WO2019223766A1 - Fgfr inhibitor, preparation method therefor and pharmaceutical application thereof - Google Patents

Fgfr inhibitor, preparation method therefor and pharmaceutical application thereof Download PDF

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Publication number
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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French (fr)
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/en
Publication of WO2019223766A1 publication Critical patent/WO2019223766A1/en

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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

Provided are an FGFR inhibitor having the structure of a formula (I), a preparation method therefor and a pharmaceutical application thereof, wherein the definition of each substituent is as described in the description and claims. The present series of compounds may be widely applicable 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.

Description

一种FGFR抑制剂、其制备方法和在药学上的应用FGFR inhibitor, preparation method thereof and pharmaceutical application 技术领域Technical field
本发明属于药物合成领域，具体涉及一种FGFR抑制剂、其制备方法和在药学上的应用。The invention belongs to the field of pharmaceutical synthesis, and particularly relates to an FGFR inhibitor, a preparation method thereof and pharmaceutical application.
技术背景technical background
成纤维细胞生长因子受体(FGFR)是和成纤维细胞生长因子配体相结合的酪氨酸激酶受体。目前已经有4种FGFR受体被发现能够结合配体，并在包括组织分化，血管生成，伤口愈合，和代谢调节的多种生理性的过程中密切相关。当配体结合时，受体会发生二聚化和磷酸化，刺激蛋白激酶活性活化，并招募许多细胞内蛋白相结合。这些蛋白相互作用能帮助一系列胞内信号传导通路的活化，包括Ras-MAPK,AKT-PI3K,以及磷酸酯酶C这些对细胞生长，增殖以及生存非常重要的信号通路。Fibroblast growth factor receptor (FGFR) is a tyrosine kinase receptor that binds to fibroblast growth factor ligands. At present, 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. When the ligand binds, 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.
该信号通路的异常激活，比如FGF配体的过表达或者通过FGFR的活化突变会带来肿瘤生长，进展以及对于传统癌症疗法的抗性。在人类肿瘤中，能带来不依赖于配体的受体激活的基因上的变化，包括基因扩增，染色体转位以及体突变等等已经有被描述。而大批量对于上千肿瘤样品的DNA测序已经揭示FGFR信号通路中的组成成分是人类癌症中高频率突变的基因。比如FGFR1的体细胞突变已经在神经胶质瘤和肺癌中被发现,FGFR2的突变多见于胃癌和子宫内膜癌，而FGFR3的突变在膀胱癌以及多发性骨髓瘤中被发现，FGFG4的突变则在原发性的横纹肌肉瘤中被发现。Abnormal activation of this signaling pathway, such as overexpression of FGF ligands or activation mutations through FGFR, can lead to tumor growth, progression, and resistance to traditional cancer therapies. In human tumors, changes in genes that can cause ligand-independent receptor activation, including gene amplification, chromosomal translocation, and somatic mutations, have been described. And large-scale DNA sequencing of thousands of tumor samples has revealed that the components in the FGFR signaling pathway are high-frequency mutation genes in human cancers. For example, somatic mutations of FGFR1 have been found in gliomas and lung cancers. FGFR2 mutations are more common in gastric and endometrial cancers, while FGFR3 mutations are found in bladder cancer and multiple myeloma, and FGFG4 mutations Found in primary rhabdomyosarcoma.
FGF/FGFR相关的肿瘤类型包括但不局限于癌症(比如膀胱癌，乳腺癌，颈椎癌，结肠癌，子宫内膜癌，胃癌，头颈癌，肾癌，肝癌，肺癌，卵巢癌，***癌)；恶性血液疾病(比如多发性骨髓瘤，慢性淋巴性淋巴瘤，成人T细胞白血病，急性骨髓性白血病，非何杰金氏淋巴瘤，骨髓增殖性肿瘤和华氏巨球蛋白血症)以及其他肿瘤(比如胶质母细胞瘤，黑色素瘤以及横纹肌肉瘤)。除了在肿瘤中的作用之外，FGFR的活化还被发现和骨骼和软骨细胞病变相关，比如软骨发育不全和颅缝早闭。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) 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) and other tumors (Such as glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in tumors, FGFR activation has also been found to be associated with bone and chondrocyte lesions, such as hypochondral hypoplasia and premature closure of cranial sutures.
虽然已经有一些FGFR抑制剂进入到了临床及临床前的研发过程中,但通常会有选择性不够好，对于c-kit,PDGFRa等其他激酶也有抑制作用，从而带来一定治疗窗口不够大的担忧。因此，研发靶向于FGFR选择性的抑制剂在临床上治疗具有升高的FGF或者FGFR活性的疾病时会非常有意义。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.
发明内容Summary of the Invention
本发明目的是提供一种FGFR抑制剂。The object of the present invention is to provide an FGFR inhibitor.
本发明第一方面提供一种式(I)化合物、其立体异构体、前药或其药学上可接受盐：The first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:
Figure PCTCN2019088158-appb-000001
Figure PCTCN2019088158-appb-000001
其中，X选自C(R 7)或N； Wherein X is selected from C (R 7 ) or N;
R 1选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1- 10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0- 8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 1 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 groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 、 -C 0-8 -OR 9 、 -C 0-8 -C (O) OR 9 、 -C 0-8 -C (O) R 10 、 -C 0-8 -OC (O) R 10 、 -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0 -8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent, and the above-mentioned group is optionally further selected by one or more members selected from deuterium, halo, cyano, nitro, azido, C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, a halo substituted C 1-10 alkyl, substituted C 1 to deuterium -10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0- 8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 substituted with a substituent;
R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3- 10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1- 10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0- 8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0 -8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0 -8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O , -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 The group is optionally further further selected from one or more selected from the group consisting of deuterium, halogen, cyano, nitro, Group, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkyl substituted with halo, deuterium substituted C 1- 10 alkyl, C 3-10 cycloalkyl, , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11) R 10, -C 0- 8 -N (R 11) -C (= NR 12) R 10, -C 0-8 -C (O) NR 11 R 12 Or substituted by -C 0-8 -N (R 11 ) -C (O) R 10 substituents;
R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基或5-10元杂芳氧基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azide, 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 heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, 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 3-10 cycloalkyl, 3-10 membered heterocyclyl , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C ( O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C ( = NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 substituted with a substituent;
R 5、R 6各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0- 8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、- C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S (O) r R 8 , -C 0-8- OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0- 8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, 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 3-10 cycloalkyl, 3 -10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or- C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent;
R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3- 10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1- 10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0- 8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0 -8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0 -8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkyl substituted with halo, deuterium substituted C 1- 10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C ( O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C ( = NR 11 ) R 10 , -C 0- 8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 substituted with a substituent;
每个R 8选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12的取代基所取代； 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 substituent;
每个R 9选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12的取代基所取代； 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;
每个R 10选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12的取代基所取代； 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 heteroaryloxy or -NR 11 R 12 substituents;
每个R 11、R 12各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； 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 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 heterocyclooxy, C 5-10 aryl, C 5-10 aromatic Substituted by oxo, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
或者，R 11、R 12和其直接相连的氮原子一起形成4-10元杂环基或4-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Alternatively, 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;
每个r各自独立地为0、1或2。Each r is independently 0, 1, or 2.
作为优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中X选自C(R 7)或N；R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0- 4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如前所述。 As a preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, X is selected from C (R 7 ) or N; R 7 is selected from hydrogen, deuterium, and halogen. , Cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0- 4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 , the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5 -8-membered heteroaryl, = O, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0- 4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 、 -C 0- 4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 is substituted by a substituent; R 8 , R 9 , R 10 , R 11 , R 12 , r is as previously described.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中X选自C(R 7)或N；R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、烯丙基、乙炔基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基、氨基羰基、二甲氨基羰基或乙酰氨基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代。 As a further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, 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; the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl , Ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中X选自C(R 7)或N；R 7选自氢、氘、氟、氯、氰基、硝基、叠氮基、甲基、乙基、异丙基、烯丙基、乙炔基、环丙基、环丙甲基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧基、乙氧基、异丙氧基、甲氧乙基、乙氧乙基、羟甲基、羟乙基、氰甲基、三氟甲基、三氘甲基、二氟甲基、二氘甲基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基、氨基甲基、氨基羰基、二甲氨基羰基或乙酰氨基。 As a further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, 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, dideutermethyl, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy Group, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetylamino.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 5、R 6各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如前所述。 As a further preferred embodiment, 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, halogen, cyano, Nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0 -4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 ,- C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O R 10 , the above-mentioned group is optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, halogen-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered hetero Aryl, = O, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C ( O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4- N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 ; R 8 , R 9 , R 10 , R 11 , R 12 and r are as described above.
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 5、R 6各自独立地选自氢、氘、氟、氯、溴、氰基、硝基、叠氮基、C 1-4烷基、烯 丙基、乙炔基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基、氨基羰基、二甲氨基羰基或乙酰氨基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代。 As a still further preferred embodiment, 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 optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, Substituted by methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxyl or amino substituents.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基或5-8元杂芳氧基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如前所述。 As a further preferred embodiment, 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. Group, nitro, azide, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3 -8-membered heterocyclyl, 3-8-membered heterocyclyl, C 5-8 aryl, C 5-8 aryloxy, 5-8-membered heteroaryl or 5-8-membered heteroaryloxy, the above-mentioned groups The group is optionally further substituted with one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O) R 10 ,- C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 )- C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 substituted with a substituent; R 8 , R 9 , R 10 , R 11 , R 12 , and r are as described above.
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C 1-4烷基、C 1-4烷氧基、烯丙基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、苯基、二氮唑或三氮唑；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代。 As a still further preferred embodiment, 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.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3- 8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0- 4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1- 4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如前所述。 As a further preferred embodiment, 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. , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 Heteroaryl, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O ) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 , the above-mentioned groups The group is further optionally one or more selected from the group consisting of deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 , -C 0- 4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0- 4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4- NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O ) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 Instead, the above-mentioned group is optionally further further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, a halogen substituted C 1- 4 alkyl group, deuterium-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl Aryl, = O, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C ( O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4- Substitution of N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 R 8 , R 9 , R 10 , R 11 , R 12 , and r are as previously described.
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 9、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰 基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9或-C 0-4-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如前所述。 As a further preferred embodiment, 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. 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -OR 9 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 Or -C 0-4 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3- 8 -cycloalkyl, 3-8-membered heterocyclyl, C 5-8 aryl, 5-8-membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 or -C 0-4 -NR 11 R 12 is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more selected from deuterium and halogen , C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideuteryl, dideuteryl, cyclopropyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy, or The carboxyl group is substituted; R 8 , R 9 , R 10 , R 11 , R 12 , and r are as described above.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐所述式(I)化合物具有如下式(Ⅱ)结构：As a further preferred embodiment, the compound of the formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a structure of the following formula (II):
Figure PCTCN2019088158-appb-000002
Figure PCTCN2019088158-appb-000002
其中，R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-6元杂芳基、-C 0-4-O-R 9或-C 0-4-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-S(O) rR 8、-O-R 9、-C(O)OR 9或-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； Wherein 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 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -S (O) r R 8 , -OR 9 , -C (O) OR 9 or -NR 11 R 12 is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkane With a substituent of C3-6 cycloalkyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl;
R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基或3-6元杂环氧基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、甲氧基、乙氧基、羟基或氨基的取代基所取代； 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、R 6各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、羟基、甲氧基、乙氧基或异丙氧基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、甲氧基、乙氧基、羟基或氨基的取代基所取代； 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如式(I)化合物所定义。 R 1 , R 8 , R 9 , R 11 , R 12 , r are as defined for the compound of formula (I).
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0- 4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如前所述。 As a further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 2- 4 -alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl or 5-8 membered heteroaryl, the above-mentioned groups are optionally further selected from one or more deuteriums , Halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic ring , C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4- N (R 11 ) -C (O) R 10 is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 、 -C 0-4 -OR 9 、 -C 0-4 -C (O) OR 9 、 -C 0-4 -C (O) R 10 、 -C 0- 4 -OC (O) R 10 、 -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0 -4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 substituted with a substituent; R 8 , R 9 , R 10 , R 11 , R 12 And r are as described above.
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自氢、氘、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-O-R 9、-C 0-4-C(O)OR 9或-C 0-4-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1- 4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代；R 9、R 10、R 11、R 12如前所述。 As a still further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, 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 above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, C 1 -4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 or -C 0-4 -NR 11 R 12 is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more selected from the group consisting of deuterium, halogen, C 1-4 alkane group, a halogen substituted C 1-4 alkyl, deuterium substituted C 1- 4 alkyl, C 3-6 cycloalkyl, = O, hydroxy, methoxy, ethoxy, isopropoxy or carboxy substituent Substituted; R 9 , R 10 , R 11 , R 12 are as previously described.
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐所述式(I)化合物具有如下式(Ⅲ)结构：As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof has a structure of formula (III):
Figure PCTCN2019088158-appb-000003
Figure PCTCN2019088158-appb-000003
其中，R 1选自氢、氘、C 1-4烷基、C 3-8环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-O-R 9、-C(O)OR 9或-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； Wherein, R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more selected from deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, = 0, -OR 9 , -C (O) OR 9 or- NR 11 R 12 is substituted with a substituent, and the above-mentioned group is optionally further substituted by one or more selected from the group consisting of deuterium, halogen, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 Substituted with alkyl, C 3-6 cycloalkyl, = O, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl substituents;
R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-6元杂芳基、-O-R 9或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-O-R 9、-C(O)OR 9或-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； 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, -OR 9 or -NR 11 R 12 , the aforementioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, = 0, -OR 9 , -C (O) OR 9 or -NR 11 R 12 substituents, the above-mentioned groups are optionally further substituted by one or more Selected from deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, = 0, hydroxyl, methoxy, ethoxy With isopropyl, isopropyloxy or carboxyl substituents;
R 9、R 11、R 12如式(I)化合物所定义。 R 9 , R 11 and R 12 are as defined for the compound of formula (I).
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自氢、氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、乙基、C 3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、＝O、羟基、甲氧基、乙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； As a still further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, and C 3- 6 -cycloalkyl or 3-6 membered heterocyclic group, the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, C 3-6 cycloalkyl, 3-6 membered Heterocyclyl, phenyl, 5- to 6-membered heteroaryl, = O, hydroxyl, methoxy, ethoxy, carboxy, amino, dimethylamino, or diethylamino Optionally, it is further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, dideutermethyl, trideutermethyl, cyclopropyl, = 0, Substituted with a hydroxy, methoxy, ethoxy, isopropoxy or carboxyl substituent;
R 2选自3-8元杂环基、5-6元杂芳基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、异丙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被 一个或多个选自氘、氟、氯、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； R 2 is selected from a 3-8 membered heterocyclic group, a 5-6 membered heteroaryl group or -NR 11 R 12. The above-mentioned group is optionally further selected from one or more members selected from the group consisting of deuterium, fluorine, chlorine, cyano, C 1 -4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy, carboxyl, amino, dimethylamino, or diethyl The amino group is substituted by a substituent of the amino group, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteryl, and tris. Substituted with deuterium methyl, cyclopropyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl substituents;
R 11、R 12各自独立地选自氢、氘、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-6芳基或5-6元杂芳基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、卤取代C 1- 4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-6芳基、C 5-6芳氧基、5-6元杂芳基、5-6元杂芳氧基、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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;
或者，R 11、R 12和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-6芳基、C 5-6芳氧基、5-6元杂芳基、5-6元杂芳氧基、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代。 Alternatively, 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.
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自氢、氘、C 1-4烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、乙基、环丙基、3-6元杂环基、苯基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基或环丙基的取代基所取代； As a further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, 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 2选自二氮唑基、三氮唑基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基或环丙基的取代基所取代； R 2 is selected from the group consisting of a diazolyl group, a triazolyl group, or -NR 11 R 12 , and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxy, methoxy, ethoxy, isopropoxy or carboxy substituents, the above-mentioned groups are optionally further substituted by one or Substituted with a plurality of substituents selected from deuterium, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, dideutermethyl, trideutermethyl or cyclopropyl;
R 11、R 12各自独立地选自氢、氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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、R 12和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、苯基、二氮唑基、三氮唑基、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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
所述杂环基各自独立地任选包含1或2个选自氮原子或氧原子的杂原子。The heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom.
作为最优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐包括但不限于如下化合物：As a most preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
Figure PCTCN2019088158-appb-000004
Figure PCTCN2019088158-appb-000004
Figure PCTCN2019088158-appb-000005
Figure PCTCN2019088158-appb-000005
本发明第二方面提供一种前所述式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，包括如下步骤：According to a second aspect of the present invention, a method for preparing the aforementioned compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof is provided, including the following steps:
Figure PCTCN2019088158-appb-000006
Figure PCTCN2019088158-appb-000006
或者，or,
Figure PCTCN2019088158-appb-000007
Figure PCTCN2019088158-appb-000007
其中，X、R 1、R 2、R 3、R 4、R 5、R 6、如式(I)化合物所定义。 Among them, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined for the compound of formula (I).
本发明第三方面提供一种药物组合物，其包括前述式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。A third aspect of the present invention provides 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.
本发明第四方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备***或癌症药物中的应用。According to 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.
作为优选的方案，所述的肿瘤或癌症选自膀胱癌、乳腺癌、***、大肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、食管癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、白血病、多发性骨髓瘤、慢性淋巴细胞淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、急性髓细胞白血病、霍奇金淋巴瘤或非霍奇金淋巴瘤、华氏巨球蛋白血症、毛发样淋巴瘤、细胞淋巴瘤、伯基特淋巴瘤、胶质母细胞瘤、黑色素瘤或横纹肌肉瘤。As a preferred solution, 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.
本发明第五方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备治疗骨髓增生性疾病、骨骼或软骨细胞紊乱、低磷血症药物中的应用。According to a fifth aspect of the present invention, 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. Applications.
作为优选的方案，所述的骨髓增生性疾病选自红细胞增多症、原发性血小板增多症或原发性骨髓纤维化；所述的骨骼或软骨细胞紊乱选自发育不良、软骨发育不良、侏儒症、致死性畸胎(TD)、阿佩尔氏综合征、Crouzon综合征、Jackson-Weiss综合征、Beare-Stevenson皮肤回纹综合征、Pfeiffer综合征或颅肌萎缩综合征；所述的低磷血症选自X-连锁低磷性佝偻病、常染色体隐性低磷性佝偻病、常染色体显性低磷性佝偻病或肿瘤诱发的卵巢软化症。As a preferred solution, 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. Disease, lethal teratosis (TD), Apel syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin pattern syndrome, Pfeiffer syndrome, or cranial muscle atrophy syndrome; said low Phosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced ovarian softening.
本发明第六方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，其用作FGFR抑制剂。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.
具体实施方式Detailed ways
本申请的发明人经过广泛而深入地研究，首次研发出一种具有式(I)结构一种FGFR抑制 剂、其制备方法和在药学上的应用，各取代基的定义如说明书和权利要求书所述。本发明系列化合物可广泛应用于制备***、癌症、骨髓增生性疾病、骨骼或软骨细胞紊乱、低磷血症的药物，有望开发成新一代FGFR抑制剂药物。在此基础上，完成了本发明。After extensive and intensive research, the inventors of the present application have developed for the first time an 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. As described. 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.
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。Detailed description: Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
“烷基”指直链或含支链的饱和脂族烃基团，例如，“C 1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。 "Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group. For example, "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-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5- Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-bis Hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched chains thereof Isomers, etc.
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, and cyanide. Radical, nitro, azide, 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 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0- 8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted with a substituent.
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，例如，“C 3-10环烷基”指包括3至10个碳原子的环烷基，分为单环环烷基、多环环烷基，其中： "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, "C 3-10 cycloalkyl" refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, of which:
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基包括但不限于：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 π-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:
Figure PCTCN2019088158-appb-000008
Figure PCTCN2019088158-appb-000008
“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于："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 π-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:
Figure PCTCN2019088158-appb-000009
Figure PCTCN2019088158-appb-000009
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于："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 π-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:
Figure PCTCN2019088158-appb-000010
Figure PCTCN2019088158-appb-000010
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。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.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 A cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 ,- C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0 -8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8- C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。例如，“5-10元杂环基”指包含5至10个环原子的环基，“3-10元杂环基”指包含3至10个环原子的环基。 "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. For example, "5-10 membered heterocyclyl" refers to a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclyl" refers to a cyclic group containing 3 to 10 ring atoms.
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。Monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于： 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 π-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:
Figure PCTCN2019088158-appb-000011
Figure PCTCN2019088158-appb-000011
Figure PCTCN2019088158-appb-000012
Figure PCTCN2019088158-appb-000012
“稠杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个(优选1、2、3或4个)环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于： "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 π 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:
Figure PCTCN2019088158-appb-000013
Figure PCTCN2019088158-appb-000013
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于： "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 π-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:
Figure PCTCN2019088158-appb-000014
Figure PCTCN2019088158-appb-000014
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：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:
Figure PCTCN2019088158-appb-000015
Figure PCTCN2019088158-appb-000015
Figure PCTCN2019088158-appb-000016
Figure PCTCN2019088158-appb-000016
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 ,- C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0 -8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8- C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，例如，“C 5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，包括但不限于苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于： "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 π-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:
Figure PCTCN2019088158-appb-000017
Figure PCTCN2019088158-appb-000017
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0- 8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8- NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O ) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“杂芳基”指包含一个或多个(优选1、2、3或4个)杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，例如，5-8元杂芳基指含有5-8个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于："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:
Figure PCTCN2019088158-appb-000018
Figure PCTCN2019088158-appb-000018
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, Cyano, nitro, azide, 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 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 ,- C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0 -8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8- C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，例如，C 2-10链烯基指含有2-10个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。 "Alkenyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, 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.
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0- 8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8- NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O ) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如，C 2-10链炔基指含有2-10个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。 "Alkynyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, C 2-10 alkynyl refers to a straight or branched chain containing 2 to 10 carbons. Alkynyl. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 The alkynyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0- 8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8- NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O ) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述，例如，“C 1-10烷氧基”指含1-10个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。 "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.
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或 -C 0-8-N(R 11)-C(O)R 10的取代基所取代。 The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium and halogen. , Cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkane , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“环烷氧基”指和-O-(未取代的环烷基)，其中环烷基的定义如上所述，例如，“C 3-10环烷氧基”指含3-10个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。 "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.
环烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 The cycloalkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen , Cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkane , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“3-10元杂环氧基”指和-O-(未取代的3-10元杂环基)，其中3-10元杂环基的定义如上所述，3-10元杂环氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 "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. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0- 8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8- NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O ) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“C 5-10芳氧基”指和-O-(未取代的C 5-10芳基)，其中C 5-10芳基的定义如上所述，C 5-10芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 "C 5-10 aryloxy" refers to -O- (unsubstituted C 5-10 aryl), wherein C 5-10 aryl is as defined above, and C 5-10 aryloxy may be optional Substituted or unsubstituted, when substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, nitro, Nitrogen, 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 3-10 cycloalkane Group, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted.
“5-10元杂芳氧基”指和-O-(未取代的5-10元杂芳基)，其中5-10元杂芳基的定义如上所述，5-10元杂芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代。 "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. When substituted, the substituent is preferably one or more (preferably 1, 2, 3, or 4) groups, independently selected from deuterium, halogen, cyano, Nitro, azide, 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 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0- 8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8- NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O ) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent.
“C 1-8烷酰基”指C 1-8烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-7-C(O)-”，例如，“C 1-C(O)-”是指乙酰基；“C 2-C(O)-”是指丙酰基；“C 3-C(O)-”是指丁酰基或异丁酰基。 "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-S(O) rR 8”指-S(O) rR 8中的硫原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -S (O) r R 8 " means that the sulfur atom in -S (O) r R 8 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1- The definition of 8- alkyl is as described above.
“-C 0-8-O-R 9”指-O-R 9中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定 义如上所述。 "-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-C(O)OR 9”指-C(O)OR 9中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -C (O) OR 9 " means that the carbonyl group in -C (O) OR 9 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1-8 alkyl group The definition is as described above.
“-C 0-8-C(O)R 10”指-C(O)R 10中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -C (O) R 10 " means that the carbonyl group in -C (O) R 10 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1-8 alkyl group The definition is as described above.
“-C 0-8-O-C(O)R 10”指-O-C(O)R 10中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1- 8烷基的定义如上所述。 "-C 0-8 -OC (O) R 10" refers to a -OC (O) oxygen atom attached to the R 10 C 0-8 alkyl, wherein C 0 alkyl means a bond, C 1- 8 alkyl The definition of base is as described above.
“-C 0-8-NR 11R 12”指-NR 11R 12中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-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.
“-C 0-8-C(＝NR 11)R 10”指-C(＝NR 11)R 10中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -C (= NR 11 ) R 10 " means that the carbonyl group in -C (= NR 11 ) R 10 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1 The definition of -8 alkyl is as described above.
“-C 0-8-N(R 11)-C(＝NR 12)R 10”指-N(R 11)-C(＝NR 12)R 10中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 " means that the carbonyl group in -N (R 11 ) -C (= NR 12 ) R 10 is attached to a C 0-8 alkyl group Where C 0 alkyl refers to a bond, and C 1-8 alkyl is as defined above.
“-C 0-8-C(O)NR 11R 12”指-C(O)NR 11R 12中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -C (O) NR 11 R 12 " means that the carbonyl group in -C (O) NR 11 R 12 is attached to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1 The definition of -8 alkyl is as described above.
“-C 0-8-N(R 12)-C(O)R 11”指-N(R 12)-C(O)R 11中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。 "-C 0-8 -N (R 12 ) -C (O) R 11 " means that the nitrogen atom in -N (R 12 ) -C (O) R 11 is attached to a C 0-8 alkyl group, where C 0 alkyl means a bond, and C 1-8 alkyl is as defined above.
“卤取代C 1-10烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷基基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。 "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.
“卤取代C 1-10烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷氧基基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。 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.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“MeOH”是指甲醇。“DMF”是指N，N-二甲基甲酰胺。“DCE”是指1,2-二氯乙烷。“THF”是指四氢呋喃。“PE”是指石油醚。“EA/EtOAc”是指乙酸乙酯。“DCM”是指二氯甲烷。“LiOH”是指氢氧化锂。“NaOH”是指氢氧化钠。“NaNO 2”是指亚硝酸钠。“CuI”是指碘化亚铜。“Na 2SO 4是指硫酸钠。”“HOAc”是指醋酸。“NH 4Oac”是指醋酸铵。“Et 3N”是指三乙胺。“NH 4Cl”是指氯化铵。“TFA”是指三氟乙酸。“m-CPBA”是指间氯过氧苯甲酸。“Pd(PPh 3) 4”是指四(三苯基膦)钯。“Pd(PPh 3) 2Cl 2“”是指”双三苯基磷二氯化钯。 "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.""HOAc" 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 ""means" bistriphenylphosphonium palladium dichloride.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "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 .
“取代的”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。"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. For example, 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.
“药学上可接受盐”在本发明中是指药学上可接受的酸加成盐，包括无机酸盐和有机酸盐，这些盐可通过本专业已知的方法制备。"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.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。The following describes the present invention in further detail and completeness with reference to the examples, but it is by no means limited to the present invention, and the present invention is not limited to the content of the examples.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts (δ) 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).
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Liquid chromatography-mass spectrometry LC-MS was performed using an Agilent 6120 mass spectrometer. For HPLC measurement, 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.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。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.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。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.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius (° C).
一、中间体的制备First, the preparation of intermediates
1、8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备1. Preparation of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
Figure PCTCN2019088158-appb-000019
Figure PCTCN2019088158-appb-000019
第一步：2,4-二氟-3-碘-1,5-二甲氧基苯的合成Step 1: Synthesis of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene
Figure PCTCN2019088158-appb-000020
Figure PCTCN2019088158-appb-000020
将化合物2,6-二氟-3,5-二甲氧基苯胺(27.0g，143mmol)加入6.0M盐酸溶液(240mL)中，冰水浴冷却下缓慢滴加NaNO 2水溶液(10.35g，150mmol，30mL水)。25分钟滴加完，继续反应15分钟，产生桔红色悬浊液，将其加入KI水溶液(94.9g，570mmol，150mL水)。升至室温，搅拌反应30分钟，析出固体。过滤，水洗，得粗产品。将粗产品加入MeOH(60mL)，室温搅拌30分钟。过滤，干燥得2,4-二氟-3-碘-1,5-二甲氧基苯(29.3g，收率：68％)。 1H NMR(400MHz,DMSO-d 6)δ6.69(t,J＝8.0Hz,1H),3.88(s,6H)。 Compound 2,6-difluoro-3,5-dimethoxyaniline (27.0 g, 143 mmol) was added to a 6.0 M hydrochloric acid solution (240 mL), and an aqueous NaNO 2 solution (10.35 g, 150 mmol, 30 mL of water). After 25 minutes of dropwise addition, the reaction was continued for 15 minutes to produce an orange-red suspension, which was added to an aqueous KI solution (94.9 g, 570 mmol, 150 mL of water). The temperature was raised to room temperature, and the reaction was stirred for 30 minutes to precipitate a solid. Filter and wash with water to obtain the crude product. The crude product was added to MeOH (60 mL) and stirred at room temperature for 30 minutes. Filtration and drying gave 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (29.3 g, yield: 68%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.69 (t, J = 8.0 Hz, 1 H), 3.88 (s, 6 H).
第二步：(2,6-二氟-3,5-二甲氧基苯乙炔)基三甲基硅烷的合成Step 2: Synthesis of (2,6-difluoro-3,5-dimethoxyphenylethynyl) trimethylsilane
Figure PCTCN2019088158-appb-000021
Figure PCTCN2019088158-appb-000021
2,4-二氟-3-碘-1,5-二甲氧基苯(25.8g，86.0mmol)、三甲基硅基乙炔(36.5mL，258mmol)CuI(817mg，4.3mmol)以及三乙胺(35.8mL，258mmol)加入DMF(250mL)。抽换气，氮气保护，然后加入Pd(PPh 3) 2Cl 2(3.15g，4.3mmol)。加热50℃，反应2小时。反应完全，加入饱和NH 4Cl水溶液淬灭，再入二氯甲烷萃取3次。合并有机相，Na 2SO 4干燥。过滤，浓缩，得粗产品(27.0g)，直接用于下步反应。 1H NMR(400MHz,CDCl 3)δ6.61(t,J＝8.0Hz,1H),3.86(s,6H),0.28(s,9H)。 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (25.8 g, 86.0 mmol), trimethylsilylacetylene (36.5 mL, 258 mmol) CuI (817 mg, 4.3 mmol), and triethyl Amine (35.8 mL, 258 mmol) was added to DMF (250 mL). Pump down, protect with nitrogen, and then add Pd (PPh 3 ) 2 Cl 2 (3.15 g, 4.3 mmol). The mixture was heated at 50 ° C for 2 hours. The reaction was completed, quenched by the addition of saturated aqueous NH 4 Cl solution, and extracted 3 times with dichloromethane. The organic phases were combined, Na 2 SO 4 dried. Filtration and concentration gave the crude product (27.0 g), which was used directly in the next reaction. 1 H NMR (400 MHz, CDCl 3 ) δ 6.61 (t, J = 8.0 Hz, 1 H), 3.86 (s, 6H), 0.28 (s, 9H).
第三步：3-乙炔基-2,4-二氟-1,5-二甲氧基苯的合成Step 3: Synthesis of 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene
Figure PCTCN2019088158-appb-000022
Figure PCTCN2019088158-appb-000022
(2,6-二氟-3,5-二甲氧基苯乙炔)基三甲基硅烷(27.0g，粗品)加入THF/MeOH(200/200mL)，再加入NaOH水溶液(8.6mL，8.6mmol，1.0N)。室温搅拌15分钟。反应完全，加入饱和NH 4Cl水溶液淬灭，二氯甲烷萃取3次。合并有机相，无水Na 2SO 4干燥。过滤，浓缩，粗品加入MeOH(50mL)打浆，室温搅拌30分钟。过滤，得到3-乙炔基-2,4-二氟-1,5-二甲氧基苯(15.0g，2步收率：88％)。 1H NMR(400MHz,CDCl 3)δ6.66(t,J＝8.0Hz,1H),3.88(s,6H),3.52(s,1H)。 (2,6-difluoro-3,5-dimethoxyphenylethynyl) trimethylsilane (27.0 g, crude) was added to THF / MeOH (200/200 mL), and then an aqueous NaOH solution (8.6 mL, 8.6 mmol) was added. , 1.0N). Stir at room temperature for 15 minutes. The reaction was complete, quenched by the addition of saturated aqueous NH 4 Cl, and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous Na 2 SO 4. Filtration and concentration, the crude product was slurried with MeOH (50 mL) and stirred at room temperature for 30 minutes. Filtration gave 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (15.0 g, 2-step yield: 88%). 1 H NMR (400 MHz, CDCl 3 ) δ 6.66 (t, J = 8.0 Hz, 1H), 3.88 (s, 6H), 3.52 (s, 1H).
第四步：5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯的合成Step 4: Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester
Figure PCTCN2019088158-appb-000023
Figure PCTCN2019088158-appb-000023
3-乙炔基-2,4-二氟-1,5-二甲氧基苯(10.0g，50.5mmol)和5-溴-2-甲硫基-嘧啶-4-羧酸甲酯(13.0g，49.5mmol)溶于DMF(100mL)，再加入CuI(479mg，2.52mmol)、Pd(PPh 3) 4(2.91g，2.52mmol)以及Et 3N(35.0mL，252.5mmol)，氮气保护。加热100℃，反应1.5小时。反应完全，冷却至室温，加入饱和NH 4Cl水溶液淬灭，二氯甲烷萃取3次。合并有机相，无水Na 2SO 4干燥，过滤，浓缩。粗品经硅胶柱层析分离(PE:EA:DCM＝10:2:1)得5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(15.4g，收率：82％)。 1H NMR(400MHz,CDCl 3)δ8.82(s,1H),6.69(t,J＝8.0Hz,1H),4.03(s,3H),3.90(s,6H),2.63(s,3H). 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (10.0 g, 50.5 mmol) and 5-bromo-2-methylthio-pyrimidine-4-carboxylic acid methyl ester (13.0 g , 49.5 mmol) was dissolved in DMF (100 mL), and CuI (479 mg, 2.52 mmol), Pd (PPh 3 ) 4 (2.91 g, 2.52 mmol), and Et 3 N (35.0 mL, 252.5 mmol) were added, and protected by nitrogen. The reaction was heated at 100 ° C for 1.5 hours. The reaction was complete, cooled to room temperature, quenched by the addition of saturated aqueous NH 4 Cl solution, and extracted 3 times with dichloromethane. The combined organic phases were dried over anhydrous Na 2 SO 4, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE: EA: DCM = 10: 2: 1) to give 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methyl Thio) pyrimidine-4-carboxylic acid methyl ester (15.4 g, yield: 82%). 1 H NMR (400MHz, CDCl 3 ) δ8.82 (s, 1H), 6.69 (t, J = 8.0Hz, 1H), 4.03 (s, 3H), 3.90 (s, 6H), 2.63 (s, 3H) .
第五步：5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸的合成Step 5: Synthesis of 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
Figure PCTCN2019088158-appb-000024
Figure PCTCN2019088158-appb-000024
5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(30.0g，78.9mmol)溶于THF(300mL)，再加入LiOH/H 2O(236.8mL，236.8mmol，1M)。室温搅拌反应2小时。反应完全，浓缩除去THF，再用稀盐酸酸化至pH约为3，析出固体。过滤，水洗，干燥得5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(28.5g，收率：99％)。 1H NMR(400MHz,DMSO-d 6)δ8.98(s,1H),7.15(t,J＝8.0Hz,1H),3.90(s,6H),2.59(s,3H)。 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester (30.0 g, 78.9 mmol) was dissolved in THF (300 mL), and then added LiOH / H 2 O (236.8 mL, 236.8 mmol, 1M). The reaction was stirred at room temperature for 2 hours. The reaction was complete. The THF was removed by concentration, and then acidified with dilute hydrochloric acid to a pH of about 3, and a solid was precipitated. Filtration, washing with water and drying gave 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (28.5 g, yield : 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 3.90 (s, 6H), 2.59 (s, 3H).
第六步：6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮的合成Step 6: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one Synthesis
Figure PCTCN2019088158-appb-000025
Figure PCTCN2019088158-appb-000025
5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(2.5g，6.83mmol)溶于DCE(50mL)，再加入TFA(0.5mL)和醋酸铜(62mg，0.34mmol)。加热回流，反应过夜。反应完全，浓缩，再加入MeOH(50mL)打浆，室温搅拌30分钟。过滤，固体再用MeOH(10mL)洗涤，干燥得6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(2.0g，收率：80％)。 1H NMR(400MHz,DMSO-d 6)δ9.23(s,1H),7.22(t,J＝8.4Hz,1H),7.17(s,1H),3.93(s,6H),2.63(s,3H). 5-((2,6-difluoro-3,5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (2.5 g, 6.83 mmol) was dissolved in DCE (50 mL ), TFA (0.5 mL) and copper acetate (62 mg, 0.34 mmol) were added. Heat to reflux and react overnight. The reaction was complete, concentrated, and MeOH (50 mL) was added to beat and stirred at room temperature for 30 minutes. Filtered, washed the solid with MeOH (10 mL), and dried to give 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3, 4-d] pyrimidin-8-one (2.0 g, yield: 80%). 1 H NMR (400MHz, DMSO-d 6 ) δ 9.23 (s, 1H), 7.22 (t, J = 8.4Hz, 1H), 7.17 (s, 1H), 3.93 (s, 6H), 2.63 (s, 3H).
第七步：6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 7: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one synthesis
Figure PCTCN2019088158-appb-000026
Figure PCTCN2019088158-appb-000026
6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(4.5g，12.3mmol)溶于HOAc(45mL)，中加入NH 4OAc(9.4g，123mmol)，反应液120℃搅拌过夜。室温冷却，加入适量水(30mL)，搅拌，抽滤，滤饼用水(20mL)洗涤，干燥得6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(4.22g，收率：94％)。 1H NMR(400MHz,DMSO-d 6)δ12.28(s,1H),9.24(s,1H),7.17(t,J＝8.4Hz,1H),6.76(s,1H),3.92(s,6H),2.63(s,3H). 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d] pyrimidin-8-one (4.5g, 12.3 mmol) was dissolved in HOAc (45 mL), NH 4 OAc (9.4 g, 123 mmol) was added, and the reaction solution was stirred at 120 ° C. overnight. Cool at room temperature, add an appropriate amount of water (30mL), stir, suction filter, wash the filter cake with water (20mL), and dry to obtain 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (formaldehyde) Thio) pyrido [3,4-d] pyrimidin-8 (7H) -one (4.22 g, yield: 94%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.28 (s, 1H), 9.24 (s, 1H), 7.17 (t, J = 8.4 Hz, 1H), 6.76 (s, 1H), 3.92 (s, 6H), 2.63 (s, 3H).
第八步：8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的合成Step 8: Synthesis of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine
Figure PCTCN2019088158-appb-000027
Figure PCTCN2019088158-appb-000027
6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(1g,2.74mmol)溶于DCE(80mL)，加热至90℃，然后加入苯膦酰二氯(3.0mL，21.92mmol)，加热搅拌16小时，冷却，在冰浴下用碳酸氢钠调节pH至中性，DCM提取，硅胶柱层析分离(DCM/EtOAc＝0-10％))得到8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(930mg，产率88％)。 1H NMR(400MHz,CDCl 3)δ9.25(s,1H),7.78(t,J＝1.2Hz,1H),6.75(t,J＝8.0Hz,1H),3.93(s,6H),2.77(s,3H)。MS m/z(ESI):384[M+H] +。 6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8 (7H) -one (1g, 2.74mmol ) Dissolved in DCE (80mL), heated to 90 ° C, then added phenylphosphonodichloride (3.0mL, 21.92mmol), heated and stirred for 16 hours, cooled, adjusted to pH neutral with sodium bicarbonate in an ice bath, DCM Extraction and silica gel column chromatography (DCM / EtOAc = 0-10%)) to give 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio ) Pyrido [3,4-d] pyrimidine (930 mg, 88% yield). 1 H NMR (400MHz, CDCl 3 ) δ9.25 (s, 1H), 7.78 (t, J = 1.2Hz, 1H), 6.75 (t, J = 8.0Hz, 1H), 3.93 (s, 6H), 2.77 (s, 3H). MS m / z (ESI): 384 [M + H] + .
2、8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的制备2. Preparation of 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidine
Figure PCTCN2019088158-appb-000028
Figure PCTCN2019088158-appb-000028
8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(930mg，2.42mmol)溶于DCM(50mL)，加入m-CPBA(1.23g，6.05mmol)，室温下搅拌2小时。反应完全，加入硫代硫酸钠淬灭，DCM提取，硅胶柱层析(DCM/EtOAc＝0-35％)分离得到8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(800mg，产率79％)。 1H NMR(400MHz,CDCl 3)δ9.76(s,1H),8.03(t,J＝1.2Hz,1H),6.80(t,J＝8.0Hz,1H),3.95(s,6H),3.58(s,3H)。MS m/z(ESI):416[M+H] +。 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (930mg, 2.42mmol) was dissolved DCM (50 mL), m-CPBA (1.23 g, 6.05 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was completed, quenched with sodium thiosulfate, extracted with DCM, and separated by silica gel column chromatography (DCM / EtOAc = 0-35%) to obtain 8-chloro-6- (2,6-difluoro-3,5-dimethyl Oxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidine (800 mg, yield 79%). 1 H NMR (400MHz, CDCl 3 ) δ 9.76 (s, 1H), 8.03 (t, J = 1.2 Hz, 1H), 6.80 (t, J = 8.0 Hz, 1H), 3.95 (s, 6H), 3.58 (s, 3H). MS m / z (ESI): 416 [M + H] + .
二、实施例化合物的制备Preparation of Example Compounds
实施例1 1-(2-((4-(二乙胺基)丁基)氨基)-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇的制备Example 1 1- (2-((4- (diethylamino) butyl) amino) -6- (2,6-difluoro-3,5-dimethoxyphenyl) pyrido [3,4 -d] Preparation of pyrimidine-8-yl) -3-methylazetidin-3-ol
Figure PCTCN2019088158-appb-000029
Figure PCTCN2019088158-appb-000029
第一步：1-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇的合成First step: 1- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8-yl) Synthesis of -3-methylazetidin-3-ol
Figure PCTCN2019088158-appb-000030
Figure PCTCN2019088158-appb-000030
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(300mg,0.782mmol)和3-甲基-3-吖啶醇盐酸盐(290mg,2.345mmol)的乙腈(6mL)溶液中，加入N,N-二异丙基乙胺(0.605mg,4.692mmol)。反应液置于封管内，在95℃下搅拌18小时。冷却后，加入乙酸乙酯(50mL)稀释,用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离[洗 脱剂:(二氯甲烷:乙酸乙酯＝0～40％)]得到1-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇(328mg，收率：96％)。MS m/z(ESI):435.4[M+H] + Between 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (300 mg, 0.782 mmol) and To a solution of 3-methyl-3-acridanol hydrochloride (290 mg, 2.345 mmol) in acetonitrile (6 mL) was added N, N-diisopropylethylamine (0.605 mg, 4.692 mmol). The reaction solution was placed in a sealed tube and stirred at 95 ° C for 18 hours. After cooling, ethyl acetate (50 mL) was added to dilute, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated after column chromatography [eluent: (dichloromethane: ethyl acetate = 0 to 40%) ] To give 1- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8-yl) -3 -Methylazetidin-3-ol (328 mg, yield: 96%). MS m / z (ESI): 435.4 [M + H] +
第二步：1-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇的合成Second step: 1- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidin-8-yl) Synthesis of -3-methylazetidin-3-ol
Figure PCTCN2019088158-appb-000031
Figure PCTCN2019088158-appb-000031
在1-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇(328mg,0.755mmol)的二氯甲烷(8mL)溶液中，一次性加入间氯过氧苯甲酸(390mg,2.265mmol)。反应液在室温下搅拌20小时。反应液依次用饱和亚硫酸钠溶液和碳酸氢钠溶液洗涤，最后用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:(二氯甲烷:乙酸乙酯＝0～80％)]得到1-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇(151mg,收率：42％)。MS m/z(ESI):467.4[M+H] +。 At 1- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidin-8-yl) -3- To a solution of methylazetidin-3-ol (328 mg, 0.755 mmol) in dichloromethane (8 mL), m-chloroperoxybenzoic acid (390 mg, 2.265 mmol) was added in one portion. The reaction solution was stirred at room temperature for 20 hours. The reaction solution was sequentially washed with a saturated sodium sulfite solution and a sodium bicarbonate solution, and finally washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated after column chromatography. 80%)] to give 1- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidin-8-yl ) -3-methylazetidin-3-ol (151 mg, yield: 42%). MS m / z (ESI): 467.4 [M + H] + .
第三步：1-(2-((4-(二乙胺基)丁基)氨基)-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇的合成Third step: 1- (2-((4- (diethylamino) butyl) amino) -6- (2,6-difluoro-3,5-dimethoxyphenyl) pyrido [3, Synthesis of 4-d] pyrimidin-8-yl) -3-methylazetidin-3-ol
Figure PCTCN2019088158-appb-000032
Figure PCTCN2019088158-appb-000032
1-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇(14mg,0.03mmol)和N 1,N 1-二乙基丁烷-1,4-二胺(13mg,0.09mmol)溶于乙腈(0.5mL)中。该反应液置于封管内，在80℃下搅拌3小时。反应液直接浓缩，反相柱层析分离[流动相:(乙腈:水(0.1％甲酸)＝5～35％)]，水相冻干得到1-(2-((4-(二乙胺基)丁基)氨基)-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-8-基)-3-甲基吖丁啶-3-醇(9mg,收率53％)。MS m/z(ESI):531.6[M+H] +。 1- (6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidin-8-yl) -3-methyl Acridine-3-ol (14 mg, 0.03 mmol) and N 1 , N 1 -diethylbutane-1,4-diamine (13 mg, 0.09 mmol) were dissolved in acetonitrile (0.5 mL). The reaction solution was placed in a sealed tube and stirred at 80 ° C for 3 hours. The reaction solution was directly concentrated and separated by reversed-phase column chromatography [mobile phase: (acetonitrile: water (0.1% formic acid) = 5 to 35%)], and the aqueous phase was lyophilized to obtain 1- (2-((4- (diethylamine Yl) butyl) amino) -6- (2,6-difluoro-3,5-dimethoxyphenyl) pyrido [3,4-d] pyrimidin-8-yl) -3-methylazetidine Pyridin-3-ol (9 mg, yield 53%). MS m / z (ESI): 531.6 [M + H] + .
1H NMR(400MHz,CDCl 3)δ8.82(s,1H),8.53(s,1H,HCO 2H),6.87(s,1H),6.66(t,J＝7.9Hz,1H),5.67(s,1H),4.43(s,4H),3.91(s,6H),3.52(s,2H),3.10–3.00(m,6H),2.12–1.64(m,4H),1.57(s,3H),1.25(t,J＝7.3Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.82 (s, 1H), 8.53 (s, 1H, HCO 2 H), 6.87 (s, 1H), 6.66 (t, J = 7.9Hz, 1H), 5.67 ( s, 1H), 4.43 (s, 4H), 3.91 (s, 6H), 3.52 (s, 2H), 3.10-3.00 (m, 6H), 2.12-1.64 (m, 4H), 1.57 (s, 3H) , 1.25 (t, J = 7.3Hz, 6H).
实施例2 N 1-(8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-N4,N4-二乙基丁烷-1,4-二胺的制备 Example 2 N 1- (8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) pyrido [3,4-d] pyrimidine- Preparation of 2-yl) -N4, N4-diethylbutane-1,4-diamine
Figure PCTCN2019088158-appb-000033
Figure PCTCN2019088158-appb-000033
第一步：8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的合成First step: 8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4 -d] Synthesis of pyrimidine
Figure PCTCN2019088158-appb-000034
Figure PCTCN2019088158-appb-000034
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(600mg,1.407mmol)和氮杂环丁烷盐酸盐(395mg,4.221mmol)的乙腈(12mL)溶液中，加入N,N-二异丙基乙胺(1.09g,8.442mmol)。反应液置于封管内，在95℃下搅拌16小时。冷却后，加入乙酸乙酯(50mL)稀释,用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:(二氯甲烷:乙酸乙酯＝0～15％)]得到8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(483mg，收率：84.9％)。MS m/z(ESI):405.4[M+H] +. Between 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (600 mg, 1.407 mmol) and To a solution of azetidine hydrochloride (395 mg, 4.221 mmol) in acetonitrile (12 mL) was added N, N-diisopropylethylamine (1.09 g, 8.442 mmol). The reaction solution was placed in a sealed tube and stirred at 95 ° C for 16 hours. After cooling, ethyl acetate (50 mL) was added to dilute, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated after column chromatography [eluent: (dichloromethane: ethyl acetate = 0 to 15%) ] To give 8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] Pyrimidine (483 mg, yield: 84.9%). MS m / z (ESI): 405.4 [M + H] + .
第二步：8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的合成Second step: 8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4 -d] Synthesis of pyrimidine
Figure PCTCN2019088158-appb-000035
Figure PCTCN2019088158-appb-000035
在8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(483mg,1.194mmol)的二氯甲烷(10mL)溶液中，一次性加入间氯过氧苯甲酸(515mg,2.986mmol)。反应液在室温下搅拌24小时。反应液依次用饱和亚硫酸钠溶液和碳酸氢钠溶液洗涤，最后用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:(二氯甲烷:甲醇＝0～5％)]得到8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(214mg,收率：41％)。MS m/z(ESI):437.4[M+H] +. In 8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] To a solution of pyrimidine (483 mg, 1.194 mmol) in dichloromethane (10 mL), m-chloroperoxybenzoic acid (515 mg, 2.986 mmol) was added in one portion. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was sequentially washed with a saturated sodium sulfite solution and a sodium bicarbonate solution, and finally with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated after column chromatography. [Eluent: (dichloromethane: methanol = 0 to 5%) )] To give 8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4- d] pyrimidine (214 mg, yield: 41%). MS m / z (ESI): 437.4 [M + H] + .
第三步：N 1-(8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-N4,N4-二乙基丁烷-1,4-二胺的合成 Third step: 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
Figure PCTCN2019088158-appb-000036
Figure PCTCN2019088158-appb-000036
在8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(40mg,0.091mmol)和N 1,N 1-二乙基丁烷-1,4-二胺(39.6mg,0.275mmol)的乙腈(2mL)溶液中，加入N,N-二异丙基乙胺(35.5mg,0.275mmol)。该反应液置于封管内，在110℃下搅拌18小时。冷却后，加入乙酸乙酯(20mL)稀释,用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后用C 18反相柱分离[流动相:(乙腈:水(0.1％甲酸)＝10～30％)]并且冻干后得到N 1-(8-(吖丁啶-1-基)-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-N4,N4-二乙基丁烷-1,4-二胺(25mg，收率：54％)。MS m/z(ESI):501.6[M+H] +. In 8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] To a solution of pyrimidine (40 mg, 0.091 mmol) and N 1 , N 1 -diethylbutane-1,4-diamine (39.6 mg, 0.275 mmol) in acetonitrile (2 mL) was added N, N-diisopropyl Ethylamine (35.5 mg, 0.275 mmol). The reaction solution was placed in a sealed tube and stirred at 110 ° C for 18 hours. After cooling, dilute with ethyl acetate (20 mL), wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration, separate with a C 18 reverse phase column [mobile phase: (acetonitrile: water (0.1% formic acid) = 10 ～ 30%)] and N 1- (8- (azetidin-1-yl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) pyrido [3, 4-d] pyrimidin-2-yl) -N4, N4-diethylbutane-1,4-diamine (25 mg, yield: 54%). MS m / z (ESI): 501.6 [M + H] + .
1H NMR(400MHz,CDCl 3)δ8.84(s,1H),8.61(s,1H,HCOOH),6.88(s,1H),6.66(t,J＝7.9Hz,1H),5.81(br s,1H),4.60-4.30(m,4H),3.91(s,6H),3.53(t,J＝6.4Hz,2H),2.98(q,J＝7.3Hz,4H),2.90(t,J＝8.0Hz,2H),2.40(p,J＝7.5Hz,2H),1.87–1.75(m,2H),1.76–1.67(m,2H),1.23(t,J＝7.2Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.84 (s, 1H), 8.61 (s, 1H, HCOOH), 6.88 (s, 1H), 6.66 (t, J = 7.9Hz, 1H), 5.81 (br s , 1H), 4.60-4.30 (m, 4H), 3.91 (s, 6H), 3.53 (t, J = 6.4Hz, 2H), 2.98 (q, J = 7.3Hz, 4H), 2.90 (t, J = 8.0Hz, 2H), 2.40 (p, J = 7.5Hz, 2H), 1.87-1.75 (m, 2H), 1.76-1.67 (m, 2H), 1.23 (t, J = 7.2Hz, 6H).
实施例3～21参照实施例1或2的合成方法制备得到：Examples 3 to 21 are prepared by referring to the synthetic method of Example 1 or 2:
Figure PCTCN2019088158-appb-000037
Figure PCTCN2019088158-appb-000037
Figure PCTCN2019088158-appb-000038
Figure PCTCN2019088158-appb-000038
Figure PCTCN2019088158-appb-000039
Figure PCTCN2019088158-appb-000039
Figure PCTCN2019088158-appb-000040
Figure PCTCN2019088158-appb-000040
实施例22 N 8-(环丙基甲基)-6-(2,6-二氟-3,5-二甲氧苯基)-N 2-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2,8-二胺的制备 Example 22 N 8 - (cyclopropylmethyl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -N 2 - (2- (4- methylpiperazine -1 -Yl) ethyl) pyrido [3,4-d] pyrimidin-2,8-diamine
Figure PCTCN2019088158-appb-000041
Figure PCTCN2019088158-appb-000041
第一步：8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-N-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2-胺的合成First step: 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyridine Synthesis of benzo [3,4-d] pyrimidin-2-amine
Figure PCTCN2019088158-appb-000042
Figure PCTCN2019088158-appb-000042
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(400mg,0.962mmol)和4-甲基-1-哌嗪乙胺(344mg,2.405mmol)的二氯甲烷(10mL)溶液中，加入N,N-二异丙基乙胺(372mg,2.886mmol)。反应液在50℃下回流搅拌2小时。冷却后，用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后得到8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-N-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2-胺。MS m/z(ESI):479.6[M+H] +. Between 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidine (400 mg, 0.962 mmol) and To a solution of 4-methyl-1-piperazineethylamine (344 mg, 2.405 mmol) in dichloromethane (10 mL) was added N, N-diisopropylethylamine (372 mg, 2.886 mmol). The reaction solution was stirred at 50 ° C under reflux for 2 hours. After cooling, it was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -N- (2- ( 4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d] pyrimidin-2-amine. MS m / z (ESI): 479.6 [M + H] + .
第二步：N 8-(环丙基甲基)-6-(2,6-二氟-3,5-二甲氧苯基)-N 2-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2,8-二胺的合成 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
Figure PCTCN2019088158-appb-000043
Figure PCTCN2019088158-appb-000043
在8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-N-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2-胺(40mg,0.084mmol)和环丙基甲胺(30mg,0.418mmol)的叔丁醇(2mL)溶液中，加入N,N-二异丙基乙胺(32.5mg,0.275mmol)。该反应液置于封管内，在115℃下搅拌18小时。浓缩后，加入乙酸乙酯(20mL)稀释,用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后用制备板分离[展开剂:(二氯甲烷:甲醇(5％氨水)＝10：1)]，得到N 8-(环丙基甲基)-6-(2,6-二氟-3,5-二甲氧苯基)-N 2-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2,8-二胺(17.7mg，收率：51％)。MS m/z(ESI):514.6[M+H] +. In 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3 , 4-d] pyrimidin-2-amine (40 mg, 0.084 mmol) and cyclopropylmethylamine (30 mg, 0.418 mmol) in a tert-butanol (2 mL) solution, and N, N-diisopropylethylamine ( 32.5 mg, 0.275 mmol). The reaction solution was placed in a sealed tube and stirred at 115 ° C for 18 hours. After concentration, dilute with ethyl acetate (20 mL), wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration, separate with a preparation plate [developing solvent: (dichloromethane: methanol (5% ammonia)) = 10: 1 )], to give N 8 - (cyclopropylmethyl) -6- (2,6-difluoro-3,5-dimethoxyphenyl) -N 2 - (2- (4- methylpiperazine - 1-yl) ethyl) pyrido [3,4-d] pyrimidine-2,8-diamine (17.7 mg, yield: 51%). MS m / z (ESI): 514.6 [M + H] + .
1H NMR(400MHz,CDCl 3)δ8.86(s,1H),6.88(s,1H),6.66(t,J＝7.9Hz,1H),6.56–6.50(m,1H),5.88(s,1H),3.91(s,6H),3.64(dd,J＝11.1,5.2Hz,2H),3.44(dd,J＝7.0,5.5Hz,2H),3.04–2.50(m,10H),2.42(s,3H),0.88(t,J＝6.9Hz,1H),0.58–0.49(m,2H),0.35–0.26(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.86 (s, 1H), 6.88 (s, 1H), 6.66 (t, J = 7.9Hz, 1H), 6.56-6.50 (m, 1H), 5.88 (s, 1H), 3.91 (s, 6H), 3.64 (dd, J = 11.1, 5.2Hz, 2H), 3.44 (dd, J = 7.0, 5.5Hz, 2H), 3.04-2.50 (m, 10H), 2.42 (s , 3H), 0.88 (t, J = 6.9 Hz, 1H), 0.58--0.49 (m, 2H), 0.35--0.26 (m, 2H).
实施例23参照实施例22的合成方法制备得到：Example 23 is prepared by referring to the synthetic method of Example 22:
Figure PCTCN2019088158-appb-000044
Figure PCTCN2019088158-appb-000044
实施例24 6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-N-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2-胺的制备Example 24 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4- Preparation of methylpiperazin-1-yl) ethyl) pyrido [3,4-d] pyrimidin-2-amine
Figure PCTCN2019088158-appb-000045
Figure PCTCN2019088158-appb-000045
第一步：6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的合成First step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) Synthesis of pyrido [3,4-d] pyrimidine
Figure PCTCN2019088158-appb-000046
Figure PCTCN2019088158-appb-000046
8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(200mg,0.52mmol),(1-甲基-1H-吡唑-4-基)硼酸(131mg,1.04mmol),磷酸钾(221mg,1.04mmol),XPhos-Pd-G2(41mg,0.052mmol)溶于四氢呋喃(10mL)和水(3mL)，氮气置换三次，反应置于45℃下搅拌过夜。冷却，用乙酸乙酯(100mL)稀释，一次用水(20mL*2)和饱和食盐水(20mL*2)洗涤，硫酸钠干燥，过滤，浓缩后硅胶柱层析分离(洗脱剂:PE/EA＝3/1)，得到6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(230mg,产率100％)。MS m/z(ESI):430.4[M+H] +. 8-chloro-6- (2,6-difluoro-3,5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d] pyrimidine (200 mg, 0.52 mmol), ( 1-methyl-1H-pyrazol-4-yl) boronic acid (131 mg, 1.04 mmol), potassium phosphate (221 mg, 1.04 mmol), XPhos-Pd-G2 (41 mg, 0.052 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), replaced with nitrogen three times, and the reaction was stirred at 45 ° C. overnight. Cool, dilute with ethyl acetate (100mL), wash once with water (20mL * 2) and saturated brine (20mL * 2), dry over sodium sulfate, filter, and concentrate after silica gel column chromatography (eluent: PE / EA = 3/1) to give 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (formaldehyde Thio) pyrido [3,4-d] pyrimidine (230 mg, 100% yield). MS m / z (ESI): 430.4 [M + H] + .
第二步：6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的合成Second step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methanesulfonyl) Synthesis of pyrido [3,4-d] pyrimidine
Figure PCTCN2019088158-appb-000047
Figure PCTCN2019088158-appb-000047
6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(230mg，0.54mmol)溶于二氯甲烷(10m L)，加入间氯过氧苯甲酸(282mg,1.38mmol),室温搅拌过夜。加入硫代硫酸钠淬灭，饱和碳酸氢钠调节至碱性，二氯甲烷萃取，一次用饱和碳酸氢钠和食盐水洗涤，浓缩得到6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的粗品(300mg)，直接用于下一步。MS m/z(ESI):462.4[M+H] +。 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrido [3 , 4-d] pyrimidine (230 mg, 0.54 mmol) was dissolved in dichloromethane (10 ml), m-chloroperoxybenzoic acid (282 mg, 1.38 mmol) was added, and the mixture was stirred at room temperature overnight. It was quenched by adding sodium thiosulfate, adjusted to basicity with saturated sodium bicarbonate, extracted with dichloromethane, washed once with saturated sodium bicarbonate and brine, and concentrated to obtain 6- (2,6-difluoro-3,5-dimethyl Oxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methanesulfonyl) pyrido [3,4-d] pyrimidine crude (300mg), used directly below step. MS m / z (ESI): 462.4 [M + H] + .
第三步：6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-N-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2-胺的合成Third step: 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4 -Methylpiperazin-1-yl) ethyl) pyrido [3,4-d] pyrimidin-2-amine Synthesis
Figure PCTCN2019088158-appb-000048
Figure PCTCN2019088158-appb-000048
6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的粗品(100mg,0.18mmol),2-(4-甲基哌嗪-1-基)乙烷-1-胺(51mg,0.36mmol),DIPEA(70mg,0.54mmol)溶于20mL乙腈中，使用封管反应，在110℃下搅拌过夜。直接浓缩，反相柱层析分离(洗脱剂：30％水/乙腈，添加5％甲酸)，水相冻干得到6-(2,6-二氟-3,5-二甲氧苯基)-8-(1-甲基-1H-吡唑-4-基)-N-(2-(4-甲基哌嗪-1-基)乙基)吡啶并[3,4-d]嘧啶-2-胺(70mg,收率72％)。MS m/z(ESI):525.6[M+H] +. 6- (2,6-difluoro-3,5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methanesulfonyl) pyrido [3 Crude, 4-d] pyrimidine (100 mg, 0.18 mmol), 2- (4-methylpiperazin-1-yl) ethane-1-amine (51 mg, 0.36 mmol), DIPEA (70 mg, 0.54 mmol) dissolved The reaction was sealed in 20 mL of acetonitrile using a tube and stirred at 110 ° C. overnight. Direct concentration, separation by reversed-phase column chromatography (eluent: 30% water / acetonitrile, 5% formic acid added), and lyophilization of the aqueous phase to obtain 6- (2,6-difluoro-3,5-dimethoxyphenyl) ) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d] pyrimidine -2-amine (70 mg, 72% yield). MS m / z (ESI): 525.6 [M + H] + .
1H NMR(400MHz,Methanol-d 4)δ9.19(s,1H),8.60(s,2H),8.48(s,2H,HCOOH),7.65(s,1H),6.99(t,J＝8.1Hz,1H),4.01(s,3H),3.95(s,6H),3.78(t,J＝6.4Hz,2H),3.27–3.08(m,8H),2.91–2.86(m,2H),2.80(s,3H). 1 H NMR (400MHz, Methanol-d 4 ) δ 9.19 (s, 1H), 8.60 (s, 2H), 8.48 (s, 2H, HCOOH), 7.65 (s, 1H), 6.99 (t, J = 8.1 Hz, 1H), 4.01 (s, 3H), 3.95 (s, 6H), 3.78 (t, J = 6.4Hz, 2H), 3.27–3.08 (m, 8H), 2.91–2.86 (m, 2H), 2.80 (s, 3H).
生物学测试评价Evaluation of biological tests
一、FGFR 1～3的体外生物化学激酶分析I. In vitro biochemical kinase analysis of FGFR 1-3
本发明采用Caliper Assay测定化合物对FGFR1,FGFR2,FGFR3抑制活性的特性。具体实验过程如下：In the present invention, Caliper Assay is used to determine the compound's inhibitory activity on FGFR1, FGFR2, and FGFR3. The specific experimental process is as follows:
1、本发明所进行的激酶反应在384孔板中进行，用一定浓度的激酶(Carna)和一定浓度的ATP以及1μM的肽FAM-P22(GL Biochem,Cat.No.112393))，在50mM HEPES,pH7.5,0.0015％Brij-35以及基础激酶缓冲液的反应体系中28℃下孵育反应一定时间；对于FGFR1，酶浓度为0.25nM,ATP浓度为382μM,反应时间为20分钟；对于FGFR2，酶浓度为2.5nM,ATP浓度为1μM,反应时间为40分钟；对于FGFR3，酶浓度为8nM,ATP浓度为4.7μM,反应时间为30分钟1. 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 μM 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 382μM, the reaction time is 20 minutes; for FGFR2 The enzyme concentration is 2.5nM, the ATP concentration is 1μM, and the reaction time is 40 minutes. For FGFR3, the enzyme concentration is 8nM, the ATP concentration is 4.7μM, and the reaction time is 30 minutes.
2、添加停止溶液(100mM HEPES,pH7.5,0.2％Caliper涂布试剂，50mM EDTA及0.015％Brij35)终止反应；2. Add stop solution (100mM HEPES, pH7.5, 0.2% Caliper coating reagent, 50mM EDTA and 0.015% Brij35) to stop the reaction;
3、将已终止激酶反应的孔板转移至Caliper读取数据；3. Transfer the wells that have stopped the kinase reaction to Caliper to read the data;
4、使用Caliper微流体迁移偏移技术分离磷酸化与未磷酸化的肽，并通过恒定缓冲液流经芯片来转移分析物，且通过其标记的荧光信号监控底物肽的迁移。利用所形成的磷酸基肽的量计算激酶活性。4. 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.
5、通过非线性回归分析不同化合物浓度下的抑制百分比来测定IC 50值。具体实施例化合物酶学活性见表1。 5. 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.
二、细胞增殖实验(Cell Titer Glo(CTG)实验)Cell proliferation experiment (Cell Titer Glo (CTG) experiment)
本发明通过存活率的实验来评价化合物对依赖于FGFR信号通路的细胞增殖抑制作用，使用CTG试剂(Promega,#G7573)来测量。挑选了能代表不同肿瘤类型的细胞系，比如来自于南京科佰的H1581肺癌细胞(有FGFR1基因的扩增)或Snu-16胃癌细胞(有FGFR2基因的扩增)具体实验过程如下：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:
1、将90ul细胞接种到组织培养基处理的96孔板(Costar#3904)，在37℃5％二氧化碳培养箱中培养过夜，随后加入10μL包含10倍其终浓度的化合物稀释液的培养基。1. Inoculate 90ul cells into a tissue culture medium-treated 96-well plate (Costar # 3904), incubate overnight at 37 ° C in a 5% carbon dioxide incubator, and then add 10 μL of the medium containing 10 times its final concentration of the compound dilution.
2、通过测试化合物系列稀释来评价剂量效应作用，从10μM或者更低浓度开始。2. Evaluate the dose-effect effect by serial dilution of the test compound, starting at 10 μM or lower.
3、将细胞在37℃，5％CO 2下孵育3天后，加入50μL CTG，使用Envision(Pelkin Elmer)进行读数，来定量细胞ATP水平将不同浓度抑制剂作用后的细胞ATP水平和加入DMSO对照组的细胞ATP水平相比，可以评价化合物对于细胞增殖/存活的抑制百分比 3. After incubating the cells for 3 days at 37 ° C and 5% CO 2 , add 50 μL of CTG, and use Envision (Pelkin Elmer) to take readings to quantify the ATP levels of the cells. Add the ATP levels of the cells after different concentrations of inhibitors to the DMSO control Compared to the group's cellular ATP levels, the compound's percent inhibition of cell proliferation / survival can be evaluated
4、使用Graphpad Prism中四参数曲线拟合来测定导致半数最大生长抑制的化合物浓度(IC 50)。具体实施例化合物细胞活性见表1。 4, using compound concentration (IC 50) Graphpad Prism four parameter curve fit of measured results in half-maximal growth inhibition. The cell activity of the specific example compounds is shown in Table 1.
表1 酶学和细胞活性检测结果Table 1 Enzymology and cell viability test results
Figure PCTCN2019088158-appb-000049
Figure PCTCN2019088158-appb-000049
Figure PCTCN2019088158-appb-000050
Figure PCTCN2019088158-appb-000050
从具体实施例化合物酶学活性数据来看，本发明系列化合物对FGFR1、FGFR2和FGFR3激酶活性均具有很强的抑制作用。从具体实施例化合物细胞活性数据来看，本发明系列化合物对FGFR1、FGFR2和FGFR3高表达的H1581肺癌细胞和/或Snu16胃癌细胞增殖活性具有很强的抑制作用。According to the enzymatic activity data of the compounds of the specific examples, 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.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are incorporated by reference in this application, as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (17)

  1. 式(I)化合物、其立体异构体、前药或其药学上可接受盐：Compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof:
    Figure PCTCN2019088158-appb-100001
    Figure PCTCN2019088158-appb-100001
    其中，among them,
    X选自C(R 7)或N； X is selected from C (R 7 ) or N;
    R 1选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1- 10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0- 8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 1 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 groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 、 -C 0-8 -OR 9 、 -C 0-8 -C (O) OR 9 、 -C 0-8 -C (O) R 10 、 -C 0-8 -OC (O) R 10 、 -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0 -8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent, and the above-mentioned group is optionally further selected by one or more members selected from deuterium, halo, cyano, nitro, azido, C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, a halo substituted C 1-10 alkyl, substituted C 1 to deuterium -10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0- 8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 substituted with a substituent;
    R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3- 10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1- 10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0- 8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0 -8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0 -8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = O , -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 The group is optionally further further selected from one or more selected from the group consisting of deuterium, halogen, cyano, nitro, Group, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkyl substituted with halo, deuterium substituted C 1- 10 alkyl, C 3-10 cycloalkyl, , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11) R 10, -C 0- 8 -N (R 11) -C (= NR 12) R 10, -C 0-8 -C (O) NR 11 R 12 Or substituted by -C 0-8 -N (R 11 ) -C (O) R 10 substituents;
    R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基或5-10元杂芳氧基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、 氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azide, 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 heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, 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 3-10 cycloalkyl, 3-10 membered heterocyclyl , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C ( O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C ( = NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 substituted with a substituent;
    R 5、R 6各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0- 8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S (O) r R 8 , -C 0-8- OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0- 8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, 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 3-10 cycloalkyl, 3 -10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, = 0, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or- C 0-8 -N (R 11 ) -C (O) R 10 is substituted by a substituent;
    R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3- 10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0-8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1- 10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8-S(O) rR 8、-C 0-8-O-R 9、-C 0-8-C(O)OR 9、-C 0-8-C(O)R 10、-C 0-8-O-C(O)R 10、-C 0-8-NR 11R 12、-C 0-8-C(＝NR 11)R 10、-C 0- 8-N(R 11)-C(＝NR 12)R 10、-C 0-8-C(O)NR 11R 12或-C 0-8-N(R 11)-C(O)R 10的取代基所取代； R 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0 -8 -C (O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0 -8 -C (= NR 11 ) R 10 , -C 0-8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkyl substituted with halo, deuterium substituted C 1- 10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl , C 5-10 aryl, 5-10 membered heteroaryl, = O, -C 0-8 -S (O) r R 8 , -C 0-8 -OR 9 , -C 0-8 -C ( O) OR 9 , -C 0-8 -C (O) R 10 , -C 0-8 -OC (O) R 10 , -C 0-8 -NR 11 R 12 , -C 0-8 -C ( = NR 11 ) R 10 , -C 0- 8 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-8 -C (O) NR 11 R 12 or -C 0-8 -N (R 11 ) -C (O) R 10 substituted with a substituent;
    每个R 8选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12的取代基所取代； 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 substituent;
    每个R 9选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12的取代基所取代； 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;
    每个R 10选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 11R 12的取代基所取代； 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 heteroaryloxy or -NR 11 R 12 substituents;
    每个R 11、R 12各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、 单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； 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-mentioned 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 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 heterocyclooxy, C 5-10 aryl, C 5-10 aromatic Substituted by oxo, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
    或者，R 11、R 12和其直接相连的氮原子一起形成4-10元杂环基或4-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代； Alternatively, 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;
    每个r各自独立地为0、1或2。Each r is independently 0, 1, or 2.
  2. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，X选自C(R 7)或N； The compound of formula 1 (I) as claimed in claim acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable prodrug, wherein, X is selected from C (R 7) or N;
    R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代； R 7 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0 -4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0 -4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl , C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C ( O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C ( = NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 substituted with a substituent;
    R 8、R 9、R 10、R 11、R 12、r如权利要求1所述； R 8 , R 9 , R 10 , R 11 , R 12 , r are as described in claim 1;
    优选的，R 7选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、烯丙基、乙炔基、C 3- 6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基、氨基羰基、二甲氨基羰基或乙酰氨基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代； Preferably, R 7 is selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1-4 alkyl, allyl, ethynyl, C 3- 6 cycloalkyl, oxetanyl , Azetidinyl, azacyclohexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropyloxy, methyl Oxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetylamino; the above-mentioned groups are optionally further selected from one or more Deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxyl or amino;
    更优选的，R 7选自氢、氘、氟、氯、氰基、硝基、叠氮基、甲基、乙基、异丙基、烯丙基、乙炔基、环丙基、环丙甲基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、甲氧基、乙氧基、异丙氧基、甲氧乙基、乙氧乙基、羟甲基、羟乙基、氰甲基、三氟甲基、三氘甲基、二氟甲基、二氘甲基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基、氨基甲基、氨基羰基、二甲氨基羰基或乙酰氨基。 More preferably, R 7 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azide, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, and cyclopropylmethyl. Yl, oxetanyl, azetidinyl, azacyclohexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy , Isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trideutermethyl, difluoromethyl, dideutermethyl, methoxy Carbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetylamino.
  3. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that:
    R 5、R 6各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2- 4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如权利要求1所述； R 5, R 6 are each independently selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 8 , -C 0-4- OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3 -8-membered heterocyclyl, C 5-8 aryl, 5-8-membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or- C 0-4 -N (R 11 ) -C (O) R 10 substituted by substituents; R 8 , R 9 , R 10 , R 11 , R 12 , r as claimed in claim 1;
    优选的，R 5、R 6各自独立地选自氢、氘、氟、氯、溴、氰基、硝基、叠氮基、C 1-4烷基、烯丙基、乙炔基、C 3-6环烷基、氧杂环丁基、氮杂环戊基、氮杂环己基、苯基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、羟基、甲氧基、乙氧基、异丙氧基、甲氧羰基、乙氧羰基、乙酰基、乙酰氧基、乙酰氧甲基、氨基、二甲基氨基、氨基羰基、二甲氨基羰基或乙酰氨基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代。 Preferably, R 5 and R 6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, C 1-4 alkyl, allyl, ethynyl, C 3- 6- Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxyl, methoxy Ethoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetylamino; above The group is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxyl or amino. .
  4. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that:
    R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5- 8芳氧基、5-8元杂芳基或5-8元杂芳氧基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代；R 8、R 9、R 10、R 11、R 12、r如权利要求1所述； R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, azido, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5-8 aryl, C 5- 8 aryloxy group, 5-8 membered heteroaryl or 5-8 membered heteroaryloxy, the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl , C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C ( O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C ( = NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 is substituted by a substituent; R 8 , R 9 , R 10 , R 11 , R 12 , r are as described in claim 1;
    优选的，R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、C 1-4烷基、C 1-4烷氧基、烯丙基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、苯基、二氮唑或三氮唑；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、苯基、甲氧基、乙氧基、羟基或氨基的取代基所取代。 Preferably, R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C 1-4 alkyl, C 1-4 alkoxy, allyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclooxy, phenyl, diazole or triazole; the above groups are optional It is further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxyl or amino.
  5. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that:
    R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8 芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代，R 8、R 9、R 10、R 11、R 12、r如权利要求1所述； R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0 -4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0 -4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O , -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 The group is optionally further further selected from one or more selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 alkane , C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic ring , C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0-4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4- N (R 11 ) -C (O) R 10 is substituted by a substituent, and R 8 , R 9 , R 10 , R 11 , R 12 , r are as described in claim 1;
    优选的，R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 9、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9或-C 0-4-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； Preferably, R 2 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl , -C 0-4 -OR 9 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C ( = NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 , the above-mentioned groups are optionally further substituted by one or Multiple selected from deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = O, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 or -C 0-4 -NR 11 R 12 The above groups are optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, C 1-4 alkyl, trifluoromethyl, difluoromethyl, trideuterylmethyl, dideuterylmethyl, and cyclo Substituted with propyl, = O, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl substituents;
    R 8、R 9、R 10、R 11、R 12、r如权利要求1所述。 R 8 , R 9 , R 10 , R 11 , R 12 , and r are as described in claim 1.
  6. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，所述式(I)化合物具有如下式(Ⅱ)结构：The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) has the structure of formula (II):
    Figure PCTCN2019088158-appb-100002
    Figure PCTCN2019088158-appb-100002
    其中，among them,
    R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-6元杂芳基、-C 0- 4-O-R 9或-C 0-4-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-S(O) rR 8、-O-R 9、-C(O)OR 9或-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； 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 , the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3 -8-membered heterocyclyl, C 5-8 aryl, 5-8-membered heteroaryl, = O, -S (O) r R 8 , -OR 9 , -C (O) OR 9 or -NR 11 R 12 is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, = 0, hydroxy, methoxy, ethoxy, isopropoxy or carboxyl substituent;
    R 3、R 4各自独立地选自氢、氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基或3-6元杂环氧基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、甲氧基、乙氧基、羟基或氨基的取代基所取代； 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、R 6各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、羟基、甲氧基、乙氧基或异丙氧基；上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、环丙基、甲氧基、乙氧基、羟基或氨基的取代基所取代； 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如权利要求1所述。 R 1 , R 8 , R 9 , R 11 , R 12 , and r are as described in claim 1.
  7. 根据权利要求6所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that:
    R 1选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0-4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-S(O) rR 8、-C 0-4-O-R 9、-C 0-4-C(O)OR 9、-C 0-4-C(O)R 10、-C 0- 4-O-C(O)R 10、-C 0-4-NR 11R 12、-C 0-4-C(＝NR 11)R 10、-C 0-4-N(R 11)-C(＝NR 12)R 10、-C 0-4-C(O)NR 11R 12或-C 0-4-N(R 11)-C(O)R 10的取代基所取代，R 8、R 9、R 10、R 11、R 12、r如权利要求6所述； R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, or 5-8 membered Heteroaryl, the aforementioned groups are optionally further selected from one or more of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 、 -C 0-4 -OR 9 、 -C 0-4 -C (O) OR 9 、 -C 0-4 -C (O) R 10 、 -C 0-4 -OC (O) R 10 、 -C 0-4 -NR 11 R 12 , -C 0-4 -C (= NR 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0 -4 -C (O) NR 11 R 12 or -C 0-4 -N (R 11 ) -C (O) R 10 is substituted by a substituent, and the above-mentioned group is optionally further selected by one or more members selected from Deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1 -4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, = 0, -C 0-4 -S (O) r R 8 , -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 , -C 0-4 -C (O) R 10 , -C 0- 4 -OC (O) R 10 , -C 0-4 -NR 11 R 12 , -C 0-4 -C (= N R 11 ) R 10 , -C 0-4 -N (R 11 ) -C (= NR 12 ) R 10 , -C 0-4 -C (O) NR 11 R 12 or -C 0-4 -N ( R 11 ) -C (O) R 10 is substituted by a substituent, and R 8 , R 9 , R 10 , R 11 , R 12 , r are as described in claim 6;
    优选的，R 1选自氢、氘、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4-O-R 9、-C 0-4-C(O)OR 9或-C 0-4-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代，R 9、R 10、R 11、R 12如权利要求6所述。 Preferably, R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, or 5-8 membered heteroaryl, as described above. The group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5 -8-membered heteroaryl, = O, -C 0-4 -OR 9 , -C 0-4 -C (O) OR 9 or -C 0-4 -NR 11 R 12 The group is optionally further further selected from one or more selected from the group consisting of deuterium, halogen, C 1-4 alkyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, = The substituents of O, hydroxy, methoxy, ethoxy, isopropoxy or carboxyl are substituted, and R 9 , R 10 , R 11 , R 12 are as described in claim 6.
  8. 根据权利要求6所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，所述式(I)化合物具有如下式(Ⅲ)结构：The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 6, wherein the compound of formula (I) has the structure of formula (III):
    Figure PCTCN2019088158-appb-100003
    Figure PCTCN2019088158-appb-100003
    其中，among them,
    R 1选自氢、氘、C 1-4烷基、C 3-8环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-8元杂芳基、＝O、-O-R 9、-C(O)OR 9或-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、 C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more selected from deuterium, halogen, C 1 -4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, = O, -OR 9 , -C (O) OR 9 or -NR 11 R 12 is substituted by a substituent, and the above-mentioned group is optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl , C 3-6 cycloalkyl, = O, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl substituent;
    R 2选自氢、氘、卤素、C 1-4烷基、C 3-8环烷基、3-8元杂环基、苯基、5-6元杂芳基、-O-R 9或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-O-R 9、-C(O)OR 9或-NR 11R 12的取代基所取代，上述基团任选再进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； 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, -OR 9 or -NR 11 R 12 , the aforementioned group is optionally further selected from one or more of deuterium, halogen, cyano, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5- 8 aryl, 5-8 membered heteroaryl, = 0, -OR 9 , -C (O) OR 9 or -NR 11 R 12 substituents, the above-mentioned groups are optionally further substituted by one or more Selected from deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, = 0, hydroxyl, methoxy, ethoxy With isopropyl, isopropyloxy or carboxyl substituents;
    R 9、R 11、R 12如权利要求6所述。 R 9 , R 11 and R 12 are as described in claim 6.
  9. 根据权利要求8所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 8, characterized in that:
    R 1选自氢、氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、乙基、C 3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基、＝O、羟基、甲氧基、乙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, and the above-mentioned group is optionally further selected from one or more selected from deuterium, fluorine, chlorine, Methyl, ethyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, = 0, hydroxyl, methoxy, ethoxy, carboxyl, amino, The dimethylamino or diethylamino substituent is substituted, and the above-mentioned group is optionally further further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl , Di-deuteryl, tri-demethyl, cyclopropyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl;
    R 2选自3-8元杂环基、5-6元杂芳基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、异丙氧基、羧基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、环丙基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代； R 2 is selected from a 3-8 membered heterocyclic group, a 5-6 membered heteroaryl group or -NR 11 R 12. The above-mentioned group is optionally further selected from one or more members selected from the group consisting of deuterium, fluorine, chlorine, cyano, C 1 -4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy, carboxyl, amino, dimethylamino, or diethyl The amino group is substituted by a substituent of the amino group, and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteryl, and tris. Substituted with deuterium methyl, cyclopropyl, = 0, hydroxyl, methoxy, ethoxy, isopropoxy or carboxyl substituents;
    R 11、R 12各自独立地选自氢、氘、C 1-4烷基、C 3-8环烷基、3-8元杂环基、C 5-6芳基或5-6元杂芳基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、卤取代C 1- 4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-6芳基、C 5-6芳氧基、5-6元杂芳基、5-6元杂芳氧基、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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;
    或者，R 11、R 12和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-6芳基、C 5-6芳氧基、5-6元杂芳基、5-6元杂芳氧基、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代。 Alternatively, 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.
  10. 根据权利要求8所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 8, characterized in that:
    R 1选自氢、氘、C 1-4烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、甲基、乙基、环丙基、3-6元杂环基、苯基、氨基、二甲基氨基或二乙基氨基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基或环丙基的取代基所取代； R 1 is selected from hydrogen, deuterium, C 1-4 alkyl, or 3-6 membered heterocyclic group, and the above group is optionally further selected from one or more of deuterium, fluorine, chlorine, methyl, ethyl, cyclopropyl Group, 3-6 membered heterocyclic group, phenyl, amino, dimethylamino or diethylamino substituent, the above-mentioned group is optionally further further selected from one or more selected from deuterium, methyl, ethyl With a substituent such as diyl, difluoromethyl, trifluoromethyl, dideuteryl, trimethyl or cyclopropyl;
    R 2选自二氮唑基、三氮唑基或-NR 11R 12，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、＝O、羟基、甲氧基、乙氧基、异丙氧基或羧基的取代基所取代，上述基团任选再进一步被一个或多个选自氘、氟、氯、甲基、乙基、二氟甲基、三氟甲基、二氘甲基、三氘甲基或环丙基的取代基所取代； R 2 is selected from the group consisting of a diazolyl group, a triazolyl group, or -NR 11 R 12 , and the above-mentioned group is optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, = 0, hydroxy, methoxy, ethoxy, isopropoxy or carboxy substituents, the above-mentioned groups are optionally further substituted by one or Substituted with a plurality of substituents selected from deuterium, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, dideutermethyl, trideutermethyl or cyclopropyl;
    R 11、R 12各自独立地选自氢、氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、环丙基、3-8元杂环基、苯基、二氮唑、三氮唑、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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、R 12和其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、C 1-4烷基、二氟甲基、三氟甲基、二氘甲基、三氘甲基、甲氧基、乙氧基、异丙氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、苯基、二氮唑、三氮唑、氨基、二甲基氨基、二乙基氨基或C 1-4烷酰基的取代基所取代； 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, diazole, triazole, amino, dimethylamino, diethylamino, or C 1-4 alkanoyl substituents Replace
    所述杂环基各自独立地任选包含1或2个选自氮原子或氧原子的杂原子。The heterocyclic groups each independently optionally include 1 or 2 heteroatoms selected from a nitrogen atom or an oxygen atom.
  11. 根据权利要求1-10任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自如下化合物：The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, characterized in that it is selected from the following compounds:
    Figure PCTCN2019088158-appb-100004
    Figure PCTCN2019088158-appb-100004
    Figure PCTCN2019088158-appb-100005
    Figure PCTCN2019088158-appb-100005
  12. 权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，包括如下步骤：The method for preparing a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 1, comprising the following steps:
    Figure PCTCN2019088158-appb-100006
    Figure PCTCN2019088158-appb-100006
    或者，or,
    Figure PCTCN2019088158-appb-100007
    Figure PCTCN2019088158-appb-100007
    其中，X、R 1、R 2、R 3、R 4、R 5、R 6如权利要求1所述。 Wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described in claim 1.
  13. 一种药物组合物，其包括权利要求1-11任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-11, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  14. 权利要求1-11任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备***或癌症药物中的应用；优选的，所述的肿瘤或癌症选自膀胱癌、乳腺癌、***、大肠癌、子宫内膜癌、胃癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、***癌、食管癌、胆囊癌、胰腺癌、甲状腺癌、皮肤癌、白血病、多发性骨髓瘤、慢性淋巴细胞淋巴瘤、成人T细胞白血病、B细胞淋巴瘤、急性髓细胞白血病、霍奇金淋巴瘤或非霍奇金淋巴瘤、华氏巨球蛋白血症、毛发样淋巴瘤、细胞淋巴瘤、伯基特淋巴瘤、胶质母细胞瘤、黑色素瘤或横纹肌肉瘤。The use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 in the preparation of a medicament for treating a tumor or cancer; preferably, the tumor or The 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, 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's lymphoma or non-Hodgkin's lymphoma, Fahrenheit macroglobulinemia , Hair-like lymphoma, cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
  15. 权利要求1-11任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备治疗骨髓增生性疾病、骨骼或软骨细胞紊乱、低磷血症药物中的应用。The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 in the preparation of a medicine for treating myeloproliferative diseases, bone or chondrocyte disorders, and hypophosphatemia Application.
  16. 根据权利要求15所述的应用，其特征在于，所述的骨髓增生性疾病选自红细胞增多症、原发性血小板增多症或原发性骨髓纤维化；所述的骨骼或软骨细胞紊乱选自发育不良、软骨发育不良、侏儒症、致死性畸胎(TD)、阿佩尔氏综合征、Crouzon综合征、Jackson-Weiss综合征、Beare-Stevenson皮肤回纹综合征、Pfeiffer综合征或颅肌萎缩综合征；所述的低磷血症选自X-连锁低磷性佝偻病、常染色体隐性低磷性佝偻病、常染色体显性低磷性佝偻病或肿瘤诱发的卵巢软化症。The use according to claim 15, wherein the myeloproliferative disease is selected from the group consisting of erythrocytosis, primary thrombocytosis, or primary myelofibrosis; and the skeletal or chondrocyte disorders are selected from Dysplasia, cartilage dysplasia, dwarfism, lethal teratosis (TD), Apel syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin pattern syndrome, Pfeiffer syndrome or cranial Atrophy syndrome; the hypophosphatemia is selected from the group consisting of X-linked hypophosphatemia rickets, autosomal recessive hypophosphatemia rickets, autosomal dominant hypophosphatemia rickets, or tumor-induced ovarian softening.
  17. 根据权利要求1-11任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其用作FGFR抑制剂。The compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is used as an FGFR inhibitor.
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