WO2021060307A1 - Imidazopyridine compound or salt thereof, and pharmaceutical composition - Google Patents

Imidazopyridine compound or salt thereof, and pharmaceutical composition Download PDF

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WO2021060307A1
WO2021060307A1 PCT/JP2020/035895 JP2020035895W WO2021060307A1 WO 2021060307 A1 WO2021060307 A1 WO 2021060307A1 JP 2020035895 W JP2020035895 W JP 2020035895W WO 2021060307 A1 WO2021060307 A1 WO 2021060307A1
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羊平 久保
一生 土井
晋 下山
松本　拓也
修平 逢阪
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富士フイルム株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic 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
    • 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 an imidazopyridine compound having an FGFR (Fibroblast Growth Factor Receptor) inhibitory action or a salt thereof.
  • FGFR Fibroblast Growth Factor Receptor
  • the FGFR (Fibroblast Growth Factor Receptor) family is a receptor tyrosine kinase consisting of four types of FGFR1, 2, 3, and 4. It is responsible for signal transduction originating from the stimulation of the FGF family, which is a ligand, and has a wide range of functions such as development, differentiation, wound healing, angiogenesis, cell migration, and cell proliferation. It has also been suggested that FGF / FGFR signals have important functions in various aspects such as cancer development, growth, angiogenesis, and metastasis.
  • the FGFR gene has been used in various cancers such as lung cancer, breast cancer, gastric cancer, bile duct cancer, cervical cancer, uterine body cancer, bladder cancer, multiple myeloma, and brain tumor. Abnormalities such as amplification, activation mutation, and chromosomal translocation have been reported. In addition to FGFR abnormalities, overexpression of the FGF family, which is a ligand, and gene amplification have also been reported in prostate cancer, liver cancer, colon cancer, lung cancer, etc. (see Non-Patent Documents 1 and 2). From the above, FGFR inhibitors are expected as therapeutic agents for various cancers.
  • kinase inhibitors for various targets have been marketed as anticancer agents so far, and while they have greatly contributed to the improvement of treatment results, resistance to these agents has become a new issue.
  • One of the major causes of resistance development is gene mutation of the target molecule.
  • the development of next-generation kinase inhibitors aiming at overcoming these resistance mutations is underway (see Non-Patent Document 3).
  • FGFR has also been shown to be resistant to known FGFR inhibitors by various gene mutations including the gatekeeper site, and clinical resistance is feared by the same mechanism (Non-Patent Document 4 and Non-Patent Document 4). 5). FGFR inhibitors that are effective against resistance mutations such as gatekeeper mutations can suppress recurrence due to the appearance of resistant cancer cells as first-line therapeutic agents, and resistance mutations against known FGFR inhibitors. It is also expected to be a second-line therapeutic agent for patients who have acquired and relapsed.
  • imidazopyridine compounds can be used as pharmaceuticals (see, for example, Patent Documents 1 to 6).
  • An object of the present invention is to provide an imidazopyridine compound having an FGFR inhibitory action or a salt thereof, and a pharmaceutical composition.
  • an imidazopyridine compound having a specific structure or a salt thereof has a FGFR inhibitory action, and have completed the present invention. That is, the imidazopyridine compound of the present invention or a salt thereof is represented by the following general formula [1].
  • A is an aromatic ring group which may have a substituent and is B is an aromatic ring group having a substituent, and the substituent has an irreversible group.
  • R 11 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
  • a is an integer of 0 to 2.
  • imidazopyridine compound a compound in which A and B are aryl groups which may independently have a substituent is preferable.
  • imidazopyridine compound a compound in which A and B are phenyl groups which may independently have a substituent is preferable.
  • the irreversible group is preferably a group having a double bond or a triple bond.
  • the imidazopyridine compound a compound in which the irreversible group is an ⁇ , ⁇ -unsaturated carbonyl group which may have a substituent is preferable.
  • the imidazopyridine compound of the present invention or a salt thereof is preferably a compound represented by the following general formula [2].
  • A, R 11 and a are synonymous with those of equation [1].
  • R 12 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
  • R 13 are each independently, C 1-6 alkylene group, -NR 21 -, - O - , - CO -, - NR 21 -CO - *, - NR 22 -CO-NR 21 - *, 2 divalent With a hydrocarbon ring group, a divalent heterocyclic group, a -NR 21- C 1-6 alkylene group, a divalent hydrocarbon ring-C 1-6 alkylene group, and a divalent heterocycle-C 1-6 alkylene group.
  • R 15 and R 16 may have a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent.
  • Good C 2-6 alkynyl group, (NR 23 R 24 ) -C 1-6 alkylene group, R 21 and R 22 independently have a hydrogen atom, a hydroxy group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, and a C 3-8.
  • R 23 and R 24 are independently hydrogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkenyl group, C 1-6 alkynyl group, C 3-8 cycloalkyl group, C 3-8. It shows a cycloalkyl group, a hydrocarbon ring group, and a hetero ring group.
  • R 31 the substituent of the aromatic ring group A is represented by the substituent R 31 , and at least one R 31 may be present.
  • R 31 each independently represent a halogen atom, C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl group, NR 23 R 24, hydrocarbon ring group, a heterocyclic group, (NR 23 R 24 ) -C 1-6 alkylene group, hydrocarbon ring-C 1-6 alkylene group, hetero ring-C 1-6 alkylene group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, acyl group, cyano group,
  • Substituent R 31 may further have substituent R 32 , and the substituent R 32 is preferably a compound showing a halogen atom and a C 1-6 alkyl group.
  • R 11 is independently a halogen atom and a C 1-6 alkyl group.
  • a is an integer from 0 to 2
  • R 12 is a halogen atom and a C 1-6 alkyl group, respectively.
  • b is an integer from 0 to 4
  • R 15 and R 16 are preferably compounds which are a hydrogen atom, a halogen atom and a C 1-6 alkyl group.
  • a method for treating a disease involving FGFR which comprises a step of administering a therapeutically effective amount of the above-mentioned imidazopyridine compound or a salt thereof to mammals including humans;
  • a method for treating a cancer disease which comprises a step of administering a therapeutically effective amount of the above-mentioned imidazopyridine compound or a salt thereof to mammals including humans;
  • the above-mentioned imidazopyridine compound or a salt thereof for use in the treatment of diseases involving FGFR The above-mentioned imidazopyridine compound or a salt thereof for use in the treatment of cancer diseases; Is provided.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Preferred halogen atoms are fluorine or chlorine atoms.
  • C 1-6 alkyl groups are direct groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 2-pentyl, 3-pentyl and hexyl groups. It means a chain or branched C 1-6 alkyl group.
  • the C 2-6 alkenyl group is a linear or branched C 2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups. means.
  • the C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.
  • the C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
  • the C 3-8 cycloalkenyl group means a C 3-8 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl group.
  • the C 1-6 alkylene group means a linear or branched C 2-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups.
  • the hydrocarbon ring-C 1-6 alkylene group or the hetero ring-C 1-6 alkylene group means a C 1-6 alkylene group substituted with a hydrocarbon ring group or a hetero ring group, and is similar.
  • the notation means a C 1-6 alkylene group substituted with a specific substituent. Examples of the hydrocarbon ring-C 1-6 alkylene group include an aryl C 1-6 alkyl group and an arylene C 1-6 alkyl group.
  • the C 3-8 cycloalkylene group means a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene group.
  • the C 3-8 cycloalkenylene group means a C 3-8 cycloalkenylene group such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene group.
  • the arylene group means an arylene group having 6 to 18 carbon atoms such as a phenylene or a naphthylene group.
  • Examples of the irreversible group include a group having a double bond or a triple bond, and an ⁇ , ⁇ -unsaturated carbonyl group is preferable.
  • the irreversible group may have a substituent.
  • Examples of the aromatic ring group include a C 6-20 aryl group and a heteroaryl group.
  • Examples of the heterocyclic group include substituents derived from a cyclic compound containing a heteroatom such as a cyclic amino group, a heterocyclic group and a heteroaryl group, which will be described later. Unless otherwise specified, a heterocyclic group means a monovalent one. A group having two bonds is called a divalent heterocyclic group.
  • C 1-6 alkyl group benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl, and aryl C 1-6 alkyl group (the alkyl moiety, such as naphthylmethyl group C 1-6 alkyl It means the aryl group).
  • C 1-6 alkoxy groups are linear, cyclic or linear or cyclic groups such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy and hexyloxy groups.
  • C 1-6 Alkoxy Group means a C 1-6 Alkoxy Group further substituted with a C 1-6 Alkoxy Group.
  • the C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
  • the aryl C 1-6 alkoxy C 1-6 alkyl group means an aryl C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyl oxymethyl group.
  • the heterocyclic carbonyl group means a fluoroyl, tenoyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridinylcarbonyl group and the like.
  • the ( ⁇ -substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, aspartic acid, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine.
  • Amino acids such as tyrosine, tryptophan, proline and hydroxyproline.
  • the acyl C 1-6 alkyl group means an acyl C 1-6 alkyl group such as an acetyl methyl, benzoyl methyl and 1-benzoyl ethyl group.
  • acyloxy C 1-6 alkyl group means acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, a benzoyloxy methyl and 1- acyloxy C 1-6 alkyl group such as (benzoyloxy) ethyl.
  • the C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 alkyloxy such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl group. It means a carbonyl group.
  • the aryl C 1-6 alkoxycarbonyl group means an aryl C 1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.
  • the aryloxycarbonyl group means an aryloxycarbonyl group having 6 to 18 carbon atoms such as a phenyloxycarbonyl group or a naphthyloxycarbonyl group.
  • C 1-6 alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, sec-butylamino, tert-butylamino, cyclobutylamino, pentylamino, cyclopentylamino, hexyl.
  • the C 1-6 alkylsulfonyl group means a C 1-6 alkylsulfonyl group such as a methylsulfonyl, ethylsulfonyl and propylsulfonyl group.
  • the arylsulfonyl group means a benzenesulfonyl, p-toluenesulfonyl, naphthalenesulfonyl group and the like.
  • the C 1-6 alkylsulfonyloxy group means a C 1-6 alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy group.
  • the arylsulfonyloxy group means a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or the like.
  • Cyclic amino groups are azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydropyridyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolydinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, triazolyl, tetrazolyl It means a cyclic amino group containing one or more nitrogen atoms as heteroatoms forming the above ring, such as tetrahydroisoquinolinyl and quinucridinyl, and may further contain one or more oxygen atoms or sulfur atoms.
  • the heterocyclic group means a monocyclic heterocyclic group, a bicyclic heterocyclic group, a spiro-type heterocyclic group and a bridged heterocyclic group.
  • Heteroaryl means a monocyclic heterocyclic group, a bicyclic heterocyclic group, a spiro-type heterocyclic group and a bridged heterocyclic group having aromaticity.
  • a monocyclic nitrogen-containing heterocyclic group having aromaticity is preferable.
  • Monocyclic heterocyclic groups are monocyclic nitrogen-containing heterocyclic groups, monocyclic oxygen-containing heterocyclic groups, monocyclic sulfur-containing heterocyclic groups, and monocyclic nitrogen-containing / oxygen heterocyclic groups.
  • the monocyclic nitrogen-containing heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, dihydropyridyl, pyridyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolydinyl, pyrazolylyl , Piperazinyl, diazepanyl, pyrazinyl, pyridadinyl, pyrimidinyl, homopiperazinyl, triazolyl and tetrazolyl groups, meaning monocyclic nitrogen-containing heterocyclic groups containing heterocyclic groups forming the above rings and also including monocyclic nitrogen-containing heteroaryls.
  • the monocyclic oxygenated heterocyclic group is an oxygen atom as a heteroatom forming the above ring such as oxetanyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, 1,3-dioxanyl and 1,4-dioxanyl group.
  • the monocyclic sulfur-containing heterocyclic group means a thienyl group, tetrahydrothiopyranyl, 1,1-dioxide tetrahydrothiopyranyl and the like.
  • the monocyclic nitrogen-containing / oxygen heterocyclic group is a monocyclic nitrogen-containing / oxygen containing only a nitrogen atom and an oxygen atom as heteroatoms forming the above ring such as oxazolyl, isooxazolyl, oxadiazolyl, morpholinyl and oxazepanyl groups. It means a heterocyclic group.
  • the monocyclic nitrogen-containing / sulfur heterocyclic group is a different term forming the above ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxide thiomorpholinyl and 1,1-dioxide thiomorpholinyl group. It means a monocyclic nitrogen-containing / sulfur heterocyclic group containing only a nitrogen atom and a sulfur atom as atoms.
  • Bicyclic heterocyclic groups are bicyclic nitrogen-containing heterocyclic groups, bicyclic oxygen-containing heterocyclic groups, bicyclic sulfur-containing heterocyclic groups, and bicyclic nitrogen-containing groups.
  • -It means an oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group.
  • Bicyclic nitrogen-containing heterocyclic groups are indolinyl, indolyl, isoindolinyl, isoindrill, benzimidazolyl, indazolyl, benzotriazolyl, pyrazolopyridinyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinoli.
  • Bicyclic nitrogen-containing atoms containing only nitrogen atoms as heteroatoms forming the above rings such as nyl, isoquinolinyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyldinyl, prynyl, pteridinyl and quinuclidinyl groups.
  • Bicyclic oxygenated heterocyclic groups are 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodi. It means a bicyclic oxygenated heterocyclic group containing only an oxygen atom as a heteroatom forming the above ring such as oxanyl and 1,4-benzodioxanyl group.
  • Bicyclic sulfur-containing heterocyclic groups are bicyclic sulfur-containing heterocyclic groups containing only sulfur atoms as heteroatoms forming the above rings, such as 2,3-dihydrobenzothienyl and benzothienyl groups.
  • Bicyclic nitrogen-containing / oxygen heterocyclic groups are benzoxazolyl, benzoisooxazolyl, benzoxaziazolyl, benzomorpholinyl, dihydropyranopyridyl, dioxoropyridyl, flopyridinyl, dihydrodio. It means a bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as heteroatoms forming the above ring such as xinopyridyl and dihydropyridoxazinyl groups.
  • Spiro-type heterocyclic groups are 2,6-diazaspiro [3.3] heptyl, 2,7-diazaspiro [3.5] nonyl, 2-oxa-6-azaspiro [3.3] heptyl, 1,4.
  • One heteroatom forming the above ring such as -dioxaspiro [4.5] decyl, 1-oxa-8-azaspiro [4.5] decyl and 1-thia-8-azaspiro [4.5] decyl group. It means a spiro-type heterocyclic group containing the above nitrogen atom, oxygen atom or sulfur atom.
  • the crosslinked heterocyclic group forms the above rings such as 3-oxa-8-azabicyclo [3.2.1] octyl, 8-oxa-3-azabicyclo [3.2.1] octyl and quinuclidinyl groups. It means a crosslinked heterocyclic group containing one or more nitrogen atoms as heteroatoms and may further contain one or more oxygen or sulfur atoms.
  • the divalent heterocyclic group means a group formed by removing one hydrogen atom from the heterocyclic group.
  • the divalent nitrogen-containing heterocyclic group means a group formed by removing one hydrogen atom from the nitrogen-containing heterocyclic group.
  • the divalent aromatic heterocyclic group is a furylene group, a thienylene group, a pyrrolylene group, a pyrazolylene group, an imidazolylene group, a triazolylen group, a tetrazolylene group, a thiazolylene group, an oxazolylene group, an isothiazolylen group, an isooxazolylene group and a thiadiazolylene group.
  • the divalent non-aromatic heterocyclic group includes oxetanilene group, azetidineylene group, pyrrolidinylene group, piperidinylene group, piperazinylene group, morpholinylene group, thiomorpholinylene group, zepanylene group, diazepanylene group, tetrahydrofurylene group, tetrahydropyrani.
  • the nitrogen atom of the divalent non-aromatic nitrogen-containing heterocyclic group is carbonyl. It is preferably bonded to carbon.
  • the divalent monocyclic nitrogen-containing heterocyclic group azetidineylene, pyrrolidinylene, piperidinylene, piperazinylene, or diazepanylene is preferable, and azetidineylene, pyrrolidinylene or piperidinile is more preferable.
  • the bonding position is preferably the position shown below. In the following formula, * indicates the bonding position.
  • the divalent spiro-type heterocyclic group is 1,6- or 2,6-diazaspiro- [3.3] heptylene, 1,6- or 2,6-diazaspiro- [3.4] octylene, 1, 7- or 2,7-diazaspiro- [4.4] means spiro-diaza-C 5-10 -alkylene such as nonylene.
  • 2,6-diazaspiro [3.3] heptylene or 2,7-diazaspiro [3.5] nonylene is preferable.
  • the bonding position is preferably the position shown below. In the following formula, * indicates the bonding position.
  • the silyl group means a trimethylsilyl, triethylsilyl, tributylsilyl group, or the like.
  • Amino protecting groups include all groups that can be used as ordinary protecting groups for amino groups, such as T.I. W. TWGreene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2007, John Wiley & Sons, The groups described in INC.) Can be mentioned.
  • aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, aryl C 1-6 alkoxycarbonyl group, aryloxycarbonyl Groups include C 1-6 alkylsulfonyl groups, arylsulfonyl groups or silyl groups.
  • Hydroxyl protecting groups include all groups that can be used as conventional hydroxyl protecting groups, such as T.I. W. TWGreene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-299, 2007, John Wiley & Sons, INC. The groups described in.) Can be mentioned.
  • C 1-6 alkyl group C 2-6 alkenyl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy C 1- 6 Alkyl groups, acyl groups, C 1-6 alkoxycarbonyl groups, aryl C 1-6 alkoxycarbonyl groups, C 1-6 alkylsulfonyl groups, arylsulfonyl groups, silyl groups, tetrahydrofuranyl groups or tetrahydropyranyl groups. ..
  • Carboxyl protecting groups include all groups that can be used as conventional protecting groups for carboxyl groups, such as T.I. W. TWGreene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007, John Wiley & Sons, The groups described in INC.) Can be mentioned. Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy. Examples thereof include C 1-6 alkyl group, acyl C 1-6 alkyl group, acyloxy C 1-6 alkyl group or silyl group.
  • Aliphatic hydrocarbons mean pentane, hexane, heptane, cyclohexane, methylcyclohexane, ethylcyclohexane and the like.
  • Halogenated hydrocarbons mean dichloromethane, chloroform or dichloroethane.
  • the ethers mean diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and the like.
  • Alcohols mean methanol, ethanol, propanol, 2-propanol, butanol, 2-methyl-2-propanol and the like.
  • Glycols mean ethylene glycol, propylene glycol, diethylene glycol and the like.
  • Ketones mean acetone, 2-butanone, 4-methyl-2-pentanone, methyl isobutyl ketone and the like.
  • the esters mean methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
  • the amides mean N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
  • Nitriles mean acetonitrile, propionitrile, and the like.
  • Sulfoxides mean dimethyl sulfoxide, sulfolane, and the like.
  • Aromatic hydrocarbons mean benzene, toluene, xylene and the like.
  • Inorganic bases include sodium hydroxide, potassium hydroxide, sodium methoxide, tert-butoxysodium, tert-butoxypotassium, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, tripotassium phosphate, potassium acetate, cesium fluoride, or It means cesium carbonate and so on.
  • the organic base means triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, N-methylmorpholine and the like. To do.
  • Examples of the salt of the compound of the general formula [1] include commonly known salts of basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.
  • preferred salts include pharmacologically acceptable salts.
  • the present invention includes those isomers, and solvates, water, etc. Includes Japanese products and crystals of various shapes.
  • Prevention means inhibition of onset, reduction of onset risk or delay of onset.
  • Treatment means improvement or suppression of progression of the disease or condition of interest.
  • Treatment means prevention or treatment of various diseases.
  • the therapeutic agent means a substance provided for the purpose of prevention or treatment for various diseases.
  • FGFR Diseases involving FGFR mean any disease that can be prevented or treated by inhibiting FGFR.
  • the FGFR family has four types of genes, FGFR1, 2, 3, and 4. Mutations in this gene are said to be the cause of cancer.
  • Cancer is a disease associated with FGFR. Examples of the cancer include lung cancer, biliary tract cancer, and bladder cancer.
  • the imidazopyridine compound of the present invention is represented by the following general formula [1], and is preferably represented by the following general formula [2].
  • the imidazopyridine compounds of the present invention also include isomers such as optical isomers, geometric isomers and tautomers.
  • A is an aromatic ring group which may have a substituent.
  • B is an aromatic ring group having a substituent, and the substituent has an irreversible group.
  • R 11 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
  • a is an integer of 0 to 2.
  • A, R 11 and a are synonymous with those in the formula [1], and the preferred range is also synonymous.
  • R 12 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
  • b is an integer from 0 to 4
  • R 13 are each independently, C 1-6 alkylene group, -NR 21 -, - O - , - CO -, - NR 21 -CO - *, - NR 22 -CO-NR 21 - *, 2 divalent With a hydrocarbon ring group, a divalent heterocyclic group, a -NR 21- C 1-6 alkylene group, a divalent hydrocarbon ring-C 1-6 alkylene group, and a divalent heterocycle-C 1-6 alkylene group.
  • R 15 and R 16 have a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. May be a C 2-6 alkynyl group, (NR 23 R 24 ) -C 1-6 alkylene group, R 21 and R 22 independently have a hydrogen atom, a hydroxy group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, and a C 3-8.
  • R 11 , R 12 , R 15 , R 16 , R 21 , R 22 , R 23 , or R 24 is not limited to the above, and is not limited to the above, and is a monovalent substituent described in the present specification. Can be used as appropriate.
  • the aromatic ring group A is preferably aryl or heteroaryl, which may have a substituent, more preferably aryl, which may have a substituent, and even more preferably phenyl, which may have a substituent.
  • a monocyclic nitrogen-containing heterocyclic group having aromaticity is preferable.
  • the substituent contained in the aromatic ring group A is represented by the substituent R 31 , and R 31 may be present at least 1 or more, and the number of the substituent R 31 is preferably 0 to 5, more preferably 1 to 3. 1 to 2 are more preferable.
  • heterocyclic group of R 31 a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, and a monocyclic nitrogen-containing / oxygen heterocyclic group are preferable.
  • C 1-6 alkyl group, NR 25 R 26 , heterocyclic group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group and cyano group are preferable, and C 1-6 Alkoxy groups are more preferred.
  • R 25 and R 26 are independently a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkenyl group, a C 1-6 alkynyl group, a C 3-8 cycloalkyl group, a hydrocarbon ring group, and a hetero.
  • a ring group (a preferred example is the same as R 31 ) is shown.
  • R 25 and R 26 are more preferably hydrogen atoms and heterocyclic groups, respectively.
  • the substituent R 31 may further have a substituent R 32 , and examples of the substituent R 32 include a halogen atom, a C 1-6 alkyl group, and a heterocyclic group (preferably the same as R 31). ..
  • the aromatic ring group B is preferably an aryl having a substituent or a heteroaryl, more preferably an aryl having a substituent, and even more preferably a phenyl having a substituent.
  • a monocyclic nitrogen-containing heterocyclic group having aromaticity is preferable.
  • the substituent of the aromatic ring group B has an irreversible group, and the irreversible group has a double bond or a triple bond.
  • an ⁇ , ⁇ -unsaturated carbonyl group which may have a substituent is preferable, and one represented by the general formula [2] is preferable.
  • R 15 and R 16 are preferably hydrogen atoms and (NR 23 R 24 ) -C 1-6 alkylene groups, respectively, and both R 15 and R 16 are hydrogen atoms. preferable.
  • R 23 and R 24 a hydrogen atom and a C 1-6 alkyl group are preferable, respectively, and it is more preferable that one is a hydrogen atom and the other is a C 1-6 alkyl group.
  • the aromatic ring group B and the irreversible group are preferably bonded via a divalent linking group, and more preferably via (R 13 ) c in the general formula [2]. ..
  • C 1-6 alkylene group -NR 21 -, - O - , - CO -, - NR 21 -CO - *, - NR 22 -CO-NR 21 - * Divalent hydrocarbon ring group, divalent heterocyclic group, -NR 21- C 1-6 alkylene group, divalent hydrocarbon ring-C 1-6 alkylene group, divalent hetero ring-C 1- 6 alkylene group is preferred C 1-6 alkylene group, -NR 21 -, a divalent heterocyclic group, -NR 21 -C 1-6 alkylene group, a divalent hydrocarbon ring -C 1-6 alkylene group, a divalent heterocyclic - A C 1-6 alkylene group is more preferred.
  • R 13 it is bonded to the carbonyl carbon of the ⁇ , ⁇ -unsaturated carbonyl group of the general formula [2]. Therefore, those that can bond with carbonyl carbon are preferable, those that have a nitrogen atom at the end, and those in which a nitrogen atom is arranged at the end are preferable.
  • c is preferably 2 to 3. More preferably, a -NR 21- C 1-6 alkylene group is linked to the benzene ring, a divalent heterocyclic group is further linked, and the nitrogen atom of the divalent heterocyclic group and the carbonyl carbon are linked. Is preferable.
  • R 12 in the general formula [2] a halogen atom and an unsubstituted C 1-6 alkyl group are more preferable.
  • b is preferably an integer of 0 to 1, more preferably 0.
  • R 11 is independently a halogen atom and a C 1-6 alkyl group.
  • a is an integer from 0 to 2
  • R 12 is a halogen atom and a C 1-6 alkyl group, respectively.
  • b is an integer from 0 to 4
  • R 15 and R 16 are preferably hydrogen atoms, halogen atoms, and C 1-6 alkyl groups.
  • it is preferable that a is 0 and b is 0.
  • the compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the following production method.
  • X 1 and X 2 are halogen atoms, boronic acid residues or boronic acid ester residues, one is a halogen atom and the other is a boronic acid residue or boronic acid ester residue.
  • B 0 is B in which nitrogen atoms such as an amino group, an alkylamino group, and a divalent heterocycle are protected.
  • A, B, R 11 , and a have the same meanings as described above.
  • B 0 has X 2 on the aromatic ring B having a substituent and does not have an irreversible group.
  • the other end of B 0 with respect to X 2 preferably has an amino group, an alkylamino group or a divalent heterocycle, which are protected.
  • -NH- of the imidazopyridine parent nucleus of the general formula [1a] may be protected.
  • an amino protecting group is used.
  • the halogen atom represented by X 1 and X 2 is preferably a chlorine atom, a bromine atom or an iodine atom, and preferably a chlorine atom or a bromine atom.
  • the boronic acid ester residues represented by X 1 and X 2 are preferably a boronic acid pinacol ester group and a cyclic triol borate salt.
  • the protecting group for the amino group is preferably a tert-butoxycarbonyl group, a tetrahydropyranyl group and a 2- (trimethylsilyl) ethoxymethyl group.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but is limited to aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones and esters. , Amidos, nitriles, sulfoxides, aromatic hydrocarbons and water. These can be used alone or in admixture of two or more.
  • Preferred solvents include alcohols, esters, amides, nitriles, ethers and water.
  • the amount of the solvent used is not particularly limited, but is preferably 1 to 500 times the amount (v mass basis), and more preferably 1 to 100 times the amount (mass basis) of the compound of the general formula [1a].
  • Examples of the base optionally used in this reaction include an inorganic base and an organic base.
  • Preferred bases include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, cesium fluoride and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine.
  • Triethylamine and organic bases such as diisopropylethylamine.
  • the amount of the base used is preferably 0.1 to 10 times mol, more preferably 0.1 to 5 times mol, and even more preferably 0.1 to 3 times mol with respect to the compound of the general formula [1a] or a salt thereof.
  • the amount of the palladium catalyst used is preferably 0.00001 to 1 times mol, more preferably 0.001 to 0.5 times mol, with respect to the compound of the general formula [1a].
  • This reaction may preferably be carried out at 0 to 170 ° C. for 1 minute to 1 week in an atmosphere of an inert gas (eg, nitrogen, argon). This reaction may be carried out under microwave irradiation.
  • an inert gas eg, nitrogen, argon
  • Deprotection includes, for example, W. W.Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-430, 2007, John Wiley & The method described in Sons, INC.) Or a method similar thereto may be used.
  • As the acid used for deprotection trifluoroacetic acid and a 4 mol / L hydrogen chloride cyclopentyl methyl ether solution are preferable. This reaction is preferably carried out at 0 to 170 ° C. for 1 minute to 1 week.
  • Amidation can be carried out by reacting with the following compounds.
  • X 3 is a halogen atom, R 15 and R 16 have the same meanings as above, and the preferred range is also the same.
  • the halogen atom represented by X 3 is preferably a chlorine atom.
  • acrylic acid chloride or methacrylic acid chloride is preferable.
  • the solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but dichloromethane is preferable. These can be used alone or in admixture of two or more. This reaction is preferably carried out at -10 to 170 ° C. for 1 minute to 24 hours.
  • isomers for example, optical isomers, geometric isomers, tautomers, etc.
  • these isomers can also be used.
  • solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used.
  • a compound having a protective substituent for example, an amino group, a hydroxyl group or a carboxyl group
  • protects these groups with an ordinary protecting group in advance In advance. However, after the reaction, these protecting groups can be removed by a method known per se.
  • the compounds obtained by the above-mentioned production methods or salts thereof are subjected to self-known reactions such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or their reactions. Can be derived to other compounds or salts thereof by appropriately combining them.
  • Additives include, for example, excipients, disintegrants, binders, lubricants, flavoring agents, colorants, flavoring agents, surfactants, coating agents and plasticizers. These additives may be used alone or in combination of two or more.
  • the blending amount is not particularly limited, and it may be blended appropriately so that the effect is sufficiently exhibited according to each purpose.
  • These can be administered orally or parenterally in the form of tablets or injections according to conventional methods.
  • the administration method, dose and frequency of administration can be appropriately selected according to the age, body weight and symptoms of the patient. For example, for adults, 0.01 to 1000 mg / kg may be administered in 1 to several divided doses daily by oral or parenteral administration.
  • MS For supercritical fluid chromatography, SFC 30 (Waters) was used.
  • the MS spectrum is ACQUITY SQD LC / MS System (Waters, ionization method: ESI (ElectroSpray Ionization, electrospray ionization) method or LCMS-2010EV (Shimadzu Seisakusho, ionization method: ESI and APCI (Atomospheric Pressure Chemical Ionization, atmospheric pressure chemistry)). Ionization) was performed at the same time, and the measurement was performed using an ionization method. Unless otherwise stated, MS in the table means MS (ESI m / z) :( M + H).
  • InitiatorTM Biotage was used as the microwave reactor.
  • the NMR spectrum was measured using Bruker AV300 (Bruker) using tetramethylsilane as an internal reference, and the total ⁇ value was shown in ppm.
  • Retention time was measured using SQD (Waters) and expressed in minutes (min).
  • Flow velocity 0.5 mL / min
  • Column temperature Room temperature Detection wavelength: 254 nm
  • each abbreviation has the following meaning.
  • Boc tert-butoxycarbonyl DIPEA: N, N-diisopropylethylamine
  • DMF N, N-dimethylformamide
  • DMSO Dimethyl sulfoxide
  • Me Methyl MeOD: Deuterated methanol (CD 3 OD) RT, rt: retention time
  • SEM 2- (trimethylsilyl) ethoxymethyl
  • WSC 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • HEPES 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid
  • FBS fetal bovine serum
  • Reference example 4-1 to 4-7 The following compounds were obtained in the same manner as in Reference Example 1-1.
  • Reference Examples 4-1 to 4-7 may be referred to as Reference Example 4.
  • Reference example 5-1 to 5-9 The phosphorus oxychloride of Reference Example 1-1 was changed to diphosphoryl chloride to obtain the following compounds.
  • Reference example 6-2 to 6-8 The following compounds were obtained in the same manner as in Reference Example 6-1.
  • Reference Examples 6-1 to 6-8 may be referred to as Reference Example 6.
  • Examples 2-2 to 2-5 The following compounds were obtained in the same manner as in Example 2-1.
  • Example 1-1 (1) Using the compound of Reference Example 4, it was carried out in the same manner as in Example 1-1 (1).
  • FGFR1-WT Enzyme Inhibition Test Assay buffer containing serially diluted test compound or DMSO (100 mmol / L HEPES pH 7.5 , 10 mmol / L MgCl 2 , 10 mmol / L MnCl 2 , 0.003% Brij-35, 1 mmol / L DTT, 0.004% Tween 20) was added to a 384-well plate (Corning) at 6 ⁇ L / well.
  • Human FGFR1-WT enzyme (Millipore, trade name: FGFR1, active, trade code: 14-582M) was diluted to 7.5 nM in assay buffer and added at 6 ⁇ L / well.
  • FGFR1-V561M Gatekeeper Variant Enzyme Inhibition Test Assay buffer containing serially diluted test compound or DMSO (100 mmol / L HEPES pH7.5 , 10 mmol / L MgCl 2 , 10 mmol / L MnCl 2 , 0.003% Brij-35, 1 mmol / L DTT, 0.004% Tween 20) was added to a 384-well plate (Corning) at 6 ⁇ L / well.
  • Human FGFR1-V561M enzyme (Millipore, trade name: FGFR1 (V561M), active, trade code: 14-734M) was diluted to 12.5 nM in assay buffer and added at 6 ⁇ L / well.
  • FGFR1 amplified cell line NCI-H1581 xenograft test 6-week-old female Balb / c nu / nu mice (Claire Japan) were used.
  • Human FGFR1 amplified lung cancer cell line NCI-H1581 (ATCC) was suspended in RPMI-1640 medium, mixed 1: 1 with Matrigel (Corning), and then subcutaneously transplanted in 5 ⁇ 10 6 cells / 100 ⁇ L / mouse. Grouping was performed so that the average tumor volume was 200-350 mm 3 10-14 days after transplantation.
  • the test compound was dissolved in a solvent and orally administered to mice at 5-50 mg / kg once a day.
  • a solvent administration group was provided as a negative control.
  • the imidazopyridine compound of the present invention or a salt thereof has an FGFR inhibitory effect and is useful as a pharmaceutical composition for the treatment of diseases associated with FGFR.

Abstract

The present invention addresses the problem of providing an imidazopyridine compound having FGFR inhibitory activity or a salt thereof, and a pharmaceutical composition. The present invention provides an imidazopyridine compound represented by the general formula [1] or a salt thereof. In the formula, A is an optionally substituted aromatic ring group, B is an aromatic ring group having a substituent, the substituent has an irreversible group, R11s are independently a substituent, and a is an integer of 0-2.

Description

イミダゾピリジン化合物またはその塩および医薬組成物Imidazopyridine compound or salt thereof and pharmaceutical composition
　本発明は、ＦＧＦＲ（Fibroblast Growth Factor Receptor）阻害作用を有するイミダゾピリジン化合物またはその塩に関する。 The present invention relates to an imidazopyridine compound having an FGFR (Fibroblast Growth Factor Receptor) inhibitory action or a salt thereof.
　ＦＧＦＲ（Fibroblast Growth Factor Receptor）ファミリーは、ＦＧＦＲ１、２、３、４の４種類からなる受容体型チロシンキナーゼである。リガンドであるＦＧＦファミリーの刺激を起点とするシグナル伝達を担い、発生、分化、創傷治癒、血管新生、細胞遊走、細胞増殖等の多岐にわたる機能を有する。また、ＦＧＦ／ＦＧＦＲシグナルががんの発生、増殖、血管新生、転移等のさまざまな局面において、重要な機能を有することが示唆されている。さらに近年の遺伝子解析技術の進歩により、肺がん、乳がん、胃がん、胆管がん、子宮頸がん、子宮体がん、膀胱がん、多発性骨髄腫、脳腫瘍等のさまざまながんにおいて、ＦＧＦＲ遺伝子の増幅、活性化変異、染色体転座等の異常が報告されている。またＦＧＦＲの異常に加え、リガンドであるＦＧＦファミリーの過剰発現や遺伝子増幅も前立腺がん、肝臓がん、大腸がん、肺がん等で報告されている（非特許文献１および２参照）。以上のことから、ＦＧＦＲ阻害剤はさまざまながんに対する治療薬として期待される。
　これまでに種々の標的に対するキナーゼ阻害剤が抗がん剤として上市され、治療成績の向上に大きく貢献している一方で、それら薬剤に対する耐性化が新たな課題となっている。耐性化の主要な原因の１つとして、標的分子の遺伝子変異が挙げられる。特にＡＴＰ結合部位付近のゲートキーパーと呼ばれる部位の遺伝子変異による耐性化は、ＢＣＲ－ＡＢＬ、ｃ－Ｋｉｔ、ＰＤＧＦＲ（Platelet-Derived Growth Factor Receptor）、ＥＧＦＲ（Epidermal Growth Factor Receptor）、ＡＬＫ（Anaplastic Lymphoma Kinase）、ＦＬＴ３（FMS-like Tyrosine Kinase 3）等で共通して報告されており、標的キナーゼ分子に関して大きな課題となっている。また、これらの耐性変異の克服を目指した次世代キナーゼ阻害剤の開発が進められている（非特許文献３参照）。 The FGFR (Fibroblast Growth Factor Receptor) family is a receptor tyrosine kinase consisting of four types of FGFR1, 2, 3, and 4. It is responsible for signal transduction originating from the stimulation of the FGF family, which is a ligand, and has a wide range of functions such as development, differentiation, wound healing, angiogenesis, cell migration, and cell proliferation. It has also been suggested that FGF / FGFR signals have important functions in various aspects such as cancer development, growth, angiogenesis, and metastasis. Furthermore, due to recent advances in gene analysis technology, the FGFR gene has been used in various cancers such as lung cancer, breast cancer, gastric cancer, bile duct cancer, cervical cancer, uterine body cancer, bladder cancer, multiple myeloma, and brain tumor. Abnormalities such as amplification, activation mutation, and chromosomal translocation have been reported. In addition to FGFR abnormalities, overexpression of the FGF family, which is a ligand, and gene amplification have also been reported in prostate cancer, liver cancer, colon cancer, lung cancer, etc. (see Non-Patent Documents 1 and 2). From the above, FGFR inhibitors are expected as therapeutic agents for various cancers.
Kinase inhibitors for various targets have been marketed as anticancer agents so far, and while they have greatly contributed to the improvement of treatment results, resistance to these agents has become a new issue. One of the major causes of resistance development is gene mutation of the target molecule. In particular, resistance to resistance by gene mutation at a site called a gatekeeper near the ATP binding site is BCR-ABL, c-Kit, PDGFR (Platelet-Derived Growth Factor Receptor), EGFR (Epidermal Growth Factor Receptor), ALK (Anaplastic Lymphoma Kinase). ), FLT3 (FMS-like Tyrosine Kinase 3), etc. have been commonly reported, and have become a major issue regarding target kinase molecules. In addition, the development of next-generation kinase inhibitors aiming at overcoming these resistance mutations is underway (see Non-Patent Document 3).
　ＦＧＦＲにおいても、既知のＦＧＦＲ阻害剤に対してゲートキーパー部位をはじめとする種々の遺伝子変異による耐性化が示されており、臨床においても同様のメカニズムによる耐性化が危惧される（非特許文献４および５参照）。
　ゲートキーパー変異をはじめとする耐性変異に対しても有効なＦＧＦＲ阻害剤は、一次治療薬として耐性がん細胞の出現による再発を抑制しうることに加え、既知のＦＧＦＲ阻害剤に対して耐性変異を獲得して再発した症例に対する二次治療薬としても期待される。 FGFR has also been shown to be resistant to known FGFR inhibitors by various gene mutations including the gatekeeper site, and clinical resistance is feared by the same mechanism (Non-Patent Document 4 and Non-Patent Document 4). 5).
FGFR inhibitors that are effective against resistance mutations such as gatekeeper mutations can suppress recurrence due to the appearance of resistant cancer cells as first-line therapeutic agents, and resistance mutations against known FGFR inhibitors. It is also expected to be a second-line therapeutic agent for patients who have acquired and relapsed.
　イミダゾピリジン化合物は、医薬になりえることが知られている（例えば、特許文献１～６参照）。 It is known that imidazopyridine compounds can be used as pharmaceuticals (see, for example, Patent Documents 1 to 6).
特表2011-526931号公報Special Table 2011-526931 特表2002-523459号公報Special Table 2002-523459 特表2017-516814号公報Special Table 2017-516814 特表2009-510161号公報Special Table 2009-510161 Gazette 特表2016-509048号公報Special Table 2016-509048 Gazette
　本発明の課題は、ＦＧＦＲ阻害作用を有するイミダゾピリジン化合物またはその塩、および医薬組成物を提供することにある。 An object of the present invention is to provide an imidazopyridine compound having an FGFR inhibitory action or a salt thereof, and a pharmaceutical composition.
　本発明者らは、上記課題に対し鋭意検討を重ねた結果、特定の構造を有するイミダゾピリジン化合物またはその塩が、ＦＧＦＲ阻害作用を有することを見出し、本発明を完成するに至った。
　すなわち、本発明のイミダゾピリジン化合物またはその塩は、下記一般式［１］で表される。
Figure JPOXMLDOC01-appb-C000003
 Ａは、置換基を有してもよい芳香環基であり、
Ｂは、置換基を有する芳香環基であり、当該置換基は、不可逆性基を有しており、
Ｒ11は、それぞれ独立に、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ1-6アルコキシ基、またはカルボキシ基であり、
ａは０～２の整数である。 As a result of diligent studies on the above problems, the present inventors have found that an imidazopyridine compound having a specific structure or a salt thereof has a FGFR inhibitory action, and have completed the present invention.
That is, the imidazopyridine compound of the present invention or a salt thereof is represented by the following general formula [1].
Figure JPOXMLDOC01-appb-C000003
 A is an aromatic ring group which may have a substituent and is
B is an aromatic ring group having a substituent, and the substituent has an irreversible group.
R 11 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
a is an integer of 0 to 2.
　上記イミダゾピリジン化合物としては、Ａ及びＢは、それぞれ独立に、置換基を有してもよいアリール基である、化合物が好ましい。
　上記イミダゾピリジン化合物としては、Ａ及びＢは、それぞれ独立に、置換基を有してもよいフェニル基である、化合物が好ましい。 As the imidazopyridine compound, a compound in which A and B are aryl groups which may independently have a substituent is preferable.
As the imidazopyridine compound, a compound in which A and B are phenyl groups which may independently have a substituent is preferable.
　上記イミダゾピリジン化合物としては、不可逆性基は、二重結合または三重結合を有する基である、化合物が好ましい。
　上記イミダゾピリジン化合物としては、不可逆性基は、置換基を有してもよいα，β－不飽和カルボニル基である、化合物が好ましい。 As the imidazopyridine compound, the irreversible group is preferably a group having a double bond or a triple bond.
As the imidazopyridine compound, a compound in which the irreversible group is an α, β-unsaturated carbonyl group which may have a substituent is preferable.
　本発明のイミダゾピリジン化合物またはその塩は、下記一般式［２］で表される化合物が好ましい。
Figure JPOXMLDOC01-appb-C000004
 Ａ、Ｒ11およびａは、式［１］のものと同義であり、
Ｒ12は、それぞれ独立に、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ1-6アルコキシ基、またはカルボキシ基であり、
ｂは０～４の整数であり、
Ｒ13は、それぞれ独立に、Ｃ1-6アルキレン基、－ＮＲ21－、－Ｏ－、－ＣＯ－、－ＮＲ21－ＣＯ－＊、－ＮＲ22－ＣＯ－ＮＲ21－＊、２価の炭化水素環基、２価のヘテロ環基、－ＮＲ21－Ｃ1-6アルキレン基、２価の炭化水素環－Ｃ1-6アルキレン基、２価のヘテロ環－Ｃ1-6アルキレン基であり、＊はイミダゾピリジン側の結合部位であることを示し、
ｃは１～３の整数であり、
Ｒ15及びＲ16は、水素原子、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ2-6アルケニル基、置換基を有してもよいＣ2-6アルキニル基、（ＮＲ23Ｒ24）－Ｃ1-6アルキレン基であり、
Ｒ21及びＲ22は、それぞれ独立に、水素原子、ヒドロキシ基、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、Ｃ2-6アルキニル基、Ｃ3-8シクロアルキル基、Ｃ3-8シクロアルケニル基、炭化水素環基、ヘテロ環基を示し、
Ｒ23及びＲ24は、それぞれ独立に、水素原子、ヒドロキシ基、Ｃ1-6アルキル基、Ｃ1-6アルケニル基、Ｃ1-6アルキニル基、Ｃ3-8シクロアルキル基、Ｃ3-8シクロアルケニル基、炭化水素環基、ヘテロ環基を示す。 The imidazopyridine compound of the present invention or a salt thereof is preferably a compound represented by the following general formula [2].
Figure JPOXMLDOC01-appb-C000004
 A, R 11 and a are synonymous with those of equation [1].
R 12 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
b is an integer from 0 to 4
R 13 are each independently, C 1-6 alkylene group, -NR 21 -, - O - , - CO -, - NR 21 -CO - *, - NR 22 -CO-NR 21 - *, 2 divalent With a hydrocarbon ring group, a divalent heterocyclic group, a -NR 21- C 1-6 alkylene group, a divalent hydrocarbon ring-C 1-6 alkylene group, and a divalent heterocycle-C 1-6 alkylene group. Yes, * indicates that it is the binding site on the imidazopyridine side,
c is an integer from 1 to 3
R 15 and R 16 may have a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. Good C 2-6 alkynyl group, (NR 23 R 24 ) -C 1-6 alkylene group,
R 21 and R 22 independently have a hydrogen atom, a hydroxy group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, and a C 3-8. Shows cycloalkenyl group, hydrocarbon ring group, heterocyclic group,
R 23 and R 24 are independently hydrogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkenyl group, C 1-6 alkynyl group, C 3-8 cycloalkyl group, C 3-8. It shows a cycloalkyl group, a hydrocarbon ring group, and a hetero ring group.
　上記イミダゾピリジン化合物としては、芳香環基Ａの置換基は、置換基Ｒ31で示され、Ｒ31は少なくとも１以上存在してもよく、
Ｒ31は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、Ｃ2-6アルキニル基、ＮＲ23Ｒ24、炭化水素環基、ヘテロ環基、（ＮＲ23Ｒ24）－Ｃ1-6アルキレン基、炭化水素環－Ｃ1-6アルキレン基、ヘテロ環－Ｃ1-6アルキレン基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、Ｃ1-6アルコキシＣ1-6アルコキシ基、アシル基、シアノ基であり、
置換基Ｒ31はさらに置換基Ｒ32を有してもよく、置換基Ｒ32はハロゲン原子、Ｃ1-6アルキル基を示す、化合物が好ましい。 In the above-mentioned imidazopyridine compound, the substituent of the aromatic ring group A is represented by the substituent R 31 , and at least one R 31 may be present.
R 31 each independently represent a halogen atom, C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl group, NR 23 R 24, hydrocarbon ring group, a heterocyclic group, (NR 23 R 24 ) -C 1-6 alkylene group, hydrocarbon ring-C 1-6 alkylene group, hetero ring-C 1-6 alkylene group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, acyl group, cyano group,
Substituent R 31 may further have substituent R 32 , and the substituent R 32 is preferably a compound showing a halogen atom and a C 1-6 alkyl group.
　上記イミダゾピリジン化合物としては、Ｒ11は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基であり、
ａは０～２の整数であり、
Ｒ12は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基であり、
ｂは０～４の整数であり、
Ｒ15及びＲ16は、水素原子、ハロゲン原子、Ｃ1-6アルキル基である、化合物が好ましい。 As the above-mentioned imidazopyridine compound, R 11 is independently a halogen atom and a C 1-6 alkyl group.
a is an integer from 0 to 2
R 12 is a halogen atom and a C 1-6 alkyl group, respectively.
b is an integer from 0 to 4
R 15 and R 16 are preferably compounds which are a hydrogen atom, a halogen atom and a C 1-6 alkyl group.
　また本発明は、
上記のイミダゾピリジン化合物またはその塩を含有する、医薬組成物；
上記のイミダゾピリジン化合物またはその塩を含有する、ＦＧＦＲが関与する疾患の処置剤；
上記のイミダゾピリジン化合物またはその塩を含有する、抗がん剤；
上記のイミダゾピリジン化合物またはその塩を含有する、がん疾患の治療のための医薬組成物：
を提供する。
　本発明のさらに別の観点からは、上記の医薬組成物、処置剤、または抗がん剤の製造のための上記イミダゾピリジン化合物またはその塩の使用；
ＦＧＦＲが関与する疾患の治療方法であって、上記イミダゾピリジン化合物またはその塩の治療有効量を、ヒトを含む哺乳動物に投与する工程を含む方法；
がん疾患の治療方法であって、上記イミダゾピリジン化合物またはその塩の治療有効量を、ヒトを含む哺乳動物に投与する工程を含む方法;
ＦＧＦＲが関与する疾患の治療において使用するための上記イミダゾピリジン化合物またはその塩；
がん疾患の治療において使用するための上記イミダゾピリジン化合物またはその塩；
が提供される。 Further, the present invention
A pharmaceutical composition containing the above-mentioned imidazopyridine compound or a salt thereof;
A therapeutic agent for FGFR-related diseases containing the above-mentioned imidazopyridine compound or a salt thereof;
An anticancer agent containing the above-mentioned imidazopyridine compound or a salt thereof;
A pharmaceutical composition for the treatment of cancer diseases, which comprises the above-mentioned imidazopyridine compound or a salt thereof:
I will provide a.
From yet another point of view of the present invention, the use of the above-mentioned imidazopyridine compound or a salt thereof for the production of the above-mentioned pharmaceutical composition, therapeutic agent, or anti-cancer agent;
A method for treating a disease involving FGFR, which comprises a step of administering a therapeutically effective amount of the above-mentioned imidazopyridine compound or a salt thereof to mammals including humans;
A method for treating a cancer disease, which comprises a step of administering a therapeutically effective amount of the above-mentioned imidazopyridine compound or a salt thereof to mammals including humans;
The above-mentioned imidazopyridine compound or a salt thereof for use in the treatment of diseases involving FGFR;
The above-mentioned imidazopyridine compound or a salt thereof for use in the treatment of cancer diseases;
Is provided.
　本発明のイミダゾピリジン化合物またはその塩は、ＦＧＦＲ阻害作用を有し、ＦＧＦＲが関与する疾患の治療のための医薬組成物として有用である。また本発明の化合物は、副作用が小さく、医薬組成物に好適である。 The imidazopyridine compound of the present invention or a salt thereof has an FGFR inhibitory effect and is useful as a pharmaceutical composition for the treatment of diseases associated with FGFR. Further, the compound of the present invention has few side effects and is suitable for a pharmaceutical composition.
　以下、本発明を詳細に説明する。
　本発明において、特に断らない限り、％は質量％である。
　本発明において、特にことわらない限り、各用語は、次の意味を有する。
　ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。好ましいハロゲン原子は、フッ素原子または塩素原子である。 Hereinafter, the present invention will be described in detail.
In the present invention,% is mass% unless otherwise specified.
In the present invention, unless otherwise specified, each term has the following meaning.
The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferred halogen atoms are fluorine or chlorine atoms.
　Ｃ1-6アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、２－メチルブチル、２－ペンチル、３－ペンチルおよびヘキシル基などの直鎖状または分枝鎖状のＣ1-6アルキル基を意味する。
　Ｃ2-6アルケニル基とは、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、１，３－ブタジエニル、ペンテニルおよびヘキセニル基などの直鎖状または分枝鎖状のＣ2-6アルケニル基を意味する。
　Ｃ2-6アルキニル基とは、エチニル、プロピニル、ブチニル、ペンチニルおよびヘキシニル基などの直鎖状または分枝鎖状のＣ2-6アルキニル基を意味する。
　Ｃ3-8シクロアルキル基とは、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルおよびシクロヘプチル基などのＣ3-8シクロアルキル基を意味する。
　Ｃ3-8シクロアルケニル基とは、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル基などのＣ3-8シクロアルケニル基を意味する。
　アリール基とは、フェニルまたはナフチル基などのＣ6-20の芳香族炭化水素環基を意味する。
　炭化水素環基とは、シクロアルキル基、シクロアルケニル基およびアリール基を意味し、特に断らない限り、1価のものを意味する。結合手が２つあるものを２価の炭化水素環基といい、Ｃ3-8シクロアルキレン基、Ｃ3-8シクロアルケニレン基、アリーレン基が挙げられる。 C 1-6 alkyl groups are direct groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 2-pentyl, 3-pentyl and hexyl groups. It means a chain or branched C 1-6 alkyl group.
The C 2-6 alkenyl group is a linear or branched C 2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups. means.
The C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.
The C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
The C 3-8 cycloalkenyl group means a C 3-8 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl group.
The aryl group means a C 6-20 aromatic hydrocarbon ring group such as a phenyl or naphthyl group.
The hydrocarbon ring group means a cycloalkyl group, a cycloalkenyl group and an aryl group, and means a monovalent group unless otherwise specified. Those bonds is in two is called the divalent hydrocarbon ring group, C 3-8 cycloalkylene group, C 3-8 cycloalkenylene group, an arylene group.
　Ｃ1-6アルキレン基とは、メチレン、エチレン、プロピレン、ブチレンおよびヘキシレン基などの直鎖状または分枝鎖状のＣ2-6アルキレン基を意味する。また、炭化水素環－Ｃ1-6アルキレン基またはヘテロ環－Ｃ1-6アルキレン基とは、Ｃ1-6アルキレン基に炭化水素環基またはヘテロ環基が置換したものを意味し、類似の表記のものも同様に、Ｃ1-6アルキレン基に特定の置換基が置換したものを意味する。炭化水素環－Ｃ1-6アルキレン基としては、アリールＣ1-6アルキル基、アリーレンＣ1-6アルキル基が挙げられる。
　Ｃ3-8シクロアルキレン基とは、シクロプロピレン、シクロブチレン、シクロペンチレン、シクロヘキシレン、シクロヘプチレンまたはシクロオクチレン基を意味する。
　Ｃ3-8シクロアルケニレン基とは、シクロプロペニレン、シクロブテニレン、シクロペンテニレン、シクロヘキセニレン基などのＣ3-8シクロアルケニレン基を意味する。
　アリーレン基とは、フェニレンまたはナフチレン基などの炭素数６～１８のアリーレン基を意味する。 The C 1-6 alkylene group means a linear or branched C 2-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene groups. Further, the hydrocarbon ring-C 1-6 alkylene group or the hetero ring-C 1-6 alkylene group means a C 1-6 alkylene group substituted with a hydrocarbon ring group or a hetero ring group, and is similar. Similarly, the notation means a C 1-6 alkylene group substituted with a specific substituent. Examples of the hydrocarbon ring-C 1-6 alkylene group include an aryl C 1-6 alkyl group and an arylene C 1-6 alkyl group.
The C 3-8 cycloalkylene group means a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene group.
The C 3-8 cycloalkenylene group means a C 3-8 cycloalkenylene group such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene group.
The arylene group means an arylene group having 6 to 18 carbon atoms such as a phenylene or a naphthylene group.
　不可逆性基としては、二重結合または三重結合を有する基が挙げられ、α，β－不飽和カルボニル基が好ましい。不可逆性基は、置換基を有してもよい。
　芳香環基としては、Ｃ6-20アリール基及びヘテロアリール基が挙げられる。
　ヘテロ環基としては、後述する環状アミノ基、複素環式基、ヘテロアリール基などのヘテロ原子を含む環状化合物に由来する置換基が挙げられる。特に断らない限り、ヘテロ環基は1価のものを意味する。結合手が２つあるものを２価のヘテロ環基という。
　アリールＣ1-6アルキル基とは、ベンジル、ジフェニルメチル、トリチル、フェネチル、２－フェニルプロピル、３－フェニルプロピルおよびナフチルメチル基などのアリールＣ1-6アルキル基（アルキル部分がＣ1-6アルキルであるアラルキル基）を意味する。
　Ｃ1-6アルコキシ基とは、メトキシ、エトキシ、プロポキシ、イソプロポキシ、シクロプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、シクロブトキシ、ペンチルオキシおよびヘキシルオキシ基などの直鎖状、環状または分枝鎖状のＣ1-6アルキルオキシ基を意味する。Ｃ1-6アルコキシ基Ｃ1-6アルコキシ基とは、Ｃ1-6アルコキシ基にさらにＣ1-6アルコキシ基が置換したものを意味する。
　Ｃ1-6アルコキシＣ1-6アルキル基とは、メトキシメチルおよび１－エトキシエチル基などのＣ1-6アルキルオキシＣ1-6アルキル基を意味する。
　アリールＣ1-6アルコキシＣ1-6アルキル基とは、ベンジルオキシメチルおよびフェネチルオキシメチル基などのアリールＣ1-6アルキルオキシＣ1-6アルキル基を意味する。 Examples of the irreversible group include a group having a double bond or a triple bond, and an α, β-unsaturated carbonyl group is preferable. The irreversible group may have a substituent.
Examples of the aromatic ring group include a C 6-20 aryl group and a heteroaryl group.
Examples of the heterocyclic group include substituents derived from a cyclic compound containing a heteroatom such as a cyclic amino group, a heterocyclic group and a heteroaryl group, which will be described later. Unless otherwise specified, a heterocyclic group means a monovalent one. A group having two bonds is called a divalent heterocyclic group.
The aryl C 1-6 alkyl group, benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl, and aryl C 1-6 alkyl group (the alkyl moiety, such as naphthylmethyl group C 1-6 alkyl It means the aryl group).
C 1-6 alkoxy groups are linear, cyclic or linear or cyclic groups such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy and hexyloxy groups. It means a branched C 1-6 alkyloxy group. C 1-6 Alkoxy Group The C 1-6 Alkoxy Group means a C 1-6 Alkoxy Group further substituted with a C 1-6 Alkoxy Group.
The C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyloxy C 1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
The aryl C 1-6 alkoxy C 1-6 alkyl group means an aryl C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyl oxymethyl group.
　アシル基とは、ホルミル基、スクシニル基、グルタリル基、マレオイル基、フタロイル基、Ｃ2-6アルカノイル基、アロイル基、複素環式カルボニル基または（α－置換）アミノアセチル基などを意味する。
　Ｃ2-6アルカノイル基とは、アセチル、プロピオニル、バレリル、イソバレリルおよびピバロイル基などの直鎖状または分枝鎖状のＣ2-6アルカノイル基を意味する。
　アロイル基とは、ベンゾイルまたはナフトイル基などを意味する。
　複素環式カルボニル基とは、フロイル、テノイル、ピロリジニルカルボニル、ピペリジニルカルボニル、ピペラジニルカルボニル、モルホリニルカルボニルまたはピリジニルカルボニル基などを意味する。
　（α－置換）アミノアセチル基とは、アミノ酸（グリシン、アラニン、バリン、ロイシン、イソロイシン、セリン、トレオニン、システイン、メチオニン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、アルギニン、リジン、ヒスチジン、ヒドロキシリジン、フェニルアラニン、チロシン、トリプトファン、プロリンおよびヒドロキシプロリンなどのアミノ酸が挙げられる。）から誘導されるＮ末端が保護されてもよい（α－置換）アミノアセチル基を意味する。 The acyl group means a formyl group, a succinyl group, a glutalyl group, a maleoil group, a phthaloyl group, a C 2-6 alkanoyl group, an aroyl group, a heterocyclic carbonyl group, a (α-substituted) aminoacetyl group and the like.
The C 2-6 alkanoyl group means a linear or branched C 2-6 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
The aloyl group means a benzoyl group, a naphthoyl group, or the like.
The heterocyclic carbonyl group means a fluoroyl, tenoyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, pyridinylcarbonyl group and the like.
The (α-substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, aspartic acid, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Amino acids such as tyrosine, tryptophan, proline and hydroxyproline.) Means an aminoacetyl group whose N-terminal may be protected (α-substituted).
　アシルＣ1-6アルキル基とは、アセチルメチル、ベンゾイルメチルおよび１－ベンゾイルエチル基などのアシルＣ1-6アルキル基を意味する。
　アシルオキシＣ1-6アルキル基とは、アセトキシメチル、プロピオニルオキシメチル、ピバロイルオキシメチル、ベンゾイルオキシメチルおよび１－（ベンゾイルオキシ）エチル基などのアシルオキシＣ1-6アルキル基を意味する。
　Ｃ1-6アルコキシカルボニル基とは、メトキシカルボニル、エトキシカルボニル、イソプロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニルおよび１，１－ジメチルプロポキシカルボニル基などの直鎖状または分枝鎖状のＣ1-6アルキルオキシカルボニル基を意味する。
　アリールＣ1-6アルコキシカルボニル基とは、ベンジルオキシカルボニルおよびフェネチルオキシカルボニル基などのアリールＣ1-6アルキルオキシカルボニル基を意味する。
　アリールオキシカルボニル基とは、フェニルオキシカルボニルまたはナフチルオキシカルボニル基などなどの炭素数６～１８のアリールオキシカルボニル基を意味する。 The acyl C 1-6 alkyl group means an acyl C 1-6 alkyl group such as an acetyl methyl, benzoyl methyl and 1-benzoyl ethyl group.
And acyloxy C 1-6 alkyl group means acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, a benzoyloxy methyl and 1- acyloxy C 1-6 alkyl group such as (benzoyloxy) ethyl.
The C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 alkyloxy such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl group. It means a carbonyl group.
The aryl C 1-6 alkoxycarbonyl group means an aryl C 1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.
The aryloxycarbonyl group means an aryloxycarbonyl group having 6 to 18 carbon atoms such as a phenyloxycarbonyl group or a naphthyloxycarbonyl group.
　Ｃ1-6アルキルアミノ基とは、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、シクロプロピルアミノ、ブチルアミノ、ｓｅｃ－ブチルアミノ、ｔｅｒｔ－ブチルアミノ、シクロブチルアミノ、ペンチルアミノ、シクロペンチルアミノ、ヘキシルアミノおよびシクロヘキシルアミノ基などの直鎖状、分枝鎖状または環状のＣ1-6アルキルアミノ基を意味する。
　ジ（Ｃ1-6アルキル）アミノ基とは、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジイソプロピルアミノ、ジブチルアミノ、ジ（ｔｅｒｔ－ブチル）アミノ、ジペンチルアミノ、ジヘキシルアミノ、（エチル）（メチル）アミノ、（メチル）（プロピル）アミノ、（シクロプロピル）（メチル）アミノ、（シクロブチル）（メチル）アミノ、（シクロヘキシル）（メチル）アミノ基などの直鎖状、分枝鎖状または環状のジ（Ｃ1-6アルキル）アミノ基を意味する。 C 1-6 alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, sec-butylamino, tert-butylamino, cyclobutylamino, pentylamino, cyclopentylamino, hexyl. Means linear, branched or cyclic C 1-6 alkylamino groups such as amino and cyclohexylamino groups.
The di (C 1-6 alkyl) amino group is dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) amino, Linear, branched or cyclic di (C 1 ) such as (methyl) (propyl) amino, (cyclopropyl) (methyl) amino, (cyclobutyl) (methyl) amino, (cyclohexyl) (methyl) amino groups -6alkyl ) means an amino group.
　Ｃ1-6アルキルスルホニル基とは、メチルスルホニル、エチルスルホニルおよびプロピルスルホニル基などのＣ1-6アルキルスルホニル基を意味する。
　アリールスルホニル基とは、ベンゼンスルホニル、ｐ－トルエンスルホニルまたはナフタレンスルホニル基などを意味する。
　Ｃ1-6アルキルスルホニルオキシ基とは、メチルスルホニルオキシおよびエチルスルホニルオキシ基などのＣ1-6アルキルスルホニルオキシ基を意味する。
　アリールスルホニルオキシ基とは、ベンゼンスルホニルオキシまたはｐ－トルエンスルホニルオキシ基などを意味する。 The C 1-6 alkylsulfonyl group means a C 1-6 alkylsulfonyl group such as a methylsulfonyl, ethylsulfonyl and propylsulfonyl group.
The arylsulfonyl group means a benzenesulfonyl, p-toluenesulfonyl, naphthalenesulfonyl group and the like.
The C 1-6 alkylsulfonyloxy group means a C 1-6 alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy group.
The arylsulfonyloxy group means a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or the like.
　環状アミノ基とは、アゼチジニル、ピロリジニル、ピロリニル、ピロリル、ピペリジニル、テトラヒドロピリジル、ホモピペリジニル、イミダゾリジニル、イミダゾリニル、イミダゾリル、ピラゾリジニル、ピラゾリニル、ピラゾリル、ピペラジニル、ホモピペラジニル、トリアゾリル、テトラゾリル、モルホリニル、チオモルホリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニルおよびキヌクリジニルなどの上記環を形成する異項原子として一つ以上の窒素原子を含み、更に、一つ以上の酸素原子または硫黄原子を含んでもよい環状アミノ基を意味する。 Cyclic amino groups are azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydropyridyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolydinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, triazolyl, tetrazolyl It means a cyclic amino group containing one or more nitrogen atoms as heteroatoms forming the above ring, such as tetrahydroisoquinolinyl and quinucridinyl, and may further contain one or more oxygen atoms or sulfur atoms.
　複素環式基とは、単環の複素環式基、二環式の複素環式基、スピロ式複素環基および架橋式複素環基を意味する。
　ヘテロアリールとは、芳香族性を有する、単環の複素環式基、二環式の複素環式基、スピロ式複素環基および架橋式複素環基を意味する。この中でも、芳香族性を有する単環の含窒素複素環式基が好ましい。
　単環の複素環式基とは、単環の含窒素複素環式基、単環の含酸素複素環式基、単環の含硫黄複素環式基、単環の含窒素・酸素複素環式基または単環の含窒素・硫黄複素環式基を意味する。
　単環の含窒素複素環式基とは、アジリジニル、アゼチジニル、ピロリジニル、ピロリニル、ピロリル、ピペリジル、テトラヒドロピリジル、ジヒドロピリジル、ピリジル、ホモピペリジニル、オクタヒドロアゾシニル、イミダゾリジニル、イミダゾリニル、イミダゾリル、ピラゾリジニル、ピラゾリニル、ピラゾリル、ピペラジニル、ジアゼパニル、ピラジニル、ピリダジニル、ピリミジニル、ホモピペラジニル、トリアゾリルおよびテトラゾリル基などの上記環を形成する異項原子を含み、単環の含窒素ヘテロアリールも含む単環の含窒素複素環式基を意味する。
　単環の含酸素複素環式基とは、オキセタニル、テトラヒドロフラニル、フラニル、テトラヒドロピラニル、ピラニル、１，３－ジオキサニルおよび１，４－ジオキサニル基などの上記環を形成する異項原子として酸素原子のみを含む単環の含酸素複素環式基を意味する。
　単環の含硫黄複素環式基とは、チエニル基、テトラヒドロチオピラニル、１，１－ジオキシドテトラヒドロチオピラニルなどを意味する。
　単環の含窒素・酸素複素環式基とは、オキサゾリル、イソオキサゾリル、オキサジアゾリル、モルホリニルおよびオキサゼパニル基などの上記環を形成する異項原子として窒素原子および酸素原子のみを含む単環の含窒素・酸素複素環式基を意味する。
　単環の含窒素・硫黄複素環式基とは、チアゾリル、イソチアゾリル、チアジアゾリル、チオモルホリニル、１－オキシドチオモルホリニルおよび１，１－ジオキシドチオモルホリニル基などの上記環を形成する異項原子として窒素原子および硫黄原子のみを含む単環の含窒素・硫黄複素環式基を意味する。 The heterocyclic group means a monocyclic heterocyclic group, a bicyclic heterocyclic group, a spiro-type heterocyclic group and a bridged heterocyclic group.
Heteroaryl means a monocyclic heterocyclic group, a bicyclic heterocyclic group, a spiro-type heterocyclic group and a bridged heterocyclic group having aromaticity. Among these, a monocyclic nitrogen-containing heterocyclic group having aromaticity is preferable.
Monocyclic heterocyclic groups are monocyclic nitrogen-containing heterocyclic groups, monocyclic oxygen-containing heterocyclic groups, monocyclic sulfur-containing heterocyclic groups, and monocyclic nitrogen-containing / oxygen heterocyclic groups. It means a group or monocyclic nitrogen-containing / sulfur heterocyclic group.
The monocyclic nitrogen-containing heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, dihydropyridyl, pyridyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolydinyl, pyrazolylyl , Piperazinyl, diazepanyl, pyrazinyl, pyridadinyl, pyrimidinyl, homopiperazinyl, triazolyl and tetrazolyl groups, meaning monocyclic nitrogen-containing heterocyclic groups containing heterocyclic groups forming the above rings and also including monocyclic nitrogen-containing heteroaryls. To do.
The monocyclic oxygenated heterocyclic group is an oxygen atom as a heteroatom forming the above ring such as oxetanyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, 1,3-dioxanyl and 1,4-dioxanyl group. Means a monocyclic oxygenated heterocyclic group containing only.
The monocyclic sulfur-containing heterocyclic group means a thienyl group, tetrahydrothiopyranyl, 1,1-dioxide tetrahydrothiopyranyl and the like.
The monocyclic nitrogen-containing / oxygen heterocyclic group is a monocyclic nitrogen-containing / oxygen containing only a nitrogen atom and an oxygen atom as heteroatoms forming the above ring such as oxazolyl, isooxazolyl, oxadiazolyl, morpholinyl and oxazepanyl groups. It means a heterocyclic group.
The monocyclic nitrogen-containing / sulfur heterocyclic group is a different term forming the above ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxide thiomorpholinyl and 1,1-dioxide thiomorpholinyl group. It means a monocyclic nitrogen-containing / sulfur heterocyclic group containing only a nitrogen atom and a sulfur atom as atoms.
　二環式の複素環式基とは、二環式の含窒素複素環式基、二環式の含酸素複素環式基、二環式の含硫黄複素環式基、二環式の含窒素・酸素複素環式基または二環式の含窒素・硫黄複素環式基を意味する。
　二環式の含窒素複素環式基とは、インドリニル、インドリル、イソインドリニル、イソインドリル、ベンズイミダゾリル、インダゾリル、ベンゾトリアゾリル、ピラゾロピリジニル、キノリル、テトラヒドロキノリニル、キノリル、テトラヒドロイソキノリニル、イソキノリニル、キノリジニル、シンノリニル、フタラジニル、キナゾリニル、ジヒドロキノキサリニル、キノキサリニル、ナフチリジニル、プリニル、プテリジニルおよびキヌクリジニル基などの上記環を形成する異項原子として窒素原子のみを含む二環式の含窒素複素環式基を意味する。
　二環式の含酸素複素環式基とは、２，３－ジヒドロベンゾフラニル、ベンゾフラニル、イソベンゾフラニル、クロマニル、クロメニル、イソクロマニル、１，３－ベンゾジオキソリル、１，３－ベンゾジオキサニルおよび１，４－ベンゾジオキサニル基などの上記環を形成する異項原子として酸素原子のみを含む二環式の含酸素複素環式基を意味する。
　二環式の含硫黄複素環式基とは、２，３－ジヒドロベンゾチエニルおよびベンゾチエニル基などの上記環を形成する異項原子として硫黄原子のみを含む二環式の含硫黄複素環式基を意味する。
　二環式の含窒素・酸素複素環式基とは、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾオキサジアゾリル、ベンゾモルホリニル、ジヒドロピラノピリジル、ジオキソロピリジル、フロピリジニル、ジヒドロジオキシノピリジルおよびジヒドロピリドオキサジニル基などの上記環を形成する異項原子として窒素原子および酸素原子のみを含む二環式の含窒素・酸素複素環式基を意味する。
　二環式の含窒素・硫黄複素環式基とは、ベンゾチアゾリル、ベンゾイソチアゾリルおよびベンゾチアジアゾリル基などの上記環を形成する異項原子として窒素原子および硫黄原子を含む二環式の含窒素・硫黄複素環式基を意味する。 Bicyclic heterocyclic groups are bicyclic nitrogen-containing heterocyclic groups, bicyclic oxygen-containing heterocyclic groups, bicyclic sulfur-containing heterocyclic groups, and bicyclic nitrogen-containing groups. -It means an oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group.
Bicyclic nitrogen-containing heterocyclic groups are indolinyl, indolyl, isoindolinyl, isoindrill, benzimidazolyl, indazolyl, benzotriazolyl, pyrazolopyridinyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinoli. Bicyclic nitrogen-containing atoms containing only nitrogen atoms as heteroatoms forming the above rings such as nyl, isoquinolinyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyldinyl, prynyl, pteridinyl and quinuclidinyl groups. Means a heterocyclic group.
Bicyclic oxygenated heterocyclic groups are 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodi. It means a bicyclic oxygenated heterocyclic group containing only an oxygen atom as a heteroatom forming the above ring such as oxanyl and 1,4-benzodioxanyl group.
Bicyclic sulfur-containing heterocyclic groups are bicyclic sulfur-containing heterocyclic groups containing only sulfur atoms as heteroatoms forming the above rings, such as 2,3-dihydrobenzothienyl and benzothienyl groups. Means.
Bicyclic nitrogen-containing / oxygen heterocyclic groups are benzoxazolyl, benzoisooxazolyl, benzoxaziazolyl, benzomorpholinyl, dihydropyranopyridyl, dioxoropyridyl, flopyridinyl, dihydrodio. It means a bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as heteroatoms forming the above ring such as xinopyridyl and dihydropyridoxazinyl groups.
The bicyclic nitrogen-containing / sulfur heterocyclic group includes a bicyclic group containing a nitrogen atom and a sulfur atom as heteroatoms forming the above ring such as benzothiazolyl, benzoisothiazolyl and benzothiasiazolyl group. It means a nitrogen / sulfur heterocyclic group.
　スピロ式複素環式基とは、２，６－ジアザスピロ［３．３］ヘプチル、２，７－ジアザスピロ［３．５］ノニル、２－オキサ－６－アザスピロ［３．３］ヘプチル、１，４－ジオキサスピロ［４．５］デシル、１－オキサ－８－アザスピロ［４．５］デシルおよび１－チア－８－アザスピロ［４．５］デシル基などの上記環を形成する異項原子として一つ以上の窒素原子、酸素原子または硫黄原子を含むスピロ式複素環式基を意味する。
　架橋式複素環式基とは、３－オキサ－８－アザビシクロ［３．２．１］オクチル、８－オキサ－３－アザビシクロ［３．２．１］オクチルおよびキヌクリジニル基などの上記環を形成する異項原子として一つ以上の窒素原子を含み、更に、一つ以上の酸素原子または硫黄原子を含んでもよい架橋式複素環式基を意味する。 Spiro-type heterocyclic groups are 2,6-diazaspiro [3.3] heptyl, 2,7-diazaspiro [3.5] nonyl, 2-oxa-6-azaspiro [3.3] heptyl, 1,4. One heteroatom forming the above ring, such as -dioxaspiro [4.5] decyl, 1-oxa-8-azaspiro [4.5] decyl and 1-thia-8-azaspiro [4.5] decyl group. It means a spiro-type heterocyclic group containing the above nitrogen atom, oxygen atom or sulfur atom.
The crosslinked heterocyclic group forms the above rings such as 3-oxa-8-azabicyclo [3.2.1] octyl, 8-oxa-3-azabicyclo [3.2.1] octyl and quinuclidinyl groups. It means a crosslinked heterocyclic group containing one or more nitrogen atoms as heteroatoms and may further contain one or more oxygen or sulfur atoms.
　２価の複素環式基とは、上記複素環式基から１個の水素原子を除去して形成される基を意味する。
　２価の含窒素複素環式基とは、上記含窒素複素環式基から１個の水素原子を除去して形成される基を意味する。 The divalent heterocyclic group means a group formed by removing one hydrogen atom from the heterocyclic group.
The divalent nitrogen-containing heterocyclic group means a group formed by removing one hydrogen atom from the nitrogen-containing heterocyclic group.
　２価の芳香族複素環式基とは、フリレン基、チエニレン基、ピロリレン基、ピラゾリレン基、イミダゾリレン基、トリアゾリレン基、テトラゾリレン基、チアゾリレン基、オキサゾリレン基、イソチアゾリレン基、イソオキサゾリレン基、チアジアゾリレン基、オキサジアゾリレン基、ピリジレン基、ピリダジニレン基、ピリミジニレン基、ピラジニレン基、トリアジニレン基、ベンゾフリレン基、ベンゾチエニレン基、インドリレン基、イソインドリレン基、インダゾリレン基、ベンズイミダゾリレン基、ベンゾチアゾリレン基、ベンゾオキサゾリレン基、ベンゾチアジアゾリレン基、ベンゾオキサジアゾリレン基、キノリレン基、イソキノリレン基、シンノリニレン基、キナゾリニレン基、キノキサリニレン基、フタラジニレン基、フロピリジレン基、チエノピリジレン基、ピロロピリジレン基、イミダゾピリジレン基、プリニレン基、ナフチリジニレン基、ピリドピリミジニレン基、プテリジニレン基、チエノフリレン基、イミダゾチアゾリレン基、イミダゾオキサゾリレン基など、２価の単環の芳香族含窒素複素環式基を含む、２価の芳香族複素環式基を意味する。
　２価の非芳香族複素環式基とは、オキセタニレン基、アゼチジニレン基、ピロリジニレン基、ピペリジニレン基、ピペラジニレン基、モルホリニレン基、チオモルホリニレン基、ゼパニレン基、ジアゼパニレン基、テトラヒドロフリレン基、テトラヒドロピラニレン基、ジオキソラニレン基、ジオキサニレン基、テトラヒドロチエニレン基、テトラヒドロチオピラニレン基、ジヒドロフリレン基、ジヒドロピラニレン基、ジヒドロピリジレン基、テトラヒドロピリジレン基、チアジナニレン基、ピラゾリニレン基、イミダゾリニレン基、チアゾリニレン基、オキサゾリニレン基、ピラゾリジニレン基、イミダゾリジニレン基、チアゾリジニレン基、オキサゾリジニレン基、テトラヒドロピリダジニレン基、ジヒドロピリダジニレン基、テトラヒドロピリミジニレン基、オキサビシクロ［２，２，１］ヘプチレン基、ジヒドロベンゾフリレン基、ベンゾピラニレン基、クロマニレン基、イソクロマニレン基、インドリニレン基、イソインドリニレン基、ジヒドロベンゾチエニレン基、ジヒドロキノリレン基、テトラヒドロキノリレン基、アザインダニレン基、アザテトラヒドロナフチレン基、アザクロマニレン基、テトラヒドロナフチリジニレン基など、２価の単環の非芳香族含窒素複素環式基を含む、２価の非芳香族複素環式基を意味する。
　本明細書において、２価の非芳香族含窒素複素環式基がα，β－不飽和カルボニル基と結合している場合、２価の非芳香族含窒素複素環式基の窒素原子がカルボニル炭素と結合していることが好ましい。２価の単環の含窒素複素環式基としては、アゼチジニレン、ピロリジニレン、ピペリジニレン、ピペラジニレン、またはジアゼパニレンが好ましく、アゼチジニレン、ピロリジニレンまたはピペリジニレがさらに好ましい。これらの複素環式基において、結合位置は以下で示される箇所で結合することが好ましい。下記式中、＊は結合位置を示す。
Figure JPOXMLDOC01-appb-C000005
 The divalent aromatic heterocyclic group is a furylene group, a thienylene group, a pyrrolylene group, a pyrazolylene group, an imidazolylene group, a triazolylen group, a tetrazolylene group, a thiazolylene group, an oxazolylene group, an isothiazolylen group, an isooxazolylene group and a thiadiazolylene group. , Oxaziazolylen group, pyridylene group, pyridadinylene group, pyrimidinylene group, pyrazinylene group, triadinylene group, benzofurylene group, benzothienylene group, indolylene group, isoindolilen group, indazolylen group, benzimidazolylene group, benzothiazolylen group, benzo Oxazolylen group, benzothiasiazolilen group, benzooxadiazolylene group, quinolylene group, isoquinolylene group, cinnolinylene group, quinazolinylene group, quinoxalinylene group, phthalazinylene group, flopyridylene group, thienopyridylene group, pyrolopyridilen group, imidazolidilen group, 2 Containing a divalent monocyclic aromatic nitrogen-containing heterocyclic group such as a prynylene group, a naphthylidylene group, a pyridopyrimidinylene group, a pteridinylene group, a thienofrylene group, an imidazothiazolylen group, and an imidazooxazolylene group. It means a valent aromatic heterocyclic group.
The divalent non-aromatic heterocyclic group includes oxetanilene group, azetidineylene group, pyrrolidinylene group, piperidinylene group, piperazinylene group, morpholinylene group, thiomorpholinylene group, zepanylene group, diazepanylene group, tetrahydrofurylene group, tetrahydropyrani. Lene group, dioxolanylene group, dioxanylene group, tetrahydrothienylene group, tetrahydrothiopyranylene group, dihydrofurylene group, dihydropyranylene group, dihydropyridylene group, tetrahydropyridylene group, thiazinanilen group, pyrazolinylene group, imidazolinylene group, thiazolinylene Group, Oxazolinylene Group, Pyrazolidinylene Group, Imidazolidinylene Group, Thiazolidinylene Group, Oxazolidinylene Group, Tetrahydropyridadinylene Group, Dihydropyridadinylene Group, Tetrahydropyrimidinylene Group, Oxabicyclo [2,2,1 ] Heptylene group, dihydrobenzofurylene group, benzopyranylene group, chromanylene group, isochromanylene group, indolinylene group, isoindolinylene group, dihydrobenzothienylene group, dihydroquinolylene group, tetrahydroquinolylene group, azaindanylene group, azatetrahydro It means a divalent non-aromatic heterocyclic group including a divalent monocyclic non-aromatic nitrogen-containing heterocyclic group such as a naphthylene group, an azachromanylene group and a tetrahydronaphthylidineylene group.
In the present specification, when a divalent non-aromatic nitrogen-containing heterocyclic group is bonded to an α, β-unsaturated carbonyl group, the nitrogen atom of the divalent non-aromatic nitrogen-containing heterocyclic group is carbonyl. It is preferably bonded to carbon. As the divalent monocyclic nitrogen-containing heterocyclic group, azetidineylene, pyrrolidinylene, piperidinylene, piperazinylene, or diazepanylene is preferable, and azetidineylene, pyrrolidinylene or piperidinile is more preferable. In these heterocyclic groups, the bonding position is preferably the position shown below. In the following formula, * indicates the bonding position.
Figure JPOXMLDOC01-appb-C000005
　２価のスピロ式複素環式基とは、１,６－または２,６－ジアザスピロ－［３.３］ヘプチレン、１,６－または２,６－ジアザスピロ－［３.４］オクチレン、１,７－または２,７－ジアザスピロ－［４.４］ノニレンなどのスピロ－ジアザ－Ｃ5-10－アルキレンを意味する。
　スピロ式複素環式基としては、２，６－ジアザスピロ［３．３］ヘプチレン、または２，７－ジアザスピロ［３．５］ノニレンが好ましい。これらの複素環式基において、結合位置は以下で示される箇所で結合することが好ましい。下記式中、＊は結合位置を示す。
Figure JPOXMLDOC01-appb-C000006
 The divalent spiro-type heterocyclic group is 1,6- or 2,6-diazaspiro- [3.3] heptylene, 1,6- or 2,6-diazaspiro- [3.4] octylene, 1, 7- or 2,7-diazaspiro- [4.4] means spiro-diaza-C 5-10 -alkylene such as nonylene.
As the spiro-type heterocyclic group, 2,6-diazaspiro [3.3] heptylene or 2,7-diazaspiro [3.5] nonylene is preferable. In these heterocyclic groups, the bonding position is preferably the position shown below. In the following formula, * indicates the bonding position.
Figure JPOXMLDOC01-appb-C000006
　シリル基とは、トリメチルシリル、トリエチルシリルまたはトリブチルシリル基などを意味する。 The silyl group means a trimethylsilyl, triethylsilyl, tributylsilyl group, or the like.
　アミノ保護基としては、通常のアミノ基の保護基として使用し得るすべての基を含み、たとえば、Ｔ．Ｗ．グリーン（T.W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第696～926頁、2007年、ジョン・ワイリー・アンド・サンズ社（John Wiley & Sons,INC.）に記載されている基が挙げられる。具体的には、たとえば、アリールＣ1-6アルキル基、Ｃ1-6アルコキシＣ1-6アルキル基、アシル基、Ｃ1-6アルコキシカルボニル基、アリールＣ1-6アルコキシカルボニル基、アリールオキシカルボニル基、Ｃ1-6アルキルスルホニル基、アリールスルホニル基またはシリル基が挙げられる。 Amino protecting groups include all groups that can be used as ordinary protecting groups for amino groups, such as T.I. W. TWGreene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2007, John Wiley & Sons, The groups described in INC.) Can be mentioned. Specifically, for example, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, aryl C 1-6 alkoxycarbonyl group, aryloxycarbonyl Groups include C 1-6 alkylsulfonyl groups, arylsulfonyl groups or silyl groups.
　ヒドロキシル保護基としては、通常のヒドロキシル基の保護基として使用し得るすべての基を含み、たとえば、Ｔ．Ｗ．グリーン（T.W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第16～299頁、2007年、ジョン・ワイリー・アンド・サンズ社（JohnWiley & Sons,INC.）に記載されている基が挙げられる。具体的には、たとえば、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、アリールＣ1-6アルキル基、Ｃ1-6アルコキシＣ1-6アルキル基、アリールＣ1-6アルコキシＣ1-6アルキル基、アシル基、Ｃ1-6アルコキシカルボニル基、アリールＣ1-6アルコキシカルボニル基、Ｃ1-6アルキルスルホニル基、アリールスルホニル基、シリル基、テトラヒドロフラニル基またはテトラヒドロピラニル基が挙げられる。 Hydroxyl protecting groups include all groups that can be used as conventional hydroxyl protecting groups, such as T.I. W. TWGreene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-299, 2007, John Wiley & Sons, INC. The groups described in.) Can be mentioned. Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy C 1- 6 Alkyl groups, acyl groups, C 1-6 alkoxycarbonyl groups, aryl C 1-6 alkoxycarbonyl groups, C 1-6 alkylsulfonyl groups, arylsulfonyl groups, silyl groups, tetrahydrofuranyl groups or tetrahydropyranyl groups. ..
　カルボキシル保護基としては、通常のカルボキシル基の保護基として使用し得るすべての基を含み、たとえば、Ｔ．Ｗ．グリーン（T.W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第533～643頁、2007年、ジョン・ワイリー・アンド・サンズ社（John Wiley & Sons,INC.）に記載されている基が挙げられる。具体的には、たとえば、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、アリール基、アリールＣ1-6アルキル基、Ｃ1-6アルコキシＣ1-6アルキル基、アリールＣ1-6アルコキシＣ1-6アルキル基、アシルＣ1-6アルキル基、アシルオキシＣ1-6アルキル基またはシリル基が挙げられる。 Carboxyl protecting groups include all groups that can be used as conventional protecting groups for carboxyl groups, such as T.I. W. TWGreene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007, John Wiley & Sons, The groups described in INC.) Can be mentioned. Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy. Examples thereof include C 1-6 alkyl group, acyl C 1-6 alkyl group, acyloxy C 1-6 alkyl group or silyl group.
　脂肪族炭化水素類とは、ペンタン、ヘキサン、ヘプタン、シクロヘキサン、メチルシクロヘキサンまたはエチルシクロヘキサンなどを意味する。
　ハロゲン化炭化水素類とは、ジクロロメタン、クロロホルムまたはジクロロエタンを意味する。
　エーテル類とは、ジエチルエーテル、ジイソプロピルエーテル、ジオキサン、テトラヒドロフラン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテルまたはジエチレングリコールジエチルエーテルなどを意味する。
　アルコール類とは、メタノール、エタノール、プロパノール、２－プロパノール、ブタノールまたは２－メチル－２－プロパノールなどを意味する。
　グリコール類とは、エチレングリコール、プロピレングリコールまたはジエチレングリコールなどを意味する。
　ケトン類とは、アセトン、２－ブタノン、４－メチル－２－ペンタノンまたはメチルイソブチルケトンなどを意味する。
　エステル類とは、酢酸メチル、酢酸エチル、酢酸プロピルまたは酢酸ブチルを意味する。
　アミド類とは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミドまたはＮ－メチルピロリドンなどを意味する。
　ニトリル類とは、アセトニトリルまたはプロピオニトリルなどを意味する。
　スルホキシド類とは、ジメチルスルホキシドまたはスルホランなどを意味する。
　芳香族炭化水素類とは、ベンゼン、トルエンまたはキシレンなどを意味する。 Aliphatic hydrocarbons mean pentane, hexane, heptane, cyclohexane, methylcyclohexane, ethylcyclohexane and the like.
Halogenated hydrocarbons mean dichloromethane, chloroform or dichloroethane.
The ethers mean diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and the like.
Alcohols mean methanol, ethanol, propanol, 2-propanol, butanol, 2-methyl-2-propanol and the like.
Glycols mean ethylene glycol, propylene glycol, diethylene glycol and the like.
Ketones mean acetone, 2-butanone, 4-methyl-2-pentanone, methyl isobutyl ketone and the like.
The esters mean methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
The amides mean N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
Nitriles mean acetonitrile, propionitrile, and the like.
Sulfoxides mean dimethyl sulfoxide, sulfolane, and the like.
Aromatic hydrocarbons mean benzene, toluene, xylene and the like.
　無機塩基とは、水酸化ナトリウム、水酸化カリウム、ナトリウムメトキシド、ｔｅｒｔ－ブトキシナトリウム、ｔｅｒｔ－ブトキシカリウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、リン酸三カリウム、酢酸カリウム、フッ化セシウム、または炭酸セシウムなどを意味する。
　有機塩基とは、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ（５．４．０）ウンデカ－７－エン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジンまたはＮ－メチルモルホリンなどを意味する。 Inorganic bases include sodium hydroxide, potassium hydroxide, sodium methoxide, tert-butoxysodium, tert-butoxypotassium, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, tripotassium phosphate, potassium acetate, cesium fluoride, or It means cesium carbonate and so on.
The organic base means triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, N-methylmorpholine and the like. To do.
　パラジウム触媒としては、パラジウム－炭素およびパラジウム黒などの金属パラジウム；塩化パラジウムなどの無機パラジウム塩；酢酸パラジウムなどの有機パラジウム塩；クロロ（２－（ジシクロヘキシルホスフィノ）－３，６－ジメトキシ－２'，４'，６'－トリイソプロピル－１，１'－ビフェニル）（２－（２－アミノエチル）フェニル）パラジウム（II）；テトラキス（トリフェニルホスフィン）パラジウム（０）、ビス（トリフェニルホスフィン）パラジウム（II）ジクロリド、ビス（ジ－ｔｅｒｔ－ブチル（４－ジメチルアミノフェニル）ホスフィン）ジクロロパラジウム（II）、１，１'－ビス（ジフェニルホスフィノ）フェロセンパラジウム（II）ジクロリド、（Ｅ）－ジ（μ－アセタート）ビス（ｏ－（ジ－ｏ－トリルホスフィノ）ベンジル）ジパラジウム（II）およびトリス（ジベンジリデンアセトン）ジパラジウム（０）などの有機パラジウム錯体ならびにポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）およびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）などのポリマー担持有機パラジウム錯体などが挙げられる。 Examples of the palladium catalyst include metal palladium such as palladium-carbon and palladium black; inorganic palladium salt such as palladium chloride; organic palladium salt such as palladium acetate; chloro (2- (dicyclohexylphosphino) -3,6-dimethoxy-2'. , 4', 6'-triisopropyl-1,1'-biphenyl) (2- (2-aminoethyl) phenyl) palladium (II); tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) Palladium (II) dichloride, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II), 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride, (E)- Organopalladium complexes such as di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) and tris (dibenzylideneacetone) dipalladium (0) and polymer-supported bis (acetate) triphenyl Examples thereof include polymer-supported organic palladium complexes such as phosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II).
　一般式［１］の化合物の塩としては、通常知られているアミノ基などの塩基性基、ヒドロキシル基およびカルボキシル基などの酸性基における塩を挙げることができる。
　上記した塩の中で、好ましい塩としては、薬理学的に許容される塩が挙げられる。 Examples of the salt of the compound of the general formula [1] include commonly known salts of basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.
Among the above-mentioned salts, preferred salts include pharmacologically acceptable salts.
　一般式［１］の化合物またはその塩において、異性体（たとえば、光学異性体および幾何異性体など）が存在する場合、本発明は、それらの異性体を包含し、また、溶媒和物、水和物および種々の形状の結晶を包含する。 When isomers (for example, optical isomers and geometric isomers, etc.) are present in the compound of the general formula [1] or a salt thereof, the present invention includes those isomers, and solvates, water, etc. Includes Japanese products and crystals of various shapes.
　予防とは、発症の阻害、発症リスクの低減または発症の遅延などを意味する。
　治療とは、対象となる疾患または状態の改善または進行の抑制などを意味する。
　処置とは、各種疾患に対する予防または治療などを意味する。
　処置剤とは、各種疾患に対して予防または治療などの目的で供せられる物質を意味する。 Prevention means inhibition of onset, reduction of onset risk or delay of onset.
Treatment means improvement or suppression of progression of the disease or condition of interest.
Treatment means prevention or treatment of various diseases.
The therapeutic agent means a substance provided for the purpose of prevention or treatment for various diseases.
　ＦＧＦＲが関与する疾患とは、ＦＧＦＲを阻害することにより予防または治療が可能なあらゆる疾患を意味する。なお、ＦＧＦＲファミリーは、ＦＧＦＲ１、２、３、４の４種類の遺伝子がある。この遺伝子で変異が起きればがんの病因になると言われている。
　ＦＧＦＲが関与する疾患としては、がんがある。そのがんとしては、例えば、肺がん、胆道がん、膀胱がんが挙げられる。 Diseases involving FGFR mean any disease that can be prevented or treated by inhibiting FGFR. The FGFR family has four types of genes, FGFR1, 2, 3, and 4. Mutations in this gene are said to be the cause of cancer.
Cancer is a disease associated with FGFR. Examples of the cancer include lung cancer, biliary tract cancer, and bladder cancer.
　本発明のイミダゾピリジン化合物は、下記一般式［１］で表され、下記一般式［２］で表されるものが好ましい。本発明のイミダゾピリジン化合物は、異性体、たとえば、光学異性体、幾何異性体および互変異性体も含む。
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000008
 The imidazopyridine compound of the present invention is represented by the following general formula [1], and is preferably represented by the following general formula [2]. The imidazopyridine compounds of the present invention also include isomers such as optical isomers, geometric isomers and tautomers.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000008
　一般式［１］において、Ａは、置換基を有してもよい芳香環基であり、
Ｂは、置換基を有する芳香環基であり、当該置換基は、不可逆性基を有しており、
Ｒ11は、それぞれ独立に、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ1-6アルコキシ基、またはカルボキシ基であり、
ａは０～２の整数である。
　一般式［２］において、Ａ、Ｒ11およびａは、式［１］のものと同義であり、好適な範囲も同義であり、
Ｒ12は、それぞれ独立に、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ1-6アルコキシ基、またはカルボキシ基であり、
ｂは０～４の整数であり、
Ｒ13は、それぞれ独立に、Ｃ1-6アルキレン基、－ＮＲ21－、－Ｏ－、－ＣＯ－、－ＮＲ21－ＣＯ－＊、－ＮＲ22－ＣＯ－ＮＲ21－＊、２価の炭化水素環基、２価のヘテロ環基、－ＮＲ21－Ｃ1-6アルキレン基、２価の炭化水素環－Ｃ1-6アルキレン基、２価のヘテロ環－Ｃ1-6アルキレン基であり、
＊はイミダゾピリジン側の結合部位であることを示し、
ｃは１～３の整数であり、
Ｒ15及びＲ16は、水素原子、または、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ2-6アルケニル基、置換基を有してもよいＣ2-6アルキニル基、（ＮＲ23Ｒ24）－Ｃ1-6アルキレン基であり、
Ｒ21及びＲ22は、それぞれ独立に、水素原子、ヒドロキシ基、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、Ｃ2-6アルキニル基、Ｃ3-8シクロアルキル基、Ｃ3-8シクロアルケニル基、炭化水素環基、ヘテロ環基を示し、
Ｒ23及びＲ24は、それぞれ独立に、水素原子、ヒドロキシ基、Ｃ1-6アルキル基、Ｃ1-6アルケニル基、Ｃ1-6アルキニル基、Ｃ3-8シクロアルキル基、Ｃ3-8シクロアルケニル基、炭化水素環基、ヘテロ環基を示す。
以下、同じ記号のものは、同義であり、好適な範囲も同一である。また、Ｒ11、Ｒ12、Ｒ15、Ｒ16、Ｒ21、Ｒ22、Ｒ23、または、Ｒ24としては、上記に限定されるものでなく、本明細書に記載の一価の置換基を適宜、利用することができる。 In the general formula [1], A is an aromatic ring group which may have a substituent.
B is an aromatic ring group having a substituent, and the substituent has an irreversible group.
R 11 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
a is an integer of 0 to 2.
In the general formula [2], A, R 11 and a are synonymous with those in the formula [1], and the preferred range is also synonymous.
R 12 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
b is an integer from 0 to 4
R 13 are each independently, C 1-6 alkylene group, -NR 21 -, - O - , - CO -, - NR 21 -CO - *, - NR 22 -CO-NR 21 - *, 2 divalent With a hydrocarbon ring group, a divalent heterocyclic group, a -NR 21- C 1-6 alkylene group, a divalent hydrocarbon ring-C 1-6 alkylene group, and a divalent heterocycle-C 1-6 alkylene group. Yes,
* Indicates the binding site on the imidazopyridine side.
c is an integer from 1 to 3
R 15 and R 16 have a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. May be a C 2-6 alkynyl group, (NR 23 R 24 ) -C 1-6 alkylene group,
R 21 and R 22 independently have a hydrogen atom, a hydroxy group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, and a C 3-8. Shows cycloalkenyl group, hydrocarbon ring group, heterocyclic group,
R 23 and R 24 are independently hydrogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkenyl group, C 1-6 alkynyl group, C 3-8 cycloalkyl group, C 3-8. It shows a cycloalkyl group, a hydrocarbon ring group, and a hetero ring group.
Hereinafter, those having the same symbol have the same meaning, and the preferable range is also the same. Further, R 11 , R 12 , R 15 , R 16 , R 21 , R 22 , R 23 , or R 24 is not limited to the above, and is not limited to the above, and is a monovalent substituent described in the present specification. Can be used as appropriate.
　上記芳香環基Ａは、置換基を有してもよい、アリールまたはヘテロアリールが好ましく、置換基を有してもよいアリールがより好ましく、置換基を有してもよいフェニルがさらに好ましい。置換基を有してもよいヘテロアリールとしては、芳香族性を有する単環の含窒素複素環式基が好ましい。
　芳香環基Ａが有する置換基としては、置換基Ｒ31で示され、Ｒ31は少なくとも１以上存在してもよく、置換基Ｒ31の数は０～５が好ましく、１～３がより好ましく、１～２がさらに好ましい。
　上記Ｒ31としては、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、Ｃ2-6アルキニル基、ＮＲ25Ｒ26、炭化水素環基、ヘテロ環基、（ＮＲ25Ｒ26）－Ｃ1-6アルキレン基、炭化水素環－Ｃ1-6アルキレン基、ヘテロ環－Ｃ1-6アルキレン基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、Ｃ1-6アルコキシＣ1-6アルコキシ基、アシル基、シアノ基が挙げられる。Ｒ31であるヘテロ環基としては、単環の含窒素複素環式基、単環の含酸素複素環式基、単環の含窒素・酸素複素環式基が好ましい。
　上記Ｒ31としては、Ｃ1-6アルキル基、ＮＲ25Ｒ26、ヘテロ環基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルコキシ基、シアノ基が好ましく、Ｃ1-6アルコキシ基がさらに好ましい。　上記Ｒ25及びＲ26は、それぞれ独立に、水素原子、Ｃ1-6アルキル基、Ｃ1-6アルケニル基、Ｃ1-6アルキニル基、Ｃ3-8シクロアルキル基、炭化水素環基、ヘテロ環基（好ましい例は、Ｒ31と同じ）を示す。Ｒ25及びＲ26は、それぞれ独立に、水素原子、ヘテロ環基がより好ましい。
　上記置換基Ｒ31はさらに置換基Ｒ32を有してもよく、置換基Ｒ32としてはハロゲン原子、Ｃ1-6アルキル基、ヘテロ環基（好ましい例は、Ｒ31と同じ）が挙げられる。 The aromatic ring group A is preferably aryl or heteroaryl, which may have a substituent, more preferably aryl, which may have a substituent, and even more preferably phenyl, which may have a substituent. As the heteroaryl which may have a substituent, a monocyclic nitrogen-containing heterocyclic group having aromaticity is preferable.
The substituent contained in the aromatic ring group A is represented by the substituent R 31 , and R 31 may be present at least 1 or more, and the number of the substituent R 31 is preferably 0 to 5, more preferably 1 to 3. 1 to 2 are more preferable.
As the R 31, each independently, a halogen atom, C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl group, NR 25 R 26, hydrocarbon ring group, a heterocyclic group, (NR 25 R 26 ) -C 1-6 alkylene group, hydrocarbon ring-C 1-6 alkylene group, hetero ring-C 1-6 alkylene group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl Groups, C 1-6 Alkoxy C 1-6 Alkoxy groups, acyl groups, cyano groups and the like. As the heterocyclic group of R 31 , a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, and a monocyclic nitrogen-containing / oxygen heterocyclic group are preferable.
As the above R 31 , C 1-6 alkyl group, NR 25 R 26 , heterocyclic group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group and cyano group are preferable, and C 1-6 Alkoxy groups are more preferred. The above R 25 and R 26 are independently a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkenyl group, a C 1-6 alkynyl group, a C 3-8 cycloalkyl group, a hydrocarbon ring group, and a hetero. A ring group (a preferred example is the same as R 31 ) is shown. R 25 and R 26 are more preferably hydrogen atoms and heterocyclic groups, respectively.
The substituent R 31 may further have a substituent R 32 , and examples of the substituent R 32 include a halogen atom, a C 1-6 alkyl group, and a heterocyclic group (preferably the same as R 31). ..
　上記芳香環基Bは、置換基を有するアリールまたはヘテロアリールが好ましく、置換基を有するアリールがより好ましく、置換基を有するフェニルがさらに好ましい。置換基を有するヘテロアリールとしては、芳香族性を有する単環の含窒素複素環式基が好ましい。
　上記芳香環基Bの置換基は、不可逆性基を有しており、不可逆性基は、二重結合または三重結合を有する。不可逆性基としては、置換基を有してもよいα，β－不飽和カルボニル基が好ましく、一般式［２］で示されるものが好ましい。
　一般式［２］における、Ｒ15及びＲ16は、それぞれ独立に、水素原子、（ＮＲ23Ｒ24）－Ｃ1-6アルキレン基が好ましく、Ｒ15及びＲ16ともに、水素原子であることが好ましい。Ｒ23及びＲ24としては、それぞれ独立に、水素原子、Ｃ1-6アルキル基が好ましく、一方が水素原子で他方がＣ1-6アルキル基であることがより好ましい。
　上記芳香環基Bと不可逆性基は、２価の連結基を介して結合していることが好ましく、一般式［２］における、（Ｒ13）cを介して結合していることがより好ましい。 The aromatic ring group B is preferably an aryl having a substituent or a heteroaryl, more preferably an aryl having a substituent, and even more preferably a phenyl having a substituent. As the heteroaryl having a substituent, a monocyclic nitrogen-containing heterocyclic group having aromaticity is preferable.
The substituent of the aromatic ring group B has an irreversible group, and the irreversible group has a double bond or a triple bond. As the irreversible group, an α, β-unsaturated carbonyl group which may have a substituent is preferable, and one represented by the general formula [2] is preferable.
In the general formula [2], R 15 and R 16 are preferably hydrogen atoms and (NR 23 R 24 ) -C 1-6 alkylene groups, respectively, and both R 15 and R 16 are hydrogen atoms. preferable. As R 23 and R 24 , a hydrogen atom and a C 1-6 alkyl group are preferable, respectively, and it is more preferable that one is a hydrogen atom and the other is a C 1-6 alkyl group.
The aromatic ring group B and the irreversible group are preferably bonded via a divalent linking group, and more preferably via (R 13 ) c in the general formula [2]. ..
　一般式［２］における、Ｒ13としては、Ｃ1-6アルキレン基、－ＮＲ21－、－Ｏ－、－ＣＯ－、－ＮＲ21－ＣＯ－＊、－ＮＲ22－ＣＯ－ＮＲ21－＊、２価の炭化水素環基、２価のヘテロ環基、－ＮＲ21－Ｃ1-6アルキレン基、２価の炭化水素環－Ｃ1-6アルキレン基、２価のヘテロ環－Ｃ1-6アルキレン基が好ましく、
Ｃ1-6アルキレン基、－ＮＲ21－、２価のヘテロ環基、－ＮＲ21－Ｃ1-6アルキレン基、２価の炭化水素環－Ｃ1-6アルキレン基、２価のヘテロ環－Ｃ1-6アルキレン基がより好ましい。
　Ｒ13としては、一般式［２］のα，β－不飽和カルボニル基のカルボニル炭素に結合する。そのため、カルボニル炭素と結合し得るものが好ましく、末端に窒素原子があるもの、末端に窒素原子が配置される組合せが好ましい。
　ｃは２～３が好ましい。
　より好ましくは、ベンゼン環に－ＮＲ21－Ｃ1-6アルキレン基が連結し、さらに２価のヘテロ環基が連結して、その２価のヘテロ環基の窒素原子とカルボニル炭素が連結している態様が好ましい。
　上記Ｒ21としては、水素原子、または、Ｃ1-6アルキル基が好ましく、Ｃ1-6アルキル基がより好ましい。
　上記２価のヘテロ環（基）としては、２価の単環の含窒素複素環式基が好ましく、アゼチジニレン、ピロリジニレン、ピペリジニレン、ピペラジニレン、またはジアゼパニレンがより好ましく、アゼチジニレン、ピロリジニレンまたはピペリジニレがさらに好ましい。
　上記２価の炭化水素環（基）としては、Ｃ3-8シクロアルキレン基、Ｃ3-8シクロアルケニレン基が好ましく、Ｃ3-8シクロアルキレン基がより好ましい。 In the general formula [2], as the R 13, C 1-6 alkylene group, -NR 21 -, - O - , - CO -, - NR 21 -CO - *, - NR 22 -CO-NR 21 - * Divalent hydrocarbon ring group, divalent heterocyclic group, -NR 21- C 1-6 alkylene group, divalent hydrocarbon ring-C 1-6 alkylene group, divalent hetero ring-C 1- 6 alkylene group is preferred
C 1-6 alkylene group, -NR 21 -, a divalent heterocyclic group, -NR 21 -C 1-6 alkylene group, a divalent hydrocarbon ring -C 1-6 alkylene group, a divalent heterocyclic - A C 1-6 alkylene group is more preferred.
As R 13, it is bonded to the carbonyl carbon of the α, β-unsaturated carbonyl group of the general formula [2]. Therefore, those that can bond with carbonyl carbon are preferable, those that have a nitrogen atom at the end, and those in which a nitrogen atom is arranged at the end are preferable.
c is preferably 2 to 3.
More preferably, a -NR 21- C 1-6 alkylene group is linked to the benzene ring, a divalent heterocyclic group is further linked, and the nitrogen atom of the divalent heterocyclic group and the carbonyl carbon are linked. Is preferable.
As the R 21 , a hydrogen atom or a C 1-6 alkyl group is preferable, and a C 1-6 alkyl group is more preferable.
As the divalent heterocycle (group), a divalent monocyclic nitrogen-containing heterocyclic group is preferable, azetidineylene, pyrrolidinylene, piperidinylene, piperazinylene, or diazepanylene is more preferable, and azetidineylene, pyrrolidinylene or piperidinile is further preferable.
As the divalent hydrocarbon ring (group), a C 3-8 cycloalkylene group and a C 3-8 cycloalkenylene group are preferable, and a C 3-8 cycloalkylene group is more preferable.
　一般式［２］における、Ｒ12としては、ハロゲン原子、無置換のＣ1-6アルキル基がより好ましい。ｂは０～１の整数が好ましく、０がより好ましい。
　一般式［２］において、Ｒ11は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基であり、
ａは０～２の整数であり、
Ｒ12は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基であり、
ｂは０～４の整数であり、
Ｒ15及びＲ16は、水素原子、ハロゲン原子、Ｃ1-6アルキル基であることが好ましい。
　また、一般式［２］において、ａは０であり、ｂは０であることが好ましい。 As R 12 in the general formula [2], a halogen atom and an unsubstituted C 1-6 alkyl group are more preferable. b is preferably an integer of 0 to 1, more preferably 0.
In the general formula [2], R 11 is independently a halogen atom and a C 1-6 alkyl group.
a is an integer from 0 to 2
R 12 is a halogen atom and a C 1-6 alkyl group, respectively.
b is an integer from 0 to 4
R 15 and R 16 are preferably hydrogen atoms, halogen atoms, and C 1-6 alkyl groups.
Further, in the general formula [2], it is preferable that a is 0 and b is 0.
　次に、本発明化合物の製造法について説明する。
　本発明化合物は、自体公知の方法を組み合わせることにより製造されるが、たとえば、次に示す製造法にしたがって製造することができる。 Next, a method for producing the compound of the present invention will be described.
The compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the following production method.
［製造法Ａ］
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｘ1およびＸ2は、ハロゲン原子、ボロン酸残基またはボロン酸エステル残基であり、一方は、ハロゲン原子であり、他方はボロン酸残基またはボロン酸エステル残基であり、
Ｂ0は、アミノ基、アルキルアミノ基、２価のヘテロ環などの窒素原子が保護されたＢであり、
Ａ、Ｂ、Ｒ11、ａは、上記と同様の意味である。
Ｂ0は、置換基を有する芳香環ＢにＸ2を有するものであり、不可逆性基は有さない。Ｘ2に対してＢ0の他端にはアミノ基、アルキルアミノ基または２価のヘテロ環を有することが好ましく、これらは保護されている。なお、一般式［１ａ］のイミダゾピリジン母核の－ＮＨ－は、保護されていてもよい。保護基はアミノ基の保護基が使用される。）
　Ｘ1およびＸ2で表わされるハロゲン原子は、塩素原子、臭素原子またはヨウ素原子が好ましく、塩素原子または臭素原子が好ましい。
　Ｘ1およびＸ2で表わされるボロン酸エステル残基は、ボロン酸ピナコールエステル基および環状トリオールボレート塩が好ましい。
　アミノ基の保護基は、tert-ブトキシカルボニル基、テトラヒドロピラニル基および2-(トリメチルシリル)エトキシメチル基が好ましい。 [Manufacturing method A]
Figure JPOXMLDOC01-appb-C000009
 (In the formula, X 1 and X 2 are halogen atoms, boronic acid residues or boronic acid ester residues, one is a halogen atom and the other is a boronic acid residue or boronic acid ester residue.
B 0 is B in which nitrogen atoms such as an amino group, an alkylamino group, and a divalent heterocycle are protected.
A, B, R 11 , and a have the same meanings as described above.
B 0 has X 2 on the aromatic ring B having a substituent and does not have an irreversible group. The other end of B 0 with respect to X 2 preferably has an amino group, an alkylamino group or a divalent heterocycle, which are protected. In addition, -NH- of the imidazopyridine parent nucleus of the general formula [1a] may be protected. As the protecting group, an amino protecting group is used. )
The halogen atom represented by X 1 and X 2 is preferably a chlorine atom, a bromine atom or an iodine atom, and preferably a chlorine atom or a bromine atom.
The boronic acid ester residues represented by X 1 and X 2 are preferably a boronic acid pinacol ester group and a cyclic triol borate salt.
The protecting group for the amino group is preferably a tert-butoxycarbonyl group, a tetrahydropyranyl group and a 2- (trimethylsilyl) ethoxymethyl group.
　一般式［１］の化合物は、一般式［１ｃ］の化合物を酸の存在下で脱保護し、アミド化することによって不可逆性基（好ましくは、α，β－不飽和カルボニル基）を導入し、製造することができる。
　一般式［１ａ］の化合物と一般式［１ｂ］の化合物との反応は、塩基の存在下または不存在下、パラジウム触媒の存在下、溶媒中で行われる。
　有機ハロゲン化物と有機ホウ素化合物とのカップリング反応における試薬、溶媒、反応温度、反応時間等は、公知の鈴木－宮浦反応を参考にして適宜設定できる。
　この反応に用いられる溶媒としては、反応に影響を及ぼさないものであれば特に限定されないが、脂肪族炭化水素類、ハロゲン化炭化水素類、アルコール類、グリコール類、エーテル類、ケトン類、エステル類、アミド類、ニトリル類、スルホキシド類、芳香族炭化水素類および水などが挙げられる。これらは１種を単独で、または２種以上を混合して用いることができる。
　好ましい溶媒としては、アルコール類、エステル類、アミド類、ニトリル類、エーテル類および水が挙げられる。
　溶媒の使用量は、特に限定されないが、一般式［１ａ］の化合物に対して、1～500倍量（ｖ質量基準）が好ましく、1～100倍量（質量基準）がより好ましい。
　この反応に所望により用いられる塩基としては、無機塩基および有機塩基が挙げられる。
　好ましい塩基としては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、カリウム　ｔｅｒｔ－ブトキシド、ナトリウム　ｔｅｒｔ－ブトキシド、フッ化セシウムおよびリン酸三カリウムなどの無機塩基ならびにピリジン、４－（ジメチルアミノ）ピリジン、トリエチルアミンおよびジイソプロピルエチルアミンなどの有機塩基が挙げられる。
　塩基の使用量は、一般式［１ａ］の化合物またはその塩に対して、0.1～10倍モルが好ましく、0.1～5倍モルがより好ましく、0.1～3倍モルがさらに好ましい。
　パラジウム触媒の使用量は、一般式［１ａ］の化合物に対して、0.00001～1倍モルが好ましく、0.001～0.5倍モルがより好ましい。
　この反応は、好ましくは、不活性気体（たとえば、窒素、アルゴン）雰囲気下、0～170℃で、1分間～1週間実施すればよい。
　この反応はマイクロウェーブ照射下で行ってもよい。 The compound of the general formula [1] introduces an irreversible group (preferably α, β-unsaturated carbonyl group) by deprotecting and amidating the compound of the general formula [1c] in the presence of an acid. , Can be manufactured.
The reaction of the compound of the general formula [1a] with the compound of the general formula [1b] is carried out in the presence or absence of a base, in the presence of a palladium catalyst, and in a solvent.
The reagent, solvent, reaction temperature, reaction time, etc. in the coupling reaction between the organic halide and the organic boron compound can be appropriately set with reference to the known Suzuki-Miyaura reaction.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but is limited to aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones and esters. , Amidos, nitriles, sulfoxides, aromatic hydrocarbons and water. These can be used alone or in admixture of two or more.
Preferred solvents include alcohols, esters, amides, nitriles, ethers and water.
The amount of the solvent used is not particularly limited, but is preferably 1 to 500 times the amount (v mass basis), and more preferably 1 to 100 times the amount (mass basis) of the compound of the general formula [1a].
Examples of the base optionally used in this reaction include an inorganic base and an organic base.
Preferred bases include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, cesium fluoride and tripotassium phosphate, and pyridine, 4- (dimethylamino) pyridine. , Triethylamine and organic bases such as diisopropylethylamine.
The amount of the base used is preferably 0.1 to 10 times mol, more preferably 0.1 to 5 times mol, and even more preferably 0.1 to 3 times mol with respect to the compound of the general formula [1a] or a salt thereof.
The amount of the palladium catalyst used is preferably 0.00001 to 1 times mol, more preferably 0.001 to 0.5 times mol, with respect to the compound of the general formula [1a].
This reaction may preferably be carried out at 0 to 170 ° C. for 1 minute to 1 week in an atmosphere of an inert gas (eg, nitrogen, argon).
This reaction may be carried out under microwave irradiation.
　脱保護は、たとえば、Ｗ．グリーン（W.Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第16～430頁、2007年、ジョン・ウィリイ・アンド・サンズ社（John Wiley & Sons,INC.）に記載された方法またはそれに準じた方法で行えばよい。
　脱保護に使用される酸としては、トリフルオロ酢酸、4 mol/L 塩化水素シクロペンチルメチルエーテル溶液が好ましい。
　この反応は、好ましくは、0～170℃で、1分間～1週間実施すればよい。 Deprotection includes, for example, W. W.Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-430, 2007, John Wiley & The method described in Sons, INC.) Or a method similar thereto may be used.
As the acid used for deprotection, trifluoroacetic acid and a 4 mol / L hydrogen chloride cyclopentyl methyl ether solution are preferable.
This reaction is preferably carried out at 0 to 170 ° C. for 1 minute to 1 week.
　アミド化は、下記化合物と反応させることによって行うことができる。
Figure JPOXMLDOC01-appb-C000010
 （式中、Ｘ3は、ハロゲン原子であり、Ｒ15、Ｒ16は上記と同様の意味であり、好適な範囲も同様である。）
　Ｘ3で表わされるハロゲン原子は、塩素原子が好ましい。
　アミド化に使用される化合物としては、アクリル酸クロリドまたはメタクリル酸クロリドが好ましい。
　この反応に用いられる溶媒としては、反応に影響を及ぼさないものであれば特に限定されないが、ジクロロメタンが好ましい。これらは１種を単独で、または２種以上を混合して用いることができる。
　この反応は、好ましくは、-10～170℃で、1分間～24時間実施すればよい。 Amidation can be carried out by reacting with the following compounds.
Figure JPOXMLDOC01-appb-C000010
 (In the formula, X 3 is a halogen atom, R 15 and R 16 have the same meanings as above, and the preferred range is also the same.)
The halogen atom represented by X 3 is preferably a chlorine atom.
As the compound used for amidation, acrylic acid chloride or methacrylic acid chloride is preferable.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, but dichloromethane is preferable. These can be used alone or in admixture of two or more.
This reaction is preferably carried out at -10 to 170 ° C. for 1 minute to 24 hours.
　上記した製造法で使用される化合物において、異性体（たとえば、光学異性体、幾何異性体および互変異性体など）が存在する場合、これらの異性体も使用することができる。また、溶媒和物、水和物および種々の形状の結晶が存在する場合、これらの溶媒和物、水和物および種々の形状の結晶も使用することができる。また、上記した製造法で使用される化合物において、保護し得る置換基（たとえば、アミノ基、ヒドロキシル基またはカルボキシル基など）を有している化合物は、予めこれらの基を通常の保護基で保護しておき、反応後、自体公知の方法でこれらの保護基を脱離することもできる。 If isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present in the compounds used in the above-mentioned production method, these isomers can also be used. Also, if solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used. Further, among the compounds used in the above-mentioned production method, a compound having a protective substituent (for example, an amino group, a hydroxyl group or a carboxyl group) protects these groups with an ordinary protecting group in advance. However, after the reaction, these protecting groups can be removed by a method known per se.
　上記した製造法で得られる化合物またはそれらの塩は、たとえば、縮合、付加、酸化、還元、転位、置換、ハロゲン化、脱水または加水分解などの自体公知の反応に付すことによって、またはそれらの反応を適宜組み合わせることによって、他の化合物またはその塩に誘導することができる。 The compounds obtained by the above-mentioned production methods or salts thereof are subjected to self-known reactions such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or their reactions. Can be derived to other compounds or salts thereof by appropriately combining them.
　本発明化合物を医薬として用いる場合、通常、薬理学的に許容される添加物を適宜混合してもよい。
　添加物としては、たとえば、賦形剤、崩壊剤、結合剤、滑沢剤、矯味剤、着色剤、着香剤、界面活性剤、コーティング剤および可塑剤が挙げられる。
　これらの添加物は、いずれか一種または二種以上を組み合わせて用いてもよい。
　配合量は、特に限定されず、それぞれの目的に応じ、その効果が充分に発現されるよう適宜配合すればよい。 When the compound of the present invention is used as a medicine, usually, a pharmacologically acceptable additive may be appropriately mixed.
Additives include, for example, excipients, disintegrants, binders, lubricants, flavoring agents, colorants, flavoring agents, surfactants, coating agents and plasticizers.
These additives may be used alone or in combination of two or more.
The blending amount is not particularly limited, and it may be blended appropriately so that the effect is sufficiently exhibited according to each purpose.
　これらは常法にしたがって、錠剤または注射剤などの形態で経口または非経口で投与することができる。また投与方法、投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択することができる。例えば、成人に対しては、経口または非経口投与により、１日、0.01～1000mg／kgを１回から数回に分割して投与すればよい。 These can be administered orally or parenterally in the form of tablets or injections according to conventional methods. The administration method, dose and frequency of administration can be appropriately selected according to the age, body weight and symptoms of the patient. For example, for adults, 0.01 to 1000 mg / kg may be administered in 1 to several divided doses daily by oral or parenteral administration.
　次に、本発明を参考例および実施例を挙げて説明するが、本発明はこれらに限定されるものではない。
　特に記載のない場合、カラムクロマトグラフィーによる精製は、自動精製装置ISOLERA（Biotage社）または中圧液体クロマトグラフYFLC W-prep 2XY（山善株式会社）を使用した。
　特に記載のない場合、シリカゲルカラムクロマトグラフィーにおける担体は、Q-PACK　SI50（Fuji Silysia社）、SNAP KP-Sil Cartridge（Biotage社）、ハイフラッシュカラムW001、W002、W003、W004またはW005（山善株式会社）を使用した。
　ＮＨシリカは、Q-PACK NH60（Fuji Silysia社）またはSNAP KP-NH Cartridge（Biotage社）を使用した。
　溶離液における混合比は、容量比である。
　たとえば、「クロロホルム:メタノール＝90:10→50:50」は、「クロロホルム:メタノール＝90:10」の溶離液を「クロロホルム:メタノール＝50:50」の溶離液へ変化させたことを意味する。 Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto.
Unless otherwise specified, purification by column chromatography was performed using an automatic purification device ISOLERA (Biotage) or a medium-pressure liquid chromatograph YFLC W-prep 2XY (Yamazen Corporation).
Unless otherwise specified, the carriers in silica gel column chromatography are Q-PACK SI50 (Fuji Silysia), SNAP KP-Sil Cartridge (Biotage), high flash columns W001, W002, W003, W004 or W005 (Yamazen Corporation). )It was used.
For NH silica, Q-PACK NH60 (Fuji Silysia) or SNAP KP-NH Cartridge (Biotage) was used.
The mixing ratio in the eluent is the volume ratio.
For example, "chloroform: methanol = 90:10 → 50:50" means that the eluate of "chloroform: methanol = 90:10" was changed to the eluate of "chloroform: methanol = 50:50". ..
　超臨界流体クロマトグラフィーは、SFC 30（Waters社）を使用した。
　ＭＳスペクトルは、ACQUITY SQD LC/MS System（Waters社、イオン化法：ESI（ElectroSpray Ionization、エレクトロスプレーイオン化）法またはLCMS-2010EV（島津製作所、イオン化法：ESIおよびAPCI（Atomospheric Pressure Chemical Ionization、大気圧化学イオン化）を同時に行うイオン化法を用いて測定した。
　特に記載のない場合、表中のMSは、MS(ESI m/z):(M+H)を意味する。 For supercritical fluid chromatography, SFC 30 (Waters) was used.
The MS spectrum is ACQUITY SQD LC / MS System (Waters, ionization method: ESI (ElectroSpray Ionization, electrospray ionization) method or LCMS-2010EV (Shimadzu Seisakusho, ionization method: ESI and APCI (Atomospheric Pressure Chemical Ionization, atmospheric pressure chemistry)). Ionization) was performed at the same time, and the measurement was performed using an ionization method.
Unless otherwise stated, MS in the table means MS (ESI m / z) :( M + H).
　マイクロウェーブ反応装置は、InitiatorTM（Biotage社）を使用した。
　NMRスペクトルは、内部基準としてテトラメチルシランを用い、Bruker AV300（Bruker社）を用いて測定し、全δ値をppmで示した。 InitiatorTM (Biotage) was used as the microwave reactor.
The NMR spectrum was measured using Bruker AV300 (Bruker) using tetramethylsilane as an internal reference, and the total δ value was shown in ppm.
　保持時間(RT)は、SQD（Waters社）を用いて測定し、分（min）で示した。
カラム：Waters社製BEHC 18 1.7μm, 2.1x30 mm
溶媒：A液：0.1％ギ酸－水
　　　B液：0.1％ギ酸－アセトニトリル
グラジエントサイクル: 0.00min（A液/B液＝95/5）、2.00min（A液/B液＝5/95）、3.00min（A液/B液＝5/95）
流速：0.5 mL/min
カラム温度：室温
検出波長:254nm Retention time (RT) was measured using SQD (Waters) and expressed in minutes (min).
Column: Waters BEHC 18 1.7 μm, 2.1x30 mm
Solvent: Solution A: 0.1% formic acid-water Solution B: 0.1% formic acid-acetonitrile gradient cycle: 0.00min (solution A / solution B = 95/5), 2.00min (solution A / solution B = 5/95), 3.00 min (Liquid A / Solution B = 5/95)
Flow velocity: 0.5 mL / min
Column temperature: Room temperature Detection wavelength: 254 nm
　各参考例と実施例において各略号は、以下の意味を有する。
Boc：tert-ブトキシカルボニル
DIPEA：N,N-ジイソプロピルエチルアミン
DMF：N,N-ジメチルホルムアミド
DMSO：ジメチルスルホキシド
Me：メチル
MeOD：重メタノール(CD3OD)
RT, rt：retention time
SEM：2-(トリメチルシリル)エトキシメチル
WSC：1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩
HEPES：4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸
FBS：ウシ胎児血清（fetal bovine serum） In each reference example and embodiment, each abbreviation has the following meaning.
Boc: tert-butoxycarbonyl
DIPEA: N, N-diisopropylethylamine
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfoxide
Me: Methyl
MeOD: Deuterated methanol (CD 3 OD)
RT, rt: retention time
SEM: 2- (trimethylsilyl) ethoxymethyl
WSC: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
HEPES: 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid
FBS: fetal bovine serum
参考例１－１
Figure JPOXMLDOC01-appb-C000011
 Reference example 1-1
Figure JPOXMLDOC01-appb-C000011
　4-クロロピリジン-2,3-ジアミン(200mg)、4-メトキシ安息香酸(260mg)およびオキシ塩化リン(1mL)の混合物にマイクロ波を照射(InitiatorTM、150℃、0.5時間、2.45GHz、0－240W)した。室温まで冷却した後、反応混合物を水に加え、1mol/L水酸化ナトリウム水溶液をpH9になるまで添加した。析出した固体をろ取し、黄色固体の7-クロロ-2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン(210mg)を得た。
MS(ESI m/z): 260(M+H)
RT(min):1.05
1H-NMR(DMSO-d6, 300MHz)δ: 8.26-8.17(3H, m), 7.35(1H, d, J=5.3Hz), 7.14(2H, d, J=9.2Hz), 3.86(3H, s) Irradiate a mixture of 4-chloropyridine-2,3-diamine (200 mg), 4-methoxybenzoic acid (260 mg) and phosphorus oxychloride (1 mL) with microwaves (InitiatorTM, 150 ° C., 0.5 hours, 2.45 GHz, 0- 240W). After cooling to room temperature, the reaction mixture was added to water and 1 mol / L aqueous sodium hydroxide solution was added until pH 9. The precipitated solid was collected by filtration to give a yellow solid, 7-chloro-2- (4-methoxyphenyl) -3H-imidazole [4,5-b] pyridine (210 mg).
MS (ESI m / z): 260 (M + H)
RT (min): 1.05
1 H-NMR (DMSO-d 6 , 300MHz) δ: 8.26-8.17 (3H, m), 7.35 (1H, d, J = 5.3Hz), 7.14 (2H, d, J = 9.2Hz), 3.86 (3H) , s)
参考例１－２～１－１３
　参考例１－１と同様にして、以下の化合物を得た。 Reference example 1-2 to 1-13
The following compounds were obtained in the same manner as in Reference Example 1-1.
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-I000013
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-I000013
参考例２－１
Figure JPOXMLDOC01-appb-C000014
 Reference example 2-1
Figure JPOXMLDOC01-appb-C000014
　tert-ブチル (S)-3-(メチルアミノ)ピロリジン-1-カルボキシラート(270mg)、2-(4-(ブロモメチル)フェニル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(200mg)、炭酸カリウム(190mg)およびDMF(2mL)の混合物を室温で3.5時間撹拌した。反応混合物に水を加え、酢酸エチルおよびノルマルヘキサンで抽出した。有機層を水および飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、無色油状のtert-ブチル (S)-3-(メチル(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジル)アミノ)ピロリジン-1-カルボキシラートを含む混合物(350mg)を得た。そのまま次の反応に用いた。
MS(ESI m/z):(M+H): 417(M+H)
RT(min): 1.19 tert-Butyl (S) -3- (methylamino) pyrrolidine-1-carboxylate (270 mg), 2- (4- (bromomethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2 -A mixture of dioxaborolane (200 mg), potassium carbonate (190 mg) and DMF (2 mL) was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and normal hexane. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to remove the colorless oil of tert-butyl (S) -3- (methyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)). A mixture (350 mg) containing benzyl) amino) pyrrolidine-1-carboxylate was obtained. It was used as it was for the next reaction.
MS (ESI m / z): (M + H): 417 (M + H)
RT (min): 1.19
参考例２－２～２－７
　参考例２－１と同様にして、以下の化合物を得た。 Reference example 2-2 to 2-7
The following compounds were obtained in the same manner as in Reference Example 2-1.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
参考例３－１
Figure JPOXMLDOC01-appb-C000016
 Reference example 3-1
Figure JPOXMLDOC01-appb-C000016
　窒素気流下、tert-ブチル (S)-3-アミノピロロジン-1-カルボキシラート(1g)、アセトアルデヒド(0.3mL)、ナトリウムトリアセトキシボロヒドリド(1.3g)およびメタノール(10mL)の混合物を室温で6.5時間撹拌した後、終夜で放置した。反応混合物をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=10:0→9:1)で精製し、無色油状のtert-ブチル (S)-3-(エチルアミノ)ピロリジン-1-カルボキシラート(0.5g)を得た。
MS(ESI m/z):(M+H):215
RT(min):0.65
1H-NMR(CDCl3, 300MHz)δ: 3.69-3.21(4H, m), 3.18-2.94(1H, m), 2.66(2H, q, J=7.0Hz),  2.14-1.98(1H, m), 1.79-1.59(1H, m), 1.46(9H, s),1.12(3H, t, J=6.9Hz) A mixture of tert-butyl (S) -3-aminopyrrolodin-1-carboxylate (1 g), acetaldehyde (0.3 mL), sodium triacetoxyborohydride (1.3 g) and methanol (10 mL) at room temperature under a nitrogen stream. After stirring for 6.5 hours, it was left overnight. The reaction mixture was purified by silica gel column chromatography (chloroform: methanol = 10: 0 → 9: 1) and tert-butyl (S) -3- (ethylamino) pyrrolidine-1-carboxylate (0.5 g) was colorless and oily. Got
MS (ESI m / z): (M + H): 215
RT (min): 0.65
1 1 H-NMR (CDCl 3 , 300MHz) δ: 3.69-3.21 (4H, m), 3.18-2.94 (1H, m), 2.66 (2H, q, J = 7.0Hz), 2.14-1.98 (1H, m) , 1.79-1.59 (1H, m), 1.46 (9H, s), 1.12 (3H, t, J = 6.9Hz)
参考例３－２
Figure JPOXMLDOC01-appb-C000017
 Reference example 3-2
Figure JPOXMLDOC01-appb-C000017
　参考例３－１と同様にして、以下の化合物を得た。
tert-ブチル (S)-3-(プロピルアミノ)ピロリジン-1-カルボキシラート
MS(ESI m/z):229(M+H)
RT(min):0.70 The following compounds were obtained in the same manner as in Reference Example 3-1.
tert-Butyl (S) -3- (propylamino) pyrrolidine-1-carboxylate
MS (ESI m / z): 229 (M + H)
RT (min): 0.70
参考例４－１～４－７
　参考例１－１と同様にして、以下の化合物を得た。以下、参考例４－１～４－７を参考例４ということがある。 Reference example 4-1 to 4-7
The following compounds were obtained in the same manner as in Reference Example 1-1. Hereinafter, Reference Examples 4-1 to 4-7 may be referred to as Reference Example 4.
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
参考例５－１～５－９
　参考例１－１のオキシ塩化リンをジホスホリルクロリドに変更して、以下の化合物を得た。 Reference example 5-1 to 5-9
The phosphorus oxychloride of Reference Example 1-1 was changed to diphosphoryl chloride to obtain the following compounds.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-I000020
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-I000020
参考例６－１
Figure JPOXMLDOC01-appb-C000021
 Reference example 6-1
Figure JPOXMLDOC01-appb-C000021
　氷浴下、参考例５－１で得られた7-クロロ-2-(チオフェン-2-イル)-3H-イミダゾ[4,5-b]ピリジン(70mg)をDMF(1mL)およびトルエン(1mL)に溶解し、DIPEA(0.21mL)および2-(トリメチルシリル)エトキシメチルクロリド(0.11mL)を加え、2.5時間撹拌した。反応溶液に水を加えて酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ノルマルヘキサン:酢酸エチル=100:0→85:15)で精製し、7-クロロ-2-(チオフェン-2-イル)-3-((2-(トリメチルシリル)エトキシ)メチル)-3H-イミダゾ[4,5-b]ピリジン(46mg)を得た。
MS(ESI m/z):366(M+H)
RT(min):2.08 Under an ice bath, 7-chloro-2- (thiophen-2-yl) -3H-imidazole [4,5-b] pyridine (70 mg) obtained in Reference Example 5-1 was added to DMF (1 mL) and toluene (1 mL). ), DIPEA (0.21 mL) and 2- (trimethylsilyl) ethoxymethyl chloride (0.11 mL) were added, and the mixture was stirred for 2.5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 → 85: 15). 7-Chloro-2- (thiophen-2-yl) -3-((2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b] pyridine (46 mg) was obtained.
MS (ESI m / z): 366 (M + H)
RT (min): 2.08
参考例６－２～６－８
　参考例６－１と同様にして、以下の化合物を得た。以下、参考例６－１～６－８を参考例６ということがある。 Reference example 6-2 to 6-8
The following compounds were obtained in the same manner as in Reference Example 6-1. Hereinafter, Reference Examples 6-1 to 6-8 may be referred to as Reference Example 6.
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
実施例１－１
Figure JPOXMLDOC01-appb-C000023
 Example 1-1
Figure JPOXMLDOC01-appb-C000023
（１）
　7-クロロ-2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン(20mg)、tert-ブチル (S)-3-(メチル(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジル)アミノ)ピロリジン-1-カルボキシラート(64mg)、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)(5mg)、リン酸三カリウム(33mg)、ジオキサン(0.7mL)および水(0.2mL)の混合物にマイクロ波を照射(InitiatorTM、130℃、0.5時間、2.45GHz、0－240W)した。反応混合物を室温まで冷却後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル：メタノール=100:0→5:95)で精製し、黄色固体のtert-ブチル (S)-3-((4-(2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)ベンジル)(メチル)アミノ)ピロリジン-1-カルボキシラート(30mg)を得た。
MS(ESI m/z):(M+H):514
RT(min): 1.04
1H-NMR(CDCl3, 300MHz)δ: 14.21(1H, s), 8.43(1H, d, J=5.3Hz), 8.36-8.25(4H, m), 7.57-7.46(3H, m), 7.12(2H, d, J=8.6Hz), 3.94(3H, s), 3.84-3.45(4H, m), 3.41-2.98(3H, m), 2.23(3H, s), 2.21-2.07(1H, m), 2.02-1.80(1H, m), 1.48(9H, s) (1)
7-Chloro-2- (4-methoxyphenyl) -3H-imidazo [4,5-b] Pyridine (20 mg), tert-butyl (S) -3- (Methyl (4- (4,4,5,5)) -Tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) amino) pyrrolidine-1-carboxylate (64 mg), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) ) (5 mg), tripotassium phosphate (33 mg), dioxane (0.7 mL) and water (0.2 mL) were irradiated with microwaves (InitiatorTM, 130 ° C., 0.5 hours, 2.45 GHz, 0-240 W). After cooling the reaction mixture to room temperature, the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 5:95) to make a yellow solid tert-butyl (S) -3-((4- (2)). -(4-Methanolphenyl) -3H-imidazo [4,5-b] pyridine-7-yl) benzyl) (methyl) amino) pyrrolidine-1-carboxylate (30 mg) was obtained.
MS (ESI m / z): (M + H): 514
RT (min): 1.04
1 1 H-NMR (CDCl 3 , 300MHz) δ: 14.21 (1H, s), 8.43 (1H, d, J = 5.3Hz), 8.36-8.25 (4H, m), 7.57-7.46 (3H, m), 7.12 (2H, d, J = 8.6Hz), 3.94 (3H, s), 3.84-3.45 (4H, m), 3.41-2.98 (3H, m), 2.23 (3H, s), 2.21-2.07 (1H, m) ), 2.02-1.80 (1H, m), 1.48 (9H, s)
（２）
　tert-ブチル (S)-3-((4-(2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)ベンジル)(メチル)アミノ)ピロリジン-1-カルボキシラート(2.29g)、4.0mol/L塩化水素/シクロペンチルメチルエーテル（22mL）、メタノール(22mL)の混合物を50℃で3時間撹拌した。減圧下で溶媒を留去し、残渣にジクロロメタン(90mL)、DIPEA(7.8mL)を加えた。氷冷下、アクリル酸クロリド(0.4mL)を4分かけて滴下し、20分間撹拌した。反応混合物にメタノールを加え、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ノルマルヘキサン：酢酸エチル=1:1→0:1、次いでクロロホルム:メタノール=10:0→9:1、NHシリカ)で精製した。得られた固体をさらにシリカゲルカラムクロマトグラフィー(酢酸エチル:メタノール=95:5→90:10、NHシリカ)で精製し、(S)-1-(3-((4-(2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)ベンジル)(メチル)アミノ)ピロリジン-1-イル)プロプ-2-エン-1-オン(0.92g)を得た。
MS(ESI m/z):(M+H):468
RT(min):0.81
1H-NMR(CDCl3, 300MHz)δ: 14.35(1H, s), 8.42(1H, dd, J=5.3, 2.0Hz), 8.37-8.25(4H, m), 7.56-7.45(3H, m), 7.12(2H, d, J=9.2Hz), 6.56-6.33(2H, m), 5.75-5.65(1H, m), 4.10-3.38(6H, m), 3.94(3H, s), 3.29-2.99(1H, m),2.35-1.82(2H, m),2.25(3H, s) (2)
tert-Butyl (S) -3-((4- (2- (4-Methoxyphenyl) -3H-imidazo [4,5-b] pyridin-7-yl) benzyl) (methyl) amino) pyrrolidine-1- A mixture of carboxylate (2.29 g), 4.0 mol / L hydrogen chloride / cyclopentylmethyl ether (22 mL) and methanol (22 mL) was stirred at 50 ° C. for 3 hours. The solvent was distilled off under reduced pressure, and dichloromethane (90 mL) and DIPEA (7.8 mL) were added to the residue. Acrylic acid chloride (0.4 mL) was added dropwise over 4 minutes under ice-cooling, and the mixture was stirred for 20 minutes. Methanol was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 1: 1 → 0: 1, then chloroform: methanol = 10: 0 → 9: 1, NH silica). The obtained solid was further purified by silica gel column chromatography (ethyl acetate: methanol = 95: 5 → 90: 10, NH silica), and (S) -1- (3-((4- (2- (4- (4-) 4-) Methoxyphenyl) -3H-imidazole [4,5-b] pyridine-7-yl) benzyl) (methyl) amino) pyrrolidine-1-yl) prop-2-en-1-one (0.92 g) was obtained.
MS (ESI m / z): (M + H): 468
RT (min): 0.81
1 1 H-NMR (CDCl 3 , 300MHz) δ: 14.35 (1H, s), 8.42 (1H, dd, J = 5.3, 2.0Hz), 8.37-8.25 (4H, m), 7.56-7.45 (3H, m) , 7.12 (2H, d, J = 9.2Hz), 6.56-6.33 (2H, m), 5.75-5.65 (1H, m), 4.10-3.38 (6H, m), 3.94 (3H, s), 3.29-2.99 (1H, m), 2.35-1.82 (2H, m), 2.25 (3H, s)
実施例１－２～１－２３
　実施例１－１と同様にして、以下の化合物を得た。 Examples 1-2 to 1-23
The following compounds were obtained in the same manner as in Example 1-1.
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-I000025
Figure JPOXMLDOC01-appb-I000026
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-I000025
Figure JPOXMLDOC01-appb-I000026
実施例２－１
Figure JPOXMLDOC01-appb-C000027
 Example 2-1
Figure JPOXMLDOC01-appb-C000027
（１）
　7-クロロ-2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン(20mg)、tert-ブチル (S)-3-(エチル(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンジル)アミノ)ピロリジン-1-カルボキシラート(66mg)、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)(6mg)、炭酸ナトリウム(16mg)、ジオキサン(0.8mL)および水(0.2mL)の混合物にマイクロ波を照射(InitiatorTM、140℃、0.5時間、2.45GHz、0－240W)した。反応混合物を室温まで冷却後、得られた残渣に酢酸エチルを加え、水及び飽和食塩水で洗浄し、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ノルマルヘキサン：酢酸エチル=10:0→7:3)で精製し、tert-ブチル (S)-3-(エチル(4-(2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)ベンジル)アミノ)ピロリジン-1-カルボキシラート(39mg)を得た。
MS(ESI m/z):528(M+H)
RT(min):1.10 (1)
7-Chloro-2- (4-Methoxyphenyl) -3H-Imidazo [4,5-b] Pyridine (20 mg), tert-Butyl (S) -3- (Ethyl (4- (4,4,5,5)) -Tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) amino) pyrrolidine-1-carboxylate (66 mg), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) ) (6 mg), sodium carbonate (16 mg), dioxane (0.8 mL) and water (0.2 mL) were irradiated with microwaves (InitiatorTM, 140 ° C., 0.5 hours, 2.45 GHz, 0-240 W). The reaction mixture was cooled to room temperature, ethyl acetate was added to the obtained residue, the mixture was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 10: 0 → 7: 3), and tert-butyl (S) -3- (ethyl (4- (2- (4-methoxyphenyl)) ) -3H-imidazole [4,5-b] pyridine-7-yl) benzyl) amino) pyrrolidine-1-carboxylate (39 mg) was obtained.
MS (ESI m / z): 528 (M + H)
RT (min): 1.10
（２）
　tert-ブチル (S)-3-(エチル(4-(2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)ベンジル)アミノ)ピロリジン-1-カルボキシラート(30mg)、4.0mol/L塩化水素/シクロペンチルメチルエーテル（2mL）、メタノール(2mL)の混合物を50℃で1.5時間撹拌した。減圧下で溶媒を留去し、得られた残渣の半分量にDMF(1mL)、DIPEA(0.27mL)、trans-4-ジメチルアミノクロトン酸(17mg)およびWSC(30mg)を加え、室温で2時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出し、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ノルマルヘキサン：酢酸エチル=1:1→0:1、次いで酢酸エチル:メタノール=100:0→85:15、NHシリカ)で精製し、黄色固体の(S,E)-4-(ジメチルアミノ)-1-(3-(エチル(4-(2-(4-メトキシフェニル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)ベンジル)アミノ)ピロリジン-1-イル)ブタ-2-エン-1-オン(15mg)を得た。
MS(ESI m/z):539(M+H)
RT(min):0.73
1H-NMR(CDCl3, 300MHz)δ: 8.41(1H, d, J=5.3Hz), 8.35-8.27(2H, m), 8.23(2H, d, J=9.0Hz), 7.55(2H, d, J=8.1Hz), 7.48(1H, d, J=4.8Hz), 7.11(2H, d, J=9.2Hz), 7.05-6.82(1H, m), 6.34-6.20(1H, m), 3.93(3H, s), 3.91-3.24(7H, m), 3.14-3.04(2H, m), 2.75-2.62(2H, m), 2.31-1.80(8H, m), 1.12-1.02(3H, m) (2)
tert-Butyl (S) -3-(Ethyl (4- (2- (4-Methoxyphenyl) -3H-Imidazo [4,5-b] Pyridine-7-yl) Benzyl) Amino) Pyrrolidine-1-carboxylate A mixture of (30 mg), 4.0 mol / L hydrogen chloride / cyclopentylmethyl ether (2 mL) and methanol (2 mL) was stirred at 50 ° C. for 1.5 hours. The solvent was distilled off under reduced pressure, DMF (1 mL), DIPEA (0.27 mL), trans-4-dimethylaminocrotonic acid (17 mg) and WSC (30 mg) were added to half of the obtained residue, and 2 at room temperature. Stirred for hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 1: 1 → 0: 1, then ethyl acetate: methanol = 100: 0 → 85: 15, NH silica), and the yellow solid (S) was purified. , E) -4- (dimethylamino) -1- (3- (ethyl (4- (2- (4-methoxyphenyl) -3H-imidazo [4,5-b] pyridine-7-yl) benzyl) amino ) Pyrrolidine-1-yl) Buta-2-en-1-one (15 mg) was obtained.
MS (ESI m / z): 539 (M + H)
RT (min): 0.73
1 1 H-NMR (CDCl 3 , 300MHz) δ: 8.41 (1H, d, J = 5.3Hz), 8.35-8.27 (2H, m), 8.23 (2H, d, J = 9.0Hz), 7.55 (2H, d) , J = 8.1Hz), 7.48 (1H, d, J = 4.8Hz), 7.11 (2H, d, J = 9.2Hz), 7.05-6.82 (1H, m), 6.34-6.20 (1H, m), 3.93 (3H, s), 3.91-3.24 (7H, m), 3.14-3.04 (2H, m), 2.75-2.62 (2H, m), 2.31-1.80 (8H, m), 1.12-1.02 (3H, m)
実施例２－２～２－５
　実施例２－１と同様にして、以下の化合物を得た。 Examples 2-2 to 2-5
The following compounds were obtained in the same manner as in Example 2-1.
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
実施例３－１～３－１４
　参考例４および参考例６の化合物を用いて、実施例１－１と同様にして、以下の化合物を得た。 Examples 3-1 to 3-14
Using the compounds of Reference Example 4 and Reference Example 6, the following compounds were obtained in the same manner as in Example 1-1.
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-I000030
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-I000030
実施例４－１～４－５ Examples 4-1 to 4-5
（１）
　参考例４の化合物を用いて、実施例１－１（１）と同様にして実施した。
（２）
　4.0mol/L塩化水素/シクロペンチルメチルエーテルをトリフルオロ酢酸に変更し、実施例１－１（２）と同様にして、以下の化合物を得た。 (1)
Using the compound of Reference Example 4, it was carried out in the same manner as in Example 1-1 (1).
(2)
The 4.0 mol / L hydrogen chloride / cyclopentyl methyl ether was changed to trifluoroacetic acid, and the following compounds were obtained in the same manner as in Example 1-1 (2).
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
FGFR1-WT酵素阻害試験
　段階希釈した試験化合物あるいはDMSOを含むアッセイバッファー（100 mmol/L HEPES pH7.5、10 mmol/L MgCl2、10 mmol/L MnCl2、0.003 % Brij-35、1 mmol/L DTT、0.004 % Tween 20）を、6 μL/ウェルで384ウェルプレート(Corning社)に添加した。ヒトFGFR1-WT酵素(Millipore社、商品名： FGFR1,active、商品コード：14-582M)をアッセイバッファーで7.5 nMに希釈し、6 μL/ウェルで添加した。アッセイバッファーのみを6 μL/ウェルで添加したウェルを陰性対照とした。7.5 μmol/L FL-peptide 22(Caliper社)および30 μmol/L ATPを含むアッセイバッファーを3 μL/ウェルで添加した後、25 ℃で90分間静置した。200 mmol/L EDTAを含むアッセイバッファーを5 μL/ウェルで添加し、酵素反応を停止した後、LabChip EZReaderを用いてFL-peptide 22のリン酸化率を検出した。各試験化合物濃度におけるリン酸化阻害率を下式にて算出した。 FGFR1-WT Enzyme Inhibition Test Assay buffer containing serially diluted test compound or DMSO (100 mmol / L HEPES pH 7.5 , 10 mmol / L MgCl 2 , 10 mmol / L MnCl 2 , 0.003% Brij-35, 1 mmol / L DTT, 0.004% Tween 20) was added to a 384-well plate (Corning) at 6 μL / well. Human FGFR1-WT enzyme (Millipore, trade name: FGFR1, active, trade code: 14-582M) was diluted to 7.5 nM in assay buffer and added at 6 μL / well. Wells to which only assay buffer was added at 6 μL / well were defined as negative controls. Assay buffer containing 7.5 μmol / L FL-peptide 22 (Caliper) and 30 μmol / L ATP was added at 3 μL / well and then allowed to stand at 25 ° C. for 90 minutes. The assay buffer containing 200 mmol / L EDTA was added at 5 μL / well to stop the enzymatic reaction, and then the phosphorylation rate of FL-peptide 22 was detected using LabChip EZ Reader. The phosphorylation inhibition rate at each test compound concentration was calculated by the following formula.
（DMSO添加ウェルのシグナル-試験化合物添加ウェルのシグナル）÷（DMSO添加ウェルのシグナル-酵素無しウェルのシグナル）×100 (Signal of DMSO-added well-Signal of test compound-added well) ÷ (Signal of DMSO-added well-Signal of enzyme-free well) x 100
　各化合物濃度におけるリン酸化阻害率を、XLfitソフトウエア（IDBS）を用いてシグモイド用量反応式による非線形回帰適合(Fit Model(205))を用いてプロットし、50 % 阻害濃度（IC50）を算出した。得られた結果を下記表に示した。 Phosphorylation inhibition rates at each compound concentration were plotted using XLfit software (IDBS) using a non-linear regression fit (Fit Model (205)) with a sigmoid dose-response equation to calculate a 50% inhibition concentration (IC 50). did. The results obtained are shown in the table below.
～評価基準～
＋＋＋　　10 nmol/L＞IC50
＋＋　　　10 nmol/L≦IC50＜20 nmol/L
＋　　　　20 nmol/L≦IC50 ~ Evaluation criteria ~
+++ 10 nmol / L> IC 50
++ 10 nmol / L ≤ IC 50 <20 nmol / L
＋ 20 nmol / L ≦ IC 50
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
FGFR1-V561M ゲートキーパー変異体酵素阻害試験
　段階希釈した試験化合物あるいはDMSOを含むアッセイバッファー（100 mmol/L HEPES pH7.5、10mmol/L MgCl2、10 mmol/L MnCl2、0.003 % Brij-35、1 mmol/L DTT、0.004 % Tween 20）を、6 μL/ウェルで384ウェルプレート(Corning社)に添加した。ヒトFGFR1-V561M酵素(Millipore社、商品名： FGFR1(V561M),active、商品コード：14-734M)をアッセイバッファーに12.5 nMに希釈し、6 μL/ウェルで添加した。アッセイバッファーのみを6 μL/ウェルで添加したウェルを陰性対照とした。7.5 μmol/L FL-peptide 22(Caliper社)および6.7 μmol/L ATPを含むアッセイバッファーを3 μL/ウェルで添加した後、25 ℃で50分間静置した。200 mmol/L EDTAを含むアッセイバッファーを5 μL/ウェルで添加し、酵素反応を停止した後、LabChip EZReaderを用いてFL-peptide 22のリン酸化率を検出した。各試験化合物濃度におけるリン酸化阻害率を下式にて算出した。 FGFR1-V561M Gatekeeper Variant Enzyme Inhibition Test Assay buffer containing serially diluted test compound or DMSO (100 mmol / L HEPES pH7.5 , 10 mmol / L MgCl 2 , 10 mmol / L MnCl 2 , 0.003% Brij-35, 1 mmol / L DTT, 0.004% Tween 20) was added to a 384-well plate (Corning) at 6 μL / well. Human FGFR1-V561M enzyme (Millipore, trade name: FGFR1 (V561M), active, trade code: 14-734M) was diluted to 12.5 nM in assay buffer and added at 6 μL / well. Wells to which only assay buffer was added at 6 μL / well were defined as negative controls. Assay buffer containing 7.5 μmol / L FL-peptide 22 (Caliper) and 6.7 μmol / L ATP was added at 3 μL / well and then allowed to stand at 25 ° C. for 50 minutes. The assay buffer containing 200 mmol / L EDTA was added at 5 μL / well to stop the enzymatic reaction, and then the phosphorylation rate of FL-peptide 22 was detected using LabChip EZ Reader. The phosphorylation inhibition rate at each test compound concentration was calculated by the following formula.
（DMSO添加ウェルのシグナル-試験化合物添加ウェルのシグナル）÷（DMSO添加ウェルのシグナル-酵素無しウェルのシグナル）×100 (Signal of DMSO-added well-Signal of test compound-added well) ÷ (Signal of DMSO-added well-Signal of enzyme-free well) x 100
　各化合物濃度におけるリン酸化阻害率を、XLfitソフトウエア（IDBS社）を用いてシグモイド用量反応式による非線形回帰適合(Fit Model(205)) を用いてプロットし、50 % 阻害濃度（IC50）を算出した。得られた結果を下記表に示した。 Phosphorylation inhibition rates at each compound concentration were plotted using XLfit software (IDBS) using a non-linear regression fit (Fit Model (205)) with a sigmoid dose-response equation to give a 50% inhibition concentration (IC 50 ). Calculated. The results obtained are shown in the table below.
～評価基準～
＋＋＋　　10nmol/L＞IC50
＋＋　　　10 nmol/L≦IC50＜20 nmol/L
＋　　　　20 nmol/L≦IC50 ~ Evaluation criteria ~
+++ 10 nmol / L> IC 50
++ 10 nmol / L ≤ IC 50 <20 nmol / L
＋ 20 nmol / L ≦ IC 50
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
FGFR1増幅細胞株NCI-H1581に対する細胞増殖阻害試験
　ヒトFGFR1増幅肺がん細胞株NCI-H1581 (ATCC)をペニシリン／ストレプトマイシンおよび終濃度10％のFBSを含有するRPMI-1640培地で4×104細胞/mLとなるように調製し、384ウェルプレート(Corning社)に25 μL/ウェルで播種した。培地のみを25 μL/ウェルで播種したウェルを陰性対照とした。翌日、段階希釈した試験化合物あるいはDMSOを含む培地を25 μL/ウェルで添加した。37 ℃、5 ％CO2条件下で3日間培養した後、Cell Titer Glo（Promega）反応液を30 μL/ウェルで添加し、Envisionプレートリーダー(Perkin Elmer)にて発光量を測定した。発光量は細胞のATP濃度に比例するため、発光量を生細胞数の指標とした。各試験化合物濃度における増殖阻害率を下式にて算出した。 Cell Growth Inhibition Test for FGFR1 Amplified Cell Line NCI-H1581 Human FGFR1 Amplified Lung Cancer Cell Line NCI-H1581 (ATCC) 4 × 10 4 cells / mL in RPMI-1640 medium containing penicillin / streptomycin and FBS at a final concentration of 10% The cells were seeded in 384-well plates (Corning) at 25 μL / well. Wells in which only the medium was seeded at 25 μL / well were used as a negative control. The next day, medium containing serially diluted test compound or DMSO was added at 25 μL / well. After culturing for 3 days under 37 ° C. and 5% CO 2 conditions, Cell Titer Glo (Promega) reaction solution was added at 30 μL / well, and the amount of luminescence was measured with an Envision plate reader (Perkin Elmer). Since the amount of luminescence is proportional to the ATP concentration of cells, the amount of luminescence was used as an index of the number of living cells. The growth inhibition rate at each test compound concentration was calculated by the following formula.
（DMSO添加ウェル発光量-試験化合物添加ウェル発光量）÷（DMSO添加ウェル発光量-培地のみウェル発光量）×100 (DMSO-added well luminescence amount-test compound-added well luminescence amount) ÷ (DMSO-added well luminescence amount-medium only well luminescence amount) x 100
　各化合物濃度における増殖阻害率を、XLfitソフトウエア（IDBS社）を用いてシグモイド用量反応式による非線形回帰適合(Fit Model(205)) を用いてプロットし、50 % 阻害濃度（IC50）を算出した。得られた結果を下記表に示した。 Growth inhibition rates at each compound concentration were plotted using XLfit software (IDBS) using a non-linear regression fit (Fit Model (205)) with a sigmoid dose-response formula to calculate a 50% inhibition concentration (IC 50). did. The results obtained are shown in the table below.
～評価基準～
＋＋＋　　5 nmol/L＞IC50
＋＋　　　5 nmol/L≦IC50＜10 nmol/L
＋　　　　10 nmol/L≦IC50 ~ Evaluation criteria ~
+++ 5 nmol / L> IC 50
++ 5 nmol / L ≤ IC 50 <10 nmol / L
＋ 10 nmol / L ≦ IC 50
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
FGFR1増幅細胞株NCI-H1581 xenograft試験
　6週齢の雌性Balb/c nu/nuマウス（日本クレア）を使用した。ヒトFGFR1増幅肺がん細胞株NCI-H1581（ATCC）をRPMI-1640培地に懸濁し、マトリゲル（Corning）と1:1で混合した後、5×106細胞/100 μL/マウスで皮下に移植した。移植10-14日後に平均腫瘍体積が200-350mm3となるように群分けを行った。試験化合物を溶媒に溶解し、5-50mg/kgで1日1回、マウスに経口投与した。陰性対照として溶媒投与群を設けた。経日的に腫瘍径を測定し、腫瘍体積を算出した。腫瘍体積は、腫瘍の長径および短径を測定し、以下の式によって算出した。
腫瘍体積（mm3）＝長径（mm）×短径（mm）×短径（mm）／2
　各群の腫瘍体積について、GraphPad PRISM を用いて、溶媒投与群に対するDunnett型多重比較検定を実施し、P<0.05を有意な差とした。
　実施例１－１の化合物を投与した試験化合物投与群の体積は、溶媒投与群に対して有意に縮小した。
　本発明化合物は、優れた腫瘍縮小効果を示した。 FGFR1 amplified cell line NCI-H1581 xenograft test 6-week-old female Balb / c nu / nu mice (Claire Japan) were used. Human FGFR1 amplified lung cancer cell line NCI-H1581 (ATCC) was suspended in RPMI-1640 medium, mixed 1: 1 with Matrigel (Corning), and then subcutaneously transplanted in 5 × 10 6 cells / 100 μL / mouse. Grouping was performed so that the average tumor volume was 200-350 mm 3 10-14 days after transplantation. The test compound was dissolved in a solvent and orally administered to mice at 5-50 mg / kg once a day. A solvent administration group was provided as a negative control. The tumor diameter was measured over time and the tumor volume was calculated. The tumor volume was calculated by measuring the major axis and the minor axis of the tumor and using the following formula.
Tumor volume (mm 3 ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
For tumor volume in each group, a Dunnett's multiplex comparison test was performed on the solvent-administered group using GraphPad PRISM, and P <0.05 was considered a significant difference.
The volume of the test compound-administered group to which the compound of Example 1-1 was administered was significantly reduced as compared with the solvent-administered group.
The compound of the present invention showed an excellent tumor shrinkage effect.
　本発明のイミダゾピリジン化合物またはその塩は、ＦＧＦＲ阻害作用を有し、ＦＧＦＲが関与する疾患の治療のための医薬組成物として有用である。 The imidazopyridine compound of the present invention or a salt thereof has an FGFR inhibitory effect and is useful as a pharmaceutical composition for the treatment of diseases associated with FGFR.

Claims (11)

  1. 下記一般式［１］で表されるイミダゾピリジン化合物またはその塩。
    Figure JPOXMLDOC01-appb-C000001
     Ａは、置換基を有してもよい芳香環基であり、
    Ｂは、置換基を有する芳香環基であり、当該置換基は、不可逆性基を有しており、
    Ｒ11は、それぞれ独立に、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ1-6アルコキシ基、またはカルボキシ基であり、
    ａは０～２の整数である。     An imidazopyridine compound represented by the following general formula [1] or a salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     A is an aromatic ring group which may have a substituent and is
    B is an aromatic ring group having a substituent, and the substituent has an irreversible group.
    R 11 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
    a is an integer of 0 to 2.
  2. Ａ及びＢは、それぞれ独立に、置換基を有してもよいアリール基である、請求項１に記載のイミダゾピリジン化合物またはその塩。 The imidazopyridine compound according to claim 1, or a salt thereof, wherein A and B are aryl groups that may independently have a substituent.
  3. Ａ及びＢは、それぞれ独立に、置換基を有してもよいフェニル基である、請求項１に記載のイミダゾピリジン化合物またはその塩。 The imidazopyridine compound according to claim 1, or a salt thereof, wherein A and B are phenyl groups which may independently have a substituent.
  4. 不可逆性基は、二重結合または三重結合を有する基である、請求項１～３のうちのいずれか一項に記載のイミダゾピリジン化合物またはその塩。 The imidazopyridine compound according to any one of claims 1 to 3, or a salt thereof, wherein the irreversible group is a group having a double bond or a triple bond.
  5. 不可逆性基は、置換基を有してもよいα，β－不飽和カルボニル基である、請求項１～３のうちのいずれか一項に記載のイミダゾピリジン化合物またはその塩。 The imidazole pyridine compound according to any one of claims 1 to 3, or a salt thereof, wherein the irreversible group is an α, β-unsaturated carbonyl group which may have a substituent.
  6. 下記一般式［２］で表される、請求項１に記載のイミダゾピリジン化合物またはその塩。
    Figure JPOXMLDOC01-appb-C000002
     Ａ、Ｒ11およびａは、式［１］のものと同義であり、
    Ｒ12は、それぞれ独立に、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ1-6アルコキシ基、またはカルボキシ基であり、
    ｂは０～４の整数であり、
    Ｒ13は、それぞれ独立に、Ｃ1-6アルキレン基、－ＮＲ21－、－Ｏ－、－ＣＯ－、－ＮＲ21－ＣＯ－＊、－ＮＲ22－ＣＯ－ＮＲ21－＊、２価の炭化水素環基、２価のヘテロ環基、－ＮＲ21－Ｃ1-6アルキレン基、２価の炭化水素環－Ｃ1-6アルキレン基、２価のヘテロ環－Ｃ1-6アルキレン基であり、＊はイミダゾピリジン側の結合部位であることを示し、
    ｃは１～３の整数であり、
    Ｒ15及びＲ16は、水素原子、ハロゲン原子、置換基を有してもよいＣ1-6アルキル基、置換基を有してもよいＣ2-6アルケニル基、置換基を有してもよいＣ2-6アルキニル基、（ＮＲ23Ｒ24）－Ｃ1-6アルキレン基であり、
    Ｒ21及びＲ22は、それぞれ独立に、水素原子、ヒドロキシ基、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、Ｃ2-6アルキニル基、Ｃ3-8シクロアルキル基、Ｃ3-8シクロアルケニル基、炭化水素環基、ヘテロ環基を示し、
    Ｒ23及びＲ24は、それぞれ独立に、水素原子、ヒドロキシ基、Ｃ1-6アルキル基、Ｃ1-6アルケニル基、Ｃ1-6アルキニル基、Ｃ3-8シクロアルキル基、Ｃ3-8シクロアルケニル基、炭化水素環基、ヘテロ環基を示す。     The imidazopyridine compound according to claim 1 or a salt thereof, which is represented by the following general formula [2].
    Figure JPOXMLDOC01-appb-C000002
     A, R 11 and a are synonymous with those of equation [1].
    R 12 is independently a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a carboxy group.
    b is an integer from 0 to 4
    R 13 are each independently, C 1-6 alkylene group, -NR 21 -, - O - , - CO -, - NR 21 -CO - *, - NR 22 -CO-NR 21 - *, 2 divalent With a hydrocarbon ring group, a divalent heterocyclic group, a -NR 21- C 1-6 alkylene group, a divalent hydrocarbon ring-C 1-6 alkylene group, and a divalent heterocycle-C 1-6 alkylene group. Yes, * indicates that it is the binding site on the imidazopyridine side,
    c is an integer from 1 to 3
    R 15 and R 16 may have a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. Good C 2-6 alkynyl group, (NR 23 R 24 ) -C 1-6 alkylene group,
    R 21 and R 22 independently have a hydrogen atom, a hydroxy group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, and a C 3-8. Shows cycloalkenyl group, hydrocarbon ring group, heterocyclic group,
    R 23 and R 24 are independently hydrogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkenyl group, C 1-6 alkynyl group, C 3-8 cycloalkyl group, C 3-8. It shows a cycloalkyl group, a hydrocarbon ring group, and a hetero ring group.
  7. 芳香環基Ａの置換基は、置換基Ｒ31で示され、Ｒ31は少なくとも１以上存在してもよく、
    Ｒ31は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基、Ｃ2-6アルケニル基、Ｃ2-6アルキニル基、ＮＲ23Ｒ24、炭化水素環基、ヘテロ環基、（ＮＲ23Ｒ24）－Ｃ1-6アルキレン基、炭化水素環－Ｃ1-6アルキレン基、ヘテロ環－Ｃ1-6アルキレン基、Ｃ1-6アルコキシ基、Ｃ1-6アルコキシＣ1-6アルキル基、Ｃ1-6アルコキシＣ1-6アルコキシ基、アシル基、シアノ基であり、
    置換基Ｒ31はさらに置換基Ｒ32を有してもよく、置換基Ｒ32はハロゲン原子、Ｃ1-6アルキル基を示す、
    請求項１～６のうちのいずれか一項に記載のイミダゾピリジン化合物またはその塩。     The substituent of the aromatic ring group A is represented by the substituent R 31 , and R 31 may be present in at least one or more.
    R 31 each independently represent a halogen atom, C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl group, NR 23 R 24, hydrocarbon ring group, a heterocyclic group, (NR 23 R 24 ) -C 1-6 alkylene group, hydrocarbon ring-C 1-6 alkylene group, hetero ring-C 1-6 alkylene group, C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, C 1-6 Alkoxy C 1-6 Alkoxy group, acyl group, cyano group,
    Substituent R 31 may further have substituent R 32 , where substituent R 32 represents a halogen atom, a C 1-6 alkyl group.
    The imidazopyridine compound according to any one of claims 1 to 6 or a salt thereof.
  8. Ｒ11は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基であり、
    ａは０～２の整数であり、
    Ｒ12は、それぞれ独立に、ハロゲン原子、Ｃ1-6アルキル基であり、
    ｂは０～４の整数であり、
    Ｒ15及びＲ16は、水素原子、ハロゲン原子、Ｃ1-6アルキル基である、
    請求項６～７のうちのいずれか一項に記載のイミダゾピリジン化合物またはその塩。     R 11 is a halogen atom and a C 1-6 alkyl group, respectively.
    a is an integer from 0 to 2
    R 12 is a halogen atom and a C 1-6 alkyl group, respectively.
    b is an integer from 0 to 4
    R 15 and R 16 are hydrogen atoms, halogen atoms, and C 1-6 alkyl groups.
    The imidazopyridine compound according to any one of claims 6 to 7 or a salt thereof.
  9. 　請求項１～８のいずれか一項に記載のイミダゾピリジン化合物またはその塩を含有する医薬組成物。 A pharmaceutical composition containing the imidazopyridine compound according to any one of claims 1 to 8 or a salt thereof.
  10. 　ＦＧＦＲが関与する疾患の処置剤である、請求項９に記載の医薬組成物。 The pharmaceutical composition according to claim 9, which is a therapeutic agent for a disease associated with FGFR.
  11. 　抗がん剤である、請求項９または１０に記載の医薬組成物。 The pharmaceutical composition according to claim 9 or 10, which is an anticancer agent.
PCT/JP2020/035895 2019-09-25 2020-09-24 Imidazopyridine compound or salt thereof, and pharmaceutical composition WO2021060307A1 (en)

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