WO2021125229A1 - Composé d'indazole ou sel de celui-ci, et composition pharmaceutique - Google Patents

Composé d'indazole ou sel de celui-ci, et composition pharmaceutique Download PDF

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WO2021125229A1
WO2021125229A1 PCT/JP2020/046984 JP2020046984W WO2021125229A1 WO 2021125229 A1 WO2021125229 A1 WO 2021125229A1 JP 2020046984 W JP2020046984 W JP 2020046984W WO 2021125229 A1 WO2021125229 A1 WO 2021125229A1
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group
substituent
indazole
methyl
esi
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Japanese (ja)
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羊平 久保
修平 逢阪
一生 土井
雅晶 井上
松本　拓也
晋 下山
俊明 辻野
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—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 or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D471/10—Spiro-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an indazole 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, 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 as a ligand and gene amplification have also been reported in prostate cancer, liver cancer, colon cancer, lung cancer and the like (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 also 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.
  • MELK Major Embryonic Leucine zipper Kinase
  • cancer stem cells are considered to be one of the major factors for cancer treatment resistance, metastasis, and recurrence, and the development of drugs targeting cancer stem cells is expected (see Non-Patent Document 7).
  • MELK inhibitors not only suppress the growth of cancer cells, but also control cancer stem cells, thereby suppressing metastasis and recurrence in addition to suppressing the progression of cancer, and have the potential for curative treatment. Expected as a therapeutic drug.
  • Indazole is known as a therapeutic agent for cancer (see, for example, Patent Documents 1 to 4). Indazole compounds are also known as therapeutic agents for inflammatory diseases (see, for example, Patent Document 5).
  • An object of the present invention is to provide an indazole compound having an FGFR inhibitory action or a salt thereof, and a pharmaceutical composition.
  • an indazole compound having a specific structure or a salt thereof has an FGFR inhibitory action, and have completed the present invention. That is, the indazole compound of the present invention or a salt thereof is represented by the following general formula (1).
  • A is a hydrocarbon cyclic group which may have a substituent or a heterocyclic group which may have a substituent.
  • B is a C 3-8 cycloalkenylene group which may have a substituent, an arylene group which may have a substituent, or a divalent heterocyclic group which may have a substituent.
  • R 1 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 carboxyl group.
  • L 1 is a C 1-6 alkylene group which may have a substituent, a C 3-8 cycloalkylene group which may have a substituent, or a carbonyl group.
  • R 2 is a C 1-6 alkyl group which may have a hydrogen atom or a substituent, and is a C 1-6 alkyl group.
  • L 2 is a C 1-6 alkylene group which may have a substituent, a C 3-8 cycloalkylene group which may have a substituent, or a carbonyl group.
  • L 3 is a divalent nitrogen-containing heterocyclic group which may have a substituent.
  • L 4 represents an optionally substituted C 1-6 alkylene group, an optionally substituted C 3-8 cycloalkylene group, or -NR 11, - (R 11 is a hydrogen atom or a substituent, C 1-6 alkyl group), which may have R 3 and R 4 are independently hydrogen atoms, C 1-6 alkyl groups which may have a substituent, or C 3-8 cycloalkylene groups which may have a substituent.
  • R 5 is a hydrogen atom or a C 1-6 alkyl group a is an integer from 0 to 3, b, c, d, e and f are independently 0 or 1, and c and e are not 0 at the same time.
  • indazole compound a compound in which R 3 , R 4 and R 5 are hydrogen atoms is preferable.
  • the indazole compound a compound in which B is an arylene group which may have a substituent or a C 3-8 cycloalkenylene group which may have a substituent is preferable.
  • B is an arylene group which may have one or more substituents selected from substituent group B 1, or one or more substituents selected from substituent group B 1
  • Compounds that are C 3-8 cycloalkenylene groups that may have are preferred.
  • Substituent group B 1 Halogen atom, C 1-6 alkyl group, which may have a halogen atom, A C 1-6 alkoxy group which may have a halogen atom.
  • the compound is preferably a compound in which the arylene group is a phenylene group or the C 3-8 cycloalkenylene group is a cyclohexenylene group.
  • L 1 is a C 1-6 alkylene group.
  • R 2 is a hydrogen atom or a C 1-6 alkyl group.
  • Compounds are preferred, where b and c are 1.
  • L 1 is a C 1-6 alkylene group.
  • L 3 is a divalent nitrogen-containing heterocyclic group which may have a hydroxyl group.
  • Compounds are preferred, where b and e are 1 and c is 0.
  • A is one or more substituents may have a cyclic hydrocarbon group selected from Substituent Group A 1 or one or more selected from Substituent Group A 1, Compounds that are heterocyclic groups that may have substituents are preferred.
  • Substituent group A 1 Halogen atom, A C 1-6 alkyl group, which may have one or more substituents selected from the substituent group A 2.
  • a C 3-8 cycloalkyl group which may have one or more substituents selected from the substituent group A 2.
  • a C 1-6 alkoxy group which may have one or more substituents selected from the substituent group A 2.
  • C 1-6 Alkoxy C 1-6 Alkyl Group which may have one or more substituents selected from Substituent Group A 2.
  • a C 2-6 alkanoyl group which may have one or more substituents selected from the substituent group A 2.
  • C 1-6 alkylsulfonyl group It may have one or more substituents selected from the substituent group A 2 heterocyclic groups.
  • Substituent group A 2 Halogen atom, May have one or more substituents selected from the substituent group A 3 C 1-6 alkyl groups, May have one or more substituents selected from the substituent group A 3 C 3-8 cycloalkyl group, May have one or more substituents selected from the substituent group A 3 C 1-6 alkoxy groups, May have one or more substituents selected from the substituent group A 3 C 1-6 alkoxy C 1-6 alkyl group, May have one or more substituents selected from the substituent group A 3 C 2-6 alkanoyl group, C 1-6 alkylsulfonyl group, May have one or more substituents selected from substituent group A 3 heterocyclic group, Hydroxy group, NR 12 R 13 (R 12 and R 13 are independent hydrogen atoms and C 1-6 alkyl groups, respectively), Nitrile group, It may have one or more substituents selected from substituent group A 3 heterocyclic group.
  • Substituent group A 3 Halogen atom, May have one or more substituents selected from the substituent group A 4 C 1-6 alkyl groups, May have one or more substituents selected from the substituent group A 4 C 1-6 alkoxy group, Hydroxy group.
  • Substituent group A 4 Halogen atom, C 1-6 Alkoxy group, Hydroxy group.
  • the present invention also comprises a pharmaceutical composition containing the above-mentioned indazole compound or a salt thereof, a pharmaceutical composition for treating a disease involving FGFR, a pharmaceutical composition for treating a disease involving FGFR and / or MELK.
  • a pharmaceutical composition for treating a disease involving FGFR a pharmaceutical composition for treating a disease involving FGFR and / or MELK.
  • a substance, an anticancer agent, and a pharmaceutical composition for the treatment of a cancer disease are provided.
  • the use of the indazole compound or a salt thereof for the production of the pharmaceutical composition a method for treating a disease involving FGFR, which is a therapeutically effective amount of the indazole compound or a salt thereof.
  • a method comprising the step of administering to a mammal including a human; a method for treating a disease involving FGFR and / or MELK, wherein a therapeutically effective amount of the indazole compound or a salt thereof is administered to the mammal including a human.
  • a method comprising the step of administering a therapeutically effective amount of the above-mentioned indazole compound or a salt thereof to a mammal including humans, which is a method for treating a cancer disease.
  • the indazole compound of the present invention or a salt thereof has an FGFR inhibitory action and / or a MELK inhibitory action, and is useful as a pharmaceutical composition for the treatment of diseases associated with FGFR and / or MELK. Further, the compound of the present invention has few side effects and is suitable for a pharmaceutical composition.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • 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 and the like.
  • the aryl group means an aryl group having 6 to 18 carbon atoms such as a phenyl or naphthyl group.
  • the hydrocarbon cyclic group means a cycloalkyl group, a cycloalkenyl group and an aryl 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 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 a cyclopropenylene, a cyclobutenylene, a cyclopentenylene, and a cyclohexenylene group.
  • the arylene group means an arylene group having 6 to 18 carbon atoms such as a phenylene or a naphthylene group.
  • the al C 1-6 alkyl group is an al C 1-6 alkyl group (alkyl moiety is C 1-6 alkyl) such as benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl and naphthylmethyl groups.
  • Benzyl 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.
  • 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 Al C 1-6 alkoxy C 1-6 alkyl group means an aralkyl C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyl oxymethyl group.
  • 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 ( ⁇ -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 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 ( ⁇ -substituted) aminoacetyl group and the like.
  • 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 al-C 1-6 alkoxycarbonyl group means an al-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 di (C 1-6 alkyl) amino groups are 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. -6 alkyl) means an amino group.
  • the C 1-6 alkyl sulfonyl group means a C 1-6 alkyl sulfonyl group such as a methyl sulfonyl, ethyl sulfonyl and propyl sulfonyl group.
  • the arylsulfonyl group means a benzenesulfonyl, p-toluenesulfonyl, naphthalenesulfonyl group and the like.
  • the C 1-6 alkyl sulfonyloxy group means a C 1-6 alkyl sulfonyl oxy group such as methyl sulfonyloxy and ethyl sulfonyl oxy 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 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 ring and also including monocyclic nitrogen-containing heteroaryl.
  • the monocyclic oxygenated heterocyclic group is an oxygen atom as a heteroatom forming the above ring such as oxetanyl, tetrahydrofuranyl, THFyl, 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.
  • 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.
  • Bicyclic nitrogen-containing heterocyclic groups include indolinyl, indrill, isoindrinyl, isoindrill, benzimidazolyl, indazolyl, benzotriazolyl, pyrazolopyridinyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinoli.
  • Bicyclic nitrogen-containing atoms containing only nitrogen atoms as heterocyclic atoms 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.
  • the bicyclic nitrogen-containing / oxygen heterocyclic groups are benzoxazolyl, benzoisooxazolyl, benzoxaziazolyl, benzomorpholinyl, dihydropyranopyridyl, dioxoropyridyl, flopyridinyl, and 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 benzothiazolizolyl group. It means a nitrogen / sulfur heterocyclic group.
  • 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.
  • 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 heterocyclic group means a monocyclic heterocyclic group, a bicyclic heterocyclic group, a spiro-type heterocyclic group and a bridged heterocyclic group.
  • 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 is oxetanilene group, azetidineylene group, pyrrolidinylene group, piperidinylene group, piperazinylene group, morpholinylene group, thiomorpholinylene group, zepanylene group, diazepanylene group, tetrahydrofurylene group, tetrahydropyrani.
  • the divalent spiro-type heterocyclic group is 1,6- or 2,6-diazaspiro- [3.3] heptene, 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.
  • the silyl group means a trimethylsilyl, triethylsilyl, tributylsilyl group, or the like.
  • Leaving groups include, for example, halogen atoms, C 1-6 alkylsulfonyloxy groups and arylsulfonyloxy groups.
  • the C 1-6 alkylsulfonyloxy group and arylsulfonyloxy group may be substituted.
  • 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, INC.) Can be mentioned. Specifically, for example, Al C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, acyl group, C 1-6 alkoxycarbonyl group, al C 1-6 alkoxycarbonyl group, aryloxycarbonyl, for example. Groups, C 1-6 alkylsulfonyl groups, arylsulfonyl groups or silyl groups can be mentioned.
  • Hydroxy protecting groups include all groups that can be used as ordinary 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, al C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, al C 1-6 alkoxy C 1- 6 Alkyl group, acyl group, C 1-6 alkoxycarbonyl group, al C 1-6 alkoxycarbonyl group, C 1-6 alkylsulfonyl group, arylsulfonyl group, silyl group, tetrahydrofuranyl group or tetrahydropyranyl group. ..
  • Carboxyl protecting groups include all groups that can be used as ordinary carboxyl protecting 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, al C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, al C 1-6 alkoxy. Examples thereof include a C 1-6 alkyl group, an acyl C 1-6 alkyl group, an acyloxy C 1-6 alkyl group or a 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.
  • the organic acid means formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like.
  • Inorganic bases include sodium hydroxide, potassium hydroxide, sodium methoxydo, 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.
  • the palladium catalyst examples 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'.
  • 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.
  • Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitrate and sulfuric acid; formic acid, acetic acid, citrate, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartrate, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N- Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidin, N-methylmorpholin, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N'-dibenzylethylenediamine. And salt etc.
  • 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.
  • 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 etiology of cancer.
  • Diseases involving MELK mean any disease that can be prevented or treated by inhibiting FGFR.
  • Diseases involving FGFR and MELK mean any disease that can be prevented or treated by inhibiting FGFR and MELK.
  • Diseases associated with FGFR and / or MELK include cancer.
  • cancers examples include squamous cell carcinoma, lung cancer, lung squamous cell carcinoma, breast cancer, gastric cancer, bile duct cancer, cervical cancer, uterine body cancer, bladder cancer, multiple myeloma, brain tumor, prostate cancer, liver cancer, and large intestine.
  • examples include cancer, pancreatic cancer, colon cancer, melanoma, head and neck cancer, thyroid cancer, renal cell cancer, glioblastoma, and testicular cancer.
  • the indazole compound of the present invention is represented by the following general formula [1].
  • A is a hydrocarbon cyclic group which may have a substituent or a heterocyclic group which may have a substituent.
  • A is a one or more substituents selected from may have one or more substituents selected from Substituent Group A 1 hydrocarbon cyclic group or a substituent group A 1, It is preferably a good heterocyclic group.
  • Substituent group A 1 Halogen atom, A C 1-6 alkyl group, which may have one or more substituents selected from the substituent group A 2.
  • a C 3-8 cycloalkyl group which may have one or more substituents selected from the substituent group A 2.
  • a C 1-6 alkoxy group which may have one or more substituents selected from the substituent group A 2.
  • Substituent group A 2 Halogen atom, May have one or more substituents selected from the substituent group A 3 C 1-6 alkyl groups, A C 3-8 cycloalkyl group, which may have one or more substituents selected from the substituent group A 2.
  • a C 1-6 alkoxy group which may have one or more substituents selected from the substituent group A 2.
  • Substituent group A 3 Halogen atom, May have one or more substituents selected from the substituent group A 4 C 1-6 alkyl groups, May have one or more substituents selected from the substituent group A 4 C 1-6 alkoxy group, Hydroxy group.
  • Substituent group A 4 Halogen atom, C 1-6 alkoxy group, hydroxyl group.
  • the hydrocarbon cyclic group represented by A is preferably an arylene group, preferably a phenylene group.
  • the heterocyclic group represented by A is preferably a monocyclic heterocyclic group, more preferably a monocyclic nitrogen-containing heterocyclic group, further preferably a monocyclic aromatic nitrogen-containing heterocyclic group, pyridyl, Pyrazolyl is particularly preferred.
  • B is preferably an arylene group, more preferably phenylene.
  • the heterocyclic group represented by the substituent group A 1 heterocyclic group of one ring are preferred, a nitrogen-containing heterocyclic group of a single ring, monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur Heterocyclic groups and monocyclic nitrogen-containing / oxygen heterocyclic groups are more preferable, and non-aromatic groups are even more preferable.
  • the nitrogen-containing heterocyclic group of a single ring is a substituent group A 1, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl are particularly preferred.
  • the oxygen-containing heterocyclic group of a single ring is a substituent group A 1, tetrahydrofuranyl, furanyl, tetrahydropyranyl being particularly preferred.
  • the sulfur-containing heterocyclic group of a single ring is a substituent group A 1, tetrahydrothiopyranyl, 1,1-dioxide tetrahydrothiopyranyl are particularly preferred.
  • Examples of the nitrogen-containing, oxygen heterocyclic group of a single ring is the substituent group A 1, morpholinyl are particularly preferred.
  • the substituent group A 1 substitution of one or more selected from a C 1-6 alkyl group or a substituent group A 2 has one or more substituents selected from the substituent group A 2 heterocyclic radical preferably have a group, C 1-6 alkyl group or a C 1-6 alkyl group which may have a heterocyclic group is particularly preferred.
  • substituent group A 1 is A C 1-6 alkyl group, which may have one or more substituents selected from the substituent group A 2.
  • a heterocyclic group which may have one or more substituents selected from the substituent group A 2 is preferable.
  • the heterocyclic group represented by the substituent group A 2 is the same as that of the substituent group A 1 , and the preferable range is also the same.
  • the substituent group A 2 is, C 1-6 alkyl or heterocyclic group, is preferable.
  • Pyrazolyl which may have a C 1-6 alkyl group
  • Pyrazolyl which may have a monocyclic nitrogen-containing heterocyclic group having a C 1-6 alkyl group
  • It has a phenyl group which may have a C 1-6 alkyl group having a monocyclic nitrogen-containing / oxygen heterocyclic group, or a C 1-6 alkyl group having a monocyclic nitrogen-containing / oxygen heterocyclic group.
  • Pyridyl may be particularly preferred.
  • B is a C 3-8 cycloalkenylene group which may have a substituent, an arylene group which may have a substituent, or a divalent heterocyclic group which may have a substituent, and is preferable.
  • the arylene group represented by B is preferably a phenylene group, or the C 3-8 cycloalkenylene group is preferably a cyclohexenylene group.
  • a divalent heterocyclic group represented by B a divalent nitrogen-containing heterocyclic group is preferable, a divalent monocyclic nitrogen-containing heterocyclic group is more preferable, and a divalent monocyclic aromatic group is preferable.
  • a nitrogen-containing heterocyclic group is more preferred.
  • a pyridylene group is preferable.
  • the pyridylene group may be bonded to the indazole ring at the 2-position or the 3-position as shown in the structure below. (In the formula, * is the connection position.)
  • the B substituent which may be a, what is preferably represented by the substituent group B 1.
  • Substituent group B 1 A halogen atom, a C 1-6 alkyl group which may have a halogen atom, and a C 1-6 alkoxy group which may have a halogen atom.
  • the halogen atom in the substituent group B 1 is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.
  • a may have one or more substituents arylene group which may have or one or more substituents selected from substituent group B 1, which is selected from substituent group B 1
  • a C 3-8 cycloalkenylene group is preferred.
  • R 1 is a halogen atom, a C 1-6 alkyl group which may have a substituent, or a C 1-6 alkoxy group which may have a substituent, respectively.
  • halogen atom a fluorine atom and a chlorine atom are preferable, and a fluorine atom is more preferable.
  • substituent of R 1 a halogen atom is preferable, and a fluorine atom and a chlorine atom are more preferable.
  • L 1 is a C 1-6 alkylene group which may have a substituent, a C 3-8 cycloalkylene group which may have a substituent, or a carbonyl group, and preferably has a substituent. It is a good C 1-6 alkylene group, a C 3-8 cycloalkylene group which may have a substituent, and more preferably a C 1-6 alkylene group and a C 3-8 cycloalkylene group.
  • a halogen atom is preferable, and a fluorine atom and a chlorine atom are more preferable.
  • R 2 is a C 1-6 alkyl group which may have a hydrogen atom or a substituent, preferably a hydrogen atom or a C 1-6 alkyl group, and more preferably a hydrogen atom or a methyl group.
  • a substituent of R 2 a halogen atom is preferable, and a fluorine atom and a chlorine atom are more preferable.
  • L 2 is a C 1-6 alkylene group which may have a substituent, a C 3-8 cycloalkylene group which may have a substituent, or a carbonyl group, preferably a C 1-6 alkylene group. is there.
  • a halogen atom is preferable, and a fluorine atom and a chlorine atom are more preferable.
  • L 3 is a divalent nitrogen-containing heterocyclic group which may have a substituent.
  • a divalent monocyclic nitrogen-containing heterocyclic group or a divalent spiro-type heterocyclic group is preferable.
  • a non-aromatic and monocyclic nitrogen-containing heterocyclic group is preferable, and a divalent monocyclic nitrogen-containing heterocyclic group containing one nitrogen atom or a divalent monocyclic nitrogen-containing heterocyclic group or A divalent monocyclic nitrogen-containing heterocyclic group containing two nitrogen atoms is more preferable.
  • the spiro-type heterocyclic group a divalent spiro-type heterocyclic group containing two nitrogen atoms is preferable.
  • the substituent of L 3 a hydroxyl group is preferable.
  • the divalent monocyclic nitrogen-containing heterocyclic group azetidineylene, pyrrolidinylene, piperidinylene, piperazinylene, or diazepanylene is preferable.
  • the bonding position is preferably the position shown below. (In the formula, * is the connection position.)
  • the spiro-type heterocyclic group 2,6-diazaspiro [3.3] heptene or 2,7-diazaspiro [3.5] nonylene is preferable.
  • the bonding position is preferably the position shown below. (In the formula, * is the connection position.)
  • L 4 represents an optionally substituted C 1-6 alkylene group, an optionally substituted C 3-8 cycloalkylene group, or -NR 11, - (R 11 is a hydrogen atom or a substituent, . a C 1-6 alkyl group which may have a hydrogen atom, or a C 1-6 alkyl group is preferred), and, -NR 11 - are preferred, -NH- is more preferable.
  • R 11 is a hydrogen atom or a substituent, . a C 1-6 alkyl group which may have a hydrogen atom, or a C 1-6 alkyl group is preferred
  • -NR 11 - are preferred, -NH- is more preferable.
  • a halogen atom is preferable, and a fluorine atom and a chlorine atom are more preferable.
  • R 3 and R 4 are independently hydrogen atoms, C 1-6 alkyl groups which may have a substituent, or C 3-8 cycloalkylene groups which may have a substituent, and R 3 and R 4 is preferably both hydrogen atoms.
  • Preferred substituents include halogen atoms, acyl groups, C 1-6 alkoxycarbonyl groups, C 1-6 alkylamino groups, di (C 1-6 alkyl) amino groups, or C 1-6 alkylsulfonyl groups. , More preferably a halogen atom, a C 1-6 alkylamino group, or a di (C 1-6 alkyl) amino group.
  • R 5 is a hydrogen atom or a C 1-6 alkyl group, and is particularly preferably a hydrogen atom.
  • A is an integer of 0 to 3
  • b, c, d, e and f are independently 0 or 1
  • c and e are not 0 at the same time.
  • L 1 is a C 1-6 alkylene group
  • R 2 is a hydrogen atom or a C 1-6 alkyl group.
  • Compounds in which b and c are 1 are preferable.
  • d is 0, e is 1, and
  • L 3 is a divalent monocyclic nitrogen-containing heterocyclic group.
  • a divalent nitrogen-containing heterocyclic group of a single ring is -N carbon atoms (R 2) - is preferably connected to.
  • the divalent monocyclic nitrogen-containing heterocyclic group a divalent monocyclic nitrogen-containing heterocyclic group containing one nitrogen atom is preferable, and azetidineylene, pyrrolidinylene or piperidinylene are particularly preferable.
  • the bonding position is preferably the position shown below. (In the formula, * is the connection position.)
  • L 1 is a C 1-6 alkylene group
  • L 3 is a divalent nitrogen-containing heterocyclic group which may have a hydroxyl group.
  • b and e are 1 and c is 0.
  • d and f are preferably 0.
  • L 3 is preferably a divalent nitrogen-containing heterocyclic group whose bond position is a nitrogen atom, and contains a divalent monocyclic nitrogen-containing heterocyclic group containing two nitrogen atoms or two nitrogen atoms.
  • a divalent spiro-type heterocyclic group is preferable.
  • the bonding position is preferably the position shown below. (In the formula, * is the connection position.)
  • A is a hydrocarbon cyclic group which may have a substituent
  • B is preferably an arylene group which may have a substituent. More preferably, A is a phenyl group which may have a substituent and B is a phenylene group which may have a substituent. It is more preferable that A is a phenyl group substituted with a C 1-6 alkylene group which may have a heterocyclic group, and B is a phenylene group substituted with a C 1-6 alkylene group. ..
  • A is a heterocyclic group which may have a substituent
  • B is preferably a C 3-8 cycloalkenylene group which may have a substituent. More preferably, A is a monocyclic aromatic nitrogen-containing heterocyclic group which may have a substituent, and B is a phenylene group which may have a substituent. A is a monocyclic aromatic nitrogen-containing heterocyclic group substituted with a C 1-6 alkylene group, and B is more preferably a cyclohexenylene group.
  • 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.
  • P 1 and P 2 are amino protecting groups and are A, B, R 1 , L 1 , R 2 , L 2 , L 3 , L 4 , a, b, c, d, e and f have the same meanings as described above.
  • 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 groups represented by P 1 and P 2 are preferably a tert-butoxycarbonyl group, a tetrahydropyranyl group and a 2- (trimethylsilyl) ethoxymethyl group.
  • the compound of the general formula [1] introduces an unsaturated double bond by reacting the compound of the general formula [2A] with the compound of the general formula [3A] to deprotect and amidate in the presence of an acid. And can be manufactured.
  • the reaction of the compound of the general formula [2A] with the compound of the general formula [3A] 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. , Amides, 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 (v / w), more preferably 1 to 100 times (v / w) with respect to the compound of the general formula [2A].
  • 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 by mole, more preferably 0.1 to 5 times by mole, and even more preferably 0.1 to 3 times by mole with respect to the compound of the general formula [2A] or a salt thereof.
  • the amount of the palladium catalyst used is preferably 0.00001 to 1 times by mole, more preferably 0.001 to 0.5 times by mole, based on the compound of the general formula [2A].
  • 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 hydrochloric acid 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 3 and R 4 have the same meanings as described above, and R 5 is a hydrogen atom or a C 1-6 alkyl group.
  • the halogen atom represented by X 3 is preferably a chlorine atom.
  • R 5 is preferably a hydrogen 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 amides are 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.
  • Examines include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and starch; ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl ⁇ - Cyclodextrins such as cyclodextrin and sulfobutyl ether ⁇ -cyclodextrin sodium; celluloses such as crystalline cellulose and microcrystalline cellulose; and starches such as corn starch, potato starch and pregelatinized starch.
  • sugar alcohols such as erythritol, mannitol, xylitol and sorbitol
  • sugars such as sucrose, powdered sugar, lactose and starch
  • Disintegrants include, for example, carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospopidone, low degree of substitution hydroxypropyl cellulose and partially pregelatinized starch.
  • Binders include, for example, hydroxypropyl cellulose, sodium carmellose and methyl cellulose.
  • Lubricants include, for example, stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid and sucrose fatty acid esters.
  • the flavoring agent include aspartame, saccharin, stevia, thaumatin and acesulfame potassium.
  • colorant examples include titanium dioxide, iron sesquioxide, yellow sesquioxide, iron black oxide, edible red No. 102, edible yellow No. 4 and edible yellow No. 5.
  • Flavors include, for example, essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, Powdered fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
  • surfactants include, for example, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polysorbate and polyoxyethylene hydrogenated castor oil.
  • the coating agent examples include hydroxypropylmethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, phthalate acetate cellulose, hydroxypropyl methyl cellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S.
  • Plasticizers include, for example, triethyl citrate, macrogol, triacetin and propylene glycol. 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.
  • the administration method, dose and frequency of administration can be appropriately selected according to the age, body weight and symptoms of the patient. In general, for adults, 0.01 to 1000 mg / kg may be administered in 1 to several divided doses daily by oral or parenteral administration (for example, injection, infusion and administration to the rectal site). Good.
  • 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 chemistry)). It was measured using an ionization method in which ionization) is performed at the same time.
  • 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: 254nm
  • each abbreviation has the following meaning.
  • Boc tert-butoxycarbonyl DIPEA: N, N-diisopropylethylamine
  • DMAc N, N-dimethylacetamide
  • DME 1,2-dimethoxyethane
  • DMF N, N-dimethylformamide
  • Et Ethyl
  • Me Methyl
  • MeOD Deuterated Methanol (MD 3 OD)
  • Ms Methanesulfonyl Ph: Phenyl RT, rt: retention time
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • THP tetrahydropyranyl
  • SEM 2- (trimethylsilyl) ethoxymethyl Py: Pyridine
  • N-iodosuccinimide (639 mg) was added to a dichloromethane solution (7.9 mL) of 5-bromo-6-methyl-1H-indazole (500 mg), and the mixture was stirred at room temperature for 1 hour. Dichloromethane (7.9 mL) was added and the mixture was stirred for 4 hours. Dichloromethane (7.9 mL) was added and the mixture was stirred for 2 hours. N-iodosuccinimide (320 mg) was added and the mixture was stirred for 1.5 hours. N-iodosuccinimide (320 mg) was added and the mixture was stirred for 19 hours.
  • Examples 2-2-35 The following compounds were obtained in the same manner as in Example 2-1.
  • Examples 8-1 to 8-5 The following compounds were obtained in the same manner as in Example 2-1.
  • Examples 13-1 to 13-35 The following compounds were obtained in the same manner as in Example 4-1.
  • Examples 17-1 to 17-3 The following compounds were obtained in the same manner as in Example 2-1.
  • FGFR1-WT Enzyme Inhibition Test Assay buffer containing serially diluted test compound or DMSO (100 mM HEPES pH 7.5 , 10 mM MgCl 2 , 10 mM MnCl 2 , 0.003% Brij-35, 1 mM 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. Wells to which only assay buffer was added at 6 ⁇ L / well were defined as negative controls.
  • Assay buffer containing 7.5 ⁇ M FL-peptide 22 (Caliper) and 30 ⁇ M ATP was added at 3 ⁇ L / well and then allowed to stand at 25 ° C. for 90 minutes.
  • the assay buffer containing 200 mM EDTA was added at 5 ⁇ L / 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.
  • the phosphorylation inhibition rate at each compound concentration was plotted using XLfit software (IDBS) using a nonlinear regression fit (Fit Model (205)) using a sigmoid dose-response formula, and a 50% inhibition concentration was calculated. The results obtained are shown in the table below.
  • Human FGFR1-V561M enzyme (Millipore, trade name: FGFR1 (V561M), active, trade code: 14-734M) was diluted to 12.5 nM in the assay buffer and added at 6 ⁇ L / well.
  • the phosphorylation inhibition rate at each compound concentration was plotted using XLfit software (IDBS) using a non-linear regression adaptation (Fit Model (205)) by a sigmoid dose-response formula, and a 50% inhibition concentration was calculated. The results obtained are shown in the table below.
  • MELK Enzyme Inhibition Test Assay buffer containing serially diluted test compound or DMSO (20 mM HEPES pH 7.5, 0.01% Triton X-100, 1 mM DTT, 5 mM MgCl 2 ) at 6 ⁇ L / well in a 384-well plate ( Added to Corning).
  • Human MELK enzyme (Carna Biosicences, trade name: MELK, trade code: 02-124) was diluted to 4.24 nM in assay buffer and added at 6 ⁇ L / well. Wells to which only assay buffer was added at 6 ⁇ L / well were defined as negative controls.
  • Assay buffer containing 2.5 ⁇ M MELK MSA assay substrate (Carna Biosicences) and 250 ⁇ M ATP was added at 3 ⁇ L / well and then allowed to stand at 25 ° C. for 5 hours.
  • the assay buffer containing 200 mM EDTA was added at 5 ⁇ L / well, the enzymatic reaction was stopped, and then the phosphorylation rate of the substrate for MELK MSA assay was detected using LabChip EZ Reader.
  • the phosphorylation inhibition rate at each test compound concentration was calculated by the following formula.
  • the phosphorylation inhibition rate at each compound concentration was plotted using XLfit software (IDBS) using a non-linear regression adaptation (Fit Model (205)) by a sigmoid dose-response formula, and a 50% inhibition concentration was calculated. The results obtained are shown in the table below.
  • the growth inhibition rate at each compound concentration was plotted using non-linear regression adaptation (Fit Model (205)) by the sigmoid dose-response formula using XLfit software (IDBS), and the 50% inhibition concentration was calculated. The results obtained are shown in the table below.
  • glioblastoma cell line U-87 MG Human glioblastoma cell line U-87 MG was used in spheroid medium (2% B-27 supplement minus vitamin A (Life Technologies), 1% N2 (Wako), 20ng. Subcultured with / mL rhEGF (Life Technologies) and DMEM / F12) containing penicillin / streptomycin for 3 weeks or longer. U-87 MG cells cultured under the above conditions were dispersed by 0.05% Trypsin-EDTA treatment, passed through a 40 ⁇ m cell strainer, and then prepared in spheroid medium to 1 ⁇ 10 4 cells / mL, and ultra-low.
  • Adsorption 384-well plates (Corning, 3827) were seeded at 20 uL / well. Wells in which only the medium was seeded at 20 ⁇ L / well were used as a negative control. After 1 hour, the test compound or DMSO-containing spheroid medium was added at 5 ⁇ L / well, and the cells were cultured under 37 ° C., 5%, and CO 2 conditions for 7 days, and then the Cell Titer Glo (Promega) reaction solution was added at 25 ⁇ L / well. The mixture was added, and the amount of luminescence was measured with an Envision plate reader (Perkin Elmer).
  • the growth inhibition rate at each test compound concentration was calculated by the following formula. (DMSO-added well emission amount-test compound-added well emission amount) ⁇ (DMSO-added well emission amount-medium only well emission amount) x 100
  • 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 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
  • P ⁇ 0.05 was regarded as a significant difference.
  • the tumor volume of the test compound-administered group to which the compound of 18-2 and Example 22-1 was administered was significantly reduced as compared with the solvent-administered group.
  • the compound of the present invention showed an excellent tumor shrinkage effect.
  • the indazole compound of the present invention or a salt thereof has an FGFR inhibitory action and / or a MELK inhibitory action, and is useful as a pharmaceutical composition for the treatment of diseases associated with FGFR and / or MELK.

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Abstract

La présente invention aborde le problème de la fourniture d'un composé d'indazole ayant une activité inhibitrice du FGFR ou un sel de celui-ci, et une composition pharmaceutique. La présente invention concerne le composé d'indazole représenté par la formule générale [1] ou un sel de celui-ci.
PCT/JP2020/046984 2019-12-17 2020-12-16 Composé d'indazole ou sel de celui-ci, et composition pharmaceutique WO2021125229A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023240138A1 (fr) * 2022-06-08 2023-12-14 Blossomhill Therapeutics, Inc. Macrocycles contenant de l'indazole et leur utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001053268A2 (fr) * 2000-01-18 2001-07-26 Agouron Pharmaceuticals, Inc. Composes d'indazole, compositions pharmaceutiques, et methodes destines a la mediation ou a l'inhibition de la proliferation cellulaire
WO2002010137A2 (fr) * 2000-07-31 2002-02-07 Signal Pharmaceuticals, Inc. Derives d'indazole utilises comme inhibiteurs de jnk et compositions et methodes associees a ceux-ci
WO2003101968A1 (fr) * 2002-05-31 2003-12-11 Eisai Co., Ltd. Compose de pyrazole et composition medicinale le contenant
WO2007058626A1 (fr) * 2005-11-16 2007-05-24 S*Bio Pte Ltd Composes d'indazole
WO2010150211A2 (fr) * 2009-06-23 2010-12-29 Centre National De La Recherche Scientifique Utilisation de dérivés d’indoles dans le traitement du cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001053268A2 (fr) * 2000-01-18 2001-07-26 Agouron Pharmaceuticals, Inc. Composes d'indazole, compositions pharmaceutiques, et methodes destines a la mediation ou a l'inhibition de la proliferation cellulaire
WO2002010137A2 (fr) * 2000-07-31 2002-02-07 Signal Pharmaceuticals, Inc. Derives d'indazole utilises comme inhibiteurs de jnk et compositions et methodes associees a ceux-ci
WO2003101968A1 (fr) * 2002-05-31 2003-12-11 Eisai Co., Ltd. Compose de pyrazole et composition medicinale le contenant
WO2007058626A1 (fr) * 2005-11-16 2007-05-24 S*Bio Pte Ltd Composes d'indazole
WO2010150211A2 (fr) * 2009-06-23 2010-12-29 Centre National De La Recherche Scientifique Utilisation de dérivés d’indoles dans le traitement du cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023240138A1 (fr) * 2022-06-08 2023-12-14 Blossomhill Therapeutics, Inc. Macrocycles contenant de l'indazole et leur utilisation

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