WO2019223766A1 - Inhibiteur de fgfr, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Inhibiteur de fgfr, son procédé de préparation et son utilisation pharmaceutique Download PDF

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WO2019223766A1
WO2019223766A1 PCT/CN2019/088158 CN2019088158W WO2019223766A1 WO 2019223766 A1 WO2019223766 A1 WO 2019223766A1 CN 2019088158 W CN2019088158 W CN 2019088158W WO 2019223766 A1 WO2019223766 A1 WO 2019223766A1
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alkyl
deuterium
substituted
group
cycloalkyl
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PCT/CN2019/088158
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English (en)
Chinese (zh)
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邓海兵
应海燕
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN201980019954.8A priority Critical patent/CN111868058B/zh
Publication of WO2019223766A1 publication Critical patent/WO2019223766A1/fr

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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
    • A61K31/436—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 six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-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 invention belongs to the field of pharmaceutical synthesis, and particularly relates to an FGFR inhibitor, a preparation method thereof and pharmaceutical application.
  • Fibroblast growth factor receptor is a tyrosine kinase receptor that binds to fibroblast growth factor ligands.
  • four FGFR receptors have been found to be able to bind ligands and are closely related in a variety of physiological processes including tissue differentiation, angiogenesis, wound healing, and metabolic regulation.
  • the receptor undergoes dimerization and phosphorylation, stimulates the activation of protein kinase activity, and recruits many intracellular proteins to bind.
  • These protein interactions can help activate a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, which are important signaling pathways for cell growth, proliferation, and survival.
  • FGF / FGFR-related tumor types include but are not limited to cancer (such as bladder cancer, breast cancer, cervical spine cancer, colon cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer)
  • cancer such as bladder cancer, breast cancer, cervical spine cancer, colon cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer
  • Malignant hematological diseases such as multiple myeloma, chronic lymphoma, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, myeloproliferative tumors and Fahrenheit macroglobulinemia
  • other tumors such as glioblastoma, melanoma, and rhabdomyosarcoma.
  • FGFR activation has also been found to be associated with bone and chondrocyte lesions, such as hypochondral hypoplasi
  • FGFR inhibitors Although some FGFR inhibitors have entered the clinical and preclinical R & D process, they usually have insufficient selectivity, and have inhibitory effects on other kinases such as c-kit, PDGFRa, which brings the concern that certain treatment windows are not large enough. . Therefore, the development of inhibitors targeted at FGFR selectivity would be of great significance in the clinical treatment of diseases with increased FGF or FGFR activity.
  • the object of the present invention is to provide an FGFR inhibitor.
  • the first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:
  • X is selected from C (R 7 ) or N;
  • Each R 8 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkoxy 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy Or -NR 11 R 12 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl , C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 11 R 12 substituted by a substitu
  • Each R 9 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, or 5- 10-membered heteroaryl, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 ring Alkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl Group, 5-10 membered heteroaryloxy group or -NR 11 R 12 substituent;
  • Each R 10 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 11 R 12 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group, C 5-10 aryl group, C 5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membered heteroaryl
  • Each R 11, R 12 are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl group, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino, or C 1-10 alkanoyl, the above groups are optionally further selected from one or more of deuterium , Halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C
  • R 11 and R 12 and the directly connected nitrogen atom together form a 4- to 10-membered heterocyclic group or a 4- to 10-membered heteroaryl group, and the above-mentioned group is optionally further selected from one or more of deuterium, halogen, and hydroxyl group.
  • C 1-10 alkyl C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, C 5-10 aryl, C 5-10 aryloxy, 5 -10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • Each r is independently 0, 1, or 2.
  • X is selected from C (R 7 ) or N; R 7 is selected from hydrogen, deuterium, and halogen.
  • X is selected from C (R 7 ) or N;
  • R 7 is selected from hydrogen, deuterium, Halogen, cyano, nitro, azide, C 1-4 alkyl, allyl, ethynyl, C 3-6 cycloalkyl, oxetanyl, azetidinyl, azacyclohexyl , Phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropyloxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetyl Oxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetylamino;
  • X is selected from C (R 7 ) or N; R 7 is selected from hydrogen and deuterium. , Fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azacyclo Pentyl, azahexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxyethyl, Ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideutermethyl, difluoromethyl, dideuter
  • R 5 and R 6 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof are each independently selected from hydrogen, deuterium, fluorine, chlorine, Bromine, cyano, nitro, azide, C 1-4 alkyl, allyl, ethynyl, C 3-6 cycloalkyl, oxetanyl, azetyl, azetyl , Phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxyl, methoxy, ethoxy, isopropyloxy, methoxycarbonyl, ethoxycarbonyl, acetyl , Acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetylamino; the aforementioned groups are
  • each of R 3 and R 4 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, hydroxyl, and cyanide.
  • R 3 and R 4 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof are each independently selected from hydrogen, deuterium, halogen, hydroxyl, Cyano, nitro, azide, C 1-4 alkyl, C 1-4 alkoxy, allyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 member Heterocyclyl, 3-6 membered heterocyclic oxy, phenyl, diazole, or triazole; the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl Group, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
  • R 2 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, and azido.
  • R 2 in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, and C.
  • the compound of the formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a structure of the following formula (II):
  • R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C 0- 4 -OR 9 or -C 0-4 -NR 11 R 12
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkane Oxygen, 3-6 membered heterocyclyl or 3-6 membered heterocyclyl; the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl Substituted with a substituent of phenyl, methoxy, ethoxy, hydroxy or amino;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, hydroxyl, methoxy, ethoxy, or isopropoxy;
  • the group is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxyl or amino;
  • R 1 , R 8 , R 9 , R 11 , R 12 , r are as defined for the compound of formula (I).
  • R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 3- 8 -cycloalkyl, 3-8-membered heterocyclyl, C 5-8 aryl or 5-8-membered heteroaryl
  • the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a structure of formula (III):
  • R 9 , R 11 and R 12 are as defined for the compound of formula (I).
  • R 2 is selected from a 3-8 membered heterocyclic group, a 5-6 membered heteroaryl group or -NR 11 R 12.
  • R 11 and R 12 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-6 aryl, or 5-6 membered heteroaryl group, the above groups optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, hydroxy, C 1-4 alkyl, halo-substituted C 1- 4 alkyl group, deuterium-substituted C 1-4 -alkyl, C 1 -4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5-6 aryl, C 5- 6 aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino, diethylamino or C 1-4 alkanoyl substituents;
  • R 11 and R 12 and the directly connected nitrogen atom together form a 4- to 8-membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl Radical, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-8 membered hetero Cyclic group, 3-8 membered heterocyclic oxy, C 5-6 aryl, C 5-6 aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino , Diethylamino or C 1-4 alkanoyl.
  • R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, or 3-6.
  • Heterocyclic group the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, cyclopropyl, 3-6 membered heterocyclyl, phenyl, amino, dimethyl An amino or diethylamino substituent is substituted, and the above-mentioned group is optionally further further selected from one or more of deuterium, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteryl, tri Substituted by a deuterium methyl or cyclopropyl substituent;
  • R 11 and R 12 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, and the above-mentioned groups are optionally further selected from one or more Deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl, difluoromethyl, trifluoromethyl, dideuteryl methyl, trideuteryl methyl, methoxy, ethoxy, isopropoxy, cyclopropyl With 3, 8-membered heterocyclyl, phenyl, diazole, triazole, amino, dimethylamino, diethylamino or C 1-4 alkanoyl substituents;
  • R 11 and R 12 and the directly connected nitrogen atom together form a 4-8 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, hydroxyl, C 1-4 alkyl, Difluoromethyl, trifluoromethyl, dideutermethyl, trideutermethyl, methoxy, ethoxy, isopropoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, phenyl, diazolyl, triazolyl, amino, dimethylamino, diethylamino or C 1-4 alkanoyl substitution Superseded by
  • the heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom.
  • the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
  • a method for preparing the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof including the following steps:
  • X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined for the compound of formula (I).
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a fourth aspect of the present invention there is provided an application of the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors or cancers.
  • the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, and esophageal cancer.
  • Gallbladder cancer pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin Gold lymphoma, Fahrenheit macroglobulinemia, hair-like lymphoma, cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
  • the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is provided for preparing a medicine for treating a myeloproliferative disease, bone or chondrocyte disorder, and hypophosphatemia.
  • the myeloproliferative disease is selected from the group consisting of erythrocytosis, primary thrombocythemia, or primary myelofibrosis; and the skeletal or chondrocyte disorders are selected from the group consisting of dysplasia, cartilage dysplasia, and dwarfism.
  • said low Phosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced ovarian softening.
  • a sixth aspect of the present invention provides the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, which is used as an FGFR inhibitor.
  • FGFR inhibitor having the structure of formula (I), its preparation method, and its pharmacological application.
  • the definitions of each substituent are as described in the specification and claims.
  • the compounds of the present invention can be widely used in the preparation of drugs for treating tumors, cancers, myeloproliferative diseases, bone or chondrocyte disorders, and hypophosphatemia, and are expected to be developed into a new generation of FGFR inhibitor drugs. Based on this, the present invention has been completed.
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group.
  • C 1-10 alkyl refers to a linear alkyl group containing 1 to 10 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylp
  • the alkyl group may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • C 3-10 cycloalkyl refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, of which:
  • Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.
  • Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl.
  • “Spirocycloalkyl” refers to polycyclic groups that share one carbon atom (called a spiro atom) between single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has A completely conjugated ⁇ -electron system.
  • Spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings.
  • Spirocycloalkyl includes but is not limited to:
  • fused cycloalkyl refers to a full-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings.
  • the fused cycloalkyl includes but is not limited to:
  • Bridged cycloalkyl refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of them The ring has a completely conjugated ⁇ -electron system. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings.
  • the bridged cycloalkyl includes but is not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl and the like.
  • a cycloalkyl group may be optionally substituted or unsubstituted.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S (O) A heteroatom of r (where r is an integer of 0, 1, 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • r is an integer of 0, 1, 2
  • Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen and oxygen Or S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system.
  • Spiro heterocyclyl is classified into monospiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings.
  • Spiro heterocyclyl includes, but is not limited to:
  • “Fused heterocyclyl” refers to a polycyclic heterocyclic group where each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more (preferably 1, 2, 3, or 4) rings may Contains one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a completely conjugated ⁇ electron system, in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected
  • a heteroatom of nitrogen, oxygen, or S (O) r where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl according to the number of constituent rings.
  • the fused heterocyclyl includes but is not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring A completely conjugated ⁇ -electron system in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer of 0, 1, 2) Heteroatom, the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include, but are not limited to:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl refers to a full-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group, a polycyclic ring having a conjugated ⁇ -electron system (i.e., a ring with adjacent pairs of carbon atoms) ) Group, for example, "C 5-10 aryl” refers to a full-carbon aryl group containing 5-10 carbons, and "5-10-membered aryl” refers to a full-carbon aryl group containing 5-10 carbons, including but Not limited to phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • the aryl group may be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3, or 4) heteroatoms including nitrogen, oxygen, and S (O) r (where r is the integer 0 , 1, 2) heteroatoms, for example, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms Family systems, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • Heteroaryl may be optionally substituted or unsubstituted.
  • Alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond.
  • C 2-10 alkenyl refers to a straight or branched chain containing 2 to 10 carbons. Alkenyl. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • Alkenyl may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • C 2-10 alkynyl refers to a straight or branched chain containing 2 to 10 carbons.
  • Alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • the alkynyl may be substituted or unsubstituted.
  • Alkoxy refers to -O- (alkyl), where alkyl is as defined above, for example, “C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • Cycloalkoxy refers to -O- (unsubstituted cycloalkyl), where cycloalkyl is as defined above, for example, "C 3-10 cycloalkoxy” refers to a group containing 3 to 10 carbons. Cycloalkyloxy includes, but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted.
  • 3-10 membered heterocyclic oxy refers to -O- (unsubstituted 3-10 membered heterocyclyl), wherein the definition of 3-10 membered heterocyclyl is as described above, and 3-10 membered heterocyclyl It may be optionally substituted or unsubstituted.
  • 5-10 membered heteroaryloxy refers to -O- (unsubstituted 5-10 membered heteroaryl), wherein the definition of 5-10 membered heteroaryl is as described above, and 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted.
  • C 1-8 alkanoyl refers to the monovalent atomic group remaining after the C 1-8 alkyl acid has been removed from the hydroxyl group, and is usually also expressed as "C 0-7 -C (O)-", for example, “C 1 -C (O)-"means acetyl;” C 2 -C (O)-"means propionyl;” C 3 -C (O)-"means butyryl or isobutyryl.
  • -C 0-8 -OR 9 means that the oxygen atom in -OR 9 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and the definition of C 1-8 alkyl group is as described above.
  • -C 0-8 -NR 11 R 12 means that the nitrogen atom in -NR 11 R 12 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and the definition of C 1-8 alkyl group is as above As described.
  • Halo-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group optionally substituted with hydrogen on the alkyl by fluorine, chlorine, bromine, or iodine atoms, including, but not limited to, difluoromethyl, di Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • the hydrogen on the "halo-substituted C 1-10 alkoxy" alkyl is optionally a 1-10 carbon alkoxy group substituted with a fluorine, chlorine, bromine, or iodine atom. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • MeOH means methanol.
  • DMF means N, N-dimethylformamide.
  • DCE refers to 1,2-dichloroethane.
  • THF means tetrahydrofuran.
  • PE means petroleum ether.
  • EA / EtOAc means ethyl acetate.
  • DCM means dichloromethane.
  • LiOH means lithium hydroxide.
  • NaOH means sodium hydroxide.
  • NaNO 2 refers to sodium nitrite.
  • CuI means cuprous iodide.
  • Na 2 SO 4 means sodium sulfate.”
  • HAc means acetic acid.
  • NH 4 Oac means ammonium acetate.
  • Et 3 N refers to triethylamine.
  • NH 4 Cl means ammonium chloride.
  • TFA means trifluoroacetic acid.
  • M-CPBA refers to m-chloroperoxybenzoic acid.
  • Pd (PPh 3 ) 4 means tetrakis (triphenylphosphine) palladium.
  • Pd (PPh 3 ) 2 Cl 2 meansmeans" bistriphenylphosphonium palladium dichloride.
  • heterocyclic group optionally substituted with alkyl group means that the alkyl group may but need not exist, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group are substituted independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom (such as an olefin) having an unsaturated bond.
  • “Pharmaceutically acceptable salt” in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, and these salts can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). Methylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was performed using an Agilent 6120 mass spectrometer.
  • an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 ⁇ 4.6 mm column) were used.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.
  • Step 4 Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester
  • Step 5 Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
  • Step 7 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one synthesis
  • Step 8 Synthesis of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
  • N 1- (8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) pyrido [3,4-d] pyrimidine Synthesis of -2-yl) -N4, N4-diethylbutane-1,4-diamine
  • Examples 3 to 21 are prepared by referring to the synthetic method of Example 1 or 2:
  • Step Two N 8 - (cyclopropylmethyl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -N 2 - (2- (4- methylpiperazine - Synthesis of 1-yl) ethyl) pyrido [3,4-d] pyrimidine-2,8-diamine
  • Example 23 is prepared by referring to the synthetic method of Example 22:
  • Caliper Assay is used to determine the compound's inhibitory activity on FGFR1, FGFR2, and FGFR3.
  • the specific experimental process is as follows:
  • the kinase reaction performed in the present invention is performed in a 384-well plate, using a certain concentration of kinase (Carna) and a certain concentration of ATP and 1 ⁇ M peptide FAM-P22 (GL Biochem, Cat. No. 112393)) at 50 mM HEPES, pH 7.5, 0.0015% Brij-35 and basic kinase buffer incubation reaction at 28 ° C for a certain time; for FGFR1, the enzyme concentration is 0.25nM, ATP concentration is 382 ⁇ M, the reaction time is 20 minutes; for FGFR2 The enzyme concentration is 2.5nM, the ATP concentration is 1 ⁇ M, and the reaction time is 40 minutes. For FGFR3, the enzyme concentration is 8nM, the ATP concentration is 4.7 ⁇ M, and the reaction time is 30 minutes.
  • stop solution 100mM HEPES, pH7.5, 0.2% Caliper coating reagent, 50mM EDTA and 0.015% Brij35
  • Caliper microfluidic migration migration technology was used to separate phosphorylated and unphosphorylated peptides, and the analytes were transferred by a constant buffer flow through the chip, and the substrate peptide migration was monitored by its labeled fluorescent signal. The amount of phosphate peptide formed was used to calculate the kinase activity.
  • IC 50 values were determined by non-linear regression analysis of percent inhibition at different compound concentrations. The enzymatic activities of the compounds of the specific examples are shown in Table 1.
  • the present invention evaluates the inhibitory effect of the compound on the cell proliferation dependent on the FGFR signaling pathway through a survival experiment, and is measured using a CTG reagent (Promega, # G7573).
  • Select the cell line that can represent different tumor types such as H1581 lung cancer cells from Nanjing Kebai (with FGFR1 gene amplification) or Snu-16 gastric cancer cells (with FGFR2 gene amplification).
  • the specific experimental process is as follows:
  • the compounds of the present invention have a strong inhibitory effect on FGFR1, FGFR2, and FGFR3 kinase activity. From the cell activity data of the compounds of the specific examples, the compounds of the present invention have a strong inhibitory effect on the proliferation activity of H1581 lung cancer cells and / or Snu16 gastric cancer cells with high expression of FGFR1, FGFR2 and FGFR3.

Abstract

L'invention concerne un inhibiteur de FGFR ayant la structure de formule (I), son procédé de préparation et son utilisation pharmaceutique, la définition de chaque substituant étant telle que décrite dans la description et les revendications. Les composés fournis par la présente invention peuvent être largement utilisés dans la préparation de médicaments pour le traitement de tumeurs, de cancers, de maladies myéloprolifératives, de troubles osseux ou chondrocytes, et d'hypophosphatémie, et sont supposés être développés en une nouvelle génération de médicaments inhibiteurs de FGFR.
PCT/CN2019/088158 2018-05-25 2019-05-23 Inhibiteur de fgfr, son procédé de préparation et son utilisation pharmaceutique WO2019223766A1 (fr)

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