5- (s) synthesized in Example 170-A) To a solution of (trifluoromethyl) phenyl) -3-oxobutanoate (8.0 g) in acetone (50 mL) was added potassium carbonate (3.97 g), and the mixture was stirred at room temperature for 5 minutes, and then iodomethane (4.66 g) was added overnight. Heated to reflux. Insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (5.3 g).
1 H NMR (300 MHz, CDCl 3 ) δ1.24-1.31 (3H, m), 1.38 (3H, d, J = 7.2 Hz), 3.62 (1H, q, J = 7.2 Hz), 3.81-4.02 (2H , m), 4.20 (2H, q, J = 7.2 Hz), 7.13 (1H, d, J = 9.1 Hz), 7.17-7.36 (2H, m).
C)5-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2,4-ジメチル-2,4-ジヒドロ-3H-ピラゾール-3-オンと3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1,4-ジメチル-1H-ピラゾール-5-オールの混合物
　実施例170-B)で合成したエチル 4-(3-フルオロ-5-(トリフルオロメチル)フェニル)-2-メチル-3-オキソブタノアート(5.3 g)のエタノール溶液(50 mL)にメチルヒドラジン (957 mg)を加え、80℃で終夜撹拌した。溶媒を減圧下留去し、残渣をエタノール-ヘキサンから結晶化させ標題化合物 (3.2 g)を得た。
MS (ESI+): [M+H]+ 289.1. C) 5- (3-Fluoro-5- (trifluoromethyl) benzyl) -2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one and 3- (3-fluoro-5- (tri Fluoromethyl) benzyl) -1,4-dimethyl-1H-pyrazol-5-ol mixture Ethyl 4- (3-fluoro-5- (trifluoromethyl) phenyl) -2- synthesized in Example 170-B) Methylhydrazine (957 mg) was added to an ethanol solution (50 mL) of methyl-3-oxobutanoate (5.3 g), and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol-hexane to obtain the title compound (3.2 g).
MS (ESI +): [M + H] + 289.1.
D)3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート
　実施例170-C)で合成した5-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-2,4-ジメチル-2,4-ジヒドロ-3H-ピラゾール-3-オンと3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1,4-ジメチル-1H-ピラゾール-5-オールの混合物(2.0 g)のピリジン溶液(30 mL)にトリフルオロメタンスルホン酸無水物(2.35 g)を0℃で加え、室温で1時間撹拌した。溶媒を減圧下留去した。残渣を酢酸エチルで希釈し、1 N塩酸を加え、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン-酢酸エチル)で精製し、標題化合物 (2.47 g)を得た。
1H NMR (300 MHz, CDCl3) δ1.88 (3H, s), 3.78 (3H, s), 3.95 (2H, s), 7.02-7.13 (1H, m), 7.13-7.23 (1H, m), 7.24-7.32 (1H, m). D) 3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1,4-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate Example 170-C) Fluoro-5- (trifluoromethyl) benzyl) -2,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one and 3- (3-fluoro-5- (trifluoromethyl) benzyl) -1 To a pyridine solution (30 mL) of a mixture of 2,4-dimethyl-1H-pyrazol-5-ol (2.0 g) was added trifluoromethanesulfonic anhydride (2.35 g) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, 1N hydrochloric acid was added, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (2.47 g).
1 H NMR (300 MHz, CDCl 3 ) δ1.88 (3H, s), 3.78 (3H, s), 3.95 (2H, s), 7.02-7.13 (1H, m), 7.13-7.23 (1H, m) , 7.24-7.32 (1H, m).
E)エチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート
　実施例170-D)で得た3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1,4-ジメチル-1H-ピラゾール-5-イル トリフルオロメタンスルホナート(2.4 g)、実施例29-B)で得たエチル 2-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾアート(1.82 g)とテトラキス(トリフェニルホスフィン)パラジウム(0)(330 mg)のDME(40 mL)- 2 M炭酸ナトリウム水溶液(10 mL)溶液を80℃で3時間撹拌した。反応混合物に水を注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/へキサン)で精製し、標題化合物(2.23 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 1.86 (3H, s), 2.65 (3H, s), 3.75 (3H, s), 4.02 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 7.03-7.24 (4H, m), 7.35 (1H, s), 8.00 (1H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 435.1. E) Ethyl 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -2-methylbenzoate Example 170-D) Obtained 3- (3-fluoro-5- (trifluoromethyl) benzyl) -1,4-dimethyl-1H-pyrazol-5-yl trifluoromethanesulfonate (2.4 g), obtained in Example 29-B) Ethyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (1.82 g) and tetrakis (triphenylphosphine) palladium (0) (330 mg) in DME (40 mL) -2 M aqueous sodium carbonate (10 mL) was stirred at 80 ° C. for 3 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.23 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (3H, t, J = 7.2 Hz), 1.86 (3H, s), 2.65 (3H, s), 3.75 (3H, s), 4.02 (2H, s) , 4.39 (2H, q, J = 7.2 Hz), 7.03-7.24 (4H, m), 7.35 (1H, s), 8.00 (1H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 435.1.
実施例171
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-2-メチル安息香酸 Example 171
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -2-methylbenzoic acid
Figure JPOXMLDOC01-appb-C000237
Figure JPOXMLDOC01-appb-C000237
　実施例170で得たエチル 4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-2-メチルベンゾアート(2.23 g)のメタノール/THF溶液 (1/4、50 mL)へ2 N水酸化ナトリウム水溶液 (5.0 mL)を加え、室温で1時間撹拌した。反応混合物へ1 N塩酸を0℃で加え中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物 (1.8 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.88 (3H, s), 2.58 (3H, s), 3.69 (3H, s), 4.04 (2H, s), 7.25-7.46 (3H, m), 7.46-7.56 (2H, m), 7.92 (1H, d, J = 7.9 Hz), COOHピークは観測されなかった.
MS (ESI+): [M+H]+ 407.2. Ethyl 4- {3- [3-fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -2-methylbenzoate (2.23 g) obtained in Example 170 ) In methanol / THF solution (1/4, 50 mL) was added 2 N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid at 0 ° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.8 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.88 (3H, s), 2.58 (3H, s), 3.69 (3H, s), 4.04 (2H, s), 7.25-7.46 (3H, m), 7.46-7.56 (2H, m), 7.92 (1H, d, J = 7.9 Hz), no COOH peak was observed.
MS (ESI +): [M + H] + 407.2.
実施例172
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-2-メチルベンズアミド Example 172
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000238
Figure JPOXMLDOC01-appb-C000238
　実施例171で得た4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(400 mg)、WSC (226 mg)、HOBtアンモニア和物(180 mg)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、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(メタノール/酢酸エチル)により精製し、標題化合物(280 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.87 (3H, s), 2.42 (3H, s), 3.68 (3H, s), 4.03 (2H, s), 7.16-7.32 (2H, m), 7.34-7.60 (5H, m), 7.80 (1H, brs).
MS (ESI+): [M+H]+ 406.1. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (400 mg) obtained in Example 171 , WSC (226 mg), HOBt ammonia hydrate (180 mg) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (methanol / ethyl acetate) to give the title compound (280 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.87 (3H, s), 2.42 (3H, s), 3.68 (3H, s), 4.03 (2H, s), 7.16-7.32 (2H, m), 7.34-7.60 (5H, m), 7.80 (1H, brs).
MS (ESI +): [M + H] + 406.1.
実施例173
4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-N-(2-ヒドロキシエチル)-2-メチルベンズアミド Example 173
4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -N- (2-hydroxyethyl) -2-methylbenzamide
Figure JPOXMLDOC01-appb-C000239
Figure JPOXMLDOC01-appb-C000239
　実施例171で得た4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1,4-ジメチル-1H-ピラゾール-5-イル}-2-メチル安息香酸(400 mg)、2－アミノエタノール(72 mg)、HOBt (160 mg)、WSC (226 mg) のDMF溶液(3 mL) を室温で終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を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、硫酸マグネシウムで乾燥した後、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(メタノール/酢酸エチル)により精製し、標題化合物(292 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.87 (3H, s), 2.38 (3H, s), 3.20-3.39 (2H, m), 3.51 (2H, q, J = 6.2 Hz), 3.67 (3H, s), 4.03 (2H, s), 4.68 (1H, s), 7.27 (2H, s), 7.34-7.63 (4H, m), 8.26 (1H, t, J = 5.7 Hz).
MS (ESI+): [M+H]+ 450.2. 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1,4-dimethyl-1H-pyrazol-5-yl} -2-methylbenzoic acid (400 mg) obtained in Example 171 , 2-aminoethanol (72 mg), HOBt (160 mg), WSC (226 mg) in DMF (3 mL) were stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (methanol / ethyl acetate) to give the title compound (292 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.87 (3H, s), 2.38 (3H, s), 3.20-3.39 (2H, m), 3.51 (2H, q, J = 6.2 Hz), 3.67 ( 3H, s), 4.03 (2H, s), 4.68 (1H, s), 7.27 (2H, s), 7.34-7.63 (4H, m), 8.26 (1H, t, J = 5.7 Hz).
MS (ESI +): [M + H] + 450.2.
実施例174
メチル 3-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)ベンゾアート Example 174
Methyl 3-({3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoate
Figure JPOXMLDOC01-appb-C000240
Figure JPOXMLDOC01-appb-C000240
　実施例71と同様の方法で合成した3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-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(1.29 g)、メチル 3-(ブロモメチル)ベンゾアート(0.700 g)、ジクロロビス(ジフェニルホスフィノフェロセン)パラジウム(II)塩化メチレン付加物(0.125 g)、リン酸三カリウム (1.30 g)のNMP溶液 (7 mL)を窒素雰囲気中マイクロウェーブ照射下150℃で15分間加熱撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、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後、硫酸マグネシウムで乾燥し、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(NH、酢酸エチル/ヘキサン)により精製し、標題化合物 (0.500 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.69 (3H, s), 3.91 (3H, s), 3.96 (2H, s), 3.99 (2H, s), 5.77 (1H, s), 7.14 (2H, d, J = 9.1 Hz), 7.28-7.44 (3H, m), 7.85 (1H, s), 7.93 (1H, d, J = 7.6 Hz).
MS (ESI+): [M+H]+ 407.2. 3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2) synthesized in the same manner as in Example 71 -Dioxaborolan-2-yl) -1H-pyrazole (1.29 g), methyl 3- (bromomethyl) benzoate (0.700 g), dichlorobis (diphenylphosphinoferrocene) palladium (II) methylene chloride adduct (0.125 g), phosphorus An NMP solution (7 mL) of tripotassium acid (1.30 g) was heated and stirred at 150 ° C. for 15 minutes under microwave irradiation in a nitrogen atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (NH, ethyl acetate / hexane) to give the title compound (0.500 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.69 (3H, s), 3.91 (3H, s), 3.96 (2H, s), 3.99 (2H, s), 5.77 (1H, s), 7.14 (2H, d, J = 9.1 Hz), 7.28-7.44 (3H, m), 7.85 (1H, s), 7.93 (1H, d, J = 7.6 Hz).
MS (ESI +): [M + H] + 407.2.
実施例175
3-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)安息香酸 Example 175
3-({3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000241
Figure JPOXMLDOC01-appb-C000241
　実施例174で得たメチル 3-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)ベンゾアート(0.400 g)のメタノール溶液(7 ml)へ1N水酸化ナトリウム水溶液(1.85 ml)を加え、室温で終夜撹拌した。反応混合物を1N塩酸で中和し、水で希釈した。不溶物をろ取し、ジイソプロピルエーテルで洗浄し、標題化合物 (0.393 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 3.63 (3H, s), 3.94 (2H, s), 4.06 (2H, s), 5.84 (1H, s), 7.36-7.55 (5H, m), 7.73-7.86 (2H, m), 12.96 (1H, brs).
MS (ESI+): [M+H]+ 393.2. Methyl 3-({3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoate (0.400 g) methanol obtained in Example 174 To the solution (7 ml) was added 1N aqueous sodium hydroxide solution (1.85 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid and diluted with water. The insoluble material was collected by filtration and washed with diisopropyl ether to give the title compound (0.393 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 3.63 (3H, s), 3.94 (2H, s), 4.06 (2H, s), 5.84 (1H, s), 7.36-7.55 (5H, m), 7.73-7.86 (2H, m), 12.96 (1H, brs).
MS (ESI +): [M + H] + 393.2.
実施例176
3-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)ベンズアミド Example 176
3-({3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzamide
Figure JPOXMLDOC01-appb-C000242
Figure JPOXMLDOC01-appb-C000242
　実施例175で得た3-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)安息香酸(0.250 g)、WSC (0.244 g)、HOBtアンモニア和物(0.194 g)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、酢酸エチル/ヘキサン) で精製し、酢酸エチル/ヘキサンより結晶化して、標題化合物 (0.108 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.69 (3H, s), 3.96 (2H, s), 4.00 (2H, s), 5.62 (1H, brs), 5.78 (1H, s), 5.98 (1H, brs), 7.15 (2H, d, J = 9.1 Hz), 7.24-7.33 (2H, m), 7.35-7.46 (1H, m), 7.60-7.71 (2H, m).
MS (ESI+): [M+H]+ 392.2. 3-({3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoic acid (0.250 g) obtained in Example 175, WSC ( 0.244 g), HOBt ammonia hydrate (0.194 g) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and crystallized from ethyl acetate / hexane to give the title compound (0.108 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.69 (3H, s), 3.96 (2H, s), 4.00 (2H, s), 5.62 (1H, brs), 5.78 (1H, s), 5.98 (1H, brs), 7.15 (2H, d, J = 9.1 Hz), 7.24-7.33 (2H, m), 7.35-7.46 (1H, m), 7.60-7.71 (2H, m).
MS (ESI +): [M + H] + 392.2.
実施例177
メチル 4-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)ベンゾアート Example 177
Methyl 4-({3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoate
Figure JPOXMLDOC01-appb-C000243
Figure JPOXMLDOC01-appb-C000243
　実施例71と同様の方法で合成した3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-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(1.29 g)、メチル 4-(ブロモメチル)ベンゾアート(0.700 g)、ジクロロビス(ジフェニルホスフィノフェロセン)パラジウム(II)塩化メチレン付加物(0.125 g)、リン酸三カリウム (1.30 g)のNMP溶液 (7 mL)を窒素雰囲気中マイクロウェーブ照射下150℃で15分間加熱撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、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後、硫酸マグネシウムで乾燥し、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(NH、酢酸エチル/ヘキサン)により精製し、標題化合物 (0.400 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.68 (3H, s), 3.91 (3H, s), 3.96 (2H, s), 3.99 (2H, s), 5.78 (1H, s), 7.10-7.24 (4H, m), 7.30 (1H, s), 7.98 (2H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 407.2. 3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2) synthesized in the same manner as in Example 71 -Dioxaborolan-2-yl) -1H-pyrazole (1.29 g), methyl 4- (bromomethyl) benzoate (0.700 g), dichlorobis (diphenylphosphinoferrocene) palladium (II) methylene chloride adduct (0.125 g), phosphorus An NMP solution (7 mL) of tripotassium acid (1.30 g) was heated and stirred at 150 ° C. for 15 minutes under microwave irradiation in a nitrogen atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (NH, ethyl acetate / hexane) to give the title compound (0.400 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.68 (3H, s), 3.91 (3H, s), 3.96 (2H, s), 3.99 (2H, s), 5.78 (1H, s), 7.10-7.24 ( 4H, m), 7.30 (1H, s), 7.98 (2H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 407.2.
実施例178
4-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)安息香酸 Example 178
4-({3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000244
Figure JPOXMLDOC01-appb-C000244
　実施例177で得たメチル 4-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)ベンゾアート(0.400 g)のメタノール溶液(7 ml)へ1N水酸化ナトリウム水溶液(1.48 ml)を加え、室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をジイソプロピルエーテルで洗浄し、標題化合物 (0.291 g)を得た。
1H NMR (300 MHz, DMSO-d6) δ 3.64 (3H, s), 3.93 (2H, s), 4.06 (2H, s), 5.85 (1H, s), 7.30 (2H, d, J = 8.0 Hz), 7.36-7.54 (3H, m), 7.88 (2H, d, J = 8.3 Hz), 12.88 (1H, brs).
MS (ESI+): [M+H]+ 393.2. Methyl 4-({3- [3-fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoate (0.400 g) of methanol obtained in Example 177 To the solution (7 ml) was added 1N aqueous sodium hydroxide solution (1.48 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (0.291 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ 3.64 (3H, s), 3.93 (2H, s), 4.06 (2H, s), 5.85 (1H, s), 7.30 (2H, d, J = 8.0 Hz), 7.36-7.54 (3H, m), 7.88 (2H, d, J = 8.3 Hz), 12.88 (1H, brs).
MS (ESI +): [M + H] + 393.2.
実施例179
4-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)ベンズアミド Example 179
4-({3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzamide
Figure JPOXMLDOC01-appb-C000245
Figure JPOXMLDOC01-appb-C000245
　実施例178で得た4-({3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}メチル)安息香酸(0.250 g)、WSC (0.244 g)、HOBtアンモニア和物(0.194 g)のDMF溶液 (3 mL)を室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー (NH、酢酸エチル/ヘキサン) で精製し、酢酸エチル/ヘキサンより結晶化して、標題化合物 (0.145 g)を得た。
1H NMR (300 MHz, CDCl3) δ 3.68 (3H, s), 3.97 (2H, s), 4.00 (2H, s), 5.56 (1H, brs), 5.78 (1H, s), 5.98 (1H, brs), 7.08-7.35 (5H, m), 7.76 (2H, d, J = 8.3 Hz).
MS (ESI+): [M+H]+ 392.0. 4-({3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} methyl) benzoic acid (0.250 g) obtained in Example 178, WSC ( 0.244 g), HOBt ammonia hydrate (0.194 g) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) and crystallized from ethyl acetate / hexane to give the title compound (0.145 g).
1 H NMR (300 MHz, CDCl 3 ) δ 3.68 (3H, s), 3.97 (2H, s), 4.00 (2H, s), 5.56 (1H, brs), 5.78 (1H, s), 5.98 (1H, brs), 7.08-7.35 (5H, m), 7.76 (2H, d, J = 8.3 Hz).
MS (ESI +): [M + H] + 392.0.
試験例１
GPR52アゴニスト活性測定試験（ヒトGPR52発現CHO細胞での細胞内cAMP濃度上昇の測定）：
　OptiPlate-384（PerkinElmer社）を用い、アッセイバッファー（HBSS(Ca2+, Mg2+含有), 0.5% BSA, 100μM IBMX, 100μM Ro20-1724, 5 mM HEPES(pH 7.55)）30μL中で、1×104個のヒトGPR52発現CHO(dhfr-)細胞を10μMまたは 1μMの被検化合物と37℃で30分間インキュベーションした。その後、AlphaScreen cAMP Assay Kit（PerkinElmer社）のプロトコールに従い、EnVision（PerkinElmer社）にて細胞内cAMP濃度を測定した。1μM N-(2-ヒドロキシエチル)-3-[2-[3-(トリフルオロメチル)ベンジル]-1-ベンゾフラン-4-イル]ベンズアミド存在下での細胞内cAMP濃度を100%、被検化合物の代わりにDMSOを添加した場合の細胞内cAMP濃度を0%として、GPR52アゴニスト活性を算出した。結果を表１に示す。 Test example 1
GPR52 agonist activity measurement test (measurement of increased intracellular cAMP concentration in human GPR52-expressing CHO cells):
Use OptiPlate-384 (PerkinElmer) in 30 μL of assay buffer (HBSS (Ca 2+ , Mg 2+ included ), 0.5% BSA, 100 μM IBMX, 100 μM Ro20-1724, 5 mM HEPES (pH 7.55)), 1 × 10 4 human GPR52-expressing CHO (dhfr − ) cells were incubated with 10 μM or 1 μM test compound at 37 ° C. for 30 minutes. Then, according to the protocol of AlphaScreen cAMP Assay Kit (PerkinElmer), intracellular cAMP concentration was measured with EnVision (PerkinElmer). 100% intracellular cAMP concentration in the presence of 1 μM N- (2-hydroxyethyl) -3- [2- [3- (trifluoromethyl) benzyl] -1-benzofuran-4-yl] benzamide, test compound GPR52 agonist activity was calculated with the intracellular cAMP concentration when DMSO was added instead of 0%. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000247
試験例２
メタンフェタミン誘導性運動亢進の阻害：
　マウスにおけるメタンフェタミン誘導性運動亢進の阻害を算定することによって、本発明の化合物を評価することができる。メタンフェタミン誘導性運動亢進の阻害を試験するために、奥山らの方法を改変した(Life Science, Vol. 65, pages 2109-2125 (1999))。
試験方法：
　ケージ(30 × 40 × 20 cm)の頂点から赤外線ビームを放射する32-チャンネル自発運動測定装置MDC-LT (BrainScience Idea Co., Ltd.製)を用いて自発運動を測定した。測定ケージ内で6～8週齢のオスICRマウスを少なくとも45分間飼い慣らした後、ビヒクル(0.5%メチルセルロース水溶液)に懸濁した試験化合物(30 mg/kg)あるいはビヒクルのみを経口投与した。この経口投与は、メタンフェタミン (2 mg/kg)の皮下投与の60分前に行われた。
活性の計算：
　自発運動を定量化するために、メタンフェタミンの投与後の90分間、測定ケージ内に放射された赤外線ビームを通り抜けた実験動物の回数を測定した。メタンフェタミン誘導性運動亢進が阻害された確率 (活性阻害率 (%))を計算するために、以下の数式が用いられた。
　阻害率 (%) = {1－(試験化合物処理群におけるメタンフェタミン処理後の自発運動量 ÷ ビヒクル処理群におけるメタンフェタミン処理後の自発運動量)}×100
　結果を表２に示す。 Test example 2
Inhibition of methamphetamine-induced hyperactivity:
The compounds of the invention can be evaluated by calculating the inhibition of methamphetamine-induced hyperactivity in mice. In order to test inhibition of methamphetamine-induced hyperactivity, the method of Okuyama et al. Was modified (Life Science, Vol. 65, pages 2109-2125 (1999)).
Test method:
Spontaneous motion was measured using a 32-channel spontaneous motion measuring device MDC-LT (manufactured by BrainScience Idea Co., Ltd.) that emits an infrared beam from the apex of the cage (30 × 40 × 20 cm). Six- to 8-week-old male ICR mice were housed in a measurement cage for at least 45 minutes, and then a test compound (30 mg / kg) suspended in a vehicle (0.5% methylcellulose aqueous solution) or a vehicle alone was orally administered. This oral administration was performed 60 minutes before the subcutaneous administration of methamphetamine (2 mg / kg).
Activity calculation:
In order to quantify the spontaneous movement, the number of experimental animals that passed through the infrared beam emitted in the measurement cage was measured for 90 minutes after administration of methamphetamine. In order to calculate the probability of inhibition of methamphetamine-induced hyperactivity (activity inhibition rate (%)), the following formula was used.
Inhibition rate (%) = {1- (Spontaneous momentum after methamphetamine treatment in the test compound treatment group ÷ Spontaneous momentum after methamphetamine treatment in the vehicle treatment group)} × 100
The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000248
　本発明の化合物が、ＧＰＲ５２に対するアゴニスト活性を有することが示された。 It was shown that the compound of the present invention has agonist activity against GPR52.
製剤例１
（１）実施例１の化合物　　　　　　　１０．０ｇ
（２）乳糖　　　　　　　　　　　　　７０．０ｇ
（３）コーンスターチ　　　　　　　　５０．０ｇ
（４）可溶性デンプン　　　　　　　　　７．０ｇ
（５）ステアリン酸マグネシウム　　　　３．０ｇ
　実施例１の化合物（１０．０ｇ）およびステアリン酸マグネシウム（３．０ｇ）を可溶性デンプンの水溶液（７０ｍＬ（可溶性デンプンとして７．０ｇ））で顆粒化した後、乾燥し、乳糖（７０．０ｇ）およびコーンスターチ（５０．０ｇ）と混合する（乳糖、コーンスターチ、可溶性デンプンおよびステアリン酸マグネシウムはいずれも日本薬局方適合品）。混合物を圧縮して錠剤を得る。 Formulation Example 1
(1) Compound of Example 1 10.0 g
(2) Lactose 70.0g
(3) Corn starch 50.0g
(4) 7.0g of soluble starch
(5) Magnesium stearate 3.0 g
The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) were granulated with an aqueous solution of soluble starch (70 mL (7.0 g as soluble starch)), then dried and lactose (70.0 g) And corn starch (50.0 g) (lactose, corn starch, soluble starch and magnesium stearate are all compatible with the Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.
　本発明の化合物は、ＧＰＲ５２に対するアゴニスト活性を有し、統合失調症などの精神疾患等の予防又は治療薬として有用である。 The compound of the present invention has agonist activity against GPR52 and is useful as a prophylactic or therapeutic agent for psychiatric disorders such as schizophrenia.
　本出願は、日本で出願された特願２０１０－１７９０１２および２０１０－２９４６０１を基礎としており、その内容は本明細書にすべて包含されるものである。 This application is based on Japanese Patent Application Nos. 2010-179012 and 2010-294601 filed in Japan, the contents of which are incorporated in full herein.

Claims (17)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    〔式中、
    　環Ａは、置換基を有していてもよい６～１０員芳香族炭化水素環、置換基を有していてもよい５～１０員非芳香族複素環、または置換基を有していてもよい５～１０員芳香族複素環を示し；
    　環Ｂは、
    （１）さらに置換基を有していてもよい６～１０員芳香族炭化水素環、
    （２）さらに置換基を有していてもよい５または６員複素環、または
    （３）さらに置換基を有していてもよい、ベンゼン環及び５または６員環が縮合した二環性縮合環を示し；
    　式（Ｉ）の部分構造式：
    Figure JPOXMLDOC01-appb-C000002
    は、
    Figure JPOXMLDOC01-appb-C000003
    （式中、Ｒ１は、ハロゲン原子、アシル基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよいＣ２－６アルケニル基、置換基を有していてもよいＣ２－６アルキニル基、置換基を有していてもよいＣ３－６シクロアルキル基、置換基を有していてもよいＣ６－１４アリール基、置換基を有していてもよいアミノ基、シアノ基、または－Ｓ（Ｏ）ｍＲａを示し；ｍは、０、１または２を示し；Ｒａは、水素原子またはＣ１－６アルキル基を示し；Ｒ３は水素原子またはＣ１－６アルキル基を示す。）を示し；
    　Ｒ２は、水素原子、ヒドロキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ１－６アルキル基、置換基を有していてもよい非芳香族複素環基、または置換基を有していてもよいＣ３－６シクロアルキル基を示し；
    　Ｌ１は、－Ｏ－、－ＣＯ－、置換基を有していてもよいＣ１－６アルキレン、または置換基を有していてもよいＣ３－６シクロアルキレンを示し；
    　Ｌ２は、－ＣＯ－、－ＣＯＹ－、－ＮＨＣＯ－、－ＹＣＯ－または－ＣＯＮＨ－を示し；
    　Ｙは、置換基を有していてもよいＣ１－３アルキレンを示し；
    　Ｌ３は、－（ＣＨ２）ｎ－（ｎは０または１を示す。）を示す。〕
    で表される化合物（但し、以下の化合物を除く：
    （１）式：
    Figure JPOXMLDOC01-appb-C000004
    （式中、Ｒｘａは、メチル基、エチル基または２－フルオロエチル基を示し；Ｒｘｂは、水素原子、フッ素原子、エトキシ基またはｔｅｒｔ－ブトキシ基を示す。）で表される化合物、
    （２）式（Ｉ）の部分構造式：
    Figure JPOXMLDOC01-appb-C000005
    が、
    Figure JPOXMLDOC01-appb-C000006
    を示し、Ｒ１が－ＣＯ－Ｒｘｃ（Ｒｘｃは置換基を示す）を示し、かつＬ１が－ＣＨ２－を示す化合物、並びに、
    （３）以下の化合物：
    3-(3-ベンジル-1-シクロヘキシル-1H-ピラゾール-5-イル)-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
    3-{1-シクロヘキシル-3-[(3,5-ジメチル-1H-ピラゾール-1-イル)メチル]-1H-ピラゾール-5-イル}-1-[2-(シクロプロピルアミノ)-2-オキソエチル]ピリジニウム、
    (6R)-5-(アセチルアミノ)-4-アミノ-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノン酸、
    tert-ブチル 4-{2-アミノ-4-[2-(4-ブロモフェニル)-1-(4-メトキシフェニル)エチル]-1H-イミダゾール-1-イル}ピペリジン-1-カルボキシラート、
    1-[4-シアノ-2-(ナフタレン-1-イルメチル)-1,3-オキサゾール-5-イル]ピペリジン-4-カルボキサミド、
    1-(2-ベンジル-4-シアノ-1,3-オキサゾール-5-イル)ピペリジン-4-カルボキサミド、
    tert-ブチル 4-(2-ベンジル-4-エチル-1,3-オキサゾール-5-イル)ピペリジン-1-カルボキシラート、
    ベンジル 4-(3-ベンジル-5-メチル-1H-1,2,4-トリアゾール-1-イル)ピペリジン-1-カルボキシラート、
    ジフェニルメチル (6R)-5-(アセチルアミノ)-2,6-アンヒドロ-6-(3-ベンジル-1-プロピル-1H-1,2,4-トリアゾール-5-イル)-4-[(tert-ブトキシカルボニル)アミノ]-3,4,5-トリデオキシ-L-threo-ヘキサ-2-エノナート、および
    ベンジル (1R,5S,6R)-6-(3-ベンジル-1-エチル-1H-ピラゾール-5-イル)-3-アザビシクロ[3.1.0]ヘキサン-3-カルボキシラート）
    またはその塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    [Where,
    Ring A has an optionally substituted 6 to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered non-aromatic heterocyclic ring, or a substituent. May represent a 5- to 10-membered aromatic heterocycle;
    Ring B is
    (1) a 6- to 10-membered aromatic hydrocarbon ring which may further have a substituent,
    (2) a 5- or 6-membered heterocyclic ring which may further have a substituent, or (3) a bicyclic condensation in which a benzene ring and a 5- or 6-membered ring which may further have a substituent are condensed. Indicates a ring;
    Partial structural formula of formula (I):
    Figure JPOXMLDOC01-appb-C000002
    Is
    Figure JPOXMLDOC01-appb-C000003
    (In the formula, R 1 has a halogen atom, an acyl group, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. Optionally having a C 2-6 alkynyl group, optionally having a C 3-6 cycloalkyl group, optionally having a C 6-14 aryl group, having a substituent Optionally represents an amino group, a cyano group, or —S (O) m Ra; m represents 0, 1 or 2; Ra represents a hydrogen atom or a C 1-6 alkyl group; R 3 represents Represents a hydrogen atom or a C 1-6 alkyl group);
    R 2 represents a hydrogen atom, a hydroxy group, an amino group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a C 1 1 which may have a substituent. A 6 alkyl group, a non-aromatic heterocyclic group which may have a substituent, or a C 3-6 cycloalkyl group which may have a substituent;
    L 1 represents —O—, —CO—, an optionally substituted C 1-6 alkylene, or an optionally substituted C 3-6 cycloalkylene;
    L 2 represents —CO—, —COY—, —NHCO—, —YCO— or —CONH—;
    Y represents C 1-3 alkylene which may have a substituent;
    L 3 represents — (CH 2 ) n — (n represents 0 or 1). ]
    A compound represented by (except the following compounds:
    (1) Formula:
    Figure JPOXMLDOC01-appb-C000004
    (Wherein R xa represents a methyl group, an ethyl group or a 2-fluoroethyl group; R xb represents a hydrogen atom, a fluorine atom, an ethoxy group or a tert-butoxy group),
    (2) Partial structural formula of formula (I):
    Figure JPOXMLDOC01-appb-C000005
    But,
    Figure JPOXMLDOC01-appb-C000006
    A compound in which R 1 represents —CO—R xc (R xc represents a substituent) and L 1 represents —CH 2 —, and
    (3) The following compounds:
    3- (3-benzyl-1-cyclohexyl-1H-pyrazol-5-yl) -1- [2- (cyclopropylamino) -2-oxoethyl] pyridinium,
    3- {1-cyclohexyl-3-[(3,5-dimethyl-1H-pyrazol-1-yl) methyl] -1H-pyrazol-5-yl} -1- [2- (cyclopropylamino) -2- Oxoethyl] pyridinium,
    (6R) -5- (Acetylamino) -4-amino-2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -3,4 , 5-trideoxy-L-threo-hex-2-enoic acid,
    tert-butyl 4- {2-amino-4- [2- (4-bromophenyl) -1- (4-methoxyphenyl) ethyl] -1H-imidazol-1-yl} piperidine-1-carboxylate,
    1- [4-cyano-2- (naphthalen-1-ylmethyl) -1,3-oxazol-5-yl] piperidine-4-carboxamide,
    1- (2-benzyl-4-cyano-1,3-oxazol-5-yl) piperidine-4-carboxamide,
    tert-butyl 4- (2-benzyl-4-ethyl-1,3-oxazol-5-yl) piperidine-1-carboxylate,
    Benzyl 4- (3-benzyl-5-methyl-1H-1,2,4-triazol-1-yl) piperidine-1-carboxylate,
    Diphenylmethyl (6R) -5- (acetylamino) -2,6-anhydro-6- (3-benzyl-1-propyl-1H-1,2,4-triazol-5-yl) -4-[(tert -Butoxycarbonyl) amino] -3,4,5-trideoxy-L-threo-hex-2-enoate and benzyl (1R, 5S, 6R) -6- (3-benzyl-1-ethyl-1H-pyrazole- 5-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate)
    Or its salt.
  2. 　環Ａが
    （１）(i) ハロゲン原子、(ii) Ｃ１－６アルコキシ－カルボニル基または１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、(iii) Ｃ３－１０シクロアルキル基、(iv) ニトロ基、(v) アミノ基、(vi) Ｃ１－６アルキルスルファニル基、(vii) Ｃ１－６アルキルスルフィニル基および(viii) Ｃ１－６アルキルスルホニル基から選ばれる１～３個の置換基で置換されていてもよいベンゼン；
    （２）(i) ハロゲン原子および(ii) Ｃ１－６アルキル基から選ばれる１～３個の置換基で置換されていてもよい、２－オキソジヒドロインドールまたは３－オキソジヒドロベンゾオキサジン；または
    （３）(i) ハロゲン原子および(ii) Ｃ１－６アルキル基から選ばれる１～３個の置換基で置換されていてもよいインダゾール
    である請求項１記載の化合物またはその塩。     Ring A is (1) (i) halogen atom, (ii) C 1-6 alkoxy - carbonyl group or one to three halogen atoms optionally substituted by a C 1-6 alkyl group, (iii) C 3 -10 cycloalkyl group, (iv) nitro group, (v) amino group, (vi) C 1-6 alkylsulfanyl group, (vii) C 1-6 alkylsulfinyl group and (viii) C 1-6 alkylsulfonyl group Benzene optionally substituted with 1 to 3 substituents selected from:
    (2) 2-oxodihydroindole or 3-oxodihydrobenzoxazine optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C 1-6 alkyl group; or (3) The compound or a salt thereof according to (1), which is indazole optionally substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) a C 1-6 alkyl group.
  3. 　環Ｂが、
    （1）Ｃ３－１０シクロアルキル基；
    （2）Ｃ１－６アルコキシ基；
    （3）ハロゲン原子；
    （4）(a) ハロゲン原子、
    　　 (b) ヒドロキシ基、
    　　 (c) シアノ基、および
    　　 (d) トリ（Ｃ１－６アルキル）シリルオキシ基
    から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
    （5）ヒドロキシ基；
    （6）１～３個のハロゲン原子で置換されていてもよいＣ１－６アルキルスルホニルオキシ基；および
    （7）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基
    から選ばれる１～３個の置換基でそれぞれさらに置換されていてもよい、
    （１）ベンゼン、
    （２）５もしくは６員芳香族複素環、
    （３）５もしくは６員非芳香族複素環、
    （４）ベンゼン環及び５もしくは６員芳香族複素環が縮合した二環性縮合環、または
    （５）ベンゼン環及び５もしくは６員非芳香族複素環が縮合した二環性縮合環
    である請求項１記載の化合物またはその塩。     Ring B is
    (1) a C 3-10 cycloalkyl group;
    (2) a C 1-6 alkoxy group;
    (3) a halogen atom;
    (4) (a) a halogen atom,
    (b) a hydroxy group,
    (c) cyano, and (d) tri (C 1-6 alkyl) 1-3 optionally substituted by a substituent a C 1-6 alkyl group selected from silyloxy groups;
    (5) hydroxy group;
    Selected from and (7) C 1-6 alkyl mono- or di-substituted by amino group which may be group; (6) 1-3 optionally substituted by a halogen atom C 1-6 alkylsulfonyloxy group Each of which may be further substituted with 1 to 3 substituents,
    (1) benzene,
    (2) 5- or 6-membered aromatic heterocycle,
    (3) a 5- or 6-membered non-aromatic heterocycle,
    (4) a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered aromatic heterocyclic ring are condensed, or (5) a bicyclic condensed ring in which a benzene ring and a 5- or 6-membered non-aromatic heterocyclic ring are condensed. Item 1. The compound according to Item 1 or a salt thereof.
  4. 　Ｒ１が、
    (i)（1）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基、
    　 （2）ヒドロキシ基、
    　 （3）Ｃ１－６アルコキシ基、および
    　 （4）Ｃ３－１０シクロアルキル基
    から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
    (ii) Ｃ３－６シクロアルキル基；
    (iii) Ｃ６－１４アリール基；
    (iv)（1）Ｃ１－６アルコキシ－カルボニル基、および
    　　（2）Ｃ１－６アルキル基
    から選ばれる１または２個の置換基で置換されていてもよいアミノ基；
    (v) ホルミル基；または
    (vi) カルボキシル基
    である請求項１記載の化合物またはその塩。     R 1 is
    (i) (1) an amino group which may be mono- or di-substituted with a C 1-6 alkyl group,
    (2) hydroxy group,
    (3) C 1-6 alkoxy group, and (4) C 3-10 optionally substituted with 1 to 3 substituents selected from cycloalkyl C 1-6 alkyl group;
    (ii) a C 3-6 cycloalkyl group;
    (iii) a C 6-14 aryl group;
    (iv) an amino group optionally substituted with 1 or 2 substituents selected from (1) a C 1-6 alkoxy-carbonyl group, and (2) a C 1-6 alkyl group;
    (v) a formyl group; or
    (vi) The compound or salt thereof according to claim 1, which is a carboxyl group.
  5. 　Ｒ２が、
    (i) 水素原子；
    (ii) ヒドロキシ基；
    (iii) Ｃ１－６アルキル基でモノまたはジ置換されていてもよいアミノ基；
    (iv) Ｃ１－６アルコキシ基；
    (v)（1）Ｃ１－６アルキル基またはＣ１－６アルキル－カルボニル基でモノまたはジ置換されていてもよいアミノ基、
    　 （2）Ｃ１－６アルキル基でモノまたはジ置換されていてもよいカルバモイル基、
    　 （3）ヒドロキシ基、
    　 （4）Ｃ１－６アルコキシ－カルボニル基、
    　 （5）Ｃ１－６アルキルスルファニル基、
    　 （6）Ｃ１－６アルキルスルフィニル基、
    　 （7）Ｃ１－６アルキルスルホニル基、
    　 （8）芳香族複素環基、および
    　 （9）非芳香族複素環基
    から選ばれる１～３個の置換基で置換されていてもよいＣ１－６アルキル基；
    (vi)（1）ヒドロキシ基で置換されていてもよいＣ１－６アルキル基、および
    　　（2）Ｃ１－６アルキル－カルボニル基
    から選ばれる１～３個の置換基で置換されていてもよい非芳香族複素環基；または
    (vii) Ｃ３－６シクロアルキル基
    である請求項１記載の化合物またはその塩。     R 2 is
    (i) a hydrogen atom;
    (ii) a hydroxy group;
    (iii) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group;
    (iv) a C 1-6 alkoxy group;
    (v) (1) an amino group which may be mono- or di-substituted with a C 1-6 alkyl group or a C 1-6 alkyl-carbonyl group,
    (2) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group,
    (3) a hydroxy group,
    (4) a C 1-6 alkoxy-carbonyl group,
    (5) a C 1-6 alkylsulfanyl group,
    (6) a C 1-6 alkylsulfinyl group,
    (7) a C 1-6 alkylsulfonyl group,
    (8) an aromatic heterocyclic group, and (9) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from non-aromatic heterocyclic groups;
    (vi) (1) a C 1-6 alkyl group optionally substituted with a hydroxy group, and (2) a substituent substituted with 1 to 3 substituents selected from a C 1-6 alkyl-carbonyl group A good non-aromatic heterocyclic group; or
    (vii) The compound or a salt thereof according to claim 1, which is a C 3-6 cycloalkyl group.
  6. 　Ｌ１がメチレンである請求項１記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein L 1 is methylene.
  7. 　Ｌ２が－ＣＯ－または－ＮＨＣＯ－である請求項１記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein L 2 is -CO- or -NHCO-.
  8. 　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-1-メチル-1H-ピラゾール-5-イル}-2-メチルベンズアミドまたはその塩。 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -1-methyl-1H-pyrazol-5-yl} -2-methylbenzamide or a salt thereof.
  9. 　6-(3-(3-フルオロ-5-(トリフルオロメチル)ベンジル)-1-メチル-1H-ピラゾール-5-イル)-2-メチルニコチンアミドまたはその塩。 6- (3- (3-Fluoro-5- (trifluoromethyl) benzyl) -1-methyl-1H-pyrazol-5-yl) -2-methylnicotinamide or a salt thereof.
  10. 　4-{3-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-5-メチル-1H-1,2,4-トリアゾール-1-イル}-2-メチルベンズアミドまたはその塩。 4- {3- [3-Fluoro-5- (trifluoromethyl) benzyl] -5-methyl-1H-1,2,4-triazol-1-yl} -2-methylbenzamide or a salt thereof.
  11. 　4-{2-[3-フルオロ-5-(トリフルオロメチル)ベンジル]-4-メチル-1,3-オキサゾール-5-イル}-2-メチルベンズアミドまたはその塩。 4- {2- [3-Fluoro-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazol-5-yl} -2-methylbenzamide or a salt thereof.
  12. 　請求項１記載の化合物またはその塩を含有する医薬。 A pharmaceutical comprising the compound according to claim 1 or a salt thereof.
  13. 　ＧＰＲ５２作動薬である請求項１２記載の医薬。 The medicament according to claim 12, which is a GPR52 agonist.
  14. 　統合失調症の予防又は治療薬である請求項１２記載の医薬。 The medicament according to claim 12, which is a prophylactic or therapeutic drug for schizophrenia.
  15. 　請求項１記載の化合物またはその塩の有効量を哺乳動物に投与することを特徴とする、統合失調症の予防又は治療方法。 A method for preventing or treating schizophrenia, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to a mammal.
  16. 　統合失調症の予防または治療薬の製造のための、請求項１記載の化合物またはその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the manufacture of a preventive or therapeutic agent for schizophrenia.
  17. 　統合失調症の予防または治療のための、請求項１記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, for the prevention or treatment of schizophrenia.
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WO2021198149A1 (en) 2020-03-30 2021-10-07 Boehringer Ingelheim International Gmbh Substituted 3-phenoxyazetidin-1-yl-pyrazines having gpr52 agonistic activity
WO2021216705A1 (en) * 2020-04-22 2021-10-28 Neurocrine Biosciences, Inc. Gpr52 modulators and methods of use
WO2023041432A1 (en) 2021-09-14 2023-03-23 Boehringer Ingelheim International Gmbh 3-phenoxyazetidin-1-yl-heteroaryl pyrrolidine derivatives and the use thereof as medicament

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