WO2012133607A1 - Pyrazole compound - Google Patents

Pyrazole compound Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
alkyl
optionally substituted
group
pyrazol
Prior art date
Application number
PCT/JP2012/058291
Other languages
French (fr)
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
Original Assignee
アステラス製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by アステラス製薬株式会社 filed Critical アステラス製薬株式会社
Publication of WO2012133607A1 publication Critical patent/WO2012133607A1/en

Links

Classifications

    • 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
    • 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
    • A61K31/444—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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and 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
    • A61K31/435—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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
    • A61K31/535—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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Addiction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

[Problem] To provide a compound useful for the prevention of and/or as a therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease. [Solution] The inventors studied compounds having PDE10A inhibitory actions, and confirmed that a pyrazole compound has PDE10A inhibitory actions, thus resulting in the present invention. This pyrazole compound has PDE10A inhibitory actions, and can be used for the prevention of and/or as a therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease.

Description

ピラゾール化合物Pyrazole compounds
　本発明は医薬組成物、例えばホスホジエステラーゼ10A(PDE10A)に関与する疾患の予防及び／又は治療用医薬組成物の有効成分として有用なピラゾール化合物に関する。 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).
　ホスホジエステラーゼ(Phosphodiesterase(PDE))は、細胞内セカンドメッセンジャーであるcyclic AMP(cAMP)及びcyclic GMP(cGMP)を分解する酵素である。PDEは、酵素化学的性質(cAMPを特異的に基質とする、cGMPを特異的に基質とする、又は両方を基質とする)、触媒部位のアミノ酸配列の相同性、及び構造モチーフ(カルモジュリン結合ドメイン、GAFドメイン、PASドメイン等)に基づいて11種類のファミリーに分類されている。上記PDEファミリーは組織特異的に発現又は細胞内に局在し、特定のタンパク質と相互作用する事から特定の臓器・組織内の細胞内シグナルに関与すると考えられる(Folia Pharmacologica Japonica.、2005年、第126巻、p.121)。 Phosphodiesterase (PDE) 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).
　PDEファミリーの中でもPDE10Aは、哺乳類において種を越えて遺伝学的に保存されており、その発現は脳内、特に線条体及び側坐核の中型有棘神経細胞に特異的かつ高発現し、cAMP及びcGMPの両方を基質とする事が報告されている(Neuropharmacology、2010年、第59巻、p.367)。PDE10Aを特異的に欠失させたマウスは、ヒトにおいて統合失調症病様の障害を誘発するフェンサイクリジンを用いた行動試験において、この誘発薬に対する感受性を低下させる(Neuropharmacology、2006年、第51巻、p.374)。更に社会性行動が野生群より高く(Journal of Neurochemistry.、2008年、第105巻、p.546)、錐体外路障害を誘発しない事も報告されている(Neuropharmacology、2008年、第54巻、p.417)。PDE10A選択的阻害薬を用いた研究において、当該阻害薬は線条体における出力神経細胞内のcAMP及びcGMPを上昇させ各種細胞内伝達を促進させる。その結果フェンサイクリジン誘発の過活動、及び統合失調症患者において特異的に観察されるauditory sensory gating障害を改善する事が報告されている（Journal of Pharmacology and Experimental Therapeutics、2008年、第325巻、p.681）。更に、統合失調症の主症状である陽性症状、陰性症状、及び認知機能障害に対応したいずれの動物モデルにおいてもPDE10A選択的阻害薬は有効性を示す。その一方で既存の抗精神病薬より、錐体外路障害誘発リスクが低い事も報告されている(Journal of Pharmacology and Experimental Therapeutics、2009年、第331巻、p.574)。以上から、PDE10A選択的阻害薬は、錐体外路障害誘発のリスクが低く、統合失調症のいずれの主症状に対しても有効な抗精神病薬になる事が期待される。 Among the PDE family, 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. 546), and it has also been reported not to induce extrapyramidal disorders (Neuropharmacology, 2008, Vol. 54, p.417). In a study using a PDE10A selective inhibitor, the inhibitor increases cAMP and cGMP in output neurons in the striatum and promotes various intracellular transmissions. As a result, it has been reported that phencyclidine-induced overactivity and the auditory sensory gating disorder specifically observed in patients with schizophrenia are improved (Journal of Pharmacology and Experimental Therapeutics, 2008, Vol. 325, p.681). Furthermore, PDE10A selective inhibitors show efficacy in any animal model corresponding to positive symptoms, negative symptoms, and cognitive impairment, which are the main symptoms of schizophrenia. On the other hand, it has also been reported that the risk of inducing extrapyramidal disorders is lower than that of existing antipsychotic drugs (Journal of Pharmacology and Experimental Therapeutics, 2009, Vol.331, p.574). Based on the above, PDE10A selective inhibitors are expected to be effective antipsychotics for any major symptom of schizophrenia with low risk of extrapyramidal induction.
　PDE10Aを遺伝的に欠損させたマウスは社会性の向上を示す事や、ハンチントン舞踏病の動物モデルにおいて、PDE10A阻害薬はその薬剤誘発神経変性を抑制する事(Neurobiology of disease、2009年、第34巻、p.450)が知られている。また統合失調症の陽性症状動物モデルに用いられる覚せい剤(アンフェタミン)及び麻薬（フェンサイクリジン）誘発の行動変化に対しPDE10A阻害薬は改善作用を示し（Journal of Pharmacology and Experimental Therapeutics、2008年、第325巻、p.681）、N-メチル-D-アスパラギン酸(NMDA)拮抗薬誘発の認知障害に対し改善効果を示す事(European Journal of Neuroscience、2005年、第21巻、p.1070)も知られている。以上からPDE10A阻害は統合失調症だけでなく、不安症、ハンチントン舞踏病、薬物依存、又はアルツハイマー病の認知障害及びその周辺症状の薬物治療の標的として有望であると考えられる。 Mice genetically deficient in PDE10A show improved sociality, and in animal models of Huntington's disease, PDE10A inhibitors suppress their drug-induced neurodegeneration (Neurobiology of disease, 2009, 34th Vol., P.450) is known. In addition, 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. Based on the above, 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.
　PDE10阻害作用を示す化合物として下記式の化合物Ａ（特許文献１）、化合物Ｂ（特許文献２）、化合物Ｃ（特許文献３）、及び化合物Ｄ（先行技術４及び５）が報告されている。
Figure JPOXMLDOC01-appb-C000002
 　[式中の記号は当該公報を参照のこと] As compounds exhibiting PDE10 inhibitory activity, Compound A (Patent Document 1), Compound B (Patent Document 2), Compound C (Patent Document 3), and Compound D (Prior Art 4 and 5) of the following formulas have been reported.
Figure JPOXMLDOC01-appb-C000002
 [See the official gazette for symbols in the formula]
　またPDE10A阻害作用を示す化合物として下記式の化合物Ｅ（特許文献６）、化合物Ｆ（特許文献７）及び化合物Ｇ（特許文献８）が報告されている。
Figure JPOXMLDOC01-appb-C000003
 　[式中の記号は当該公報を参照のこと] In addition, compounds E (Patent Document 6), Compound F (Patent Document 7) and Compound G (Patent Document 8) of the following formulas have been reported as compounds showing PDE10A inhibitory action.
Figure JPOXMLDOC01-appb-C000003
 [See the official gazette for symbols in the formula]
　しかし、本発明に係る式（Ｉ）の化合物又はその塩についての開示や示唆は、上記のいずれの文献にもない。 However, there is no disclosure or suggestion about the compound of formula (I) or a salt thereof according to the present invention in any of the above documents.
国際公開第ＷＯ２００６／０７２８２８号パンフレットInternational Publication No. WO2006 / 072828 Pamphlet 国際公開第ＷＯ２００７／０７７４９０号パンフレットInternational Publication No. WO2007 / 077490 Pamphlet 国際公開第ＷＯ２００７／１２９１８３号パンフレットInternational Publication No. WO2007 / 129183 Pamphlet 国際公開第ＷＯ２００９／１５８３９３号パンフレットInternational Publication No. WO2009 / 158393 Pamphlet 国際公開第ＷＯ２００９／１５８４７３号パンフレットInternational Publication No. WO2009 / 158473 Pamphlet 国際公開第ＷＯ２００４／００２４８４号パンフレットInternational Publication No. WO2004 / 002484 Pamphlet 国際公開第ＷＯ２００６／０３４４９１号パンフレットInternational Publication No. WO2006 / 034491 Pamphlet 国際公開第ＷＯ２００８／０８４２９９号パンフレットInternational Publication No. WO2008 / 084299 Pamphlet
　医薬組成物、例えば統合失調症治療用医薬組成物の有効成分として有用な化合物を提供する。 Provided is a compound useful as an active ingredient of a pharmaceutical composition such as a pharmaceutical composition for treating schizophrenia.
　本発明者らは、PDE10A阻害作用を有する化合物について鋭意検討した結果、本発明のピラゾール化合物がPDE10A阻害作用を有することを知見して本発明を完成した。
　即ち、本発明は、式（Ｉ）の化合物又はその塩、並びに、式（Ｉ）の化合物又はその塩、及び賦形剤を含有する医薬組成物に関する。
Figure JPOXMLDOC01-appb-C000004
 （式中、
環Aは、置換されていてもよい芳香族ヘテロ環であり、
Bは、C1-6アルキル、ハロゲン、-O-C1-6アルキル、置換されていてもよいシクロアルキル、及び置換されていてもよい非芳香族へテロ環からなる群より選択される同一又は異なる1以上の基でそれぞれ置換されていてもよいフェニレン、ピリジンジイル、若しくはチオフェンジイル、又は-C≡C-であり、
nは0又は1の整数であり、
L1は、-C1-6アルキレン-、-C1-6アルキレン-T-、又は-T-C1-6アルキレン-であり、但し、nが0である場合は、L1は-トリメチレン-T-又は-テトラメチレン-T-であり、
XはCR0又はNであり、
R1はハロゲン、-OH、-O-C1-6アルキル、-CN、-C(O)OH、及び-C(O)O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル又はHであり、
環Eは、置換されていてもよいシクロアルキル、置換されていてもよいアリール、置換されていてもよい芳香族ヘテロ環、又は置換されていてもよい非芳香族へテロ環であり、
TはO、S、-NH-、又は-N(C1-6アルキル)-であり、
R0はH又はC1-6アルキルである。） As a result of intensive studies on a compound having a PDE10A inhibitory action, 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.
Figure JPOXMLDOC01-appb-C000004
 (Where
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 (O) OC 1-6 alkyl. 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. )
　なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。 Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol has the same meaning.
　また、本発明は式（Ｉ）の化合物又はその塩を含有する統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防並びに／又は治療用医薬組成物に関する。なお当該医薬組成物は、式（Ｉ）の化合物又はその塩を含有する統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防並びに／又は治療剤を包含する。
　また、本発明は統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療用医薬組成物の製造のための式（Ｉ）の化合物又はその塩の使用、統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療のための式（Ｉ）の化合物又はその塩の使用、統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療のための式（Ｉ）の化合物又はその塩、並びに、式（Ｉ）の化合物又はその塩の有効量を対象に投与することからなる統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療方法に関する。なお、「対象」とは、その予防又は治療を必要とするヒト又はその他の動物であり、ある態様としては、その予防又は治療を必要とするヒトである。 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. Use of 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 From administering to 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.
　式（Ｉ）の化合物又はその塩は、PDE10A阻害作用を有し、統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／又はアルツハイマー病の予防並びに／又は治療剤として使用できる。 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.
　以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本明細書において、「アルキル」とは、直鎖状のアルキル及び分枝状のアルキルを含む。従って、「C1-6アルキル」とは、直鎖又は分枝状の炭素数１～６のアルキルであり、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、tert-ブチル、ペンチル、ヘキシル等であり、別の態様としては、メチル、エチル、プロピル、イソプロピルであり、更に別の態様としてはメチル、エチル、イソプロピルである。
　「アルキレン」とは、上記「アルキル」の任意の水素原子１個を除去してなる二価基である。従って、「C1-6アルキレン」とは、直鎖又は分枝状の炭素数が１～６のアルキレンであり、例えばメチレン、エチレン、トリメチレン、テトラメチレン、ペンタメチレン、ヘキサメチレン、メチルメチレン、ジメチルメチレン、エチルメチレン、メチルエチレン、ジメチルエチレン、エチルエチレン等であり、別の態様としてはメチレン、エチレンである。 In the present specification, “alkyl” includes linear alkyl and branched alkyl. Accordingly, “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. In another embodiment, 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”. Accordingly, “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.
　「シクロアルキル」とは、環員数３～８の飽和炭化水素環基であり、当該シクロアルキルは架橋を有していてもよく、ベンゼン環と縮合していてもよく、一部の結合が不飽和であってもよい。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等であり、別の態様としてはC3-6シクロアルキルである。 “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.
　「アリール」とは、炭素数６～１４の単環乃至三環式芳香族炭化水素環基である。具体的には、例えばフェニル、ナフチル等である。 “Aryl” is a monocyclic to tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Specifically, for example, phenyl, naphthyl and the like.
　「芳香族へテロ環」とは、O、N及び、Sから選択される1つ以上のヘテロ原子を環構成原子として含む、環員数5から6の単環芳香族へテロ環基であり、当該単環芳香族へテロ環はシクロヘキサン、ベンゼン、若しくはチオフェン、イミダゾール、ピラゾール、ピリジン、トリアゾール、及びピラジンからなる群より選択される環と縮合していてもよい。また、環構成原子の窒素は酸化されていてもよい。具体的には、例えばピリジル、ピロリル、ピラジニル、ピリミジニル、ピリダジニル、イミダゾリル、トリアゾリル、トリアジニル、テトラゾリル、チアゾリル、ピラゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、チアジアゾリル、オキサジアゾリル、チエニル、フリル、インドリル、イソインドリル、ベンゾイミダゾリル、インダゾリル、キノリル、イソキノリル、キナゾリニル、キノキサリニル、フタラジニル、ベンゾチアゾリル、ベンゾイソチアゾリル、ベンゾチアジアゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾフラニル、ベンゾチエニル、ベンゾトリアゾリル、チエノピリジル、チエノピリミジニル、チエノピラジル、5,6,7,8-テトラヒドロキノリル、イミダゾ[1,2-a]ピリジル、イミダゾ[1,2-a]ピリミジニル、イミダゾ[1,2-b]ピリダジニル、ピラゾロ[1,5-a]ピリミジニル、イミダゾ[4,5-b]ピリジル、1,8-ナフチリジニル、イミダゾ[2,1-b][1,3]チアゾリル、[1,2,4]トリアゾロ[1,5-a]ピリジル、ピリド[2,3-b]ピラジニル、N-オキシドピリジル等が挙げられる。 `` 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. Moreover, the nitrogen of the ring constituent atom may be oxidized. Specifically, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, indolyl, isoindolyl, benzoimidazolyl, indazolyl, indazolyl, indazolyl Quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothienyl, benzotriazolyl, thienopyridyl, thienopyrimidinyl, thienopyrazyl, 5,6,7,8-tetrahydroquinolyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrim Dinyl, imidazo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyrimidinyl, imidazo [4,5-b] pyridyl, 1,8-naphthyridinyl, imidazo [2,1-b] [1,3 ] Thiazolyl, [1,2,4] triazolo [1,5-a] pyridyl, pyrido [2,3-b] pyrazinyl, N-oxide pyridyl and the like.
　「非芳香族へテロ環」とは、O、N及び、Sから選択される1から4のヘテロ原子を環構成原子として含む、環員数4から8の単環非芳香族へテロ環基である。当該単環非芳香族へテロ環はベンゼン環と縮合していてもよい。また、環構成原子である硫黄原子は酸化されていてもよく、環の一部の結合が不飽和であってもよい。具体的には、例えばアゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル、アゼパニル、ジアゼパニル、モルホリニル、スルホラニル、チオモルホリニル、1,1-ジオキシドチオモルホリニル、テトラヒドロピリジル、テトラヒドロピリミジニル、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、ジオキソラニル、ジオキサニル、テトラヒドロチオピラニル、インドリニル、1,2-ジヒドロピリジル、1,2-ジヒドロピリミジニル、1,2-ジヒドロピラジニル、1,2-ジヒドロピリダジニル等が挙げられる。 The “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. Moreover, the sulfur atom which is a ring-constituting atom may be oxidized, and a partial bond of the ring may be unsaturated. Specifically, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, morpholinyl, sulfolanyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl, tetrahydropyridyl, tetrahydropyrimidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, Examples include dioxolanyl, dioxanyl, tetrahydrothiopyranyl, indolinyl, 1,2-dihydropyridyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,2-dihydropyridazinyl and the like.
　「ハロゲン」とは、F、Cl、Br、Iである。 “Halogen” means F, Cl, Br, I.
　「フェニレン」のある態様としては、1,4-フェニレンであり、「ピリジンジイル」のある態様としては、ピリジン-2,5-ジイル、「チオフェンジイル」のある態様としては、チオフェン-2,5-ジイルである。 One embodiment of “phenylene” is 1,4-phenylene, one embodiment of “pyridinediyl” is pyridine-2,5-diyl, and one embodiment of “thiophenediyl” is thiophene-2,5. -It's a diyl.
　本明細書において、「置換されていてもよい」とは、無置換、若しくは置換基を１～５個有していることを意味する。なお、複数個の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。 In the present specification, “optionally substituted” means unsubstituted or having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.
　式（Ｉ）の環Aにおける「置換されていてもよい芳香族へテロ環」において許容される置換基としては、
（１）ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
（２）ハロゲン、
（３）-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
（４）-NH2、
（５）-NH(C1-6アルキル)、
（６）-N(C1-6アルキル)2、
（７）-CN、
（８）シクロアルキル、
（９）-C(O)O-C1-6アルキル、
（１０）-C(O)H、
を挙げる事ができる。 As the substituent allowed in the “optionally substituted aromatic heterocycle” in ring A of formula (I),
(1) 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.
　式（Ｉ）のBにおける置換されていてもよいフェニレン、ピリジンジイル、若しくはチオフェンジイルの置換基として許容される「置換されていてもよいシクロアルキル」、「置換されていてもよい非芳香族へテロ環」において許容される置換基としては、C1-6アルキル、ハロゲン、及び-OHを挙げることができる。 “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.
　式（Ｉ）の環Eにおける「置換されていてもよいシクロアルキル」において許容される置換基としては、C1-6アルキル、-OH、-C(O)NH2、-C(O)NH(C1-6アルキル)、-C(O)N(C1-6アルキル)2、-CN、=N-O-C1-6アルキル、及びオキソを挙げることができる。 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.
　式（Ｉ）の環Eにおける「置換されていてもよいアリール」において許容される置換基としては、C1-6アルキル、ハロゲン、及び-OHを挙げることができる。 Substituents allowed in “optionally substituted aryl” in ring E of formula (I) include C 1-6 alkyl, halogen, and —OH.
　式（Ｉ）の環Eにおける「置換されていてもよい芳香族へテロ環」において許容される置換基としては、i)ハロゲン、-OH、-O-C1-6アルキル、-O-tert-ブチルジメチルシリル（以下-O-TBS）、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-O-C1-6アルキル、iv)-OH、並びにv)シクロアルキルを挙げることができる。 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.
　式（Ｉ）の環Eにおける「置換されていてもよい非芳香族へテロ環」において許容される置換基としては、
（１）ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
（２）ハロゲン、
（３）-OH、
（４）-S(O)2-C1-6アルキル、
（５）-C(O)-(-O-C1-6アルキルで置換されていてもよいC1-6アルキル)、
（６）-C(O)-N(C1-6アルキル)2、
（７）-C(O)O-C1-6アルキル、
（８)オキソ、
を挙げることができる。 As the substituent allowed in the “optionally substituted non-aromatic heterocycle” in the ring E of the formula (I),
(1) 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.
　式（Ｉ）の化合物又はその塩のある態様を以下に示す。 Certain embodiments of the compound of formula (I) or a salt thereof are shown below.
（１）環Aがi)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、iv)-N(C1-6アルキル)2、v)-CN、並びにvi)シクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環である式（Ｉ）の化合物又はその塩。
別の態様としては、環Aがi)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、iv)-N(C1-6アルキル)2、v)-CN、並びにvi)シクロアルキルからなる群より選択される同一又は異なる1以上の基でそれぞれ置換されていてもよいベンゾイミダゾリル、ピリジル、キノリル、イミダゾ[1,2-a]ピリジル、イミダゾ[4,5-b]ピリジル、1,8-ナフチリジニル、又はイミダゾ[1,2-b]ピリダジニルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環AがC1-6アルキルで置換されていてもよいベンゾイミダゾリルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環AがC1-6アルキルで置換されていてもよいベンゾイミダゾール-4-イルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがメチル又はエチルで置換されていてもよいベンゾイミダゾール-4-イルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環AがC1-6アルキル、-O-C1-6アルキル、-N(C1-6アルキル)2、及びシクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいピリジルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環AがC1-6アルキル及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいピリジン-2-イルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがメチルで置換されていてもよいピリジン-2-イルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがi)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、iv)-N(C1-6アルキル)2、v)-CN、並びにvi)シクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがi)ハロゲン及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、並びにiii)-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがメチル、エチル、ジフルオロメチル、ジメチルアミノメチル、F、及び-O-メチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがメチル、エチル、ジフルオロメチル、ジメチルアミノメチル、F、及び-O-メチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-2-イルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがメチル、エチル、F、及び-O-メチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-2-イルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Aがメチル、エチル、ジフルオロメチル、ジメチルアミノメチル、F、及び-O-メチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-8-イルである式（Ｉ）の化合物又はその塩。
また更に別の態様としては、環Aがメチル、エチル、F、及び-O-メチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-8-イルである式（Ｉ）の化合物又はその塩。 (1) 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.
In another embodiment, 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] pyridazinyl.
In yet another embodiment, a compound of formula (I) or a salt thereof, wherein ring A is benzimidazolyl optionally substituted with C 1-6 alkyl.
In yet another embodiment, the compound of formula (I) or a salt thereof, wherein ring A is benzoimidazol-4-yl optionally substituted with C 1-6 alkyl.
In yet another embodiment, the compound of formula (I) or a salt thereof, wherein ring A is benzimidazol-4-yl optionally substituted with methyl or ethyl.
In yet another embodiment, 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.
In still another embodiment, 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.
In yet another embodiment, 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.
As still another embodiment, 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.
In yet another embodiment, 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.
In yet another embodiment, 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.
In yet another embodiment, 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.
In yet another embodiment, 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.
In yet another embodiment, 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.
（２）BがC1-6アルキル、ハロゲン、-O-C1-6アルキル、置換されていてもよいシクロアルキル、及び置換されていてもよい非芳香族へテロ環からなる群より選択される同一又は異なる1以上の基でそれぞれ置換されていてもよいフェニレン又はピリジンジイルである式（Ｉ）の化合物又はその塩。
別の態様としては、Bが-C≡C-である式（Ｉ）の化合物又はその塩。
更に別の態様としては、BがC1-6アルキル、ハロゲン、-O-C1-6アルキル、置換されていてもよいシクロアルキル、及び置換されていてもよい非芳香族へテロ環からなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレンである式（Ｉ）の化合物又はその塩。
更に別の態様としては、BがC1-6アルキル、ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレンである式（Ｉ）の化合物又はその塩。
更に別の態様としては、Bがメチル、F、及び-O-メチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレンである式（Ｉ）の化合物又はその塩。
更に別の態様としては、Bがメチル、F、及び-O-メチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい1,4-フェニレンである式（Ｉ）の化合物又はその塩。
更に別の態様としては、Bが1,4-フェニレンである式（Ｉ）の化合物又はその塩。
更に別の態様としては、BがC1-6アルキル、ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいピリジンジイルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、BがC1-6アルキル、ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいピリジン-2,5-ジイルである式（Ｉ）の化合物又はその塩。
また更に別の態様としては、Bがピリジン-2,5-ジイルである式（Ｉ）の化合物又はその塩。 (2) 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 formula (I) or a salt thereof which is phenylene or pyridinediyl each optionally substituted by one or more different groups.
In another embodiment, the compound of formula (I) or a salt thereof, wherein B is —C≡C—.
In yet another embodiment, 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.
In yet another embodiment, 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. A compound of I) or a salt thereof.
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.
In yet another embodiment, 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.
In yet another embodiment, a compound of formula (I) or a salt thereof wherein B is 1,4-phenylene.
In yet another embodiment, 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.
In still another embodiment, 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. -A compound of formula (I) or a salt thereof which is diyl.
In yet another embodiment, the compound of formula (I) or a salt thereof, wherein B is pyridine-2,5-diyl.
（３）nが1である式（Ｉ）の化合物又はその塩。 (3) A compound of the formula (I) wherein n is 1 or a salt thereof.
（４）L1が-C1-6アルキレン-T-又は-T-C1-6アルキレンである式（Ｉ）の化合物又はその塩。
別の態様としては、L1が-C1-6アルキレン-である式（Ｉ）の化合物又はその塩。
更に別の態様としては、L1が-C1-6アルキレン-O-又は-O-C1-6アルキレンである式（Ｉ）の化合物又はその塩。
更に別の態様としては、L1が-C1-6アルキレン-NH-又は-NH-C1-6アルキレンである式（Ｉ）の化合物又はその塩。
更に別の態様としては、L1が-CH2-O-又は-O-CH2-である式（Ｉ）の化合物又はその塩。
更に別の態様としては、L1が-CH2-O-である式（Ｉ）の化合物又はその塩。更に別の態様としては、L1が-O-CH2-である式（Ｉ）の化合物又はその塩。
また更に別の態様としては、L1がエチレンである式（Ｉ）の化合物又はその塩。 (4) A compound of the formula (I) or a salt thereof, wherein L 1 is —C 1-6 alkylene-T— or —TC 1-6 alkylene.
In another embodiment, the compound of formula (I) or a salt thereof, wherein L 1 is —C 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-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 the formula (I) or a salt thereof, wherein L 1 is —CH 2 —O— or —O—CH 2 —.
Yet another embodiment is a compound of formula (I) or a salt thereof, wherein L 1 is —CH 2 —O—. In yet another embodiment, the compound of formula (I) or a salt thereof, wherein L 1 is —O—CH 2 —.
Yet another embodiment is a compound of the formula (I) or a salt thereof, wherein L 1 is ethylene.
（５）XがCH又はNである式（Ｉ）の化合物又はその塩。
別の態様としては、XがCHである式（Ｉ）の化合物又はその塩。
更に別の態様としては、XがNである式（Ｉ）の化合物又はその塩。 (5) A compound of the formula (I) or a salt thereof, wherein X is CH or N.
In another embodiment, a compound of formula (I) or a salt thereof, wherein X is CH.
Yet another embodiment is a compound of formula (I) or a salt thereof, wherein X is N.
（６）R1がハロゲン、-OH、-O-C1-6アルキル、-CN、-C(O)OH、及び-C(O)O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルである式（Ｉ）の化合物又はその塩。
別の態様としては、R1がF、-OH、-O-メチル、-CN、-C(O)OH、及び-C(O)O-エチルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、R1がFで置換されていてもよいC1-6アルキルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、R1がトリフルオロメチルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、R1が-OHで置換されていてもよいC1-6アルキルである式（Ｉ）の化合物又はその塩。
また更に別の態様としては、R1がメチルである式（Ｉ）の化合物又はその塩。 (6) 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.
In another embodiment, 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. A compound of the formula (I) or a salt thereof, which is C 1-6 alkyl optionally substituted by
In yet another embodiment, the compound of formula (I) or a salt thereof, wherein R 1 is C 1-6 alkyl optionally substituted with F.
Yet another embodiment is a compound of formula (I) or a salt thereof, wherein R 1 is trifluoromethyl.
Yet another embodiment is a compound of the formula (I) or a salt thereof, wherein R 1 is C 1-6 alkyl optionally substituted with —OH.
Yet another embodiment is a compound of the formula (I) or a salt thereof, wherein R 1 is methyl.
（７）環Eが置換されていてもよい芳香族へテロ環又は非芳香族へテロ環である式（Ｉ）の化合物又はその塩。別の態様としては、環Eが置換されていてもよい芳香族へテロ環である式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eが置換されていてもよい非芳香族へテロ環である式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eがi)ハロゲン、-OH、-O-C1-6アルキル、-O-TBS、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-O-C1-6アルキル、iv)-OH、並びにv)シクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環である式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eがハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよい芳香族へテロ環である式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eが-O-C1-6アルキル及び-OHからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよい芳香族へテロ環である式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eが-O-C1-6アルキル及び-OHからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよいピリジルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eが-O-C1-6アルキル及び-OHからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよいN-オキシドピリジルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eが-O-C1-6アルキル及び-OHからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよいピリダジニルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eが-O-C1-6アルキル及び-OHからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよいピラゾリルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eがi)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-OH、iv)-S(O)2-C1-6アルキル、v)-C(O)-(-O-C1-6アルキルで置換されていてもよいC1-6アルキル)、vi)-C(O)-N(C1-6アルキル)2、vii)-C(O)O-C1-6アルキル、並びにviii)オキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよい非芳香族へテロ環である式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eがハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル並びにオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよい非芳香族へテロ環である式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eがハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル並びにオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよい1,2-ジヒドロピリジルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環EがC1-6アルキル及びオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよい1,2-ジヒドロピリジルである式（Ｉ）の化合物又はその塩。
更に別の態様としては、環Eがハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル並びにオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよいピぺリジニルである式（Ｉ）の化合物又はその塩。
また更に別の態様としては、環EがC1-6アルキル及びオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよいピペリジニルである式（Ｉ）の化合物又はその塩。 (7) A compound of the formula (I) or a salt thereof, in which ring E is an optionally substituted aromatic hetero ring or non-aromatic hetero ring. In another embodiment, the compound of formula (I) or a salt thereof, wherein ring E is an optionally substituted aromatic heterocycle.
In yet another embodiment, the compound of formula (I) or a salt thereof, wherein ring E is a non-aromatic heterocyclic ring which may be substituted.
In yet another embodiment, 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 A compound of the formula (I) or a salt thereof which is an aromatic heterocyclic ring optionally substituted with one or more groups.
In yet another embodiment, 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 an aromatic hetero ring optionally substituted with an optionally substituted C 1-6 alkyl.
In yet another embodiment, 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. A compound of formula (I) or a salt thereof which is a good aromatic heterocycle.
In yet another embodiment, 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. A compound of formula (I) or a salt thereof which is also good pyridyl.
In yet another embodiment, 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. A compound of formula (I) or a salt thereof which is also a good N-oxide pyridyl.
In yet another embodiment, 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. A compound of formula (I) or a salt thereof which may be pyridazinyl.
In yet another embodiment, 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. A compound of formula (I) or a salt thereof which is also good pyrazolyl.
In yet another embodiment, 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. Optionally substituted C 1-6 alkyl, ii) halogen, iii) -OH, iv) -S (O) 2 -C 1-6 alkyl, v) -C (O)-(-OC 1-6 C 1-6 alkyl optionally substituted with alkyl), vi) -C (O) -N (C 1-6 alkyl) 2 , vii) -C (O) OC 1-6 alkyl, and viii) oxo 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
In yet another embodiment, 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 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.
In yet another embodiment, 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 formula (I) or a salt thereof, which is 1,2-dihydropyridyl optionally substituted with one or more groups selected from the group consisting of optionally selected C 1-6 alkyl and oxo.
In yet another embodiment, Formula (I) wherein 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.
In yet another embodiment, 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.
In yet another embodiment, 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.
（８）上記（１）から（７）に記載の基の二以上の組み合わせである式（Ｉ）の化合物又はその塩。 (8) A compound of the formula (I) or a salt thereof, which is a combination of two or more of the groups described in (1) to (7) above.
　本発明には、上記（８）に記載したような、上記（１）から（７）に記載の基の二以上の組み合わせである化合物又はその塩が包含されるが、その具体例を含めて以下の態様も挙げられる。 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.
（９）BがC1-6アルキル、ハロゲン、-O-C1-6アルキル、置換されていてもよいシクロアルキル、及び置換されていてもよい非芳香族へテロ環からなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレン、nが１、L1が-C1-6アルキレン-T-又は-T-C1-6アルキレンである式（Ｉ）の化合物又はその塩。
（１０）BがC1-6アルキル、ハロゲン、-O-C1-6アルキル、置換されていてもよいシクロアルキル、及び置換されていてもよい非芳香族へテロ環からなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレン、nが１、L1が-C1-6アルキレン-である式（Ｉ）の化合物又はその塩。
（１１）Bが-C≡C-、nが１、L1が-C1-6アルキレン-T-である式（Ｉ）の化合物又はその塩。
（１２）L1が-C1-6アルキレン-O-又は-O-C1-6アルキレンである（９）記載の化合物又はその塩。
（１３）L1がエチレンである（１０）記載の化合物又はその塩。
（１４）L1が-C1-6アルキレン-O-である（１０）記載の化合物又はその塩。
（１５）環Aがi)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、iv)-N(C1-6アルキル)2、v)-CN、並びにvi)シクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環である（１２）、（１３）、又は（１４）記載の化合物又はその塩。
（１６）R1がハロゲン、-OH、-O-C1-6アルキル、-CN、-C(O)OH、及び-C(O)O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルである（１５）記載の化合物又はその塩。
（１７）XがCH又はNである（１６）記載の化合物又はその塩。
（１８）環Eがi)ハロゲン、-OH、-O-C1-6アルキル、-O-TBS、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-O-C1-6アルキル、iv)-OH、並びにv)シクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環である（１７）記載の化合物又はその塩。
（１９）環Eがi)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、ii)ハロゲン、iii)-OH、iv)-S(O)2-C1-6アルキル、v)-C(O)-(-O-C1-6アルキルで置換されていてもよいC1-6アルキル)、vi)-C(O)-N(C1-6アルキル)2、vii)-C(O)O-C1-6アルキル、並びにviii)オキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよい非芳香族へテロ環である（１７）記載の化合物又はその塩。 (9) 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.
(10) 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-.
(11) A compound of the formula (I) or a salt thereof, wherein B is —C≡C—, n is 1, and L 1 is —C 1-6 alkylene-T—.
(12) The compound or salt thereof according to (9), wherein L 1 is —C 1-6 alkylene-O— or —OC 1-6 alkylene.
(13) The compound or salt thereof according to (10), wherein L 1 is ethylene.
(14) The compound or a salt thereof according to (10), wherein L 1 is —C 1-6 alkylene-O—.
(15) 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.
(16) 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 The compound or a salt thereof according to (15), which is C 1-6 alkyl optionally substituted with the above groups.
(17) The compound or salt thereof according to (16), wherein X is CH or N.
(18) one or more groups in which 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 One or more of the same or different groups selected from the group consisting of C 1-6 alkyl optionally substituted with ii) halogen, iii) —OC 1-6 alkyl, iv) —OH, and v) cycloalkyl The compound or a salt thereof according to (17), which is an aromatic hetero ring optionally substituted with
(19) Ring E 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. May be substituted with C 1-6 alkyl, ii) halogen, iii) -OH, iv) -S (O) 2 -C 1-6 alkyl, v) -C (O)-(-OC 1-6 alkyl C 1-6 alkyl optionally), vi) -C (O) -N (C 1-6 alkyl) 2, vii) -C (O ) OC 1-6 alkyl, and viii) from the group consisting of oxo The compound or a salt thereof according to (17), which is a non-aromatic heterocyclic ring optionally substituted with one or more selected same or different groups.
　式（Ｉ）の化合物又はその塩の別の態様を以下に示す。 Another embodiment of the compound of the formula (I) or a salt thereof is shown below.
（２０）
（２０－１）
環Aが、
（i）ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
（ii）ハロゲン、
（iii）-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
（iv）-N(C1-6アルキル)2、
（v）-CN、
（vi）シクロアルキル、
（vii）-C(O)H、
からなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環である式（Ｉ）の化合物又はその塩。
（２０－２）
（２０－２－１）
環Aが、
i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)ハロゲン、
iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
iv)-CN、
v)シクロアルキル、並びに
vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリル、
i)-OH及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)-O-(C1-6アルキル)、並びに
iii）-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいピリジル、又は、
i)ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)シクロアルキル、並びに、
iii)ハロゲンからなる群より選択される同一又は異なる1以上の基で置換されていてもよいベンゾイミダゾリルである式（Ｉ）の化合物又はその塩。
（２０－２－２）
環Aが、
ハロゲン、C1-6アルキル及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリル、
同一又は異なる1以上のC1-6アルキルで置換されていてもよいピリジル、又は、
同一又は異なる1以上のC1-6アルキルで置換されていてもよいベンゾイミダゾリルである式（Ｉ）の化合物又はその塩。
（２０－３）
（２０－３－１）
環Aが、
i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)ハロゲン、
iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
iv)-CN、
v)シクロアルキル、並びに
vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリル、又は、
i)ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)シクロアルキル、並びに、
iii)ハロゲンからなる群より選択される同一又は異なる1以上の基で置換されていてもよいベンゾイミダゾリルである式（Ｉ）の化合物又はその塩。
（２０－３－２）
環Aが、
i)ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)シクロアルキル、並びに、
iii)ハロゲンからなる群より選択される同一又は異なる1以上の基で置換されていてもよいベンゾイミダゾリルである式（Ｉ）の化合物又はその塩。
（２０－３－３）
環Aが、
ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい、同一又は異なる1以上のC1-6アルキルで置換されていてもよいベンゾイミダゾリルである式（Ｉ）の化合物又はその塩。
（２０－３－４）
環Aが1-メチルベンゾイミダゾール-4-イルである式（Ｉ）の化合物又はその塩。
（２０－４）
（２０－４－１）
環Aが、
i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)ハロゲン、
iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
iv)-CN、
v)シクロアルキル、並びに
vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリルである式（Ｉ）の化合物又はその塩。
（２０－４－２）
環Aが、
ハロゲン、C1-6アルキル及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリルである式（Ｉ）の化合物又はその塩。
（２０－４－３）
環Aが、
i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)ハロゲン、
iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
iv)-CN、
v)シクロアルキル、並びに
vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-2-イル、あるいは、
C1-6アルキル及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-8-イルである式（Ｉ）の化合物又はその塩。
（２０－４－４）
環Aが、
i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)ハロゲン、
iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
iv)-CN、
v)シクロアルキル、並びに
vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－５）
環Aが、
C1-6アルキル及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-8-イルである式（Ｉ）の化合物又はその塩。
（２０－４－６）
環Aが、キノリン-2-イル、3-メチルキノリン-2-イル、3-ヒドロキシメチルキノリン-2-イル、3-メトキシキノリン-2-イル、6-フルオロキノリン-2-イル、6-メトキシキノリン-2-イル、6-メトキシ-3-メチルキノリン-2-イル、又は、キノリン-8-イルである式（Ｉ）の化合物又はその塩。
（２０－４－７）
環Aが、キノリン-2-イル、3-メチルキノリン-2-イル、3-ヒドロキシメチルキノリン-2-イル、3-メトキシキノリン-2-イル、6-フルオロキノリン-2-イル、6-メトキシキノリン-2-イル、又は、6-メトキシ-3-メチルキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－８）
環Aが、キノリン-2-イル、3-ヒドロキシメチルキノリン-2-イル、3-メトキシキノリン-2-イル、6-フルオロキノリン-2-イル、6-メトキシキノリン-2-イル、6-メトキシ-3-メチルキノリン-2-イル、又は、キノリン-8-イルである式（Ｉ）の化合物又はその塩。
（２０－４－９）
環Aが、キノリン-2-イル、3-ヒドロキシメチルキノリン-2-イル、3-メトキシキノリン-2-イル、6-フルオロキノリン-2-イル、6-メトキシキノリン-2-イル、又は、6-メトキシ-3-メチルキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１０）
環Aが、キノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１１）
環Aが、3-メチルキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１２）
環Aが、3-ヒドロキシメチルキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１３）
環Aが、3-メトキシキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１４）
環Aが、6-フルオロキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１５）
環Aが、6-メトキシキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１６）
環Aが、6-メトキシ-3-メチルキノリン-2-イルである式（Ｉ）の化合物又はその塩。
（２０－４－１７）
環Aが、キノリン-8-イルである式（Ｉ）の化合物又はその塩。
（２１）
（２１－１）
Bが、C1-6アルキル、ハロゲン、-O-C1-6アルキル、
シクロアルキル、及び
非芳香族へテロ環
からなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレン、
ピリジンジイル、
若しくはチオフェンジイル、
又は-C≡C-である式（Ｉ）の化合物又はその塩。
（２１－２）
Bが、C1-6アルキル、ハロゲン、-O-C1-6アルキル、
シクロアルキル、及び
非芳香族へテロ環
からなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレン、
ピリジンジイル、
若しくはチオフェンジイルである式（Ｉ）の化合物又はその塩。
（２２）
R1がC1-6アルキルである式（Ｉ）の化合物又はその塩。
（２３）
（２３－１）
環Eが
C1-6アルキル、-OH、-C(O)NH2、-C(O)NH(C1-6アルキル)、-C(O)N(C1-6アルキル)2、-CN、=N-O-C1-6アルキル、及びオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよいシクロアルキル、
アリール、
i)ハロゲン、-OH、-O-C1-6アルキル、-O-TBS、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)ハロゲン、
iii)-O-C1-6アルキル、
iv)-OH、並びに
v)シクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環、又は、
i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
ii)-OH、
iii)-S(O)2-C1-6アルキル、
iv)-C(O)-(-O-C1-6アルキルで置換されていてもよいC1-6アルキル)、
v)-C(O)-N(C1-6アルキル)2、
vi)-C(O)O-C1-6アルキル、並びに
vii)オキソ
からなる群より選択される同一又は異なる1以上の基で置換されていてもよい非芳香族へテロ環である式（Ｉ）の化合物又はその塩。
（２３－２）
環Eが1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イルである式（Ｉ）の化合物又はその塩。
（２３－３）
環Eが2-メチルピリジン-4-イルである式（Ｉ）の化合物又はその塩。 (20)
(20-1)
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,
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 by one or more groups selected from the group consisting of -C (O) H,
i) -OH 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) -O- (C 1-6 alkyl), and
iii) pyridyl optionally substituted with one or more groups selected from the group consisting of —N (C 1-6 alkyl) 2 , 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 halogen.
(20-2-2)
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.
(20-3)
(20-3-1)
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 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 halogen.
(20-3-2)
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.
(20-3-3)
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.
(20-3-4)
A compound of formula (I) or a salt thereof, wherein 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.
(20-4-2)
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.
(20-4-3)
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 consisting of C 1-6 alkyl and —OC 1-6 alkyl.
(20-4-4)
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.
(20-4-5)
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.
(20-4-6)
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.
(20-4-7)
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.
(20-4-8)
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.
(20-4-9)
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.
(20-4-13)
A compound of formula (I) or a salt thereof, wherein Ring A is 3-methoxyquinolin-2-yl.
(20-4-14)
A compound of formula (I) or a salt thereof, wherein Ring A is 6-fluoroquinolin-2-yl.
(20-4-15)
A compound of formula (I) or a salt thereof, wherein Ring A is 6-methoxyquinolin-2-yl.
(20-4-16)
A compound of formula (I) or a salt thereof, wherein Ring A is 6-methoxy-3-methylquinolin-2-yl.
(20-4-17)
A compound of formula (I) or a salt thereof, wherein Ring A is quinolin-8-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.
(22)
A compound of formula (I) or a salt thereof, wherein R 1 is C 1-6 alkyl.
(23)
(23-1)
Ring E is
C 1-6 alkyl, -OH, -C (O) NH 2 , -C (O) NH (C 1-6 alkyl), -C (O) N (C 1-6 alkyl) 2 , -CN, = NOC 1-6 alkyl, and cycloalkyl optionally substituted with one or more same or different groups selected from the group consisting of oxo,
Aryl,
i) substituted with one or more groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, —O—TBS, and —N (C 1-6 alkyl) 2 Good C 1-6 alkyl,
ii) halogen,
iii) -OC 1-6 alkyl,
iv) -OH, and
v) an aromatic heterocyclic ring optionally substituted with one or more groups selected from the group consisting of cycloalkyl, or
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) -OH,
iii) -S (O) 2 -C 1-6 alkyl,
iv) -C (O)-(C 1-6 alkyl optionally substituted with -OC 1-6 alkyl),
v) -C (O) -N (C 1-6 alkyl) 2 ,
vi) -C (O) OC 1-6 alkyl, and
vii) 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 oxo.
(23-2)
A compound of formula (I) or a salt thereof, wherein Ring E is 1-methyl-6-oxo-1,6-dihydropyridin-3-yl.
(23-3)
A compound of formula (I) or a salt thereof, wherein Ring E is 2-methylpyridin-4-yl.
（２４）上記（１）から（７）及び（２０）から（２３）に記載の基の二以上の組み合わせである式（Ｉ）の化合物又はその塩。 (24) A compound of the formula (I) or a salt thereof, which is a combination of two or more of the groups described in (1) to (7) and (20) to (23) above.
　本発明には、上記（２４）に記載したような、上記（１）から（７）及び（２０）から（２３）に記載の基の二以上の組み合わせである化合物又はその塩が包含されるが、その具体例を含めて以下の態様も挙げられる。
（２５）環Aが、（１）、又は、（２０）である式（Ｉ）の化合物又はその塩。
（２６）Bが、（２）、又は、（２１）である（２５）記載の化合物又はその塩。
（２７）nが、（３）である（２５）～（２６）記載の化合物又はその塩。
（２８）L1が、（４）である（２５）～（２７）記載の化合物又はその塩。
（２９）Xが、（５）である（２５）～（２８）記載の化合物又はその塩。
（３０）R1が、（６）、又は、（２２）である（２５）～（２９）記載の化合物又はその塩。
（３１）環Eが、（７）、又は、（２３）である（２５）～（３０）記載の化合物又はその塩。 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. However, 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).
(29) The compound or a salt thereof according to (25) to (28), wherein X is (5).
(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).
　式（Ｉ）の化合物又はその塩に包含される具体的化合物の例として、以下の化合物が挙げられる。
8-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン、
1-メチル-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
2-(3-{[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}プロプ-1-イン-1-イル)キノリン、
1-メチル-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピペリジン-2-オン、
4-(3-{[4-(6-フルオロ-3-メチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
5-(3-{[4-(6-メトキシ-3-メチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
1-メチル-4-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール、
5-(3-{[4-(3-エチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
3-メチル-2-(4-{[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン、
3-メチル-2-[4-({[1-メチル-4-(ピリダジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン、
2-(4-{[(1,1'-ジメチル-1H,1'H-4,4'-ビピラゾール-3-イル)オキシ]メチル}フェニル)-3-メチルキノリン、
1-メチル-5-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
1-エチル-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)-1-プロピルピリジン-2(1H)-オン、
5-(3-{[4-(6-フルオロ-3-メチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
1-メチル-5-(2-メチル-5-{[4-(3-メチルキノリン-2-イル)フェノキシ]メチル}-2H-1,2,3-トリアゾール-4-イル)ピリジン-2(1H)-オン、
3-メチル-2-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン、
2-(4-{[4-(2,6-ジメチルピリジン-4-イル)-1-メチル-1H-ピラゾール-3-イル]メトキシ}フェニル)-3-メチルキノリン、
1-メチル-4-(1-メチル-3-{2-[4-(3-メチルキノリン-2-イル)フェニル]エチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
1-メチル-4-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
1-メチル-4-(4-{[1-メチル-4-(2-メチル-1-オキシドピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール、
1-メチル-4-(4-{[1-メチル-4-(ピリダジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール、
1-メチル-4-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
1'-エチル-1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H,1'H-4,4'-ビピラゾール、
1-メチル-5-(1-メチル-3-{[4-(キノリン-8-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
5-(3-{[4-(6-メトキシ-3-メチルキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
8-(4-{[1-メチル-4-(ピラジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン、
1-メチル-5-(1-メチル-3-{[4-(キノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
5-(3-{[4-(3-メトキシキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
5-(3-{[4-(6-フルオロキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
5-(3-{[4-(6-メトキシキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
3-メチル-8-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)イミダゾ[1,2-a]ピリジン、
1,1'-ジメチル-3-{[4-(3-メチルイミダゾ[1,2-a]ピリジン-8-イル)フェノキシ]メチル}-1H,1'H-4,4'-ビピラゾール、
2-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン
及びこれらの塩。 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-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} prop-1-in-1-yl) quinoline,
1-methyl-5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) piperidin-2-one,
4- (3-{[4- (6-Fluoro-3-methylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
5- (3-{[4- (6-Methoxy-3-methylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
1-methyl-4- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) -1H-benzimidazole,
5- (3-{[4- (3-ethylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
3-methyl-2- (4-{[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline,
3-methyl-2- [4-({[1-methyl-4- (pyridazin-4-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline,
2- (4-{[(1,1′-dimethyl-1H, 1′H-4,4′-bipyrazol-3-yl) oxy] methyl} phenyl) -3-methylquinoline,
1-methyl-5- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
1-ethyl-5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) -1-propylpyridin-2 (1H) -one,
5- (3-{[4- (6-Fluoro-3-methylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
1-methyl-5- (2-methyl-5-{[4- (3-methylquinolin-2-yl) phenoxy] methyl} -2H-1,2,3-triazol-4-yl) pyridine-2 ( 1H) -On,
3-methyl-2- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline,
2- (4-{[4- (2,6-dimethylpyridin-4-yl) -1-methyl-1H-pyrazol-3-yl] methoxy} phenyl) -3-methylquinoline,
1-methyl-4- (1-methyl-3- {2- [4- (3-methylquinolin-2-yl) phenyl] ethyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one ,
1-methyl-4- (1-methyl-3-{[4- (3-methylquinolin-2-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
1-methyl-4- (4-{[1-methyl-4- (2-methyl-1-oxidepyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) -1H-benzimidazole,
1-methyl-4- (4-{[1-methyl-4- (pyridazin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) -1H-benzimidazole,
1-methyl-4- (1-methyl-3-{[4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridine-2 (1H) -on,
1'-ethyl-1-methyl-3-{[4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl} -1H, 1'H-4,4'-bipyrazole,
1-methyl-5- (1-methyl-3-{[4- (quinolin-8-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
5- (3-{[4- (6-Methoxy-3-methylquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
8- (4-{[1-methyl-4- (pyrazin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline,
1-methyl-5- (1-methyl-3-{[4- (quinolin-2-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
5- (3-{[4- (3-methoxyquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
5- (3-{[4- (6-fluoroquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
5- (3-{[4- (6-methoxyquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
3-methyl-8- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) imidazo [1,2-a] pyridine,
1,1′-dimethyl-3-{[4- (3-methylimidazo [1,2-a] pyridin-8-yl) phenoxy] methyl} -1H, 1′H-4,4′-bipyrazole,
2- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline and salts thereof.
　L1の結合様式は、例えば-C1-6アルキレン-T-と記載されている場合、Tが２つの窒素原子とXを環構成原子として含む5員環へテロ環に結合し、-C1-6アルキレン-が(B)n又は環Aと結合することを意味する。例として、後記表58記載のEx.１である。また、-T-C1-6アルキレン-と記載されている場合、-C1-6アルキレン-が２つの窒素原子とXを環構成原子として含む5員環へテロ環に結合し、Tが(B)n又は環Aと結合することを意味する。例えば、後記表60記載のEx.12である。 When the bonding mode of L 1 is described as, for example, —C 1-6 alkylene-T—, T is bonded to a 5-membered heterocyclic ring containing two nitrogen atoms and X as ring-constituting atoms, and —C 1-6 alkylene- means that (B) n or ring A is bonded. An example is Ex.1 described in Table 58 below. When -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, and T is (B ) Means binding to n or ring A. For example, Ex.12 described in Table 60 below.
　式（Ｉ）の化合物には、置換基の種類によって互変異性体や幾何異性体が存在しうる。本明細書中、式（Ｉ）の化合物が異性体の一形態のみで記載されることがあるが、本発明はそれ以外の異性体も包含し、異性体の分離されたもの、あるいはそれらの混合物も包含する。
　また、式（Ｉ）の化合物には不斉炭素原子や軸不斉を有する場合があり、これに基づく光学異性体が存在しうる。本発明は、式（Ｉ）の化合物の光学異性体の分離されたもの、あるいはそれらの混合物も包含する。 In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, 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.
In addition, 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.
　更に、本発明は式（Ｉ）の化合物の製薬学的に許容されるプロドラッグも包含する。製薬学的に許容されるプロドラッグとは、加溶媒分解により又は生理学的条件下で、アミノ基、水酸基、カルボキシル等に変換できる基を有する化合物である。プロドラッグを形成する基としては、例えば、Prog. Med., 5, 2157-2161 (1985)や「医薬品の開発」（廣川書店、1990年）第７巻　分子設計163-198に記載の基が挙げられる。 Furthermore, the present invention includes 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.
　また、式（Ｉ）の化合物は、置換基の種類によって酸付加塩又は塩基との塩を形成する場合があり、かかる塩が製薬学的に許容される塩である限りにおいて本発明に包含される。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチルアミン、エチルアミン、エタノールアミン、リシン、オルニチン等の有機塩基との塩、アセチルロイシン等の各種アミノ酸及びアミノ酸誘導体との塩やアンモニウム塩等が挙げられる。 In addition, 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. The Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition 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, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.
　更に、本発明は式（Ｉ）の化合物及びその製薬学的に許容される塩の各種の水和物や溶媒和物、及び結晶多形の物質も包含する。また、本発明は種々の放射性又は非放射性同位体でラベルされた化合物も包含する。 Furthermore, 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.
（製造法）
　式（Ｉ）の化合物及びその製薬学的に許容される塩は、その基本骨格あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造する事ができる。その際、官能基の種類によっては、当該官能基を原料から中間体の段階で適当な保護基（容易に当該官能基に転化可能な基）に置き換えておくことが製造技術上効果的な場合がある。このような官能基としては、例えばアミノ基、水酸基、カルボキシル基等であり、それらの保護基としては、例えばグリーン(Greene)及びウッツ(Wuts)著、「Protective Groups in Organic Synthesis（第３版、１９９９年）」に記載の保護基等を挙げることができ、これらの反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行ったあと、必要に応じて保護基を除去することにより、所望の化合物を得る事ができる。
　また、式（Ｉ）の化合物のプロドラッグは、上記保護基と同様、原料乃至中間体の段階で特定の基を導入、あるいは得られた式（Ｉ）の化合物を用いて更に反応を行うことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者により公知の方法を適用することにより行う事ができる。
　以下、式（Ｉ）の化合物の代表的な製造法を説明する。各製法は、当該説明に付した参考文献を参照して行う事もできる。なお、各発明の製造法は以下に示した例に限定されない。 (Production method)
The compound of the formula (I) and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) from the raw material to the intermediate stage. There is. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of 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. In such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
In addition, 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. Can be manufactured. 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.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of each invention is not limited to the example shown below.
（第１製法）
Figure JPOXMLDOC01-appb-C000005
 　（式中、R2A及びR2Bのいずれか一方が-OHを、他方は-C1-6アルキレン-OHを、L2は-C1-6アルキレン-O-又は-O-C1-6アルキレン-を示す。以下同様。） (First manufacturing method)
Figure JPOXMLDOC01-appb-C000005
 (In the formula, one of R 2A and R 2B is —OH, the other is —C 1-6 alkylene-OH, and L 2 is —C 1-6 alkylene-O— or —OC 1-6 alkylene- The same shall apply hereinafter.)
　本発明化合物（Ｉ－１）は、化合物１aと化合物１bとの光延反応により得る事ができる。
　本反応は、化合物１aと化合物１bとを当量若しくは一方を過剰量用い、反応に不活性な溶媒中又は無溶媒下、ホスフィン試薬、アゾジカルボン酸ジエチル（ＤＥＡＤ）の存在下、冷却下から加熱還流下、好ましくは0℃から100℃において、通常0.1時間から5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類等が挙げられる。ホスフィン試薬としては、特に限定されないがトリフェニルホスフィンやトリブチルホスフィンが挙げられる。ＤＥＡＤの代わりに、1,1'-(アゾジカルボニル)ジピペリジンを用いると反応を円滑に進行させる上で有利な場合がある。また角田試薬であるシアノメチレントリブチルホスホランが反応を円滑に進行させる上で有利な場合がある。
　上記の方法以外に、R2A又はR2Bの-C1-6アルキレン-OHの水酸基部分を所定の脱離基、例えばハロゲン等に変換した化合物とを当量若しくは一方を過剰量用い、塩基の存在下、反応に不活性な溶媒中又は無溶媒下、冷却下から加熱還流下、好ましくは0℃から100℃において、通常0.1時間から5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、N,N-ジメチルホルムアミド等が挙げられる。塩基としては、炭酸カリウム等の無機塩基等が挙げられる。 The compound (I-1) of the present invention can be obtained by Mitsunobu reaction between compound 1a and compound 1b.
In this reaction, 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. Under stirring, preferably at 0 ° C. to 100 ° C., usually for 0.1 hour to 5 days. 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.
In addition to the above method, 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. Examples of the solvent used here are not particularly limited, but include N, N-dimethylformamide and the like. Examples of the base include inorganic bases such as potassium carbonate.
（第2製法）
Figure JPOXMLDOC01-appb-C000006
 　（式中、R3は-C0-5アルキレン-C(O)Hを、L3は-C1-6アルキレン-を示す。以下同様。） (Second manufacturing method)
Figure JPOXMLDOC01-appb-C000006
 (In the formula, R 3 represents —C 0-5 alkylene-C (O) H, L 3 represents —C 1-6 alkylene-, and so on.)
　本発明化合物（Ｉ－２）は、化合物１cと化合物１dとの還元的アミノ化反応により得る事ができる。
　本反応は、化合物１cと化合物１dとを当量若しくは一方を過剰量用い、これらの混合物を、還元剤の存在下、反応に不活性な溶媒中、-45℃から加熱還流下、通常0.1時間から5日間撹拌する。ここで用いられる溶媒の例としては、特に限定されないが、メタノール、エタノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、及びこれらの混合物が挙げられる。還元剤としては、シアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム等が挙げられる。モレキュラーシーブス等の脱水剤、又は酢酸、塩酸、チタニウム（IV）イソプロポキシド錯体等の酸存在下で反応を行うことが好ましい場合がある。反応によっては、化合物１cと化合物１dとの縮合によりイミンが生成し、安定な中間体として単離できる場合がある。そのような場合には、このイミン中間体の還元反応により化合物（Ｉ－２）を得ることができる。また、前記還元剤での処理の代わりに、メタノール、エタノール、酢酸エチル等の溶媒中、酢酸、塩酸等の酸の存在下又は非存在下で、還元触媒（例えば、パラジウム炭素、ラネーニッケル等）を用いて反応を行うこともできる。この場合、反応を常圧から50気圧の水素雰囲気下で、冷却下から加熱下で行うことが好ましい。
〔文献〕
A. R. Katritzky及びR. J. K. Taylor著、「Comprehensive Organic Functional Group Transformations II」、第2巻、Elsevier Pergamon、2005年
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) The compound (I-2) of the present invention can be obtained by a reductive amination reaction between the compound 1c and the compound 1d.
In this reaction, 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. Examples of the solvent used here include, but are not limited to, alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, and mixtures thereof. Examples of the reducing agent 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. Depending on the reaction, 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. Further, instead of the treatment with the reducing agent, a reduction catalyst (for example, palladium carbon, Raney nickel, etc.) is used in a solvent such as methanol, ethanol, ethyl acetate, in the presence or absence of an acid such as acetic acid or hydrochloric acid. Can also be used to carry out the reaction. In this case, it is preferable to carry out the reaction under a hydrogen atmosphere at normal pressure to 50 atm and under cooling to heating.
[Reference]
A. R. Katritzky and R. J. K. Taylor, `` Comprehensive Organic Functional Group Transformations II '', Volume 2, Elsevier Pergamon, 2005 The Chemical Society of Japan `` Experimental Chemistry Course (5th Edition) '' Volume 14 (2005) (Maruzen)
（第3製法）
Figure JPOXMLDOC01-appb-C000007
 　（式中、mは0から4の整数を、pは1から5の整数を、L4は-C2-6アルキレン-を示す。但しmとpの合計は1から5である。） (3rd manufacturing method)
Figure JPOXMLDOC01-appb-C000007
 (In the formula, m represents an integer of 0 to 4, p represents an integer of 1 to 5, and L 4 represents —C 2-6 alkylene-, provided that the sum of m and p is 1 to 5.)
　本発明化合物（Ｉ－３）は、化合物１eと化合物１fとのWittig反応、続く水素添加反応により得る事ができる。但し、Bが-C≡C-は除く。
　まず、化合物１eと化合物１fとを当量若しくは一方を過剰量用い、反応に不活性な溶媒中又は無溶媒下、塩基の存在下、冷却下から加熱還流下、好ましくは0℃から100℃において、通常0.1時間から5日間撹拌する。ここで用いられる溶媒の例としては、特に限定はされないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類等が挙げられる。また塩基としては、特に限定されないが、ジアザビシクロウンデセン等の有機塩基が挙げられる。
　次に得られた２重結合を有する化合物を水素雰囲気下、反応に不活性な溶媒中、金属触媒存在下で、通常1時間～5日間撹拌する。この反応は、通常、冷却下から加熱下、好ましくは室温で行われる。ここで用いられる溶媒の例としては、特に限定されないが、メタノール、エタノール、2-プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、水、酢酸エチル、N,N-ジメチルホルムアミド、ジメチルスルホキシド及びこれらの混合物が挙げられる。金属触媒としては、パラジウム炭素、パラジウム黒、水酸化パラジウム等のパラジウム触媒、白金板、酸化白金等の白金触媒、還元ニッケル、ラネーニッケル等のニッケル触媒、テトラキストリフェニルホスフィンクロロロジウム等のロジウム触媒、還元鉄等の鉄触媒等が好適に用いられる。水素ガスの代わりに、２重結合を有する化合物に対し当量から過剰量のギ酸またはギ酸アンモニウムを水素源として用いることもできる。
〔文献〕
M. Hudlicky著、「Reductions in Organic Chemistry, 2nd ed (ACS Monograph :188)」、ACS、1996年
日本化学会編「実験化学講座(第5版)」19巻(2005年)(丸善) The compound (I-3) of the present invention can be obtained by Wittig reaction of compound 1e and compound 1f, followed by hydrogenation reaction. However, B excludes -C≡C-.
First, 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. Examples of 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.
Next, 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. Examples of 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. As metal catalysts, 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 An iron catalyst such as iron is preferably used. Instead of 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.
[Reference]
M. Hudlicky, `` Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188) '', ACS, 1996 Chemical Society of Japan, `` Experimental Chemistry Course (5th edition) '' Volume 19 (2005) (Maruzen)
（第4製法）
Figure JPOXMLDOC01-appb-C000008
 　（式中、LG1A及びLG1Bのいずれか一方は脱離基を、他方は-B(OH)2若しくは-B(OZ)OWを示す。ここで、Z及びWは同一又は互いに異なってC1-6アルキル又はZ及びWが一体となってC1-6アルキレンを示す。） (4th manufacturing method)
Figure JPOXMLDOC01-appb-C000008
 (In the formula, either one of LG 1A and LG 1B represents a leaving group, and the other represents -B (OH) 2 or -B (OZ) OW. Here, 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.)
　本発明化合物（Ｉ－４）は、化合物１gと化合物１hとのカップリング反応により得る事ができる。
　本反応は、化合物１gと化合物１hとを当量若しくは一方を過剰量用い、反応に不活性な溶媒中、塩基及びパラジウム触媒の存在下、室温から加熱還流下で、通常0.1時間から5日間撹拌することによって行なわれる。本反応は不活性ガス雰囲気下で行うことが好ましい。ここで用いられる溶媒の例としては、特に限定はされないが、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、塩化メチレン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、2-プロパノール、ブタノール等のアルコール類、N,N-ジメチルホルムアミド、ジメチルスルホキシド、及びこれらの混合溶媒が挙げられる。塩基としては、Na2CO3、K2CO3、水酸化ナトリウム等の無機塩基が好ましい。パラジウム触媒としては、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、塩化パラジウム-1,1'-ビス（ジフェニルホスフィノ）フェロセン等が好ましい。また脱離基としては、ハロゲン、トリフルオロメタンスルホナート基が挙げられる。
〔文献〕
A. d. Meijere及びF. Diederich編、「Metal-Catalyzed Cross-Coupling Reactions」、第1版、VCH Publishers Inc.、1997年
日本化学会編「実験化学講座(第5版)」13巻(2005年)(丸善) The compound (I-4) of the present invention can be obtained by a coupling reaction of compound 1g and compound 1h.
In this reaction, 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. As the base, inorganic bases such as Na 2 CO 3 , K 2 CO 3 and sodium hydroxide are preferable. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable. Examples of leaving groups include halogen and trifluoromethanesulfonate groups.
[Reference]
A. d. Meijere and F. Diederich, "Metal-Catalyzed Cross-Coupling Reactions", 1st edition, VCH Publishers Inc., 1997 Chemical Society of Japan, "Experimental Chemistry Course (5th edition)", Volume 13 (2005 (Year) (Maruzen)
（第5製法）
Figure JPOXMLDOC01-appb-C000009
 　（式中、LG2はハロゲンを、LG3は-B(OH)2若しくは-B(OZ)OWを示す。） (5th manufacturing method)
Figure JPOXMLDOC01-appb-C000009
 (In the formula, LG 2 represents halogen, and LG 3 represents —B (OH) 2 or —B (OZ) OW.)
　本発明化合物（Ｉ－５）は、化合物１iをハロゲン化した化合物１jと化合物１kとのカップリング反応により得る事ができる。 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.
（第１工程）
　本工程は、化合物１iをハロゲン化し化合物１jを得る工程である。
　本工程は、化合物１iと所定のハロゲン化剤とを当量若しくは一方を過剰量用い、反応に不活性な溶媒中、室温から加熱還流下で、通常0.1時間から5日間撹拌することによって行なわれる。ここで用いられる溶媒の例としては、特に限定はされないが、アセトニトリル等が挙げられる。ハロゲン化剤としては、N-ブロモスクシンイミド、N-ヨードスクシンイミド、ヨウ素等が挙げられる。 (First step)
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. Examples of the solvent used here are not particularly limited, but include acetonitrile and the like. Examples of the halogenating agent include N-bromosuccinimide, N-iodosuccinimide, iodine and the like.
（第２工程）
　本工程は、化合物１jと化合物１kとのカップリング反応により本発明化合物（Ｉ－5）を得る工程である。
　反応条件は第４製法と同様である。 (Second step)
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.
　式（Ｉ）の化合物におけるR1、環Ａ、環Ｂ，及び環Ｅ上の種々の置換基は、式（Ｉ）の化合物を原料として、後述の実施例記載の反応、当業者にとって自明である反応又は、これらの変法を用いることにより、他の官能基へと容易に変換する事ができる。例えば、O-アルキル化、N-アルキル化、酸化、還元、還元的アルキル化、環化、加水分解、アミド化、アシル化、脱保護等、当業者が通常採用し得る工程を任意に組み合わせて行う事ができる。 The various substituents on 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). By using a certain reaction or these modified methods, it can be easily converted to other functional groups. For example, 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.
（原料化合物の製造）
　上記製造法における原料化合物は、例えば下記の方法、後述の製造例に記載の方法、公知の方法、あるいはそれらの変法を用いて製造する事ができる。 (Manufacture of raw material compounds)
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.
（原料合成１）
Figure JPOXMLDOC01-appb-C000010
 　（式中、R4は-CN又は-C(O)O-C1-6アルキルを、R5は-NH2又は-OHを示す。但し、化合物2aのR4が-CNの場合は、化合物2bのR5は-NH2であり、化合物2aのR4が-C(O)O-C1-6アルキルの場合は、化合物2bのR5は-OHである。） (Raw material synthesis 1)
Figure JPOXMLDOC01-appb-C000010
 (Wherein R 4 represents —CN or —C (O) OC 1-6 alkyl, and R 5 represents —NH 2 or —OH, provided that when R 4 of compound 2a is —CN, compound 2b R 5 of the formula is —NH 2 , and when R 4 of the compound 2a is —C (O) OC 1-6 alkyl, R 5 of the compound 2b is —OH.
　本製法は第１製法の原料化合物１aのうちR2Aが-OH、XがCHである化合物、及び第2製法の原料化合物１cのうちXがCHである化合物2bをそれぞれ製造する方法である。 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.
　化合物2bは化合物2aの環化により製造する事ができる。
　本反応は、化合物2aと例えばN,N-ジメチルホルムアミドジメチルアセタール及びR1NH-NH2とを当量若しくは一方を過剰量用い、反応に不活性な溶媒中、室温から加熱還流下で、通常0.1時間から5日間撹拌することによって行なわれる。ここで用いられる溶媒の例としては、特に限定はされないが、N,N-ジメチルホルムアミド等が挙げられる。 Compound 2b can be produced by cyclization of compound 2a.
In this reaction, 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. Examples of the solvent used here are not particularly limited, but include N, N-dimethylformamide and the like.
（原料合成２）
Figure JPOXMLDOC01-appb-C000011
 (Raw material synthesis 2)
Figure JPOXMLDOC01-appb-C000011
　本製法は第１製法の原料化合物１aのうちR2Aが-OHである化合物3dを製造する方法である。 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.
　化合物3dは化合物3aのハロゲン部分をホウ素化した後、得られた化合物3bと化合物3cとのカップリング反応により得ることができる。 Compound 3d can be obtained by boronating the halogen moiety of compound 3a and then coupling reaction of compound 3b and compound 3c obtained.
（第１工程）
　本工程は、化合物3aをホウ素化し化合物3bを得る工程である。
　化合物3aと所定のホウ素試薬とを当量若しくは一方を過剰量用い、反応に不活性な溶媒中、所定の塩基及びパラジウム試薬の存在下、室温から加熱還流下で通常0.1時間から5日間撹拌することによって行なわれる。ここで用いられる溶媒の例としては、特に限定はされないが、ジオキサン等が挙げられる。所定のホウ素試薬の例としては、ビス（ピナコラート）ジボロン等が挙げられる。所定の塩基としては、酢酸カリウム等が挙げられる。パラジウム試薬の例としては、1,1'-ビス（ジフェニルホスフィノ）フェロセン-パラジウム（II）ジクロリド等が挙げられる。 (First step)
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. Examples of 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.
（第２工程）
　本工程は、化合物3bと化合物3cとのカップリング反応により化合物3dを得る工程である。
　反応条件は第4製法と同様である。 (Second step)
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.
（原料合成３）
Figure JPOXMLDOC01-appb-C000012
 　（式中、R6はC1-6アルキルを示す。） (Raw material synthesis 3)
Figure JPOXMLDOC01-appb-C000012
 (In the formula, R 6 represents C 1-6 alkyl.)
　本製法は第１製法の原料化合物１aのうちR2Aが-C1-6アルキレン-OHである化合物４ｄ、及び第３製法の原料化合物１eをそれぞれ製造する方法である。 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.
（第１工程）
　本工程は化合物4aをハロゲン化し化合物4bを得る工程である。
　反応条件は第5製法の第１工程と同様である。 (First step)
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.
（第２工程）
　本工程は化合物4ｂと化合物１kとのカップリング反応により化合物4cを得る工程である。
　反応条件は第4製法と同様である。 (Second step)
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.
（第３工程）
　本工程は化合物4cを還元し化合物4dを得る工程である。
　化合物4cと所定の還元剤とを当量若しくは一方を過剰量用い、反応に不活性な溶媒中、氷冷下から加熱還流下で、通常0.1時間から5日間撹拌することによって行なわれる。所定の還元剤としては、水素化リチウムアルミニウム、水素化ジイソブチルアルミニウム、水素化ホウ素リチウム、水素化ホウ素ナトリウム等が挙げられる。ここで用いられる溶媒の例としては、特に限定はされないが、ジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類等が挙げられる。 (Third step)
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. Examples of the predetermined reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride and the like. Examples of the solvent used here are not particularly limited, and examples include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane.
（第４工程）
　本工程は化合物4dを酸化し化合物１eを得る工程である。
　化合物4ｄと所定の酸化剤とを当量、或いは過剰に用い、反応に不活性な溶媒中、氷冷下から加熱還流下で、通常0.1時間から5日間撹拌することによって行なわれる。所定の酸化剤としては、酸化マンガン等が挙げられる。ここで用いられる溶媒の例としては、特に限定はされないが、塩化メチレン、1,2-ジクロロエタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類等が挙げられる。 (4th process)
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. Examples of the predetermined oxidizing agent include manganese oxide. Examples of 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.
（原料合成４）
Figure JPOXMLDOC01-appb-C000013
 (Raw material synthesis 4)
Figure JPOXMLDOC01-appb-C000013
　本製法は第一製法の原料化合物１bのうちnが1の化合物5cを製造する方法である。
　反応条件は第４製法と同様である。 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.
（原料合成５）
Figure JPOXMLDOC01-appb-C000014
 (Raw material synthesis 5)
Figure JPOXMLDOC01-appb-C000014
　本製法は第４製法の原料化合物１gのうちL1が-C1-6アルキレン-O-又は-O-C1-6アルキレン-である化合物6bを製造する方法である。
　反応条件は第１製法と同様である。 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.
（原料合成６）
Figure JPOXMLDOC01-appb-C000015
 (Raw material synthesis 6)
Figure JPOXMLDOC01-appb-C000015
　本製法は第５製法の原料化合物１iのうちL1が-C1-6アルキレン-O-又は-O-C1-6アルキレン-、nが1である化合物7cを製造する方法である。
　反応条件は第１製法と同様である。 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.
　式（Ｉ）の化合物は、遊離化合物、その製薬学的に許容される塩、水和物、溶媒和物、あるいは結晶多形の物質として単離され、精製される。式（Ｉ）の化合物の製薬学的に許容される塩は、常法の造塩反応に付すことにより製造することもできる。
　単離、精製は、抽出、分別結晶化、各種分画クロマトグラフィー等、通常の化学操作を適用して行われる。
　各種の異性体は、適当な原料化合物を選択することにより製造でき、あるいは異性体間の物理化学的性質の差を利用して分離する事ができる。例えば、光学異性体は、ラセミ体の一般的な光学分割法（例えば、光学活性な塩基若しくは酸とのジアステレオマー塩に導く分別結晶化や、キラルカラム等を用いたクロマトグラフィー等）により得られ、また、適当な光学活性な原料化合物から製造することもできる。 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. For example, 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.
　式（Ｉ）の化合物の薬理活性は、以下の試験により確認した。
１．PDE10A酵素阻害活性
　被検薬のPDE10A酵素阻害活性を測定するため、ヒトPDE10A遺伝子をクローニングし、バキュロウィルスにてSf9細胞に発現する事で酵素を取得した。
　測定にはcAMP測定キット（セティ社、cAMP femto 2 kit）及び抽出、上述したヒトPDE10A酵素(参考文献：Eur. J. Biochem. 266, 1118-1127 (1999))を使用した。測定方法は添付の説明書に従った。以下に概略を示す。
　PDE10A酵素及び試験化合物を反応バッファー(40mM Tris-HCl、5mM MgCl2、pH 7.5)中にて384穴プレートで混和し(total 8μL)、室温で30分間インキュベートした。基質であるcAMP（最終濃度100nM、4μL/well）を混和し、更に室温で1時間インキュベートした。cAMP femto 2 kit試薬であるcAMP-d2液及びanti cAMP-cryptate液をそれぞれ4μL添加し、反応を停止させた。1時間以上室温インキュベートした後、蛍光測定機（PerkinElmer社製、マルチラベル・プレートリーダー：EnVision）を用いて測定した。酵素未添加時の反応率を0%、酵素添加で試験化合物未添加時の反応率を100％とし、logistic法により化合物のIC50値（nM）を算出した。 The pharmacological activity of the compound of formula (I) was confirmed by the following test.
1. 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 μL) and incubated at room temperature for 30 minutes. The substrate cAMP (final concentration 100 nM, 4 μL / well) was mixed and further incubated at room temperature for 1 hour. 4 μL 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%, and the IC 50 value (nM) of the compound was calculated by the logistic method.
　表1にいくつかの式（Ｉ）の化合物の本試験における結果を示す。表中のExは実施例番号を示す。

Table 1 shows the results in this test for some compounds of formula (I). Ex in the table indicates an example number.

Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
２．マウス・フェンサイクリジン誘発過活動抑制試験
　実験には、雄性ICRマウス(日本エスエルシー株式会社)(5週齢、約30g)を用いた。試験化合物は0.5％メチルセルロース溶液に懸濁し、10mL/kgで試験化合物又は溶媒を経口投与した。投与後、速やかに運動量測定装置（室町機械株式会社製、自発運動量測定システム・スーパーメックス）に動物を入れ、測定を開始した。過活動は測定開始1時間後に、各動物にフェンサイクリジン(2.5mg/10mL/kg)を皮下投与する事で誘発し、この過活動に対する化合物の抑制作用を1時間測定し薬効を評価した。溶媒-溶媒投与群の運動量を0%、溶媒-フェンサイクリジン投与群の運動量を100%とし、直線回帰法により試験化合物のED50値を算出した。本発明化合物のうち代表的な化合物の試験結果を以下の表に示す。尚、本試験結果は、化合物によっては、30mg/kgにおける抑制効果(%)でその結果を示した。 2. Mouse phencyclidine-induced overactivity suppression test 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. 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.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
　上記マウス・フェンサイクリジン誘発過活動抑制試験において式（Ｉ）の化合物のいくつかはフェンサイクリジン誘発の過活動を抑制した。 In the mouse phencyclidine-induced overactivity suppression test, some of the compounds of formula (I) suppressed phencyclidine-induced overactivity.
　上記試験の結果、式（Ｉ）の化合物はPDE10A阻害活性が確認され、統合失調症の予防及び／又は治療に使用できる。 As a result of the above test, the compound of formula (I) was confirmed to have PDE10A inhibitory activity and can be used for the prevention and / or treatment of schizophrenia.
　チトクロームＰ４５０（ＣＹＰ）３Ａ４酵素阻害試験において、式（Ｉ）の化合物又はその塩のいくつかは、医薬品としての使用が可能な程度にチトクロームＰ４５０の代謝酵素の阻害能が小さい化合物であることを確認した。 In the 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.
　また、チトクロームＰ４５０（ＣＹＰ）１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６酵素阻害試験においても、式（Ｉ）の化合物又はその塩のいくつかは、医薬品としての使用が可能な程度にチトクロームＰ４５０の代謝酵素の阻害能が小さい化合物であることを確認した。その結果（IC50（μM））を以下の表に示す。 In addition, in the cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 enzyme inhibition test, the compound of formula (I) or some of its salts inhibits the metabolic enzyme of cytochrome P450 to such an extent that it can be used as a medicine. It was confirmed that the compound had a small ability. The results (IC 50 (μM)) are shown in the following table.
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
　式（Ｉ）の化合物又はその塩の１種又は２種以上を有効成分として含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち薬剤用賦形剤や薬剤用担体等を用いて、通常使用されている方法によって調製する事ができる。
　投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。 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. Can be prepared by a commonly used method.
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.
　経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、1種又は２種以上の有効成分を、少なくとも1種の不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、及び／又はメタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウムのような滑沢剤やカルボキシメチルスターチナトリウム等のような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
　経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。 As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or 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.
　非経口投与のための注射剤は、無菌の水性若しくは非水性の溶剤、懸濁剤、又は乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液が含まれる。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール若しくはオリーブ油のような植物油、エタノールのようなアルコール類、又はポリソルベート８０（局方名）等がある。このような組成物は、更に等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合、又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。 The injection for parenteral administration contains a sterile aqueous or non-aqueous solvent, suspension, or emulsion. Examples of the 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.
　外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏又はローション基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアルコール、セチルアルコール、ラウロマクロゴール、セスキオレイン酸ソルビタン等が挙げられる。 External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
　吸入剤や経鼻剤等の経粘膜剤は固体、液体又は半固体状のものが用いられ、従来公知の方法に従って製造する事ができる。例えば公知の賦形剤や、更に、pH調整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。投与は、適当な吸入又は吹送のためのデバイスを使用する事ができる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独で又は処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせて溶液又は懸濁液として投与する事ができる。乾燥粉末吸入器等は、単回又は多数回の投与用のものであってもよく、乾燥粉末又は粉末含有カプセルを利用する事ができる。あるいは、適当な駆出剤、例えば、クロロフルオロアルカン、ヒドロフルオロアルカン又は二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。 As 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. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. 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.
　通常経口投与の場合、1日の投与量は、体重当たり約0.001～100 mg/kg、好ましくは0.1～30 mg/kg、更に好ましくは0.1～10 mg/kgが適当であり、これを1回であるいは2回～4回に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.0001～10 mg/kgが適当で、1日1回～複数回に分けて投与する。また、経粘膜剤としては、体重当たり約0.001～100 mg/kgを1日1回～複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 In general, in the case of oral administration, 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. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As 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.
　投与経路、剤形、投与部位、賦形剤や添加剤の種類によって異なるが、本発明の医薬組成物は、0.01～100重量%、ある態様としては0.01～50重量%の有効成分である１種又はそれ以上の式（Ｉ）の化合物又はその塩を含有する。 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.
　式（Ｉ）の化合物は、前述の式（Ｉ）の化合物が有効性を示すと考えられる疾患の種々の治療又は予防剤と併用する事ができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。
（実施例） 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.
(Example)
　以下、実施例に基づき式（Ｉ）の化合物及びその原料化合物の製造法を更に詳細に説明する。なお本発明は、下記実施例に記載の化合物に限定されるものではない。また、原料化合物の製法を製造例に示す。また、式（Ｉ）の化合物の製造法は、以下に示される具体的実施例の製造法のみに限定されるものではなく、式（Ｉ）の化合物はこれらの製造法の組み合わせ、あるいは当業者に自明である方法によっても製造されうる。 Hereinafter, the production method of the compound of formula (I) and its raw material compound will be described in more detail based on Examples. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown to a manufacture example. Further, 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.
　また製造例、実施例、及び後記表中以下の略号を用いることがある。
PEx： 製造例番号、Ex: 実施例番号、Syn： 同様の方法で製造した実施例番号、PSyn：同様の方法で製造した製造例番号、Str: 構造式、Data： 物理化学データ、ESI+: 質量分析におけるm/z値(イオン化法ESI、断りのない場合(M+H)+)、ESI-: m/z値(イオン化法ESI、断りのない場合(M-H)-)、EI+: 質量分析におけるm/z値(イオン化法EI、断りのない場合(M)+を表す)、CI+:質量分析におけるm/z値（化学イオン化法CI、断りのない限り(M)+を表す）、NMR1： ジメチルスルホキシド-d6中の1H NMRにおけるδ(ppm)、製造例及び実施例中の[M]：[mol/L]を、WSCは1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩を、tBuはtert-ブチルを、TIPSはトリイソプロピルシリルを、TBSはtert-ブチルジメチルシリルを示す。
　また実施例表中のSyn部分にPEx番号が記載されている場合があるが、当該実施例化合物はPEx番号の化合物と同様の方法で製造した事を示す(例えば、Ex.131はPEx.60と同様の方法により製造した事を示す)。
　また構造式中のHClは塩酸塩を、Oxaはシュウ酸塩を、Sucはコハク酸塩を、TFAはトリフルオロ酢酸塩を、Fumはフマル酸塩を、Phoはリン酸塩を、TarはL-(+)-酒石酸塩を、MalはL-(-)-リンゴ酸塩であることを示し、HClの前の数字はモル比を示す。例えば2HClは二塩酸塩であり、0.5Oxa及び0.5Sucはそれぞれヘミシュウ酸塩、ヘミコハク酸塩、1.5Phoはセスキリン酸塩であることを意味する。
　また構造式中で2重結合部分が交差している化合物はシス体とトランス体の混合物を示す。
　なお化合物によっては例えば塩酸塩とする工程を行わず、フリー体の合成法のみで最終体としている化合物がある（例えばEx.201等）。 In addition, the following abbreviations may be used in Production Examples, Examples, and Tables below.
PEx: Production example number, Ex: Example number, Syn: Example number produced by the same method, PSyn: Production example number produced by the same method, Str: Structural formula, Data: Physicochemical data, ESI +: Mass M / z value in analysis (ionization method ESI, unless otherwise noted (M + H) + ), ESI-: m / z value (ionization method ESI, unless otherwise noted (MH) - ), EI +: in mass spectrometry m / z value (ionization method EI, unless otherwise indicated (M) +), CI +: m / z value in mass spectrometry (chemical ionization method CI, unless otherwise noted, represents (M) +), NMR1: Δ (ppm) in 1 H NMR in dimethyl sulfoxide-d 6 , [M]: [mol / L] in Production Examples and Examples, WSC is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride, tBu represents tert-butyl, TIPS represents triisopropylsilyl, and TBS represents tert-butyldimethylsilyl.
In addition, 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. For example, 2HCl is a dihydrochloride salt, 0.5Oxa and 0.5Suc mean hemisuccinate and hemisuccinate, and 1.5Pho is sesquiphosphate, respectively.
A compound in which the double bond portion intersects in the structural formula indicates a mixture of a cis isomer and a trans isomer.
Some compounds, for example, are not subjected to the step of converting to hydrochloride, and are made into a final product only by a free synthesis method (for example, Ex. 201).
製造例１
　4-ピリジルアセトニトリル塩酸塩(2.01g)、テトラヒドロフラン(30mL)とエタノール(30mL)の混合物に攪拌下1M 水酸化ナトリウム水溶液を加え、反応液をろ過し、ろ液を減圧濃縮した。残渣にN,N-ジメチルホルムアミドジメチルアセタールのN,N-ジメチルホルムアミド(10mL)溶液を加え、80℃で1時間攪拌した後、反応液を減圧濃縮した。残渣にメタノール(20mL)、酢酸（780mg)、メチルヒドラジン(718mg)を加え、60℃で12時間攪拌した。反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製し、1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-アミン(400mg)を得た。 Production Example 1
To a mixture of 4-pyridylacetonitrile hydrochloride (2.01 g), tetrahydrofuran (30 mL) and ethanol (30 mL) was added 1M aqueous sodium hydroxide solution with stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added a solution of N, N-dimethylformamide dimethylacetal in N, N-dimethylformamide (10 mL), and the mixture was stirred at 80 ° C. for 1 hour, and then the reaction solution was concentrated under reduced pressure. Methanol (20 mL), acetic acid (780 mg), and methyl hydrazine (718 mg) were added to the residue, and the mixture was stirred at 60 ° C. for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-amine (400 mg).
製造例２
　アルゴン気流下、2-クロロキノリン(3.0g)のN,N-ジメチルホルムアミド(30mL)溶液にホモプロパルギルアルコール(1.54g)、トリエチルアミン(5.1mL)、ヨウ化銅（I）(173mg)、及びビストリフェニルホスフィンパラジウムジクロリド(257mg)を加え室温で5時間攪拌した。反応液を酢酸エチルで希釈後、飽和炭酸水素ナトリウム水溶液で洗浄した。水層から再度酢酸エチルで抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/クロロホルム)にて精製し、4-(キノリン-2-イル)ブト-3-イン-1-オール（4.2g）を得た。 Production Example 2
Under a stream of argon, 2-chloroquinoline (3.0 g) in N, N-dimethylformamide (30 mL) was added to homopropargyl alcohol (1.54 g), triethylamine (5.1 mL), copper (I) iodide (173 mg), Phenylphosphine palladium dichloride (257 mg) was added and stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform), and 4- (quinolin-2-yl ) But-3-yn-1-ol (4.2 g) was obtained.
製造例３
　アルゴン気流下、氷冷下に4-ヨード-1H-ピラゾール-3-カルボン酸メチル(980mg)のテトラヒドロフラン(20mL)混合物に55%水素化ナトリウム(203mg)を加え、20分間攪拌した。ヨウ化メチル(830mg)を加え、室温にて14時間攪拌した。氷冷下飽和炭酸水素ナトリウム水溶液及び飽和食塩水を加え、酢酸エチルにて抽出した。有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/クロロホルム）にて精製し、4-ヨード-1-メチル-1H-ピラゾール-3-カルボン酸メチル（915mg）を得た。 Production Example 3
Under a stream of argon and ice cooling, 55% sodium hydride (203 mg) was added to a tetrahydrofuran (20 mL) mixture of methyl 4-iodo-1H-pyrazole-3-carboxylate (980 mg) and stirred for 20 minutes. Methyl iodide (830 mg) was added, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution and saturated brine were added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain methyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (915 mg).
製造例４
　4-(キノリン-2-イル)ブト-3-イン-1-オール(3.65g)のエタノール(36mL)溶解に10%パラジウム-炭素(788mg)を加え、水素気流下常圧で22時間攪拌した。セライトろ過後、ろ液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/クロロホルム）にて精製し、4-(キノリン-2-イル)ブタン-1-オール（2.90g）を得た。 Production Example 4
10% palladium-carbon (788 mg) was added to ethanol (36 mL) dissolved in 4- (quinolin-2-yl) but-3-in-1-ol (3.65 g), and the mixture was stirred at normal pressure under a hydrogen stream for 22 hours. . After filtration through celite, the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to obtain 4- (quinolin-2-yl) butan-1-ol (2.90 g).
製造例５
　1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-カルボン酸エチル(257mg)、エタノール(2.6mL)、及びテトラヒドロフラン(1.3mL)の混合物に1M 水酸化ナトリウム水溶液(1.3mL)を加え、70℃にて11時間攪拌した。反応液を放冷後、1M 塩酸で中和した。生じた沈殿を濾取し、減圧乾燥し1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-カルボン酸(137mg)を得た。 Production Example 5
To a mixture of ethyl 1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazole-4-carboxylate (257 mg), ethanol (2.6 mL), and tetrahydrofuran (1.3 mL) 1M Aqueous sodium hydroxide solution (1.3 mL) was added, and the mixture was stirred at 70 ° C. for 11 hr. The reaction solution was allowed to cool and then neutralized with 1M hydrochloric acid. The resulting precipitate was collected by filtration and dried under reduced pressure to obtain 1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazole-4-carboxylic acid (137 mg).
製造例６
　4-{3-[(4-ブロモベンジル)オキシ]-1-メチル-1H-ピラゾール-4-イル}ピリジン(292 mg)、ビス(ピナコラート)ジボロン(259 mg)、酢酸カリウム(250 mg)、ジオキサン(3 mL)の混合物に1,1'-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-塩化メチレン錯体(69 mg)を加え、アルゴン雰囲気下、100℃で3時間攪拌した。放冷後、セライト濾過し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製し、4-(1-メチル-3-{[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン（135 mg）を得た。 Production Example 6
4- {3-[(4-bromobenzyl) oxy] -1-methyl-1H-pyrazol-4-yl} pyridine (292 mg), bis (pinacolato) diboron (259 mg), potassium acetate (250 mg), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-methylene chloride complex (69 mg) was added to a mixture of dioxane (3 mL), and the mixture was stirred at 100 ° C. for 3 hours under an argon atmosphere. After allowing to cool, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) and 4- (1-methyl-3-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2). -Yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridine (135 mg) was obtained.
製造例７
　アルゴン気流下、水素化アルミニウムリチウム(104mg)のテトラヒドロフラン(10mL)混合物に、氷冷下2-フルオロ-4-(キノリン-2-イル)安息香酸メチル(515mg)のテトラヒドロフラン(10mL)混合物を滴下し同温で2時間攪拌した。同温にて発泡しなくなるまで少量ずつ28%アンモニア水を滴下し、メタノール及びクロロホルム（1:9）の混合溶媒(100mL)を加え室温にて2時間攪拌した。無水硫酸マグネシウム及びセライトを加えた後、不溶物をセライトろ過しろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム)にて精製し、[2-フルオロ-4-(キノリン-2-イル)フェニル]メタノール（460mg）を得た。 Production Example 7
Under a stream of argon, a tetrahydrofuran (10 mL) mixture of methyl 2-fluoro-4- (quinolin-2-yl) benzoate (515 mg) was added dropwise to a tetrahydrofuran (10 mL) mixture of lithium aluminum hydride (104 mg) under ice cooling. The mixture was stirred at the same temperature for 2 hours. 28% aqueous ammonia was added dropwise little by little until no foaming occurred at the same temperature, a mixed solvent (100 mL) of methanol and chloroform (1: 9) was added, and the mixture was stirred at room temperature for 2 hours. After anhydrous magnesium sulfate and celite were added, the insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to obtain [2-fluoro-4- (quinolin-2-yl) phenyl] methanol (460 mg).
製造例８
　4-(ブロモアセチル)安息香酸エチル(1.11 g)、2-アミノピリジン(385 mg)のエタノール(10 mL)混合物を1時間加熱還流した。放冷後、反応液を減圧濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加え攪拌した。生じた沈殿を濾取し、水で洗浄後、得られた固体をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)にて精製し、4-(イミダゾ[1,2-a]ピリジン-2-イル)安息香酸エチル（1.09 g）を得た。 Production Example 8
A mixture of ethyl 4- (bromoacetyl) benzoate (1.11 g) and 2-aminopyridine (385 mg) in ethanol (10 mL) was heated to reflux for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue and stirred. The resulting precipitate was collected by filtration, washed with water, and the resulting solid was purified by silica gel column chromatography (ethyl acetate / hexane) to give 4- (imidazo [1,2-a] pyridin-2-yl) Ethyl benzoate (1.09 g) was obtained.
製造例９
　4-(ピリジン-4-イル)-1H-ピラゾール-3-オール(7.84g)のピリジン(78mL)混合物に無水酢酸(4.8mL)を加え、100℃で2時間攪拌した。反応液を減圧濃縮し残渣に水を加えて、生じた沈殿を濾取した。固体をヘキサンで洗浄し、減圧乾燥し、1-[3-ヒドロキシ-4-(ピリジン-4-イル)-1H-ピラゾール-1-イル]エタノン(10g)を得た。 Production Example 9
Acetic anhydride (4.8 mL) was added to a mixture of 4- (pyridin-4-yl) -1H-pyrazol-3-ol (7.84 g) in pyridine (78 mL), and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting precipitate was collected by filtration. The solid was washed with hexane and dried under reduced pressure to obtain 1- [3-hydroxy-4- (pyridin-4-yl) -1H-pyrazol-1-yl] ethanone (10 g).
製造例１０
　4-ピリジル酢酸エチル(25g)のN,N-ジメチルホルムアミド(100mL)溶液にN,N-ジメチルホルムアミドジメチルアセタール(50mL)を加え、80℃で2時間攪拌した。反応液を放冷し、減圧濃縮した。氷冷下、エタノール(250mＬ)、メチルヒドラジン(16mL)、及び酢酸(60mL)を加え室温で16時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。粗精製物を酢酸エチル及びヘキサンの混合溶媒で洗浄し、1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-オール(15.3g)を得た。 Production Example 10
N, N-dimethylformamide dimethyl acetal (50 mL) was added to a solution of ethyl 4-pyridylacetate (25 g) in N, N-dimethylformamide (100 mL), and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was allowed to cool and concentrated under reduced pressure. Under ice cooling, ethanol (250 mL), methylhydrazine (16 mL), and acetic acid (60 mL) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform). The crude product was washed with a mixed solvent of ethyl acetate and hexane to obtain 1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-ol (15.3 g).
製造例１１
　氷冷下5-(キノリン-2-イル)チオフェン-2-カルボアルデヒド(630mg)のエタノール(19mL)混合物に水素化ホウ素ナトリウム(100mg)を加え、同温にて2時間攪拌した。水及び飽和食塩水を加え、酢酸エチルにて抽出した。有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し[5-(キノリン-2-イル)-2-チエニル]メタノール（504mg）を得た。 Production Example 11
Under ice-cooling, sodium borohydride (100 mg) was added to an ethanol (19 mL) mixture of 5- (quinolin-2-yl) thiophene-2-carbaldehyde (630 mg) and stirred at the same temperature for 2 hours. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain [5- (quinolin-2-yl) -2-thienyl] methanol (504 mg).
製造例１２
　4-ヨード安息香酸メチル(700 mg)、インドール(376 mg)、ヨウ化銅(I)(254 mg)、DL-プロリン(308 mg)、炭酸カリウム(1.11 g)のジメチルスルホキシド(3 mL)混合物を、アルゴン雰囲気下、100℃で20時間攪拌した。放冷後、水を加え、酢酸エチルにて抽出した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)にて精製し4-(1H-インドール-1-イル)安息香酸メチル（542 mg）を得た。 Production Example 12
Methyl 4-iodobenzoate (700 mg), indole (376 mg), copper iodide (I) (254 mg), DL-proline (308 mg), potassium carbonate (1.11 g) in dimethyl sulfoxide (3 mL) Was stirred at 100 ° C. for 20 hours under an argon atmosphere. After allowing to cool, water was added 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 (ethyl acetate / hexane) to obtain methyl 4- (1H-indol-1-yl) benzoate (542 mg).
製造例１３
　4-(3-メチルキノリン-2-イル)フェノール(170mg)、4-ブロモ-5-(ブロモメチル)-2-メチル-2H-1,2,3-トリアゾール(184mg)、及びN,N-ジメチルホルムアミド(3.4mL)の混合物に炭酸カリウム(250mg)を加え、60℃にて4時間攪拌した。放冷後水及び飽和食塩水を加え、クロロホルムにて抽出した。有機層を無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、2-{4-[(5-ブロモ-2-メチル-2H-1,2,3-トリアゾール-4-イル)メトキシ]フェニル}-3-メチルキノリン（295mg）を得た。 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. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 2- {4-[(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl) methoxy] phenyl}- 3-methylquinoline (295 mg) was obtained.
製造例１４
　{4-[(3-ニトロピリジン-2-イル)アミノ]フェニル}メタノール (2.13 g)のエタノール(30 mL)及び水(7.5 mL)の混合物に塩化アンモニウム(232 mg)、鉄(2.42 g)を加え、30分加熱還流した。放冷後、クロロホルム、水を加え、セライト濾過をした。濾液をクロロホルムで抽出し、有機層を減圧濃縮し、{4-[(3-アミノピリジン-2-イル)アミノ]フェニル}メタノールの粗精製物（2.42 g）を得た。当該粗生成物(2.42 g)、オルトギ酸トリエチル(3.3 mL)、及びテトラヒドロフラン(25 mL)の混合物にパラトルエンスルホン酸一水和物(149 mg)を加え、60℃で15分攪拌した。放冷後、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製し、[4-(3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル]メタノール（639 mg）を得た。 Production Example 14
{4-[(3-Nitropyridin-2-yl) amino] phenyl} methanol (2.13 g) in ethanol (30 mL) and water (7.5 mL) in ammonium chloride (232 mg), iron (2.42 g) And heated to reflux for 30 minutes. 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 a crude product (2.42 g) of {4-[(3-aminopyridin-2-yl) amino] phenyl} methanol. To a mixture of the crude product (2.42 g), triethyl orthoformate (3.3 mL), and tetrahydrofuran (25 mL) was added paratoluenesulfonic acid monohydrate (149 mg), and the mixture was stirred at 60 ° C. for 15 minutes. After allowing to cool, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform), [4- (3H-imidazo [4,5-b] pyridin-3-yl) phenyl] methanol (639 mg) Got.
製造例１５
　1-メチル-1H-ピラゾール-3-オール(8.1g)、ベンジルブロミド(16.9g)と炭酸カリウム(13.7g)のN,N-ジメチルホルムアミド(100mL)混合物を室温で1.5時間、50℃で4時間攪拌した。水と酢酸エチルを加え、有機層を飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、3-(ベンジルオキシ)-1-メチル-1H-ピラゾール（13.0g）を得た。 Production Example 15
A mixture of 1-methyl-1H-pyrazol-3-ol (8.1 g), benzyl bromide (16.9 g) and potassium carbonate (13.7 g) in N, N-dimethylformamide (100 mL) was stirred at room temperature for 1.5 hours and at 50 ° C. for 4 hours. Stir for hours. Water and ethyl acetate were added, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 3- (benzyloxy) -1-methyl-1H-pyrazole (13.0 g).
製造例１６
　2-(4-メトキシフェニル)イミダゾ[1,2-a]ピリジン(4.89g)の塩化メチレン(120mL)溶液に氷冷下、1molの三臭化ホウ素の塩化メチレン溶液（65mL）を加え、室温で18時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液に加え生じた沈殿を濾取した。濾液は10%メタノール－クロロホルムで抽出した。有機層と固体をあわせ、減圧濃縮し、残渣をメタノール及び水の順に洗浄し、4-イミダゾ[1,2-a]ピリジン-2-イルフェノール（3.37g）を得た。 Production Example 16
To a solution of 2- (4-methoxyphenyl) imidazo [1,2-a] pyridine (4.89 g) in methylene chloride (120 mL) was added 1 mol of boron tribromide in methylene chloride (65 mL) under ice-cooling, and room temperature. For 18 hours. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution, and the resulting precipitate was collected by filtration. The filtrate was extracted with 10% methanol-chloroform. The organic layer and the solid were combined and concentrated under reduced pressure, and the residue was washed with methanol and water in this order to obtain 4-imidazo [1,2-a] pyridin-2-ylphenol (3.37 g).
製造例１７
　2-(4-{[(4-ヨード-1-メチル-1H-ピラゾール-3-イル)オキシ]メチル}フェニル)キノリン(2.0g)のテトラヒドロフラン(40mL)混合物に-10℃以下で、２Ｍ イソプロピルマグネシウムクロライドのテトラヒドロフラン溶液（0.5mL）を加えた。-18℃から-10℃で45分撹拌し、2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(2.6mL)を加え、室温で1.5時間撹拌した。再度-15℃に冷却して2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(1.0mL)を加え、室温で1時間撹拌した。反応液に飽和塩化アンモニウム水溶液と酢酸エチルを加え、有機層を飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、2-[4-({[1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン（1.67g）を得た。 Production Example 17
2- (4-{[(4-Iodo-1-methyl-1H-pyrazol-3-yl) oxy] methyl} phenyl) quinoline (2.0 g) in tetrahydrofuran (40 mL) at −10 ° C. or lower with 2M isopropyl A solution of magnesium chloride in tetrahydrofuran (0.5 mL) was added. The mixture was stirred at −18 ° C. to −10 ° C. for 45 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The mixture was cooled again to −15 ° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and 2- [4-({[1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane]. -2-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (1.67 g) was obtained.
製造例１８
　氷冷下、4-(イミダゾ[1,2-a]ピリジン-2-イル)安息香酸エチル(3.11g)のテトラヒドロフラン(50mL)混合物に水素化ホウ素リチウム(806mg)、エタノール(2.2mL)を加え2時間加熱還流した。反応液を放冷し、飽和炭酸水素ナトリウム水溶液を加えた。反応液を酢酸エチルで抽出し、有機層を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製して[4-(イミダゾ[1,2-a]ピリジン-2-イル)フェニル]メタノール（2.46g）を得た。 Production Example 18
Under ice cooling, lithium borohydride (806 mg) and ethanol (2.2 mL) were added to a tetrahydrofuran (50 mL) mixture of ethyl 4- (imidazo [1,2-a] pyridin-2-yl) benzoate (3.11 g). Heated to reflux for 2 hours. The reaction solution was allowed to cool and a saturated aqueous sodium hydrogen carbonate solution was added. The reaction solution was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to obtain [4- (imidazo [1,2-a] pyridin-2-yl) phenyl] methanol (2.46 g).
製造例１９
　2-クロロ-3-メチルキノリン(533 mg)、[4-(ヒドロキシメチル)フェニル]ボロン酸(501 mg)の1,2-ジメトキシエタン(20 mL)懸濁液にテトラキス(トリフェニルホスフィン)パラジウム(173 mg)、1 M炭酸ナトリウム水溶液(7.5 mL)を加え、アルゴン雰囲気下、90℃で19時間攪拌した。放冷後、反応液に水を加え酢酸エチルで抽出し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製し、[4-(3-メチルキノリン-2-イル)フェニル]メタノール（696 mg）を得た。 Production Example 19
Tetrakis (triphenylphosphine) palladium was added to a suspension of 2-chloro-3-methylquinoline (533 mg) and [4- (hydroxymethyl) phenyl] boronic acid (501 mg) in 1,2-dimethoxyethane (20 mL). (173 mg) and 1 M aqueous sodium carbonate solution (7.5 mL) were added, and the mixture was stirred at 90 ° C. for 19 hours under an argon atmosphere. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to obtain [4- (3-methylquinolin-2-yl) phenyl] methanol (696 mg).
製造例２０
　2-(4-{[(1-メチル-1H-ピラゾール-3-イル)オキシ]メチル}フェニル)キノリン(5.32g)のアセトニトリル(140ｍＬ)溶液に硝酸二アンモニウムセリウム(5.55g)、及びヨウ素(2.57g)を加え、室温で10分撹拌した。反応液に氷冷下、5%亜硫酸水素ナトリウム水溶液と酢酸エチルを加え、有機層を飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、2-(4-{[(4-ヨード-1-メチル-1H-ピラゾール-3-イル)オキシ]メチル}フェニル)キノリン（4.94g）を得た。 Production Example 20
2- (4-{[(1-Methyl-1H-pyrazol-3-yl) oxy] methyl} phenyl) quinoline (5.32 g) in acetonitrile (140 mL) in diammonium cerium nitrate (5.55 g) and iodine ( 2.57 g) was added and stirred at room temperature for 10 minutes. Under ice-cooling, 5% aqueous sodium hydrogen sulfite solution and ethyl acetate were added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2- (4-{[(4-iodo-1-methyl-1H-pyrazol-3-yl) oxy] methyl} phenyl) quinoline (4.94 g) was obtained.
製造例２１
　1-[4-(ヒドロキシメチル)フェニル]プロパン-1-オン(710 mg)のテトラヒドロフラン(10 mL)溶液にピリジニウムブロミドペルブロミド(1.45 g)を加え、室温で1.5時間攪拌した。濾過後、減圧濃縮し、2-ブロモ-1-[4-(ヒドロキシメチル)フェニル]プロパン-1-オンの粗精製物（2.02 g）を得た。 Production Example 21
Pyridinium bromide perbromide (1.45 g) was added to a solution of 1- [4- (hydroxymethyl) phenyl] propan-1-one (710 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1.5 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (2.02 g) of 2-bromo-1- [4- (hydroxymethyl) phenyl] propan-1-one.
製造例２２
　１Ｍリチウムヘキサメチルジシラジドのテトラヒドロフラン溶液（30mL）をテトラヒドロフラン(45mL)に加え、1,4-ジオキサスピロ[4.5]デシ-8-イル酢酸エチル(6.55g)のテトラヒドロフラン（20mL）溶液を-78℃にて加えた。同温で50分間攪拌後、ギ酸メチル（3.5mL）を加えた。同温で10分間攪拌後、室温で3時間攪拌した。氷冷後1M 塩酸及び飽和食塩水を加え、クロロホルムにて抽出した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、2-(1,4-ジオキサスピロ[4.5]デシ-8-イル)-3-ヒドロキシアクリル酸エチルを得た。得られた2-(1,4-ジオキサスピロ[4.5]デシ-8-イル)-3-ヒドロキシアクリル酸エチルのエタノール(60mL)溶液にメチルヒドラジン（3.0mL）を加え、100℃で3時間攪拌した。放冷後減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、4-(1,4-ジオキサスピロ[4.5]デシ-8-イル)-1-メチル-1H-ピラゾール-3-オールを位置異性体混合物（2.91g）として得た。 Production Example 22
Add 1M lithium hexamethyldisilazide in tetrahydrofuran (30mL) to tetrahydrofuran (45mL) and add 1,4-dioxaspiro [4.5] dec-8-yl ethyl acetate (6.55g) in tetrahydrofuran (20mL) at -78 ° C. Added at. After stirring at the same temperature for 50 minutes, methyl formate (3.5 mL) was added. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 3 hours. After ice cooling, 1M hydrochloric acid and saturated brine were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain ethyl 2- (1,4-dioxaspiro [4.5] dec-8-yl) -3-hydroxyacrylate. Methylhydrazine (3.0 mL) was added to a solution of the obtained ethyl 2- (1,4-dioxaspiro [4.5] dec-8-yl) -3-hydroxyacrylate in ethanol (60 mL), and the mixture was stirred at 100 ° C. for 3 hours. . The mixture was allowed to cool and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 4- (1,4-dioxaspiro [4.5] dec-8-yl) -1-methyl-1H-pyrazole-3. -Ole was obtained as a mixture of regioisomers (2.91 g).
製造例２３
　氷冷下、5,6,7,8-テトラヒドロキノリン-2(1H)-オン(1.03 g)、トリエチルアミン(1.9 mL)の塩化メチレン(20 mL)溶液にトリフルオロメタンスルホン酸無水物(1.7 mL)を加え、同温にて1時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液で中和し、クロロホルムで抽出した。有機層を減圧濃縮し、5,6,7,8-テトラヒドロキノリン-2-イル トリフルオロメタンスルホネート(2.653 g)を得た。 Production Example 23
Under ice cooling, trifluoromethanesulfonic anhydride (1.7 mL) was added to a solution of 5,6,7,8-tetrahydroquinolin-2 (1H) -one (1.03 g) and triethylamine (1.9 mL) in methylene chloride (20 mL). And stirred at the same temperature for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (2.653 g).
製造例２４
　[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]メタノール(1.00g)のクロロホルム(30mL)溶液に二酸化マンガン(10.0g)を加え50℃で12時間攪拌した。反応液をセライト濾過し残渣を減圧濃縮し、1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-カルバルデヒド（576mg）を得た。 Production Example 24
Manganese dioxide (10.0 g) was added to a solution of [1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] methanol (1.00 g) in chloroform (30 mL) and stirred at 50 ° C. for 12 hours. . The reaction solution was filtered through Celite, and the residue was concentrated under reduced pressure to obtain 1-methyl-4- (pyridin-4-yl) -1H-pyrazole-3-carbaldehyde (576 mg).
製造例２５
　2-[4-(クロロメチル)フェニル]-3-メチルキノリン(1.78g)のアセトニトリル(120mL)溶液にトリフェニルホスフィン(2.62g)を加え、70℃で10時間攪拌した。反応液を減圧濃縮し残渣をジエチルエーテルで洗浄し、塩化[4-(3-メチルキノリン-2-イル)ベンジル]トリフェニルホスホニウム（2.66g）を得た。 Production Example 25
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).
製造例２６
　1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-カルバルデヒド（576mg）のテトラヒドロフラン(20mL)溶液に塩化[4-(3-メチルキノリン-2-イル)ベンジル]トリフェニルホスホニウム(1.63g)、ジアザビシクロウンデセン(703mg)を加え室温で48時間攪拌した。反応液を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製し、3-メチル-2-(4-{2-[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]ビニル}フェニル)キノリン（967mg）を得た。 Production Example 26
[4- (3-Methylquinolin-2-yl) benzyl] triphenyl chloride in a solution of 1-methyl-4- (pyridin-4-yl) -1H-pyrazole-3-carbaldehyde (576 mg) in tetrahydrofuran (20 mL) Phosphonium (1.63 g) and diazabicycloundecene (703 mg) were added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give 3-methyl-2- (4- {2- [1-methyl-4- (pyridin-4-yl) -1H -Pyrazol-3-yl] vinyl} phenyl) quinoline (967 mg) was obtained.
製造例２７
　1-ブロモ-3-フルオロ-2-ニトロベンゼン(1.00 g)、炭酸カリウム(942 mg)のN,N-ジメチルホルムアミド(3 mL)混合液に9.8 Mメチルアミンのメタノール溶液(2.3 mL)を加え、室温で3時間攪拌した。反応液に酢酸エチルを加え、有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後減圧濃縮し、3-ブロモ-N-メチル-2-ニトロアニリン(1.05 g)を得た。 Production Example 27
To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.00 g) and potassium carbonate (942 mg) in N, N-dimethylformamide (3 mL) was added 9.8 M methylamine in methanol (2.3 mL), Stir at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and concentrated under reduced pressure to give 3-bromo-N-methyl-2-nitroaniline (1.05 g).
製造例２８
　3-ブロモ-N-メチル-2-ニトロアニリン(1.05 g)、エタノール(8 mL)、及び水(2 mL)の混合物に塩化アンモニウム(122 mg)、鉄(1.27 g)を加え、2時間加熱還流した。放冷後、クロロホルム、水を加え、セライト濾過をした。濾液をクロロホルムで抽出し、有機層を減圧濃縮し、2-アミノ-3-ブロモ-N-メチルアニリン(914 mg)を得た。 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).
製造例２９
　2-アミノ-3-ブロモ-N-メチルアニリン(914 mg)、オルトギ酸トリエチル(1.9 mL)のテトラヒドロフラン(10 mL)溶液にパラトルエンスルホン酸一水和物(86 mg)を加え、1時間加熱還流した。放冷後、反応液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)にて精製し、4-ブロモ-1-メチル-1H-ベンズイミダゾール（826 mg）を得た。 Production Example 29
Add 2-toluenesulfonic acid monohydrate (86 mg) to a solution of 2-amino-3-bromo-N-methylaniline (914 mg) and triethyl orthoformate (1.9 mL) in tetrahydrofuran (10 mL) and heat for 1 hour. Refluxed. After allowing to cool, ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 4-bromo-1-methyl-1H-benzimidazole (826 mg).
製造例３０
　5-(3-ヒドロキシ-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン(285mg)、酸化白金(50mg)、及び酢酸(10mL)の混合物を水素雰囲気下、室温、3気圧にて15時間撹拌した。反応液をセライト濾過し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、5-(3-ヒドロキシ-1-メチル-1H-ピラゾール-4-イル)-1-メチルピペリジン-2(1H)-オン（193mg）を得た。 Production Example 30
A mixture of 5- (3-hydroxy-1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one (285 mg), platinum oxide (50 mg), and acetic acid (10 mL) was hydrogenated. The mixture was stirred at room temperature and 3 atm for 15 hours under atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform), and 5- (3-hydroxy-1-methyl-1H-pyrazol-4-yl) -1-methylpiperidin-2 (1H) -one (193 mg) Got.
製造例３１
　5-ブロモ-2(1H)-ピリドン(2.0g)、炭酸セシウム(11.24g)、2-クロロ-N,N-ジメチルエタンアミン塩酸塩(2.06g)、及びN,N-ジメチルホルムアミド(40mL)の混合物を60℃で20時間攪拌した。反応液に水と酢酸エチルを加え、有機層を飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、5-ブロモ-1-[2-(ジメチルアミノ)エチル]ピリジン-2(1H)-オン（1.63g）を得た。 Production Example 31
5-Bromo-2 (1H) -pyridone (2.0 g), cesium carbonate (11.24 g), 2-chloro-N, N-dimethylethanamine hydrochloride (2.06 g), and N, N-dimethylformamide (40 mL) The mixture was stirred at 60 ° C. for 20 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to obtain 5-bromo-1- [2- (dimethylamino) ethyl] pyridin-2 (1H) -one (1.63 g).
製造例３２
　(1-メチル-1H-ピラゾール-3-イル)メタノール(4.00g)、4-(3-メチルキノリン-2-イル)フェノール(8.53g)、シアノメチレントリブチルホスホラン(13.1g)、トルエン(120mL)の混合物を100℃で8時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた3-メチル-2-{4-[(1-メチル-1H-ピラゾール-3-イル)メトキシ]フェニル}キノリンにアセトニトリル(250mL)、硝酸セリウムアンモニウム(16.0g)、ヨウ素（14.9g）を加え室温で45分間攪拌した。反応液を減圧濃縮し、残渣にクロロホルムを加え飽和チオ硫酸ナトリウム水溶液で洗浄した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製した。得られた固体を酢酸エチル-ヘキサン洗浄して2-{4-[(4-ヨード-1-メチル-1H-ピラゾール-3-イル)メトキシ]フェニル}-3-メチルキノリン（10.63g）を得た。 Production Example 32
(1-Methyl-1H-pyrazol-3-yl) methanol (4.00 g), 4- (3-methylquinolin-2-yl) phenol (8.53 g), cyanomethylenetributylphosphorane (13.1 g), toluene (120 mL ) Was 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). The resulting 3-methyl-2- {4-[(1-methyl-1H-pyrazol-3-yl) methoxy] phenyl} quinoline was mixed with acetonitrile (250 mL), ceric ammonium nitrate (16.0 g), iodine (14.9 g) And stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure, chloroform was added to the residue, and the mixture was washed with a saturated aqueous sodium thiosulfate solution. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained solid was washed with ethyl acetate-hexane to give 2- {4-[(4-iodo-1-methyl-1H-pyrazol-3-yl) methoxy] phenyl} -3-methylquinoline (10.63 g). It was.
製造例３３
　塩化銅(II)(795 mg)及び水(10 mL)の混合物に(2-メトキシキノリン-3-イル)ボロン酸(300 mg)のメタノール(10 mL)溶液を加え、90℃で1時間攪拌した。放冷後、酢酸エチルと水を加え、有機層を飽和食塩水で洗浄した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/ヘキサン)にて精製し、3-クロロ-2-メトキシキノリン（246 mg）を得た。 Production Example 33
Add a solution of (2-methoxyquinolin-3-yl) boronic acid (300 mg) in methanol (10 mL) to a mixture of copper (II) chloride (795 mg) and water (10 mL), and stir at 90 ° C. for 1 hour. did. After allowing to cool, ethyl acetate and water were added, and the organic layer was washed with saturated brine. The residue was purified by silica gel column chromatography (chloroform / hexane) to obtain 3-chloro-2-methoxyquinoline (246 mg).
製造例３４
　6-[4-(ヒドロキシメチル)フェニル]ニコチン酸(2.91g)のメタノール(50mL)混合物に氷冷下、硫酸(2.04mL)を加え60℃で96時間攪拌した。反応液を氷水に加え、炭酸水素ナトリウムで中和し酢酸エチルで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、6-[4-(ヒドロキシメチル)フェニル]ニコチン酸メチル（1.72g）を得た。 Production Example 34
To a mixture of 6- [4- (hydroxymethyl) phenyl] nicotinic acid (2.91 g) in methanol (50 mL) was added sulfuric acid (2.04 mL) under ice cooling, and the mixture was stirred at 60 ° C. for 96 hours. The reaction mixture was added to ice water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to obtain methyl 6- [4- (hydroxymethyl) phenyl] nicotinate (1.72 g).
製造例３５
　3-クロロ-2-メトキシキノリン(804 mg)のアセトニトリル(20 mL)溶液にヨウ化ナトリウム(1.56 g)、トリメチルクロロシラン(1.3 mL)を加え、50℃で1時間攪拌した。放冷後、飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)にて精製し、3-クロロキノリン-2-オール（603 mg）を得た。 Production Example 35
Sodium iodide (1.56 g) and trimethylchlorosilane (1.3 mL) were added to a solution of 3-chloro-2-methoxyquinoline (804 mg) in acetonitrile (20 mL), and the mixture was stirred at 50 ° C. for 1 hour. After allowing to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 3-chloroquinolin-2-ol (603 mg).
製造例３６
　3-(ベンジルオキシ)-1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)-1H-ピラゾール(4.66g)、5-ブロモ-1-メチルピリジン-2(1H)-オン(3.37g)、1,1'-ビス(ジフェニルホスフィノ)フェロセン-パラジウムジクロリド-塩化メチレン錯体(723mg)、炭酸ナトリウム(4.72g)、N,N-ジメチルホルムアミド(56mL)、及び水(11mL)の混合物をアルゴン雰囲気下、100℃で1時間攪拌した。反応液に酢酸エチル及び水を加え、生じた不溶物をセライトにて濾別した。有機層を飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、5-[3-(ベンジルオキシ)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン（2.57g）を得た。 Production Example 36
3- (Benzyloxy) -1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H-pyrazole (4.66 g), 5-bromo- 1-methylpyridin-2 (1H) -one (3.37 g), 1,1'-bis (diphenylphosphino) ferrocene-palladium dichloride-methylene chloride complex (723 mg), sodium carbonate (4.72 g), N, N- A mixture of dimethylformamide (56 mL) and water (11 mL) was stirred at 100 ° C. for 1 hour under an argon atmosphere. Ethyl acetate and water were added to the reaction mixture, and the resulting insoluble material was filtered off through celite. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform), and 5- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] -1-methylpyridin-2 (1H) -one (2.57 g) was obtained.
製造例３７
　2-クロロキノリン-3-オール(1.27 g)、炭酸カリウム(2.44 g)のN,N-ジメチルホルムアミド(20 mL)混合液にヨウ化メチル(0.485mL)を加え、室温で15分攪拌した。酢酸エチルを加え飽和食塩水で洗浄した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)にて精製し、2-クロロ-3-メトキシキノリン(1.28 g)を得た。 Production Example 37
Methyl iodide (0.485 mL) was added to a mixture of 2-chloroquinolin-3-ol (1.27 g) and potassium carbonate (2.44 g) in N, N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 15 minutes. Ethyl acetate was added and washed with saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2-chloro-3-methoxyquinoline (1.28 g).
製造例３８
　5-[3-(ベンジルオキシ)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン(2.57g)、20%水酸化パラジウム(350mg)、及びエタノール(40mL)の混合物を水素雰囲気下、室温、3気圧にて終夜撹拌した。反応液をセライトを用いて濾過した。濾液を減圧濃縮し、5-(3-ヒドロキシ-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン（1.49g）を得た。 Production Example 38
5- [3- (Benzyloxy) -1-methyl-1H-pyrazol-4-yl] -1-methylpyridin-2 (1H) -one (2.57 g), 20% palladium hydroxide (350 mg), and ethanol (40 mL) was stirred in a hydrogen atmosphere at room temperature and 3 atm overnight. The reaction was filtered using celite. The filtrate was concentrated under reduced pressure to give 5- (3-hydroxy-1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one (1.49 g).
製造例３９
　アルゴン雰囲気下、3-(ベンジロキシ)-4-ヨード-1-メチル-1H-ピラゾール(7g)、アクリル酸エチル(7.3mL)、酢酸パラジウム(250mg)、N,N-ジイソプロピルエチルアミン(19mL)、N,N-ジメチルホルムアミド(28mL)の混合物を、100℃にて24時間攪拌した。反応液を室温に戻してセライトろ過後、ろ液を水、飽和食塩水にて順次洗浄後、無水硫酸ナトリウムにて乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、(2E)-3-[3-(ベンジロキシ)-1-メチル-1H-ピラゾール-4-イル]アクリル酸エチル（5.217g）を得た。 Production Example 39
Under argon atmosphere, 3- (benzyloxy) -4-iodo-1-methyl-1H-pyrazole (7 g), ethyl acrylate (7.3 mL), palladium acetate (250 mg), N, N-diisopropylethylamine (19 mL), N , N-dimethylformamide (28 mL) was stirred at 100 ° C. for 24 hours. The reaction solution was returned to room temperature and filtered through celite. The filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate), and ethyl (2E) -3- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] acrylate (5.217 g) was obtained. Obtained.
製造例４０
　[4-(3-メチルキノリン-2-イル)フェニル]メタノール(12g)の塩化メチレン(200mL)懸濁液に塩化チオニル(10mL)を加え、室温で1時間攪拌した。反応液を減圧濃縮し、残渣に飽和重曹水を加えてクロロホルムで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄した。無水硫酸ナトリウムにて乾燥後減圧濃縮し、2-[4-(クロロメチル)フェニル]-3-メチルキノリン（13.345g）を得た。 Production Example 40
Thionyl chloride (10 mL) was added to a suspension of [4- (3-methylquinolin-2-yl) phenyl] methanol (12 g) in methylene chloride (200 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2- [4- (chloromethyl) phenyl] -3-methylquinoline (13.345 g).
製造例４１
　アルゴン雰囲気下、 (2E)-3-[3-(ベンジロキシ)-1-メチル-1H-ピラゾール-4-イル]アクリル酸エチル(2.6g)のテトラヒドロフラン(20mL)溶液にニトロメタン(2.5mL)、ジアザビシクロウンデセン(1.7mL)を加えて、60℃で17時間攪拌した。ニトロメタン(2.5mL)、ジアザビシクロウンデセン(1.7mL)を追加し、70℃で19時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、3-[3-(ベンジロキシ)-1-メチル-1H-ピラゾール-4-イル]-4-ニトロブタン酸エチル（2.266g）を得た。 Production Example 41
Under an argon atmosphere, a solution of ethyl (2E) -3- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] acrylate (2.6 g) in tetrahydrofuran (20 mL) was added with nitromethane (2.5 mL), dia Zabicycloundecene (1.7 mL) was added, and the mixture was stirred at 60 ° C. for 17 hours. Nitromethane (2.5 mL) and diazabicycloundecene (1.7 mL) were added, and the mixture was stirred at 70 ° C. for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 3- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] -4-nitrobutanoic acid. Ethyl (2.266 g) was obtained.
製造例４２
　3-[3-(ベンジロキシ)-1-メチル-1H-ピラゾール-4-イル]-4-ニトロブタン酸エチル(2.246g)、鉄(1.81g)、塩化アンモニウム(1.73g)、エタノール(19mL)、及び水(7.2mL)の混合物を90℃で6時間攪拌した。鉄(1.81g)、塩化アンモニウム(1.73 g)を追加し、90℃にて2時間攪拌した。セライトろ過後、減圧濃縮した。残渣にトリエチルアミン(2.7mL)、トルエン(100mL)を加え、5時間加熱還流した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製し、4-[3-(ベンジロキシ)-1-メチル-1H-ピラゾール-4-イル]ピロリジン-2-オン（1.41g）を得た。 Production Example 42
Ethyl 3- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] -4-nitrobutanoate (2.246 g), iron (1.81 g), ammonium chloride (1.73 g), ethanol (19 mL), And a mixture of water (7.2 mL) was stirred at 90 ° C. for 6 hours. Iron (1.81 g) and ammonium chloride (1.73 g) were added, and the mixture was stirred at 90 ° C. for 2 hr. After filtration through celite, the filtrate was concentrated under reduced pressure. 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.
製造例４３
　窒素気流下、テトラヒドロフラン(15mL)を氷冷し、水素化リチウムアルミニウム(325mg)を加えた。次いで、4-[3-(ベンジロキシ)-1-メチル-1H-ピラゾール-4-イル]ピロリジン-2-オン(1.161g)のテトラヒドロフラン(8mL)溶液を加え、50℃にて10時間攪拌した。反応液を氷冷後、硫酸ナトリウム10水和物を加え撹拌した。セライトろ過後、ろ液にジ-tert-ブチルジカーボネート(1.12g)のテトラヒドロフラン溶液を加え、室温で4時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、tert-ブチル3-[3-(ベンジロキシ)-1-メチル-1H-ピラゾール-4-イル]ピロリジン-1-カルボキシラート（1.08g）を得た。 Production Example 43
Under a nitrogen stream, tetrahydrofuran (15 mL) was ice-cooled, and lithium aluminum hydride (325 mg) was added. Next, a solution of 4- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] pyrrolidin-2-one (1.161 g) in tetrahydrofuran (8 mL) was added and stirred at 50 ° C. for 10 hours. The reaction mixture was ice-cooled, sodium sulfate decahydrate was added and stirred. After filtration through Celite, a tetrahydrofuran solution of di-tert-butyl dicarbonate (1.12 g) was added to the filtrate, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate), and tert-butyl 3- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] pyrrolidine- 1-carboxylate (1.08 g) was obtained.
製造例４４
　1-メチル-4-ピリジン-4-イル-1H-ピラゾール-3-オール(1.00g)に(4-ブロモフェニル)メタノール(1.60g)、テトラヒドロフラン(100mL)、1,1'-(アゾジカルボニル)ジピペリジン(2.88g)、トリ-n-ブチルホスフィン(2.31g)を加え室温で12時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物をヘキサンで洗浄し、4-{3-[(4-ブロモベンジル)オキシ]-1-メチル-1H-ピラゾール-4-イル}ピリジン（1.26g）を得た。 Production Example 44
1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (1.00 g) to (4-bromophenyl) methanol (1.60 g), tetrahydrofuran (100 mL), 1,1 ′-(azodicarbonyl ) Dipiperidine (2.88 g) and tri-n-butylphosphine (2.31 g) were added, 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). The obtained crude product was washed with hexane to obtain 4- {3-[(4-bromobenzyl) oxy] -1-methyl-1H-pyrazol-4-yl} pyridine (1.26 g).
製造例４５
　4-ブロモ-2,5-ジメチル-2H-1,2,3-トリアゾール（545mg）の四塩化炭素(10mL)溶液にN-ブロモスクシイミド（606mg）及び2,2'-アゾビス(イソブチロニトリル)（51mg）を加え、90℃で19時間攪拌した。沈殿物をろ別して減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し4-ブロモ-5-(ブロモメチル)-2-メチル-2H-1,2,3-トリアゾール（185mg）を得た。 Production Example 45
4-Bromo-2,5-dimethyl-2H-1,2,3-triazole (545 mg) in carbon tetrachloride (10 mL) was added to N-bromosuccinimide (606 mg) and 2,2'-azobis (isobutyrate). (Nitrile) (51 mg) was added, and the mixture was stirred at 90 ° C. for 19 hours. The precipitate was filtered off and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 4-bromo-5- (bromomethyl) -2-methyl-2H-1,2,3-triazole (185 mg). )
製造例４６
　2-アミノピリジン(4.82g)、p-トルニトリル(5.00g)、臭化銅（I）(306mg)、ヨウ化亜鉛(681mg)、1,10-フェナンスロリン(770mg)、及びトルエン(100mL)の混合物を110℃で24時間攪拌した。反応液を減圧濃縮し残渣を酢酸エチルで希釈してセライト濾過した。濾液を水洗し、有機層を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製して2-(4-メチルフェニル)[1,2,4]トリアゾロ[1,5-a]ピリジン（1.00g）を得た。 Production Example 46
2-aminopyridine (4.82g), p-tolunitrile (5.00g), copper (I) bromide (306mg), zinc iodide (681mg), 1,10-phenanthroline (770mg), and toluene (100mL) The mixture was stirred at 110 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2- (4-methylphenyl) [1,2,4] triazolo [1,5- a] Pyridine (1.00 g) was obtained.
製造例４７
　2-フルオロ-4-(3-メチルキノリン-2-イル)安息香酸メチル(700mg)のジメチルスルホキシド(5.0mL)溶液に、室温にてモルホリン(0.25mL)、ジイソプロピルエチルアミン(0.61mL)を滴下し、80℃で15時間撹拌した。更にモルホリン(0.5mL)、ジイソプロピルエチルアミン(1.2mL)を追加し、100℃で48時間撹拌した。水を加え酢酸エチルで抽出した。有機層を分離した後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製して、4-(3-メチルキノリン-2-イル)-2-(モルホリン-4-イル)安息香酸メチル（467mg）を得た。 Production Example 47
To a solution of methyl 2-fluoro-4- (3-methylquinolin-2-yl) benzoate (700 mg) in dimethyl sulfoxide (5.0 mL), morpholine (0.25 mL) and diisopropylethylamine (0.61 mL) are added dropwise at room temperature. And stirred at 80 ° C. for 15 hours. Morpholine (0.5 mL) and diisopropylethylamine (1.2 mL) were further added, and the mixture was stirred at 100 ° C. for 48 hours. Water was added and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 4- (3-methylquinolin-2-yl) -2- (morpholin-4-yl) benzoate ( 467 mg).
製造例４８
　氷冷下、1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-カルボン酸メチル(812mg)のテトラヒドロフラン(20mL)混合物に水素化ホウ素リチウム(143mg)、エタノール(0.57mL)を加え2時間加熱還流した。反応液を放冷し、1M塩酸(10mL)を加えた。反応を飽和炭酸水素ナトリウム水溶液で中和し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、5-[3-(ヒドロキシメチル)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン（205mg）を得た。 Production Example 48
Under ice cooling, hydrogen was added to a mixture of methyl 1-methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H-pyrazole-3-carboxylate (812 mg) in tetrahydrofuran (20 mL). Lithium borohydride (143 mg) and ethanol (0.57 mL) were added, and the mixture was heated to reflux for 2 hours. The reaction was allowed to cool and 1M hydrochloric acid (10 mL) was added. The reaction was neutralized with saturated aqueous sodium hydrogen carbonate solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) and 5- [3- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl] -1-methylpyridin-2 (1H) -one (205 mg) was obtained.
製造例４９
　5-(3-メチルキノリン-2-イル)ピリジン-2-カルボン酸メチル(182mg)、テトラヒドロフラン(4.0mL)、及びメタノール(4.0mL)の混合物に、室温で1M水酸化ナトリウム水溶液(1.5mL)を加え、同温で7時間撹拌した。氷冷下、1M塩酸(1.5mL)で中和した後、減圧濃縮した。残渣に水を加えて析出した固体をろ取した。得られた固体にテトラヒドロフラン(5.0m)を加え、氷冷下、カルボニルジイミダゾール(130mg)を加えて攪拌した後、室温で2時間攪拌した。氷冷下、水素化ホウ素ナトリウム(60mg)の水溶液(0.5mL)を滴下し、同温で15分攪拌した後、室温で一晩攪拌した。反応溶液に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、[5-(3-メチルキノリン-2-イル)ピリジン-2-イル]メタノール（70mg）を得た。 Production Example 49
To a mixture of methyl 5- (3-methylquinolin-2-yl) pyridine-2-carboxylate (182 mg), tetrahydrofuran (4.0 mL), and methanol (4.0 mL), 1 M aqueous sodium hydroxide solution (1.5 mL) at room temperature And stirred at the same temperature for 7 hours. The mixture was neutralized with 1M hydrochloric acid (1.5 mL) under ice cooling, and concentrated under reduced pressure. Water was added to the residue and the precipitated solid was collected by filtration. 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).
製造例５０
　N,N-ジメチルホルムアミド(1.4mL)に氷冷下でオキシ塩化リン(3.3mL)を加え、同温で30分間攪拌した。混合物にN-(4-フルオロフェニル)プロパンアミド(2g)、ヘキサデシルトリメチルアンモニウムブロミド(436mg)、及びアセトニトリル(20mL)を加え、80℃で8時間攪拌後、100℃で4時間撹拌した。反応液を減圧濃縮し、残渣を氷に注ぎ撹拌後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、2-クロロ-6-フルオロ-3-メチルキノリン（558mg）を得た。 Production Example 50
Phosphorous oxychloride (3.3 mL) was added to N, N-dimethylformamide (1.4 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. N- (4-Fluorophenyl) propanamide (2 g), hexadecyltrimethylammonium bromide (436 mg), and acetonitrile (20 mL) were added to the mixture, and the mixture was stirred at 80 ° C. for 8 hours and then at 100 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into ice and stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-chloro-6-fluoro-3-methylquinoline (558 mg).
製造例５１
　氷冷下、(1,5-ジメチル-1H-ピラゾール-3-イル)メタノール(2.0g)に塩化メチレン(100mL)、塩化チオニル(3.6mL)を加え、室温にて2時間攪拌した。反応液を減圧濃縮し、残渣を減圧乾燥した。N,N-ジメチルホルムアミド(180mL)、4-(3-メチルキノリン-2-イル)フェノール (3.53g)、及び炭酸カリウム(5.18g)を加え70℃で8時間攪拌した。反応液を減圧濃縮し残渣に水を加えて、酢酸エチルで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、2-{4-[(1,5-ジメチル-1H-ピラゾール-3-イル)メトキシ]フェニル}-3-メチルキノリン（5.05g）を得た。 Production Example 51
Under ice cooling, methylene chloride (100 mL) and thionyl chloride (3.6 mL) were added to (1,5-dimethyl-1H-pyrazol-3-yl) methanol (2.0 g), and the mixture was 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 (180 mL), 4- (3-methylquinolin-2-yl) phenol (3.53 g), and potassium carbonate (5.18 g) were added, and the mixture was stirred at 70 ° C. for 8 hr. 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) to give 2- {4-[(1,5-dimethyl-1H-pyrazol-3-yl) methoxy] phenyl} -3- Methyl quinoline (5.05 g) was obtained.
製造例５２
　3-ブロモ-1-N-メチルベンゼン-1,2-ジアミン(970mg)の4M塩酸(3.0mL)混合物に、室温で酢酸(0.35mL)を加え、120℃で18時間攪拌した。氷冷下、飽和炭酸水素ナトリウム水溶液で中和し、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、4-ブロモ-1,2-ジメチル-1H-ベンズイミダゾール（549mg）を得た。 Production Example 52
Acetic acid (0.35 mL) was added to a 4M hydrochloric acid (3.0 mL) mixture of 3-bromo-1-N-methylbenzene-1,2-diamine (970 mg) at room temperature, and the mixture was stirred at 120 ° C. for 18 hours. Under ice-cooling, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to obtain 4-bromo-1,2-dimethyl-1H-benzimidazole (549 mg).
製造例５３
　氷冷下、6-[4-(ヒドロキシメチル)フェニル]ニコチン酸メチル(1.72g)に塩化メチレン(60mL)、塩化チオニル(1.56mL)を加え、室温にて2時間攪拌した。反応液を減圧濃縮し、残渣を減圧乾燥した。得られた固体にN,N-ジメチルホルムアミド(50mL)、5-(3-ヒドロキシ-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン(1.00g)、炭酸カリウム(1.68g)を加え70℃で8時間攪拌した。反応液を減圧濃縮し残渣に水を加えて、メタノール及びクロロホルムの混合溶媒（１：１０）で抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物を酢酸エチル及びヘキサンで順次洗浄し、6-[4-({[1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]ニコチン酸メチル（1.48g）を得た。 Production Example 53
Under ice cooling, methylene chloride (60 mL) and thionyl chloride (1.56 mL) were added to methyl 6- [4- (hydroxymethyl) phenyl] nicotinate (1.72 g), and the mixture was 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 (50 mL), 5- (3-hydroxy-1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one (1.00 g) was added to the obtained solid. Potassium carbonate (1.68 g) was 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 a mixed solvent of methanol and chloroform (1:10). 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 washed successively with ethyl acetate and hexane to give 6- [4-({[1-methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)- 1H-pyrazol-3-yl] oxy} methyl) phenyl] methyl nicotinate (1.48 g) was obtained.
製造例５４
　3,4-ジフルオロアニリン(6.46g)、炭酸カリウム(6.91g)、及び塩化メチレン(200mL)の混合物に-15℃で臭素(7.99g)の塩化メチレン(50mL)溶液を加え、同温で15分間攪拌した。反応液を氷水に加えクロロホルムで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、2-ブロモ-4,5-ジフルオロアニリン(9.84g)を得た。 Production Example 54
To a mixture of 3,4-difluoroaniline (6.46 g), potassium carbonate (6.91 g), and methylene chloride (200 mL) was added a solution of bromine (7.99 g) in methylene chloride (50 mL) at −15 ° C. Stir for minutes. The reaction solution was added to ice water and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 2-bromo-4,5-difluoroaniline (9.84 g).
製造例５５
　(5-ブロモピリジン-2-イル)メタノール(2.77g)、ルチジン(4.7mL)、及びテトラヒドロフラン(30mL)の混合物にトリイソプロピルシリルトリフレート(2.0mL)を加え、室温で1時間撹拌した。反応液に水及び酢酸エチルを加え、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、5-ブロモ-2-{[(トリイソプロピルシリル)オキシ]メチル}ピリジン（3.61g）を得た。 Production Example 55
Triisopropylsilyl triflate (2.0 mL) was added to a mixture of (5-bromopyridin-2-yl) methanol (2.77 g), lutidine (4.7 mL), and tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate / hexane) to obtain 5-bromo-2-{[(triisopropylsilyl) oxy] methyl} pyridine (3.61 g).
製造例５６
　1-メチル-4-(6-{[(トリイソプロピルシリル)オキシ]メチル}ピリジン-3-イル)-1H-ベンズイミダゾール(2.37g)のテトラヒドロフラン(20mL)溶液にテトラブチルアンモニウムフルオリド(9.0mL)を加え、室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、[5-(1-メチル-1H-ベンズイミダゾール-4-イル)ピリジン-2-イル]メタノール（0.974g）を得た。 Production Example 56
To a solution of 1-methyl-4- (6-{[(triisopropylsilyl) oxy] methyl} pyridin-3-yl) -1H-benzimidazole (2.37 g) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (9.0 mL). ) Was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give [5- (1-methyl-1H-benzimidazol-4-yl) pyridin-2-yl] methanol (0.974 g). )
製造例５７
　アルゴン雰囲気下、2-ブロモ-4,5-ジメトキシアニリン(4.73g)、メタクリル酸メチル(6.5mL)、酢酸パラジウム(229mg)、トリス（2-メチルフェニル）ホスフィン(620mg)、N,N-ジイソプロピルエチルアミン(11mL)、及びN,N-ジメチルホルムアミド(50mL)の混合物を100℃で48時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後減圧濃縮した。残渣に6M塩酸(70mL)を加え、100℃にて1時間攪拌した。反応液を氷冷し、析出した固体をろ取、減圧乾燥し、6,7-ジメトキシ-3-メチルキノリン-2(1H)-オン（0.85g）を得た。 Production Example 57
Under an argon atmosphere, 2-bromo-4,5-dimethoxyaniline (4.73 g), methyl methacrylate (6.5 mL), palladium acetate (229 mg), tris (2-methylphenyl) phosphine (620 mg), N, N-diisopropyl A mixture of ethylamine (11 mL) and N, N-dimethylformamide (50 mL) was stirred at 100 ° C. for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 6M hydrochloric acid (70 mL) was added to the residue, and the mixture was stirred at 100 ° C. for 1 hr. The reaction mixture was ice-cooled, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 6,7-dimethoxy-3-methylquinolin-2 (1H) -one (0.85 g).
製造例５８
　6,7-ジメトキシ-3-メチルキノリン-2(1H)-オン(840mg)に氷冷下、塩化ホスホリル(4mL)を加え100℃で1時間攪拌した。反応液を減圧濃縮し、残渣をクロロホルムで希釈後、氷に注いだ。飽和炭酸水素ナトリウム水溶液を加えクロロホルムで抽出後、有機層を飽和重曹水にて洗浄した。無水硫酸ナトリウムにて乾燥後減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、2-クロロ-6,7-ジメトキシ-3-メチルキノリン（569mg）を得た。 Production Example 58
Phosphoryl chloride (4 mL) was added to 6,7-dimethoxy-3-methylquinolin-2 (1H) -one (840 mg) under ice cooling, and the mixture was stirred at 100 ° C. for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with chloroform and poured into ice. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 2-chloro-6,7-dimethoxy-3-methylquinoline (569 mg).
製造例５９
　1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-オール(5g)のメタノール(250mL)溶液に75%のm-クロロ過安息香酸(8.53g)を加え、室温で24時間撹拌した。反応液にチオ硫酸ナトリウム(2.25g)を水(25mL)に溶解させて加え、室温で5分間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製し、1-メチル-4-(1-オキシドピリジン-4-イル)-1H-ピラゾール-3-オール（3.957g）を得た。 Production Example 59
To a solution of 1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-ol (5 g) in methanol (250 mL) was added 75% m-chloroperbenzoic acid (8.53 g) and 24 hours at room temperature. Stir for hours. Sodium thiosulfate (2.25 g) was added to the reaction solution dissolved in water (25 mL), and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give 1-methyl-4- (1-oxidepyridin-4-yl) -1H-pyrazol-3-ol (3.957 g )
製造例６０
　4-ヨード-1-メチル-1H-ピラゾール-3-カルボン酸メチル(9.00g)、1-メチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン-2(1H)-オン(11.9g)、N,N-ジメチルホルムアミド(240mL)、及び水(72mL)に炭酸セシウム(22.0g)、テトラキストリフェニルホスフィンパラジウム(3.65g)を加え、80℃で9時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-カルボン酸メチル(8.24g)を得た。 Production Example 60
4-Iodo-1-methyl-1H-pyrazole-3-carboxylate methyl (9.00 g), 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) pyridin-2 (1H) -one (11.9 g), N, N-dimethylformamide (240 mL), and water (72 mL) were added cesium carbonate (22.0 g), tetrakistriphenylphosphine palladium (3.65 g), The mixture was stirred at 80 ° C. for 9 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give 1-methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H. -Methyl pyrazole-3-carboxylate (8.24 g) was obtained.
製造例６１
　アルゴン雰囲気下、4-ブロモ-1-メチル-1H-ベンズイミダゾール（920mg）、アクリル酸エチル（1.4mL）、ビス（トリ-tert-ブチルホスフィン）パラジウム（111mg）、N,N-ジシクロヘキシルメチルアミン（936mg）、及びジオキサン (4.6mL)の混合物を、100℃にて12時間撹拌した。ビス（トリ-tert-ブチルホスフィン）パラジウム（111mg）を追加し、100℃にて3時間撹拌した。減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、 (2E)-3-(1-メチル-1H-ベンズイミダゾール-4-イル)アクリル酸エチル(600mg)を得た。 Production Example 61
Under an argon atmosphere, 4-bromo-1-methyl-1H-benzimidazole (920 mg), ethyl acrylate (1.4 mL), bis (tri-tert-butylphosphine) palladium (111 mg), N, N-dicyclohexylmethylamine ( 936 mg) and dioxane (4.6 mL) were stirred at 100 ° C. for 12 hours. Bis (tri-tert-butylphosphine) palladium (111 mg) was added, and the mixture was stirred at 100 ° C. for 3 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain ethyl (2E) -3- (1-methyl-1H-benzimidazol-4-yl) acrylate (600 mg). .
製造例６２
　アルゴン雰囲気下、 (2E)-3-(1-メチル-1H-ベンズイミダゾール-4-イル)アクリル酸エチル（568mg）のテトラヒドロフラン（12mL）溶液に-50℃で1.01Mの水素化ジイソブチルアルミニウムのトルエン溶液(7.4mL)を加えた。3時間かけて-30℃に昇温後、飽和ロッシェル塩水溶液と酢酸エチルを加え、しばらく撹拌した。酢酸エチルで抽出後、有機層を無水硫酸ナトリウムにて乾燥、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール)にて精製し、(2E)-3-(1-メチル-1H-ベンズイミダゾール-4-イル)プロプ-2-エン-1-オール（241 mg）を得た。 Production Example 62
(2E) -3- (1-Methyl-1H-benzimidazol-4-yl) ethyl acrylate (568mg) in tetrahydrofuran (12mL) in tetrahydrofuran (12mL) at -50 ° C with 1.01M diisobutylaluminum hydride in toluene Solution (7.4 mL) was added. After raising the temperature to −30 ° C. over 3 hours, a saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred for a while. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give (2E) -3- (1-methyl-1H-benzimidazol-4-yl) prop-2-en-1-ol (241 mg). Obtained.
製造例６３
　アルゴン雰囲気下、3-(ベンジルオキシ)-1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール（2g）、4-クロロ-3-フルオロピリジン（925mg）、トリス(ジベンジリデンアセトン)ジパラジウム（290mg）、トリシクロヘキシルホスフィン（215mg）、リン酸カリウム（4.06g）、ジオキサン（30mL）、及び水（15mL）の混合物を、100℃にて5時間撹拌した。反応液を室温に戻した後、酢酸エチルを加え、飽和食塩水にて洗浄した。有機層を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル)にて精製し、4-[3-(ベンジルオキシ)-1-メチル-1H-ピラゾール-4-イル]-3-フルオロピリジン(830 mg)を得た。 Production Example 63
Under argon atmosphere, 3- (benzyloxy) -1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (2 g), 4 -Chloro-3-fluoropyridine (925 mg), tris (dibenzylideneacetone) dipalladium (290 mg), tricyclohexylphosphine (215 mg), potassium phosphate (4.06 g), dioxane (30 mL), and water (15 mL) Was stirred at 100 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] -3-fluoro. Pyridine (830 mg) was obtained.
製造例６４
　4-[3-(ベンジルオキシ)-1-メチル-1H-ピラゾール-4-イル]-3-フルオロピリジン（820mg）、ペンタメチルベンゼン（858mg）、及びトリフルオロ酢酸（4.5mL）の混合物を室温にて12時間撹拌した。酢酸エチルを加え、固体をろ取、減圧乾燥し、4-(3-フルオロピリジン-4-イル)-1-メチル-1H-ピラゾール-3-オール トリフルオロ酢酸塩(713 mg)を得た。 Production Example 64
A mixture of 4- [3- (benzyloxy) -1-methyl-1H-pyrazol-4-yl] -3-fluoropyridine (820 mg), pentamethylbenzene (858 mg), and trifluoroacetic acid (4.5 mL) at room temperature For 12 hours. Ethyl acetate was added, and the solid was collected by filtration and dried under reduced pressure to give 4- (3-fluoropyridin-4-yl) -1-methyl-1H-pyrazol-3-ol trifluoroacetate (713 mg).
製造例６５
　(4-ヨード-1-メチル-1H-ピラゾール-3-イル)メタノール（1.284g）、イミダゾール（1.06g）、N,N-ジメチルホルムアミド（13mL）の混合物にtert-ブチルジメチルクロロシラン（1g）を加えて室温にて1時間撹拌した。水を加えて酢酸エチルにて抽出した。有機層を水、飽和食塩水にて順次洗浄後、無水硫酸ナトリウムにて乾燥、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製し、3-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-4-ヨード-1-メチル-1H-ピラゾール(1.564 g)を得た。 Production Example 65
To a mixture of (4-iodo-1-methyl-1H-pyrazol-3-yl) methanol (1.284 g), imidazole (1.06 g) and N, N-dimethylformamide (13 mL), tert-butyldimethylchlorosilane (1 g) was added. In addition, the mixture was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate), and 3-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4-iodo-1-methyl-1H-pyrazole (1.564 g) Got.
製造例６６
　1-メチル-1H-ピラゾール-3-オール（9.92g）のN,N-ジメチルホルムアミド(120mL)溶液に炭酸カリウム(16.8g)、ベンジルブロミド(20.8g)を加え50℃で4時間加熱攪拌した。反応液を減圧濃縮し、残渣に水を加えて酢酸エチルで抽出した。有機相を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル-ヘキサン）で分離精製して3-(ベンジルオキシ)-1-メチル-1H-ピラゾール（13.8g）を得た。 Production Example 66
To a solution of 1-methyl-1H-pyrazol-3-ol (9.92 g) in N, N-dimethylformamide (120 mL) was added potassium carbonate (16.8 g) and benzyl bromide (20.8 g), and the mixture was heated and stirred at 50 ° C. for 4 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 phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 3- (benzyloxy) -1-methyl-1H-pyrazole (13.8 g).
製造例３７１
　1-メチル-1H-ベンゾトリアゾール-4-アミン（333mg）とアセトニトリル（8ml）の混合物に、臭化銅(II)（552mg）と亜硝酸アミル（319mg）を加え、室温で2時間攪拌した。反応液をセライト濾過し、酢酸エチルで洗浄後、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、4-ブロモ-1-メチル-1H-ベンゾトリアゾール（181mg）を得た。 Production Example 371
Copper (II) bromide (552 mg) and amyl nitrite (319 mg) were added to a mixture of 1-methyl-1H-benzotriazol-4-amine (333 mg) and acetonitrile (8 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-bromo-1-methyl-1H-benzotriazole (181 mg).
製造例３７２　8-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]イミダゾ[1,2-a]ピリジン（535mg）、炭酸水素ナトリウム（679mg）、N-ブロモコハク酸イミド（324mg）およびクロロホルム（10ml）の混合物を、室温で4時間攪拌した。反応液の飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）で精製し、3-ブロモ-8-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]イミダゾ[1,2-a]ピリジン（540mg）を得た。 Production Example 372 8- [4- (Tetrahydro-2H-pyran-2-yloxy) phenyl] imidazo [1,2-a] pyridine (535 mg), sodium bicarbonate (679 mg), N-bromosuccinimide (324 mg) and A mixture of chloroform (10 ml) was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 3-bromo-8- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] imidazo [1,2-a] pyridine (540 mg) Got.
製造例３８５
　4-メトキシ安息香酸(1.52g)、N-メチル-1,2-ベンゼンジアミン・塩酸塩(2.52g)、1-ヒドロキシベンゾトリアゾール(1.62g)、トリエチルアミン(3.48 mL)のN,N-ジメチルホルムアミド(50 ml)溶液に1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド・塩酸塩(2.30 g)を加え室温で12時間攪拌した。反応液に酢酸エチルを加え、有機相を水、飽和食塩水で洗浄後、減圧濃縮をした。得られた粗精製物を酢酸（46 mL）に溶解し、90℃で12時間加熱攪拌した。放冷後、反応液を減圧濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加えクロロホルムで抽出した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)で分離精製して2-(4-メトキシフェニル)-1-メチル-1H-ベンズイミダゾール(1.98 g)を得た。 Production Example 385
N, N-dimethylformamide of 4-methoxybenzoic acid (1.52 g), N-methyl-1,2-benzenediamine hydrochloride (2.52 g), 1-hydroxybenzotriazole (1.62 g), triethylamine (3.48 mL) 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.30 g) was added to the (50 ml) solution, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate was added to the reaction mixture, and the organic phase was washed with water and saturated brine, and concentrated under reduced pressure. 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).
製造例３８７
　3-ブロモ-N-1-メチルベンゼン-1,2-ジアミン二塩酸塩(350 mg)をトルエン(5.9 ml)に溶解し、室温にてトリフルオロ酢酸(2.9 ml)を加えて、80℃で6時間加熱撹拌した。反応溶液を放冷し、減圧下濃縮し、残渣をカラムクロマトグラフィー(ヘキサン/酢酸エチル)にて分離精製し、4-ブロモ-1-メチル-2-(トリフルオロメチル)-1H-ベンズイミダゾール(388 mg)を得た。 Production Example 387
3-Bromo-N-1-methylbenzene-1,2-diamine dihydrochloride (350 mg) is dissolved in toluene (5.9 ml), and trifluoroacetic acid (2.9 ml) is added at room temperature. The mixture was heated and stirred for 6 hours. The reaction solution was allowed to cool, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (hexane / ethyl acetate) to give 4-bromo-1-methyl-2- (trifluoromethyl) -1H-benzimidazole ( 388 mg) was obtained.
製造例３８９
　3-ブロモ-N-1-メチルベンゼン-1,2-ジアミン二塩酸塩(350 mg)のテトラヒドロフラン溶液(5.0 ml)に、氷冷下、ピリジン(0.36 ml)とメトキシアセチルクロリド(0.12 ml)を順に加え、室温で1時間撹拌した。反応溶液に1M塩酸 (2.0 ml)を加え、酢酸エチルで抽出した。分離した有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、濃縮して得られた残渣に、酢酸(3.5 ml)を加え、90℃で15時間撹拌した。室温に放冷後、反応溶液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（塩基性シリカゲル;酢酸エチル-ヘキサン=70:30→50:50）で分離精製して、4-ブロモ-2-(メトキシメチル)-1-メチル-1H-ベンズイミダゾール(165 mg)を得た。 Production Example 389
To a tetrahydrofuran solution (5.0 ml) of 3-bromo-N-1-methylbenzene-1,2-diamine dihydrochloride (350 mg), add pyridine (0.36 ml) and methoxyacetyl chloride (0.12 ml) under ice cooling. It added in order and stirred at room temperature for 1 hour. To the reaction solution was added 1M hydrochloric acid (2.0 ml), and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Acetic acid (3.5 ml) was added to the resulting residue, and the mixture was stirred at 90 ° C. for 15 hr. After cooling to room temperature, the reaction solution is concentrated, and the residue is separated and purified by silica gel column chromatography (basic silica gel; ethyl acetate-hexane = 70: 30 → 50: 50) to give 4-bromo-2- (methoxy Methyl) -1-methyl-1H-benzimidazole (165 mg) was obtained.
製造例３９１
　メタノール(1.2 ml)のテトラヒドロフラン溶液(12.0ml)に氷冷下、60%油性水素化ナトリウム(200 mg)を加えて、同温度にて15分間撹拌後、8-ブロモ-4-クロロキノリン(600 mg)を加えて室温に戻した後、80℃で2時間加熱撹拌した。氷冷下、反応液に酢酸(0.28 ml)を加えて中和した後、酢酸エチルと水を加えて有機層を分離した。分離した有機層を無水硫酸マグネシウムで乾燥後、濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）で精製して、8-ブロモ-4-メトキシキノリン(327mg)を得た。 Production Example 391
60% oily sodium hydride (200 mg) was added to a tetrahydrofuran solution (12.0 ml) of methanol (1.2 ml) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes, and then 8-bromo-4-chloroquinoline (600 mg) was added and the temperature was returned to room temperature, followed by stirring with heating at 80 ° C. for 2 hours. Under ice cooling, acetic acid (0.28 ml) was added to the reaction solution for neutralization, and then ethyl acetate and water were added to separate the organic layer. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 8-bromo-4-methoxyquinoline (327 mg).
製造例３９８
　6-クロロ-8-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]イミダゾ[1,2-b]ピリダジン（304mg）、10% パラジウム/炭素（100mg; 55%含水）およびエタノール（20ml）の混合物を、常圧の水素雰囲気下、室温で2時間攪拌した。反応液をセライト濾過し、減圧下濃縮した。残渣をテトラヒドロフラン（10ml）に懸濁させ1M 塩酸（2ml）を加え室温で2時間攪拌した。反応液に1M 水酸化ナトリウム水溶液（2ml）を加え、クロロホルムで抽出した。有機層を乾燥後、減圧下濃縮し、4-(イミダゾ[1,2-b]ピリダジン-8-イル)フェノール（169mg）を得た。 Production Example 398
6-chloro-8- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] imidazo [1,2-b] pyridazine (304 mg), 10% palladium / carbon (100 mg; 55% water) and ethanol ( 20 ml) was stirred for 2 hours at room temperature under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (10 ml), 1M hydrochloric acid (2 ml) was added, and the mixture was stirred at room temperature for 2 hr. To the reaction solution was added 1M aqueous sodium hydroxide solution (2 ml), and the mixture was extracted with chloroform. The organic layer was dried and concentrated under reduced pressure to obtain 4- (imidazo [1,2-b] pyridazin-8-yl) phenol (169 mg).
製造例４０９
　2-メチル-3-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]キノキサリン（1.345g）のテトラヒドロフラン（10mL）溶液を氷冷し、1M塩酸（9mL）を加え5時間撹拌した。反応液を1mol/l水酸化ナトリウム水溶液（9mL）で中和し、酢酸エチルで抽出した。反応溶液を無水硫酸ナトリウム乾燥後、減圧濃縮した。残渣を酢酸エチル-ヘキサンで洗浄して4-(3-メチルキノキサリン-2-イル)フェノール(960mg)を得た。 Production Example 409
A solution of 2-methyl-3- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] quinoxaline (1.345 g) in tetrahydrofuran (10 mL) was ice-cooled, 1M hydrochloric acid (9 mL) was added, and the mixture was stirred for 5 hr. The reaction solution was neutralized with 1 mol / l aqueous sodium hydroxide solution (9 mL) and extracted with ethyl acetate. The reaction solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate-hexane to give 4- (3-methylquinoxalin-2-yl) phenol (960 mg).
製造例４３２
　4-[4-（テトラヒドロ-2H-ピラン-2-イルオキシ）フェニル-1,3-ベンゾオキサゾール（359mg）、ピリジニウム パラ-トルエンスルホナート（31mg）およびエタノール（12ml）の混合物を、油温80℃で30分加熱攪拌した。室温に冷却後、飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、減圧下濃縮し、得られた残渣を水で洗浄し、4-(1,3-ベンゾオキサゾール-4-イル)フェノール（206mg）を得た。 Production Example 432
A mixture of 4- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl-1,3-benzoxazole (359 mg), pyridinium para-toluenesulfonate (31 mg) and ethanol (12 ml) was added at an oil temperature of 80 ° C. And stirred for 30 minutes. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The obtained residue was washed with water to give 4- (1,3-benzoxazol-4-yl) phenol (206 mg).
製造例４６１
　4-ブロモ-1-メチル-1H-ベンゾイミダゾール（300mg）、2,6-ジフルオロ-4-メトキシフェニルボロン酸（267mg）、トリス(ジベンジリデンアセトン)ジパラジウム(0)（65mg）、トリ-t-ブチルホスホニウムテトラフルオロホウ酸塩（52mg）、フッ化カリウム（273mg）、テトラヒドロフラン（4ml）および水（0.4ml）の混合物を、油温65℃で1日間加熱攪拌した。室温に冷却後、反応液を酢酸エチルで希釈し、水、次いで飽和食塩水で洗浄後、乾燥、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）で精製し、4-(2,6-ジフルオロ-4-メトキシフェニル)-1-メチル-1H-ベンゾイミダゾール（31mg）を得た。 Production Example 461
4-bromo-1-methyl-1H-benzimidazole (300 mg), 2,6-difluoro-4-methoxyphenylboronic acid (267 mg), tris (dibenzylideneacetone) dipalladium (0) (65 mg), tri-t A mixture of -butylphosphonium tetrafluoroborate (52 mg), potassium fluoride (273 mg), tetrahydrofuran (4 ml) and water (0.4 ml) was stirred with heating at an oil temperature of 65 ° C. for 1 day. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and then saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 4- (2,6-difluoro-4-methoxyphenyl) -1-methyl-1H-benzimidazole (31 mg).
製造例４６２
　4-クロロ-8-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]キノリン(200 mg)、トリメチルボロキシン(0.1 ml)の1,2-ジメトキシエタン(2.0 ml)懸濁液にテトラキス(トリフェニルホスフィン)パラジウム(0)(70 mg)、2 M炭酸ナトリウム水溶液(0.4 ml)を加え、マイクロウェーブにて120℃で1時間反応した。放冷後、不溶物をセライトろ過し、ろ液に水を加え酢酸エチルで抽出し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル)で分離精製して、4-メチル-8-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]キノリン(164 mg)を得た。 Production Example 462
4-Chloro-8- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] quinoline (200 mg), trimethylboroxine (0.1 ml) in 1,2-dimethoxyethane (2.0 ml) suspension Tetrakis (triphenylphosphine) palladium (0) (70 mg) and 2 M aqueous sodium carbonate solution (0.4 ml) were added, and the mixture was reacted at 120 ° C. for 1 hour in a microwave. After standing to cool, the insoluble material was filtered through Celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-methyl-8- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] quinoline (164 mg).
製造例４６３
　3-ブロモ-8-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]イミダゾ[1,2-a]ピリジン（284mg）とトルエン（6.3ml）の混合物に、水（0.43ml）、トリメチルボロキシン（96mg）、リン酸三カリウム（291mg）、酢酸パラジウム(II)（17mg）およびトリシクロヘキシルホスフィン（43mg）を加え、油温110℃で24時間加熱撹拌した。室温に冷却後、酢酸エチルを加え、水で洗浄した。有機層を飽和食塩水で洗浄後、乾燥、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル)で精製し、更に塩基性シリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、3-メチル-8-[4-(テトラヒドロ-2H-ピラン-2-イルオキシ)フェニル]イミダゾ[1,2-a]ピリジン（102mg）を得た。
Production Example 463
To a mixture of 3-bromo-8- [4- (tetrahydro-2H-pyran-2-yloxy) phenyl] imidazo [1,2-a] pyridine (284 mg) and toluene (6.3 ml), water (0.43 ml), Trimethylboroxine (96 mg), tripotassium phosphate (291 mg), palladium (II) acetate (17 mg) and tricyclohexylphosphine (43 mg) were added, and the mixture was heated and stirred at an oil temperature of 110 ° C. for 24 hours. After cooling to room temperature, ethyl acetate was added and washed with water. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate), and further purified by basic silica gel column chromatography (hexane / ethyl acetate) to give 3-methyl-8- [4- (tetrahydro-2H-pyran-2 -Iloxy) phenyl] imidazo [1,2-a] pyridine (102 mg) was obtained.
製造例４６６
　2-アミノ-4'-メトキシビフェニル-3-カルボン酸（975mg）、ホルムアミジン酢酸塩（1.3g）およびエタノール（10ml）の混合物を、油温75℃で16時間加熱攪拌した。室温に冷却後、析出物を濾取し、8-(4-メトキシフェニル)キナゾリン-4-オール（852mg）を得た。 Production Example 466
A mixture of 2-amino-4′-methoxybiphenyl-3-carboxylic acid (975 mg), formamidine acetate (1.3 g) and ethanol (10 ml) was stirred with heating at an oil temperature of 75 ° C. for 16 hours. After cooling to room temperature, the precipitate was collected by filtration to give 8- (4-methoxyphenyl) quinazolin-4-ol (852 mg).
製造例４６７
8-(4-メトキシフェニル)キナゾリン-4-オール（300mg）、五塩化リン（500mg）およびオキシ塩化リン（1.8ml）の混合物を、油温105℃で8時間加熱攪拌した。室温に冷却後、減圧下濃縮し、残渣にトルエンを加え減圧下濃縮した。残渣にクロロホルムを加え、飽和炭酸水素ナトリウム水溶液、次いで飽和食塩水で洗浄後、乾燥、濾過し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）で精製し、4-クロロ-8-(4-メトキシフェニル)キナゾリン（142mg）を得た。
Production Example 467
A mixture of 8- (4-methoxyphenyl) quinazolin-4-ol (300 mg), phosphorus pentachloride (500 mg) and phosphorus oxychloride (1.8 ml) was heated and stirred at an oil temperature of 105 ° C. for 8 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated under reduced pressure. Chloroform was added to the residue, washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-chloro-8- (4-methoxyphenyl) quinazoline (142 mg).
製造例４６９
　4-クロロ-8-(4-メトキシフェニル)キナゾリン（177mg）のジクロロメタン（5ml）溶液にp-トルエンスルホニルヒドラジド（125mg）を加え、室温で5時間攪拌した。反応液を減圧下濃縮し、残渣にエタノール（2ml）と1M 水酸化ナトリウム水溶液（2ml）を加え、油温85℃で4時間加熱攪拌した。室温に冷却後、水を加え、ジエチルエーテルで抽出した。有機層を乾燥後、濾過、減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサ/:酢酸エチル）で生成し、8-(4-メトキシフェニル)キナゾリン（101mg）を得た。 Production Example 469
To a solution of 4-chloro-8- (4-methoxyphenyl) quinazoline (177 mg) in dichloromethane (5 ml) was added p-toluenesulfonyl hydrazide (125 mg), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, ethanol (2 ml) and 1M aqueous sodium hydroxide solution (2 ml) were added to the residue, and the mixture was heated with stirring at 85 ° C. for 4 hours. After cooling to room temperature, water was added and extracted with diethyl ether. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was produced by silica gel column chromatography (hexa /: ethyl acetate) to obtain 8- (4-methoxyphenyl) quinazoline (101 mg).
製造例４８１
　氷冷下、5-[3-(ヒロドキシメチル)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン(33.3g)の塩化メチレン(330mL)混合物に塩化チオニル(16.6mL)を加え、室温にて5時間攪拌した。反応液に酢酸エチルを加えた後、析出した固体をろ取し、減圧乾燥して5-[3-(クロロメチル)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン 塩酸塩(36.1g)を得た。 Production Example 481
Under ice-cooling, chlorinate a mixture of 5- [3- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl] -1-methylpyridin-2 (1H) -one (33.3 g) in methylene chloride (330 mL). Thionyl (16.6 mL) was added, and the mixture was stirred at room temperature for 5 hours. After adding ethyl acetate to the reaction solution, the precipitated solid was collected by filtration and dried under reduced pressure to give 5- [3- (chloromethyl) -1-methyl-1H-pyrazol-4-yl] -1-methylpyridine- 2 (1H) -one hydrochloride (36.1 g) was obtained.
　上記製造例の方法と同様にして、後記表に示す製造例の化合物を製造した。製造例化合物の化学構造式、物理化学的データ及び製造法を表６から表５７及び表１４８から表１６６に示す。 The compounds of the production examples shown in the table below were produced in the same manner as in the above production examples. Tables 6 to 57 and Tables 148 to 166 show the chemical structural formulas, physicochemical data and production methods of the production example compounds.
実施例１
　1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-アミン(177mg)、4-(キノリン-2-イル)ベンズアルデヒド(284mg)、及び1,2-ジクロロエタン(1mL)の混合物に、オルトチタン酸テトライソプロピル(0.45mL)を加え85℃で2時間攪拌した。反応液を氷冷し、メタノール(5mL)及び水素化ホウ素ナトリウム（130mg)を加え、室温で3時間攪拌した。水素化ホウ素ナトリウム（140mg)を追加し、更に2時間攪拌した。炭酸水素ナトリウム溶液を加え、クロロホルムで希釈後、セライトろ過し、ろ液の有機層をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製し、1-メチル-4-(ピリジン-4-イル)-N-[4-キノリン-2-イル)ベンジル]-1H-ピラゾール-3-アミン（138mg）を得た。 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.
実施例２
　1-メチル-4-(ピリジン-4-イル)-N-[4-(キノリン-2-イル)ベンジル]-1H-ピラゾール-3-アミン(77mg)、塩化メチレン(4mL)、及び酢酸(0.80mL)の混合物にホルムアルデヒド(164mg)を加え、10分間攪拌した。ナトリウムトリアセトキシボロヒドリド(167mg)を加え、室温で2時間攪拌した。ホルムアルデヒド(164mg)及びナトリウムトリアセトキシボロヒドリド(167mg)を追加し室温で終夜攪拌した。再度ホルムアルデヒド(164mg)及びナトリウムトリアセトキシボロヒドリド(167mg)を加え、室温で12時間攪拌した。炭酸水素ナトリウム溶液を加え、クロロホルムで抽出した。有機層をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製し、得られた残渣をメタノールに溶解し、4M塩化水素-酢酸エチル溶液を加え減圧濃縮した。残渣をジイソプロピルエーテル/2-プロパノールで洗浄し、N,1-ジメチル-4-(ピリジン-4-イル)-N-[4-(キノリン-2-イル)ベンジル]-1H-ピラゾール-3-アミン 二塩酸塩（21mg）を得た。 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. Sodium hydrogen carbonate solution was added and extracted with chloroform. The organic layer was purified by silica gel column chromatography (chloroform / methanol), the resulting residue was dissolved in methanol, 4M hydrogen chloride-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. The residue was washed with diisopropyl ether / 2-propanol and N, 1-dimethyl-4- (pyridin-4-yl) -N- [4- (quinolin-2-yl) benzyl] -1H-pyrazol-3-amine Dihydrochloride (21 mg) was obtained.
実施例３
　1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-カルボン酸（137mg）の塩化メチレン(4mL)溶液にカルボニルジイミダゾール(105mg)を室温で加え、同温度で15分撹拌した。更にN-ヒドロキシアセトアミジン（48mg）を加え室温で0.5時間撹拌後、混合物を減圧濃縮した。残渣にトルエンを加え、110℃で12時間撹拌後、トシル酸一水和物(7mg)を加え4時間同温にて撹拌した。続いて、N-メチルピロリドン(2mL)を加え、同温にて更に4時間撹拌した。放冷後、水及び飽和食塩水を加えクロロホルムにて抽出した。有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣はエタノール及び酢酸エチルの混合溶媒(4:1)に懸濁し、4M塩化水素の酢酸エチル溶液を加え、室温で3時間攪拌し、2-[4-({[1-メチル-4-(3-メチル-1,2,4-オキサジアゾール-5-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン 一塩酸塩（70mg）を得た。 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. Subsequently, 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. , 2- [4-({[1-Methyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline Monohydrochloride (70 mg) was obtained.
実施例４
　4-{3-[(4-ブロモベンジル)オキシ]-1-メチル-1H-ピラゾール-4-イル}ピリジン(137 mg)、0.5M 2-ピリジルジンクブロミドのテトラヒドロフラン溶液(1.6 mL)、及びテトラヒドロフラン(1 mL)の混合物に、テトラキス(トリフェニルホスフィン)パラジウム(92 mg)を加え、封管チューブ中、120℃、1時間、マイクロ波照射した。放冷後、反応液に水を加えて反応を停止した。混合物をセライト濾過し、残渣に酢酸エチルを加えた。有機層を飽和塩化アンモニウム水溶液、飽和食塩水で洗浄した。減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/ヘキサン)にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で1時間攪拌した。ジエチルエーテルを加え、生じた沈殿を濾取し、ジエチルエーテルで洗浄し、2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]ピリジン 二塩酸塩（30 mg）を得た。 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. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine. The residue was purified by silica gel column chromatography (chloroform / hexane). 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. Diethyl ether was added and the resulting precipitate was filtered off and washed with diethyl ether to give 2- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy. } Methyl) phenyl] pyridine dihydrochloride (30 mg) was obtained.
実施例５
　4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)安息香酸(400 mg)、1,2-フェニレンジアミン(154 mg)、1-ヒドロキシベンゾトリアゾール(210 mg)、トリエチルアミン(0.27mL)、及びN,N-ジメチルホルムアミド(5 mL)混合物にWSC塩酸塩(296 mg)を加え室温で1時間攪拌した。反応液に酢酸エチルを加え、有機層を水、飽和食塩水で洗浄後、減圧濃縮をした。得られた粗精製物を酢酸に溶解し、90℃で12時間攪拌した。放冷後、反応液を減圧濃縮し、残渣に飽和炭酸水素ナトリウム水溶液(40 mL)、水(20 mL)、飽和食塩水(20 mL)、及びクロロホルムを加え1時間攪拌した。クロロホルムで抽出後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(メタノール/酢酸エチル)にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で15時間攪拌した。反応液にジエチルエーテルを加え、生じた沈殿を濾取し、ジエチルエーテルで洗浄し、2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]-1H-ベンズイミダゾール 二塩酸塩（148 mg）を得た。 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. After allowing to cool, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (40 mL), water (20 mL), saturated brine (20 mL) and chloroform were added to the residue, and the mixture was stirred for 1 hr. After extraction with chloroform and concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / ethyl acetate). 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 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration, washed with diethyl ether, and 2- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazole-3- [Il] oxy} methyl) phenyl] -1H-benzimidazole dihydrochloride (148 mg) was obtained.
実施例６
　2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]-1H-ベンズイミダゾール(124 mg)、炭酸カリウム(135 mg)、及びN,N-ジメチルホルムアミド(3 mL)混合物にヨウ化メチル(0.041mL)を加え、室温で2時間攪拌した。反応液に酢酸エチルを加え、有機層を飽和食塩水で洗浄し、減圧濃縮をした。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム)にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で15時間攪拌した。生じた沈殿を濾取し、ジエチルエーテルで洗浄し、1-メチル-2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]-1H-ベンズイミダゾール 二塩酸塩（76 mg）を得た。 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). 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 hours. The resulting precipitate was collected by filtration, washed with diethyl ether, and 1-methyl-2- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} Methyl) phenyl] -1H-benzimidazole dihydrochloride (76 mg) was obtained.
実施例７
　4-{3-[(4-ブロモベンジル)オキシ]-1-メチル-1H-ピラゾール-4-イル}ピリジン(413mg)、キノリン-8-イルボロン酸(311mg)、及び1,2-ジメトキシエタン(30mL)の混合物にテトラキス(トリフェニルホスフィン)パラジウム(277mg)及び1M炭酸ナトリウム水溶液(3mL)を加え90℃で5時間攪拌した。反応液を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加え30分間攪拌した。生じた沈殿を濾取し、酢酸エチルで洗浄し、8-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン 二塩酸塩(468mg)を得た。 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). The obtained crude product was dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration, washed with ethyl acetate, and 8- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] Quinoline dihydrochloride (468 mg) was obtained.
実施例８
　2-[4-({[4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン(567mg)のN,N-ジメチルホルムアミド(20mL)溶液に1,1,1-トリフルオロ-2-ヨードエタン(630mg)、及び炭酸セシウム(1.46g)を加え60℃で5時間攪拌した。反応液を減圧濃縮し残渣に水を加え、酢酸エチルで抽出した。有機層をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加えて30分間攪拌した。生じた沈殿を濾取し、酢酸エチルで洗浄し、2-[4-({[4-(ピリジン-4-イル)-1-(2,2,2-トリフルオロメチル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン 二塩酸塩（650mg）を得た。 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). The crude product was dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration, washed with ethyl acetate, and 2- [4-({[4- (pyridin-4-yl) -1- (2,2,2-trifluoromethyl) -1H-pyrazole- 3-yl] oxy} methyl) phenyl] quinoline dihydrochloride (650 mg) was obtained.
実施例９
　[4-(ピリジン-4-イル)-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-1-イル]酢酸エチル(380mg)のエタノール(15mL)溶液に1M水酸化ナトリウム水溶液(2.5mL)を加え、60℃で5時間攪拌した。反応液を減圧濃縮し、1N塩酸で中和した。生じた沈殿を濾取し、濾液を酢酸エチルで抽出した。有機層と沈殿をあわせシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製した。得られた粗精製物を酢酸エチル-ヘキサンで洗浄し、[4-(ピリジン-4-イル)-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-1-イル]酢酸（57mg）を得た。 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). The obtained crude product was washed with ethyl acetate-hexane, and [4- (pyridin-4-yl) -3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazole-1- Yl] acetic acid (57 mg) was obtained.
実施例１０
　2-[4-({[1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン(300mg)、3-クロロピリダジン塩酸塩(228mg)、1,1'-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-塩化メチレン錯体(33mg)、炭酸ナトリウム(288mg)、N,N-ジメチルホルムアミド(3mL)、及び水(1mL)の混合物をアルゴン雰囲気下、100℃で12時間攪拌した。酢酸エチル及び水を加え、生じた不溶物をセライトにて濾別した。有機層を飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物をエタノール-酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加え、溶液を減圧濃縮した。生じた固体をエタノール－エーテルで洗浄して濾取し2-[4-({[1-メチル-4-(ピリダジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン 二塩酸塩（56mg）を得た。 Example 10
2- [4-({[1-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H-pyrazol-3-yl] oxy} methyl ) Phenyl] quinoline (300 mg), 3-chloropyridazine hydrochloride (228 mg), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-methylene chloride complex (33 mg), sodium carbonate (288 mg), A mixture of N, N-dimethylformamide (3 mL) and water (1 mL) was stirred at 100 ° C. for 12 hours under an argon atmosphere. Ethyl acetate and water were added, and the resulting insoluble material was filtered off through celite. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was dissolved in ethanol-ethyl acetate, 4M hydrogen chloride in ethyl acetate was added, and the solution was concentrated under reduced pressure. The resulting solid was washed with ethanol-ether and collected by filtration. 2- [4-({[1-Methyl-4- (pyridazin-3-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] Quinoline dihydrochloride (56 mg) was obtained.
実施例１１
　氷冷下、[4-(ピリジン-4-イル)-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-1-イル]酢酸エチル(600mg)のテトラヒドロフラン(40mL)混合物に1M水素化ジイソブチルアルミニウム のトルエン溶液(3.9mL)を加え室温で1時間攪拌した。反応液を氷冷し、メタノールを加えて反応を停止した。生じたゲルをセライト濾過し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え減圧濃縮した。残渣を酢酸エチルで洗浄して[4-(ピリジン-4-イル)-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-1-イル]エタノール二塩酸塩（189mg）を得た。 Example 11
Under ice cooling, [4- (pyridin-4-yl) -3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-1-yl] ethyl acetate (600 mg) in tetrahydrofuran (40 mL ) To the mixture was added 1M diisobutylaluminum hydride in toluene (3.9 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled and methanol was added to stop the reaction. The resulting gel was filtered through Celite, and the filtrate was concentrated 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 concentrated under reduced pressure. The residue was washed with ethyl acetate to give [4- (pyridin-4-yl) -3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-1-yl] ethanol dihydrochloride ( 189 mg) was obtained.
実施例１２
　4-(イミダゾ[1,2-a]ピリジン-2-イル)フェノール(330mg)、[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]メタノール(330mg)のトルエン(10mL) 混合物にシアノメチレントリブチルホスホラン(570mg)を加え100℃で8時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）、続いて塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル-ヘキサン)にて精製した。得られた粗精製物にエタノール、4M塩化水素の酢酸エチル溶液を加え室温で30分間攪拌した。反応液を減圧濃縮し残渣を酢酸エチルで洗浄し、2-(4-{[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)イミダゾ[1,2-a]ピリジン 二塩酸塩（459mg）を得た。 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). Ethanol and 4M hydrogen chloride in ethyl acetate were added to the resulting crude product, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give 2- (4-{[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) imidazo [1 , 2-a] pyridine dihydrochloride (459 mg) was obtained.
実施例１３
　1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-カルボン酸(246mg)のN,N-ジメチルホルムアミド(7mL)溶液にカルボニルジイミダゾール(166mg)を加え、室温で15時間攪拌した。アセチルヒドラジド(0.40mL)を加え60℃で18時間攪拌した。氷冷下飽和炭酸水素ナトリウム水溶液及び飽和食塩水を加え、クロロホルムにて抽出した。有機層を無水硫酸マグネシウムで乾燥後減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/クロロホルム）にて精製し、N'-アセチル-1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-カルボヒドラジド（198mg）を得た。得られたN'-アセチル-1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-カルボヒドラジド(267mg)、Burgess試薬(459mg)、及びジクロロエタン(8mL)混合物を封管チューブ中、130℃20分間、マイクロ波照射した。放冷後飽和炭酸水素ナトリウム水溶液及び飽和食塩水を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた固体をエタノールに懸濁後4M塩化水素の酢酸エチル溶液を加え30分間撹拌し、生じた固体をろ取し、2-[4-({[1-メチル-4-(5-メチル-1,3,4-オキサジアゾール-2-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン 一塩酸塩（219mg）を得た。 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. The resulting residue was purified by silica gel column chromatography (ethyl acetate / chloroform), and N'-acetyl-1-methyl-3-{[4- ( Quinolin-2-yl) benzyl] oxy} -1H-pyrazole-4-carbohydrazide (198 mg) was obtained. The resulting N′-acetyl-1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazole-4-carbohydrazide (267 mg), Burgess reagent (459 mg), and dichloroethane (8 mL) The mixture was microwaved in a sealed tube at 130 ° C. for 20 minutes. After allowing to cool, saturated aqueous sodium hydrogen carbonate solution 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, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform). The obtained solid was suspended in ethanol, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred for 30 min. The resulting solid was collected by filtration, and 2- [4-({[1-methyl-4- (5-methyl -1,3,4-oxadiazol-2-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline monohydrochloride (219 mg) was obtained.
実施例１４
　1-メチル-4-ピリジン-4-イル-1H-ピラゾール-3-オール(200 mg)、[4-(イミダゾ[1,2-a]ピリジン-3-イル)フェニル]メタノール(300 mg)、及びトルエン(15 mL)の混合物にシアノメチレントリブチルホスホラン(413 mg)を加え、100℃で24時間攪拌した。放冷後、反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で2時間攪拌した。反応液にジエチルエーテルを加え、生じた沈殿を濾取し、ジエチルエーテルで洗浄し、3-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]イミダゾ[1,2-a]ピリジン 二塩酸塩（117 mg）を得た。 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. Diethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration, washed with diethyl ether, and 3- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazole-3- [Il] oxy} methyl) phenyl] imidazo [1,2-a] pyridine dihydrochloride (117 mg) was obtained.
実施例１５
　2-[4-(クロロメチル)フェニル]キノリン塩酸塩(950mg)、4-(1,4-ジオキサスピロ[4.5]デシ-8-イル)-1-メチル-1H-ピラゾール-3-オール(819mg)、及びN,N-ジメチルホルムアミド(9.5mL)の混合物に炭酸カリウム(1.13g)を加え、60℃にて1時間攪拌した。放冷後、水及び飽和食塩水を加え、メタノール及びクロロホルムの混合溶媒にて抽出し、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム→酢酸エチル/ヘキサン)にて精製し、2-[4-({[4-(1,4-ジオキサスピロ[4.5]デシ-8-イル)-1-メチル-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン（738mg）を得た。得られた2-[4-({[4-(1,4-ジオキサスピロ[4.5]デシ-8-イル)-1-メチル-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン(1.095g)、テトラヒドロフラン(11mL)、及び水(11mL)の混合物にトシル酸(229mg)を加え室温で3日間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液及び飽和食塩水を加えクロロホルムにて抽出した。無水硫酸マグネシムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物を酢酸エチル溶解し、4M塩化水素の酢酸エチル溶液を加え、同温で15分間攪拌した。生じた固体をろ取し、4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノン 一塩酸塩（105mg）を得た。 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. The residue was purified by silica gel column chromatography (methanol / chloroform → ethyl acetate / hexane) to give 2- [4-({[4- (1,4-dioxaspiro [4.5] dec-8-yl) -1-methyl. -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (738 mg) was obtained. The resulting 2- [4-({[4- (1,4-dioxaspiro [4.5] dec-8-yl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (1.095 Tosic acid (229 mg) was added to a mixture of g), tetrahydrofuran (11 mL), and water (11 mL), and the mixture was stirred at room temperature for 3 days. Saturated aqueous sodium hydrogen carbonate solution and saturated brine were added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate 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 the same temperature for 15 min. The resulting solid was collected by filtration to give 4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanone monohydrochloride (105 mg) It was.
実施例１６
　アルゴン気流下，ヨウ化トリメチルスルホキソニウム(94mg)のジメチルスルホキシド(1.3mL)混合物にカリウムtert‐ブトキシドを加え、室温で1.5時間撹拌した。反応混合物に4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノン(160mg)のトルエン(3mL)溶液を加え、室温で9時間撹拌した。水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮し、2-[4-({[1-メチル-4-(1-オキサスピロ[2.5]オクト-6-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン（150mg）を得た。アルゴン気流下、水素化リチウムアルミニウム(40mg)のテトラヒドロフラン(3mL)混合物に氷冷下、2-[4-({[1-メチル-4-(1-オキサスピロ[2.5]オクト-6-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン(150mg)のテトラヒドロフラン(4.5mL)溶液を氷冷下加え、同温にて1時間撹拌した。アンモニア水を氷冷下加え、メタノール及びクロロホルムの混合溶媒(1:9)で希釈後、室温で1時間攪拌した。生じた固体をセライトでろ別し、ろ液を減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、1-メチル-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール（97mg）を得た。得られた1-メチル-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール(56mg)のN,N-ジメチルホルムアミド(2mL)溶液にイミダゾール(45mg)及びtert‐ブチルジメチルクロロシラン(49mg)を加え、室温にて15時間攪拌し、次いで50℃にて24時間攪拌した。反応液のままシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、酢酸エチルに溶解後、4M塩化水素の酢酸エチル溶液を加え、室温にて1時間攪拌した。生じた固体をろ取し、1-メチル-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール 二塩酸塩（25mg）を得た。 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. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2- [4-({[1-methyl-4- (1-oxaspiro [2.5] oct-6-yl). -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (150 mg) was obtained. Under a stream of argon, a mixture of lithium aluminum hydride (40 mg) in tetrahydrofuran (3 mL) was cooled with ice, and 2- [4-({[1-methyl-4- (1-oxaspiro [2.5] oct-6-yl)- A solution of 1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (150 mg) in tetrahydrofuran (4.5 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. 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. The resulting 1-methyl-4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanol (56 mg) N, N- To a dimethylformamide (2 mL) solution were added imidazole (45 mg) and tert-butyldimethylchlorosilane (49 mg), and the mixture was stirred at room temperature for 15 hours and then at 50 ° C. for 24 hours. The 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.
実施例１７
　4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノン(300mg)、エタノール(6mL)、及び水(1.2mL)の混合物にヒドロキシルアミン塩酸塩(61mg)及び酢酸ナトリウム(78mg)を加え、室温にて1時間攪拌した。飽和食塩水を加え、クロロホルムで抽出した。無水硫酸マグネシウムで乾燥後減圧濃縮し、N-ヒドロキシ-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサンイミン（310mg）を得た。N-ヒドロキシ-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサンイミン(310mg)のテトラヒドロフラン(3mL)溶液に、3M 水酸化ナトリウム水溶液(606μL)を加え、塩化4-メチルベンゼンスルホニル(166mg)のテトラヒドロフラン(3.2mL)溶液を加えた。50℃で6時間攪拌後、飽和食塩水を加えクロロホルムにて抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、5-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)アゼパン-2-オン（288mg）を得た。得られた5-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)アゼパン-2-オン(116mg)の酢酸エチル(4.6mL)溶液に4M塩化水素のジオキサン溶液を加え、室温にて2時間攪拌した。生じた固体をろ取し、5-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)アゼパン-2-オン 二塩酸塩（102mg）を得た。 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. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, N-hydroxy-4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexaneimine ( 310 mg) was obtained. To a solution of N-hydroxy-4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexaneimine (310 mg) in tetrahydrofuran (3 mL), A 3M aqueous sodium hydroxide solution (606 μL) was added, and a solution of 4-methylbenzenesulfonyl chloride (166 mg) in tetrahydrofuran (3.2 mL) was added. After stirring at 50 ° C. for 6 hours, saturated brine was 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 purified by silica gel column chromatography (methanol / chloroform) to give 5- (1-methyl-3-{[4- (quinoline-2- Yl) benzyl] oxy} -1H-pyrazol-4-yl) azepan-2-one (288 mg) was obtained. The resulting 5- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) azepan-2-one (116 mg) in ethyl acetate (4.6 mL The solution was added with 4M hydrogen chloride in dioxane and stirred at room temperature for 2 hours. The resulting solid was collected by filtration, and 5- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) azepan-2-one dihydrochloride ( 102 mg) was obtained.
実施例１８
　アルゴン気流下、4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノン(462mg)、1,2-ジメトキシエタン(7mL)、及びtert‐ブタノール(2.8mL)の混合物に、氷冷下p-トルエンスルホニルメチルイソシアニド(329mg)及びカリウムtert‐ブトキシド(227mg)を加え同温で30分間攪拌した。更に室温で7時間攪拌した。水及び飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサンカルボニトリル（167mg）を得た。 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. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform), and 4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanecarbo Nitrile (167 mg) was obtained.
実施例１９
　4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサンカルボニトリル(166mg、トランス体及びシス体の混合物)のエタノール(8.3mL)溶液に氷冷下、1M 水酸化ナトリウム水溶液(1.38mL)及び30%過酸化水素水(0.28mL)を加え室温で4日間攪拌した。水を加え酢酸エチルで抽出し、有機層を希亜硫酸ナトリウム水溶液、飽和食塩水で順次洗浄した。水層を酢酸エチルにて抽出し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/酢酸エチル）にて精製した。得られたトランス体を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加え室温にて攪拌後、生じた固体をろ取し、トランス-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサンカルボキサミド 二塩酸塩（26mg、Ex.19）を得た。シス体も同様に処理し、シス-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサンカルボキサミド 二塩酸塩（58mg、Ex.149）を得た。 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. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained trans isomer was dissolved in ethyl acetate, 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature. The resulting solid was collected by filtration, and trans-4- (1-methyl-3-{[4- (Quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanecarboxamide dihydrochloride (26 mg, Ex. 19) was obtained. The cis isomer was treated in the same manner to give cis-4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanecarboxamide dihydrochloride (58 mg Ex.149).
実施例２０
　3-メチル-2-(4-{2-[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]ビニル}フェニル)キノリン(950mg)のエタノール(10mL)溶液に10%水酸化パラジウム-炭素(200mg)を加え、水素雰囲気下、加圧し室温で5日間攪拌した。セライト濾過し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で15分間攪拌した。溶媒を減圧濃縮し、残渣に2-プロパノール－ジイソプロピルエーテルを加え固化し、3-メチル-2-(4-{2-[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]エチル}フェニル)キノリン 二塩酸塩（27mg）を得た。 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. The solvent was concentrated under reduced pressure, 2-propanol-diisopropyl ether was added to the residue and solidified, and 3-methyl-2- (4- {2- [1-methyl-4- (pyridin-4-yl) -1H-pyrazole- 3-yl] ethyl} phenyl) quinoline dihydrochloride (27 mg) was obtained.
実施例２１
　4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノン(183mg)、エタノール(3.7mL)、及び水(0.7mL)の混合物にアミノオキシメタン塩酸塩(45mg)及び酢酸ナトリウム(47mg)を加え、室温にて2時間攪拌した。飽和食塩水を加え、クロロホルムで抽出した。無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（エタノール/ヘキサン)にて精製し、残渣を酢酸エチル(5mL)に溶解し、4M塩化水素の酢酸エチル溶液を加え室温で１時間撹拌後、生じた固体をろ取し、N-メトキシ-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサンイミン 二塩酸塩（157mg）を得た。 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. The obtained residue was purified by silica gel column chromatography (ethanol / hexane), the residue was dissolved in ethyl acetate (5 mL), 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 1 hr. N-methoxy-4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexaneimine dihydrochloride (157 mg) was collected by filtration. Obtained.
実施例２２
　氷冷下4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノン(203mg)のエタノール(4mL)溶液に水素化ホウ素ナトリウム(22mg)を加え、1時間攪拌した。水及び飽和食塩水を加え、クロロホルムで抽出した。無水硫酸マグネシウムで乾燥後減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、トランス-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール（150mg）を無色油状物として、更にシス-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール（25mg）を白色固体として得た。トランス体はエタノール(4mL)に溶解し、シュウ酸(22mg)を加え、30分間攪拌した。減圧濃縮し、エタノール及び酢酸エチルの混合溶媒で固化し、トランス-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール シュウ酸塩（74mg、Ex.22）を得た。シス体は酢酸エチル(6mL)溶液に、4M塩化水素の酢酸エチル溶液を加え、室温で1時間撹拌後、シス-4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール 二塩酸塩（28mg、Ex.154）を得た。 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. Concentrate under reduced pressure, solidify with a mixed solvent of ethanol and ethyl acetate, trans-4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) Cyclohexanol oxalate (74 mg, Ex. 22) was obtained. 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.
実施例２３
　1-(2-{[tert-ブチル(ジメチル)シリル]オキシ}エチル)-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン(143mg)のテトラヒドロフラン(3mL)溶液にテトラブチルアンモニウムフルオリド(0.4mL)を加え、室温で3時間撹拌した。反応液を減圧濃縮して、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加えた。生じた沈殿を濾取し、酢酸エチルで洗浄し、1-(2-ヒドロキシエチル)-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン 二塩酸塩（80mg）を得た。 Example 23
1- (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). The obtained crude product was dissolved in ethyl acetate, and 4M hydrogen chloride in ethyl acetate was added. The resulting precipitate was collected by filtration, washed with ethyl acetate, and 1- (2-hydroxyethyl) -5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridin-2 (1H) -one dihydrochloride (80 mg) was obtained.
実施例２４
　2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン-3-カルバルデヒド(175 mg)、ジメチルアミン塩酸塩(68 mg)、及び塩化メチレン(5 mL)混合物に、トリエチルアミン(116μL)及びトリアセトキシ水素化ホウ素ナトリウム(264 mg)を加え、室温で22時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液で中和し、クロロホルムで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で13時間攪拌した。反応液にジエチルエーテルを加え、生じた沈殿を濾取、更にジエチルエーテルで洗浄し、N,N-ジメチル-1-{2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン-3-イル}メタンアミン 三塩酸塩（118 mg）を得た。 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 μL) 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). 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 13 hours. Diethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration, further washed with diethyl ether, and washed with N, N-dimethyl-1- {2- [4-({[1-methyl-4- (pyridine-4- Yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinolin-3-yl} methanamine trihydrochloride (118 mg) was obtained.
実施例２５
　氷冷下、{2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン-3-イル}メタノール(270 mg)のN,N-ジメチルホルムアミド(5 mL)溶液に55%水素化ナトリウム(42 mg)を加え、同温にて15分攪拌した。ヨウ化メチル(60μL)を加え室温に昇温し、12時間攪拌した。反応液を氷冷し、55%水素化ナトリウム(42 mg)、ヨウ化メチル(60μL)を加え室温に昇温し、1時間攪拌した。反応液に水を加え反応を停止し、酢酸エチルを加え、有機層を飽和食塩水で洗浄した。減圧濃縮をし、残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で1時間攪拌した。反応液にジエチルエーテルを加え、生じた沈殿を濾取し、ジエチルエーテルで洗浄して3-(メトキシメチル)-2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン 二塩酸塩（84 mg）を得た。 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 μL) 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 μL) 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. Diethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and washed with diethyl ether to give 3- (methoxymethyl) -2- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline dihydrochloride (84 mg) was obtained.
実施例２６
　2-(4-{[(4-ヨード-1-メチル-1H-ピラゾール-3-イル)オキシ]メチル}フェニル)-3-メチルキノリン(338mg)、モルホリン(2.7mL)、銅(142mg)、リン酸三カリウム(473mg)、2-(ジメチルアミノ)エタノール(2.7mL)の混合物を110℃で15時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）にて精製した。粗精製物に酢酸エチル、エタノール、4M塩化水素の酢酸エチル溶液を加え室温で30分間攪拌した。生じた固体をろ取、酢酸エチルで洗浄し、3-メチル-2-[4-({[1-メチル-4-(モルホリン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン 二塩酸塩（164mg）を得た。 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). Ethyl acetate, ethanol, and 4M hydrogen chloride in ethyl acetate were added to the crude product, followed by stirring at room temperature for 30 minutes. The resulting solid was collected by filtration, washed with ethyl acetate, and 3-methyl-2- [4-({[1-methyl-4- (morpholin-4-yl) -1H-pyrazol-3-yl] oxy} methyl ) Phenyl] quinoline dihydrochloride (164 mg) was obtained.
実施例２７
　2-{4-[(4-ヨード-1-メチル-1H-ピラゾール-3-イル)メトキシ]フェニル}-3-メチルキノリン(6.00g)のテトラヒドロフラン(120mL)溶液を冷却し、2M塩化イソプロピルマグネシウムの テトラヒドロフラン溶液(16.5mL)を加えた。同温で45分間攪拌し、2-イソプロポキシ-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(4.30mL)を加えた。室温で2時間攪拌後、塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、3-メチル-2-(4-{[1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン（2.32g）を得た。
3-メチル-2-(4-{[1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン(500mg)、5-ブロモ-1-メチルピリジン-2(1H)-オン(413mg)、N,N-ジメチルホルムアミド(5mL)、及び水(1mL)の混合物に[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)の塩化メチレン付加体(54mg)及び炭酸ナトリウム(349mg)を加え100℃で1時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で30分間攪拌した。反応液を減圧濃縮し残渣を酢酸エチルで洗浄して1-メチル-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン 二塩酸塩（80mg）を得た。 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. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 3-methyl-2- (4-{[1-methyl-4- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline (2.32 g) was obtained.
3-Methyl-2- (4-{[1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-3-yl] [1,1 to a mixture of (methoxy} phenyl) quinoline (500 mg), 5-bromo-1-methylpyridin-2 (1H) -one (413 mg), N, N-dimethylformamide (5 mL), and water (1 mL). '-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) methylene chloride adduct (54 mg) and sodium carbonate (349 mg) were added, and the mixture was stirred at 100 ° C for 1 hour. 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 (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 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give 1-methyl-5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) phenoxy] methyl} -1H-pyrazole- 4-yl) pyridin-2 (1H) -one dihydrochloride (80 mg) was obtained.
実施例２８
　氷冷下、1-[4-(ヒドロキシメチル)フェニル]-2-メチル-1H-ベンズイミダゾール(1.19g)の塩化メチレン(50mL)混合物に塩化チオニル(1.1mL)を加え、室温にて2時間攪拌した。反応液を減圧濃縮し、残渣を減圧乾燥した。得られた固体(483mg)に1-メチル-4-ピリジン-4-イル-1H-ピラゾール-3-オール(263mg)、炭酸カリウム(520mg)、N,N-ジメチルホルムアミド(15mL)を加え70℃で8時間攪拌した。反応液を減圧濃縮し残渣に水を加えて、酢酸エチルで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で15分間攪拌した。生じた沈殿を濾取し、酢酸エチルで洗浄後、2-メチル-1-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]-1H-ベンズイミダゾール 二塩酸塩（445mg）を得た。 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. The resulting precipitate was collected by filtration, washed with ethyl acetate, and then 2-methyl-1- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} Methyl) phenyl] -1H-benzimidazole dihydrochloride (445 mg) was obtained.
実施例２９
　氷冷下4-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノン(213mg)のエタノール溶液(8.5mL)に水素化ホウ素ナトリウム(23mg)を加え、1時間攪拌した。水及び飽和食塩水を加え、クロロホルムで抽出した。無水硫酸マグネシウムで乾燥後減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、4-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール（214mg）を得た。得られた4-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール(214mg)のN,N-ジメチルホルムアミド(3.2mL)溶液にイミダゾール(136mg)、tert‐ブチルジメチルクロロシラン(151mg)及びN, N-ジメチル-4-アミノピリジン(18mg)を加え室温にて14時間攪拌した。水を加え、酢酸エチルで抽出した。有機層は飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、2-[4-({[4-(トランス-4-{[tert-ブチル(ジメチル)シリル]オキシ}シクロヘキシル)-1-メチル-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]-3-メチルキノリン（160mg）を得た。得られた2-[4-({[4-(トランス-4-{[tert-ブチル(ジメチル)シリル]オキシ}シクロヘキシル)-1-メチル-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]-3-メチルキノリン(160mg)のテトラヒドロフラン(3.2mL)溶液に、フッ化テトラ-N-ブチルアンモニウム（886μL）を加え、室温にて7時間攪拌した。濃縮後、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム)にて精製し、残渣を酢酸エチル(6.4mL)に溶解後、4M塩化水素の酢酸エチル溶液(295μL)を加え、室温にて1時間攪拌した。生じた固体をろ取し、トランス-4-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)シクロヘキサノール 二塩酸塩（104mg）を得た。 Example 29
Hydrogenate 4- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanone (213 mg) in ethanol (8.5 mL) under ice cooling Sodium boron (23 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 resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 4- (1-methyl-3-{[4- (3-methylquinoline-2 -Yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanol (214 mg) was obtained. The resulting 4- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanol (214 mg) in N, N-dimethyl To a formamide (3.2 mL) solution were added imidazole (136 mg), tert-butyldimethylchlorosilane (151 mg) and N, N-dimethyl-4-aminopyridine (18 mg), and the mixture was stirred at room temperature for 14 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 2- [4-({[4- (trans-4-{[tert-butyl (dimethyl) silyl] oxy} cyclohexyl)- 1-Methyl-1H-pyrazol-3-yl] oxy} methyl) phenyl] -3-methylquinoline (160 mg) was obtained. The resulting 2- [4-({[4- (trans-4-{[tert-butyl (dimethyl) silyl] oxy} cyclohexyl) -1-methyl-1H-pyrazol-3-yl] oxy} methyl) phenyl ] To a solution of 3-methylquinoline (160 mg) in tetrahydrofuran (3.2 mL) was added tetra-N-butylammonium fluoride (886 μL), and the mixture was stirred at room temperature for 7 hours. After concentration, the residue was purified by silica gel column chromatography (methanol / chloroform). The residue was dissolved in ethyl acetate (6.4 mL), 4M hydrogen chloride in ethyl acetate (295 μL) was added, and the mixture was stirred at room temperature for 1 hr. did. The resulting solid was collected by filtration and trans-4- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) cyclohexanol dihydrochloride Salt (104 mg) was obtained.
実施例３０
　3-メチル-2-[4-({[1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-yl)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン(507mg)、5-ブロモ-2-(tert-ブトキシ)ピリジン(384mg)、1,1'-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-塩化メチレン錯体(54mg)、炭酸ナトリウム(354mg)、N,N-ジメチルホルムアミド(7.5mL)、及び水(1.5mL)の混合物をアルゴン雰囲気下、100℃で1時間攪拌した。酢酸エチル及び水を加え、生じた不溶物をセライトにて濾別した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた化合物をを塩化メチレン(2mL)に溶解後、トリフルオロ酢酸(2mL)を加え、室温で2時間撹拌した。反応液を減圧濃縮し、飽和炭酸水素ナトリウム溶液及び酢酸エチルを加えた。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物をエタノールに溶解し、4M塩化水素の酢酸エチル溶液を加えた。溶液を減圧濃縮した。生じた沈殿を濾取し、エーテルで洗浄し、6-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン 二塩酸塩（160mg）を得た。 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. Ethyl acetate and water were added, and the resulting insoluble material was filtered off through celite. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained compound was dissolved in methylene chloride (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was dissolved in ethanol, and 4M hydrogen chloride in ethyl acetate was added. The solution was concentrated under reduced pressure. The resulting precipitate was collected by filtration, washed with ether, and 6- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridine -2 (1H) -one dihydrochloride (160 mg) was obtained.
実施例３１
　2-{4-[(5-ブロモ-2-メチル-2H-1,2,3-トリアゾール-4-イル)メトキシ]フェニル}-3-メチルキノリン(290mg)、4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン(436mg)、N,N-ジメチルホルムアミド(2.9mL)、及び水(1.2mL)の混合物に、炭酸セシウム(462mg)及びテトラキストリフェニルホスフィンパラジウム(123mg)を加え、80℃で18時間攪拌した。放冷後、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）にて精製し、残渣を酢酸エチル(12mL)に溶解し、4M塩化水素のジオキサン溶液を加え、室温にて1時間攪拌した。生じた固体をろ取し、3-メチル-2-(4-{[2-メチル-5-(ピリジン-4-イル)-2H-1,2,3-トリアゾール-4-イル]メトキシ}フェニル)キノリン 二塩酸塩（99mg）を得た。 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. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), the residue was dissolved in ethyl acetate (12 mL), 4M hydrogen chloride in dioxane was added, and the mixture was stirred at room temperature for 1 hr. The resulting solid was collected by filtration and 3-methyl-2- (4-{[2-methyl-5- (pyridin-4-yl) -2H-1,2,3-triazol-4-yl] methoxy} phenyl ) Quinoline dihydrochloride (99 mg) was obtained.
実施例３２
　氷冷下、5-[3-(ヒロドキシメチル)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン(394mg)の塩化メチレン(20mL)混合物に塩化チオニル(0.4mL)を加え、室温にて2時間攪拌した。反応液を減圧濃縮し、残渣を減圧乾燥した。N,N-ジメチルホルムアミド(16mL)、4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノール(270mg)、及び炭酸カリウム(414mg)を加え70℃で8時間攪拌した。反応液を減圧濃縮し残渣に水を加えて、酢酸エチルで抽出した。減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で10分間攪拌した。溶媒を減圧濃縮し残渣を酢酸エチルで洗浄し、1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン 二塩酸塩（206mg）を得た。 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. The solvent was concentrated under reduced pressure and the residue was washed with ethyl acetate, and 1-methyl-5- (1-methyl-3-{[4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl} -1H -Pyrazol-4-yl) pyridin-2 (1H) -one dihydrochloride (206 mg) was obtained.
実施例３３
　3-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピロリジン-1-カルボン酸tert-ブチル(152mg)の塩化メチレン(0.3mL)溶液にトリフルオロ酢酸(0.3mL)を加え、室温で2時間撹拌した。反応液を氷冷し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過、減圧濃縮した。残渣を塩化メチレン（3mL）に溶解させて氷冷し、トリエチルアミン(51μL)、アセチルクロリド(24μL)を加えた後、室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製した。得られた粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加え室温で30分間攪拌した。生じた固体をろ取、酢酸エチルで洗浄し、1-[3-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピロリジン-1-イル]エタノン 二塩酸塩（125mg）を得た。 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. The residue was dissolved in methylene chloride (3 mL), ice-cooled, triethylamine (51 μL) and acetyl chloride (24 μL) were added, and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol). 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 30 min. The resulting solid was collected by filtration, washed with ethyl acetate, and 1- [3- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazole-4- Yl) pyrrolidin-1-yl] ethanone dihydrochloride (125 mg) was obtained.
実施例３４
　2-[4-({[1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン-3-カルボアルデヒド(569mg)、メタノール(5mL)、及びテトラヒドロフラン(5mL)混合物に水素化ホウ素ナトリウム(96mg)を加え、室温にて22時間撹拌した。反応液に水を加え、クロロホルムにて抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物をメタノールに溶解し、4M塩化水素のジオキサン溶液を加え、溶液を減圧濃縮した。生じた固体をメタノール－エーテルで洗浄後濾取し、5-[3-({4-[3-(ヒドロキシメチル)キノリン-2-イル]ベンジル}オキシ)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン 一塩酸塩（74mg）を得た。 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). The obtained crude product was dissolved in methanol, 4M hydrogen chloride in dioxane was added, and the solution was concentrated under reduced pressure. The resulting solid was washed with methanol-ether and collected by filtration to give 5- [3-({4- [3- (hydroxymethyl) quinolin-2-yl] benzyl} oxy) -1-methyl-1H-pyrazole-4 -Il] -1-methylpyridin-2 (1H) -one monohydrochloride (74 mg) was obtained.
実施例３５
　2-[4-({[1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン-3-カルボアルデヒド(150mg)の塩化メチレン(3mL)溶液にビス(2-メトキシエチル)アミノサルファートリフルオリド (0.1mL)を加え、室温にて終夜撹拌した。水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣を塩基性シリカゲルカラムクロマトグラフィー（クロロホルム/ヘキサン）にて精製した。得られた粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加えた。生じた沈殿を濾取し、酢酸エチルで洗浄し、5-[3-({4-[3-(ジフルオロメチル)キノリン-2-イル]ベンジル}オキシ)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン 二塩酸塩（83mg）を得た。 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. The residue was purified by basic silica gel column chromatography (chloroform / hexane). The obtained crude product was dissolved in ethyl acetate, and 4M hydrogen chloride in ethyl acetate was added. The resulting precipitate was collected by filtration, washed with ethyl acetate, and 5- [3-({4- [3- (difluoromethyl) quinolin-2-yl] benzyl} oxy) -1-methyl-1H-pyrazole-4 -Il] -1-methylpyridin-2 (1H) -one dihydrochloride (83 mg) was obtained.
実施例３６
　2-[4-({[1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン-3-カルボアルデヒド(155mg)、テトラヒドロフラン(3.5mL)、及びメタノール(0.4mL)混合物にヒドロキシアミン塩酸塩(48mg)及び粉末炭酸カリウム(143mg)を加え、室温にて0.5時間撹拌した。減圧濃縮し、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた化合物の塩化メチレン(3mL)溶液に、トリエチルアミン(0.056mL)、トリフルオロ無水酢酸(0.052mL)を加え、室温にて2時間撹拌した。トリエチルアミン(0.216mL)及びトリフルオロ無水酢酸(0.219mL)を追加し5時間室温にて撹拌した。反応液に水を加え、クロロホルムにて抽出した。有機層を無水硫酸マグネシウムで乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた固体をエタノールで洗浄後濾取し、2-[4-({[1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン-3-カルボニトリル（83mg）を得た。 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. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 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. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained solid was washed with ethanol and collected by filtration, and 2- [4-({[1-methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H-pyrazole] was collected. -3-yl] oxy} methyl) phenyl] quinoline-3-carbonitrile (83 mg) was obtained.
実施例３７
　氷冷下、6-[4-({[1-メチル-4-(1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]ニコチン酸メチル(1.47g)のテトラヒドロフラン(50mL)混合物に水素化ホウ素リチウム(148mg)、エタノール(0.60mL)を加え2時間加熱還流した。反応液を放冷し、飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を減圧濃縮し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム)にて精製した。得られた粗精製物を酢酸エチル及ぶヘキサンで順次洗浄し、5-[3-({4-[5-(ヒドロキシメチル)ピリジン-2-イル]ベンジル}オキシ)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン（770mg）を得た。 Example 37
6- [4-({[1-Methyl-4- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -1H-pyrazol-3-yl] oxy} methyl) under ice cooling To a mixture of methyl phenyl] nicotinate (1.47 g) in tetrahydrofuran (50 mL) were added lithium borohydride (148 mg) and ethanol (0.60 mL), and the mixture was heated to reflux for 2 hours. 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. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was washed successively with ethyl acetate and hexane to give 5- [3-({4- [5- (hydroxymethyl) pyridin-2-yl] benzyl} oxy) -1-methyl-1H-pyrazole. -4-yl] -1-methylpyridin-2 (1H) -one (770 mg) was obtained.
実施例３８
　4-[4-(クロロメチル)フェニル]-1-メチル-1H-ベンズイミダゾール塩酸塩(143mg)、5-(3-ヒドロキシ-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン(100mg)、炭酸カリウム(168mg)、及びN,N-ジメチルホルムアミド(2mL)の混合物を、60℃で5時間攪拌した。水を加え、生じた固体を濾取し、シリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。得られた粗精製物を酢酸エチルに溶解し、生じた沈殿を濾取し、1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン(75mg)を得た。 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). The obtained crude product was dissolved in ethyl acetate, and the resulting precipitate was collected by filtration to give 1-methyl-5- (1-methyl-3-{[4- (1-methyl-1H-benzimidazole-4- Yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridin-2 (1H) -one (75 mg) was obtained.
実施例３９
　1-メチル-4-ピリジン-4-イル-1H-ピラゾール-3-オール(90mg)、[4-(イミダゾ[1,2-a]ピリジン-2-イル)フェニル]メタノール(174mg)のテトラヒドロフラン(9mL)混合物に1,1'-(アゾジカルボニル)ジピペリジン(259mg)、トリ-n-ブチルホスフィン(208mg)を加え室温で12時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）、続いて塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル-ヘキサン）にて精製した。得られた粗精製物にエタノール、4M塩化水素の酢酸エチル溶液を加え室温で30分間攪拌した。反応液を減圧濃縮し残渣をエタノール-酢酸エチルにて洗浄し、2-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]イミダゾ[1,2-a]ピリジン 二塩酸塩（122mg）を得た。 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). Ethanol and 4M hydrogen chloride in ethyl acetate were added to the resulting crude product, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol-ethyl acetate to give 2- [4-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} methyl. ) Phenyl] imidazo [1,2-a] pyridine dihydrochloride (122 mg) was obtained.
実施例４０
　1-メチル-4-(テトラヒドロ-2H-ピラン-4-イル)-1H-ピラゾール-3-オール（250mg）及び4-(キノリン-2-イル)ブタン-1-オール（360mg）のトルエン（18ml）溶液にシアノメチレントリブチルホスホラン（497mg）を加え100℃で2.5時間加熱攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）及び塩基性シリカゲルカラムクロマトグラフィー（メタノール/酢酸エチル）で精製した。このものを酢酸エチルに溶解しシュウ酸（62mg）を加え、室温にて攪拌した。減圧下濃縮し得られた固体をろ取し2-(4-{[1-メチル-4-(テトラヒドロ-2H-ピラン-4-イル)-1H-ピラゾール-3-イル]オキシ}ブチル)キノリン シュウ酸塩（250mg）を得た。 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). This was dissolved in ethyl acetate, oxalic acid (62 mg) was added, and the mixture was stirred at room temperature. The solid obtained by concentration under reduced pressure was collected by filtration and 2- (4-{[1-methyl-4- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-3-yl] oxy} butyl) quinoline Oxalate (250 mg) was obtained.
実施例４１
　[5-(キノリン-2-イル)-2-チエニル]メタノール（320mg）の塩化メチレン（6mL）溶液に塩化チオニル（290μL）を加え、室温にて3時間攪拌した。トルエンを加え、生じた固体をろ取した。得られた2-[5-(クロロメチル)-2-チエニル]キノリン 塩酸塩（302mg）及び1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-オール（179mg）のN,N-ジメチルホルムアミド（6mL）懸濁液に炭酸カリウム（352mg）を加え、室温で20分間攪拌後60℃に昇温して7時間攪拌した。放冷後水及び飽和食塩水を加え、酢酸エチルで抽出し、硫酸マグネシウムで乾燥後減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製した。このものを酢酸エチルに溶解後、コハク酸（35mg）を加え室温にて1時間攪拌した。生じた固体をろ取し、2-[5-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)-2-チエニル]キノリン 0.5コハク酸塩（205mg）を得た。 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 μL), and the mixture was stirred at room temperature for 3 hours. Toluene was added and the resulting solid was collected by filtration. The resulting 2- [5- (chloromethyl) -2-thienyl] quinoline hydrochloride (302 mg) and 1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-ol (179 mg) N , N-dimethylformamide (6 mL) suspension was added with potassium carbonate (352 mg), stirred at room temperature for 20 minutes, then warmed to 60 ° C. and stirred for 7 hours. After allowing to cool, water and saturated brine were added, and the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform). This was dissolved in ethyl acetate, succinic acid (35 mg) was added, and the mixture was stirred at room temperature for 1 hr. The resulting solid was collected by filtration, and 2- [5-({[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} methyl) -2-thienyl] quinoline 0.5 The acid salt (205 mg) was obtained.
実施例４２
　1-メチル-4-ピリジン-4-イル-1H-ピラゾール-3-オール（550mg）及び3-(キノリン-2-イル)プロプ-2-イン-1-オール（603mg）のトルエン（55mL）溶液にシアノメチレントリブチルホスホラン（953mg）を加え100℃で2.5時間加熱攪拌した。反応液を減圧濃縮し、残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル-クロロホルム）で精製した。このものをエタノール（3mL）に溶解しコハク酸(13mg)を加え、5分間加熱撹拌した。放冷後、減圧下濃縮し、残渣を酢酸エチルで固体化することにより2-(3-{[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}プロプ-1-イン-1-イル)キノリン コハク酸塩（59mg）を得た。 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. After allowing to cool, the mixture was concentrated under reduced pressure, and the residue was solidified with ethyl acetate to give 2- (3-{[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} Prop-1-in-1-yl) quinoline succinate (59 mg) was obtained.
実施例４３
　1-[3-ヒドロキシ-4-(ピリジン-4-イル)-1H-ピラゾール-1-イル]エタノン(3.19g)、2-[4-(クロロメチル)フェニル]キノリン塩酸塩(4.15g)、炭酸カリウムのN,N-ジメチルホルムアミド(80mL)混合物を60℃で3時間攪拌した。反応液を減圧濃縮し残渣にメタノール(80mL)及び水(20mL)を加え60℃で3時間攪拌した。反応液を減圧濃縮し、生じた沈殿を濾取し水洗した。固体をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）いて精製し2-[4-({[4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン（1.52g）を得た。 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. The solid was purified by silica gel column chromatography (methanol / chloroform) to give 2- [4-({[4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline (1.52 g )
実施例４４
　3-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジロキシ}-1H-ピラゾール-4-イル)ピロリジン-1-カルボン酸tert-ブチル(916mg)の塩化メチレン(1.8mL)溶液に、トリフルオロ酢酸(1.8mL)を加えて、室温で2時間撹拌した。反応液を氷冷し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後減圧濃縮し、3-メチル-2-[4-({[1-メチル-4-(ピロリジン-3-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン（806 mg）を得た。 Example 44
3- (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. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-methyl-2- [4-({[1-methyl-4- (pyrrolidin-3-yl) -1H-pyrazol-3-yl] oxy} methyl ) Phenyl] quinoline (806 mg) was obtained.
実施例４５
　氷冷下、1-メチル-4-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾロ-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール（731mg）のクロロホルム（30mL）溶液に、75%のm-クロロ過安息香酸（534mg）を加え、室温で24時間撹拌した。反応液にチオ硫酸ナトリウム(570mg)を水(5 mL)に溶解させて加え、5分間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製し、1-メチル-4-(4-{[1-メチル-4-(2-メチル-1-オキシドピリジン-4-イル)-1H-ピラゾロ-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール(503mg)を得た。 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. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give 1-methyl-4- (4-{[1-methyl-4- (2-methyl-1-oxidepyridine- 4-yl) -1H-pyrazolo-3-yl] methoxy} phenyl) -1H-benzimidazole (503 mg) was obtained.
実施例４６
　3-(1-メチル-1H-ベンズイミダゾール-4-イル)プロパン-1-オール（62mg）の塩化メチレン（1.5mL）混合物を氷冷し、トリエチルアミン（82μL）及びメシルクロリド（38μL）を加えて、同温で30分撹拌した。飽和炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出後、有機層を無水硫酸ナトリウムにて乾燥、ろ過、減圧濃縮した。残渣に5-(3-ヒドロキシ-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン トリフルオロ酢酸塩（115mg）、炭酸カリウム（135mg）、N,N-ジメチルホルムアミド（1.5mL）を加えて、60℃にて12時間撹拌した。飽和塩化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムにて乾燥、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製した。得られた粗精製物を酢酸エチルに溶解し、4M塩化水素の酢酸エチル溶液を加え室温にて30分撹拌した。析出した固体をろ取、減圧乾燥し、1-メチル-5-{1-メチル-3-[3-(1-メチル-1H-ベンズイミダゾール-4-イル)プロポキシ]-1H-ピラゾール-4-イル}ピリジン-2(1H)-オン 三塩酸塩(16 mg)を得た。 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 μL) and mesyl chloride (38 μL) 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. 5- (3-Hydroxy-1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one trifluoroacetate (115 mg), potassium carbonate (135 mg), N, N -Dimethylformamide (1.5 mL) was added, and the mixture was stirred at 60 ° C for 12 hours. A saturated aqueous sodium chloride 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. The residue was purified by silica gel column chromatography (chloroform / methanol). 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 30 min. The precipitated solid was collected by filtration, dried under reduced pressure, and 1-methyl-5- {1-methyl-3- [3- (1-methyl-1H-benzimidazol-4-yl) propoxy] -1H-pyrazole-4- IL} pyridin-2 (1H) -one trihydrochloride (16 mg) was obtained.
実施例４７
　1-メチル-5-(1-メチル-3-{[4-(1-トリチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン（311mg）のジオキサン(8mL）溶液に4M塩化水素のジオキサン溶液（0.6mL）を加え70℃で1.5時間撹拌した。反応液を減圧濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加えた。飽和塩化ナトリウムを加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムにて乾燥、ろ過、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製した。得られた粗精製物をエタノールに溶解させ、4M塩化水素の酢酸エチル溶液を加えて室温で30分撹拌した。酢酸エチルを加え、析出した固体をろ取、減圧乾燥し、5-(3-{[4-(1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン 三塩酸塩(160 mg)を得た。 Example 47
1-methyl-5- (1-methyl-3-{[4- (1-trityl-1H-benzimidazol-4-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridine-2 (1H) To a solution of -one (311 mg) in dioxane (8 mL) was added 4M hydrogen chloride in dioxane (0.6 mL), and the mixture was stirred at 70 ° C for 1.5 hr. 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. The residue was purified by silica gel column chromatography (chloroform / methanol). 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 30 min. Ethyl acetate was added, and the precipitated solid was collected by filtration, dried under reduced pressure, and 5- (3-{[4- (1H-benzimidazol-4-yl) phenoxy] methyl} -1-methyl-1H-pyrazole-4- Yl) -1-methylpyridin-2 (1H) -one trihydrochloride (160 mg) was obtained.
実施例３３８
　アルゴン雰囲気下、2-{4-[(4-ヨード-1-メチル-1H-ピラゾール-3-イル)メトキシ]フェニル}-3-メチルキノリン（500 mg）のトルエン（10 mL）溶液に4-(トリブチルスタニル)ピリダジン（500 mg）、トリス(ジベンジリデンアセトン)ジパラジウム(0)（50 mg）、2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピルビフェニル（52 mg）を加え、110℃で12時間加熱攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）で分離精製した。得られた粗精製物を酢酸エチル-ヘキサンで洗浄して3-メチル-2-(4-{[1-メチル-4-(ピリダジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン(255 mg)を得た。 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. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was washed with ethyl acetate-hexane to give 3-methyl-2- (4-{[1-methyl-4- (pyridazin-4-yl) -1H-pyrazol-3-yl] methoxy} Phenyl) quinoline (255 mg) was obtained.
実施例３９７
　2-{4-[(4-ヨード-1-メチル-1H-ピラゾール-3-イル)メトキシ]フェニル}-3-メチルキノリン（200mg）、5-メチルピリダジン-3-ボロン酸ピナコールエステル（116mg）、トリ-t-ブチルホスホニウムテトラフルオロホウ酸塩（16mg）、トリス(ジベンジリデンアセトン)ジパラジウム(0)（20mg）、リン酸三カリウム（308mg）、アセトニトリル（3ml）の混合物を、油温80℃で4時間加熱攪拌後、N,N-ジメチルホルムアミド（2ml）を加え、油温90℃で更に18時間加熱攪拌した。室温に冷却後、反応液を酢酸エチルで希釈し、飽和食塩水で洗浄後、乾燥、減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）で精製し、3-メチル-2-(4-{[1-メチル-4-(6-メチルピリダジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン（9mg）を得た。 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. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol), and 3-methyl-2- ( 4-{[1-Methyl-4- (6-methylpyridazin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline (9 mg) was obtained.
実施例４０４
　5-[3-(クロロメチル)-1-メチル-1H-ピラゾール-4-イル]-1-メチルピリジン-2(1H)-オン 塩酸塩(180mg)、4-(キノリン-2-イル)フェノール(120mg)、炭酸カリウム(205mg)及びN,N-ジメチルホルムアミド(13mL)の混合物を70℃で8時間攪拌した。反応液に水を加えて、酢酸エチルで抽出した。有機層を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）、塩基性シリカゲルカラムクロマトグラフィー（メタノール/クロロホルム）にて精製して1-メチル-5-(1-メチル-3-{[4-(キノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン（90mg）を得た。 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. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) and basic silica gel column chromatography (methanol / chloroform) to give 1-methyl-5- (1-methyl-3-{[4 -(Quinolin-2-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one (90 mg) was obtained.
実施例４１２
　1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン(2.5g)のメタノール(30mL)懸濁液をバス温60℃にて加熱して溶解させた。そのままの温度で0.1Mリン酸-エタノール溶液を118mL加えて、同じ温度で30分撹拌した。反応液を室温に戻した後、減圧濃縮した。残渣にエタノール(500mL)と水 (50mL)を加え、バス温90℃にて2時間撹拌した。室温に戻して1時間撹拌後、固体をろ取、エタノールにて洗浄した。50℃にて終夜減圧乾燥し、1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン・リン酸塩を2.96g得た。 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. After returning to room temperature and stirring for 1 hour, the solid was collected by filtration and washed with ethanol. Dried under reduced pressure at 50 ° C. overnight, 1-methyl-5- (1-methyl-3-{[4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl} -1H-pyrazole-4 2.96 g of -yl) pyridin-2 (1H) -one phosphate was obtained.
　上記の実施例の方法と同様にして、後記表に示す実施例の化合物製造した。実施例化合物の化学構造式を表５８から表１２５及び表１６７から表１８２に、物理化学的データ及び製造法を表１２６から表１４７及び表１８３から表１８８にそれぞれ示す。



In the same manner as in the above Examples, the compounds of Examples shown in the table below were produced. The chemical structural formulas of the example compounds are shown in Table 58 to Table 125 and Table 167 to Table 182, and the physicochemical data and production methods are shown in Table 126 to Table 147 and Table 183 to Table 188, respectively.



Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000203
　式（Ｉ）の化合物又はその塩は、PDE10A阻害作用を有し、統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防並びに／又は治療剤として使用できる。 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.

Claims (26)

  1. 下記式（Ｉ）の化合物またはその塩。
    Figure JPOXMLDOC01-appb-C000001
     （式中、
    環Aは、置換されていてもよい芳香族ヘテロ環であり、
    Bは、C1-6アルキル、ハロゲン、-O-C1-6アルキル、置換されていてもよいシクロアルキル、及び置換されていてもよい非芳香族へテロ環からなる群より選択される同一又は異なる1以上の基でそれぞれ置換されていてもよいフェニレン、ピリジンジイル、若しくはチオフェンジイル、又は-C≡C-であり、
    nは0又は1の整数であり、
    L1は、-C1-6アルキレン-、-C1-6アルキレン-T-、又は-T-C1-6アルキレン-であり、但し、nが0である場合は、L1は-トリメチレン-T-又は-テトラメチレン-T-であり、
    XはCR0又はNであり、
    R1はハロゲン、-OH、-O-C1-6アルキル、-CN、-C(O)OH、及び-C(O)O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル又はHであり、
    環Eは、置換されていてもよいシクロアルキル、置換されていてもよいアリール、置換されていてもよい芳香族ヘテロ環、又は置換されていてもよい非芳香族へテロ環であり、
    TはO、S、-NH-、又は-N(C1-6アルキル)-であり、
    R0はH又はC1-6アルキルである。）     A compound of the following formula (I) or a salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     (Where
    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 (O) OC 1-6 alkyl. 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. )
  2. 環Aが、
    （i）ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    （ii）ハロゲン、
    （iii）-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
    （iv）-N(C1-6アルキル)2、
    （v）-CN、
    （vi）シクロアルキル、
    （vii）-C(O)H、
    からなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環であり、
    Bが、C1-6アルキル、ハロゲン、-O-C1-6アルキル、
    シクロアルキル、及び
    非芳香族へテロ環からなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレン、
    ピリジンジイル、
    若しくはチオフェンジイル、
    又は-C≡C-であり、
    nは0又は1の整数であり、
    L1は、-C1-6アルキレン-、-C1-6アルキレン-T-、又は-T-C1-6アルキレン-であり、但し、nが0である場合は、L1は-トリメチレン-T-又は-テトラメチレン-T-であり、
    XはCR0又はNであり、
    R1はハロゲン、-OH、-O-C1-6アルキル、-CN、-C(O)OH、及び-C(O)O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル又はHであり、
    環Eが
    C1-6アルキル、-OH、-C(O)NH2、-C(O)NH(C1-6アルキル)、-C(O)N(C1-6アルキル)2、-CN、=N-O-C1-6アルキル、及びオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよいシクロアルキル、
    アリール、
    i)ハロゲン、-OH、-O-C1-6アルキル、-O-(tert-ブチルジメチルシリル)、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)ハロゲン、
    iii)-O-C1-6アルキル、
    iv)-OH、並びに
    v)シクロアルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよい芳香族へテロ環、又は、
    i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)-OH、
    iii)-S(O)2-C1-6アルキル、
    iv)-C(O)-(-O-C1-6アルキルで置換されていてもよいC1-6アルキル)、
    v)-C(O)-N(C1-6アルキル)2、
    vi)-C(O)O-C1-6アルキル、並びに
    vii)オキソ
    からなる群より選択される同一又は異なる1以上の基で置換されていてもよい非芳香族へテロ環である請求項１記載の化合物又はその塩。     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,
    An aromatic heterocycle optionally substituted with one or more groups selected from the group consisting of:
    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 -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 (O) OC 1-6 alkyl. C 1-6 alkyl or H optionally substituted with
    Ring E is
    C 1-6 alkyl, -OH, -C (O) NH 2 , -C (O) NH (C 1-6 alkyl), -C (O) N (C 1-6 alkyl) 2 , -CN, = NOC 1-6 alkyl, and cycloalkyl optionally substituted with one or more same or different groups selected from the group consisting of oxo,
    Aryl,
    i) one or more identical or different groups selected from the group consisting of halogen, —OH, —OC 1-6 alkyl, —O- (tert-butyldimethylsilyl), and —N (C 1-6 alkyl) 2 C 1-6 alkyl, optionally substituted by
    ii) halogen,
    iii) -OC 1-6 alkyl,
    iv) -OH, and
    v) an aromatic heterocyclic ring optionally substituted with one or more groups selected from the group consisting of cycloalkyl, or
    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) -OH,
    iii) -S (O) 2 -C 1-6 alkyl,
    iv) -C (O)-(C 1-6 alkyl optionally substituted with -OC 1-6 alkyl),
    v) -C (O) -N (C 1-6 alkyl) 2 ,
    vi) -C (O) OC 1-6 alkyl, and
    The compound according to claim 1 or a salt thereof, which is a non-aromatic heterocyclic ring optionally substituted with one or more groups selected from the group consisting of vii) oxo.
  3. 環Eがハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル並びにオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよい非芳香族へテロ環である請求項２記載の化合物又はその塩。 Halogen ring E, -OH, -OC 1-6 alkyl, and -N (C 1-6 alkyl) optionally substituted by 2 identical or is selected from the group consisting of one or more different groups C 1- The compound or a salt thereof according to claim 2, which is a non-aromatic heterocyclic ring optionally substituted with one or more groups selected from the group consisting of 6 alkyl and oxo.
  4. 環Aが、
    i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)ハロゲン、
    iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
    iv)-CN、
    v)シクロアルキル、並びに
    vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリル、
    i)-OH及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)-O-(C1-6アルキル)、並びに
    iii）-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいピリジル、又は、
    i)ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)シクロアルキル、並びに、
    iii)ハロゲンからなる群より選択される同一又は異なる1以上の基で置換されていてもよいベンゾイミダゾリルであり、
    BがC1-6アルキル、ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレンであり、
    nが1であり、
    L1が-C1-6アルキレン-O-又は-O-C1-6アルキレンであり、
    XがCHであり、
    R1がC1-6アルキルである請求項３記載の化合物又はその塩。     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 by one or more groups selected from the group consisting of -C (O) H,
    i) -OH 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) -O- (C 1-6 alkyl), and
    iii) pyridyl optionally substituted with one or more groups selected from the group consisting of —N (C 1-6 alkyl) 2 , 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) benzimidazolyl optionally substituted with one or more groups selected from the group consisting of halogen,
    B is phenylene optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl, halogen, and —OC 1-6 alkyl,
    n is 1,
    L 1 is -C 1-6 alkylene-O- or -OC 1-6 alkylene;
    X is CH,
    The compound or a salt thereof according to claim 3, wherein R 1 is C 1-6 alkyl.
  5. 環EがC1-6アルキル及びオキソからなる群より選択される同一又は異なる1以上の基で置換されていてもよい1,2-ジヒドロピリジルである請求項４記載の化合物又はその塩。 The compound or a salt thereof according to claim 4, wherein 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.
  6. 環Eが1-メチル-6-オキソ-1,6-ジヒドロピリジン-3-イルである請求項５記載の化合物又はその塩。 6. The compound or a salt thereof according to claim 5, wherein ring E is 1-methyl-6-oxo-1,6-dihydropyridin-3-yl.
  7. 環Aが、
    i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)ハロゲン、
    iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
    iv)-CN、
    v)シクロアルキル、並びに
    vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリル、又は、
    i)ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)シクロアルキル、並びに、
    iii)ハロゲンからなる群より選択される同一又は異なる1以上の基で置換されていてもよいベンゾイミダゾリルである請求項６記載の化合物又はその塩。     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) The compound or a salt thereof according to claim 6, which is benzimidazolyl optionally substituted with one or more groups selected from the group consisting of halogen.
  8. 環Aが、
    i)ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)シクロアルキル、並びに、
    iii)ハロゲンからなる群より選択される同一又は異なる1以上の基で置換されていてもよいベンゾイミダゾリルである請求項７記載の化合物又はその塩。     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
    The compound according to claim 7 or a salt thereof, which is benzimidazolyl optionally substituted with one or more groups selected from the group consisting of iii) halogen.
  9. 環AがC1-6アルキルで置換されていてもよいベンゾイミダゾール-4-イルである請求項８記載の化合物又はその塩。 The compound or a salt thereof according to claim 8, wherein ring A is benzimidazol-4-yl optionally substituted with C 1-6 alkyl.
  10. 環Aが1-メチルベンゾイミダゾール-4-イルである請求項９記載の化合物又はその塩。 The compound or a salt thereof according to claim 9, wherein ring A is 1-methylbenzimidazol-4-yl.
  11. Bが1,4-フェニレンである請求項１０記載の化合物。 The compound according to claim 10, wherein B is 1,4-phenylene.
  12. 環Aが、
    i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)ハロゲン、
    iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
    iv)-CN、
    v)シクロアルキル、並びに
    vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリルである請求項７記載の化合物又はその塩。     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
    The compound or salt thereof according to claim 7, which is quinolyl optionally substituted with one or more groups selected from the group consisting of vi) -C (O) H.
  13. 環Aが、
    i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)ハロゲン、
    iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
    iv)-CN、
    v)シクロアルキル、並びに
    vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-2-イル、あるいは、
    C1-6アルキル及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリン-8-イルである請求項１２記載の化合物又はその塩。     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
    13. The compound or a salt thereof according to claim 12, 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.
  14. 環Aが、キノリン-2-イル、3-メチルキノリン-2-イル、3-ヒドロキシメチルキノリン-2-イル、3-メトキシキノリン-2-イル、6-フルオロキノリン-2-イル、6-メトキシキノリン-2-イル、6-メトキシ-3-メチルキノリン-2-イル、又は、キノリン-8-イルである請求項１３記載の化合物又はその塩。 Ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxy The compound or a salt thereof according to claim 13, which is quinolin-2-yl, 6-methoxy-3-methylquinolin-2-yl, or quinolin-8-yl.
  15. Bが1,4-フェニレンである請求項１４記載の化合物。 The compound according to claim 14, wherein B is 1,4-phenylene.
  16. 環Eがハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよい芳香族へテロ環である請求項２記載の化合物又はその塩。 Halogen ring E, -OH, -OC 1-6 alkyl, and -N (C 1-6 alkyl) optionally substituted by 2 identical or is selected from the group consisting of one or more different groups C 1- The compound or a salt thereof according to claim 2, which is an aromatic hetero ring optionally substituted with 6 alkyl.
  17. 環Aが、
    i)ハロゲン、-OH、-O-C1-6アルキル、及び-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)ハロゲン、
    iii)-O-(同一又は異なる1以上のハロゲンで置換されていてもよいC1-6アルキル)、
    iv)-CN、
    v)シクロアルキル、並びに
    vi）-C(O)Hからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリル、
    i)-OH及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)-O-(C1-6アルキル)、並びに
    iii）-N(C1-6アルキル)2からなる群より選択される同一又は異なる1以上の基で置換されていてもよいピリジル、又は、
    i)ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキル、
    ii)シクロアルキル、並びに、
    iii)ハロゲンからなる群より選択される同一又は異なる1以上の基で置換されていてもよいベンゾイミダゾリルであり、
    BがC1-6アルキル、ハロゲン、及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいフェニレンであり、
    nが1であり、
    L1が-C1-6アルキレン-O-又は-O-C1-6アルキレンであり、
    XがCHであり、
    R1がC1-6アルキルであり、
    環Eが-O-C1-6アルキル及び-OHからなる群より選択される同一又は異なる1以上の基で置換されていてもよいC1-6アルキルで置換されていてもよいピリジルである請求項１６記載の化合物又はその塩。     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 by one or more groups selected from the group consisting of -C (O) H,
    i) -OH 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) -O- (C 1-6 alkyl), and
    iii) pyridyl optionally substituted with one or more groups selected from the group consisting of —N (C 1-6 alkyl) 2 , 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) benzimidazolyl optionally substituted with one or more groups selected from the group consisting of halogen,
    B is phenylene optionally substituted with one or more groups selected from the group consisting of C 1-6 alkyl, halogen, and —OC 1-6 alkyl,
    n is 1,
    L 1 is -C 1-6 alkylene-O- or -OC 1-6 alkylene;
    X is CH,
    R 1 is C 1-6 alkyl;
    The ring E is pyridyl optionally substituted with C 1-6 alkyl optionally substituted with one or more same or different groups selected from the group consisting of —OC 1-6 alkyl and —OH. 16. The compound according to 16, or a salt thereof.
  18. 環Eが2-メチルピリジン-4-イルである請求項１７記載の化合物又はその塩。 The compound or a salt thereof according to claim 17, wherein Ring E is 2-methylpyridin-4-yl.
  19. 環Aが、
    ハロゲン、C1-6アルキル及び-O-C1-6アルキルからなる群より選択される同一又は異なる1以上の基で置換されていてもよいキノリル、
    同一又は異なる1以上のC1-6アルキルで置換されていてもよいピリジル、又は、
    同一又は異なる1以上のC1-6アルキルで置換されていてもよいベンゾイミダゾリルであり、
    Bが1,4-フェニレンである請求項１８記載の化合物。     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
    Benzimidazolyl optionally substituted with one or more same or different C 1-6 alkyl,
    The compound according to claim 18, wherein B is 1,4-phenylene.
  20. 8-[4-({[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン、
    1-メチル-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    1-メチル-5-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    2-(3-{[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]オキシ}プロプ-1-イン-1-イル)キノリン、
    1-メチル-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピペリジン-2-オン、
    4-(3-{[4-(6-フルオロ-3-メチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    5-(3-{[4-(6-メトキシ-3-メチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    1-メチル-4-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール、
    5-(3-{[4-(3-エチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    3-メチル-2-(4-{[1-メチル-4-(ピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン、
    3-メチル-2-[4-({[1-メチル-4-(ピリダジン-4-イル)-1H-ピラゾール-3-イル]オキシ}メチル)フェニル]キノリン、
    2-(4-{[(1,1'-ジメチル-1H,1'H-4,4'-ビピラゾール-3-イル)オキシ]メチル}フェニル)-3-メチルキノリン、
    1-メチル-5-(1-メチル-3-{[4-(キノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    1-エチル-5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    5-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)ベンジル]オキシ}-1H-ピラゾール-4-イル)-1-プロピルピリジン-2(1H)-オン、
    5-(3-{[4-(6-フルオロ-3-メチルキノリン-2-イル)ベンジル]オキシ}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    1-メチル-5-(2-メチル-5-{[4-(3-メチルキノリン-2-イル)フェノキシ]メチル}-2H-1,2,3-トリアゾール-4-イル)ピリジン-2(1H)-オン、
    3-メチル-2-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン、
    2-(4-{[4-(2,6-ジメチルピリジン-4-イル)-1-メチル-1H-ピラゾール-3-イル]メトキシ}フェニル)-3-メチルキノリン、
    1-メチル-4-(1-メチル-3-{2-[4-(3-メチルキノリン-2-イル)フェニル]エチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    1-メチル-4-(1-メチル-3-{[4-(3-メチルキノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    1-メチル-4-(4-{[1-メチル-4-(2-メチル-1-オキシドピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール、
    1-メチル-4-(4-{[1-メチル-4-(ピリダジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)-1H-ベンズイミダゾール、
    1-メチル-4-(1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    1'-エチル-1-メチル-3-{[4-(1-メチル-1H-ベンズイミダゾール-4-イル)フェノキシ]メチル}-1H,1'H-4,4'-ビピラゾール、
    1-メチル-5-(1-メチル-3-{[4-(キノリン-8-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    5-(3-{[4-(6-メトキシ-3-メチルキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    8-(4-{[1-メチル-4-(ピラジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリン、
    1-メチル-5-(1-メチル-3-{[4-(キノリン-2-イル)フェノキシ]メチル}-1H-ピラゾール-4-イル)ピリジン-2(1H)-オン、
    5-(3-{[4-(3-メトキシキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    5-(3-{[4-(6-フルオロキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    5-(3-{[4-(6-メトキシキノリン-2-イル)フェノキシ]メチル}-1-メチル-1H-ピラゾール-4-イル)-1-メチルピリジン-2(1H)-オン、
    3-メチル-8-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)イミダゾ[1,2-a]ピリジン、
    1,1'-ジメチル-3-{[4-(3-メチルイミダゾ[1,2-a]ピリジン-8-イル)フェノキシ]メチル}-1H,1'H-4,4'-ビピラゾール、又は、
    2-(4-{[1-メチル-4-(2-メチルピリジン-4-イル)-1H-ピラゾール-3-イル]メトキシ}フェニル)キノリンである請求項１記載の化合物又はその塩。     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-4- (pyridin-4-yl) -1H-pyrazol-3-yl] oxy} prop-1-in-1-yl) quinoline,
    1-methyl-5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) piperidin-2-one,
    4- (3-{[4- (6-Fluoro-3-methylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
    5- (3-{[4- (6-Methoxy-3-methylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
    1-methyl-4- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) -1H-benzimidazole,
    5- (3-{[4- (3-ethylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
    3-methyl-2- (4-{[1-methyl-4- (pyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline,
    3-methyl-2- [4-({[1-methyl-4- (pyridazin-4-yl) -1H-pyrazol-3-yl] oxy} methyl) phenyl] quinoline,
    2- (4-{[(1,1′-dimethyl-1H, 1′H-4,4′-bipyrazol-3-yl) oxy] methyl} phenyl) -3-methylquinoline,
    1-methyl-5- (1-methyl-3-{[4- (quinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
    1-ethyl-5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
    5- (1-methyl-3-{[4- (3-methylquinolin-2-yl) benzyl] oxy} -1H-pyrazol-4-yl) -1-propylpyridin-2 (1H) -one,
    5- (3-{[4- (6-Fluoro-3-methylquinolin-2-yl) benzyl] oxy} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
    1-methyl-5- (2-methyl-5-{[4- (3-methylquinolin-2-yl) phenoxy] methyl} -2H-1,2,3-triazol-4-yl) pyridine-2 ( 1H) -On,
    3-methyl-2- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline,
    2- (4-{[4- (2,6-dimethylpyridin-4-yl) -1-methyl-1H-pyrazol-3-yl] methoxy} phenyl) -3-methylquinoline,
    1-methyl-4- (1-methyl-3- {2- [4- (3-methylquinolin-2-yl) phenyl] ethyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one ,
    1-methyl-4- (1-methyl-3-{[4- (3-methylquinolin-2-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
    1-methyl-4- (4-{[1-methyl-4- (2-methyl-1-oxidepyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) -1H-benzimidazole,
    1-methyl-4- (4-{[1-methyl-4- (pyridazin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) -1H-benzimidazole,
    1-methyl-4- (1-methyl-3-{[4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridine-2 (1H) -on,
    1'-ethyl-1-methyl-3-{[4- (1-methyl-1H-benzimidazol-4-yl) phenoxy] methyl} -1H, 1'H-4,4'-bipyrazole,
    1-methyl-5- (1-methyl-3-{[4- (quinolin-8-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
    5- (3-{[4- (6-Methoxy-3-methylquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridine-2 (1H) -on,
    8- (4-{[1-methyl-4- (pyrazin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline,
    1-methyl-5- (1-methyl-3-{[4- (quinolin-2-yl) phenoxy] methyl} -1H-pyrazol-4-yl) pyridin-2 (1H) -one,
    5- (3-{[4- (3-methoxyquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
    5- (3-{[4- (6-fluoroquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
    5- (3-{[4- (6-methoxyquinolin-2-yl) phenoxy] methyl} -1-methyl-1H-pyrazol-4-yl) -1-methylpyridin-2 (1H) -one,
    3-methyl-8- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) imidazo [1,2-a] pyridine,
    1,1′-dimethyl-3-{[4- (3-methylimidazo [1,2-a] pyridin-8-yl) phenoxy] methyl} -1H, 1′H-4,4′-bipyrazole, or ,
    The compound or a salt thereof according to claim 1, which is 2- (4-{[1-methyl-4- (2-methylpyridin-4-yl) -1H-pyrazol-3-yl] methoxy} phenyl) quinoline.
  21. 請求項１に記載の化合物又はその塩、及び製薬学的に許容される賦形剤を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.
  22. 請求項１に記載の化合物又はその塩を含有する統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防並びに／又は治療剤。 A prophylactic and / or therapeutic agent for schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease comprising the compound according to claim 1 or a salt thereof.
  23. 統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療用医薬組成物の製造のための請求項１に記載の化合物又はその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease.
  24. 統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療のための請求項１に記載の化合物又はその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the prevention and / or treatment of schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease.
  25. 請求項１に記載の化合物又はその塩の有効量を対象に投与することからなる統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療方法。 A method for preventing and / or treating schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease, comprising administering an effective amount of the compound or salt thereof according to claim 1 to a subject.
  26. 統合失調症、不安症、ハンチントン舞踏病、薬物依存、及び／若しくはアルツハイマー病の予防及び／又は治療のための請求項１に記載の化合物又はその塩。 The compound according to claim 1 or a salt thereof for the prevention and / or treatment of schizophrenia, anxiety, Huntington's chorea, drug dependence, and / or Alzheimer's disease.
PCT/JP2012/058291 2011-03-31 2012-03-29 Pyrazole compound WO2012133607A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-077864 2011-03-31
JP2011077864A JP2014122161A (en) 2011-03-31 2011-03-31 Pyrazole compounds

Publications (1)

Publication Number Publication Date
WO2012133607A1 true WO2012133607A1 (en) 2012-10-04

Family

ID=46931309

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/058291 WO2012133607A1 (en) 2011-03-31 2012-03-29 Pyrazole compound

Country Status (3)

Country Link
JP (1) JP2014122161A (en)
TW (1) TW201302730A (en)
WO (1) WO2012133607A1 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014133046A1 (en) * 2013-02-27 2014-09-04 持田製薬株式会社 Novel pyrazole derivative
WO2014142322A1 (en) 2013-03-15 2014-09-18 第一三共株式会社 Benzothiophene derivative
WO2015000715A1 (en) 2013-07-02 2015-01-08 Syngenta Participations Ag Pesticidally active bi- or tricyclic heterocycles with sulfur containing substituents
WO2015051045A3 (en) * 2013-10-04 2015-07-30 Novartis Ag 3'END CAPS FOR RNAi AGENTS FOR USE IN RNA INTERFERENCE
WO2018095795A1 (en) 2016-11-23 2018-05-31 Syngenta Participations Ag Pesticidally active polycyclic derivatives with sulfur containing substituents
WO2018206348A1 (en) 2017-05-08 2018-11-15 Syngenta Participations Ag Imidazopyrimidine derivatives with sulfur containing phenyl and pyridyl substituents
WO2019070044A1 (en) 2017-10-06 2019-04-11 武田薬品工業株式会社 Heterocyclic compounds
WO2020016443A1 (en) 2018-07-20 2020-01-23 Boehringer Ingelheim International Gmbh Difluoromethyl-phenyl triazoles as gaba receptor modulators
WO2020141135A1 (en) 2018-12-31 2020-07-09 Syngenta Crop Protection Ag Pesticidally active heterocyclic derivatives with sulfur containing substituents
WO2020250183A1 (en) 2019-06-13 2020-12-17 Pi Industries Ltd. Fused heterocyclic compounds and their use as pest control agents
WO2021171035A1 (en) 2020-02-28 2021-09-02 Benevolentai Cambridge Limited Compositions and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018195155A1 (en) * 2017-04-18 2018-10-25 Celgene Quanticel Research, Inc. Therapeutic compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006072828A2 (en) * 2005-01-07 2006-07-13 Pfizer Products Inc. Heteroaromatic quinoline compounds and their use as pde10 inhibitors
WO2007077490A2 (en) * 2006-01-05 2007-07-12 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors
WO2007129183A2 (en) * 2006-05-02 2007-11-15 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors
WO2008131000A2 (en) * 2007-04-16 2008-10-30 Abbott Laboratories 7-substituted indole mcl-1 inhibitors
WO2010100606A1 (en) * 2009-03-03 2010-09-10 Pfizer Inc. Novel phenyl imidazoles and phenyl triazoles as gamma-secretase modulators

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006072828A2 (en) * 2005-01-07 2006-07-13 Pfizer Products Inc. Heteroaromatic quinoline compounds and their use as pde10 inhibitors
WO2007077490A2 (en) * 2006-01-05 2007-07-12 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors
WO2007129183A2 (en) * 2006-05-02 2007-11-15 Pfizer Products Inc. Bicyclic heteroaryl compounds as pde10 inhibitors
WO2008131000A2 (en) * 2007-04-16 2008-10-30 Abbott Laboratories 7-substituted indole mcl-1 inhibitors
WO2010100606A1 (en) * 2009-03-03 2010-09-10 Pfizer Inc. Novel phenyl imidazoles and phenyl triazoles as gamma-secretase modulators

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9458157B2 (en) 2013-02-27 2016-10-04 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
CN106957317B (en) * 2013-02-27 2019-12-31 持田制药株式会社 Novel pyrazole derivatives
US8980889B2 (en) 2013-02-27 2015-03-17 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
US9440970B2 (en) 2013-02-27 2016-09-13 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
CN106957317A (en) * 2013-02-27 2017-07-18 持田制药株式会社 Novel pyrazole derivative
US8980888B2 (en) 2013-02-27 2015-03-17 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
US9453015B2 (en) 2013-02-27 2016-09-27 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
US9777000B2 (en) 2013-02-27 2017-10-03 Mochida Pharmaceutical Co., Ltd. Pyrazole derivative
WO2014133046A1 (en) * 2013-02-27 2014-09-04 持田製薬株式会社 Novel pyrazole derivative
US9464076B2 (en) 2013-03-15 2016-10-11 Daiichi Sankyo Company, Limited Benzothiophene derivative
WO2014142322A1 (en) 2013-03-15 2014-09-18 第一三共株式会社 Benzothiophene derivative
EP3778598A2 (en) 2013-07-02 2021-02-17 Syngenta Participations Ag Pesticidally active bi- or tricyclic heterocycles with sulfur containing substituents
WO2015000715A1 (en) 2013-07-02 2015-01-08 Syngenta Participations Ag Pesticidally active bi- or tricyclic heterocycles with sulfur containing substituents
WO2015051045A3 (en) * 2013-10-04 2015-07-30 Novartis Ag 3'END CAPS FOR RNAi AGENTS FOR USE IN RNA INTERFERENCE
US11008570B2 (en) 2013-10-04 2021-05-18 Novartis Ag 3′ end caps for RNAi agents for use in RNA interference
JP2019135236A (en) * 2013-10-04 2019-08-15 ノバルティス アーゲー 3' TERMINAL CAP FOR RNAi AGENT USED FOR RNA INTERFERENCE
EP3722277A3 (en) * 2013-10-04 2021-01-20 Novartis AG 3'end caps for rna-interferring agents for use in rna
WO2018095795A1 (en) 2016-11-23 2018-05-31 Syngenta Participations Ag Pesticidally active polycyclic derivatives with sulfur containing substituents
WO2018206348A1 (en) 2017-05-08 2018-11-15 Syngenta Participations Ag Imidazopyrimidine derivatives with sulfur containing phenyl and pyridyl substituents
WO2019070044A1 (en) 2017-10-06 2019-04-11 武田薬品工業株式会社 Heterocyclic compounds
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
WO2020016443A1 (en) 2018-07-20 2020-01-23 Boehringer Ingelheim International Gmbh Difluoromethyl-phenyl triazoles as gaba receptor modulators
WO2020141135A1 (en) 2018-12-31 2020-07-09 Syngenta Crop Protection Ag Pesticidally active heterocyclic derivatives with sulfur containing substituents
WO2020250183A1 (en) 2019-06-13 2020-12-17 Pi Industries Ltd. Fused heterocyclic compounds and their use as pest control agents
WO2021171035A1 (en) 2020-02-28 2021-09-02 Benevolentai Cambridge Limited Compositions and uses thereof

Also Published As

Publication number Publication date
JP2014122161A (en) 2014-07-03
TW201302730A (en) 2013-01-16

Similar Documents

Publication Publication Date Title
WO2012133607A1 (en) Pyrazole compound
US10730863B2 (en) Bridged bicyclic compounds as farnesoid X receptor modulators
US9085540B2 (en) Pyrazinecarboxamide compound
US20230128041A1 (en) Parp1 inhibitors and uses thereof
AU2011251321B2 (en) Nitrogen-containing heterocyclic compound having kynurenine production inhibitory activity
JP5918774B2 (en) Triazole derivatives and their use for neurological disorders
JP5800814B2 (en) Heterocyclic compounds and uses thereof
JP2017522346A (en) Compounds active against bromodomain
KR20160132041A (en) Azaspiro derivatives as trpm8 antagonists
JP2017095366A (en) Novel biaryl amide derivative
EP2474540A1 (en) Gpr119 agonist
US20130165483A1 (en) Heteroaryls and uses thereof
JP2011524881A (en) 2-Arylaminoquinazolines for the treatment of proliferative diseases
JP2022532718A (en) ACSS2 inhibitor and its usage
WO2021079962A1 (en) Pharmaceutical composition for prevention and/or treatment of hearing loss
CN105884695B (en) Heterocyclic derivatives species tyrosine kinase inhibitor
US9266840B2 (en) Bicyclic heterocyclic compound
JP2019511466A (en) Halo substituted piperidines as orexin receptor modulators
US20160159814A1 (en) Glycine transporter inhibitor
KR20140025326A (en) Novel indole or indazole derivative or salt thereof
US20150166505A1 (en) Pyridinyl-substituted pyrazolyl carboxamides
KR20160018686A (en) Bicyclic nitrogen-containing aromatic heterocyclic amide compound
CN100572381C (en) The pyrazolo naphthyridines derivatives
WO2018130227A1 (en) Aromatic ring-containing compound, preparation method therefor, pharmaceutical composition, and use
CN108779100A (en) 3,4- bipyridyls pyrazole derivatives, preparation method and its application in medicine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12764589

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12764589

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP