WO2014181813A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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WO2014181813A1
WO2014181813A1 PCT/JP2014/062307 JP2014062307W WO2014181813A1 WO 2014181813 A1 WO2014181813 A1 WO 2014181813A1 JP 2014062307 W JP2014062307 W JP 2014062307W WO 2014181813 A1 WO2014181813 A1 WO 2014181813A1
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group
ring
optionally substituted
compound
pyridin
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PCT/JP2014/062307
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Japanese (ja)
Inventor
智也 湯川
佐々木　聡
慶英 遠又
徹哉 塚本
善久 中田
隆文 高井
正記 瀬藤
泰祐 加藤
正司 福本
弥生 吉富
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武田薬品工業株式会社
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Publication of WO2014181813A1 publication Critical patent/WO2014181813A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterocyclic compound having an inhibitory action on protein kinase C (sometimes abbreviated as “PKC” in the present specification) and useful for the treatment of immune diseases, inflammatory diseases, and the like, and a medicament containing them It relates to compositions and the like.
  • PKC protein kinase C
  • T cells play an important role as part of an acquired immune mechanism that eliminates foreign antigens such as viruses and bacteria and cancer.
  • foreign antigens such as viruses and bacteria and cancer.
  • T cell activation is involved in the development of autoimmune diseases and causes adverse reactions to the human body such as rejection associated with transplantation. It is considered to be a promising therapeutic target in these diseases (Non-patent Document 1).
  • the PKC family consists of at least 12 types and is known to be expressed in various tissues.
  • the PKC family is expressed in immunocompetent cells such as T cells, B cells, and macrophages and plays an important role in various immune responses, and is therefore considered to be involved in immune diseases and inflammatory diseases (non-) Patent Document 4).
  • PKC- ⁇ is a phosphorylase that is selectively expressed in T cells, plays a role in the activation of T cells, is responsible for the transmission of stimuli to T cell receptors into cells.
  • Inhibition of PKC- ⁇ is known to suppress T cell activation (Non-patent Document 5), and PKC- ⁇ -deficient mice are used in multiple sclerosis models, inflammatory bowel disease models, grafts.
  • PKC eg, PKC- ⁇
  • organ transplantation such as kidney transplantation, liver transplantation, heart transplantation, lung transplantation, pancreatic transplantation, small intestine transplantation, rejection reaction in bone marrow transplantation, graft Anti-host disease, Behcet's disease, psoriasis vulgaris, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, aplastic anemia, erythroblastosis, nephrotic syndrome, systemic myasthenia gravis, atopic dermatitis It becomes a prophylactic or therapeutic agent in various immune diseases and inflammatory diseases such as ulcerative colitis and asthma.
  • R 1 is —NR 9 R 10 , —NR 9 COR 9 , —S (O) n R 12 and the like (R 9 , R 10 and R 12 are each independently C 3-6 cycloalkyl, C 4 ⁇ 7 represents cycloalkylalkyl, n represents 0-2), cyano, C 1-4 haloalkyl, etc., or C 1-6 alkyl, C 3-6 cycloalkyl, etc.
  • a 1 and A 2 independently represent N or CR 5 ; W represents ⁇ O, ⁇ S, —H or (—H, —H); X represents N or CR 1 ; Y represents —C (R Y ) 2 —, —NR Y — or the like (R Y represents H or the like); R 2 represents H, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl and the like; B represents R 3 , NHR 3 or the like; R 3 represents C 1-10 alkyl or the like; R 4 represents H, —OR 10 , —COR 9 , halogen, C 1-6 alkyl, C 3-6 cycloalkyl and the like; R 5 represents H, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-6 cycloalkyl or
  • R 1 and R 2 are independently H, halogen, —OR ′ (R ′ is substituted with H, C 1-6 alkyl (—OR, —N (R) 2 , cyano, oxo, etc. And cyano, C 1-10 aliphatic compounds (optionally substituted with halogen, —OR, —N (R) 2 , cyano, etc.)]
  • R ′ is substituted with H, C 1-6 alkyl (—OR, —N (R) 2 , cyano, oxo, etc.
  • cyano C 1-10 aliphatic compounds (optionally substituted with halogen, —OR, —N (R) 2 , cyano, etc.)]
  • B represents an optionally substituted 5-membered aromatic heterocyclic ring
  • R 1 and R 2 independently represent H, halogen, —OR ′, cyano, C 1-10 aliphatic compound (halogen, —OR, —N (R) 2 , —C (O) R, cyano, Optionally substituted with oxo, etc.), C 3-8 alicyclic compounds (halogen, —OR, —N (R) 2 , cyano, oxo, C 1-6 alkyl (halogen, —OR, —N ( R) 2 , —C (O) R, optionally substituted with cyano, oxo and the like)) and the like;
  • X represents C or N;
  • R X is absent or represents H;
  • C is an optionally substituted 3-8 membered monocycle (having 0-3 heteroatoms), an optionally substituted C 8-12 bicyclic ring (0-5 heteroatoms) Having R represents H or C 1-6 al
  • B represents an optionally substituted 6-membered aromatic heterocyclic ring or the like
  • R 1 and R 2 independently represent H, halogen, —OR ′, cyano, C 1-10 aliphatic compound (halogen, —OR, —N (R) 2 , —C (O) R, cyano, Optionally substituted with oxo, etc.), C 3-8 alicyclic compounds ( optionally substituted with halogen, —OR, —N (R) 2 , cyano, oxo, C 1-6 alkyl, etc.) Etc .
  • R 3 is absent or represents H, C 1-6 alkyl (optionally substituted with halogen, —OR, —N (R) 2 , —C (O) R, cyano, oxo, etc.)
  • R 4 is an optionally substituted C 1-10 aliphatic compound, an optionally substituted 3-8 membered monocycle (having 0-3 heteroatoms), an optionally substituted
  • B represents an optionally substituted 5-membered aromatic heterocyclic ring
  • R 1 and R 2 independently represent H, halogen, cyano, —OR ′, C 1-10 aliphatic compound (halogen, —OR, —N (R) 2 , —C (O) R, cyano, Optionally substituted with oxo, etc.), C 3-8 alicyclic compounds (halogen, —OR, —N (R) 2 , cyano, oxo, C 1-6 alkyl (halogen, —OR, —N ( R) 2 , —C (O) R, optionally substituted with cyano, oxo, etc.))
  • R 3 is absent or is H, C 1-6 alkyl (optionally substituted with halogen, —OR, —N (R) 2 , —C (O) R, cyano, oxo, etc.)
  • R 4 is an optionally substituted C 1-10 aliphatic compound, an
  • An object of the present invention is to provide a compound having excellent PKC inhibitory activity and useful as a preventive or therapeutic agent for immune diseases, inflammatory diseases and the like.
  • Ring A represents an optionally substituted monocyclic nitrogen-containing aromatic heterocycle (the heterocycle may be condensed) (wherein,
  • X represents a carbon atom or a nitrogen atom;
  • Y represents a bond, a C 1-6 alkylene group, —NR 4 —, —O—, —CO—, —CONH—, —NHCO—, —S—, —S (O) —, —S (O).
  • R 4 represents a hydrogen atom or a C 1-6 alkyl group;
  • Ring B represents a benzene ring which may be further substituted, or a heterocyclic ring which may be further substituted.
  • R 2 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a cyano group, or an amino optionally substituted by 1 to 2 C 1-6 alkyl groups
  • R 1 , R 2 and R 3 independently represent a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-10 cycloalkyl group, An optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-10 cycloalkyloxy group or an optionally substituted C 6-14 aryl group
  • Ring A is each (1) a halogen atom, (2) a cyano group, (3) Nitro group, (4) an optionally substituted C 1-6 alkyl group, (5) an optionally substituted C 3-10 cycloalkyl group, (6) an optionally substituted C
  • the present invention also provides: [1A] Formula (I):
  • Ring A represents an optionally substituted monocyclic nitrogen-containing aromatic heterocycle (the heterocycle may be condensed) (wherein,
  • X represents a carbon atom or a nitrogen atom;
  • Y represents a bond, a C 1-6 alkylene group, —NR 4 —, —O—, —CO—, —CONH—, —NHCO—, —S—, —S (O) —, —S (O).
  • R 4 represents a hydrogen atom or a C 1-6 alkyl group;
  • Ring B represents a benzene ring which may be further substituted, or a heterocyclic ring which may be further substituted.
  • R 2 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group optionally substituted with 1 to 2 C 1-6 alkyl groups, or cyano
  • R 2 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group optionally substituted with 1 to 2 C 1-6 alkyl groups, or cyano
  • [3A] A medicament comprising the compound of [1A] above or a salt thereof;
  • [5A] The medicament according to [3A] above, which is a prophylactic or therapeutic agent for immune diseases or inflammatory diseases;
  • [6A] The compound of the above-mentioned [1A] or a salt thereof
  • Compound (I) has excellent PKC (eg, PKC ⁇ ) inhibitory activity, high PKC ⁇ selectivity, high HERG inhibitory activity, low cytotoxicity, low ability to induce phospholipidosis, immune disease and inflammation It is useful as a preventive or therapeutic agent for sexually transmitted diseases.
  • PKC eg, PKC ⁇
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
  • the "optionally halogenated C 1-6 alkyl group" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkyl group is mentioned.
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
  • examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
  • the "optionally halogenated C 3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 3- A 10 cycloalkyl group.
  • Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • examples of the “C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
  • examples of the “C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • the "optionally halogenated C 1-6 alkoxy group" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkoxy group is mentioned.
  • Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl.
  • Examples include oxy and hexyloxy.
  • examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • the "optionally halogenated C 1-6 alkylthio group optionally" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6
  • An alkylthio group is mentioned. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
  • examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
  • examples of the “ optionally halogenated C 1-6 alkyl-carbonyl group” include, for example, C 1 which may have 1 to 7, preferably 1 to 5, halogen atoms.
  • a -6 alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
  • examples of the “C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the “C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
  • examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
  • examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
  • examples of the “mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
  • examples of the “C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
  • the "optionally halogenated C 1-6 alkyl sulfonyl group" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1- 6 alkylsulfonyl group is mentioned.
  • Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
  • examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
  • examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group.
  • An optionally substituted amino group an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
  • examples of the “hydrocarbon group” include, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, Examples thereof include a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, and a C 7-16 aralkyl group.
  • examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
  • substituent group A (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy), (8) C 7-16 aralkyloxy group (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy), (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), (12) C 6-14 aryl-carbony
  • the number of the above substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom.
  • heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom.
  • an aromatic heterocyclic group (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .
  • the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyri
  • non-aromatic heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • non-aromatic heterocyclic group examples include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyr
  • preferable examples of the “7 to 10-membered hetero-bridged cyclic group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
  • examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring constituent atom in the “heterocyclic group”.
  • examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
  • the number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • acyl group is, for example, “1 selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group.
  • acyl group examples include a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
  • the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded
  • the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded
  • the hydrocarbon-sulfinyl group is a hydrocarbon group.
  • a sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
  • acyl group a formyl group, a carboxy group, a C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (eg, crotonoyl), a C 3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl)
  • Diallylcarbamoyl mono- or di-C 3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C 7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di -C 2-6 alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di cycl
  • examples of the “optionally substituted amino group” include, for example, a C 1-6 alkyl group each having 1 to 3 substituents selected from the substituent group A, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7- 16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group Mono- or di-C 1-6 alkyl-carbamoyl group, mono- or di-C 7-16 aralkyl-carbamoyl group, C 1-6 alkylsulfonyl group and C 6-1 And an amino group optionally
  • Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C 1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino groups (eg, diallylamino), mono- or di-C 3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 arylamino group (eg, phenylamino), mono- or di-C 7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C 1-6 alkyl) - carbonyl amino group (e.g., a Chiru
  • examples of the “optionally substituted carbamoyl group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - 1 or 2 substituents selected from a carbamoyl group
  • Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group).
  • Mono- or di-C 3-10 cycloalkyl-carbamoyl groups eg cyclopropylcarbamoyl, cyclohexylcarbamoyl
  • mono- or di-C 6-14 aryl-carbamoyl groups eg phenylcarbamoyl
  • mono- or Di-C 7-16 aralkyl-carbamoyl group mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl)
  • a 5- to 14-membered aromatic heterocyclic carbamoyl group eg, pyridylcarbamoyl
  • pyridylcarbamoyl pyridylcarb
  • examples of the “optionally substituted thiocarbamoyl group” include, for example, “C 1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - one or two location selected from a carbamoyl
  • thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio).
  • examples of the “optionally substituted sulfamoyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - 1 or 2 substituents selected from a carbamoyl group
  • the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C 1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl).
  • examples of the “optionally substituted hydroxy group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy).
  • C 3-10 cycloalkyloxy group eg, cyclohexyloxy
  • C 6-14 aryloxy group eg, phenoxy, naphthyloxy
  • C 7-16 aralkyloxy group eg, benzyloxy, phenethyloxy
  • C 1-6 alkyl-carbonyloxy group eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • C 6-14 aryl-carbonyloxy group eg, benzoyloxy
  • C 7-16 aralkyl- A carbonyloxy group eg benzylcarbonyloxy)
  • 5 to 14-membered aromatic heterocyclic carbonyloxy group e.g., nicotinoyl oxy
  • 3 to 14-membered non-aromatic heterocyclic carbonyloxy group e.g., piperidinylcarbonyl oxy
  • examples of the “optionally substituted sulfanyl group” include a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”.
  • C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
  • the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio group (eg, cyclohexylthio), C 6-14 arylthio group (eg, phenylthio, naphthylthio), C 7-16 aralkylthio group (eg, benzylthio, phenethylthio), C 1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonylthio group (eg, benzoylthio), 5-
  • examples of the “optionally substituted silyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”
  • a silyl group optionally having 1 to 3 substituents selected from a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group ” Can be mentioned.
  • the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).
  • examples of the “C 1-6 alkylene group” include —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 —, — (CH 2 ) 4 —, — (CH 2 ) 5 —, — (CH 2 ) 6 —, —CH (CH 3 ) —, —C (CH 3 ) 2 —, —CH (C 2 H 5 ) —, —CH (C 3 H 7 ) —, —CH (CH (CH 3 ) 2 ) —, — (CH (CH 3 )) 2 —, —CH 2 —CH (CH 3 ) —, —CH (CH 3 ) —CH 2 —, —CH 2 —CH 2 -C (CH 3) 2 - , - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2
  • heterocycle examples include aromatic heterocycles each containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom.
  • Non-aromatic heterocycles may be mentioned.
  • the “aromatic heterocycle” includes, for example, a 5- to 14-membered ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom ( Preferred is a 5- to 10-membered aromatic heterocyclic ring.
  • Suitable examples of the “aromatic heterocycle” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi 5- to 6-membered monocyclic aromatic heterocycle such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazol
  • non-aromatic heterocyclic ring is, for example, a 3 to 14 member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. (Preferably 4 to 10 membered) non-aromatic heterocycle.
  • non-aromatic heterocycle examples include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline.
  • examples of the “nitrogen-containing heterocycle” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocycle”.
  • R 1 , R 2 and R 3 independently represent a hydrogen atom or a substituent.
  • substituents include a halogen atom (eg, fluorine atom), a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group. (Eg, methoxy, ethoxy), a cyano group, an optionally substituted amino group, and the like.
  • R 1 is preferably a hydrogen atom.
  • R 2 is preferably a hydrogen atom, a halogen atom (eg, fluorine atom), a C 1-6 alkyl group, a C 1-6 alkoxy group, or one or two C 1-6 alkyl groups.
  • a good amino group or a cyano group more preferably a hydrogen atom or a halogen atom (eg, fluorine atom).
  • R 3 is preferably a hydrogen atom, a C 1-6 alkyl group (eg, methyl), or a C 1-6 alkoxy group (eg, methoxy, ethoxy).
  • R 1 , R 2 and R 3 are preferably independently a hydrogen atom, a halogen atom (eg, a fluorine atom, a chlorine atom), an optionally substituted C 1- 6 alkyl group (eg, methyl), optionally substituted C 3-10 cycloalkyl group (eg, cyclopropyl), optionally substituted C 1-6 alkoxy group (eg, methoxy, ethoxy), substituted An optionally substituted C 3-10 cycloalkyloxy group (eg, cyclobutyloxy) or an optionally substituted C 6-14 aryl group (eg, phenyl), more preferably independently atom, a halogen atom (e.g., fluorine atom, chlorine atom), C 1-6 alkyl group (e.g., methyl), C 3-10 cycloalkyl group (e.g., cyclopropyl), C 3-10 cycloalkyl group (e.g.
  • a C 1-6 alkoxy group e.g. optionally substituted cyclopropyl, methoxy, ethoxy
  • C 3-10 cycloalkyl group e.g., cyclobutyloxy
  • C 6-14 aryl group e.g., phenyl
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom or a halogen atom (eg, fluorine atom, chlorine atom)
  • R 3 is a hydrogen atom, C 1-6 alkyl C 1-6 alkoxy group (eg, optionally substituted with a group (eg, methyl), C 3-10 cycloalkyl group (eg, cyclopropyl), C 3-10 cycloalkyl group (eg, cyclopropyl) Methoxy, ethoxy), a C 3-10 cycloalkyloxy group (eg, cyclobutyloxy) or a C 6-14 aryl group (eg, pheny
  • Ring A represents a monocyclic nitrogen-containing aromatic heterocycle which may be further substituted (the heterocycle may be condensed), wherein ring A
  • N- or -N .
  • Examples of the “monocyclic nitrogen-containing aromatic heterocycle” of the “optionally substituted monocyclic nitrogen-containing aromatic heterocycle” represented by ring A include, for example, a 5- to 6-membered monocyclic nitrogen-containing aromatic Group heterocycles (eg, thiazole ring, pyridine ring, pyrimidine ring), and preferred are thiazole ring, pyridine ring, pyrimidine ring and the like.
  • the “monocyclic nitrogen-containing aromatic heterocycle” of the “optionally substituted monocyclic nitrogen-containing aromatic heterocycle” represented by ring A may be condensed, for example, 5 to 6-membered It may be condensed with a monocyclic aromatic heterocycle (eg, thiophene ring). Examples of such a condensed ring include a thienopyrimidine ring.
  • the “monocyclic nitrogen-containing aromatic heterocycle” of the “optionally substituted monocyclic nitrogen-containing aromatic heterocycle” represented by ring A is 1,3-dihydro-2H at the substitutable position.
  • -1 to 4 preferably 1 to 3, more preferably 1 or 2
  • substituents other than imidazo [4,5-b] pyridin-2-one ring group and ring BY- group May be substituted.
  • substituents include substituents selected from the above-mentioned substituent group A, and include halogen atoms (eg, fluorine atoms), cyano groups, carboxy groups, C 1-6 alkoxy-carbonyl groups (eg, Ethoxycarbonyl), a carbamoyl group and the like are preferable.
  • Ring A is preferably a thiazole ring, pyridine ring, pyrimidine ring, or thienopyrimidine ring, each of which may be further substituted, and more preferably a halogen atom (eg, fluorine atom), cyano group, Further substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) substituents selected from a carboxy group, a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and a carbamoyl group A thiazole ring, a pyridine ring, a pyrimidine ring, or a thienopyrimidine ring.
  • a halogen atom eg, fluorine atom
  • cyano group cyano group
  • ring A more preferably, (1) a thiazole ring, (2) 1 to 4 (preferably 1 to 3) selected from a halogen atom (eg, fluorine atom), a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and a carbamoyl group , More preferably 1 or 2) substituents which may be further substituted with substituents, (3) A pyrimidine ring optionally substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) halogen atoms (eg, fluorine atom), or (4) a thienopyrimidine ring It is.
  • 1 to 4 preferably 1 to 3
  • halogen atoms eg, fluorine atom
  • ring A is preferably each (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) Nitro group, (4) an optionally substituted C 1-6 alkyl group (eg, methyl, isopropyl), (5) an optionally substituted C 3-10 cycloalkyl group (eg, cyclopropyl), (6) an optionally substituted C 1-6 alkoxy group (eg, methoxy), (7) an optionally substituted amino group, (8) a carboxy group, (9) an optionally substituted C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), (10) an optionally substituted carbamoyl group, (11) an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl), and (12) an optionally substituted 5- to 6-membered monocyclic aromatic heterocyclic group (E
  • X represents a carbon atom or a nitrogen atom. X is preferably a carbon atom.
  • Y represents a bond, a C 1-6 alkylene group, —NR 4 — (wherein R 4 represents a hydrogen atom or a C 1-6 alkyl group), —O—, —CO—, —CONH— , -NHCO -, - S -, - S (O) -, - S (O) 2 -, - S (O) 2 NH-, or -NHS (O) 2 - it shows a.
  • Y is preferably a bond, —O— or —NR 4 — (wherein R 4 is a hydrogen atom or a C 1-6 alkyl group), and more preferably a bond, — O— or —NR 4 — (wherein R 4 is a hydrogen atom).
  • Ring B represents a benzene ring which may be further substituted or a heterocyclic ring which may be further substituted.
  • the “benzene ring” of the “optionally substituted benzene ring” or the “heterocycle” of the “optionally substituted heterocycle” represented by ring B is the -ring A— It may be further substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) substituents other than Y-group.
  • a substituent for example, (1) a cyano group, (2) an oxo group, (3) a hydroxy group, (4) an optionally substituted C 1-6 alkyl group, (5) an optionally substituted C 3-10 cycloalkyl group, (6) a C 6-14 aryl group, (7) an optionally substituted amino group, (8)
  • An optionally substituted carbamoyl group may be mentioned, preferably (1) a cyano group, (2) an oxo group, (3) a hydroxy group, (4) 1 to 4 selected from a halogen atom (eg, fluorine atom), a hydroxy group, a C 1-6 alkoxy group (eg, methoxy), a C 3-10 cycloalkyl group (eg, cyclobutyl), and an amino group C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, isobutyl, 3-methylbutan-2-yl) which may be substituted with (preferably 1 to
  • ring B preferably (1) a cyano group, (2) an oxo group, (3) a hydroxy group, (4) an optionally substituted C 1-6 alkyl group, (5) an optionally substituted C 3-10 cycloalkyl group, (6) a C 6-14 aryl group, 1 to 4 (preferably 1 to 3, more preferably 1 or 2) substituents selected from (7) an optionally substituted amino group and (8) an optionally substituted carbamoyl group
  • Ring B is more preferably (A) a pyrazole ring, (B) each (1) a cyano group, (2) an oxo group, (3) a hydroxy group, (4) 1 to 4 selected from a halogen atom (eg, fluorine atom), a hydroxy group, a C 1-6 alkoxy group (eg, methoxy), a C 3-10 cycloalkyl group (eg, cyclobutyl), and an amino group C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, isobutyl, 3-methylbutan-2-yl) which may be substituted with (preferably 1 to 3, more preferably 1 or 2) substituents 2-methylpentan-3-yl), (5) a C 3-10 cycloalkyl group (eg, cyclopropyl) optionally substituted with a hydroxy group, (6) C 6-14 aryl group (eg, phenyl), (7) an amino group optionally substituted with
  • ring B is preferably each (1) a halogen atom (eg, a fluorine atom), (2) a cyano group, (3) an oxo group, (4) a hydroxy group, (5) an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, isobutyl, 3-methyl-butan-2-yl, 4-methyl-pentan-3-yl, 3, 3-dimethyl-butan-2-yl), (6) an optionally substituted C 3-10 cycloalkyl group (eg, cyclopropyl), (7) an optionally substituted C 6-14 aryl group (eg, phenyl), (8) an optionally substituted C 1-6 alkyl-carbonyl group (eg, acetyl), (9) an optionally substituted amino group, (10) an optionally substituted carbamoyl group, (11) an optionally substituted 3- to 8-membered monocycl
  • R 1 , R 2 and R 3 independently represent a hydrogen atom, a halogen atom (eg, fluorine atom), a C 1-6 alkyl group (eg, methyl), a C 1-6 alkoxy group (eg, methoxy, ethoxy ), A cyano group, or an optionally substituted amino group;
  • Ring A is a thiazole ring, pyridine ring, pyrimidine ring, or thienopyrimidine ring, each of which may be further substituted;
  • X is a carbon atom;
  • Y is a bond, —O— or —NR 4 — (wherein R 4 is a hydrogen atom or a C 1-6 alkyl group);
  • Ring B is each (1) a cyano group, (2) an oxo group, (3) a hydroxy group, (4) an optionally substituted C 1-6 alkyl group, (5) an optionally substituted C 3-10 cycl
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom, a halogen atom (eg, a fluorine atom), a C 1-6 alkyl group, a C 1-6 alkoxy group, or an amino group optionally substituted by 1 to 2 C 1-6 alkyl groups Or a cyano group
  • R 3 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), or a C 1-6 alkoxy group (eg, methoxy, ethoxy)
  • Ring A is 1 to 4 (preferably 1 to 4) each selected from a halogen atom (eg, fluorine atom), a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and a carbamoyl group.
  • a thiazole ring, a pyridine ring, a pyrimidine ring, or a thienopyrimidine ring which may be further substituted with 3 (and more preferably 1 or 2) substituents;
  • X is a carbon atom;
  • Y is a bond, —O— or —NR 4 — (wherein R 4 is a hydrogen atom);
  • Ring B is each (1) a cyano group, (2) an oxo group, (3) a hydroxy group, (4) 1 to 4 selected from a halogen atom (eg, fluorine atom), a hydroxy group, a C 1-6 alkoxy group (eg, methoxy), a C 3-10 cycloalkyl group (eg, cyclobutyl), and an amino group C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, isobutyl, 3-methylbutan-2-yl) which may be substituted with (preferably 1 to
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom or a halogen atom (eg, fluorine atom)
  • R 3 is a hydrogen atom, a C 1-6 alkyl group (eg, methyl), or a C 1-6 alkoxy group (eg, methoxy, ethoxy)
  • Ring A is (1) a thiazole ring, (2) 1 to 4 (preferably 1 to 3) selected from a halogen atom (eg, fluorine atom), a cyano group, a carboxy group, a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and a carbamoyl group , More preferably 1 or 2) substituents which may be further substituted with substituents, (3) a pyrimidine ring optionally substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) halogen atoms (eg, fluorine atom), or (4) a thienopyrim
  • R 1 , R 2 and R 3 are independently a hydrogen atom, a halogen atom (eg, a fluorine atom, a chlorine atom), an optionally substituted C 1-6 alkyl group (eg, methyl), a substituted An optionally substituted C 3-10 cycloalkyl group (eg, cyclopropyl), an optionally substituted C 1-6 alkoxy group (eg, methoxy, ethoxy), an optionally substituted C 3-10 cycloalkyloxy A group (eg, cyclobutyloxy) or an optionally substituted C 6-14 aryl group (eg, phenyl); Ring A is each (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) Nitro group, (4) an optionally substituted C 1-6 alkyl group (eg, methyl, isopropyl), (5) an optionally substituted C 3-10 cyclo
  • R 1 , R 2 and R 3 independently represent a hydrogen atom, a halogen atom (eg, fluorine atom, chlorine atom), a C 1-6 alkyl group (eg, methyl), a C 3-10 cycloalkyl group (eg, , Cyclopropyl), a C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with a C 3-10 cycloalkyl group (eg, cyclopropyl), a C 3-10 cycloalkyloxy group (eg, be cyclobutyloxy) or C 6-14 aryl group (e.g., phenyl); Ring A is each (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) Nitro group, (4) a C 1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 substituent
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom or a halogen atom (eg, fluorine atom, chlorine atom)
  • R 3 is substituted with a hydrogen atom, a C 1-6 alkyl group (eg, methyl), a C 3-10 cycloalkyl group (eg, cyclopropyl), a C 3-10 cycloalkyl group (eg, cyclopropyl)
  • An optionally substituted C 1-6 alkoxy group eg, methoxy, ethoxy
  • a C 3-10 cycloalkyloxy group eg, cyclobutyloxy
  • Ring A is each (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (2) a cyano group, (3) Nitro group, (4) a C 1-6 alkyl group (eg, methyl, isopropyl) optional
  • R 1 , R 2 and R 3 are independently a hydrogen atom, a C 1-6 alkoxy group (eg, ethoxy) or a C 3-10 cycloalkyloxy group (eg, cyclobutyloxy); Ring A is each (1) a halogen atom (eg, fluorine atom, chlorine atom), (2) a cyano group, (3) Nitro group, (4) a C 1-6 alkyl group (eg, methyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom (eg, fluorine atom) and a hydroxy group, (5) C 1-6 alkoxy group (eg, methoxy), (6) an amino group, and (7) a carbamoyl group, A 5- to 6-membered monocyclic aromatic heterocycle (eg, furan) which may be further substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) substituents selected from A monocyclic nitrogen-containing aromatic
  • R 1 , R 2 and R 3 are hydrogen atoms;
  • X is a carbon atom;
  • Y is a bond;
  • Each ring B is (1) a hydroxy group, and (2) a C 6-14 aryl group (eg, phenyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atoms).
  • a 3- to 8-membered monocyclic non-aromatic heterocycle (eg, piperidine) which may be further substituted with 1 to 4 (preferably 1 to 3, more preferably 1 or 2) substituents selected from Ring, piperazine ring); Compound (I).
  • Specific examples of the compound (I) include compounds of Examples 1 to 89, 93, 96 to 128, 130 to 170, 173 to 187, 189 to 225, and 227 to 376 described later.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like.
  • examples include salts.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the raw material compound or intermediate may be a salt, and examples of such a salt include the same salts as the compound (I).
  • the starting compound or intermediate when the starting compound or intermediate has an amino group, carboxyl group or hydroxy group as a substituent, these groups are protected with a protecting group generally used in peptide chemistry and the like. It may be.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • These protecting groups can be introduced or removed by methods known per se, for example, “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. W. W. W. W. The method may be performed according to the above method.
  • Examples of the protecting group for the amino group include a C 1-6 alkyl group, a C 7-14 aralkyl group (eg, benzyl, 4-methoxybenzyl) optionally substituted with a C 1-6 alkoxy group, a formyl group, A C 1-6 alkyl-carbonyl group, a C 1-6 alkoxy-carbonyl group (eg, a tert-butoxycarbonyl group (sometimes abbreviated as “Boc” in the specification)), a benzoyl group, a 4-fluorobenzoyl group, C 7-14 aralkyl-carbonyl group (eg, benzylcarbonyl etc.), C 7-14 aralkyloxy-carbonyl group (eg benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl etc.), trityl group, phthaloyl group, N, N- dimethylaminomethylene group, C 1-6 alkyl silyl group which may
  • Examples of the carboxyl-protecting group include a C 1-6 alkyl group, a C 7-14 aralkyl group (eg, benzyl etc.), a phenyl group, a trityl group, and a silyl group optionally substituted with a C 1-6 alkyl group.
  • Groups eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.
  • C 2-6 alkenyl groups eg, 1-allyl, etc.
  • Examples of the protecting group for hydroxy group include C 1-6 alkyl group, phenyl group, trityl group, C 7-14 aralkyl group (eg, benzyl etc.), formyl group, C 1-6 alkyl-carbonyl group, benzoyl group C 7-14 aralkyl-carbonyl group (eg, benzylcarbonyl etc.), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl group optionally substituted with C 1-6 alkyl group (eg, trimethylsilyl, Triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C 2-6 alkenyl groups (eg, 1-allyl, etc.) and the like. These protecting groups may be further substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl
  • the above-mentioned protecting group is a method known per se, for example, the method described by Wiley-Interscience 2006 published in “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. et al.). Can be removed. Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide, etc.) The method used, the reduction method, etc. can be used.
  • the intermediate obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from a reaction mixture according to a conventional method. In the case of isolation, it can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.
  • Each step described below can be performed without a solvent or by dissolving or suspending in an appropriate solvent, and a solvent in which two or more solvents are mixed at an appropriate ratio may be used.
  • Specific examples of the solvent used in the production method of the compound of the present invention include the following solvents.
  • Alcohols Methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol, tert-amyl alcohol and the like; Ethers: Diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc .; Aromatic hydrocarbons: Benzene, chlorobenzene, toluene, xylene, etc .; Saturated hydrocarbons: Cyclohexane, hexane, etc .; Amides: N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, N-methylpyrrolidone, etc .; Halogenated hydrocarbons: Dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc .; Nitriles:
  • base or deoxidizing agent used in the production method of the compound of the present invention include the following bases or deoxidizing agents.
  • Inorganic bases Sodium hydroxide, potassium hydroxide, magnesium hydroxide, potassium fluoride, etc .
  • Basic salts Sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, etc .
  • Organic bases Triethylamine, diethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5- Diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, imidazole
  • Specific examples of the acid or acidic catalyst used in the production method of the compound of the present invention include the following acids or acidic catalysts.
  • Inorganic acids Hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .
  • Organic acids Acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .
  • Lewis acid Boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
  • Compound (I) can be produced, for example, using the following Method A, Method B, or Method C. (Method A)
  • PG represents an amino-protecting group
  • LG represents a leaving group
  • other symbols have the same meanings as described above.
  • Examples of the protecting group represented by PG include a C 1-6 alkyl group, a C 7-14 aralkyl group (eg, benzyl, 4-methoxybenzyl) optionally substituted with a C 1-6 alkoxy group, a formyl group C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, 4-fluorobenzoyl group, C 7-14 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.), C 7-14 aralkyloxy -Carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, silyl group optionally substituted by C 1-6
  • a halogen atom for example, a chlorine atom, a bromine atom, an iodine atom, etc.
  • an optionally substituted sulfonyloxy group for example, 1 to 3 halogen atoms are substituted.
  • which may be C 1-6 alkylsulfonyloxy group (e.g., methanesulfonyloxy group, ethanesulfonyloxy group, etc.
  • trifluoromethanesulfonyloxy group 1 to be substituted with 3 C 1-6 alkyl groups Good C 6-14 arylsulfonyloxy group (eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc.); C 7-14 aralkylsulfonyloxy group (eg, benzylsulfonyloxy group, etc.), [(oxide) Phenyl- ⁇ 4-sulfanilidene] dimethylammonium group, etc. It is below.
  • C 6-14 arylsulfonyloxy group eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc.
  • C 7-14 aralkylsulfonyloxy group eg, benzylsulfonyloxy group, etc.
  • This step is a step of converting to compound (III) by protecting the amino group of compound (II).
  • This step can be carried out in the presence of a base or acid, without solvent, or in a solvent that does not adversely influence the reaction, if necessary.
  • “PG” is preferably a trimethylsilylethoxymethyl group.
  • the introduction of PG can be performed by selecting from methods described in Greene's protective groups in organic synthesis 4 th edition (Wiley-International Publication). For example, when a trimethylsilylethoxymethyl group is used, it can be carried out according to the method described in Bioorganic & Medicinal Chemistry, 18 (17), 6526-6537 (2010). Compound (III) obtained in this step may be used for the next reaction without isolation.
  • Compound (II) used as a raw material in this method may be a commercially available product, or may be produced by a method known per se or a method analogous thereto.
  • This step is a step of converting the compound (III) into the compound (IV) by reducing the nitro group.
  • “Reduction of nitro group” means, for example, a method by catalytic reduction reaction using a transition metal catalyst such as palladium, platinum, rhodium, Raney nickel, and the like; It can be carried out by a method using a metal hydride; a method using metal powder such as zinc, iron or tin under acidic conditions; Among these reactions, a method using a catalytic reduction reaction is preferable. For example, in the case of a method using palladium, it can be carried out according to the method described in WO2012 / 058125. Compound (IV) obtained in this step may be used for the next reaction without isolation.
  • Step A-3 This step is a step of converting compound (IV) to compound (V) by intramolecular cyclization reaction.
  • the “intramolecular cyclization reaction” is performed in the presence of a base, without solvent, or in a solvent that does not adversely influence the reaction.
  • Base is, for example, 1) Alkali metal or alkaline earth metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (eg, lithium amide, sodium) Amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide), alkali metal or alkaline earth metal C 1-6 alkoxide (eg, sodium) Strong bases such as methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide); 2) Alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, Inorgan
  • alkali metal or alkaline earth metal C 1-6 alkoxides (such as sodium methoxide) are preferable.
  • the amount of these bases to be used is about 0.1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (IV).
  • the intramolecular cyclization reaction in this step can be performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons and amides, or a mixed solvent thereof are preferable.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 0 to 150 ° C.
  • the compound (V) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography, and the like.
  • Step A-4 In this step, compound (V) and compound (VI) are condensed to convert to compound (VII). If necessary, this step can be carried out in the presence of a base by adding a metal catalyst, without solvent, or in a solvent that does not adversely influence the reaction.
  • metal catalyst metal composites having various ligands are used.
  • metal complexes include palladium compounds [eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium.
  • a ligand for example, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2,2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl, 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy-1,1′-biphenyl, 5- (di-t -Butylphosphino) -1 ', 3', 5'-triphenyl-1,4'-bi-1H-pyrazole, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1 '-Biphenyl, triphenylphosphine, tri-tert-butylphosphine, etc.) may be added.
  • a ligand
  • Compound (VI) is used in an amount of about 0.5 to 10 mol, preferably about 0.5 to 3 mol, per 1 mol of compound (V).
  • the metal catalyst is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (V).
  • the ligand is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (V). This reaction is preferably performed in the presence of a base.
  • bases examples include inorganic bases, organic bases, metal alkoxides, alkali metal hydrides, metal amides, and the like.
  • the base is used in an amount of about 1-20 mol, preferably about 1-5 mol, per 1 mol of compound (V).
  • the reaction is preferably performed in an inert gas stream such as argon gas or nitrogen gas.
  • the condensation reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 50 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • compound (VII) is converted to compound (I) by deprotection.
  • “Deprotection” is, for example, can be carried out according to the method described in Greene's protective groups in organic synthesis 4 th edition (Wiley-International Publication). For example, when a trimethylsilylethoxymethyl group is used, the method described in Journal of the Chemical Society, Perkin Transactions 1, (4), 429-436 (2001) and Tetrahedron Letters, 29 (28), 3411-14 (1988). It can be done according to this.
  • Compound (VI) can be obtained by a method known per se, for example, any of the production methods of compound (VI 1 ), compound (VI 2 ), compound (VI 3 ), compound (VI 4 ) and compound (VI 5 ) shown below. Can be manufactured according to.
  • This step is a step of converting compound (VI 1 ) by introducing compound (IX) into compound (VIII) by nucleophilic substitution reaction or coupling reaction.
  • Y 1 is O
  • Mitsunobu reaction may be used.
  • the “nucleophilic substitution reaction” is generally performed in the presence of a base.
  • a base for example, the base in Step A-3 can be used, and potassium fluoride and diisopropylethylamine are particularly preferable.
  • the amount of these bases to be used is about 0.1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (VIII).
  • Compound (IX) is used in an amount of about 0.5 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (VIII).
  • This reaction can be carried out using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 50 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • the “coupling reaction” can be carried out according to a method known per se [eg, Chemical Science, 2011, Volume 2, Page 27, etc.]. For example, in the presence of a transition metal catalyst and a base, The reaction can be carried out without solvent or in a solvent that does not adversely influence the reaction.
  • transition metal catalyst used in the coupling reaction examples include a palladium catalyst (for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), palladium (II) chloride, tetrakis (triphenylphosphine) palladium ( 0), (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium (II)) and the like, and nickel catalysts (for example, nickel chloride) and the like, and ligands (for example, 4,5- Bis (diphenylphosphino) -9,9-dimethylxanthene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2,2′-bis (di-p-tolylphosphino) -1,1 '-Binaphthyl, 2-dicyclohexylphosphino-2',
  • the transition metal catalyst is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (VIII).
  • the ligand is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (VIII).
  • Compound (IX) is used in an amount of about 0.5 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (VIII).
  • This reaction is preferably performed in the presence of a base.
  • the base in Step A-3 can be used, and alkali metal salts (sodium carbonate, potassium carbonate, cesium carbonate, etc.) are preferable.
  • the amount of these bases to be used is about 0.1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (VIII).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 50 to 150 ° C.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • Mitsunobu reaction is a method known per se [eg, Synthesis, pp. 1-27, 1981, Tetrahedron Lett. , 36, pp. 6373-6374, 1995, Tetrahedron Lett. , 38, pp. 5831-5834, 1997, etc.], for example, azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipiperidine, and triphenyl
  • the reaction can be carried out in the presence of phosphines such as phosphine and tributylphosphine without solvent or in a solvent that does not adversely influence the reaction.
  • the Mitsunobu reaction can be performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; benzene, toluene and the like
  • Aromatic hydrocarbons saturated hydrocarbons such as cyclohexane and hexane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoryltriamide; dichloromethane, chloroform, carbon tetrachloride, 1
  • Halogenated hydrocarbons such as 1,2-dichloroethane
  • nitriles such as acetonitrile and propionitrile
  • ketones such as acetone and ethyl methyl ketone
  • the reaction time is usually 5 minutes to 100 hours, preferably 30 minutes to 72 hours.
  • the reaction temperature is usually ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • Compound (IX) is used in an amount of about 0.5 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (VIII).
  • the amount of the azodicarboxylates and phosphines to be used is about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (VIII).
  • This step is a step of converting the compound (VI 1 ) (when Y 1 is S) into (VI 2 ) by an oxidation reaction.
  • an oxidizing agent such as 3-chlorophenyl perbenzoic acid, sodium periodate, hydrogen peroxide, peracetic acid, Oxone (trademark) or the like is used.
  • the oxidizing agent 3-chlorophenyl perbenzoic acid and the like are particularly preferable.
  • This step can be performed, for example, according to the method described in Journal of Organic Chemistry 68, 5075-5083 (2003).
  • the compound (VI 2 ) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In addition, compound (VI 2 ) may be used for the next reaction without isolation.
  • This step is a step of converting compound (X) to compound (VI 3 ) by a condensation reaction.
  • Z 1 is COOH or SO 2 Cl
  • it is converted to a compound (VI 3 ) (when Y 3 is CONH or SO 2 NH) by a condensation reaction with the corresponding amine compound (XV-1).
  • Z 1 is NH 2
  • compound (VI 3 ) (when Y 3 is NHCO or NHSO 2 ) is obtained by a condensation reaction with the corresponding carboxylic acid compound (XV-2) or sulfonic acid chloride compound (XV-3). Convert to.
  • the “condensation reaction” can be carried out according to a method known per se.
  • “amidation” is a method using a reactive derivative such as acid halide, acid azide and acid anhydride, dicyclohexylcarbodiimide, 1-ethyl
  • a method of condensing a compound having a carboxylic acid in the presence of a condensing agent such as -3- (3-dimethylaminopropyl) carbodiimide and carbonyldiimidazole is used.
  • “Sulfonamidation” can be prepared by reaction with a compound having a sulfonyl chloride in the presence of a base.
  • the same base as used in Step A-3 can be used, and among them, a tertiary amine such as triethylamine is preferable.
  • the amine compound (XV-1), the carboxylic acid compound (XV-2), and the sulfonic acid chloride compound (XV-3) are each about 0.1 to 10 mol, preferably about 0.1 mol, relative to 1 mol of the compound (X). 0.5 to 3 mol is used.
  • compound (X), compound (XV-1), compound (XV-2) and compound (XV-3) used as starting materials in this method commercially available products may be used as they are, or they are known per se or It can also be produced by a method according to it.
  • This step is a step of converting compound (XI) to compound (VI 4 ) by a substitution reaction with compound (XVI).
  • “Substitution reaction” is generally carried out in the presence of a base.
  • Compound (XVI) is used in an amount of about 0.5 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (XI).
  • compound (XI) and compound (XVI) used as raw materials in this method commercially available products may be used as they are, respectively, or they can be produced by a method known per se or a method analogous thereto.
  • This step is a step of converting compound (XVII) to compound (VI 5 ) by a coupling reaction with compound (XVIII).
  • This step can be performed in accordance with, for example, the method described in Journal of Organic Chemistry 71, 5725-5731 (2006).
  • This step can be carried out in the absence of solvent or in a solvent that does not adversely influence the reaction.
  • Compound (XVIII) is used in an amount of about 0.5-10 mol, preferably about 1-3 mol, per 1 mol of compound (XVII).
  • Compound (I) can also be produced by Method B shown below. (Method B)
  • compound (VI) is allowed to act on compound (XII) to convert it into compound (I). If necessary, this step can be performed in the presence of a base by adding a transition metal catalyst, without solvent, or in a solvent that does not adversely influence the reaction.
  • Compound (VI) is used in an amount of about 0.2 to 10 mol, preferably about 0.5 to 3 mol, per 1 mol of compound (XII).
  • the base in Step A-3 can be used, and among them, cesium carbonate and sodium-tert-butoxide are preferable.
  • the amount of these bases to be used is about 0.1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (XII).
  • transition metal catalyst examples include a palladium catalyst (for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), (1 , 1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II)) and the like, and nickel catalysts (for example, nickel chloride and the like).
  • a palladium catalyst for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), (1 , 1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II)
  • nickel catalysts for example, nickel chloride and the like.
  • this reaction may be carried out with a ligand (for example, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, , 2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, triphenylphosphine, tri -Tert-butylphosphine, 2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl, 5- (di-t-butylphosphino) -1', 3 ', 5'- Triphenyl-1,4′-bi-1H-pyrazole or the like
  • the transition metal catalyst is used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (XII).
  • the ligand and the metal oxide are each used in an amount of about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, per 1 mol of compound (XII).
  • the solvent used in the reaction in this step is not particularly limited as long as the reaction proceeds.
  • hydrocarbons eg, benzene, toluene, xylene, hexane, heptane, etc.
  • halogenated hydrocarbons eg, , Chloroform, dichloromethane, etc.
  • ethers eg, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.
  • nitriles eg, acetonitrile, etc.
  • aprotic polar solvents eg, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, hexamethylphosphoramide, etc.
  • protic polar solvent for example, water, methanol, ethanol, 1-propanol, 2-propanol, 1-but
  • the reaction temperature in this step is usually about ⁇ 50 to about 200 ° C., preferably about 0 ° C. to about 180 ° C.
  • the reaction time in this step is usually about 0.1 hour to about 100 hours.
  • microwaves may be irradiated for the purpose of promoting the reaction.
  • compound (XII) and compound (VI) used as raw materials in this method commercially available products may be used as they are, or they can be produced by a method known per se or a method analogous thereto.
  • Compound (I) can also be produced by Method C shown below. (Method C)
  • Z 2 represents LG, COOH, SO 2 Cl or NH 2
  • Y 3 represents a bond, O, S, SO, SO 2 , NR 4 , CONH, SO 2 NH, NHCO or NHSO 2
  • the other symbols have the same meanings as described above.
  • compound (XII) and compound (XIII) used as raw materials in this method commercially available products may be used as they are, or they can be produced by a method known per se or a method analogous thereto.
  • This step is a step of converting compound (XIV) to compound (I 2 ). This step can be carried out according to any of the steps A-6, A-7, and A-8 according to the type of Z 2.
  • the compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography, and the like.
  • the compound of the present invention obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like.
  • each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above.
  • the compound (I) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and synthetic methods and separation methods known per se (for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product.
  • synthetic methods and separation methods known per se for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
  • a method known per se for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, various buffer solutions (eg, phosphate buffer) are added.
  • buffer solutions eg, phosphate buffer
  • an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
  • Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). And then obtaining an optical isomer by separating the optically active reagent site by chemical treatment such as hydrolysis reaction.
  • the compound (I) when the compound (I) has hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( -)-Menthoxyacetic acid etc.) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
  • an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Compound (I) may be a crystal. Crystals of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
  • the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
  • the “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent.
  • a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method.
  • solvent used examples include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane).
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • saturated hydrocarbons eg, hexane, heptane, cyclohexane.
  • Etc. ethers
  • ethers eg, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, etc.
  • nitriles eg, acetonitrile, etc.
  • ketones eg, acetone, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • Acid amides eg, N, N-dimethylformamide, etc.
  • esters eg, ethyl acetate, etc.
  • alcohols eg, methanol, ethanol, isopropyl alcohol, etc.
  • water and the like eg, water and the like.
  • solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
  • a seed crystal can also be used as needed.
  • Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
  • crystallization from the melt examples include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). , Liquid phase epitaxy method) and the like.
  • compound (I) is dissolved in an appropriate solvent (eg, alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved.
  • an appropriate solvent eg, alcohol such as methanol, ethanol, etc.
  • Examples thereof include a method of cooling to a temperature or lower (for example, 0 to 50 ° C., preferably 0 to 20 ° C.).
  • the crystals of the present invention thus obtained can be isolated by, for example, filtration.
  • a method for analyzing the obtained crystal a crystal analysis method by powder X-ray diffraction is generally used.
  • examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • crystal of the present invention has high purity, high quality, low hygroscopicity, and is stored for a long time under normal conditions. Is very stable. In addition, it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of drug efficacy, etc.) and is extremely useful as a medicine.
  • the specific optical rotation ([ ⁇ ] D ) is a ratio measured using, for example, an optical polarimeter (JASCO, P-1030 polarimeter (No. AP-2)) or the like.
  • the melting point means a melting point measured using, for example, a micro melting point measuring device (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000).
  • Compound (I) may be used as a prodrug.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which amino of compound (I) is acylated, alkylated or phosphorylated for example, amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2- Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropylcarbonylated compounds, etc.); (2) Compound in which hydroxy of compound (I) is acylated, alkylated, phosphorylated, borated (for example, hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succiny
  • compound (I) and prodrugs thereof may be collectively abbreviated as “the compound of the present invention”.
  • Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
  • Compounds labeled with isotopes eg, 3 H, 14 C, 35 S, 125 I, etc.
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • Tautomers are also encompassed in compound (I).
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) may be used as a PET tracer.
  • the compound of the present invention has an excellent PKC (particularly PKC- ⁇ ) inhibitory action, it is also useful as a safe pharmaceutical based on this action.
  • the medicament of the present invention comprising the compound of the present invention is a PKC (in particular, a mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It can be used as a prophylactic or therapeutic agent for PKC- ⁇ ) -related diseases and T cell-related diseases, more specifically, as prophylactic or therapeutic agents for the diseases described in (1) to (5) below.
  • Inflammatory diseases eg, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis Systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia, nephritis, meningitis, cystitis, sore throat, gastric mucosal damage, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia , Bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, purulent dysplasia, ventilation, etc.); (2) Immune diseases (eg, rheumatoid arthritis), psoriasis (psoriasis), inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, etc.) , Sjogren's
  • the medicament of the present invention is preferably an immune disease, inflammatory disease, bone or joint degenerative disease, central disease or neoplastic disease, more preferably graft-versus-host disease, aplasticity Anemia (aplastic ⁇ anemia), systemic lupus erythematosus, lupus nephritis, pemphigus, inflammatory bowel disease (preferably Crohn's disease) or ulcerative Colitis (ulcerative colitis), erythroblast ⁇ (pure red cell aplasia), myasthenia Gravis, asthma, vasculitis, ankylosing spondylitis (spondylarthritis ankylopoietica), rheumatoid arthritis (Rheumatoid arthritis), psoriasis (psoriasis), Sjogren's syndrome (Sjogren's syndrome), atopic dermatitis, Behcet's disease (Beh cet's syndrome, multiple sclerosis, Alzheimer's disease (
  • prevention of the disease refers to, for example, a patient who has not developed the disease, which is expected to have a high risk of onset due to some factor related to the disease, or who has developed the subjective symptom. This means that a drug containing the compound of the present invention is administered to a patient who is not, or that a drug containing the compound of the present invention is administered to a patient who is concerned about recurrence of the disease after treatment of the disease.
  • the medicament of the present invention has excellent pharmacokinetics (eg, blood drug half-life), low toxicity (eg, HERG inhibition, CYP inhibition, CYP induction), and reduction in drug interaction is observed.
  • the compound of the present invention is mixed with a pharmacologically acceptable carrier as it is or according to a method known per se generally used in the preparation of pharmaceutical preparations to form a pharmaceutical composition, which is used as the pharmaceutical of the present invention. be able to.
  • the medicament of the present invention is given orally or parenterally to mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.). Safe to administer.
  • the medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier to be prepared.
  • a method for producing a pharmaceutical preparation eg, a method described in the Japanese Pharmacopoeia
  • It can be used as a pharmaceutical composition mixed with a carrier to be prepared.
  • examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • the content of the compound of the present invention in the medicament of the present invention is about 0.01% to about 100% by weight of the whole medicament.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, disease and the like.
  • the active ingredient (compound (I ) Of about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 50 mg / kg body weight, more preferably about 1 mg / kg body weight to 30 mg / kg body weight. It may be administered once to several times a day.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials.
  • excipients and lubricants in solid preparations Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of preservatives include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compound of the present invention can be used together with other drugs.
  • the pharmaceutical used when the compound of the present invention is used in combination with another drug is referred to as “the combination agent of the present invention”.
  • the compound of the present invention can be used in combination with the following drugs.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (I) Classic NSAIDs Arcofenac, aceclofenac, sulindac, tolmetine, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, teoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, migrenin, aspirin, fefenamic acid, mefenamic acid Diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, fructaphenine, piroxicam, epilisol, thiaramide hydrochloride, zal
  • cyclooxygenase inhibitors COX-1 selective inhibitors, COX-2 selective inhibitors, etc.
  • Salicylic acid derivatives eg, celecoxib, aspirin
  • etoroxib etoroxib
  • valdecoxib diclofenac
  • indomethacin loxoprofen
  • Nitric oxide free NSAIDs Iv) JAK inhibitors Tofacitinib (Tofacitinib), Ruxolitinib (Ruxolitinib) and the like.
  • Anti-cytokine drug protein preparation
  • TNF inhibitor etanercept TNF inhibitor etanercept, infliximab, adalimumab, certolizumab Pegor, golimumab, PASSTNF- ⁇ , soluble TNF- ⁇ receptor, TNF- ⁇ binding protein, anti-TNF- ⁇ antibody etc.
  • Interleukin-1 inhibitor Anakinra interleukin-1 receptor antagonist
  • soluble interleukin-1 receptor and the like.
  • Interleukin-6 inhibitor Tocilizumab anti-interleukin-6 receptor antibody
  • Iv Interleukin-10 drug Interleukin-10 and the like.
  • V Interleukin-12 / 23 inhibitor Ustekinumab, briakinumab (anti-interleukin-12 / 23 antibody) and the like.
  • II Non-protein preparation
  • Ii Gene regulators Inhibitors of molecules related to signal transduction such as NF- ⁇ , NF- ⁇ B, IKK-1, IKK-2, AP-1.
  • Iv TNF- ⁇ converting enzyme inhibitor
  • VX-765 interleukin-1 ⁇ converting enzyme inhibitor
  • Vi Interleukin-6 antagonist HMPL-004 and the like.
  • Interleukin-8 inhibitor IL-8 antagonist Interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparexin and the like.
  • Chemokine antagonist CCR9 antagonist CCX-282, CCX-025), MCP-1 antagonist and the like.
  • Ix Interleukin-2 receptor antagonist Denileukine, Defuchitox and the like.
  • Therapeutic vaccines TNF- ⁇ vaccine and the like.
  • Gene therapy drug Gene therapy drug for enhancing expression of genes having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF- ⁇ receptor .
  • Immunomodulatory drugs immunosuppressive drugs
  • Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, estriol propionate, estriol etc.
  • Angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
  • Angiotensin II receptor antagonist candesartan, cilexetil (TCV-116), valsartan, irbesartan, olmesartan, eprosartan, and the like.
  • (11) ⁇ receptor antagonist carvedilol, metoprolol, atenolol and the like.
  • Antiplatelet drugs anticoagulants heparin, aspirin, warfarin and the like.
  • HMG-CoA reductase inhibitor atorvastatin atorvastatin, simvastatin and the like.
  • Contraceptives Sex hormones or derivatives thereof Progesterone or derivatives thereof (progesterone, 17 ⁇ -hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodrel, levonorgestrel , Norgestrel, etinodiol diacetate, desogestrel, norgestimate, guestden, progestin, etonogestrel, drospirenone, dienogest, trimegestone, nestron, chromadianone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525) or Progesterone or its derivative and follicular hormone or its derivative (Ladiol, estradiol benzoate,
  • T cell inhibitor Inosine monophosphate dehydrogenase (IMPDH) inhibitor Mycophenolate mofetil and the like.
  • thalidomide v) cathepsin inhibitor
  • MMPs matrix metalloprotease
  • V-85546 Glucose-6-phosphate dehydrogenase inhibitor
  • DHODH Dihydrorotate dehydrogenase
  • PDEIV Phosphodiesterase IV
  • X Phospholipase A2 inhibitor
  • xi iNOS inhibitor VAS-203 and the like.
  • Xii Microtubule stimulant paclitaxel and the like.
  • Xiii Microtubule inhibitor Rheumacon and the like.
  • Xiv MHC class II antagonist
  • xv Prostacyclin agonist iloprost and the like.
  • CD4 antagonist zanolimumab and the like.
  • Xvii CD23 antagonist
  • xviii LTB4 receptor antagonist DW-1305 and the like.
  • Xix 5-lipoxygenase inhibitor zileuton and the like.
  • Xx Cholinesterase inhibitor galantamine and the like.
  • Glucosamine sulfate (xxxi) Amiprirose (xxxi) CD-20 inhibitor Rituximab, ibritumomab, tositumomab, ofatumuma and the like. (Xxxii) BAFF inhibitor belimumab, tabalumab, atacicept, A-623 and the like. (Xxxiii) CD52 inhibitor alemtuzumab and the like. (Xxxiv) IL-17 inhibitor secukinumab (AIN-457), LY-2439821, AMG827 and the like. (Xxxv) PDE4 inhibitor Roflumilast, Apremilast.
  • concomitant drugs other than the above include, for example, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antibiotics, antitussives and expectorants, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, antihypertensive diuretics, anticoagulants Drugs, tranquilizers, antipsychotics, antitumor drugs, antihyperlipidemic drugs, muscle relaxants, antiepileptic drugs, antidepressants, antiallergic drugs, cardiotonic drugs, antiarrhythmic drugs, vasodilators, vasoconstriction Drugs, antihypertensive diuretics, antidiabetics, narcotic antagonists, vitamins, vitamin derivatives, anti-asthma, frequent urinary / urinary incontinence, antidiarrheal, atopic dermatitis, allergic rhinitis, hypertension
  • examples include drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory mediator activity inhibitors
  • Antibacterial drugs Sulfa drugs Sulfamethizol, sulfisoxazole, sulfamonomethoxine, sulfamethizol, salazosulfapyridine, sulfadiazine silver and the like.
  • Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
  • Antituberculosis drugs Isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, etionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
  • Mycobacterial drugs Diaphenylsulfone, rifampicillin and the like.
  • Antiviral drugs idoxuridine, acyclovir, vitarabine, ganciclovir, foscarnet and the like.
  • Anti-HIV drugs zidovudine, didanosine, zarcitabine, indinavir sulfate ethanol adduct, ritonavir and the like.
  • Antispirocheta drugs (viii) Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, cannendomycin, libidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, loritetracycline, doxycycline, doxycycline, doxycycline Piperacillin, ticarcillin, cephalothin, cefapirin, cephaloridine, cefaclor, cephalexin, cefloxazine, cefadroxyl, cefamandol, cephoam, cefuroxime, cefothium, cefothium hexetyl
  • azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy- 1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoro Propoxy) phenyl] -3- (2H, 4H) -1,2,4- triazolone, fluconazole, itraconazole, imipenem, meropenem, trimethoprim, sulfamethoxazole, etc.] and the like.
  • Antifungal drugs Polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin) (Ii) griseofulvin, pyrrolnitrin, etc. (iii) cytosine antimetabolite (eg, flucytosine) (Iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole) (V) Triazole derivatives (eg, fluconazole, itraconazole) (Vi) thiocarbamic acid derivatives (eg, trinaphthol) and the like.
  • Polyethylene antibiotics eg, amphotericin B, nystatin, tricomycin
  • cytosine antimetabolite eg, flucytosine
  • Iv Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate,
  • Ephedrine hydrochloride noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, aloclamide, chlorfedianol, picoperidamine, cloperastine, protochlorol , Isoproterenol, salbutamol, tereptaline, oxypetebanol, morphine hydrochloride, dextropetrphan hydrobromide, oxycodone hydrochloride, dimorphan phosphate, tipipedin hibenzate, pentoxyberine citrate, clofedanol hydrochloride, benzonate, guaifenesin, Bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine,
  • Anesthetic (6-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein and the like.
  • Anti-ulcer drugs Histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesasein, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, tepregone, prostaglandin, etc.
  • Arrhythmia drug (i) Sodium channel blocker (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin), (Ii) ⁇ -blockers (eg, propranolol, alprenolol, bufetrol, hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride), (Iii) potassium channel blockers (eg, amiodarone), (Iv) Calcium channel blockers (eg, verapamil, diltiazem) and the like.
  • Sodium channel blocker eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin
  • ⁇ -blockers eg
  • Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine and the like.
  • Antiepileptic drugs Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
  • Antiallergic drugs diphenhydramine, chlorpheniramine, tripelenamine, methodiramine, clemizole, diphenylpyraline, methoxyphenamine, cromoglycate sodium, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine hydrochloride , Pranlukast hydrate, seratrodast, etc.
  • Cardiotonic drugs Transbioxocamphor, telephilol, aminophylline, ethylephrine, dopamine, dobutamine, denopamine, vesinaline, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
  • Vasodilators Oxyfedrine, diltiazem, tolazoline, hexobenzine, bamethane, clonidine, methyldopa, guanabenz and the like.
  • Antihypertensive diuretics Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
  • Antidiabetic drugs Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, grimidine, glipzide, phenformin, pformin, metformin, and the like.
  • narcotic antagonists levalorphan, nalolphine, naloxone or a salt thereof.
  • Vitamin A Vitamin A1, Vitamin A2 and Retinol palmitate
  • Vitamin D Vitamin D1, D2, D3, D4 and D5
  • Vitamin E ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, dl- ⁇ -tocopherol nicotinate
  • Vitamin K vitamins K1, K2, K3 and K4
  • Folic acid vitamin M
  • Vitamin derivatives Various vitamin derivatives, for example, vitamin D3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1- ⁇ -hydroxycholecalciferol, 5,6-trans -Vitamin D2 derivatives such as ergocalciferol.
  • vitamin D3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1- ⁇ -hydroxycholecalciferol, 5,6-trans -Vitamin D2 derivatives such as ergocalciferol.
  • Anti-asthma drugs Isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone hydrocolicone , Beclomethasone prop
  • Atopic dermatitis therapeutic agent sodium cromoglycate and the like.
  • Allergic rhinitis therapeutic agent Sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, fexofenadine, mequitazine and the like.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the combination is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) obtained by separately formulating the compound of the present invention and the concomitant drug.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • the dose varies depending on the type of the compound of the present invention, administration route, symptom, patient age, etc.
  • 1 kg body weight per day about 0.1 mg / kg body weight to about 50 mg / kg body weight, preferably about 1 mg / kg body weight to 30 mg / kg body weight per day as a free form of compound (I) may be administered once to several times a day. Good.
  • the dosage is the type and content of compound (I), the dosage form, the duration of drug release, the animal to be administered (for example, mouse, rat, hamster, guinea pig) Mammals such as rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.), depending on the purpose of administration, for example, about 0.1 per week when applied by parenteral administration About 100 mg of compound (I) may be released from the dosage formulation.
  • the animal to be administered for example, mouse, rat, hamster, guinea pig
  • Mammals such as rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.
  • about 100 mg of compound (I) may be released from the dosage formulation.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg per kg body weight of the mammal by oral administration, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg. This is usually administered in 1 to 4 divided doses per day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, or may be administered with a time difference.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
  • the concomitant drug when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. Is mentioned.
  • Root temperature in the following examples usually indicates about 10 ° C. to about 35 ° C.
  • the ratio shown in the mixed solvent is a volume ratio unless otherwise specified.
  • silica gel column chromatography when described as basic silica gel, aminopropylsilane-bonded silica gel was used.
  • HPLC high performance liquid chromatography
  • octadecyl-bonded silica gel when it was described as C18, octadecyl-bonded silica gel was used.
  • the ratio of elution solvent indicates a volume ratio unless otherwise specified.
  • MS mass spectrum
  • LC / MS liquid chromatograph mass spectrometer
  • ESI ElectroSpray Ionization
  • APCI Admospheric Pressure Chemical Ionization
  • Potassium fluoride (133 mg) was added to a solution of 2,6-dichloroisonicotinonitrile (264 mg) and tert-butyl 3-phenylpiperazine-1-carboxylate (200 mg) in DMF (3.8 mL) at 130 ° C. And stirred overnight. Distilled water was added to the reaction mixture, followed by extraction with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the diluted solution was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel chromatography (hexane / ethyl acetate). Ethanol (225 mL) was added to the obtained residue, 10% palladium carbon (2.5 g) was added under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After removing insoluble materials by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate), and ethanol (225 mL) was added again.
  • Examples 12-61 The compounds of Examples 12 to 61 are prepared according to the same method as in Step F of Example 11, or Steps F and G of Example 11, or a method analogous thereto. Such a compound can be prepared according to a method known per se. MS in the table indicates actual measurement.
  • Examples 63-69 The compounds of Examples 63 to 69 were obtained according to the same method as in Example 11 and Example 62 or a method analogous thereto. MS in the table indicates actual measurement.
  • Example 70 (6-((3RS) -3-((2SR) -2-hydroxy-3-methylbutan-2-yl) piperazin-1-yl) pyridin-2-yl) -1,3-dihydro-2H- Imidazo [4,5-b] pyridin-2-one
  • Methyl isopropyl ketone (39.6 mL) was added to the reaction mixture, and the mixture was stirred for 3 hours under ice cooling. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The diluted solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (8.64 g).
  • Examples 71-81 The compounds of Examples 71-81 use 1- (6-fluoropyridin-2-yl) -1H-imidazo [4,5-b] pyridin-2 (3H) -one, step E of Example 70, Where necessary, it was obtained using the corresponding amine compound (such a compound can be produced according to a method known per se) according to Step G of Example 1 or a method analogous thereto. MS in the table indicates actual measurement.
  • Examples 82, 83 The compounds of Examples 82 and 83 were obtained in the same manner as in Steps B and G of Example 1 and Steps C, D and E of Example 70, or a method analogous thereto. MS in the table indicates actual measurement.
  • Example 116 6-((2R) -2-phenylpiperazin-1-yl) pyridin-2-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (35.9 mg).
  • Example 158 1- (6-((2R)-(3-Fluorophenyl) piperazin-1-yl) pyridin-2-yl) -1,3-dihydro-2H-imidazo [4,5-b] pyridin-2-one Hydrochloride
  • 2- (3-Fluorophenyl) pyrazine 2-Chloropyrazine (2.0 g), (3-Fluorophenyl) boronic acid (3.66 g) and potassium carbonate (6.03 g) in dimethoxyethane (38.8 mL) and water (19.4 mL) was mixed with palladium acetate (0.392 g) and triphenylphosphine (0.916 g) at room temperature.
  • the reaction mixture was stirred at 80 ° C. under a nitrogen atmosphere overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (2.71 g).
  • SFC columnumn: CHIRALCEL OD-H (trade name), 20 mmID x 250 mmL, mobile phase: carbon dioxide / methanol
  • SFC columnumn: CHIRALCEL OD-H (trade name), 20 mmID x 250 mmL, mobile phase: carbon dioxide / methanol
  • Example 363 1- (3-Chloro-6-((3S, 4R) -4-hydroxy-3-phenylpiperidin-1-yl) pyridin-2-yl) -1,3-dihydro-2H-imidazo [4,5- b] pyridin-2-one A) (3R, 4R) -tert-butyl 4-hydroxy-3-phenylpiperidine-1-carboxylate A glass autoclave was charged with tert-butyl 4-oxo-3-phenylpiperidine-1-carboxylate (47 g) and dichloro [ (S)-(?)-2,2'-bis [di (3,5-xylyl) phosphino] -1,1'-binaphthyl] [(1S, 2S]-(?)-1,2-diphenylethylenediamine Ruthenium (II) (1 mg) was added, and the atmosphere in the system was replaced with argon, and potassium t-butoxide (1.0 M t-
  • Example 365 (3-Fluoro-6-((3S, 4R) -4-hydroxy-3-phenylpiperidin-1-yl) pyridin-2-yl) -1,3-dihydro-2H-imidazo [4,5- b] pyridin-2-one
  • A) 1- (3,6-Difluoropyridin-2-yl) -3-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazo [4,5-b] pyridin-2 (3H) -one 3 -((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (5.0 g) and 2,3,6-trifluoropyridine (3.51 g) To the DMSO (100 mL) solution was added potassium carbonate (5.21 g), and the mixture was stirred at 130 ° C.
  • Example 372 (5-Fluoro-2-((3S, 4R) -4-hydroxy-3-phenylpiperidin-1-yl) pyrimidin-4-yl) -1,3-dihydro-2H-imidazo [4,5- b] pyridin-2-one
  • A) 1- (2-Chloro-5-fluoropyrimidin-4-yl) -3-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazo [4,5-b] pyridine-2 (3H)- On 3-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazo [4,5-b] pyridin-2 (3H) -one (2.0 g) and 2,4-dichloro-5-fluoropyrimidine (3.77 To a solution of g) in N-methylpiperidone (15.07 mL) was added N-ethyldiisopropylamine (3.95 mL), and the mixture was
  • Example 373 (5-Chloro-2-((3S, 4R) -4-hydroxy-3-phenylpiperidin-1-yl) pyrimidin-4-yl) -1,3-dihydro-2H-imidazo [4,5- b] pyridin-2-one
  • Examples 84-89, 93, 96-115, 117-128, 130-157, 159-170, 173-187, 189-225, 227-304, 307-323, 325-362, 364, 366-371 and Compounds 374 to 376 were produced according to the methods described above or methods analogous thereto.
  • Example compounds are shown in the table below. MS in the table indicates actual measurement.
  • Test Example 1 PKC Theta Enzyme Inhibition Test
  • the PKC theta enzyme inhibitory activity of the test compound was measured by the TR-FRET method. First, it was diluted with assay buffer (20 mM Tris-HCl (pH 7.5), 5 mM MgAcetate, 0.1 mM CaCl 2 , 1 mM DTT, 0.01% Tween 20, 0.05% BSA, 10% PKC Activator (Millipore)). 2 uL of test compound was added to each 384 well plate.
  • assay buffer 20 mM Tris-HCl (pH 7.5), 5 mM MgAcetate, 0.1 mM CaCl 2 , 1 mM DTT, 0.01% Tween 20, 0.05% BSA, 10% PKC Activator (Millipore)
  • Test Example 2 Jurkat Reporter Test Anti-human CD3 antibody (BDDPharmingen) was diluted to 5 ⁇ g / mL with PBS (phosphate buffered saline) (Invitrogen) and added to a 96-well white plate (Corning) at 100 ⁇ L per well. It was left at 4 ° C. overnight.
  • Jurkat cells used for the reporter test were cultured in a culture medium (RPMI (Invitrogen), 10% FCS (AusGeneX), 100 U / mL penicillin, 100 ⁇ g / mL streptomycin). On the test day, 40 million cells were collected by centrifugation (1000 rpm, 5 minutes) and suspended in PBS.
  • the cells were recovered again by centrifugation, and suspended in 2 mL of R buffer (NEON transfection kit, Invitrogen). Thereafter, 80 ⁇ g of a vector pHTS-NFkB (Biomyx) incorporating an NFkB response element upstream of luciferase was added to the cell suspension. Gene introduction was performed with an electroporation apparatus (NEON, Invitrogen) under the conditions of a pulse voltage of 1350 V, an interval of 10 milliseconds, and a frequency of 3 times. The cells after gene transfer were suspended in 40 mL of culture medium.
  • the plate treated with the anti-human CD3 antibody on the previous day was washed twice with 200 ⁇ L of PBS per well, and the transfected cells were seeded in a 96-well plate with 80 ⁇ L per well. Thereafter, 10 ⁇ L of a test compound diluted in a culture medium is added, and then 10 ⁇ L of anti-human CD28 antibody (BDP harmingen) diluted to 5 ⁇ g / mL in the culture medium is added per well. Cultured overnight. 100 ⁇ L of Bright-Glo (Promega) was added, stirred for 10 minutes at room temperature, and the amount of luminescence was measured with Envision (Perkin Elmer). The results are shown in Table 36.
  • Test Example 3 Mouse Whole Blood Assay Blood was collected from the heart from a BALB / c mouse (8 weeks old, female, purchased from Charles River) under pentobarbital anesthesia using a heparinized syringe. 300 ⁇ L of blood and 180 ⁇ L of RPMI medium were mixed using a 2 mL microtube. Then, 30 ⁇ L of a compound (I) / 1% DMSO solution having a concentration 10 times the final target concentration (10 4 to 10 7 ) was added, and the mixture was cultured at 37 ° C. in a 5% CO 2 environment for 30 minutes.
  • a compound (I) / 1% DMSO solution having a concentration 10 times the final target concentration (10 4 to 10 7 ) was added, and the mixture was cultured at 37 ° C. in a 5% CO 2 environment for 30 minutes.
  • RNA protect Animal Blood Tubes (Qiagen, # 76544), incubated at room temperature for 2 hours, and stored at ⁇ 20 ° C. RNA extraction was performed according to the protocol of the RNeasy Protect Animal Blood Kit (Qiagen, # 73224).
  • RNA-to-cDNA The amount of extracted RNA was converted to cDNA using High Capacity RNA-to-cDNA (Applied Biosystems, # 4387406).
  • IL-2 Applied Biosystems, 4331182
  • ⁇ -Actin Applied Biosystems, 4352341E
  • TaqMan registered trademark
  • Test Example 4 Mouse PD Assay
  • Balb / c mice (8 weeks old, female, purchased from Charles River) were forcibly orally administered with a drug solution suspended in a 0.5% (w / v) methylcellulose solution, and 1 hour later Mouse CD3 antibody (Bio X cell, catalog code; BE0001-1) or IgG1 isotype (eBioScience, catalog code; 14-4888-85) was intraperitoneally administered at 5 ⁇ g / mouse.
  • Mouse IL-2 concentration in plasma was measured by ELISA.
  • As the ELISA kit a kit (catalog code; DY402) manufactured by R & D Systems was used. The results are shown in Table 38.
  • HEK was maintained and passaged in MEM medium containing 10% FCS, 1 mM MEM non-essential amino acid, 1 mM sodium pyruvate, 500 ⁇ g / ml geneticin in the presence of 37 ° C., 5% CO 2 . 80-90% confluent cells were harvested by trypsinization and seeded on IVF dishes (Falcon, Franklin Lakes, NJ).
  • the solution in the electrode (7 mM NaCl, 130 mM KCl) was perfused with extracellular fluid (137 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 1.8 mM CaCl 2 , 10 mM HEPES, 11 mM dextrose: pH 7.4).
  • the cells When measuring the HERG current when the test compound was added, the cells were first perfused with the extracellular fluid, and after the waveform was stabilized, the cells were perfused with the extracellular fluid containing 10 ⁇ M of the test compound. When the current waveform under each perfusion condition was stabilized, the HERG current was measured. The HERG current inhibition rate (%) by the test compound was calculated with the HERG current value when no test compound was added as 100%. The results are shown in Table 39.
  • the compounds of the present invention have a low HERG inhibitory activity and a low toxicity.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 Manufacture of tablets
  • the compound of the present invention has excellent PKC inhibitory action, high PKC ⁇ selectivity, high HERG inhibitory activity, low cytotoxicity, low ability to induce phospholipidosis, prevention of immune diseases, inflammatory diseases, etc. It is useful as a therapeutic agent.

Abstract

L'invention a pour objet de fournir un composé qui présente une excellente activité inhibitrice de la protéine kinase C (PKC) et est utile comme agent prophylactique ou thérapeutique contre des maladies immunologiques ou inflammatoires, etc.; ou un sel dudit composé. Le composé indiqué par la formule (dans la formule, chaque symbole est tel que défini dans la description), ou son sel, présente une excellente activité inhibitrice de la protéine kinase C (PKC) et est utile comme agent prophylactique ou thérapeutique contre des maladies immunologiques ou inflammatoires, etc.
PCT/JP2014/062307 2013-05-10 2014-05-08 Composé hétérocyclique WO2014181813A1 (fr)

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Cited By (6)

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WO2015146929A1 (fr) * 2014-03-24 2015-10-01 武田薬品工業株式会社 Composé hétérocyclique
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
WO2021182490A1 (fr) * 2020-03-11 2021-09-16 キッセイ薬品工業株式会社 Cristal d'un composé d'imidazopyridinone ou d'un sel de celui-ci
EP3901152A1 (fr) * 2020-04-23 2021-10-27 F. Hoffmann-La Roche AG Nouveaux composés hétérocycliques pour le traitment des maladies cognitives
RU2776844C1 (ru) * 2018-09-13 2022-07-27 Киссеи Фармасьютикал Ко., Лтд. Соединение имидазопиридинона
WO2023119098A1 (fr) 2021-12-20 2023-06-29 Galderma Holding SA Inhibiteurs de protéine kinase c thêta

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JP2010508278A (ja) * 2006-10-31 2010-03-18 シェーリング コーポレイション アニリノピペラジン誘導体およびアニリノピペラジン誘導体を使用する方法
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015146929A1 (fr) * 2014-03-24 2015-10-01 武田薬品工業株式会社 Composé hétérocyclique
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
RU2776844C1 (ru) * 2018-09-13 2022-07-27 Киссеи Фармасьютикал Ко., Лтд. Соединение имидазопиридинона
JP7458987B2 (ja) 2018-09-13 2024-04-01 キッセイ薬品工業株式会社 イミダゾピリジノン化合物
WO2021182490A1 (fr) * 2020-03-11 2021-09-16 キッセイ薬品工業株式会社 Cristal d'un composé d'imidazopyridinone ou d'un sel de celui-ci
CN115279761A (zh) * 2020-03-11 2022-11-01 橘生药品工业株式会社 咪唑并吡啶酮化合物或其盐的晶体
EP3901152A1 (fr) * 2020-04-23 2021-10-27 F. Hoffmann-La Roche AG Nouveaux composés hétérocycliques pour le traitment des maladies cognitives
WO2023119098A1 (fr) 2021-12-20 2023-06-29 Galderma Holding SA Inhibiteurs de protéine kinase c thêta

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