WO2022042612A1 - Dihydropyrrolo[2,3-d]pyridazin-7-one derivative, preparation method therefor, and application thereof - Google Patents

Dihydropyrrolo[2,3-d]pyridazin-7-one derivative, preparation method therefor, and application thereof Download PDF

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Publication number
WO2022042612A1
WO2022042612A1 PCT/CN2021/114580 CN2021114580W WO2022042612A1 WO 2022042612 A1 WO2022042612 A1 WO 2022042612A1 CN 2021114580 W CN2021114580 W CN 2021114580W WO 2022042612 A1 WO2022042612 A1 WO 2022042612A1
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alkyl
deuterium
substituted
membered
halogen
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PCT/CN2021/114580
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French (fr)
Chinese (zh)
Inventor
邓海兵
辛文群
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 CN202180047630.2A priority Critical patent/CN116096720A/en
Publication of WO2022042612A1 publication Critical patent/WO2022042612A1/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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, in particular to a dihydropyrrolo[2,3-d]pyridazin-7-one derivative, a preparation method and application thereof.
  • Fibroblast growth factor receptor is a tyrosine kinase receptor that binds to fibroblast growth factor ligands.
  • FGF fibroblast growth factor
  • FGF When FGF binds to its receptor, the receptor dimerizes and phosphorylates, stimulates the activation of protein kinase activity, and helps activate a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphorylation Esterase C These signaling pathways are very important for cell growth, proliferation and survival.
  • FGFR inhibitors in clinical trials that have shown clinical responses in patients with abnormal FGFR, and FGFR inhibitors have recently been approved for marketing. However, the rapid emergence of acquired resistance to FGFR inhibitors has been found in clinical trials, resulting in relatively short progression-free survival. Mutations affecting FGFR amino acids may confer resistance to or reduce the activity of FGFR inhibitors.
  • the generation of secondary FGFR kinase domain mutations in response to FGFR inhibitors is an important mechanism for acquiring resistance to FGFR inhibition.
  • Corresponding FGFR point mutations are also present in tumors.
  • Gatekeeper mutations have been reported to be one of the main mechanisms of resistance to tyrosine kinases, and FGFR-resistant mutations have been reported in in vitro cell systems and clinical experiments. Gatekeeper mutations include FGFR3V555M, FGFR2V565F/V565I/V565L, and more. A recent study reported the gatekeeper mutation of FGFR2V565F in three of BGJ398-treated cholangiocarcinoma patients, and two of them had other mutations in other FGFR2 kinase regions.
  • the series of compounds of the present invention have good activity against mutated FGFR, especially against FGFR with gatekeeper mutation, especially against FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and non-gatekeeper mutation FGFR2 N550K mutation, and are expected to develop new A first-generation FGFR inhibitor.
  • a first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X is C or N;
  • Y is CR 5 , N, NR 6 , O or S;
  • Z is CR 5 or N;
  • Ring A is a 3-12-membered nitrogen-containing heterocyclic group, and the nitrogen atom is connected to a carbonyl group;
  • R 4 is selected from vinyl or ethynyl, and the above groups are independently optionally further substituted by one or more selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, Deuterium substituted C 1-10 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C( O) R 10 , -C 0-8 alkyl-C(O)-NR 7a R 7b and -C 0-8 alkyl-NR 7a R 7b are substituted by substituents;
  • R 6 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl and 5-10 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heterocycle
  • Aryl, O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9
  • Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 11 R 12 ;
  • Each R 9 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 11 R 12 ;
  • Each R 10 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5 -10 -aryloxy, 5-10-membered heteroaryl, 5
  • R 11 and R 12 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen
  • R 11 and R 12 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group
  • the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected by one or more selected from 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 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5 -10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and Substituents of
  • n 0, 1, 2 or 3;
  • n 0, 1, 2, 3, or 4;
  • Each r is independently 0, 1, or 2.
  • R 4 , R 8 , R 9 , R 10 , R 11 , R 12 and r are as defined in the compound of formula (I).
  • the compound of formula (I) is the following compound of formula (IIa) or formula (IIb):
  • Y 1 is NR 6 , O or S
  • Y 2 is CR 5 or N
  • each Z is independently CR 5 or N;
  • Each Ring A is independently a 3-8 membered nitrogen-containing heterocyclic group, and the nitrogen atom is attached to a carbonyl group;
  • Each R 4 is each independently vinyl, and the aforementioned groups are independently optionally further substituted with one or more C 1-4 alkyl groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl , deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C (O) R 10 , -C 0-4 alkyl-C(O)-NR 7a R 7b and -C 0-4 alkyl-NR 7a R 7b substituents;
  • R 8 , R 9 , R 10 , R 11 , R 12 and r are as defined in the compound of formula (I).
  • each ring A is independently:
  • the compound of formula (I) is the compound of formula (IIIa) or formula (IIIb):
  • Y 1 is O or S
  • R 2a and R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halo-substituted C1-4 alkyl, deuterium substituted C1-4 alkyl, C 3-6 cycloalkyl, -SF 5 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 and -NR 11 R 12 ;
  • R 9 , R 10 , R 11 and R 12 are as defined in the compound of formula (I).
  • each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl and -NR 11 R 12 independently optionally further selected by one or more selected from deuterium, halogen, hydroxyl, oxo, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy , 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -Replaced by the substituent of NR 11 R 12 ;
  • Each R is independently selected from hydrogen, deuterium , C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 substituents;
  • Each R 10 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryl substituted by the substituents of oxy, 5-8-membered
  • R 11 and R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4
  • R 11 and R 12 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, 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 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5 -8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and Substitu
  • Each R 2a and R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, Di-deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, -SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.
  • the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
  • the second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
  • Rings A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , m and n are as defined for compounds of formula (I).
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of tumor patients resistant to FGFR inhibitors.
  • the tumor patient is a tumor patient with mutations in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550;
  • the tumor patient is preferred, and the tumor patient is a tumor patient with FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q mutations;
  • the tumor patient is a tumor patient with mutations in FGFR3 V555M/L and/or N540K.
  • the present invention also relates to compounds of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of disease states or disorders mediated by FGFR kinases.
  • the present invention also relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of tumors or cancers mediated by FGFR kinases.
  • 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, 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 lymphoma Lymphoma, Waldenstrom's macroglobulinemia, hair-like lymphoma, cellular lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, or rhabdomyosarcoma.
  • the present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of myeloproliferative diseases, skeletal or chondrocyte disorders, or hypophosphatemia.
  • the present invention also relates to said myeloproliferative disease selected from polycythemia, essential thrombocythemia or primary myelofibrosis; said bone or chondrocyte disorder selected from dysplasia, chondrodysplasia, dwarfism , Lethal Teratosis (TD), Appel's Syndrome, Crusson's Syndrome, Jackson-Weiss Syndrome, Beare-Stevenson's Syndrome, Pfeiffer's Syndrome or Muscular Dystrophy Syndrome; said The hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced ovarian softening.
  • the present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, for use with a selective FGFR2 and/or FGFR3 inhibitor for the treatment of and FGFR2 or Use in diseases related to abnormal expression of FGFR3 receptor, abnormal expression and abnormal activity of mutation or corresponding ligand.
  • the present invention also relates to a method of treating a patient with a tumor resistant to an FGFR inhibitor, comprising administering to a patient in need thereof a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method of treating a patient with a tumor having a mutation in FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q, comprising administering to a patient in need thereof a compound of formula (I), its A stereoisomer or a pharmaceutically acceptable salt thereof.
  • the series of compounds of the present invention have good activity against mutated FGFR, especially against FGFR with gatekeeper mutation, especially against FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and FGFR2 N550K mutations.
  • Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl,
  • C 1-10 alkyl refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups
  • C 1-4 alkyl refers to straight-chain alkyl groups including 1 to 4 carbon atoms and A branched-chain alkyl group
  • C 0-8 alkyl refers to a straight-chain alkyl group containing 0 to 8 carbon atoms and a branched alkyl group
  • C 0-4 alkyl refers to a group containing 0 to 4 carbon atoms straight-chain and branched-chain alkyl groups.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated ⁇ electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to cycloalkyl groups including 3 to 12 carbon atoms, “C 3-8 cycloalkyl” refers to cycloalkyl groups including 3 to 8 carbon atoms atomic cycloalkyl, “C 3-6 cycloalkyl” refers to a cycloalkyl group including 3 to 6 carbon atoms, "C 3-4 cyclic
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • Spiroheterocyclyl groups include, but are not limited to:
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • Aryl or “aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 5-10 or 5-8 carbons, for example, “C 5-10 aryl” refers to all-carbon aryl groups containing 5-10 carbons, “C 5-8 aryl” refers to a full carbon aryl group containing 5-8 carbons, including but not limited to phenyl and naphthyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • 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, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl” means containing 5-8 ring atoms Heteroaromatic systems of ring atoms, "5-10 membered heteroaryl” refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons
  • C 2-10 alkenyl refers to a straight-chain or branched alkenyl containing 2-10 carbons
  • C 2-4 alkenyl refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl.
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons,
  • C 2-10 alkynyl refers to a straight or branched chain alkynyl group containing 2-10 carbons
  • C 2-4 alkynyl refers to a straight or branched chain containing 2-4 carbons alkynyl.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above, eg, "C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, C 1-4 alkoxy "Oxy” refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • Cycloalkoxy refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, “C 3-12 cycloalkoxy” refers to a cycloalkyloxy group containing 3-12 carbons, “C 3-6 cycloalkoxy” refers to a cycloalkyloxy group containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Heterocyclyloxy refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, and heterocyclyloxy, including but not limited to azetidinyloxy, oxetanyloxy, nitrogen Heterocyclopentyloxy, nitrogen, oxhexyloxy, etc.
  • C 1-10 alkanoyl refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, usually also expressed as "C 0-9 -C(O)-", for example, "C 1 -C (O)-” means acetyl; “C2 - C(O)-” means propionyl; “C3 - C(O)-” means butyryl or isobutyryl.
  • -C 0-8 alkyl-C(O)R 10 means that the carbonyl group in -C(O)R 10 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
  • Halo-substituted C 1-10 alkyl refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine and iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halo-substituted C 1-10 alkoxy refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
  • Deuterium-substituted C1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to deuteromethyl, di-deuteromethyl, tri-deuteromethyl and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • PE refers to petroleum ether.
  • EtOAc refers to ethyl acetate.
  • DCM dichloromethane.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted .
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the 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, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
  • Stereoisomer its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories.
  • the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations.
  • geometric isomers also known as cis-trans isomers, which are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations.
  • the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.
  • “Pharmaceutically acceptable salts” in the present invention refer to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic and organic acid salts, which 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 physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS Methylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and 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 can be synthesized using or according to methods known in the art.
  • the first step Synthesis of 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine
  • the second step Synthesis of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine
  • the first step Synthesis of 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine
  • the second step Synthesis of 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine
  • the first step the synthesis of N-(5-bromo-2-hydroxyphenyl) cyclopropanecarboxamide
  • the second step the synthesis of 5-bromo-2-cyclopropylbenzo[d]oxazole
  • N-(5-Bromo-2-hydroxyphenyl)cyclopropanecarboxamide (1.04 g, 4.06 mmol) was dissolved in acetonitrile (30 mL), and triphenylphosphine (4.26 g, 16.2 mmol) was added successively at room temperature.
  • Carbon chloride (1.25 g, 8.1 mmol).
  • the mixture was stirred at 60°C for 1 hour, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 5-bromo-2-cyclopropylbenzoic acid.
  • Oxazole (548 mg, yield: 55%).
  • the third step Synthesis of 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole
  • the fourth step the synthesis of 2-cyclopropyl-5-ethynylbenzo[d]oxazole
  • the first step the synthesis of N-(5-bromo-2,4-difluorophenyl) cyclopropanecarboxamide
  • the second step the synthesis of N-(5-bromo-2,4-difluorophenyl) cyclopropylmethylthioamide
  • N-(5-Bromo-2,4-difluorophenyl)cyclopropanecarboxamide 1.0 g, 3.6 mmol
  • Lawson's reagent 750 mg, 1.85 mmol
  • acetonitrile 25 mL
  • the third step Synthesis of 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole
  • the fourth step the synthesis of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole
  • the first step the synthesis of N-(2,4-difluorophenyl) cyclopropanecarboxamide
  • the third step synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole
  • N-(2,4-difluorophenyl)cyclopropylmethylthioamide (1 g, 4.69 mmol) was dissolved in sodium hydroxide solution (1.69 g, 42.21 mmol, 5 mL of ethanol and 10 mL of water), and the resulting solution was added dropwise to Preheated to a K 3 Fe(CN) 6 aqueous solution (6.18 g, 18.78 mmol, 10 mL of water) at 90° C. After stirring for 2 hours, the heating was stopped immediately. After cooling, it was adjusted to weakly acidic with concentrated hydrochloric acid, and extracted with ethyl acetate.
  • the fourth step the synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carbaldehyde
  • the fifth step the synthesis of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole
  • Intermediate 12 is prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 11:
  • the first step the synthesis of 2-amino-4-bromo-5-fluorophenol
  • the second step the synthesis of 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione
  • the third step Synthesis of 5-bromo-2-chloro-6-fluorobenzo[d]oxazole
  • the fourth step the synthesis of 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine
  • the fifth step the synthesis of 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine
  • the first step synthesis of 2-amino-3,5-difluorophenol
  • the third step synthesis of 2-chloro-4,6-difluorobenzo[d]oxazole
  • the fourth step the synthesis of 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole
  • the fifth step the synthesis of 2-(azetidine-1-yl)-4,6-difluorobenzo[d]oxazole-5-carbaldehyde
  • the sixth step the synthesis of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole
  • the first step Synthesis of diethyl(2E,4E,6E)-3,6-dicyano-2,7-dihydroxyoctane-2,4,6-trienedioate
  • the second step the synthesis of ethyl 3-cyano-1H-pyrrole-2-carboxylate
  • the third step synthesis of ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-1H-pyrrole-2-carboxylate
  • the fourth step ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-4-iodo-1H-pyrrole-2-carboxylate synthesis
  • Step 7 (S)-1-(1-Acryloylpyrrolidin-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridine Synthesis of oxazin-7-ones
  • Embodiment 2 ⁇ 18 selects corresponding raw material to prepare with reference to all or part of the synthetic method of embodiment 1:
  • the compounds of the examples of the present invention are used to stably express the TEL-FGFR2WT intracellular kinase domain fusion protein by transfection in Baf cells, or the intracellular domain fusion protein containing FGFR2 V564I, V564F, V564L, N549K, K659M mutations
  • the cell lines were used to measure the proliferation effect of Baf3-Tel-FGFR2WT and various mutant FGFR2 cells.
  • the specific test process is as follows:
  • CCG CellTiter Glo
  • the compounds of the examples of the present invention were used to stably express TEL-FGFR3WT intracellular kinase domain fusion protein by transfection in Baf cells, or a cell line containing FGFR3V555M or FGFR3N540K mutant intracellular domain fusion protein to measure cell proliferation Effect.
  • the specific test process is as follows:
  • CCG CellTiter Glo
  • the series of compounds of the present invention have strong inhibitory effects on both the wild-type FGFR and the mutant FGFR at the cellular level, and the inhibitory effect in the mutation is not weakened.

Abstract

A dihydropyrrolo[2,3-d]pyridazin-7-one derivative having the structure of formula (I), a preparation method therefor, a pharmaceutical composition containing same, as well as a use thereof as an FGFR and mutation inhibitor, and a use thereof in the preparation of a drug for treating and/or preventing a tumor or cancer at least partly mediated by an FGFR kinase and a tumor in a patient having resistance to an FGFR inhibitor, and especially in the preparation of a drug for treating and/or preventing a tumor in a patient having a mutation in V561, V565, N550, N540, V555, E566, K660, and/or V550 on an FGFR signaling pathway. The substituents in formula (I) have the same definitions as those in the description.

Description

二氢吡咯并[2,3-d]哒嗪-7-酮衍生物，其制备方法和应用Dihydropyrrolo[2,3-d]pyridazin-7-one derivatives, preparation methods and uses thereof 技术领域technical field
本发明属于药物合成领域，具体涉及一种二氢吡咯并[2,3-d]哒嗪-7-酮衍生物，其制备方法和应用。The invention belongs to the field of pharmaceutical synthesis, in particular to a dihydropyrrolo[2,3-d]pyridazin-7-one derivative, a preparation method and application thereof.
背景技术Background technique
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。成纤维细胞生长因子(FGF)信号通路被认为在很多过程中起着重要的作用，比如胚胎生成，组织分化，伤口愈合，代谢调节，也被认为和很多肿瘤的特征强相关。当FGF和其受体相结合时，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. Four FGFR receptors have been found to bind ligands. The fibroblast growth factor (FGF) signaling pathway is thought to play an important role in many processes, such as embryogenesis, tissue differentiation, wound healing, and metabolic regulation, and is also thought to be strongly associated with many tumor characteristics. When FGF binds to its receptor, the receptor dimerizes and phosphorylates, stimulates the activation of protein kinase activity, and helps activate a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphorylation Esterase C These signaling pathways are very important for cell growth, proliferation and survival.
在FGFR家族成员中的基因变化通常和肿瘤的生长，转移，血管生成以及存活相关。有很多FGFR抑制剂在临床实验中，在有FGFR异常的病人中表现出了临床上的响应，最近也有FGFR抑制剂获批上市。但是，在临床实验中发现，有获得性的对FGFR抑制剂的抗性的迅速出现，使得无进展的生存期相对较短。影响FGFR氨基酸的突变，可能会引起对FGFR抑制剂的抗性或者使FGFR抑制剂的活性降低。在FGFR抑制剂的作用下产生次生的FGFR激酶结构域突变是获得对FGFR抑制抗性的重要机制。相对应的FGFR点突变也在肿瘤中存在。守门突变被报道是对于酪氨酸激酶产生抗性的主要机制之一，FGFR有抗性的突变在体外细胞***和临床实验中均有报道。守门突变包括FGFR3V555M，FGFR2V565F/V565I/V565L等等。最近的研究报道了在BGJ398治疗的胆管癌患者中有三位都发现了FGFR2V565F的守门突变，其中两位还有其他FGFR2激酶区域其他突变的发生。因此，为了突破在临床上对于一代FGFR抑制剂治疗产生的获得性的抗性，目前临床上急需新一代FGFR抑制剂能在具有FGFR信号通路中基因突变的肿瘤中具有更为持久的活性。而这样的二代的FGFR抑制剂需要能在维持对FGFR抑制活性的同时，对那些一代抑制剂活性减弱的守门突变也能维持同样的活性。Genetic changes in FGFR family members are often associated with tumor growth, metastasis, angiogenesis, and survival. There are many FGFR inhibitors in clinical trials that have shown clinical responses in patients with abnormal FGFR, and FGFR inhibitors have recently been approved for marketing. However, the rapid emergence of acquired resistance to FGFR inhibitors has been found in clinical trials, resulting in relatively short progression-free survival. Mutations affecting FGFR amino acids may confer resistance to or reduce the activity of FGFR inhibitors. The generation of secondary FGFR kinase domain mutations in response to FGFR inhibitors is an important mechanism for acquiring resistance to FGFR inhibition. Corresponding FGFR point mutations are also present in tumors. Gatekeeper mutations have been reported to be one of the main mechanisms of resistance to tyrosine kinases, and FGFR-resistant mutations have been reported in in vitro cell systems and clinical experiments. Gatekeeper mutations include FGFR3V555M, FGFR2V565F/V565I/V565L, and more. A recent study reported the gatekeeper mutation of FGFR2V565F in three of BGJ398-treated cholangiocarcinoma patients, and two of them had other mutations in other FGFR2 kinase regions. Therefore, in order to break through the acquired resistance to the first-generation FGFR inhibitor treatment in the clinic, there is an urgent need for a new generation of FGFR inhibitors that can have more durable activity in tumors with gene mutations in the FGFR signaling pathway. Such second-generation FGFR inhibitors need to be able to maintain the same activity against gatekeeper mutations that have weakened the activity of the first-generation inhibitors while maintaining the inhibitory activity against FGFR.
发明内容SUMMARY OF THE INVENTION
本申请的发明人经过广泛而深入地研究，首次研发出一种二氢吡咯并[2,3-d]哒嗪-7-酮衍生物，其制备方法和应用。本发明系列化合物针对突变的FGFR，特别是针对具有守门突变的FGFR，特别是针对FGFR3 V555M，FGFR2 V565I，FGFR2 V565F，FGFR2 V565L以及非守门突变的FGFR2 N550K突变具有很好的活性，有望开发出新一代FGFR抑制剂。After extensive and in-depth research, the inventors of the present application have developed a dihydropyrrolo[2,3-d]pyridazin-7-one derivative, its preparation method and application for the first time. The series of compounds of the present invention have good activity against mutated FGFR, especially against FGFR with gatekeeper mutation, especially against FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and non-gatekeeper mutation FGFR2 N550K mutation, and are expected to develop new A first-generation FGFR inhibitor.
本发明第一方面提供一种式(I)化合物、其立体异构体或其药学上可接受盐：A first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021114580-appb-000001
Figure PCTCN2021114580-appb-000001
其中，
Figure PCTCN2021114580-appb-000002
是单键或双键； in,
Figure PCTCN2021114580-appb-000002
is a single or double bond;
X为C或N；Y为CR 5、N、NR 6、O或S；Z为CR 5或N； X is C or N; Y is CR 5 , N, NR 6 , O or S; Z is CR 5 or N;
环A为3-12元含氮杂环基，所述氮原子与羰基连接；Ring A is a 3-12-membered nitrogen-containing heterocyclic group, and the nitrogen atom is connected to a carbonyl group;
R 1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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代； R 1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl , 3-12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl- OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 ) -C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 , the above-mentioned groups The group is optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O) OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0- 8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituents are substituted;
每个R 2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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10； Each R2 is independently selected from hydrogen , deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0 -8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl -C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
每个R 3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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0 -8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl -C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
R 4选自乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、氰基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-8环烷基、3-8元杂环基、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-C(O)-NR 7aR 7b和-C 0-8烷基-NR 7aR 7b的取代基所 取代； R 4 is selected from vinyl or ethynyl, and the above groups are independently optionally further substituted by one or more selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, Deuterium substituted C 1-10 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C( O) R 10 , -C 0-8 alkyl-C(O)-NR 7a R 7b and -C 0-8 alkyl-NR 7a R 7b are substituted by substituents;
每个R 5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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10； Each R 5 is independently selected from hydrogen, 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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0 -8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl -C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
R 6选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 5-10芳基和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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代； R 6 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl and 5-10 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heterocycle Aryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkane base-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl- C(O)NR 11 R 12 and the substituents of -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
R 7a和R 7b各自独立地选自氢、氘、羟基、C 1-10烷基、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-C(＝NR 11)R 10和-C 0-8烷基-C(O)NR 11R 12，或者，R 7a和R 7b与其直接相连的氮原子一起形成一个4-10元杂环基，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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O) R 10 , -C 0-8 alkyl-C(=NR 11 )R 10 and -C 0-8 alkyl-C(O)NR 11 R 12 , or, alternatively, the nitrogen atom to which R 7a and R 7b are directly attached together form a 4-10 membered heterocyclic group, the above-mentioned groups are optionally further substituted by one or more C 1- 10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl base, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0- 8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , - C 0-8 alkyl-C(O)NR 11 R 12 and the substituents of -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
每个R 8各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基和-NR 11R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 11 R 12 ;
每个R 9各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 5-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12的取代基所取代； Each R 9 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 11 R 12 ;
每个R 10各自独立地选自氢、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 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12，上述基团独立地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 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 11 R 12 substituents;
每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12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C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基，上述基团独立地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 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12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C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Each of R 11 and R 12 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl groups, independently optionally further selected by one or more From 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 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5- Substitution of 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl base substituted;
或者，R 11和R 12与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基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 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12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C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 11 and R 12 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected by one or more selected from 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 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5 -10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and Substituents of C 1-10 alkanoyl groups are substituted;
m为0、1、2或3；m is 0, 1, 2 or 3;
n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and
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，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-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 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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10的取代基所取代； As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 Alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C (=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 , the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0 -4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 substituents;
每个R 2各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10； Each R 2 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0- 4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(= NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0- 4 alkyl-N(R 11 )-C(O)R 10 ;
每个R 3各自独立地选自氢、氘、卤素、氰基、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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10； Each R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, Deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl -C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 ) R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl -N(R 11 )-C(O)R 10 ;
每个R 5各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10； Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0- 4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(= NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0- 4 alkyl-N(R 11 )-C(O)R 10 ;
R 6选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基和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、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10的取代基所取代； R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl and 5-8 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heterocyclyl Aryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkane base-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl- C(O)NR 11 R 12 and the substituents of -C 0-4 alkyl-N(R 11 )-C(O)R 10 ;
R 7a和R 7b各自独立地选自氢、氘、羟基、C 1-4烷基、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-C(＝NR 11)R 10和-C 0-4烷基-C(O)NR 11R 12，或者，R 7a和R 7b与其直接相连的氮原子一起形成一个4-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C(O) R 10 , -C 0-4 alkyl-C(=NR 11 )R 10 and -C 0-4 alkyl-C(O)NR 11 R 12 , or, alternatively, the nitrogen atom to which R 7a and R 7b are directly attached together form a 4-8 membered heterocyclic group, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heterocycle Aryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkane base-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl- C(O)NR 11 R 12 and the substituents of -C 0-4 alkyl-N(R 11 )-C(O)R 10 ;
其中，R 4、R 8、R 9、R 10、R 11、R 12和r如式(I)化合物中所定义。 wherein R 4 , R 8 , R 9 , R 10 , R 11 , R 12 and r are as defined in the compound of formula (I).
作为进一步优选的方案，式(I)化合物为如下式(Ⅱa)或式(Ⅱb)化合物：As a further preferred solution, the compound of formula (I) is the following compound of formula (IIa) or formula (IIb):
Figure PCTCN2021114580-appb-000003
Figure PCTCN2021114580-appb-000003
其中，在式(Ⅱa)化合物中，Y 1为NR 6、O或S；在式(Ⅱb)化合物中，Y 2为CR 5或N； Wherein, in the compound of formula (IIa), Y 1 is NR 6 , O or S; in the compound of formula (IIb), Y 2 is CR 5 or N;
每个Z各自独立地为CR 5或N； each Z is independently CR 5 or N;
每个环A各自独立地为3-8元含氮杂环基，所述氮原子与羰基连接；Each Ring A is independently a 3-8 membered nitrogen-containing heterocyclic group, and the nitrogen atom is attached to a carbonyl group;
每个R 1各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、 -C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-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 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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10的取代基所取代； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O ) R 10 , the above-mentioned groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, =O, - SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(= Substituents substituted by NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;
每个R 2a和R 2b各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10； Each of R 2a and R 2b is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C (O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 ) R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;
每个R 4各自独立地为乙烯基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、氰基、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、3-6元杂环基、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-C(O)-NR 7aR 7b和-C 0-4烷基-NR 7aR 7b的取代基所取代； Each R 4 is each independently vinyl, and the aforementioned groups are independently optionally further substituted with one or more C 1-4 alkyl groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl , deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C (O) R 10 , -C 0-4 alkyl-C(O)-NR 7a R 7b and -C 0-4 alkyl-NR 7a R 7b substituents;
每个R 5各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10； Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O) OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;
R 6选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基和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、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10的取代基所取代； R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl and 5-8 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heterocyclyl Aryl, =O, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O) Replaced by the substituent of R 10 ;
每个R 7a和R 7b各自独立地选自氢、氘、羟基、C 1-4烷基、-C(O)OR 9、-C(O)R 10、-C(＝NR 11)R 10和-C(O)NR 11R 12，或者，R 7a和R 7b与其直接相连的氮原子一起各自独立地形成一个4-6元杂环基，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、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10的取代基所取代； Each of R 7a and R 7b is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, -C(O)OR 9 , -C(O)R 10 , -C(=NR 11 )R 10 and -C(O)NR 11 R 12 , alternatively, R 7a and R 7b together with the nitrogen atom to which they are directly attached each independently form a 4-6 membered heterocyclic group optionally further selected by one or more From deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC (O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N (R 11 )-C(O) R 10 is substituted by the substituent;
其中，R 8、R 9、R 10、R 11、R 12和r如式(I)化合物中所定义。 wherein R 8 , R 9 , R 10 , R 11 , R 12 and r are as defined in the compound of formula (I).
作为更进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个环A各自独立地为：
Figure PCTCN2021114580-appb-000004
As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each ring A is independently:
Figure PCTCN2021114580-appb-000004
作为更进一步优选的方案，式(I)化合物为下式(Ⅲa)或式(Ⅲb)化合物：As a further preferred scheme, the compound of formula (I) is the compound of formula (IIIa) or formula (IIIb):
Figure PCTCN2021114580-appb-000005
Figure PCTCN2021114580-appb-000005
其中，在式(Ⅲa)化合物中，Y 1为O或S； Wherein, in the compound of formula (IIIa), Y 1 is O or S;
每个R 1各自独立地选自氢、氘、卤素、氰基、甲基、C 3-4环烷基、3-4元杂环基、-SF 5、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10和-NR 11R 12，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、C 1-2烷基、卤取代C 1-2烷基、氘取代C 1-2烷基、C 3-6环烷基、3-6元杂环基、＝O、-SF 5、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10和-NR 11R 12的取代基所取代； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl, C 3-4 cycloalkyl, 3-4 membered heterocyclyl, -SF 5 , -OR 9 , -C(O) OR 9 , -C(O)R 10 , -OC(O)R 10 and -NR 11 R 12 , the above-mentioned groups are optionally further selected by one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, C 1-2 alkyl, halogen-substituted C 1-2 alkyl, deuterium-substituted C 1-2 alkyl, C 3-6 cycloalkyl, 3-6-membered heterocyclyl, =O, -SF 5 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 and -NR 11 R 12 are substituted with substituents;
每个R 2a和R 2b各自独立地选自氢、氘、氟、氯、溴、氰基、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、-SF 5、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10和-NR 11R 12； Each of R 2a and R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halo-substituted C1-4 alkyl, deuterium substituted C1-4 alkyl, C 3-6 cycloalkyl, -SF 5 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 and -NR 11 R 12 ;
其中，R 9、R 10、R 11和R 12如式(I)化合物中所定义。 wherein R 9 , R 10 , R 11 and R 12 are as defined in the compound of formula (I).
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个R 8独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基和-NR 11R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12的取代基所取代； As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl and -NR 11 R 12 independently optionally further selected by one or more selected from deuterium, halogen, hydroxyl, oxo, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy , 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -Replaced by the substituent of NR 11 R 12 ;
每个R 9独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、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、3-6元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12的取代基所取代； Each R is independently selected from hydrogen, deuterium , C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 substituents;
每个R 10选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、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、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12，上述基团独立地任选进一步被一个或多个选自氘、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、3-6元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12的取代基所取代； Each R 10 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryl substituted by the substituents of oxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 ;
每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8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C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、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 1-4烷氧基、 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、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each of R 11 and R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, 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 1 -4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5- Substitution of 8 -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl base substituted;
或者，R 11和R 12与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、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 1-4烷氧基、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、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 11 and R 12 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, 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 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5 -8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and Substituents of C 1-4 alkanoyl.
作为更进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个R 1各自独立地选自氢、氘、卤素、氰基、甲基、乙基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、-SF 5、甲氧基、乙氧基、羧基、乙酰基、乙酰氧基、氨基、甲氨基和二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、＝O、-SF 5、甲氧基、乙氧基、羧基、乙酰基、乙酰氧基、氨基、甲氨基和二甲氨基的取代基所取代； As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl , ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, -SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and Dimethylamino, the above-mentioned groups are optionally further selected by one or more groups selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, propyl, cyclobutyl, oxetanyl, azetidine, =O, -SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethyl Substituted by amino substituent;
每个R 2a和R 2b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、-SF 5、甲氧基、乙氧基、羧基、乙酰基、乙酰氧基、氨基、甲氨基和二甲氨基。 Each R 2a and R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, Di-deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, -SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.
作为最优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐包括但不限于如下化合物：As the most preferred solution, the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
Figure PCTCN2021114580-appb-000006
Figure PCTCN2021114580-appb-000006
Figure PCTCN2021114580-appb-000007
Figure PCTCN2021114580-appb-000007
本发明第二方面提供式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：The second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
Figure PCTCN2021114580-appb-000008
Figure PCTCN2021114580-appb-000008
或者，or,
Figure PCTCN2021114580-appb-000009
Figure PCTCN2021114580-appb-000009
其中，环A、X、Y、Z、R 1、R 2、R 3、R 4、m和n如式(I)化合物中所定义。 wherein Rings A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , m and n are as defined for compounds of formula (I).
本发明第三方面提供一种药物组合物，其包括式(I)化合物、其立体异构体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 a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐在制备用于治疗对FGFR抑制剂具有耐受性的肿瘤患者的药物中的应用。The present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of tumor patients resistant to FGFR inhibitors.
作为优选的方案，所述肿瘤患者为在FGFR V561、V565、N550、N540、V555、E566、K660和/或V550具有突变的肿瘤患者；As a preferred solution, the tumor patient is a tumor patient with mutations in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550;
作为进一步优选的方案，所述肿瘤患者为优选的，所述肿瘤患者为在具有FGFR2 V565F、V565I、V565L、V565M、N550K、N550H、E566A、E566G、K660M和/或K660Q突变的肿瘤患者；As a further preferred solution, the tumor patient is preferred, and the tumor patient is a tumor patient with FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q mutations;
作为更进一步优选的方案，所述肿瘤患者为具有在FGFR3 V555M/L和/或N540K突变的肿瘤患者。As a further preferred solution, the tumor patient is a tumor patient with mutations in FGFR3 V555M/L and/or N540K.
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐，其用于预防或治疗由FGFR激酶介导的疾病状态或病症。The present invention also relates to compounds of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of disease states or disorders mediated by FGFR kinases.
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐，其用于预防或治疗由FGFR激酶介导的肿瘤或癌症。The present invention also relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of tumors or cancers mediated by FGFR kinases.
作为优选的方案，所述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, 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 lymphoma Lymphoma, Waldenstrom's macroglobulinemia, hair-like lymphoma, cellular lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, or rhabdomyosarcoma.
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐在制备用于治疗骨髓增生性疾病、骨骼或软骨细胞紊乱、或低磷血症的药物中的应用。The present invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of myeloproliferative diseases, skeletal or chondrocyte disorders, or hypophosphatemia.
本发明还涉及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)、阿佩尔氏综合症、克鲁松氏综合症、Jackson-Weiss综合症、Beare-Stevenson皮肤回纹综合症、Pfeiffer综合症或颅肌萎缩综合症；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 present invention also relates to said myeloproliferative disease selected from polycythemia, essential thrombocythemia or primary myelofibrosis; said bone or chondrocyte disorder selected from dysplasia, chondrodysplasia, dwarfism , Lethal Teratosis (TD), Appel's Syndrome, Crusson's Syndrome, Jackson-Weiss Syndrome, Beare-Stevenson's Syndrome, Pfeiffer's Syndrome or Muscular Dystrophy Syndrome; said The hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, or tumor-induced ovarian softening.
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐，或根前述药物组合物，其用于选择性的FGFR 2和/或FGFR 3抑制剂来治疗和FGFR2或FGFR3受体异常表达，突变或相应配体异常表达及活性异常相关的疾病的用途。The present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, for use with a selective FGFR2 and/or FGFR3 inhibitor for the treatment of and FGFR2 or Use in diseases related to abnormal expression of FGFR3 receptor, abnormal expression and abnormal activity of mutation or corresponding ligand.
本发明还涉及一种治疗FGFR抑制剂具有耐受性的肿瘤患者的方法，包括对需要的患者施用式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method of treating a patient with a tumor resistant to an FGFR inhibitor, comprising administering to a patient in need thereof a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
本发明还涉及一种治疗FGFR2 V565F、V565I、V565L、V565M、N550K、N550H、E566A、E566G、K660M和/或K660Q具有突变的肿瘤患者的方法，包括对需要的患者施用式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method of treating a patient with a tumor having a mutation in FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q, comprising administering to a patient in need thereof a compound of formula (I), its A stereoisomer or a pharmaceutically acceptable salt thereof.
具体实施方式detailed description
本申请的发明人经过广泛而深入地研究，首次研发出一种二氢吡咯并[2,3-d]哒嗪-7-酮衍生物，其制备方法和应用。本发明系列化合物针对突变的FGFR，特别是针对具有守门突变的FGFR，特别是针对FGFR3 V555M，FGFR2 V565I，FGFR2 V565F，FGFR2 V565L以及FGFR2 N550K突变具有很好的活性。After extensive and in-depth research, the inventors of the present application have developed a dihydropyrrolo[2,3-d]pyridazin-7-one derivative, its preparation method and application for the first time. The series of compounds of the present invention have good activity against mutated FGFR, especially against FGFR with gatekeeper mutation, especially against FGFR3 V555M, FGFR2 V565I, FGFR2 V565F, FGFR2 V565L and FGFR2 N550K mutations.
详细说明：除非有相反陈述或特别说明，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 or specifically stated, 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，优选包括1至10个或1至6个碳原子或1至4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。“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，“C 1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基，“C 0-8烷基”指包括0至8个碳原子的直链烷基和含支链烷基，“C 0-4烷基”指包括0至4个碳原子的直链烷基和含支链烷基。 "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl base, 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-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. "C 1-10 alkyl" refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups, "C 1-4 alkyl" refers to straight-chain alkyl groups including 1 to 4 carbon atoms and A branched-chain alkyl group, "C 0-8 alkyl" refers to a straight-chain alkyl group containing 0 to 8 carbon atoms and a branched alkyl group, "C 0-4 alkyl" refers to a group containing 0 to 4 carbon atoms straight-chain and branched-chain alkyl groups.
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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8 烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 Alkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, 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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0 -8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N(R 11 ) Substituents of -C(O)R 10 are substituted.
“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃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***，环烷基分为单环环烷基、多环环烷基，优选包括3至12个或3至8个或3至6个碳原子的环烷基，例如，“C 3-12环烷基”指包括3至12个碳原子的环烷基，“C 3-8环烷基”指包括3至8个碳原子的环烷基，“C 3-6环烷基”指包括3至6个碳原子的环烷基，“C 3-4环烷基”指包括3至4个碳原子的环烷基，其中： "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl" refers to cycloalkyl groups including 3 to 12 carbon atoms, "C 3-8 cycloalkyl" refers to cycloalkyl groups including 3 to 8 carbon atoms atomic cycloalkyl, "C 3-6 cycloalkyl" refers to a cycloalkyl group including 3 to 6 carbon atoms, "C 3-4 cycloalkyl" refers to a cycloalkyl group including 3 to 4 carbon atoms, in:
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 groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
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、双螺环烷基或多螺环烷基，螺环烷基包括但不限于：Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
Figure PCTCN2021114580-appb-000010
Figure PCTCN2021114580-appb-000010
“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 an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
Figure PCTCN2021114580-appb-000011
Figure PCTCN2021114580-appb-000011
“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 an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
Figure PCTCN2021114580-appb-000012
Figure PCTCN2021114580-appb-000012
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 can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O) R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituent.
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃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***，杂环基其中一个或多个(优选1、2、3或4个)环原子选自氮、氧、S(O)(＝NH)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，优选包括3至12个或3至8个或3至6个环原子的杂环基，例如，“3-8元杂环基”指包含3至8个环原子的环基，“3-6元杂环基”指包含3至6个环原子的环基，“3-4元杂环基”指包含3至4个环原子的环基，“4-6元杂环基”指包含4至6个环原子的环基，“4-10元杂环基”指包含4至10个环原子的环基，“4-8元杂环基”指包含4至8个环原子的环基，“3-12元杂环基”指包含3至12个环原子的环基。 "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, heterocyclyl wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O ) (=NH) or S(O) r (where r is an integer 0, 1, 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon, Heterocyclyl groups including 3 to 12 or 3 to 8 or 3 to 6 ring atoms are preferred, for example, "3-8 membered heterocyclyl" refers to a ring group containing 3 to 8 ring atoms, "3-6 "Membered heterocyclyl" refers to a ring group containing 3 to 6 ring atoms, "3-4 membered heterocyclyl" refers to a ring group containing 3 to 4 ring atoms, and "4-6 membered heterocyclyl" refers to a ring group containing 4 A ring group of up to 6 ring atoms, "4-10 membered heterocyclyl" refers to a ring group containing 4 to 10 ring atoms, and "4-8 membered heterocyclyl" refers to a ring group containing 4 to 8 ring atoms , "3-12 membered heterocyclyl" refers to a ring group containing 3 to 12 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 heterocyclyl groups 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、S(O)(＝NH)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(优选1、2或3个)，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 heterocyclyls include spiro, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen , S(O)(=NH) or S(O) r (where r is an integer 0, 1, 2) heteroatoms and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system. Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings. Spiroheterocyclyl groups include, but are not limited to:
Figure PCTCN2021114580-appb-000013
Figure PCTCN2021114580-appb-000013
“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、S(O)(＝NH)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 heterocyclic group" refers to a polycyclic heterocyclic group in which 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 be contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from Heteroatoms of nitrogen, oxygen, S(O)(=NH) or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:
Figure PCTCN2021114580-appb-000014
Figure PCTCN2021114580-appb-000014
“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、S(O)(＝NH)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 none of the rings have a fully conjugated pi electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S(O)(=NH) or S(O) r (where r are heteroatoms of integers 0, 1, 2), and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:
Figure PCTCN2021114580-appb-000015
Figure PCTCN2021114580-appb-000015
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 heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
Figure PCTCN2021114580-appb-000016
Figure PCTCN2021114580-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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O) R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituent.
“芳基”或“芳环”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，优选含有5-10个或5-8个碳的全碳芳基，例如，“C 5-10芳基”指含有5-10个碳的全碳芳基，“C 5-8芳基”指含有5-8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" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 5-10 or 5-8 carbons, for example, "C 5-10 aryl" refers to all-carbon aryl groups containing 5-10 carbons, "C 5-8 aryl" refers to a full carbon aryl group containing 5-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
Figure PCTCN2021114580-appb-000017
Figure PCTCN2021114580-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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 "Aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, 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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0 -8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N(R 11 ) Substituents of -C(O)R 10 are substituted.
“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，优选含有5-10个或5-8个或5-6个环原子的杂芳族体系，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, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered heteroaryl" means containing 5-8 ring atoms Heteroaromatic systems of ring atoms, "5-10 membered heteroaryl" refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
Figure PCTCN2021114580-appb-000018
Figure PCTCN2021114580-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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 "Heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C( O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N( R 11 )-C(O)R 10 is substituted with the substituent.
“链烯基”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，优选含有2-10个或2-4个碳的直链或含支链烯基，例如，“C 2-10链烯基”指含有2-10个碳的直链或含支链烯基，“C 2-4链烯基”指含有2-4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" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons For example, "C 2-10 alkenyl" refers to a straight-chain or branched alkenyl containing 2-10 carbons, and "C 2-4 alkenyl" refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
“链烯基”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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 "Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O) R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituent.
“链炔基”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，优选含有2-10个或2-4个碳的直链或含支链炔基，例如，“C 2-10链炔基”指含有2-10个碳的直链或含支链炔基，“C 2-4链炔基”指含有2-4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" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons, For example, "C 2-10 alkynyl" refers to a straight or branched chain alkynyl group containing 2-10 carbons, and "C 2-4 alkynyl" refers to a straight or branched chain containing 2-4 carbons alkynyl. Including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
“链炔基”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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 "Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O) R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N(R 11 )-C(O)R 10 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，C 1-4烷氧基”指含1-4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, eg, "C 1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbons, C 1-4 alkoxy "Oxy" refers to an alkyloxy group containing 1-4 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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 "Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from 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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C (O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N (R 11 )-C(O)R 10 is substituted with a substituent.
“环烷氧基”指-O-环烷基，其中环烷基的定义如上所述，例如，“C 3-12环烷氧基”指含3-12个碳的环烷基氧基，“C 3-6环烷氧基”指含3-6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-cycloalkyl, where cycloalkyl is as defined above, for example, "C 3-12 cycloalkoxy" refers to a cycloalkyloxy group containing 3-12 carbons, "C 3-6 cycloalkoxy" refers to a cycloalkyloxy group containing 3-6 carbons, including but 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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基 -N(R 11)-C(O)R 10的取代基所取代。 "Cycloalkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from 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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C (O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N (R 11 )-C(O)R 10 is substituted with a substituent.
“杂环氧基”指-O-杂环基，其中杂环基的定义如上所述，杂环基氧基，包括但不限于氮杂环丁基氧基、氧杂环丁氧基、氮杂环戊基氧基、氮、氧杂环己基氧基等。"Heterocyclyloxy" refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, and heterocyclyloxy, including but not limited to azetidinyloxy, oxetanyloxy, nitrogen Heterocyclopentyloxy, nitrogen, oxhexyloxy, etc.
“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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12或-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代。 "Heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from 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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C (O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 or -C 0-8 alkyl-N (R 11 )-C(O)R 10 is substituted with a substituent.
“C 1-10烷酰基”指C 1-10烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-9-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 1-10 alkanoyl" refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, usually also expressed as "C 0-9 -C(O)-", for example, "C 1 -C (O)-" means acetyl; "C2 - C(O)-" means propionyl; "C3 - C(O)-" means butyryl or isobutyryl.
“-C 0-8烷基-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 0-8烷基的定义如上所述。 "-C 0-8 alkyl-S(O) r R 8 " means that the sulfur atom in -S(O) r R 8 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above said.
“-C 0-8烷基-O-R 9”指-O-R 9中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-OR 9 " means that the oxygen atom in -OR 9 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8烷基-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 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)OR 9 " means that the carbonyl group in -C(O)OR 9 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8烷基-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 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)R 10 " means that the carbonyl group in -C(O)R 10 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined 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 0-8烷基的定义如上所述。 "-C 0-8 -OC(O)R 10 " means that the oxygen atom in -OC(O)R 10 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined 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 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, wherein the C 1-8 alkyl group is as defined above.
“-C 0-8-C(＝NR 11)R 10”指-C(＝NR 11)R 10中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -C(=NR 11 )R 10 " means that the nitrogen atom in -C(=NR 11 )R 10 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above said.
“-C 0-8-N(R 11)-C(＝NR 12)R 10”指-N(R 11)-C(＝NR 12)R 10中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -N(R 11 )-C(=NR 12 )R 10 " means that the nitrogen atom in -N(R 11 )-C(=NR 12 )R 10 is attached to a C 0-8 alkyl group above, wherein Co- 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 0-8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, wherein the C 0-8 alkyl group is as defined above described.
“-C 0-8-N(R 11)-C(O)R 10”指-N(R 11)-C(O)R 10中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -N(R 11 )-C(O)R 10 " means that the nitrogen atom in -N(R 11 )-C(O)R 10 is attached to the C 0-8 alkyl group, wherein C 0-8 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 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine and iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
“卤取代C 1-10烷氧基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷氧基团。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。 "Halo-substituted C 1-10 alkoxy" refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
“氘取代C 1-10烷基”指烷基上的氢任选的被氘原子取代的1-10个碳烷基团。包括但不限 于一氘甲基、二氘甲基、三氘甲基等。 "Deuterium-substituted C1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to deuteromethyl, di-deuteromethyl, tri-deuteromethyl and the like.
“卤素”指氟、氯、溴或碘。“PE”指石油醚。“EtOAc”指乙酸乙酯。“DCM”指二氯甲烷。"Halogen" refers to fluorine, chlorine, bromine or iodine. "PE" refers to petroleum ether. "EtOAc" refers to ethyl acetate. "DCM" refers to dichloromethane.
“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，也即包括取代的或未取代的两种情形。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 subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted . For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the 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，符合化学上的价键理论，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, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
“立体异构体”，其英文名称为stereoisomer，是指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer)，有时也称为旋转异构体(rotamer)。因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer)，构型异构体又分为两类。其中因双键或成环碳原子的单键不能自由旋转而引起的异构体成为几何异构体(geometric isomer)，也称为顺反异构体(cis-trans isomer)，分为Z、E两种构型。例如：顺-2-丁烯和反-2-丁烯是一对几何异构体，因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体称为旋光异构体(optical isomer)，分为R、S构型。在本发明中所述“立体异构体”如未特别指明，可理解为包含上述对映异构体、构型异构体和构象异构体中的一种或几种。"Stereoisomer", its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations. In the present invention, the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.
“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或碱加成盐，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 salts" in the present invention refer to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic and organic acid salts, which 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 physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert 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 present invention will be further described in detail and completely below in conjunction with the examples, but the present invention is by no means limited, and the present invention is not limited to the contents 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 structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four 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)。An Agilent 6120 mass spectrometer was used for LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).
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 used for TLC are 0.15mm ~ 0.20mm, and the specifications used for TLC separation and 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 can be synthesized using or 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 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 is in degrees Celsius (°C).
一、中间体的制备1. Preparation of intermediates
中间体1：2-环丙基-7-乙炔基-6,8-二氟咪唑并[1,2-a]吡啶的制备Intermediate 1: Preparation of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine
Figure PCTCN2021114580-appb-000019
Figure PCTCN2021114580-appb-000019
第一步：2-环丙基-6,8-二氟-7-碘咪唑并[1,2-a]吡啶的合成The first step: Synthesis of 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine
Figure PCTCN2021114580-appb-000020
Figure PCTCN2021114580-appb-000020
将3,5-二氟-4-碘吡啶-2-胺(1.0g，4.0mmol)溶于DMF(10mL)中，加入2-溴-1-环丙基乙烷-1-酮(0.98g，6.0mmol)。混合物在60℃下搅拌16小时。冷却到室温，然后过滤得到2-环丙基-6,8-二氟-7-碘咪唑并[1,2-a]吡啶(640mg，收率：50％)。MS m/z(ESI):321[M+H] +。 3,5-Difluoro-4-iodopyridin-2-amine (1.0 g, 4.0 mmol) was dissolved in DMF (10 mL), 2-bromo-1-cyclopropylethane-1-one (0.98 g) was added , 6.0 mmol). The mixture was stirred at 60°C for 16 hours. It was cooled to room temperature and then filtered to give 2-cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine (640 mg, yield: 50%). MS m/z (ESI): 321 [M+H] + .
第二步：2-环丙基-7-乙炔基-6,8-二氟咪唑并[1,2-a]吡啶的合成The second step: Synthesis of 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine
Figure PCTCN2021114580-appb-000021
Figure PCTCN2021114580-appb-000021
将2-环丙基-6,8-二氟-7-碘咪唑并[1,2-a]吡啶(320mg，1.0mmol)溶于DMF(5mL)中，加入三丁基(乙炔基)锡烷(472mg，1.5mmol)和四三苯基膦钯(115.5mg，0.1mmol)。混合物微波130℃下搅拌1小时。冷却到室温，浓缩后柱层析分离得到2-环丙基-7-乙炔基-6,8-二氟咪唑并[1,2-a]吡啶(120mg，收率：55％)。MS m/z(ESI):219[M+H] +。 2-Cyclopropyl-6,8-difluoro-7-iodoimidazo[1,2-a]pyridine (320 mg, 1.0 mmol) was dissolved in DMF (5 mL) and tributyl(ethynyl)tin was added alkane (472 mg, 1.5 mmol) and tetrakistriphenylphosphine palladium (115.5 mg, 0.1 mmol). The mixture was stirred in the microwave at 130°C for 1 hour. It was cooled to room temperature, concentrated and separated by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine (120 mg, yield: 55%). MS m/z (ESI): 219 [M+H] + .
中间体2：2-环丙基-7-乙炔基-6-氟咪唑并[1,2-a]吡啶的制备Intermediate 2: Preparation of 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine
Figure PCTCN2021114580-appb-000022
Figure PCTCN2021114580-appb-000022
第一步：2-环丙基-6-氟-7-碘咪唑并[1,2-a]吡啶的合成The first step: Synthesis of 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine
Figure PCTCN2021114580-appb-000023
Figure PCTCN2021114580-appb-000023
将5-氟-4-碘吡啶-2-胺(2.38g，10.0mmol)溶于DMF(20mL)中，加入2-溴-1-环丙基乙烷-1-酮(2.44g，15.0mmol)。混合物在60℃下搅拌16小时。冷却到室温，过滤得到2-环丙基-6-氟-7-碘咪唑并[1,2-a]吡啶(2.20mg，收率：73％)。MS m/z(ESI):303[M+H] +。 5-Fluoro-4-iodopyridin-2-amine (2.38 g, 10.0 mmol) was dissolved in DMF (20 mL) and 2-bromo-1-cyclopropylethan-1-one (2.44 g, 15.0 mmol) was added ). The mixture was stirred at 60°C for 16 hours. It was cooled to room temperature and filtered to obtain 2-cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine (2.20 mg, yield: 73%). MS m/z (ESI): 303 [M+H] + .
第二步：2-环丙基-7-乙炔基-6-氟咪唑并[1,2-a]吡啶的合成The second step: Synthesis of 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine
Figure PCTCN2021114580-appb-000024
Figure PCTCN2021114580-appb-000024
将2-环丙基-6-氟-7-碘咪唑并[1,2-a]吡啶(540mg，2.0mmol)溶于DMF(10mL)中，加入三丁基(乙炔基)锡烷(1260mg，4.0mmol)和四三苯基膦钯(116mg，0.1mmol)。混合物60℃下搅拌16小时。冷却到室温，浓缩后柱层析分离得到2-环丙基-7-乙炔基-6-氟咪唑并[1,2-a]吡啶(140mg，收率：40％)。MS m/z(ESI):175[M+H] +。 2-Cyclopropyl-6-fluoro-7-iodoimidazo[1,2-a]pyridine (540 mg, 2.0 mmol) was dissolved in DMF (10 mL) and tributyl(ethynyl)stannane (1260 mg) was added , 4.0 mmol) and tetrakistriphenylphosphine palladium (116 mg, 0.1 mmol). The mixture was stirred at 60°C for 16 hours. It was cooled to room temperature, concentrated and separated by column chromatography to obtain 2-cyclopropyl-7-ethynyl-6-fluoroimidazo[1,2-a]pyridine (140 mg, yield: 40%). MS m/z (ESI): 175 [M+H] + .
中间体3：2-环丙基-5-乙炔基苯并[d]噁唑的制备Intermediate 3: Preparation of 2-cyclopropyl-5-ethynylbenzo[d]oxazole
Figure PCTCN2021114580-appb-000025
Figure PCTCN2021114580-appb-000025
第一步：N-(5-溴-2-羟基苯基)环丙甲酰胺的合成The first step: the synthesis of N-(5-bromo-2-hydroxyphenyl) cyclopropanecarboxamide
Figure PCTCN2021114580-appb-000026
Figure PCTCN2021114580-appb-000026
将2-氨基-4-溴苯酚(2.0g，10.6mmol)溶于DCM(30mL)中，0℃下依次加入三乙胺(1.29g，12.8mmol)，环丙基甲酰氯(1.11g，10.6mmol)。混合物在0℃下搅拌1小时，用碳酸氢钠水溶液稀释并用DCM萃取，有机相用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离得到N-(5-溴-2-羟基苯基)环丙甲酰胺(1.34g，收率：49％)。MS m/z(ESI):256/258[M+H] +。 2-Amino-4-bromophenol (2.0 g, 10.6 mmol) was dissolved in DCM (30 mL), triethylamine (1.29 g, 12.8 mmol), cyclopropylcarbonyl chloride (1.11 g, 10.6 mmol) were added successively at 0 °C mmol). The mixture was stirred at 0°C for 1 hour, diluted with aqueous sodium bicarbonate solution and extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, column chromatography was performed to obtain N-(5-bromo-2- Hydroxyphenyl)cyclopropanecarboxamide (1.34 g, yield: 49%). MS m/z (ESI): 256/258 [M+H] + .
第二步：5-溴-2-环丙基苯并[d]噁唑的合成The second step: the synthesis of 5-bromo-2-cyclopropylbenzo[d]oxazole
Figure PCTCN2021114580-appb-000027
Figure PCTCN2021114580-appb-000027
将N-(5-溴-2-羟基苯基)环丙甲酰胺(1.04g，4.06mmol)溶于乙腈(30mL)中，室温下依次加入三苯基膦(4.26g，16.2mmol)，四氯化碳(1.25g，8.1mmol)。混合物在60℃下搅拌1小时，用水稀释并用乙酸乙酯萃取，有机相用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离得到5-溴-2-环丙基苯并[d]噁唑(548mg，收率：55％)。MS m/z(ESI):238/240[M+H] +。 N-(5-Bromo-2-hydroxyphenyl)cyclopropanecarboxamide (1.04 g, 4.06 mmol) was dissolved in acetonitrile (30 mL), and triphenylphosphine (4.26 g, 16.2 mmol) was added successively at room temperature. Carbon chloride (1.25 g, 8.1 mmol). The mixture was stirred at 60°C for 1 hour, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 5-bromo-2-cyclopropylbenzoic acid. [d] Oxazole (548 mg, yield: 55%). MS m/z (ESI): 238/240 [M+H] + .
第三步：2-环丙基-5-((三甲基甲硅烷基)乙炔基)苯并[d]噁唑的合成The third step: Synthesis of 2-cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole
Figure PCTCN2021114580-appb-000028
Figure PCTCN2021114580-appb-000028
将5-溴-2-环丙基苯并[d]噁唑(200mg，0.84mmol)置于DMF(3mL)中，室温下依次加入三乙胺(1mL)，碘化亚铜(16mg，0.084mmol)，三甲基硅乙炔(825mg，8.4mmol)，四三苯基膦钯(49mg，0.042mmol)。混合物在80℃下搅拌16小时，用水稀释并用乙酸乙酯萃取，有机相用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离得到2-环丙基-5-((三甲基甲硅烷基)乙炔基)苯并[d]噁唑(204mg，收率：95％)。MS m/z(ESI):256[M+H] +。 5-Bromo-2-cyclopropylbenzo[d]oxazole (200 mg, 0.84 mmol) was placed in DMF (3 mL), triethylamine (1 mL) was added successively at room temperature, cuprous iodide (16 mg, 0.084 mmol), trimethylsilylacetylene (825 mg, 8.4 mmol), tetrakistriphenylphosphine palladium (49 mg, 0.042 mmol). The mixture was stirred at 80° C. for 16 hours, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by column chromatography to obtain 2-cyclopropyl-5-((tri) Methylsilyl)ethynyl)benzo[d]oxazole (204 mg, yield: 95%). MS m/z (ESI): 256 [M+H] + .
第四步：2-环丙基-5-乙炔基苯并[d]噁唑的合成The fourth step: the synthesis of 2-cyclopropyl-5-ethynylbenzo[d]oxazole
Figure PCTCN2021114580-appb-000029
Figure PCTCN2021114580-appb-000029
将2-环丙基-5-((三甲基甲硅烷基)乙炔基)苯并[d]噁唑(204mg，0.8mmol)溶于甲醇(8mL)中，室温下加入碳酸钾(1.1g，8mmol)。混合物在室温下搅拌1小时，用水稀释并用乙酸乙酯萃取，有机相用饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离得到2-环丙基-5-乙炔基苯并[d]噁唑(112mg，收率：76％)。MS m/z(ESI):184[M+H] +。 2-Cyclopropyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazole (204 mg, 0.8 mmol) was dissolved in methanol (8 mL), potassium carbonate (1.1 g) was added at room temperature , 8mmol). The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 2-cyclopropyl-5-ethynylbenzoyl [d] Oxazole (112 mg, yield: 76%). MS m/z (ESI): 184 [M+H] + .
中间体4-7参照中间体3的全部或部分合成方法选择相应原料制备：Intermediates 4-7 are prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 3:
Figure PCTCN2021114580-appb-000030
Figure PCTCN2021114580-appb-000030
中间体8：2-环丙基-5-乙炔基-6-氟苯并[d]噻唑的制备Intermediate 8: Preparation of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole
Figure PCTCN2021114580-appb-000031
Figure PCTCN2021114580-appb-000031
第一步：N-(5-溴-2,4-二氟苯基)环丙甲酰胺的合成The first step: the synthesis of N-(5-bromo-2,4-difluorophenyl) cyclopropanecarboxamide
Figure PCTCN2021114580-appb-000032
Figure PCTCN2021114580-appb-000032
将5-溴-2,4-二氟苯胺(1.04g，5.0mmol)，溶于二氯甲烷(20mL)，加入环丙酰氯(572mg，5.5mmol)，室温下搅拌过夜，直接旋干后柱层析分离得到N-(5-溴-2,4-二氟苯基)环丙甲酰胺(1.0g，收率：72％)。MS m/z(ESI):276/278[M+H] +。 Dissolve 5-bromo-2,4-difluoroaniline (1.04 g, 5.0 mmol) in dichloromethane (20 mL), add cyclopropionyl chloride (572 mg, 5.5 mmol), stir at room temperature overnight, and spin to dry directly. Chromatography gave N-(5-bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, yield: 72%). MS m/z (ESI): 276/278 [M+H] + .
第二步：N-(5-溴-2,4-二氟苯基)环丙甲硫代酰胺的合成The second step: the synthesis of N-(5-bromo-2,4-difluorophenyl) cyclopropylmethylthioamide
Figure PCTCN2021114580-appb-000033
Figure PCTCN2021114580-appb-000033
将N-(5-溴-2,4-二氟苯基)环丙甲酰胺(1.0g，3.6mmol)，劳森试剂(750mg，1.85mmol)，溶于乙腈(25mL)，加热至85℃，搅拌过夜。反应结束后直接将该N-(5-溴-2,4-二氟苯基)环丙甲硫代酰胺溶液用于下一步实验。MS m/z(ESI):292/294[M+H] +。 N-(5-Bromo-2,4-difluorophenyl)cyclopropanecarboxamide (1.0 g, 3.6 mmol), Lawson's reagent (750 mg, 1.85 mmol), dissolved in acetonitrile (25 mL), heated to 85°C , and stirred overnight. After the reaction, the N-(5-bromo-2,4-difluorophenyl)cyclopropylmethylthioamide solution was directly used in the next experiment. MS m/z (ESI): 292/294 [M+H] + .
第三步：5-溴-2-环丙基-6-氟苯并[d]噻唑的合成The third step: Synthesis of 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole
Figure PCTCN2021114580-appb-000034
Figure PCTCN2021114580-appb-000034
将叔丁醇钠(1.7g，18mmol)加入冷却后的N-(5-溴-2,4-二氟苯基)环丙甲硫代酰胺溶液中，加热到50℃搅拌16小时。浓缩后柱层析分离得到5-溴-2-环丙基-6-氟苯并[d]噻唑(0.82g，收率：83％)。MS m/z(ESI):2712/274[M+H] +。 Sodium tert-butoxide (1.7 g, 18 mmol) was added to the cooled N-(5-bromo-2,4-difluorophenyl)cyclopropylmethylthioamide solution, heated to 50°C and stirred for 16 hours. After concentration, column chromatography gave 5-bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, yield: 83%). MS m/z (ESI): 2712/274 [M+H] + .
第四步：2-环丙基-5-乙炔基-6-氟苯并[d]噻唑的合成The fourth step: the synthesis of 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole
Figure PCTCN2021114580-appb-000035
Figure PCTCN2021114580-appb-000035
将5-溴-2-环丙基-6-氟苯并[d]噻唑(0.82g，3.0mmol)溶于DMF(15mL)，加入三丁基(乙炔基)锡烷(1.9g，6.0mmol)和四三苯基膦钯(173mg，0.15mmol)，并在微波反应器中130℃搅拌0.5小时。浓缩后柱层析分离得到2-环丙基-5-乙炔基-6-氟苯并[d]噻唑(0.16g，收率：25％)。MS m/z(ESI):218[M+H] +。 5-Bromo-2-cyclopropyl-6-fluorobenzo[d]thiazole (0.82 g, 3.0 mmol) was dissolved in DMF (15 mL) and tributyl(ethynyl)stannane (1.9 g, 6.0 mmol) was added ) and tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol) and stirred in a microwave reactor at 130° C. for 0.5 h. After concentration, column chromatography gave 2-cyclopropyl-5-ethynyl-6-fluorobenzo[d]thiazole (0.16 g, yield: 25%). MS m/z (ESI): 218 [M+H] + .
中间体9-10参照中间体8的全部或部分合成方法选择相应原料制备：Intermediates 9-10 are prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 8:
Figure PCTCN2021114580-appb-000036
Figure PCTCN2021114580-appb-000036
中间体11：2-环丙基-5-乙炔基-4,6-二氟苯并[d]噻唑的制备Intermediate 11: Preparation of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole
Figure PCTCN2021114580-appb-000037
Figure PCTCN2021114580-appb-000037
第一步：N-(2,4-二氟苯基)环丙甲酰胺的合成The first step: the synthesis of N-(2,4-difluorophenyl) cyclopropanecarboxamide
Figure PCTCN2021114580-appb-000038
Figure PCTCN2021114580-appb-000038
将2,4-二氟苯胺(10g，77.45mmol)溶于二氯甲烷(100mL)中，加入三乙胺(15.64g，154.9mmol)，冰浴下滴加环丙基甲酰氯(8.1g，77.45mmol)，室温下搅拌过夜。反应液分别使用适量饱和氯化铵水溶液和饱和食盐水洗涤，无水硫酸钠干燥后浓缩，硅胶柱层析分离得到 N-(2,4-二氟苯基)环丙甲酰胺(10.1g，收率：66％)。MS m/z(ESI):196[M+H] +。 2,4-Difluoroaniline (10 g, 77.45 mmol) was dissolved in dichloromethane (100 mL), triethylamine (15.64 g, 154.9 mmol) was added, and cyclopropylcarbonyl chloride (8.1 g, 77.45 mmol) and stirred overnight at room temperature. The reaction solution was washed with an appropriate amount of saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain N-(2,4-difluorophenyl)cyclopropanecarboxamide (10.1 g, Yield: 66%). MS m/z (ESI): 196 [M+H] + .
第二步：N-(2,4-二氟苯基)环丙甲硫代酰胺的合成Step 2: Synthesis of N-(2,4-difluorophenyl)cyclopropylmethylthioamide
Figure PCTCN2021114580-appb-000039
Figure PCTCN2021114580-appb-000039
将N-(2,4-二氟苯基)环丙甲酰胺(5g，25.36mmol)溶于二甲苯(80mL)，加入劳森试剂(7.18g，17.75mmol)，加热至120℃并搅拌过夜。浓缩后直接硅胶柱层析分离得到N-(2,4-二氟苯基)环丙甲硫代酰胺(4.1g，收率：75％)。MS m/z(ESI):212[M+H] +。 Dissolve N-(2,4-difluorophenyl)cyclopropanecarboxamide (5 g, 25.36 mmol) in xylene (80 mL), add Lawson's reagent (7.18 g, 17.75 mmol), heat to 120 °C and stir overnight . After concentration, it was directly separated by silica gel column chromatography to obtain N-(2,4-difluorophenyl)cyclopropylmethylthioamide (4.1 g, yield: 75%). MS m/z (ESI): 212 [M+H] + .
第三步：2-环丙基-4,6-二氟苯并[d]噻唑的合成The third step: synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole
Figure PCTCN2021114580-appb-000040
Figure PCTCN2021114580-appb-000040
将N-(2,4-二氟苯基)环丙甲硫代酰胺(1g，4.69mmol)溶于氢氧化钠溶液(1.69g，42.21mmol，5mL乙醇和10mL水)，所得溶液滴加到预加热到90℃的K 3Fe(CN) 6水溶液(6.18g，18.78mmol，10mL水)中，搅拌2小时后立刻停止加热，冷却后用浓盐酸调节至弱酸性，用乙酸乙酯萃取，所得萃取液用饱和食盐水洗涤，浓缩后硅胶柱层析分离得到2-环丙基-4,6-二氟苯并[d]噻唑(500mg，收率：51％)。MS m/z(ESI):212[M+H] +。 N-(2,4-difluorophenyl)cyclopropylmethylthioamide (1 g, 4.69 mmol) was dissolved in sodium hydroxide solution (1.69 g, 42.21 mmol, 5 mL of ethanol and 10 mL of water), and the resulting solution was added dropwise to Preheated to a K 3 Fe(CN) 6 aqueous solution (6.18 g, 18.78 mmol, 10 mL of water) at 90° C. After stirring for 2 hours, the heating was stopped immediately. After cooling, it was adjusted to weakly acidic with concentrated hydrochloric acid, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, concentrated and separated by silica gel column chromatography to obtain 2-cyclopropyl-4,6-difluorobenzo[d]thiazole (500 mg, yield: 51%). MS m/z (ESI): 212 [M+H] + .
第四步：2-环丙基-4,6-二氟苯并[d]噻唑-5-甲醛的合成The fourth step: the synthesis of 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carbaldehyde
Figure PCTCN2021114580-appb-000041
Figure PCTCN2021114580-appb-000041
将2-环丙基-4,6-二氟苯并[d]噻唑(980mg，4.64mmol)溶于四氢呋喃(15mL)并冷却至-70℃，滴加LDA(2.55mL，5.104mmol，2M)，保持该温度2小时后加入DMF(1.01g，13.92mmol)，保持该温度2小时后加入适量氯化铵水溶液淬灭反应并升至室温，乙酸乙酯萃取反应液，无水硫酸钠干燥后过滤并浓缩，硅胶柱层析分离得到2-环丙基-4,6-二氟苯并[d]噻唑-5-甲醛(675mg，收率：65％)。MS m/z(ESI):240[M+H] +。 2-Cyclopropyl-4,6-difluorobenzo[d]thiazole (980 mg, 4.64 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to -70°C, LDA (2.55 mL, 5.104 mmol, 2M) was added dropwise , DMF (1.01 g, 13.92 mmol) was added after maintaining the temperature for 2 hours, an appropriate amount of ammonium chloride aqueous solution was added after maintaining the temperature for 2 hours to quench the reaction and the temperature was raised to room temperature, the reaction solution was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Filtration and concentration, and separation by silica gel column chromatography gave 2-cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carbaldehyde (675 mg, yield: 65%). MS m/z (ESI): 240 [M+H] + .
第五步：2-环丙基-5-乙炔基-4,6-二氟苯并[d]噻唑的合成The fifth step: the synthesis of 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole
Figure PCTCN2021114580-appb-000042
Figure PCTCN2021114580-appb-000042
将2-环丙基-4,6-二氟苯并[d]噻唑-5-甲醛(122mg，0.51mmol)溶于甲醇(10mL)，依次加入碳酸钾(211mg，1.53mmol)和(1-重氮-2-氧代-丙醇)-膦酸二甲酯(159mg，0.76mmol)，室温下搅拌过夜。直接浓缩后硅胶柱层析分离得到2-环丙基-5-乙炔基-4,6-二氟苯并[d]噻唑(73mg，收率：61％)。MS m/z(ESI):236[M+H] +。 2-Cyclopropyl-4,6-difluorobenzo[d]thiazole-5-carbaldehyde (122 mg, 0.51 mmol) was dissolved in methanol (10 mL), followed by potassium carbonate (211 mg, 1.53 mmol) and (1- Diazo-2-oxo-propanol)-phosphonic acid dimethyl ester (159 mg, 0.76 mmol) and stirred at room temperature overnight. After direct concentration, it was separated by silica gel column chromatography to obtain 2-cyclopropyl-5-ethynyl-4,6-difluorobenzo[d]thiazole (73 mg, yield: 61%). MS m/z (ESI): 236 [M+H] + .
中间体12参照中间体11的全部或部分合成方法选择相应原料制备：Intermediate 12 is prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of intermediate 11:
Figure PCTCN2021114580-appb-000043
Figure PCTCN2021114580-appb-000043
中间体13：5-乙炔基-6-氟-N-甲基苯并[d]噁唑-2-胺的制备Intermediate 13: Preparation of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine
Figure PCTCN2021114580-appb-000044
Figure PCTCN2021114580-appb-000044
第一步：2-氨基-4-溴-5-氟苯酚的合成The first step: the synthesis of 2-amino-4-bromo-5-fluorophenol
Figure PCTCN2021114580-appb-000045
Figure PCTCN2021114580-appb-000045
将4-溴-5-氟-2-硝基苯酚(5.00g，21.2mmol)溶于四氢呋喃/水(60mL/30mL)中，室温下依次加入氯化铵(5.66g，105.9mmol)和锌粉(6.89g，105.9mmol)。混合物在室温下搅拌反应1小时。反应液过滤，乙酸乙酯(50mL)洗涤，分液萃取，有机相浓缩后柱层析分离得到2-氨基-4-溴-5-氟苯酚(3.2g，收率：73％)。MS m/z(ESI):206/208[M+H] +。 4-Bromo-5-fluoro-2-nitrophenol (5.00 g, 21.2 mmol) was dissolved in tetrahydrofuran/water (60 mL/30 mL), and ammonium chloride (5.66 g, 105.9 mmol) and zinc powder were added in sequence at room temperature (6.89 g, 105.9 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, washed with ethyl acetate (50 mL), and extracted by liquid separation. After the organic phase was concentrated, column chromatography was performed to obtain 2-amino-4-bromo-5-fluorophenol (3.2 g, yield: 73%). MS m/z (ESI): 206/208 [M+H] + .
第二步：5-溴-6-氟苯并[d]噁唑-2(3H)-硫酮的合成The second step: the synthesis of 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione
Figure PCTCN2021114580-appb-000046
Figure PCTCN2021114580-appb-000046
将2-氨基-4-溴-5-氟苯酚(3.2g，15.5mmol)置于乙醇(50mL)中，室温下加入乙基磺原酸钾(2.48g，15.5mmol)。混合物在80℃下搅拌反应17小时。反应液直接浓缩后柱层析分离得到5-溴-6-氟苯并[d]噁唑-2(3H)-硫酮(1.80g，收率：47％)。MS m/z(ESI):248/250[M+H] +。 2-Amino-4-bromo-5-fluorophenol (3.2 g, 15.5 mmol) was taken up in ethanol (50 mL) and potassium ethylsulfonate (2.48 g, 15.5 mmol) was added at room temperature. The mixture was stirred at 80°C for 17 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain 5-bromo-6-fluorobenzo[d]oxazole-2(3H)-thione (1.80 g, yield: 47%). MS m/z (ESI): 248/250 [M+H] + .
第三步：5-溴-2-氯-6-氟苯并[d]噁唑的合成The third step: Synthesis of 5-bromo-2-chloro-6-fluorobenzo[d]oxazole
Figure PCTCN2021114580-appb-000047
Figure PCTCN2021114580-appb-000047
将5-溴-6-氟苯并[d]噁唑-2(3H)-硫酮(1.76g，7.1mmol)溶于二氯甲烷(15mL)中，室温下依次加入N,N-二甲基甲酰胺(0.5mL)和氯化亚砜(5.0mL，68.9mmol)。混合物在室温下搅拌反应2小时。反应液浓缩，残留物加入二氯甲烷(100mL)稀释，依次用饱和碳酸氢钠溶液(50mL)和食盐水(50mL)洗涤，并用无水硫酸钠干燥。抽滤，滤液浓缩后柱层析分离得到5-溴-2-氯-6-氟苯并[d]噁唑(1.30g，收率：73％)。5-Bromo-6-fluorobenzo[d]oxazole-2(3H)-thione (1.76 g, 7.1 mmol) was dissolved in dichloromethane (15 mL), and N,N-dimethylmethane was added sequentially at room temperature formamide (0.5 mL) and thionyl chloride (5.0 mL, 68.9 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was diluted with dichloromethane (100 mL), washed successively with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated and separated by column chromatography to obtain 5-bromo-2-chloro-6-fluorobenzo[d]oxazole (1.30 g, yield: 73%).
第四步：5-溴-6-氟-N-甲基苯并[d]噁唑-2-胺的合成The fourth step: the synthesis of 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine
Figure PCTCN2021114580-appb-000048
Figure PCTCN2021114580-appb-000048
将5-溴-2-氯-6-氟苯并[d]噁唑(250mg，1.0mmol)置于乙腈(5mL)中，室温下加入甲胺水溶液(1.0mL，质量分数25-30％)。混合物在室温下搅拌1小时。反应液加入食盐水(50mL)稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，浓缩后得到5-溴-6-氟-N-甲基苯并[d]噁唑-2-胺(245mg，收率：100％)。MS m/z(ESI):245/247[M+H] +。 5-Bromo-2-chloro-6-fluorobenzo[d]oxazole (250 mg, 1.0 mmol) was placed in acetonitrile (5 mL), and methylamine aqueous solution (1.0 mL, mass fraction 25-30%) was added at room temperature . The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with brine (50 mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 5-bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine (245 mg, yield: 100%). MS m/z (ESI): 245/247 [M+H] + .
第五步：6-氟-N-甲基-5-((三甲基甲硅烷基)乙炔基)苯并[d]噁唑-2-胺的合成The fifth step: the synthesis of 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine
Figure PCTCN2021114580-appb-000049
Figure PCTCN2021114580-appb-000049
将5-溴-6-氟-N-甲基苯并[d]噁唑-2-胺(190mg，0.78mmol)置于1,4-二氧六环/N,N-二甲基甲酰胺(10mL/1mL)中，室温下加入三丁基(三甲基甲硅烷基乙炔基)锡(600mg，1.55mmol)和四三苯基膦钯(90mg，0.08mmol)。混合物在微波120℃下反应6小时。反应液直接浓缩后柱层析分离得到6-氟-N-甲基-5-((三甲基甲硅烷基)乙炔基)苯并[d]噁唑-2-胺(158mg，收率：78％)。MS m/z(ESI):263[M+H] +。 5-Bromo-6-fluoro-N-methylbenzo[d]oxazol-2-amine (190 mg, 0.78 mmol) was placed in 1,4-dioxane/N,N-dimethylformamide (10 mL/1 mL), tributyl(trimethylsilylethynyl)tin (600 mg, 1.55 mmol) and tetrakistriphenylphosphine palladium (90 mg, 0.08 mmol) were added at room temperature. The mixture was reacted in the microwave at 120°C for 6 hours. The reaction solution was directly concentrated and separated by column chromatography to obtain 6-fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine (158 mg, yield: 78%). MS m/z (ESI): 263 [M+H] + .
第六步：5-乙炔基-6-氟-N-甲基苯并[d]噁唑-2-胺的合成Step 6: Synthesis of 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine
Figure PCTCN2021114580-appb-000050
Figure PCTCN2021114580-appb-000050
将6-氟-N-甲基-5-((三甲基甲硅烷基)乙炔基)苯并[d]噁唑-2-胺(158mg，0.60mmol)置于甲醇(10mL)中，室温下加入碳酸钾(248mg，1.80mmol)。混合物在室温下搅拌反应1小时。反应液直接浓缩后柱层析分离得到5-乙炔基-6-氟-N-甲基苯并[d]噁唑-2-胺(95mg，收率：83％)。MS m/z(ESI):191[M+H] +。 6-Fluoro-N-methyl-5-((trimethylsilyl)ethynyl)benzo[d]oxazol-2-amine (158 mg, 0.60 mmol) was placed in methanol (10 mL) at room temperature Potassium carbonate (248 mg, 1.80 mmol) was added at the bottom. The mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated and separated by column chromatography to obtain 5-ethynyl-6-fluoro-N-methylbenzo[d]oxazol-2-amine (95 mg, yield: 83%). MS m/z (ESI): 191 [M+H] + .
中间体14-16参照中间体13的全部或部分合成方法选择相应原料制备：Intermediates 14-16 are prepared by selecting corresponding raw materials with reference to the whole or part of the synthesis method of intermediate 13:
Figure PCTCN2021114580-appb-000051
Figure PCTCN2021114580-appb-000051
中间体17：2-(吖丁啶-1-基)-5-乙炔基-4,6-二氟苯并[d]噁唑的制备Intermediate 17: Preparation of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole
Figure PCTCN2021114580-appb-000052
Figure PCTCN2021114580-appb-000052
第一步：2-氨基-3,5-二氟苯酚的合成The first step: synthesis of 2-amino-3,5-difluorophenol
Figure PCTCN2021114580-appb-000053
Figure PCTCN2021114580-appb-000053
将3,5-二氟-2-硝基苯酚(10g，57.11mmol)溶于甲醇(100mL)中，加入钯碳(1g)，室温搅拌过夜，过滤，滤液旋干，得到2-氨基-3,5-二氟苯酚(8.5g，收率：100％)，MS m/z(ESI):146[M+H] +。 Dissolve 3,5-difluoro-2-nitrophenol (10 g, 57.11 mmol) in methanol (100 mL), add palladium on carbon (1 g), stir at room temperature overnight, filter, and spin dry the filtrate to obtain 2-amino-3 ,5-difluorophenol (8.5 g, yield: 100%), MS m/z (ESI): 146 [M+H] + .
第二步：4,6-二氟苯并[d]噁唑-2-硫醇的合成Step 2: Synthesis of 4,6-difluorobenzo[d]oxazole-2-thiol
Figure PCTCN2021114580-appb-000054
Figure PCTCN2021114580-appb-000054
将2-氨基-3,5-二氟苯酚(8.5g，58.62mmol)溶于乙醇(100mL)中，加入O-乙基二硫酸钾(1.13g，70.34mmol)，加热至95℃过夜。冷却过滤，滤液浓缩后硅胶柱层析分离得到4,6-二氟-1,3-苯并恶唑-2-硫醇(11g，收率：95.31％)。MS m/z(ESI):188[M+H] +。 2-Amino-3,5-difluorophenol (8.5 g, 58.62 mmol) was dissolved in ethanol (100 mL), potassium O-ethyldisulfate (1.13 g, 70.34 mmol) was added, and the mixture was heated to 95°C overnight. After cooling and filtration, the filtrate was concentrated and separated by silica gel column chromatography to obtain 4,6-difluoro-1,3-benzoxazole-2-thiol (11 g, yield: 95.31%). MS m/z (ESI): 188 [M+H] + .
第三步：2-氯-4,6-二氟苯并[d]噁唑的合成The third step: synthesis of 2-chloro-4,6-difluorobenzo[d]oxazole
Figure PCTCN2021114580-appb-000055
Figure PCTCN2021114580-appb-000055
将4,6-二氟-1,3-苯并恶唑-2-硫醇(4g，21.37mmol)溶于二氯甲烷(50mL)中，加入草酰氯(10.85g，85.48mmol)和N,N-二甲基甲酰胺(0.16g，2.14mmol)，室温搅拌2小时，旋干，得到2-氯-4,6-二氟苯并[d]噁唑的粗品(4.05g，收率：100％)，直接用于下一步反应。MS m/z(ESI):190[M+H] +。 4,6-Difluoro-1,3-benzoxazole-2-thiol (4 g, 21.37 mmol) was dissolved in dichloromethane (50 mL), oxalyl chloride (10.85 g, 85.48 mmol) and N, N-dimethylformamide (0.16 g, 2.14 mmol), stirred at room temperature for 2 hours, and spin-dried to obtain a crude product of 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, yield: 100%), which was directly used in the next reaction. MS m/z (ESI): 190 [M+H] + .
第四步：2-(吖丁啶-1-基)-4,6-二氟苯并[d]噁唑的合成The fourth step: the synthesis of 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole
Figure PCTCN2021114580-appb-000056
Figure PCTCN2021114580-appb-000056
将2-氯-4,6-二氟苯并[d]噁唑的粗品(4.05g，21.36mmol)溶于四氢呋喃(50mL)中，加入N,N-二异丙基乙胺(5.51g，42.72mmol)和杂氮环丁烷盐酸盐(2.40g，25.63mmol)，室温搅拌2小时，反应液旋干，加入乙酸乙酯，用饱和氯化铵水溶液洗涤两次，饱和食盐水洗涤两次后，加入硫酸钠干燥并过滤，滤液浓缩后硅胶柱层析分离得到2-(吖丁啶-1-基)-4,6-二氟苯并[d]噁唑(3.2g，收率：72％)。MS m/z(ESI):211[M+H] +。 The crude product of 2-chloro-4,6-difluorobenzo[d]oxazole (4.05 g, 21.36 mmol) was dissolved in tetrahydrofuran (50 mL), and N,N-diisopropylethylamine (5.51 g, 42.72 mmol) and azetidine hydrochloride (2.40 g, 25.63 mmol), stirred at room temperature for 2 hours, the reaction solution was spin-dried, ethyl acetate was added, washed twice with saturated aqueous ammonium chloride, and twice with saturated brine. After three times, sodium sulfate was added to dry and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole (3.2 g, yield : 72%). MS m/z (ESI): 211 [M+H] + .
第五步：2-(吖丁啶-1-基)-4,6-二氟苯并[d]噁唑-5-甲醛的合成The fifth step: the synthesis of 2-(azetidine-1-yl)-4,6-difluorobenzo[d]oxazole-5-carbaldehyde
Figure PCTCN2021114580-appb-000057
Figure PCTCN2021114580-appb-000057
将2-(吖丁啶-1-基)-4,6-二氟苯并[d]噁唑(3g，14.28mmol)溶于四氢呋喃(100ml)，冷却到-70℃，滴加二异丙基氨基锂的四氢呋喃溶液(10.7mL，21.41mmol，2M)，保持低温搅拌1个小时，然后一次性加入N,N-二甲基甲酰胺(11.04mL,142.73mmol)，低温搅拌2小时，加入适量饱和氯化铵水溶液淬灭反应，升至室温后，乙酸乙酯萃取两次，合并乙酸乙酯相，用饱和食盐水洗涤两次，硫酸钠干燥后过滤得到滤液，浓缩后硅胶柱层析分离得到2-(吖丁啶-1-基)-4,6-二氟苯并[d]噁唑-5-甲醛(0.8g，收率：24％)。MS m/z(ESI):239[M+H] +。 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole (3g, 14.28mmol) was dissolved in tetrahydrofuran (100ml), cooled to -70°C, and diisopropyl was added dropwise A solution of lithium amide in tetrahydrofuran (10.7 mL, 21.41 mmol, 2 M) was stirred at low temperature for 1 hour, then N,N-dimethylformamide (11.04 mL, 142.73 mmol) was added at one time, stirred at low temperature for 2 hours, and added An appropriate amount of saturated aqueous ammonium chloride solution was used to quench the reaction. After warming to room temperature, extraction with ethyl acetate was performed twice. The ethyl acetate phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered to obtain a filtrate. After concentration, silica gel column chromatography was performed. 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole-5-carbaldehyde was isolated (0.8 g, yield: 24%). MS m/z (ESI): 239 [M+H] + .
第六步：2-(吖丁啶-1-基)-5-乙炔基-4,6-二氟苯并[d]噁唑的合成The sixth step: the synthesis of 2-(azetidin-1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole
Figure PCTCN2021114580-appb-000058
Figure PCTCN2021114580-appb-000058
将2-(吖丁啶-1-基)-4,6-二氟苯并[d]噁唑-5-甲醛(0.8g，3.40mmol)溶于甲醇(10mL)和四氢呋喃(10mL)，加入碳酸钾(1.17g，8.5mmol)和(1-重氮基-2-氧代丙基)膦酸二甲酯(1.31g,6.80mmol)，室温搅拌两个小时，浓缩，加入适量饱和氯化铵水溶液淬灭反应，升至室温后，乙酸乙酯萃取两次，合并后用饱和食盐水洗涤两次，硫酸钠干燥后过滤得到滤液，浓缩后硅胶柱层析分离得到2-(吖丁啶-1-基)-5-乙炔基-4,6-二氟苯并[d]噁唑(0.75g，收率：94％)。MS m/z(ESI):235[M+H] +。 2-(azetidin-1-yl)-4,6-difluorobenzo[d]oxazole-5-carbaldehyde (0.8 g, 3.40 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), added Potassium carbonate (1.17g, 8.5mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.31g, 6.80mmol) were stirred at room temperature for two hours, concentrated, and an appropriate amount of saturated chloride was added. Aqueous ammonium solution was used to quench the reaction. After warming to room temperature, it was extracted twice with ethyl acetate. After the combination, it was washed twice with saturated brine. After drying over sodium sulfate, the filtrate was filtered to obtain the filtrate. -1-yl)-5-ethynyl-4,6-difluorobenzo[d]oxazole (0.75 g, yield: 94%). MS m/z (ESI): 235 [M+H] + .
中间体18参照中间体17的全部或部分合成方法选择相应原料制备：Intermediate 18 is prepared by selecting the corresponding raw materials with reference to the whole or part of the synthesis method of intermediate 17:
Figure PCTCN2021114580-appb-000059
Figure PCTCN2021114580-appb-000059
中间体19：(S)-1-(1-丙烯酰吡咯烷-3-基)-4-氨基-3-碘-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的制备Intermediate 19: (S)-1-(1-Acryloylpyrrolidin-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridin Preparation of oxazin-7-ones
Figure PCTCN2021114580-appb-000060
Figure PCTCN2021114580-appb-000060
第一步：二乙基(2E,4E,6E)-3,6-二氰基-2,7-二羟基辛-2,4,6-三烯二酸酯的合成The first step: Synthesis of diethyl(2E,4E,6E)-3,6-dicyano-2,7-dihydroxyoctane-2,4,6-trienedioate
Figure PCTCN2021114580-appb-000061
Figure PCTCN2021114580-appb-000061
将乙醇钠(21％，100mL，270.0mmol)溶于乙醇(80mL)中，0℃下加入草酸二乙酯(40mL，270.0mmol)并搅拌30分钟，然后加入(E)-己-3-烯二腈(9.56g，90.0mmol)。混合物在室温搅 拌16小时。冷却到0℃，将固体过滤，然后用240mL水将固体溶解，并用稀盐酸调节pH到4左右，析出大量固体，过滤得到二乙基(2E,4E,6E)-3,6-二氰基-2,7-二羟基辛-2,4,6-三烯二酸酯(10.0g，收率：36％)。MS m/z(ESI):307[M+H] +。 Sodium ethoxide (21%, 100 mL, 270.0 mmol) was dissolved in ethanol (80 mL), diethyl oxalate (40 mL, 270.0 mmol) was added at 0°C and stirred for 30 minutes, then (E)-hex-3-ene was added Dinitrile (9.56 g, 90.0 mmol). The mixture was stirred at room temperature for 16 hours. Cool to 0°C, filter the solid, then dissolve the solid with 240 mL of water, and adjust the pH to about 4 with dilute hydrochloric acid, a large amount of solid is precipitated, and filtered to obtain diethyl(2E,4E,6E)-3,6-dicyano -2,7-Dihydroxyoctane-2,4,6-trienedioate (10.0 g, yield: 36%). MS m/z (ESI): 307 [M+H] + .
第二步：乙基3-氰基-1H-吡咯-2-羧酸酯的合成The second step: the synthesis of ethyl 3-cyano-1H-pyrrole-2-carboxylate
Figure PCTCN2021114580-appb-000062
Figure PCTCN2021114580-appb-000062
二乙基(2E,4E,6E)-3,6-二氰基-2,7-二羟基辛-2,4,6-三烯二酸酯(3.0g，10.0mmol)溶于乙酸乙酯(50mL)中，加热到60℃，加入氨/二氧六环溶液(50mL，20.0mmol)并搅拌16小时。冷却到室温，浓缩后柱层析分离得到乙基3-氰基-1H-吡咯-2-羧酸酯(380mg，收率：23％)。MS m/z(ESI):165[M+H] +。 Diethyl(2E,4E,6E)-3,6-dicyano-2,7-dihydroxyocta-2,4,6-trienedioate (3.0 g, 10.0 mmol) was dissolved in ethyl acetate (50 mL), heated to 60°C, added ammonia/dioxane solution (50 mL, 20.0 mmol) and stirred for 16 hours. It was cooled to room temperature, concentrated and separated by column chromatography to obtain ethyl 3-cyano-1H-pyrrole-2-carboxylate (380 mg, yield: 23%). MS m/z (ESI): 165 [M+H] + .
第三步：乙基(S)-1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-3-氰基-1H-吡咯-2-羧酸酯的合成The third step: synthesis of ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-1H-pyrrole-2-carboxylate
Figure PCTCN2021114580-appb-000063
Figure PCTCN2021114580-appb-000063
乙基3-氰基-1H-吡咯-2-羧酸酯(380.0mg，2.3mmol)，叔-丁基(R)-3-((甲磺酰)氧基)吡咯烷-1-羧酸酯(676mg，2.5mmol)，碳酸铯(1.6g，5.0mmol)溶于N,N-二甲基甲酰胺(10mL)中，加热到80℃搅拌16小时。然后冷却到室温，旋干，通过柱层析分离得到乙基(S)-1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-3-氰基-1H-吡咯-2-羧酸酯(650mg，收率：85％)。MS m/z(ESI):334[M+H] +。 Ethyl 3-cyano-1H-pyrrole-2-carboxylate (380.0 mg, 2.3 mmol), tert-butyl(R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid Ester (676 mg, 2.5 mmol), cesium carbonate (1.6 g, 5.0 mmol) were dissolved in N,N-dimethylformamide (10 mL), heated to 80°C and stirred for 16 hours. Then cooled to room temperature, spun dry, and isolated by column chromatography to obtain ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-1H-pyrrole- 2-carboxylate (650 mg, yield: 85%). MS m/z (ESI): 334 [M+H] + .
第四步：乙基(S)-1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-3-氰基-4-碘-1H-吡咯-2-羧酸酯的合成The fourth step: ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-4-iodo-1H-pyrrole-2-carboxylate synthesis
Figure PCTCN2021114580-appb-000064
Figure PCTCN2021114580-appb-000064
将乙基(S)-1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-3-氰基-1H-吡咯-2-羧酸酯(100mg，0.3mmol)，N-碘代丁二酰亚胺(675mg，0.9mmol)，溶于N,N-二甲基甲酰胺和醋酸1:1混合溶剂(4mL)中，室温搅拌16小时。旋干，通过柱层析分离得到乙基(S)-1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-3-氰基-4-碘-1H-吡咯-2-羧酸酯(100mg，收率：72％)。MS m/z(ESI):460[M+H] +。 Ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-1H-pyrrole-2-carboxylate (100 mg, 0.3 mmol), N - Iodosuccinimide (675 mg, 0.9 mmol) was dissolved in a 1:1 mixed solvent of N,N-dimethylformamide and acetic acid (4 mL), and stirred at room temperature for 16 hours. Spin dry and separate by column chromatography to obtain ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-4-iodo-1H-pyrrole-2 - Carboxylic acid ester (100 mg, yield: 72%). MS m/z (ESI): 460 [M+H] + .
第五步：叔-丁基(S)-3-(4-氨基-3-碘-7-氧代-6,7-二氢-1H-吡咯并[2,3-d]哒嗪-1-基)吡咯烷-1-羧酸酯的合成The fifth step: tert-butyl (S)-3-(4-amino-3-iodo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-1 Synthesis of -yl)pyrrolidine-1-carboxylate
Figure PCTCN2021114580-appb-000065
Figure PCTCN2021114580-appb-000065
将乙基(S)-1-(1-(叔-丁氧基羰基)吡咯烷-3-基)-3-氰基-4-碘-1H-吡咯-2-羧酸酯(100mg，0.2mmol)，溶于乙醇(5mL)中加入1mL水合肼，在70℃下搅拌16小时。旋干，得到叔-丁基(S)-3-(4-氨基-3-碘-7-氧代-6,7-二氢-1H-吡咯并[2,3-d]哒嗪-1-基)吡咯烷-1-羧酸酯(100mg，收率：100％)。MS m/z(ESI):446[M+H] +。 Ethyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-cyano-4-iodo-1H-pyrrole-2-carboxylate (100 mg, 0.2 mmol), dissolved in ethanol (5 mL), added 1 mL of hydrazine hydrate, and stirred at 70° C. for 16 hours. Spin dry to give tert-butyl(S)-3-(4-amino-3-iodo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-1 -yl)pyrrolidine-1-carboxylate (100 mg, yield: 100%). MS m/z (ESI): 446 [M+H] + .
第六步：(S)-4-氨基-3-碘-1-(吡咯烷-3-基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的合成The sixth step: (S)-4-amino-3-iodo-1-(pyrrolidin-3-yl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazine-7- Synthesis of Ketones
Figure PCTCN2021114580-appb-000066
Figure PCTCN2021114580-appb-000066
将叔-丁基(S)-3-(4-氨基-3-碘-7-氧代-6,7-二氢-1H-吡咯并[2,3-d]哒嗪-1-基)吡咯烷-1-羧酸酯(100mg，0.2mmol)，溶于二氯甲烷(5mL)中加入1mL三氟乙酸，在室温下搅拌2小时。将体系旋干，得到乙基(S)-4-氨基-3-碘-1-(吡咯烷-3-基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(70mg，收率：97％)。MS m/z(ESI):346[M+H] +。 tert-Butyl(S)-3-(4-amino-3-iodo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-1-yl) Pyrrolidine-1-carboxylate (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The system was spun dry to obtain ethyl (S)-4-amino-3-iodo-1-(pyrrolidin-3-yl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridin Azin-7-one (70 mg, yield: 97%). MS m/z (ESI): 346 [M+H] + .
第七步：(S)-1-(1-丙烯酰吡咯烷-3-基)-4-氨基-3-碘-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的合成Step 7: (S)-1-(1-Acryloylpyrrolidin-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridine Synthesis of oxazin-7-ones
Figure PCTCN2021114580-appb-000067
Figure PCTCN2021114580-appb-000067
将乙基(S)-4-氨基-3-碘-1-(吡咯烷-3-基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(70mg，0.2mmol)，溶于N,N-二甲基甲酰胺(5mL)中加入丙烯酸(22mg，0.3mmol)，然后加入O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(115mg，0.3mmol)，再加入二异丙基乙胺(129mg，1.0mmol)，在室温下搅拌2小时。旋干，柱层析分离得到(S)-1-(1-丙烯酰吡咯烷-3-基)-4-氨基-3-碘-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(40.0mg，收率：50％)。MS m/z(ESI):400[M+H] +。 Ethyl(S)-4-amino-3-iodo-1-(pyrrolidin-3-yl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (70 mg, 0.2 mmol), dissolved in N,N-dimethylformamide (5 mL), acrylic acid (22 mg, 0.3 mmol) was added, followed by O-(7-nitrobenzotriazole)-N,N, N,N-Tetramethylurea hexafluorophosphate (115 mg, 0.3 mmol) was further added with diisopropylethylamine (129 mg, 1.0 mmol), and the mixture was stirred at room temperature for 2 hours. Spin to dryness and column chromatography to obtain (S)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3 -d]pyridazin-7-one (40.0 mg, yield: 50%). MS m/z (ESI): 400 [M+H] + .
二、具体实施例的制备Two, the preparation of specific embodiment
实施例1(S)-1-(1-丙烯酰吡咯烷-3-基)-4-氨基-3-((2-环丙基-6,8-二氟咪唑并[1,2-a]吡啶-7-基)乙炔基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的制备Example 1(S)-1-(1-Acryloylpyrrolidin-3-yl)-4-amino-3-((2-cyclopropyl-6,8-difluoroimidazo[1,2-a ]pyridin-7-yl)ethynyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one
Figure PCTCN2021114580-appb-000068
Figure PCTCN2021114580-appb-000068
将(S)-1-(1-丙烯酰吡咯烷-3-基)-4-氨基-3-碘-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(40mg，0.1mmol)，2-环丙基-7-乙炔基-6,8-二氟咪唑并[1,2-a]吡啶(30mg，0.13mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(4.0mg，0.01mmol)，碘化亚铜(1.9mg，0.01mmol)溶于N,N-二甲基甲酰胺(2.5mL)中加入三乙胺(0.5mL)，在60℃下搅拌1小时。旋干，通过柱层析分离得到(S)-1-(1-丙烯酰吡咯烷-3-基)-4-氨基-3-((2-环丙基-6,8-二氟咪唑并[1,2-a]吡啶-7-基)乙炔基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮(5.0mg，收率：10.2％)。MS m/z(ESI):490[M+H] +。 (S)-1-(1-Acryloylpyrrolidin-3-yl)-4-amino-3-iodo-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazine-7 -ketone (40 mg, 0.1 mmol), 2-cyclopropyl-7-ethynyl-6,8-difluoroimidazo[1,2-a]pyridine (30 mg, 0.13 mmol), [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (4.0 mg, 0.01 mmol), cuprous iodide (1.9 mg, 0.01 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) Triethylamine (0.5 mL) was added, and the mixture was stirred at 60°C for 1 hour. Spin dry and separate by column chromatography to obtain (S)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-((2-cyclopropyl-6,8-difluoroimidazolium [1,2-a]pyridin-7-yl)ethynyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (5.0 mg, yield: 10.2% ). MS m/z (ESI): 490 [M+H] + .
1H NMR(400MHz,DMSO-d 6)：δ11.57(d,J＝3.6Hz,1H),8.72(d,J＝4.6Hz,1H),8.09(d,J＝21.0Hz,1H),7.92(d,J＝3.2Hz,1H),6.75-6.45(m,1H),6.24-6.12(m,1H),6.11-5.92(m,1H),5.76-5.64(m,1H),5.57(brs,2H),4.15-3.91(m,1H),3.90-3.49(m,3H),2.47-2.27(m,2H),2.18-2.01(m,1H),1.04-0.96(m,2H),0.91(d,J＝6.7Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.57 (d, J=3.6 Hz, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.09 (d, J=21.0 Hz, 1H), 7.92(d, J＝3.2Hz, 1H), 6.75-6.45(m, 1H), 6.24-6.12(m, 1H), 6.11-5.92(m, 1H), 5.76-5.64(m, 1H), 5.57( brs,2H),4.15-3.91(m,1H),3.90-3.49(m,3H),2.47-2.27(m,2H),2.18-2.01(m,1H),1.04-0.96(m,2H), 0.91(d,J=6.7Hz,2H).
实施例2～18参照实施例1的全部或部分合成方法选择相应的原料进行制备:Embodiment 2～18 selects corresponding raw material to prepare with reference to all or part of the synthetic method of embodiment 1:
Figure PCTCN2021114580-appb-000069
Figure PCTCN2021114580-appb-000069
Figure PCTCN2021114580-appb-000070
Figure PCTCN2021114580-appb-000070
Figure PCTCN2021114580-appb-000071
Figure PCTCN2021114580-appb-000071
Figure PCTCN2021114580-appb-000072
Figure PCTCN2021114580-appb-000072
Figure PCTCN2021114580-appb-000073
Figure PCTCN2021114580-appb-000073
Figure PCTCN2021114580-appb-000074
Figure PCTCN2021114580-appb-000074
Figure PCTCN2021114580-appb-000075
Figure PCTCN2021114580-appb-000075
上述实施例制备得到的化合物核磁数据如下:The NMR data of the compounds prepared in the above-described examples are as follows:
Figure PCTCN2021114580-appb-000076
Figure PCTCN2021114580-appb-000076
Figure PCTCN2021114580-appb-000077
Figure PCTCN2021114580-appb-000077
生物学测试评价Biological Test Evaluation
一、BaF3-Tel-FGFR2WT及各种突变FGFR2细胞增殖测定1. Proliferation assay of BaF3-Tel-FGFR2WT and various mutant FGFR2 cells
本发明实施例化合物采用在Baf细胞中通过转染的方法稳定的表达TEL-FGFR2WT胞内激酶结构域融合蛋白，或是包含FGFR2 V564I，V564F，V564L，N549K，K659M突变的胞内结构域融合蛋白的细胞株来测定Baf3-Tel-FGFR2WT及各种突变FGFR2细胞增殖效果。具体试验过程如下：The compounds of the examples of the present invention are used to stably express the TEL-FGFR2WT intracellular kinase domain fusion protein by transfection in Baf cells, or the intracellular domain fusion protein containing FGFR2 V564I, V564F, V564L, N549K, K659M mutations The cell lines were used to measure the proliferation effect of Baf3-Tel-FGFR2WT and various mutant FGFR2 cells. The specific test process is as follows:
1)将90μL细胞悬液在生长培养基(含有1％Glutamax、10％FBS和1％Pen/Strep的DMEM)中每孔总共2000～4000个细胞)接种在96孔板中，然后在37℃和5％CO 2下温育过夜。 1) Seed 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen/Strep in total 2000-4000 cells per well) in a 96-well plate, then incubate at 37°C and 5% CO 2 overnight.
2)将10μL含有测试化合物的10倍储备溶液的生长培养基添加到细胞培养物中(9个剂量点，3x连续稀释，从1μM开始，最终0.3％DMSO)。2) Add 10 [mu]L of growth medium containing 10x stock solutions of test compounds to cell cultures (9 dose points, 3x serial dilutions, starting at 1 [mu]M, final 0.3% DMSO).
3)在37℃和5％CO 2下温育48小时。 3) Incubate for 48 hours at 37°C and 5% CO2 .
4)将50μL体积的CellTiter Glo(CTG)试剂添加到含有细胞的96孔板中，将该板在室温下温育10分钟。4) A 50 μL volume of CellTiter Glo (CTG) reagent was added to a 96-well plate containing cells and the plate was incubated at room temperature for 10 minutes.
5)在具有发光检测模块的微板读数器上测量RLU(相对光单位)。将RLU值标准化为存活％，并且使用Prism绘制浓度-响应曲线，以计算IC 50(单位：nM)，试验结果如下表所示。 5) Measure RLU (relative light units) on a microplate reader with a luminescence detection module. RLU values were normalized to % survival and concentration-response curves were drawn using Prism to calculate IC50 (unit: nM) and the results of the experiments are shown in the table below.
Figure PCTCN2021114580-appb-000078
Figure PCTCN2021114580-appb-000078
Figure PCTCN2021114580-appb-000079
Figure PCTCN2021114580-appb-000079
二、BaF3-Tel-FGFR3WT，FGFR3V555M和FGFR3N540K细胞增殖测定2. BaF3-Tel-FGFR3WT, FGFR3V555M and FGFR3N540K cell proliferation assays
本发明实施例化合物采用在Baf细胞中通过转染的方法稳定的表达TEL-FGFR3WT胞内激酶结构域融合蛋白，或是包含FGFR3V555M或FGFR3N540K突变的胞内结构域融合蛋白的细胞株来测定细胞增殖效果。具体试验过程如下：The compounds of the examples of the present invention were used to stably express TEL-FGFR3WT intracellular kinase domain fusion protein by transfection in Baf cells, or a cell line containing FGFR3V555M or FGFR3N540K mutant intracellular domain fusion protein to measure cell proliferation Effect. The specific test process is as follows:
1)将90μL细胞悬液在生长培养基(含有1％Glutamax、10％FBS和1％Pen/Strep的DMEM)中每孔总共2000～4000个细胞)接种在96孔板中，然后在37℃和5％CO 2下温育过夜。 1) Seed 90 μL of cell suspension in growth medium (DMEM containing 1% Glutamax, 10% FBS, and 1% Pen/Strep in total 2000-4000 cells per well) in a 96-well plate, then incubate at 37°C and 5% CO 2 overnight.
2)将10μL含有测试化合物的10倍储备溶液的生长培养基添加到细胞培养物中(9个剂量点，3x连续稀释，从1μM开始，最终0.3％DMSO)。2) Add 10 [mu]L of growth medium containing 10x stock solutions of test compounds to cell cultures (9 dose points, 3x serial dilutions, starting at 1 [mu]M, final 0.3% DMSO).
3)在37℃和5％CO 2下温育48小时。 3) Incubate for 48 hours at 37°C and 5% CO2 .
4)将50μL体积的CellTiter Glo(CTG)试剂添加到含有细胞的96孔板中，将该板在室温下温育10分钟。4) A 50 μL volume of CellTiter Glo (CTG) reagent was added to a 96-well plate containing cells and the plate was incubated at room temperature for 10 minutes.
5)在具有发光检测模块的微板读数器上测量RLU(相对光单位)。将RLU值标准化为存活％，并且使用Prism绘制浓度-响应曲线，以计算IC 50(单位：nM)，试验结果如下表所示。 5) Measure RLU (relative light units) on a microplate reader with a luminescence detection module. RLU values were normalized to % survival and concentration-response curves were drawn using Prism to calculate IC50 (unit: nM) and the results of the experiments are shown in the table below.
Figure PCTCN2021114580-appb-000080
Figure PCTCN2021114580-appb-000080
Figure PCTCN2021114580-appb-000081
Figure PCTCN2021114580-appb-000081
从具体实施例化合物生物活性数据来看，本发明系列化合物在细胞水平上对野生型的FGFR和突变的FGFR都具有很强的抑制作用，且在突变中的抑制作用没有被削弱。Judging from the biological activity data of the compounds in the specific examples, the series of compounds of the present invention have strong inhibitory effects on both the wild-type FGFR and the mutant FGFR at the cellular level, and the inhibitory effect in the mutation is not weakened.
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公开内容之后，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 herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above disclosure 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 (14)

  1. 式(I)化合物、其立体异构体或其药学上可接受盐：A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021114580-appb-100001
    Figure PCTCN2021114580-appb-100001
    其中，
    Figure PCTCN2021114580-appb-100002
    是单键或双键；     in,
    Figure PCTCN2021114580-appb-100002
    is a single or double bond;
    X为C或N；Y为CR 5、N、NR 6、O或S；Z为CR 5或N； X is C or N; Y is CR 5 , N, NR 6 , O or S; Z is CR 5 or N;
    环A为3-12元含氮杂环基，所述氮原子与羰基连接；Ring A is a 3-12-membered nitrogen-containing heterocyclic group, and the nitrogen atom is connected to a carbonyl group;
    R 1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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-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 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代； R 1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl , 3-12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl- OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 ) -C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 , the above-mentioned groups The group is optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O) OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0- 8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 substituents are substituted;
    每个R 2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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10； Each R2 is independently selected from hydrogen , deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0 -8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl -C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
    每个R 3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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10； Each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0 -8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl -C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
    R 4选自乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、 氰基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-8环烷基、3-8元杂环基、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-C(O)-NR 7aR 7b和-C 0-8烷基-NR 7aR 7b的取代基所取代； R 4 is selected from vinyl or ethynyl, and the aforementioned groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, Deuterium substituted C 1-10 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C( O) R 10 , -C 0-8 alkyl-C(O)-NR 7a R 7b and -C 0-8 alkyl-NR 7a R 7b are substituted by substituents;
    每个R 5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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10； Each R 5 is independently selected from hydrogen, 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 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0 -8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl -C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl-C(O)NR 11 R 12 and -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
    R 6选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 5-10芳基和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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代； R 6 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl and 5-10 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from 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 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heterocycle Aryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkane base-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0-8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-8 alkyl- C(O)NR 11 R 12 and the substituents of -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
    R 7a和R 7b各自独立地选自氢、氘、羟基、C 1-10烷基、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-C(＝NR 11)R 10和-C 0-8烷基-C(O)NR 11R 12，或者，R 7a和R 7b与其直接相连的氮原子一起形成一个4-10元杂环基，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、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 8、-C 0-8烷基-O-R 9、-C 0-8烷基-C(O)OR 9、-C 0-8烷基-C(O)R 10、-C 0-8烷基-O-C(O)R 10、-C 0-8烷基-NR 11R 12、-C 0-8烷基-C(＝NR 11)R 10、-C 0-8烷基-N(R 11)-C(＝NR 12)R 10、-C 0-8烷基-C(O)NR 11R 12和-C 0-8烷基-N(R 11)-C(O)R 10的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O) R 10 , -C 0-8 alkyl-C(=NR 11 )R 10 and -C 0-8 alkyl-C(O)NR 11 R 12 , or, alternatively, the nitrogen atom to which R 7a and R 7b are directly attached together form a 4-10 membered heterocyclic group, the above-mentioned groups are optionally further substituted by one or more C 1- 10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl base, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 8 , -C 0-8 alkyl-OR 9 , -C 0-8 alkyl-C(O)OR 9 , -C 0-8 alkyl-C(O)R 10 , -C 0-8 alkyl-OC(O)R 10 , -C 0- 8 alkyl-NR 11 R 12 , -C 0-8 alkyl-C(=NR 11 )R 10 , -C 0-8 alkyl-N(R 11 )-C(=NR 12 )R 10 , - C 0-8 alkyl-C(O)NR 11 R 12 and the substituents of -C 0-8 alkyl-N(R 11 )-C(O)R 10 ;
    每个R 8各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 5-10芳基、5-10元杂芳基和-NR 11R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 11 R 12 ;
    每个R 9各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 5-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12的取代基所取代； Each R 9 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 5-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 11 R 12 ;
    每个R 10各自独立地选自氢、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 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12，上述基团独立地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 3-12环烷基、C 3-12环烷氧基、3-12元杂环 基、3-12元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 11R 12的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 11 R 12 substituents;
    每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12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C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基，上述基团独立地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 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12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C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Each of R 11 and R 12 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 5-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl groups, independently optionally further selected by one or more From 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 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5-10 aryl, C 5- Substitution of 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl base substituted;
    或者，R 11和R 12与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基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 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12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C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 11 and R 12 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected by one or more selected from 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 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 5 -10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and Substituents of C 1-10 alkanoyl groups are substituted;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    n为0、1、2、3或4；且n is 0, 1, 2, 3, or 4; and
    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、其立体异构体或其药学上可接受盐，其特征在于，R 1选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-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 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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10的取代基所取代； The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0 -4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl -C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 , the above-mentioned groups are optionally further selected by one or more groups selected from deuterium, halogen, cyano, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5 -8 -aryl, 5-8-membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl -OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , - C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , substituted by the substituents of -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl-N(R 11 )-C(O)R 10 ;
    每个R 2各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10； Each R 2 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0- 4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(= NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0- 4 alkyl-N(R 11 )-C(O)R 10 ;
    每个R 3各自独立地选自氢、氘、卤素、氰基、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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4 烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10； Each R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, Deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl -C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 ) R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0-4 alkyl -N(R 11 )-C(O)R 10 ;
    每个R 5各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10； Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkyl-C(O)OR 9 , -C 0- 4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(= NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl-C(O)NR 11 R 12 and -C 0- 4 alkyl-N(R 11 )-C(O)R 10 ;
    R 6选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基和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、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10的取代基所取代； R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl and 5-8 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heterocyclyl Aryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkane base-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl- C(O)NR 11 R 12 and the substituents of -C 0-4 alkyl-N(R 11 )-C(O)R 10 ;
    R 7a和R 7b各自独立地选自氢、氘、羟基、C 1-4烷基、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-C(＝NR 11)R 10和-C 0-4烷基-C(O)NR 11R 12，或者，R 7a和R 7b与其直接相连的氮原子一起形成一个4-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 8、-C 0-4烷基-O-R 9、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-O-C(O)R 10、-C 0-4烷基-NR 11R 12、-C 0-4烷基-C(＝NR 11)R 10、-C 0-4烷基-N(R 11)-C(＝NR 12)R 10、-C 0-4烷基-C(O)NR 11R 12和-C 0-4烷基-N(R 11)-C(O)R 10的取代基所取代； R 7a and R 7b are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C(O) R 10 , -C 0-4 alkyl-C(=NR 11 )R 10 and -C 0-4 alkyl-C(O)NR 11 R 12 , or, alternatively, the nitrogen atom to which R 7a and R 7b are directly attached together form a 4-8 membered heterocyclic group, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heterocycle Aryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-OR 9 , -C 0-4 alkane base-C(O)OR 9 , -C 0-4 alkyl-C(O)R 10 , -C 0-4 alkyl-OC(O)R 10 , -C 0-4 alkyl-NR 11 R 12 , -C 0-4 alkyl-C(=NR 11 )R 10 , -C 0-4 alkyl-N(R 11 )-C(=NR 12 )R 10 , -C 0-4 alkyl- C(O)NR 11 R 12 and the substituents of -C 0-4 alkyl-N(R 11 )-C(O)R 10 ;
    其中，R 4、R 8、R 9、R 10、R 11、R 12和r如权利要求1所定义。 wherein R 4 , R 8 , R 9 , R 10 , R 11 , R 12 and r are as defined in claim 1 .
  3. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，所述的式(I)化合物具有式(Ⅱa)或式(Ⅱb)化合物结构：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound of formula (I) has the structure of compound of formula (IIa) or formula (IIb) :
    Figure PCTCN2021114580-appb-100003
    Figure PCTCN2021114580-appb-100003
    其中，在式(Ⅱa)化合物中，Y 1为NR 6、O或S；在式(Ⅱb)化合物中，Y 2为CR 5或N； Wherein, in the compound of formula (IIa), Y 1 is NR 6 , O or S; in the compound of formula (IIb), Y 2 is CR 5 or N;
    每个Z各自独立地为CR 5或N； each Z is independently CR 5 or N;
    每个环A各自独立地为3-8元含氮杂环基，所述氮原子与羰基连接；Each Ring A is independently a 3-8 membered nitrogen-containing heterocyclic group, and the nitrogen atom is attached to a carbonyl group;
    每个R 1各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-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 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 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10的取代基所取代； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O ) R 10 , the above-mentioned groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, =O, - SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(= Substituents substituted by NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;
    每个R 2a和R 2b各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10； Each of R 2a and R 2b is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C (O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 ) R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;
    每个R 4各自独立地为乙烯基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、氰基、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、3-6元杂环基、-C 0-4烷基-C(O)OR 9、-C 0-4烷基-C(O)R 10、-C 0-4烷基-C(O)-NR 7aR 7b和-C 0-4烷基-NR 7aR 7b的取代基所取代； Each R 4 is each independently vinyl, and the aforementioned groups are independently optionally further substituted with one or more C 1-4 alkyl groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl , deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-C(O)OR 9 , -C 0-4 alkyl-C (O) R 10 , -C 0-4 alkyl-C(O)-NR 7a R 7b and -C 0-4 alkyl-NR 7a R 7b substituents;
    每个R 5各自独立地选自氢、氘、卤素、氰基、硝基、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 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10； Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O) OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O)R 10 ;
    R 6选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基和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、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10的取代基所取代； R 6 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl and 5-8 membered Heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from 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 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heterocyclyl Aryl, =O, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N(R 11 )-C(O) Replaced by the substituent of R 10 ;
    每个R 7a和R 7b各自独立地选自氢、氘、羟基、C 1-4烷基、-C(O)OR 9、-C(O)R 10、-C(＝NR 11)R 10和-C(O)NR 11R 12，或者，R 7a和R 7b与其直接相连的氮原子一起各自独立地形成一个4-6元杂环基，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、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-SF 5、-S(O) rR 8、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10、-NR 11R 12、-C(＝NR 11)R 10、-N(R 11)-C(＝NR 12)R 10、-C(O)NR 11R 12和-N(R 11)-C(O)R 10的取代基所取代； Each of R 7a and R 7b is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, -C(O)OR 9 , -C(O)R 10 , -C(=NR 11 )R 10 and -C(O)NR 11 R 12 , alternatively, R 7a and R 7b together with the nitrogen atom to which they are directly attached each independently form a 4-6 membered heterocyclic group optionally further selected by one or more From deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF 5 , -S(O) r R 8 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC (O)R 10 , -NR 11 R 12 , -C(=NR 11 )R 10 , -N(R 11 )-C(=NR 12 )R 10 , -C(O)NR 11 R 12 and -N (R 11 )-C(O) R 10 is substituted by the substituent;
    其中，R 8、R 9、R 10、R 11、R 12和r如权利要求1所定义。 wherein R 8 , R 9 , R 10 , R 11 , R 12 and r are as defined in claim 1 .
  4. 根据权利要求3所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在 于，每个环A各自独立地为：
    Figure PCTCN2021114580-appb-100004
    The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, wherein each ring A is independently:
    Figure PCTCN2021114580-appb-100004
  5. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，所述的式(I)化合物具有式(Ⅲa)或式(Ⅲb)化合物结构：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound of formula (I) has the structure of compound of formula (IIIa) or (IIIb) :
    Figure PCTCN2021114580-appb-100005
    Figure PCTCN2021114580-appb-100005
    其中，在式(Ⅲa)化合物中，Y 1为O或S； Wherein, in the compound of formula (IIIa), Y 1 is O or S;
    每个R 1各自独立地选自氢、氘、卤素、氰基、甲基、C 3-4环烷基、3-4元杂环基、-SF 5、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10和-NR 11R 12，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、C 1-2烷基、卤取代C 1-2烷基、氘取代C 1-2烷基、C 3-6环烷基、3-6元杂环基、＝O、-SF 5、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10和-NR 11R 12的取代基所取代； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl, C 3-4 cycloalkyl, 3-4 membered heterocyclyl, -SF 5 , -OR 9 , -C(O) OR 9 , -C(O)R 10 , -OC(O)R 10 and -NR 11 R 12 , the above-mentioned groups are optionally further selected by one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, C 1-2 alkyl, halogen-substituted C 1-2 alkyl, deuterium-substituted C 1-2 alkyl, C 3-6 cycloalkyl, 3-6-membered heterocyclyl, =O, -SF 5 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 and -NR 11 R 12 are substituted with substituents;
    每个R 2a和R 2b各自独立地选自氢、氘、氟、氯、溴、氰基、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、-SF 5、-O-R 9、-C(O)OR 9、-C(O)R 10、-O-C(O)R 10和-NR 11R 12； Each of R 2a and R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-4 alkyl, halo-substituted C1-4 alkyl, deuterium substituted C1-4 alkyl, C 3-6 cycloalkyl, -SF 5 , -OR 9 , -C(O)OR 9 , -C(O)R 10 , -OC(O)R 10 and -NR 11 R 12 ;
    其中，R 9、R 10、R 11和R 12如权利要求1所述。 wherein, R 9 , R 10 , R 11 and R 12 are as described in claim 1 .
  6. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 8独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基和-NR 11R 12，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12的取代基所取代； The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl , C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl and -NR 11 R 12 , the above groups are independent optionally further selected by one or more selected from deuterium, halogen, hydroxyl, oxo, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy base, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 11 R 12 substituents are substituted;
    每个R 9独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 5-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、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、3-6元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12的取代基所取代； Each R is independently selected from hydrogen, deuterium , C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl and 5-8-membered heteroaryl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5 -8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 substituents;
    每个R 10选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、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、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12，上述基团独立地任选进一步被一个或多个选自氘、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、3-6元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 11R 12的取代基所取代； Each R 10 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5-8 aryl substituted by the substituents of oxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 11 R 12 ;
    每个R 11和R 12各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8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C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、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 1-4烷氧基、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、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each of R 11 and R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, 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 1 -4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5-8 aryl, C 5- Substitution of 8 -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl base substituted;
    或者，R 11和R 12与其直接相连的氮原子一起形成一个4-10元杂环基或5-10元杂芳基，所述4-10元杂环基或5-10元杂芳基任选进一步被一个或多个选自氘、卤素、羟基、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 1-4烷氧基、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、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 11 and R 12 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 5-10-membered heteroaryl group, the 4-10-membered heterocyclic group or the 5-10-membered heteroaryl group being either is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, 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 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 5 -8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and Substituents of C 1-4 alkanoyl.
  7. 根据权利要求6所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 1各自独立地选自氢、氘、卤素、氰基、甲基、乙基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、-SF 5、甲氧基、乙氧基、羧基、乙酰基、乙酰氧基、氨基、甲氨基和二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、＝O、-SF 5、甲氧基、乙氧基、羧基、乙酰基、乙酰氧基、氨基、甲氨基和二甲氨基的取代基所取代； The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 6, wherein each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, methyl , ethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, -SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and Dimethylamino, the above-mentioned groups are optionally further selected by one or more groups selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, propyl, cyclobutyl, oxetanyl, azetidine, =O, -SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethyl Substituted by amino substituent;
    每个R 2a和R 2b各自独立地选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丁基、氮杂环丁基、-SF 5、甲氧基、乙氧基、羧基、乙酰基、乙酰氧基、氨基、甲氨基和二甲氨基。 Each R 2a and R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, Di-deuteromethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidine, -SF5 , methoxy, ethoxy, carboxyl, acetyl, acetoxy, amino, methylamino and dimethylamino.
  8. 根据权利要求1-7任一项所述的式(I)化合物、其立体异构体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), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that, it is selected from the following compounds:
    Figure PCTCN2021114580-appb-100006
    Figure PCTCN2021114580-appb-100006
    Figure PCTCN2021114580-appb-100007
    Figure PCTCN2021114580-appb-100007
  9. 权利要求1-8任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：The preparation method of the compound of formula (I) according to any one of claims 1-8, its stereoisomer or its pharmaceutically acceptable salt, comprising the steps:
    Figure PCTCN2021114580-appb-100008
    Figure PCTCN2021114580-appb-100008
    或者，or,
    Figure PCTCN2021114580-appb-100009
    Figure PCTCN2021114580-appb-100009
    其中，环A、X、Y、Z、R 1、R 2、R 3、R 4、m和n如权利要求1所定义。 wherein rings A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , m and n are as defined in claim 1 .
  10. 一种药物组合物，其包括权利要求1-8任一项所述的式(I)化合物、其立体异构体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 1-8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  11. 权利要求1-8任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备用于治疗对FGFR抑制剂具有耐受性的肿瘤患者的药物中的应用，所述肿瘤患者为在FGFR V561、V565、N550、N540、V555、E566、K660和/或V550具有突变的肿瘤患者；The application of the compound of formula (I) described in any one of claims 1-8, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a medicine for the treatment of a tumor patient that is resistant to an FGFR inhibitor , the tumor patient is a tumor patient with a mutation in FGFR V561, V565, N550, N540, V555, E566, K660 and/or V550;
    优选的，所述肿瘤患者为在具有FGFR2 V565F、V565I、V565L、V565M、N550K、N550H、E566A、E566G、K660M和/或K660Q突变的肿瘤患者；Preferably, the tumor patient is a tumor patient with FGFR2 V565F, V565I, V565L, V565M, N550K, N550H, E566A, E566G, K660M and/or K660Q mutations;
    优选的，所述肿瘤患者为具有FGFR3 V555M、V555L和/或N540K突变的肿瘤患者。Preferably, the tumor patient is a tumor patient with FGFR3 V555M, V555L and/or N540K mutations.
  12. 权利要求1-8任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其用于预防或治疗由FGFR激酶介导的肿瘤或癌症，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 compound of formula (I) described in any one of claim 1-8, its stereoisomer or its pharmaceutically acceptable salt, it is used for preventing or treating tumor or cancer mediated by FGFR kinase, described tumor Or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, stomach 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, Waldenstrom's macroglobulinemia disease, hair-like lymphoma, cellular lymphoma, Burkitt lymphoma, glioblastoma, melanoma, or rhabdomyosarcoma.
  13. 权利要求1-8任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备用于治疗骨髓增生性疾病、骨骼或软骨细胞紊乱、或低磷血症的药物中的应用；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)、阿佩尔氏综合症、克鲁松氏综合症、Jackson-Weiss综合症、Beare-Stevenson皮肤回纹综合症、Pfeiffer综合症或颅肌萎缩综合症；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。A compound of formula (I) according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in preparation for the treatment of myeloproliferative diseases, skeletal or chondrocyte disorders, or hypophosphatemia the application in the medicine; the myeloproliferative disease is selected from polycythemia, essential thrombocythemia or primary myelofibrosis; the bone or chondrocyte disorder is selected from dysplasia, chondrodysplasia, Dwarfism, fatal teratogenicity (TD), Appel's syndrome, Crusson's syndrome, Jackson-Weiss syndrome, Beare-Stevenson dermatoglyphic syndrome, Pfeiffer syndrome, or cranial muscular dystrophy syndrome; The hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or tumor-induced ovarian softening.
  14. 根据权利要求1-8任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其用于选择性的FGFR 2和/或FGFR 3抑制剂来治疗和FGFR2或FGFR3受体异常表达，突变或相应配体异常表达及活性异常相关的疾病的用途。A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, for use as a selective FGFR2 and/or FGFR3 inhibitor for the treatment of and FGFR2 Or the use of FGFR3 receptor abnormal expression, mutation or abnormal expression and activity of corresponding ligand related diseases.
PCT/CN2021/114580 2020-08-27 2021-08-25 Dihydropyrrolo[2,3-d]pyridazin-7-one derivative, preparation method therefor, and application thereof WO2022042612A1 (en)

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