WO2021060307A1 - Composé imidazopyridine ou sel de celui-ci, et composition pharmaceutique - Google Patents

Composé imidazopyridine ou sel de celui-ci, et composition pharmaceutique 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

La présente invention aborde le problème consistant à fournir un composé imidazopyridine ayant une activité inhibitrice de FGFR ou un sel de celui-ci, et une composition pharmaceutique. La présente invention concerne un composé imidazopyridine représenté par la formule générale [1] ou un sel de celui-ci. Dans la formule, A représente un groupe cyclique aromatique éventuellement substitué, B est un groupe cyclique aromatique ayant un substituant, le substituant a un groupe irréversible, les R11 sont indépendamment un substituant, et a est un nombre entier de 0 à 2.
PCT/JP2020/035895 2019-09-25 2020-09-24 Composé imidazopyridine ou sel de celui-ci, et composition pharmaceutique WO2021060307A1 (fr)

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