WO2012020738A1 - Composé hétérocyclique et utilisation de celui-ci - Google Patents

Composé hétérocyclique et utilisation de celui-ci Download PDF

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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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Japanese (ja)
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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/zh
Priority to ARP120100397A priority patent/AR085323A1/es
Publication of WO2012020738A1 publication Critical patent/WO2012020738A1/fr

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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

La présente invention concerne un composé qui a une activité agoniste contre GPR52 et qui est utile en tant que médicament préventif ou thérapeutique pour des troubles mentaux et similaire tels que la schizophrénie. Le composé est un composé représenté par la formule générale (I) [où chaque symbole est tel que défini dans la spécification] ou un sel de celui-ci.
PCT/JP2011/068087 2010-08-09 2011-08-08 Composé hétérocyclique et utilisation de celui-ci WO2012020738A1 (fr)

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ARP120100397A AR085323A1 (es) 2011-08-08 2012-02-07 Compuestos heterociclicos que tienen actividad agonista sobre gpr52

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015097713A1 (fr) 2013-11-14 2015-07-02 Cadila Healthcare Limited Nouveaux composés hétérocycliques
US9862708B2 (en) 2014-02-14 2018-01-09 Tempest Therapeutics, Inc. Pyrazolone compounds and uses thereof
JP2020007282A (ja) * 2018-07-11 2020-01-16 ユニマテック株式会社 フルオロアルキルピリジンの製造方法
CN110759902A (zh) * 2019-11-01 2020-02-07 海南一龄医疗产业发展有限公司 Set8赖氨酸甲基转移酶抑制剂及其制备方法和用途
WO2021198149A1 (fr) 2020-03-30 2021-10-07 Boehringer Ingelheim International Gmbh 3-phénoxyazétidin-1-yl-pyrazines substituées ayant une activité agoniste de gpr52
WO2021216705A1 (fr) * 2020-04-22 2021-10-28 Neurocrine Biosciences, Inc. Modulateurs de gpr52 et procédés d'utilisation
WO2023041432A1 (fr) 2021-09-14 2023-03-23 Boehringer Ingelheim International Gmbh Dérivés de 3-phénoxyazétidin-1-yl-hétéroaryl-pyrrolidine et leur utilisation en tant que médicament

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085897A1 (fr) * 2001-04-05 2002-10-31 Alangudi Sankaranarayanan Composes heterocycliques pour des complications vasculaires diabetiques et liees au vieillissement
WO2006116355A1 (fr) * 2005-04-22 2006-11-02 Kalypsys, Inc. Inhibiteurs ortho-terphenyle de kinase p38 et procedes de traitement des troubles inflammatoires
WO2009107391A1 (fr) * 2008-02-27 2009-09-03 武田薬品工業株式会社 Composé contenant un cycle aromatique à 6 chaînons
WO2009157196A1 (fr) * 2008-06-25 2009-12-30 武田薬品工業株式会社 Composé amide
WO2010018874A1 (fr) * 2008-08-12 2010-02-18 Takeda Pharmaceutical Company Limited Composé amide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085897A1 (fr) * 2001-04-05 2002-10-31 Alangudi Sankaranarayanan Composes heterocycliques pour des complications vasculaires diabetiques et liees au vieillissement
WO2006116355A1 (fr) * 2005-04-22 2006-11-02 Kalypsys, Inc. Inhibiteurs ortho-terphenyle de kinase p38 et procedes de traitement des troubles inflammatoires
WO2009107391A1 (fr) * 2008-02-27 2009-09-03 武田薬品工業株式会社 Composé contenant un cycle aromatique à 6 chaînons
WO2009157196A1 (fr) * 2008-06-25 2009-12-30 武田薬品工業株式会社 Composé amide
WO2010018874A1 (fr) * 2008-08-12 2010-02-18 Takeda Pharmaceutical Company Limited Composé amide

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Publication number Priority date Publication date Assignee Title
WO2015097713A1 (fr) 2013-11-14 2015-07-02 Cadila Healthcare Limited Nouveaux composés hétérocycliques
US10011609B2 (en) 2013-11-14 2018-07-03 Cadila Healthcare Limited Heterocyclic compounds
US10246470B2 (en) 2013-11-14 2019-04-02 Cadila Healthcare Limited Heterocyclic compounds
US9862708B2 (en) 2014-02-14 2018-01-09 Tempest Therapeutics, Inc. Pyrazolone compounds and uses thereof
JP2020007282A (ja) * 2018-07-11 2020-01-16 ユニマテック株式会社 フルオロアルキルピリジンの製造方法
JP7021017B2 (ja) 2018-07-11 2022-02-16 ユニマテック株式会社 フルオロアルキルピリジンの製造方法
CN110759902A (zh) * 2019-11-01 2020-02-07 海南一龄医疗产业发展有限公司 Set8赖氨酸甲基转移酶抑制剂及其制备方法和用途
EP3842430A4 (fr) * 2019-11-01 2021-07-28 Hainan Yiling Medical Industry & Development Co. Ltd Inhibiteur de la lysine méthyltransférase set8, son procédé de préparation et son utilisation
CN110759902B (zh) * 2019-11-01 2022-04-22 海南一龄医疗产业发展有限公司 Set8赖氨酸甲基转移酶抑制剂及其制备方法和用途
WO2021198149A1 (fr) 2020-03-30 2021-10-07 Boehringer Ingelheim International Gmbh 3-phénoxyazétidin-1-yl-pyrazines substituées ayant une activité agoniste de gpr52
WO2021216705A1 (fr) * 2020-04-22 2021-10-28 Neurocrine Biosciences, Inc. Modulateurs de gpr52 et procédés d'utilisation
WO2023041432A1 (fr) 2021-09-14 2023-03-23 Boehringer Ingelheim International Gmbh Dérivés de 3-phénoxyazétidin-1-yl-hétéroaryl-pyrrolidine et leur utilisation en tant que médicament

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