WO2012133607A1 - Composé de pyrazole - Google Patents

Composé de pyrazole Download PDF

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Publication number
WO2012133607A1
WO2012133607A1 PCT/JP2012/058291 JP2012058291W WO2012133607A1 WO 2012133607 A1 WO2012133607 A1 WO 2012133607A1 JP 2012058291 W JP2012058291 W JP 2012058291W WO 2012133607 A1 WO2012133607 A1 WO 2012133607A1
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Prior art keywords
methyl
alkyl
optionally substituted
group
pyrazol
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PCT/JP2012/058291
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English (en)
Japanese (ja)
Inventor
直之 増田
聡 宮本
重俊 菊池
清寛 三水
史恵 佐藤
康裕 椎名
渉 ▲濱▼口
竜志 瀬尾
拓真 三原
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Astellas Pharma Inc
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Astellas Pharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pyrazole compound useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for preventing and / or treating a disease associated with phosphodiesterase 10A (PDE10A).
  • a pharmaceutical composition for preventing and / or treating a disease associated with phosphodiesterase 10A PDE10A
  • Phosphodiesterase is an enzyme that degrades intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP).
  • PDE has enzymatic chemistry (cAMP specific substrate, cGMP specific substrate or both), catalytic site amino acid sequence homology, and structural motif (calmodulin binding domain). , GAF domain, PAS domain, etc.).
  • the PDE family is tissue-specifically expressed or localized in cells, and is thought to be involved in intracellular signals in specific organs / tissues by interacting with specific proteins (Folia Pharmacologica Japonica., 2005, 126, p. 121).
  • PDE10A is genetically conserved across mammals in mammals, and its expression is specifically and highly expressed in the brain, especially in the medium spiny neurons of the striatum and nucleus accumbens, It has been reported that both cAMP and cGMP are used as substrates (Neuropharmacology, 2010, Vol. 59, p.367). Mice specifically lacking PDE10A have reduced susceptibility to this inducer in behavioral studies with phencyclidine that induces schizophrenia-like disorders in humans (Neuropharmacology, 2006, 51st Volume, p.374). Furthermore, social behavior is higher than in the wild group (Journal of Neurochemistry., 2008, Vol. 105, p.
  • PDE10A inhibitors suppress their drug-induced neurodegeneration (Neurobiology of disease, 2009, 34th Vol., P.450) is known.
  • PDE10A inhibitors showed an improving effect on stimulant (amphetamine) and narcotic (phencyclidine) -induced behavioral changes used in animal models of positive symptoms of schizophrenia (Journal of Pharmacology and Experimental Therapeutics, 2008, No. 1) 325, p.681), N-methyl-D-aspartate (NMDA) antagonist-induced cognitive impairment (European Journal of Neuroscience, 2005, Vol. 21, p.1070) are known.
  • PDE10A inhibition is considered to be a promising target for drug treatment of not only schizophrenia but also anxiety, Huntington's disease, drug dependence, or cognitive impairment of Alzheimer's disease and its peripheral symptoms.
  • a compound useful as an active ingredient of a pharmaceutical composition such as a pharmaceutical composition for treating schizophrenia.
  • the present inventors have found that the pyrazole compound of the present invention has a PDE10A inhibitory action and completed the present invention. That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing the compound of formula (I) or a salt thereof and an excipient.
  • Ring A is an optionally substituted aromatic heterocycle
  • B is the same or different selected from the group consisting of C 1-6 alkyl, halogen, —OC 1-6 alkyl, optionally substituted cycloalkyl, and optionally substituted non-aromatic heterocycle Phenylene, pyridinediyl, or thiophenediyl, each optionally substituted with one or more groups, or -C ⁇ C-;
  • n is an integer of 0 or 1
  • L 1 is, -C 1-6 alkylene -, - C 1-6 alkylene -T-, or -TC 1-6 alkylene -, and provided that when n is 0, L 1 is - trimethylene -T -Or-tetramethylene-T-,
  • X is CR 0 or N;
  • R 1 is one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, —CN, —C (O) OH, and
  • C 1-6 alkyl or H optionally substituted with Ring E is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted aromatic heterocycle, or an optionally substituted non-aromatic heterocycle
  • T is O, S, —NH—, or —N (C 1-6 alkyl) —
  • R 0 is H or C 1-6 alkyl.
  • the present invention also relates to a pharmaceutical composition for preventing and / or treating schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease comprising a compound of formula (I) or a salt thereof.
  • the pharmaceutical composition includes a prophylactic and / or therapeutic agent for schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease containing the compound of formula (I) or a salt thereof.
  • the present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of schizophrenia, anxiety, Huntington's chorea, drug dependence and / or Alzheimer's disease.
  • a compound of formula (I) or a salt thereof for the prevention and / or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and / or Alzheimer's disease, schizophrenia, anxiety, Huntington's choreography
  • a subject an effective amount of a compound of formula (I) or a salt thereof and a compound of formula (I) or a salt thereof for the prevention and / or treatment of disease, drug dependence and / or Alzheimer's disease
  • the present invention relates to a method for preventing and / or treating schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease.
  • the “subject” is a human or other animal that needs the prevention or treatment, and as a certain aspect, it is a human that needs the prevention or treatment.
  • the compound of formula (I) or a salt thereof has a PDE10A inhibitory action and can be used as a prophylactic and / or therapeutic agent for schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease.
  • alkyl includes linear alkyl and branched alkyl.
  • C 1-6 alkyl is linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
  • methyl, ethyl, propyl and isopropyl are used, and in another embodiment, methyl, ethyl and isopropyl are used.
  • Alkylene is a divalent group formed by removing any one hydrogen atom of the above “alkyl”.
  • C 1-6 alkylene is a linear or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethyl. Examples include methylene, ethylmethylene, methylethylene, dimethylethylene, and ethylethylene. In another embodiment, methylene and ethylene.
  • Cycloalkyl is a saturated hydrocarbon ring group having 3 to 8 ring members, and the cycloalkyl may have a bridge, may be condensed with a benzene ring, and some of the bonds are not bonded. It may be saturated. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, and another embodiment is C 3-6 cycloalkyl.
  • Aryl is a monocyclic to tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Specifically, for example, phenyl, naphthyl and the like.
  • Aromatic heterocycle '' is a monocyclic aromatic heterocyclic group having 5 to 6 ring members and containing one or more heteroatoms selected from O, N and S as ring constituent atoms
  • the monocyclic aromatic heterocycle may be condensed with a ring selected from the group consisting of cyclohexane, benzene, or thiophene, imidazole, pyrazole, pyridine, triazole, and pyrazine.
  • the nitrogen of the ring constituent atom may be oxidized.
  • non-aromatic heterocycle is a monocyclic non-aromatic heterocyclic group having 4 to 8 ring members and containing 1 to 4 heteroatoms selected from O, N and S as ring members. is there.
  • the monocyclic non-aromatic hetero ring may be condensed with a benzene ring.
  • sulfur atom which is a ring-constituting atom may be oxidized, and a partial bond of the ring may be unsaturated.
  • Examples include dioxolanyl, dioxanyl, tetrahydrothiopyranyl, indolinyl, 1,2-dihydropyridyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,2-dihydropyridazinyl and the like.
  • Halogen means F, Cl, Br, I.
  • phenylene is 1,4-phenylene
  • pyridinediyl is pyridine-2,5-diyl
  • thiophenediyl is thiophene-2,5. -It's a diyl.
  • optionally substituted means unsubstituted or having 1 to 5 substituents.
  • those substituents may be the same or may mutually differ.
  • C 1- which may be substituted with one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2 6 alkyl, (2) halogen, (3) —O— (C 1-6 alkyl optionally substituted with one or more halogens), (4) -NH 2, (5) -NH (C 1-6 alkyl), (6) -N (C 1-6 alkyl) 2 , (7) -CN, (8) cycloalkyl, (9) -C (O) OC 1-6 alkyl, (10) -C (O) H, Can be mentioned.
  • Optionally substituted cycloalkyl “optionally substituted non-aromatic” which is acceptable as a substituent of optionally substituted phenylene, pyridinediyl, or thiophenediyl in B of formula (I)
  • Substituents that are acceptable in “terocycle” include C 1-6 alkyl, halogen, and —OH.
  • Substituents allowed in “optionally substituted cycloalkyl” in ring E of formula (I) include C 1-6 alkyl, —OH, —C (O) NH 2 , —C (O) NH. Mention may be made of (C 1-6 alkyl), —C (O) N (C 1-6 alkyl) 2 , —CN, ⁇ NOC 1-6 alkyl, and oxo.
  • Substituents allowed in “optionally substituted aryl” in ring E of formula (I) include C 1-6 alkyl, halogen, and —OH.
  • the substituents allowed in the “optionally substituted aromatic heterocycle” in ring E of formula (I) include i) halogen, —OH, —OC 1-6 alkyl, —O-tert-butyl. dimethylsilyl (hereinafter -O-TBS), and -N (C 1-6 alkyl) same or is selected from the group consisting of 2 different 1 or more C 1-6 alkyl optionally substituted by group, ii) Mention may be made of halogen, iii) —OC 1-6 alkyl, iv) —OH, and v) cycloalkyl.
  • C 1- which may be substituted with one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2 6 alkyl, (2) halogen, (3) -OH, (4) -S (O) 2 -C 1-6 alkyl, (5) —C (O) — (C 1-6 alkyl optionally substituted with —OC 1-6 alkyl), (6) —C (O) —N (C 1-6 alkyl) 2 , (7) -C (O) OC 1-6 alkyl, (8) Oxo, Can be mentioned.
  • Ring A is substituted with one or more groups selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2 C 1-6 alkyl, ii) halogen also, iii) -O- (same or different one or more halogens optionally substituted by C 1-6 alkyl), iv) -N (C 1-6 alkyl) 2 , v) -CN, and vi) a compound of the formula (I) or a salt thereof which is an aromatic heterocyclic ring optionally substituted with one or more groups selected from the group consisting of cycloalkyl.
  • ring A is substituted with one or more groups that are the same or different selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2. which may also be C 1-6 alkyl, ii) halogen, iii) -O- (same or different one or more are optionally C 1-6 alkyl substituted with halogen), iv) -N (C 1- 6 alkyl) 2 , v) -CN, and vi) benzoimidazolyl, pyridyl, quinolyl, imidazo [1,2-a each optionally substituted with one or more groups selected from the group consisting of cycloalkyl A compound of formula (I) or a salt thereof which is pyridyl, imidazo [4,5-b] pyridyl, 1,8-naphthyridinyl, or imidazo [1,2-b] pyrid
  • a compound of formula (I) or a salt thereof, wherein ring A is benzimidazolyl optionally substituted with C 1-6 alkyl.
  • the compound of formula (I) or a salt thereof, wherein ring A is benzoimidazol-4-yl optionally substituted with C 1-6 alkyl.
  • the compound of formula (I) or a salt thereof, wherein ring A is benzimidazol-4-yl optionally substituted with methyl or ethyl.
  • ring A is one or more same or different selected from the group consisting of C 1-6 alkyl, —OC 1-6 alkyl, —N (C 1-6 alkyl) 2 , and cycloalkyl.
  • a compound of formula (I) or a salt thereof which is pyridyl optionally substituted by a group.
  • ring A is pyridin-2-yl optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl and —OC 1-6 alkyl.
  • a compound of formula (I) or a salt thereof In yet another embodiment, a compound of formula (I) or a salt thereof, wherein ring A is pyridin-2-yl optionally substituted with methyl.
  • ring A is i) one or more groups identical or different selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2. optionally substituted C 1-6 alkyl, ii) halogen, iii) -O- (same or different one or more halogens optionally substituted by C 1-6 alkyl), iv) -N (C 1 -6alkyl ) 2 , v) -CN, and vi) a compound of formula (I) or a salt thereof which is quinolyl optionally substituted with one or more groups selected from the group consisting of cycloalkyl.
  • ring A is i) halogen and -N (C 1-6 alkyl) optionally substituted by the same or different one or more groups selected from the group consisting of 2 C 1-6 alkyl Ii) a halogen, and iii) a compound of formula (I) or a salt thereof which is quinolyl optionally substituted with one or more groups selected from the group consisting of —OC 1-6 alkyl.
  • ring A is optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and —O-methyl.
  • a compound of formula (I) or a salt thereof is i) halogen and -N (C 1-6 alkyl) optionally substituted by the same or different one or more groups selected from the group consisting of 2 C 1-6 alkyl Ii) a halogen, and iii) a compound of formula (I) or a salt thereof which is quinoly
  • ring A is optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl.
  • a compound of formula (I) or a salt thereof which is -2-yl.
  • the formula wherein ring A is quinolin-2-yl optionally substituted by one or more groups selected from the group consisting of methyl, ethyl, F, and -O-methyl A compound of (I) or a salt thereof.
  • ring A is optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl.
  • a compound of formula (I) or a salt thereof which is -8-yl.
  • ring A is quinolin-8-yl optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, F, and —O-methyl.
  • a compound of formula (I) or a salt thereof is optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl.
  • B is selected from the group consisting of C 1-6 alkyl, halogen, —OC 1-6 alkyl, optionally substituted cycloalkyl, and optionally substituted non-aromatic heterocycle
  • a compound of formula (I) or a salt thereof which is phenylene or pyridinediyl each optionally substituted by one or more different groups.
  • B is selected from the group consisting of C 1-6 alkyl, halogen, —OC 1-6 alkyl, optionally substituted cycloalkyl, and optionally substituted non-aromatic heterocycle.
  • a compound of formula (I) or a salt thereof which is phenylene optionally substituted with one or more selected identical or different groups.
  • B is a phenylene that is optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl, halogen, and —OC 1-6 alkyl.
  • Yet another embodiment is a compound of formula (I) wherein B is phenylene optionally substituted with one or more groups selected from the group consisting of methyl, F, and -O-methyl, or a compound thereof salt.
  • the formula (I) wherein B is 1,4-phenylene optionally substituted with one or more groups selected from the group consisting of methyl, F, and -O-methyl Or a salt thereof.
  • a compound of formula (I) or a salt thereof wherein B is 1,4-phenylene.
  • the formula wherein B is pyridinediyl optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl, halogen, and —OC 1-6 alkyl A compound of (I) or a salt thereof.
  • B may be substituted with one or more of the same or different groups selected from the group consisting of C 1-6 alkyl, halogen, and —OC 1-6 alkyl.
  • the compound of formula (I) or a salt thereof, wherein L 1 is —C 1-6 alkylene- is a compound of the formula (I) or a salt thereof, wherein L 1 is —C 1-6 alkylene-O— or —OC 1-6 alkylene.
  • Yet another embodiment is a compound of the formula (I) or a salt thereof, wherein L 1 is —C 1-6 alkylene-NH— or —NH—C 1-6 alkylene.
  • Yet another embodiment is a compound of formula (I) or a salt thereof, wherein X is N.
  • R 1 is the same or different 1 selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, —CN, —C (O) OH, and —C (O) OC 1-6 alkyl A compound of formula (I) or a salt thereof, which is C 1-6 alkyl optionally substituted with the above groups.
  • R 1 is the same or different one or more selected from the group consisting of F, —OH, —O-methyl, —CN, —C (O) OH, and —C (O) O-ethyl.
  • ring E is the same or different selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, —O—TBS, and —N (C 1-6 alkyl) 2.
  • C 1-6 alkyl optionally substituted with one or more groups, ii) halogen, iii) —OC 1-6 alkyl, iv) —OH, and v) the same or different selected from the group consisting of cycloalkyl
  • Ring E is substituted with one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2.
  • ring E is substituted with C 1-6 alkyl optionally substituted with one or more groups selected from the group consisting of —OC 1-6 alkyl and —OH.
  • ring E is substituted with C 1-6 alkyl optionally substituted with one or more groups selected from the group consisting of —OC 1-6 alkyl and —OH.
  • ring E is substituted with C 1-6 alkyl optionally substituted with one or more groups selected from the group consisting of —OC 1-6 alkyl and —OH.
  • ring E is substituted with C 1-6 alkyl optionally substituted with one or more groups selected from the group consisting of —OC 1-6 alkyl and —OH.
  • ring E is substituted with C 1-6 alkyl optionally substituted with one or more groups selected from the group consisting of —OC 1-6 alkyl and —OH.
  • ring E is i) one or more groups identical or different selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2.
  • a compound of the formula (I) or a salt thereof which is a non-aromatic hetero ring optionally substituted with one or more groups selected from the group consisting of
  • Ring E is substituted with one or more groups selected from the group consisting of halogen, —OH
  • a compound of formula (I) or a salt thereof which is a non-aromatic heterocyclic ring which may be substituted with one or more groups selected from the group consisting of optionally selected C 1-6 alkyl and oxo.
  • Ring E is substituted with one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2.
  • Ring E is 1,2-dihydropyridyl optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl and oxo. Or a salt thereof.
  • Ring E is substituted with one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2.
  • a compound of the formula (I) or a salt thereof which is piperidinyl optionally substituted by one or more groups selected from the group consisting of optionally selected C 1-6 alkyl and oxo.
  • the compound of formula (I), wherein ring E is piperidinyl optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl and oxo, or a compound thereof salt.
  • the present invention includes a compound or a salt thereof, which is a combination of two or more groups described in (1) to (7) as described in (8) above, including specific examples thereof. The following embodiments are also included.
  • Identical B selected from the group consisting of C 1-6 alkyl, halogen, —OC 1-6 alkyl, optionally substituted cycloalkyl, and optionally substituted non-aromatic heterocycle Or a compound of formula (I) or a salt thereof, wherein phenylene optionally substituted with one or more different groups, n is 1, and L 1 is —C 1-6 alkylene-T— or —TC 1-6 alkylene.
  • the same B is selected from the group consisting of C 1-6 alkyl, halogen, —OC 1-6 alkyl, optionally substituted cycloalkyl, and optionally substituted non-aromatic heterocycle Or a compound of the formula (I) or a salt thereof, wherein phenylene may be substituted with one or more different groups, n is 1, and L 1 is —C 1-6 alkylene-.
  • Ring A is substituted with one or more groups selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2.
  • C 1-6 alkyl ii) halogen also, iii) -O- (same or different one or more halogens optionally substituted by C 1-6 alkyl), iv) -N (C 1-6 alkyl) 2 , v) -CN, and vi) an aromatic heterocycle optionally substituted by one or more groups selected from the group consisting of cycloalkyl (12), (13), or ( 14) The compound or a salt thereof according to the above.
  • R 1 is the same or different 1 selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, —CN, —C (O) OH, and —C (O) OC 1-6 alkyl
  • X is CH or N.
  • ring E is selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, —O—TBS, and —N (C 1-6 alkyl) 2
  • ring E is selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, —O—TBS, and —N (C 1-6 alkyl) 2
  • ring E is selected from the group consisting of i) halogen, —OH, —OC 1-6 alkyl, —O—TBS, and —N (C 1-6 alkyl) 2
  • ii) halogen iii) —OC 1-6 alkyl, iv) —OH, and v) cycloalkyl
  • Ring E is substituted with one or more groups selected from the group consisting of i) halogen, —OH,
  • Ring A is (I) C 1- optionally substituted by one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, and —N (C 1-6 alkyl) 2 6 alkyl, (Ii) halogen, (Iii) -O- (C 1-6 alkyl optionally substituted with one or more halogens), (Iv) -N (C 1-6 alkyl) 2 , (V) -CN, (Vi) cycloalkyl, (Vii) -C (O) H, A compound of the formula (I) or a salt thereof which is an aromatic hetero ring optionally substituted with one or more groups selected from the group consisting of (20-2) (20-2-1) Ring A is i) halogen, -OH, -OC 1-6 alkyl, and optionally substituted by the same or different one or more groups selected from the group consisting of -N (C 1-6 alkyl) 2 C 1-6 Alkyl
  • Ring A is Quinolyl optionally substituted by one or more groups selected from the group consisting of halogen, C 1-6 alkyl and —OC 1-6 alkyl; Pyridyl optionally substituted with one or more same or different C 1-6 alkyl, or A compound of the formula (I) or a salt thereof which is benzimidazolyl optionally substituted with one or more same or different C 1-6 alkyl.
  • Ring A is i) halogen, -OH, -OC 1-6 alkyl, and optionally substituted by the same or different one or more groups selected from the group consisting of -N (C 1-6 alkyl) 2 C 1-6 Alkyl, ii) halogen, iii) -O- (C 1-6 alkyl optionally substituted with one or more halogens), iv) -CN, v) cycloalkyl, and vi) a quinolyl optionally substituted with one or more groups selected from the group consisting of —C (O) H, or i) halogen, and -OC 1-6 identical or different one or more C 1-6 alkyl optionally substituted with a group selected from the group consisting of alkyl, ii) cycloalkyl, and iii) A compound of the formula (I) or a salt thereof which is benzimidazolyl optionally substituted with one or more groups selected from the group consisting of -N
  • Ring A is i) halogen, and -OC 1-6 identical or different one or more C 1-6 alkyl optionally substituted with a group selected from the group consisting of alkyl, ii) cycloalkyl, and iii) A compound of the formula (I) or a salt thereof which is benzimidazolyl optionally substituted with one or more groups selected from the group consisting of halogen.
  • Ring A is Benzimidazolyl optionally substituted with one or more identical or different C 1-6 alkyls, optionally substituted with one or more identical or different groups selected from the group consisting of halogen and —OC 1-6 alkyl A compound of formula (I) or a salt thereof.
  • Ring A is 1-methylbenzimidazol-4-yl.
  • (20-4) (20-4-1) Ring A is i) halogen, -OH, -OC 1-6 alkyl, and optionally substituted by the same or different one or more groups selected from the group consisting of -N (C 1-6 alkyl) 2 C 1-6 Alkyl, ii) halogen, iii) -O- (C 1-6 alkyl optionally substituted with one or more halogens), iv) -CN, v) cycloalkyl, and vi) A compound of formula (I) or a salt thereof which is quinolyl optionally substituted with one or more groups selected from the group consisting of —C (O) H.
  • Ring A is A compound of the formula (I) or a salt thereof which is quinolyl optionally substituted by one or more groups selected from the group consisting of halogen, C 1-6 alkyl and —OC 1-6 alkyl.
  • Ring A is i) halogen, -OH, -OC 1-6 alkyl, and optionally substituted by the same or different one or more groups selected from the group consisting of -N (C 1-6 alkyl) 2 C 1-6 Alkyl, ii) halogen, iii) -O- (C 1-6 alkyl optionally substituted with one or more halogens), iv) -CN, v) cycloalkyl, and vi) quinolin-2-yl optionally substituted with one or more groups selected from the group consisting of -C (O) H, or A compound of the formula (I) or a salt thereof which is quinolin-8-yl optionally substituted with one or more groups selected from the group consist
  • Ring A is i) halogen, -OH, -OC 1-6 alkyl, and optionally substituted by the same or different one or more groups selected from the group consisting of -N (C 1-6 alkyl) 2 C 1-6 Alkyl, ii) halogen, iii) -O- (C 1-6 alkyl optionally substituted with one or more halogens), iv) -CN, v) cycloalkyl, and vi) A compound of the formula (I) or a salt thereof which is quinolin-2-yl optionally substituted with one or more groups selected from the group consisting of —C (O) H.
  • Ring A is A compound of the formula (I) or a salt thereof which is quinolin-8-yl optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl and —OC 1-6 alkyl.
  • Ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxy
  • a compound of the formula (I) or a salt thereof which is quinolin-2-yl, 6-methoxy-3-methylquinolin-2-yl, or quinolin-8-yl.
  • Ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxy A compound of the formula (I) or a salt thereof which is quinolin-2-yl or 6-methoxy-3-methylquinolin-2-yl.
  • Ring A is quinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxyquinolin-2-yl, 6-methoxy A compound of formula (I) or a salt thereof which is -3-methylquinolin-2-yl or quinolin-8-yl.
  • Ring A is quinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxyquinolin-2-yl, or 6 A compound of formula (I) or a salt thereof which is -methoxy-3-methylquinolin-2-yl.
  • (20-4-10) A compound of formula (I) or a salt thereof, wherein Ring A is quinolin-2-yl.
  • (20-4-11) A compound of formula (I) or a salt thereof, wherein Ring A is 3-methylquinolin-2-yl.
  • (20-4-12) A compound of formula (I) or a salt thereof, wherein Ring A is 3-hydroxymethylquinolin-2-yl.
  • (21) (21-1) B is C 1-6 alkyl, halogen, —OC 1-6 alkyl, Phenylene, optionally substituted by one or more identical or different groups selected from the group consisting of non-aromatic heterocycles, Pyridinediyl, Or thiophene diyl, Or a compound of formula (I) or a salt thereof wherein -C ⁇ C-.
  • (21-2) B is C 1-6 alkyl, halogen, —OC 1-6 alkyl, Phenylene, optionally substituted by one or more identical or different groups selected from the group consisting of non-aromatic heterocycles, Pyridinediyl, Or a compound of formula (I) or a salt thereof which is thiophenediyl.
  • the present invention includes a compound or a salt thereof which is a combination of two or more groups described in (1) to (7) and (20) to (23) as described in (24) above.
  • the following aspects are also mentioned including the specific example.
  • (25) The compound of formula (I) or a salt thereof, wherein ring A is (1) or (20).
  • (26) The compound or a salt thereof according to (25), wherein B is (2) or (21).
  • (27) The compound or a salt thereof according to (25) to (26), wherein n is (3).
  • (28) The compound or a salt thereof according to (25) to (27), wherein L 1 is (4).
  • (30) The compound or a salt thereof according to (25) to (29), wherein R 1 is (6) or (22).
  • (31) The compound or a salt thereof according to (25) to (30), wherein ring E is (7) or (23).
  • Examples of specific compounds included in the compound of formula (I) or a salt thereof include the following compounds. 8- [4-( ⁇ [1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] quinoline, 1-methyl-5- (1-methyl-3- ⁇ [4- (3-methylquinolin-2-yl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) pyridin-2 (1H) -one, 1-methyl-5- (1-methyl-3- ⁇ [4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) pyridine-2 (1H) -on, 1-methyl-5- (1-methyl-3- ⁇ [4- (1-methyl-1H-benzimidazol-4-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) pyridine-2 (1H) -on, 2- (3- ⁇ [1-methyl
  • T is bonded to a 5-membered heterocyclic ring containing two nitrogen atoms and X as ring-constituting atoms
  • —C 1-6 alkylene- means that (B) n or ring A is bonded.
  • An example is Ex.1 described in Table 58 below.
  • -TC 1-6 alkylene- is described
  • -C 1-6 alkylene- is bonded to a 5-membered heterocyclic ring containing two nitrogen atoms and X as ring-constituting atoms
  • T is (B ) Means binding to n or ring A.
  • tautomers and geometric isomers may exist depending on the type of substituent.
  • the compound of the formula (I) may be described in only one form of an isomer, but the present invention also includes other isomers, separated isomers, or those isomers. Also includes mixtures.
  • the compound of formula (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers based on this may exist.
  • the present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
  • the present invention includes a pharmaceutically acceptable prodrug of the compound of formula (I).
  • Pharmaceutically acceptable prodrugs are compounds having groups that can be converted to amino groups, hydroxyl groups, carboxyls, etc. by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Can be mentioned.
  • the compound of formula (I) may form an acid addition salt or a salt with a base depending on the type of substituent, and is included in the present invention as long as such a salt is a pharmaceutically acceptable salt.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium,
  • the present invention also includes various hydrates and solvates of the compound of formula (I) and pharmaceutically acceptable salts thereof, and crystalline polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the formula (I) and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • an appropriate protecting group a group that can be easily converted into the functional group
  • Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like
  • protective groups thereof include, for example, “Protective Groups in Organic Synthesis (Third Edition), by Greene and Wuts. 1999) ”and the like, and may be appropriately selected and used according to these reaction conditions.
  • a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
  • the prodrug of the compound of formula (I) may be further reacted by introducing a specific group at the stage of the raw material or intermediate, or by using the obtained compound of formula (I), in the same manner as the above protecting group.
  • the reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
  • the manufacturing method of each invention is not limited to the example shown below.
  • the compound (I-1) of the present invention can be obtained by Mitsunobu reaction between compound 1a and compound 1b.
  • Compound 1a and Compound 1b are used in an equivalent amount or in excess, and heated under reflux in the presence of a phosphine reagent or diethyl azodicarboxylate (DEAD) in a solvent inert to the reaction or without solvent.
  • DEAD diethyl azodicarboxylate
  • Examples of the solvent used here are not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane.
  • the phosphine reagent is not particularly limited, and examples thereof include triphenylphosphine and tributylphosphine. If 1,1 ′-(azodicarbonyl) dipiperidine is used in place of DEAD, it may be advantageous for the reaction to proceed smoothly. In addition, cyanomethylene tributylphosphorane, the Kakuda reagent, may be advantageous for allowing the reaction to proceed smoothly.
  • the presence of a base using an equivalent amount or an excess of a compound in which the hydroxyl portion of -C 1-6 alkylene-OH of R 2A or R 2B is converted to a predetermined leaving group, such as halogen is used.
  • the reaction mixture is then stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling to heating under reflux, preferably at 0 ° C. to 100 ° C., usually for 0.1 hour to 5 days.
  • the solvent used here are not particularly limited, but include N, N-dimethylformamide and the like.
  • the base include inorganic bases such as potassium carbonate.
  • R 3 represents —C 0-5 alkylene-C (O) H
  • L 3 represents —C 1-6 alkylene-, and so on.
  • the compound (I-2) of the present invention can be obtained by a reductive amination reaction between the compound 1c and the compound 1d.
  • compound 1c and compound 1d are used in an equivalent amount or in excess of one, and these mixtures are heated in a solvent inert to the reaction in the presence of a reducing agent from ⁇ 45 ° C. under heating to reflux, usually from 0.1 hour. Stir for 5 days.
  • a solvent inert examples include, but are not limited to, alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, and mixtures thereof.
  • the reducing agent examples include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride and the like. It may be preferable to carry out the reaction in the presence of a dehydrating agent such as molecular sieves or an acid such as acetic acid, hydrochloric acid, titanium (IV) isopropoxide complex.
  • a dehydrating agent such as molecular sieves or an acid such as acetic acid, hydrochloric acid, titanium (IV) isopropoxide complex.
  • imine may be generated by condensation between compound 1c and compound 1d, and may be isolated as a stable intermediate. In such a case, compound (I-2) can be obtained by the reduction reaction of this imine intermediate.
  • a reduction catalyst for example, palladium carbon, Raney nickel, etc.
  • a solvent such as methanol, ethanol, ethyl acetate
  • an acid such as acetic acid or hydrochloric acid.
  • the compound (I-3) of the present invention can be obtained by Wittig reaction of compound 1e and compound 1f, followed by hydrogenation reaction.
  • B excludes -C ⁇ C-.
  • compound 1e and compound 1f are used in an equivalent amount or in excess, in a solvent inert to the reaction or in the absence of a solvent, in the presence of a base, under cooling to heating under reflux, preferably at 0 ° C. to 100 ° C. Stir normally for 0.1 to 5 days.
  • the solvent used here are not particularly limited, and examples include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane.
  • the base is not particularly limited, and examples thereof include organic bases such as diazabicycloundecene.
  • the obtained compound having a double bond is stirred under a hydrogen atmosphere in a solvent inert to the reaction in the presence of a metal catalyst, usually for 1 to 5 days. This reaction is usually carried out under cooling to heating, preferably at room temperature.
  • the solvent used here are not particularly limited, but alcohols such as methanol, ethanol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, water, ethyl acetate, N, N- Examples include dimethylformamide, dimethyl sulfoxide, and mixtures thereof.
  • palladium catalysts such as palladium carbon, palladium black and palladium hydroxide, platinum catalysts such as platinum plate and platinum oxide, nickel catalysts such as reduced nickel and Raney nickel, rhodium catalysts such as tetrakistriphenylphosphine chlororhodium, reduction
  • iron catalyst such as iron is preferably used.
  • hydrogen gas an equivalent to excess amount of formic acid or ammonium formate relative to the compound having a double bond can be used as the hydrogen source.
  • LG 1A and LG 1B represents a leaving group, and the other represents -B (OH) 2 or -B (OZ) OW.
  • Z and W are the same or different from each other and represent C 1-6 alkyl or Z and W together represent C 1-6 alkylene.
  • the compound (I-4) of the present invention can be obtained by a coupling reaction of compound 1g and compound 1h.
  • 1 g of compound and 1 h of compound are used in an equivalent amount or in excess, and the mixture is stirred in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux, usually for 0.1 hour to 5 days. Is done.
  • This reaction is preferably performed in an inert gas atmosphere.
  • Examples of the solvent used here are not particularly limited, but include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, methylene chloride, 1,2- Examples thereof include halogenated hydrocarbons such as dichloroethane or chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide, dimethyl sulfoxide, and mixed solvents thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane
  • methylene chloride 1,2- Examples thereof include halogenated hydrocarbons such as dichloroethane or chloroform, alcohols such as methanol, ethanol, 2-propanol
  • tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
  • leaving groups include halogen and trifluoromethanesulfonate groups.
  • LG 2 represents halogen
  • LG 3 represents —B (OH) 2 or —B (OZ) OW.
  • the compound (I-5) of the present invention can be obtained by a coupling reaction between compound 1j obtained by halogenating compound 1i and compound 1k.
  • This step is a step of halogenating compound 1i to obtain compound 1j.
  • This step is carried out by using an equivalent amount of compound 1i and a predetermined halogenating agent or an excess of one of them, and stirring in a solvent inert to the reaction from room temperature to heating under reflux, usually for 0.1 hour to 5 days.
  • the solvent used here are not particularly limited, but include acetonitrile and the like.
  • the halogenating agent include N-bromosuccinimide, N-iodosuccinimide, iodine and the like.
  • This step is a step of obtaining the compound (I-5) of the present invention by a coupling reaction between the compound 1j and the compound 1k.
  • the reaction conditions are the same as in the fourth production method.
  • R 1 , ring A, ring B, and ring E in the compound of formula (I) are self-evident to those skilled in the art from the reactions described in the examples below, starting from the compound of formula (I).
  • it can be easily converted to other functional groups.
  • O-alkylation, N-alkylation, oxidation, reduction, reductive alkylation, cyclization, hydrolysis, amidation, acylation, deprotection, etc. can be combined in any combination commonly used by those skilled in the art. Can be done.
  • the raw material compound in the above production method can be produced using, for example, the following method, the method described in the production examples described later, a known method, or a modified method thereof.
  • This production method is a method for producing a compound in which R 2A is —OH and X is CH in the raw material compound 1a in the first production method, and a compound 2b in which X is CH in the raw material compound 1c in the second production method.
  • Compound 2b can be produced by cyclization of compound 2a.
  • the compound 2a and, for example, N, N-dimethylformamide dimethyl acetal and R 1 NH—NH 2 are used in an equivalent amount or in excess, and usually 0.1 to 0.1 in a solvent inert to the reaction from room temperature to heating under reflux. It is carried out by stirring for 5 days from time.
  • the solvent used here are not particularly limited, but include N, N-dimethylformamide and the like.
  • This production method is a method for producing a compound 3d in which R 2A is —OH among the raw material compounds 1a of the first production method.
  • Compound 3d can be obtained by boronating the halogen moiety of compound 3a and then coupling reaction of compound 3b and compound 3c obtained.
  • This step is a step of boronizing compound 3a to obtain compound 3b.
  • the compound 3a and the prescribed boron reagent are used in an equivalent amount or in excess, and the mixture is stirred in a solvent inert to the reaction in the presence of the prescribed base and palladium reagent, usually from room temperature to reflux for 5 hours to 5 days. Is done by.
  • the solvent used here are not particularly limited, and examples thereof include dioxane.
  • Examples of the predetermined boron reagent include bis (pinacolato) diboron.
  • Examples of the predetermined base include potassium acetate.
  • Examples of the palladium reagent include 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride and the like.
  • This step is a step of obtaining compound 3d by a coupling reaction between compound 3b and compound 3c.
  • the reaction conditions are the same as in the fourth production method.
  • This production method is a method for producing the compound 4d in which R 2A is —C 1-6 alkylene-OH among the raw material compound 1a of the first production method and the raw material compound 1e of the third production method.
  • This step is a step of halogenating compound 4a to obtain compound 4b.
  • the reaction conditions are the same as in the first step of the fifth production method.
  • This step is a step of obtaining compound 4c by a coupling reaction between compound 4b and compound 1k.
  • the reaction conditions are the same as in the fourth production method.
  • This step is a step of reducing compound 4c to obtain compound 4d.
  • the reaction is carried out usually by stirring for 0.1 hour to 5 days in an solvent inert to the reaction under ice-cooling to heating under reflux using an equivalent amount of compound 4c and a predetermined reducing agent in excess.
  • the predetermined reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride and the like.
  • the solvent used here are not particularly limited, and examples include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane.
  • This step is a step of oxidizing compound 4d to obtain compound 1e.
  • the reaction is carried out by using compound 4d and a predetermined oxidizing agent in an equivalent amount or in excess, and stirring in an inert solvent for reaction under ice cooling to heating under reflux, usually for 0.1 hour to 5 days.
  • the predetermined oxidizing agent include manganese oxide.
  • the solvent used here are not particularly limited, and examples thereof include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride.
  • This production method is a method for producing a compound 5c in which n is 1 among the raw material compounds 1b of the first production method.
  • the reaction conditions are the same as in the fourth production method.
  • This production method is a method for producing a compound 6b in which L 1 is —C 1-6 alkylene-O— or —OC 1-6 alkylene- out of 1 g of the raw material compound of the fourth production method.
  • the reaction conditions are the same as in the first production method.
  • This production method is a method for producing a compound 7c in which L 1 is —C 1-6 alkylene-O— or —OC 1-6 alkylene- and n is 1 among the raw material compounds 1i of the fifth production method.
  • the reaction conditions are the same as in the first production method.
  • the compounds of formula (I) are isolated and purified as free compounds, pharmaceutically acceptable salts, hydrates, solvates or crystalline polymorphic substances thereof.
  • the pharmaceutically acceptable salt of the compound of formula (I) can also be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing the difference in physicochemical properties between the isomers.
  • optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
  • the pharmacological activity of the compound of formula (I) was confirmed by the following test.
  • PDE10A enzyme inhibitory activity In order to measure the PDE10A enzyme inhibitory activity of the test drug, the human PDE10A gene was cloned and the enzyme was obtained by expressing it in Sf9 cells with baculovirus. For the measurement, a cAMP measurement kit (Seti, cAMP femto 2 kit) and extraction, and the above-mentioned human PDE10A enzyme (reference: Eur. J. Biochem. 266, 1118-1127 (1999)) were used. The measurement method followed the attached instructions. An outline is shown below.
  • PDE10A enzyme and test compound were mixed in a reaction buffer (40 mM Tris-HCl, 5 mM MgCl 2 , pH 7.5) in a 384-well plate (total 8 ⁇ L) and incubated at room temperature for 30 minutes.
  • the substrate cAMP (final concentration 100 nM, 4 ⁇ L / well) was mixed and further incubated at room temperature for 1 hour.
  • 4 ⁇ L each of cAMP femto 2 kit cAMP-d2 solution and anti cAMP-cryptate solution were added to stop the reaction. After incubating at room temperature for 1 hour or longer, the measurement was performed using a fluorometer (PerkinElmer, multi-label plate reader: EnVision).
  • the reaction rate when the enzyme was not added was 0%
  • the reaction rate when the test compound was not added when the enzyme was added was 100%
  • the IC 50 value (nM) of the compound was calculated by the logistic method.
  • Table 1 shows the results in this test for some compounds of formula (I). Ex in the table indicates an example number.
  • mice Male ICR mice (Japan SLC, Inc.) (5 weeks old, about 30 g) were used in the experiments. The test compound was suspended in a 0.5% methylcellulose solution, and the test compound or solvent was orally administered at 10 mL / kg. Immediately after the administration, the animal was placed in a momentum measuring device (manufactured by Muromachi Kikai Co., Ltd., Spontaneous momentum measuring system / Supermex), and measurement was started. Overactivity was induced by phencyclidine (2.5 mg / 10 mL / kg) administered subcutaneously to each animal 1 hour after the start of measurement, and the inhibitory effect of the compound on this overactivity was measured for 1 hour to evaluate the drug efficacy.
  • a momentum measuring device manufactured by Muromachi Kikai Co., Ltd., Spontaneous momentum measuring system / Supermex
  • the ED 50 value of the test compound was calculated by the linear regression method, assuming that the momentum of the solvent-solvent administration group was 0% and that of the solvent-phencyclidine administration group was 100%.
  • the test results of representative compounds among the compounds of the present invention are shown in the following table. In addition, this test result showed the result by the inhibitory effect (%) in 30 mg / kg depending on the compound.
  • the compound of formula (I) was confirmed to have PDE10A inhibitory activity and can be used for the prevention and / or treatment of schizophrenia.
  • cytochrome P450 (CYP) 3A4 enzyme inhibition test it was confirmed that the compound of formula (I) or some of its salts are compounds that have an ability to inhibit cytochrome P450 metabolizing enzymes to such an extent that they can be used as pharmaceuticals. did.
  • a pharmaceutical composition containing one or more compounds of the formula (I) or a salt thereof as an active ingredient is an excipient normally used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier, etc.
  • Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or injection such as intraarticular, intravenous, intramuscular, suppository, eye drops, ophthalmic ointment, transdermal solution, ointment Any form of parenteral administration using an agent, a transdermal patch, a transmucosal liquid, a transmucosal patch, an inhalant, etc. may be used.
  • a solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. .
  • tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solvent, suspension, or emulsion.
  • aqueous solvent include distilled water for injection or physiological saline.
  • Non-aqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide, or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
  • a transmucosal agent such as an inhalant or a nasal agent
  • a solid, liquid or semi-solid agent is used and can be produced according to a conventionally known method.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer
  • the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. I can do things.
  • the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the pharmaceutical composition of the present invention is an active ingredient of 0.01 to 100% by weight, and in some embodiments, 0.01 to 50% by weight, although it varies depending on the administration route, dosage form, administration site, excipient and additive type. Contains one or more compounds of formula (I) or salts thereof.
  • the compound of the formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a combination drug or may be separately formulated.
  • the production method of the compound of formula (I) and its raw material compound will be described in more detail based on Examples.
  • this invention is not limited to the compound as described in the following Example.
  • the manufacturing method of a raw material compound is shown to a manufacture example.
  • the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.
  • the Pex number may be described in the Syn part of the Example Table, but the Example compound indicates that it was produced in the same manner as the compound with the PEx number (for example, Ex.131 is PEx.60). It shows that it was manufactured by the same method).
  • HCl in the structural formula is hydrochloride, Oxa is oxalate, Suc is succinate, TFA is trifluoroacetate, Fum is fumarate, Pho is phosphate, Tar is L -(+)-Tartrate, Mal indicates L-(-)-malate, and the number before HCl indicates the molar ratio.
  • 2HCl is a dihydrochloride salt
  • 0.5Oxa and 0.5Suc mean hemisuccinate and hemisuccinate
  • 1.5Pho sesquiphosphate
  • a compound in which the double bond portion intersects in the structural formula indicates a mixture of a cis isomer and a trans isomer.
  • Production Example 13 4- (3-methylquinolin-2-yl) phenol (170 mg), 4-bromo-5- (bromomethyl) -2-methyl-2H-1,2,3-triazole (184 mg), and N, N-dimethyl To a mixture of formamide (3.4 mL) was added potassium carbonate (250 mg), and the mixture was stirred at 60 ° C. for 4 hours. After allowing to cool, water and saturated brine were added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Triphenylphosphine (2.62 g) was added to a solution of 2- [4- (chloromethyl) phenyl] -3-methylquinoline (1.78 g) in acetonitrile (120 mL), and the mixture was stirred at 70 ° C. for 10 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was washed with diethyl ether to obtain [4- (3-methylquinolin-2-yl) benzyl] triphenylphosphonium chloride (2.66 g).
  • Production Example 28 Add ammonium chloride (122 mg) and iron (1.27 g) to a mixture of 3-bromo-N-methyl-2-nitroaniline (1.05 g), ethanol (8 mL), and water (2 mL), and heat for 2 hours. Refluxed. After allowing to cool, chloroform and water were added, followed by filtration through celite. The filtrate was extracted with chloroform, and the organic layer was concentrated under reduced pressure to obtain 2-amino-3-bromo-N-methylaniline (914 mg).
  • Triethylamine (2.7 mL) and toluene (100 mL) were added to the residue, and the mixture was heated to reflux for 5 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give 4- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] pyrrolidin-2-one ( 1.41 g) was obtained.
  • Tetrahydrofuran (5.0 m) was added to the obtained solid, carbonyldiimidazole (130 mg) was added and stirred under ice cooling, and the mixture was stirred at room temperature for 2 hr. Under ice-cooling, an aqueous solution (0.5 mL) of sodium borohydride (60 mg) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes, and then stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain [5- (3-methylquinolin-2-yl) pyridin-2-yl] methanol (70 mg).
  • the obtained crude product was dissolved in acetic acid (46 mL), and heated and stirred at 90 ° C. for 12 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / chloroform) to obtain 2- (4-methoxyphenyl) -1-methyl-1H-benzimidazole (1.98 g).
  • Tables 6 to 57 and Tables 148 to 166 show the chemical structural formulas, physicochemical data and production methods of the production example compounds.
  • Example 1 Mixture of 1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-amine (177 mg), 4- (quinolin-2-yl) benzaldehyde (284 mg), and 1,2-dichloroethane (1 mL) was added with tetraisopropyl orthotitanate (0.45 mL), and the mixture was stirred at 85 ° C. for 2 hours.
  • the reaction mixture was ice-cooled, methanol (5 mL) and sodium borohydride (130 mg) were added, and the mixture was stirred at room temperature for 3 hr. Sodium borohydride (140 mg) was added, and the mixture was further stirred for 2 hours.
  • a sodium hydrogen carbonate solution was added, diluted with chloroform, and filtered through Celite.
  • the organic layer of the filtrate was purified by silica gel column chromatography (chloroform / methanol), and 1-methyl-4- (pyridin-4-yl)- N- [4-Quinolin-2-yl) benzyl] -1H-pyrazol-3-amine (138 mg) was obtained.
  • Example 2 1-methyl-4- (pyridin-4-yl) -N- [4- (quinolin-2-yl) benzyl] -1H-pyrazol-3-amine (77 mg), methylene chloride (4 mL), and acetic acid (0.80 formaldehyde (164 mg) was added to the mixture and stirred for 10 minutes.
  • Sodium triacetoxyborohydride (167 mg) was added and stirred at room temperature for 2 hours.
  • Formaldehyde (164 mg) and sodium triacetoxyborohydride (167 mg) were added, and the mixture was stirred at room temperature overnight.
  • Formaldehyde (164 mg) and sodium triacetoxyborohydride (167 mg) were added again, and the mixture was stirred at room temperature for 12 hours.
  • Example 3 To a solution of 1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazole-4-carboxylic acid (137 mg) in methylene chloride (4 mL) was added carbonyldiimidazole (105 mg) at room temperature. In addition, the mixture was stirred at the same temperature for 15 minutes. Further, N-hydroxyacetamidine (48 mg) was added and stirred at room temperature for 0.5 hour, and then the mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was stirred at 110 ° C. for 12 hours. Tosylic acid monohydrate (7 mg) was added, and the mixture was stirred at the same temperature for 4 hours.
  • N-methylpyrrolidone (2 mL) was added, and the mixture was further stirred at the same temperature for 4 hours. After allowing to cool, water and saturated brine were added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was suspended in a mixed solvent of ethanol and ethyl acetate (4: 1), 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 3 hours.
  • Example 4 4- ⁇ 3-[(4-Bromobenzyl) oxy] -1-methyl-1H-pyrazol-4-yl ⁇ pyridine (137 mg), 0.5M 2-pyridylzinc bromide in tetrahydrofuran (1.6 mL), and tetrahydrofuran Tetrakis (triphenylphosphine) palladium (92 mg) was added to the (1 mL) mixture, and microwave irradiation was performed in a sealed tube at 120 ° C. for 1 hour. After allowing to cool, water was added to the reaction solution to stop the reaction. The mixture was filtered through celite, and ethyl acetate was added to the residue.
  • Example 5 4-( ⁇ [1-Methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) benzoic acid (400 mg), 1,2-phenylenediamine (154 mg), 1 WSC hydrochloride (296 mg) was added to a mixture of -hydroxybenzotriazole (210 mg), triethylamine (0.27 mL), and N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The obtained crude product was dissolved in acetic acid and stirred at 90 ° C. for 12 hours.
  • Example 6 2- [4-( ⁇ [1-Methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] -1H-benzimidazole (124 mg), potassium carbonate (135 mg) and N, N-dimethylformamide (3 mL) were added with methyl iodide (0.041 mL), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform).
  • Example 7 4- ⁇ 3-[(4-Bromobenzyl) oxy] -1-methyl-1H-pyrazol-4-yl ⁇ pyridine (413 mg), quinolin-8-ylboronic acid (311 mg), and 1,2-dimethoxyethane ( 30 mL) was added tetrakis (triphenylphosphine) palladium (277 mg) and 1M aqueous sodium carbonate (3 mL), and the mixture was stirred at 90 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform).
  • Example 8 2- [4-( ⁇ [4- (Pyridin-4-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] quinoline (567 mg) in N, N-dimethylformamide (20 mL) solution 1, 1,1-trifluoro-2-iodoethane (630 mg) and cesium carbonate (1.46 g) were added, and the mixture was stirred at 60 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography (methanol / chloroform).
  • Example 9 1-M in [4- (pyridin-4-yl) -3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-1-yl] ethyl acetate (380 mg) in ethanol (15 mL) A sodium hydroxide aqueous solution (2.5 mL) was added, and the mixture was stirred at 60 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and neutralized with 1N hydrochloric acid. The resulting precipitate was collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer and the precipitate were combined and purified by silica gel column chromatography (methanol / chloroform).
  • Example 12 4- (imidazo [1,2-a] pyridin-2-yl) phenol (330 mg), [1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] methanol (330 mg) Cyanomethylenetributylphosphorane (570 mg) was added to the toluene (10 mL) mixture and stirred at 100 ° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform), followed by basic silica gel column chromatography (ethyl acetate-hexane).
  • Example 13 1-Methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazole-4-carboxylic acid (246 mg) in N, N-dimethylformamide (7 mL) solution in carbonyldiimidazole (166 mg ) And stirred at room temperature for 15 hours. Acetyl hydrazide (0.40 mL) was added, and the mixture was stirred at 60 ° C. for 18 hours. A saturated aqueous sodium hydrogen carbonate solution and saturated brine were added under ice cooling, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.
  • Example 14 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (200 mg), [4- (imidazo [1,2-a] pyridin-3-yl) phenyl] methanol (300 mg), Cyanomethylenetributylphosphorane (413 mg) was added to a mixture of toluene and 15 mL, and the mixture was stirred at 100 ° C. for 24 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was dissolved in ethanol, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 2 hours.
  • Example 15 2- [4- (Chloromethyl) phenyl] quinoline hydrochloride (950 mg), 4- (1,4-dioxaspiro [4.5] dec-8-yl) -1-methyl-1H-pyrazol-3-ol (819 mg) , And N, N-dimethylformamide (9.5 mL) was added potassium carbonate (1.13 g), and the mixture was stirred at 60 ° C. for 1 hour. After allowing to cool, water and saturated brine were added, and the mixture was extracted with a mixed solvent of methanol and chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 16 Under a stream of argon, potassium tert-butoxide was added to a mixture of trimethylsulfoxonium iodide (94 mg) in dimethylsulfoxide (1.3 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanone (160 mg) in toluene (3 mL), and room temperature. For 9 hours. Water was added and extracted with chloroform.
  • Aqueous ammonia was added under ice-cooling, diluted with a mixed solvent of methanol and chloroform (1: 9), and stirred at room temperature for 1 hour.
  • the resulting solid was filtered off through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform) to give 1-methyl-4- (1-methyl-3- ⁇ [4 -(Quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanol (97 mg) was obtained.
  • reaction mixture was purified by silica gel column chromatography (methanol / chloroform), dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 1 hr. The resulting solid was collected by filtration, and 1-methyl-4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanol dihydrochloride (25 mg) was obtained.
  • Example 17 4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanone (300 mg), ethanol (6 mL), and water (1.2 mL) Hydroxylamine hydrochloride (61 mg) and sodium acetate (78 mg) were added to the mixture, and the mixture was stirred at room temperature for 1 hr. Saturated saline was added, and the mixture was extracted with chloroform.
  • N-hydroxy-4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexaneimine 310 mg was obtained.
  • Example 18 Under an argon stream, 4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanone (462 mg), 1,2-dimethoxyethane (7 mL) ) And tert-butanol (2.8 mL), p-toluenesulfonylmethyl isocyanide (329 mg) and potassium tert-butoxide (227 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was further stirred at room temperature for 7 hours. Water and saturated brine were added, and the mixture was extracted with ethyl acetate.
  • Example 19 4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanecarbonitrile (166 mg, mixture of trans and cis) ethanol ( (8.3 mL) The solution was added with 1M aqueous sodium hydroxide solution (1.38 mL) and 30% aqueous hydrogen peroxide (0.28 mL) under ice-cooling and stirred at room temperature for 4 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute aqueous sodium sulfite and saturated brine.
  • Example 20 3-Methyl-2- (4- ⁇ 2- [1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] vinyl ⁇ phenyl) quinoline (950 mg) in ethanol (10 mL) solution 10% Palladium hydroxide-carbon (200 mg) was added, and the mixture was pressurized under a hydrogen atmosphere and stirred at room temperature for 5 days. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 15 min.
  • Example 21 4- (1-Methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanone (183 mg), ethanol (3.7 mL), and water (0.7 mL) To the mixture were added aminooxymethane hydrochloride (45 mg) and sodium acetate (47 mg), and the mixture was stirred at room temperature for 2 hours. Saturated saline was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example 22 Boron hydride in ethanol (4 mL) solution of 4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanone (203 mg) under ice cooling Sodium (22 mg) was added and stirred for 1 hour. Water and saturated brine were added, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) and trans-4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl].
  • Oxy ⁇ -1H-pyrazol-4-yl) cyclohexanol 150 mg as a colorless oil, cis-4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanol (25 mg) was obtained as a white solid.
  • the trans isomer was dissolved in ethanol (4 mL), oxalic acid (22 mg) was added, and the mixture was stirred for 30 minutes.
  • the cis isomer was added to a solution of ethyl acetate in 4M hydrogen chloride in an ethyl acetate (6 mL) solution, stirred at room temperature for 1 hour, and then cis-4- (1-methyl-3- ⁇ [4- (quinolin-2-yl) [Benzyl] oxy ⁇ -1H-pyrazol-4-yl) cyclohexanol dihydrochloride (28 mg, Ex.154) was obtained.
  • Example 23 (2- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ ethyl) -5- (1-methyl-3- ⁇ [4- (3-methylquinolin-2-yl) benzyl] oxy ⁇ -1H- Tetrabutylammonium fluoride (0.4 mL) was added to a solution of pyrazol-4-yl) pyridin-2 (1H) -one (143 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform).
  • Example 24 2- [4-( ⁇ [1-Methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] quinoline-3-carbaldehyde (175 mg), dimethylamine hydrochloride Triethylamine (116 ⁇ L) and sodium triacetoxyborohydride (264 mg) were added to a salt (68 mg) and methylene chloride (5 mL) mixture, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform).
  • Example 25 Under ice cooling, ⁇ 2- [4-( ⁇ [1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] quinolin-3-yl ⁇ methanol (270 mg) in N, N-dimethylformamide (5 mL) was added 55% sodium hydride (42 mg), and the mixture was stirred at the same temperature for 15 min. Methyl iodide (60 ⁇ L) was added, the temperature was raised to room temperature, and the mixture was stirred for 12 hours.
  • the reaction mixture was ice-cooled, 55% sodium hydride (42 mg) and methyl iodide (60 ⁇ L) were added, the temperature was raised to room temperature, and the mixture was stirred for 1 hr. Water was added to the reaction solution to stop the reaction, ethyl acetate was added, and the organic layer was washed with saturated brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was dissolved in ethanol, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour.
  • Example 26 2- (4- ⁇ [(4-iodo-1-methyl-1H-pyrazol-3-yl) oxy] methyl ⁇ phenyl) -3-methylquinoline (338 mg), morpholine (2.7 mL), copper (142 mg), A mixture of tripotassium phosphate (473 mg) and 2- (dimethylamino) ethanol (2.7 mL) was stirred at 110 ° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate).
  • Example 27 A solution of 2- ⁇ 4-[(4-iodo-1-methyl-1H-pyrazol-3-yl) methoxy] phenyl ⁇ -3-methylquinoline (6.00 g) in tetrahydrofuran (120 mL) was cooled to 2 M isopropylmagnesium chloride. Of tetrahydrofuran (16.5 mL) was added. The mixture was stirred at the same temperature for 45 minutes, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.30 mL) was added. After stirring at room temperature for 2 hours, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.
  • Example 28 Under ice-cooling, thionyl chloride (1.1 mL) was added to a mixture of 1- [4- (hydroxymethyl) phenyl] -2-methyl-1H-benzimidazole (1.19 g) in methylene chloride (50 mL) at room temperature for 2 hours. Stir. The reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure. 1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (263 mg), potassium carbonate (520 mg), N, N-dimethylformamide (15 mL) were added to the obtained solid (483 mg) at 70 ° C. For 8 hours.
  • the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform).
  • the obtained crude product was dissolved in ethanol, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 15 minutes.
  • Example 30 3-methyl-2- [4-( ⁇ [1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-3-yl ] Oxy ⁇ methyl) phenyl] quinoline (507 mg), 5-bromo-2- (tert-butoxy) pyridine (384 mg), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-methylene chloride complex A mixture of (54 mg), sodium carbonate (354 mg), N, N-dimethylformamide (7.5 mL), and water (1.5 mL) was stirred at 100 ° C. for 1 hour under an argon atmosphere.
  • Example 31 2- ⁇ 4-[(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl) methoxy] phenyl ⁇ -3-methylquinoline (290 mg), 4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (436 mg), N, N-dimethylformamide (2.9 mL), and water (1.2 mL) in a mixture of cesium carbonate (462 mg) and Tetrakistriphenylphosphine palladium (123 mg) was added, and the mixture was stirred at 80 ° C. for 18 hours. After allowing to cool, water was added and the mixture was extracted with ethyl acetate.
  • Example 32 Thionyl chloride was added to a mixture of 5- [3- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl] -1-methylpyridin-2 (1H) -one (394 mg) in methylene chloride (20 mL) under ice cooling. (0.4 mL) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dried under reduced pressure. N, N-dimethylformamide (16 mL), 4- (1-methyl-1H-benzimidazol-4-yl) phenol (270 mg), and potassium carbonate (414 mg) were added and stirred at 70 ° C. for 8 hours.
  • the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 10 min.
  • Example 33 Chloride of tert-butyl 3- (1-methyl-3- ⁇ [4- (3-methylquinolin-2-yl) benzyl] oxy ⁇ -1H-pyrazol-4-yl) pyrrolidine-1-carboxylate (152 mg) Trifluoroacetic acid (0.3 mL) was added to a methylene (0.3 mL) solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 34 2- [4-( ⁇ [1-Methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] quinoline- Sodium borohydride (96 mg) was added to a mixture of 3-carbaldehyde (569 mg), methanol (5 mL), and tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform).
  • Example 35 2- [4-( ⁇ [1-Methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] quinoline- Bis (2-methoxyethyl) aminosulfur trifluoride (0.1 mL) was added to a solution of 3-carbaldehyde (150 mg) in methylene chloride (3 mL), and the mixture was stirred at room temperature overnight. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 36 2- [4-( ⁇ [1-Methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) phenyl] quinoline- Hydroxyamine hydrochloride (48 mg) and powdered potassium carbonate (143 mg) were added to a mixture of 3-carbaldehyde (155 mg), tetrahydrofuran (3.5 mL), and methanol (0.4 mL), and the mixture was stirred at room temperature for 0.5 hr. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
  • Triethylamine (0.056 mL) and trifluoroacetic anhydride (0.052 mL) were added to a methylene chloride (3 mL) solution of the obtained compound, and the mixture was stirred at room temperature for 2 hours.
  • Triethylamine (0.216 mL) and trifluoroacetic anhydride (0.219 mL) were added, and the mixture was stirred for 5 hours at room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example 37 [4-( ⁇ [1-Methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H-pyrazol-3-yl] oxy ⁇ methyl) under ice cooling
  • lithium borohydride 148 mg
  • ethanol 0.60 mL
  • the reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was concentrated under reduced pressure and concentrated under reduced pressure.
  • Example 38 4- [4- (Chloromethyl) phenyl] -1-methyl-1H-benzimidazole hydrochloride (143 mg), 5- (3-hydroxy-1-methyl-1H-pyrazol-4-yl) -1-methylpyridine A mixture of -2 (1H) -one (100 mg), potassium carbonate (168 mg), and N, N-dimethylformamide (2 mL) was stirred at 60 ° C. for 5 hours. Water was added, and the resulting solid was collected by filtration and purified by silica gel column chromatography (methanol / chloroform).
  • Example 39 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (90 mg), [4- (imidazo [1,2-a] pyridin-2-yl) phenyl] methanol (174 mg) in tetrahydrofuran ( 9 mL) 1,1 ′-(Azodicarbonyl) dipiperidine (259 mg) and tri-n-butylphosphine (208 mg) were added to the mixture, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform), followed by basic silica gel column chromatography (ethyl acetate-hexane).
  • Example 40 1-methyl-4- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-ol (250 mg) and 4- (quinolin-2-yl) butan-1-ol (360 mg) in toluene (18 ml ) Cyanomethylenetributylphosphorane (497 mg) was added to the solution, and the mixture was heated and stirred at 100 ° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) and basic silica gel column chromatography (methanol / ethyl acetate).
  • Example 41 To a solution of [5- (quinolin-2-yl) -2-thienyl] methanol (320 mg) in methylene chloride (6 mL) was added thionyl chloride (290 ⁇ L), and the mixture was stirred at room temperature for 3 hours. Toluene was added and the resulting solid was collected by filtration.
  • Example 42 A solution of 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (550 mg) and 3- (quinolin-2-yl) prop-2-yn-1-ol (603 mg) in toluene (55 mL) Cyanomethylenetributylphosphorane (953 mg) was added to the mixture, and the mixture was heated with stirring at 100 ° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate-chloroform). This was dissolved in ethanol (3 mL), succinic acid (13 mg) was added, and the mixture was stirred with heating for 5 min.
  • Example 43 1- [3-hydroxy-4- (pyridin-4-yl) -1H-pyrazol-1-yl] ethanone (3.19 g), 2- [4- (chloromethyl) phenyl] quinoline hydrochloride (4.15 g), A mixture of potassium carbonate in N, N-dimethylformamide (80 mL) was stirred at 60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, methanol (80 mL) and water (20 mL) were added to the residue, and the mixture was stirred at 60 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the resulting precipitate was collected by filtration and washed with water.
  • Example 44 (1-methyl-3- ⁇ [4- (3-methylquinolin-2-yl) benzyloxy ⁇ -1H-pyrazol-4-yl) pyrrolidine-1-carboxylate tert-butyl (916 mg) in methylene chloride ( 1.8 mL) solution was added with trifluoroacetic acid (1.8 mL) and stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform.
  • Example 45 Under ice cooling, 1-methyl-4- (4- ⁇ [1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazolo-3-yl] methoxy ⁇ phenyl) -1H-benzimidazole ( 731 mg) in chloroform (30 mL) was added 75% m-chloroperbenzoic acid (534 mg), and the mixture was stirred at room temperature for 24 hours. Sodium thiosulfate (570 mg) was dissolved in water (5 mL) and added to the reaction solution, and the mixture was stirred for 5 minutes.
  • Example 46 A mixture of 3- (1-methyl-1H-benzimidazol-4-yl) propan-1-ol (62 mg) in methylene chloride (1.5 mL) was ice-cooled, and triethylamine (82 ⁇ L) and mesyl chloride (38 ⁇ L) were added. The mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 47 1-methyl-5- (1-methyl-3- ⁇ [4- (1-trityl-1H-benzimidazol-4-yl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) pyridine-2 (1H)
  • 4M hydrogen chloride in dioxane 0.6 mL
  • the reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the residue.
  • Saturated sodium chloride was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 338 In an argon atmosphere, 2- ⁇ 4-[(4-iodo-1-methyl-1H-pyrazol-3-yl) methoxy] phenyl ⁇ -3-methylquinoline (500 mg) in toluene (10 mL) was added to 4- (Tributylstannyl) pyridazine (500 mg), tris (dibenzylideneacetone) dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (52 mg) In addition, the mixture was heated and stirred at 110 ° C. for 12 hours.
  • Example 397 2- ⁇ 4-[(4-Iodo-1-methyl-1H-pyrazol-3-yl) methoxy] phenyl ⁇ -3-methylquinoline (200 mg), 5-methylpyridazine-3-boronic acid pinacol ester (116 mg) , Tri-t-butylphosphonium tetrafluoroborate (16 mg), tris (dibenzylideneacetone) dipalladium (0) (20 mg), tripotassium phosphate (308 mg), acetonitrile (3 ml) After stirring with heating at 4 ° C. for 4 hours, N, N-dimethylformamide (2 ml) was added and the mixture was further heated with stirring at an oil temperature of 90 ° C. for 18 hours.
  • Example 404 5- [3- (Chloromethyl) -1-methyl-1H-pyrazol-4-yl] -1-methylpyridin-2 (1H) -one hydrochloride (180 mg), 4- (quinolin-2-yl) phenol A mixture of (120 mg), potassium carbonate (205 mg) and N, N-dimethylformamide (13 mL) was stirred at 70 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 412 1-methyl-5- (1-methyl-3- ⁇ [4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) pyridine-2 (1H) -A methanol (30 mL) suspension of ON (2.5 g) was heated and dissolved at a bath temperature of 60 ° C. At the same temperature, 118 mL of 0.1 M phosphoric acid-ethanol solution was added and stirred at the same temperature for 30 minutes. The reaction solution was returned to room temperature and then concentrated under reduced pressure. Ethanol (500 mL) and water (50 mL) were added to the residue, and the mixture was stirred at a bath temperature of 90 ° C. for 2 hours.
  • the compound of formula (I) or a salt thereof has a PDE10A inhibitory action and can be used as a prophylactic and / or therapeutic agent for schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease.

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Abstract

L'invention concerne un composé utile pour la prévention et/ou le traitement de la schizophrénie, de l'anxiété, de la chorée d'Huntington, de la toxicodépendance et/ou de la maladie d'Alzheimer. Après examen de l'action inhibitrice de composés sur PDE10, il a été confirmé qu'un composé de pyrazole avait une telle action inhibitrice et que ce composé était utile pour la prévention et/ou le traitement des pathologies susmentionnées.
PCT/JP2012/058291 2011-03-31 2012-03-29 Composé de pyrazole Ceased WO2012133607A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014133046A1 (fr) * 2013-02-27 2014-09-04 持田製薬株式会社 Nouveau dérivé de pyrazole
WO2014142322A1 (fr) 2013-03-15 2014-09-18 第一三共株式会社 Dérivé du benzothiophène
WO2015000715A1 (fr) 2013-07-02 2015-01-08 Syngenta Participations Ag Hétérocycles bi- ou tricycliques à action pesticide avec substituants soufrés
WO2015051045A3 (fr) * 2013-10-04 2015-07-30 Novartis Ag Extrémités 3' pour agents arni destinés à être utilisés dans l'interférence arn
WO2018095795A1 (fr) 2016-11-23 2018-05-31 Syngenta Participations Ag Dérivés polycycliques à activité pesticide comportant des substituants contenant du soufre
WO2018206348A1 (fr) 2017-05-08 2018-11-15 Syngenta Participations Ag Dérivés d'imidazopyrimidine à substituants phényle et pyridyle contenant du soufre
WO2019070044A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composés hétérocycliques
WO2020016443A1 (fr) 2018-07-20 2020-01-23 Boehringer Ingelheim International Gmbh Difluorométhyl-phényl-triazoles en tant que modulateurs des récepteurs gaba
WO2020141135A1 (fr) 2018-12-31 2020-07-09 Syngenta Crop Protection Ag Dérivés hétérocycliques à action pesticide comprenant des substituants contenant du soufre
WO2020250183A1 (fr) 2019-06-13 2020-12-17 Pi Industries Ltd. Composés hétérocycliques fusionnés et leur utilisation en tant qu'agents de lutte contre les nuisibles
WO2021171035A1 (fr) 2020-02-28 2021-09-02 Benevolentai Cambridge Limited Compositions et leurs utilisations
US20240293381A1 (en) * 2017-04-18 2024-09-05 Celgene Quanticel Research, Inc. Therapeutic Compounds
EP4326712A4 (fr) * 2021-04-21 2025-03-05 The Regents of The University of California Compositions et méthodes de traitement de maladies neurodégénératives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2022211957B2 (en) * 2021-01-29 2024-05-23 Txinno Bioscience Inc. Novel benzotriazole derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase, and use thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006072828A2 (fr) * 2005-01-07 2006-07-13 Pfizer Products Inc. Composes de quinoline heteroaromatiques
WO2007077490A2 (fr) * 2006-01-05 2007-07-12 Pfizer Products Inc. Composés d'hétéroaryles bicycliques comme inhibiteurs de la pde10
WO2007129183A2 (fr) * 2006-05-02 2007-11-15 Pfizer Products Inc. Composés d'hétéroaryle bicyclique utilisés comme inhibiteurs de la pde10
WO2008131000A2 (fr) * 2007-04-16 2008-10-30 Abbott Laboratories Inhibiteurs mcl-1 indole 7-substitués
WO2010100606A1 (fr) * 2009-03-03 2010-09-10 Pfizer Inc. Nouveaux phényl imidazoles et phényl triazoles en tant que modulateurs de la gamma sécrétase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006072828A2 (fr) * 2005-01-07 2006-07-13 Pfizer Products Inc. Composes de quinoline heteroaromatiques
WO2007077490A2 (fr) * 2006-01-05 2007-07-12 Pfizer Products Inc. Composés d'hétéroaryles bicycliques comme inhibiteurs de la pde10
WO2007129183A2 (fr) * 2006-05-02 2007-11-15 Pfizer Products Inc. Composés d'hétéroaryle bicyclique utilisés comme inhibiteurs de la pde10
WO2008131000A2 (fr) * 2007-04-16 2008-10-30 Abbott Laboratories Inhibiteurs mcl-1 indole 7-substitués
WO2010100606A1 (fr) * 2009-03-03 2010-09-10 Pfizer Inc. Nouveaux phényl imidazoles et phényl triazoles en tant que modulateurs de la gamma sécrétase

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9777000B2 (en) 2013-02-27 2017-10-03 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
WO2014133046A1 (fr) * 2013-02-27 2014-09-04 持田製薬株式会社 Nouveau dérivé de pyrazole
US8980889B2 (en) 2013-02-27 2015-03-17 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
US8980888B2 (en) 2013-02-27 2015-03-17 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
CN106957317B (zh) * 2013-02-27 2019-12-31 持田制药株式会社 新型吡唑衍生物
US9440970B2 (en) 2013-02-27 2016-09-13 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
US9453015B2 (en) 2013-02-27 2016-09-27 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
US9458157B2 (en) 2013-02-27 2016-10-04 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
CN106957317A (zh) * 2013-02-27 2017-07-18 持田制药株式会社 新型吡唑衍生物
WO2014142322A1 (fr) 2013-03-15 2014-09-18 第一三共株式会社 Dérivé du benzothiophène
US9464076B2 (en) 2013-03-15 2016-10-11 Daiichi Sankyo Company, Limited Benzothiophene derivative
EP3778598A2 (fr) 2013-07-02 2021-02-17 Syngenta Participations Ag Les hétérocycles bi- ou tricycliques à activité pesticide avec des substituants contenant du soufre
WO2015000715A1 (fr) 2013-07-02 2015-01-08 Syngenta Participations Ag Hétérocycles bi- ou tricycliques à action pesticide avec substituants soufrés
EP3722277A3 (fr) * 2013-10-04 2021-01-20 Novartis AG 3 embouts pour des agents arni utilisés dans l'arn
JP2019135236A (ja) * 2013-10-04 2019-08-15 ノバルティス アーゲー ＲＮＡ干渉に使用するためのＲＮＡｉ剤用の３’末端キャップ
WO2015051045A3 (fr) * 2013-10-04 2015-07-30 Novartis Ag Extrémités 3' pour agents arni destinés à être utilisés dans l'interférence arn
US11008570B2 (en) 2013-10-04 2021-05-18 Novartis Ag 3′ end caps for RNAi agents for use in RNA interference
WO2018095795A1 (fr) 2016-11-23 2018-05-31 Syngenta Participations Ag Dérivés polycycliques à activité pesticide comportant des substituants contenant du soufre
US20240293381A1 (en) * 2017-04-18 2024-09-05 Celgene Quanticel Research, Inc. Therapeutic Compounds
WO2018206348A1 (fr) 2017-05-08 2018-11-15 Syngenta Participations Ag Dérivés d'imidazopyrimidine à substituants phényle et pyridyle contenant du soufre
US11447488B2 (en) 2017-10-06 2022-09-20 Takeda Pharmaceutical Company Limited Heterocyclic compounds
US11939327B2 (en) 2017-10-06 2024-03-26 Takeda Pharmaceutical Company Limited Heterocyclic compounds
WO2019070044A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composés hétérocycliques
WO2020016443A1 (fr) 2018-07-20 2020-01-23 Boehringer Ingelheim International Gmbh Difluorométhyl-phényl-triazoles en tant que modulateurs des récepteurs gaba
WO2020141135A1 (fr) 2018-12-31 2020-07-09 Syngenta Crop Protection Ag Dérivés hétérocycliques à action pesticide comprenant des substituants contenant du soufre
WO2020250183A1 (fr) 2019-06-13 2020-12-17 Pi Industries Ltd. Composés hétérocycliques fusionnés et leur utilisation en tant qu'agents de lutte contre les nuisibles
US12384787B2 (en) 2019-06-13 2025-08-12 Pi Industries Ltd. Fused heterocyclic compounds and their use as pest control agents
WO2021171035A1 (fr) 2020-02-28 2021-09-02 Benevolentai Cambridge Limited Compositions et leurs utilisations
EP4326712A4 (fr) * 2021-04-21 2025-03-05 The Regents of The University of California Compositions et méthodes de traitement de maladies neurodégénératives

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