WO2024002223A1 - Dérivé hétérocyclique utilisé comme inhibiteur, son procédé de préparation et son utilisation - Google Patents

Dérivé hétérocyclique utilisé comme inhibiteur, son procédé de préparation et son utilisation Download PDF

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WO2024002223A1
WO2024002223A1 PCT/CN2023/103743 CN2023103743W WO2024002223A1 WO 2024002223 A1 WO2024002223 A1 WO 2024002223A1 CN 2023103743 W CN2023103743 W CN 2023103743W WO 2024002223 A1 WO2024002223 A1 WO 2024002223A1
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alkyl
group
alkoxy
deuterated
amino
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PCT/CN2023/103743
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Chinese (zh)
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曾蜜
高鹏
曾明高
杜坚钢
程宇
俞文胜
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Publication of WO2024002223A1 publication Critical patent/WO2024002223A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to a heterocyclic derivative inhibitor and its preparation method and application.
  • FGFR Fibroblast Growth Factor Receptor
  • FGFR a tyrosine kinase
  • FGFR1 FGFR2, FGFR3, and FGFR4.
  • FGFR dimerizes and autophosphorylates, thereby activating downstream signaling pathways: RAS-RAF-MAPK, PI3K-AKT, STAT and PLC ⁇ .
  • FGFR-mediated signal transduction plays an important role in cell proliferation, migration, differentiation and survival.
  • FGFR1 amplification aberrations are present in approximately 20% of lung squamous cell carcinomas and approximately 20% of breast cancers.
  • FGFR2 rearrangement aberrations are present in approximately 15% of cholangiocarcinomas, FGFR2 point mutations are present in approximately 10% of endometrial cancers, and FGFR2b amplification is present in approximately 10% of gastric cancers.
  • FGFR3 point mutations are present in approximately 20% of metastatic urothelial carcinomas.
  • FGFR inhibitors have good application prospects as drugs in the pharmaceutical industry. They are expected to become first-line therapy for cholangiocarcinoma and a new option for targeted cancer treatment regardless of cancer types. They are expected to be used for cancer patients with multiple FGFR aberrations.
  • the current standard treatment for cholangiocarcinoma is chemotherapy, which has a poor prognosis and no second-line therapy.
  • the current main problem with FGFR inhibitors is that patients develop drug resistance about 7 months after taking the drugs.
  • drugs related to FGFR1 targets are associated with hyperphosphatemia. toxicity.
  • the object of the present invention is to provide novel compounds having FGFR inhibitory activity and useful as anticancer agents.
  • the object of the present invention is to provide a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows:
  • Ring A is a monocyclic heteroaryl group
  • M 1 is N or CR m1 ;
  • M 2 is N or CR m2 ;
  • L 1 , L 2 and L 3 are each independently selected from bond, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CH 2 ) n C(O) (CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CR aa R bb ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH 2 ) n NR cc -, -(CH 2 ) n NR aa (CR b
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkyl Oxygen, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a , -C(O)R a , -SR a , S(O)R a or S(O) 2 R a , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl
  • the radical may optionally be further substituted;
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b , -C(O)R b , -SR b , S(O)R b or S(O ) 2 R b , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups may optionally be further substituted;
  • R 3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR c , -C(O)R c , -SR c , S(O)R c or S(O ) 2 R c , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups may optionally be further substituted;
  • R 4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR d , -C(O)R d , -SR d , S(O)R d or S(O ) 2 R d , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;
  • R 5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR e , -C(O)R e , -SR e , S(O)R e or S(O ) 2 R e , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl groups may optionally be further substituted;
  • R m1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkyl Oxygen, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR f , -C(O)R f , -SR f , S(O)R f or S(O) 2 R f , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl
  • the radical may optionally be further substituted;
  • R m2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkyl Oxygen, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g , -C(O)R g , -SR g , S(O)R g or S(O) 2 Rg , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl
  • the radical may optionally be further substituted;
  • one of R 2 and one of R 3 are connected to adjacent atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups Optionally may be further substituted;
  • one of R 3 and one of R 4 are connected to adjacent atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups Optionally may be further substituted;
  • R a , R b , R c , R d , Re , R f and R g are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, Oxo group, thio group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, the amino group, alkyl group , alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl any Site selections can be further substituted;
  • R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, Haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkyl Oxygen, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be further substituted;
  • R aa and R bb form a cycloalkyl, heterocyclyl, aryl or heteroaryl group with adjacent atoms, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further replace;
  • R bb and R cc form a cycloalkyl, heterocyclyl, aryl or heteroaryl group with adjacent atoms, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further replace;
  • x 0, 1, 2, 3, 4, 5 or 6;
  • y is 0, 1, 2, 3, 4, 5 or 6;
  • z 0, 1, 2, 3, 4, 5 or 6;
  • p 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • n, n1, n2, n3 and n4 are each independently 0, 1, 2 or 3.
  • the compound is represented by formula (II), formula (II-1), formula (II-2) or formula (II-3),
  • Ring A is a heteroaryl group, and the heteroaryl group is a monocyclic heteroaryl group or a polycyclic heteroaryl group;
  • L 1 is selected from -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CR aa R bb ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH 2 ) n1 -;
  • R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3 -8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , Deuterated C 1-6 alkyl, Halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 ring Alkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 aryl or 5-14-membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3- 8- cycloalkyl, 3-12-membered heterocyclyl, C 6-14 aryl,
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 3- 8 cycloalkyl substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halosubstituted C 1-6 alkyl, C 1-6 alkyl Oxygen group, halogenated C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 aryl group, 5-14 membered heteroaryl group base, -C 1-6 alkyl -R c , -NHR c , -OR c , -C(O)R c , -SR c , S(O)R c or S(O) 2 R c
  • R c is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , C 1- 6- hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclyl, C 6-14- membered aryl or 5-14-membered heteroaryl, the amino, hydroxyl, C 1-6 alkyl substituted Amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl
  • R c is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 yuan Heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3- 8- cycloalkyl, 3-12-membered heterocyclyl, C 6-14- membered aryl or 5-14-membered heteroaryl;
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano , nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl base, 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group , Deuterated C 1-6 alkyl, Halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 ring Alkyl, 3-12-membered heterocyclyl, C 6-14 aryl
  • one of R 2 and one of R 3 are connected to adjacent atoms to form a C 3-8 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, so
  • the above-mentioned C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl may optionally be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano , nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14
  • one of R 3 and one of R 4 are connected to adjacent atoms to form a C 3-8 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, so
  • the above-mentioned C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl may optionally be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano , nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14
  • x 0, 1, 2, 3, 4, 5 or 6;
  • y is 0, 1, 2, 3, 4, 5 or 6;
  • z 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2 or 3;
  • n1 0, 1, 2 or 3;
  • n2 is 0, 1, 2 or 3.
  • Ring A is selected from monocyclic heteroaryl or polycyclic heteroaryl
  • the monocyclic heteroaryl group is preferably a 5- to 12-membered heteroaryl group; more preferably a 5- or 6-membered heteroaryl group; and further preferably a 5- to 6-membered heteroaryl group containing 1 to 3 N, O or S atoms. base;
  • the monocyclic heteroaryl group is preferably
  • the monocyclic heteroaryl group is more preferably the following group:
  • the compound is such as formula (III), formula (III-1), formula (III-2), formula (III-3), formula (III-4), formula (III -5), formula (III-6), formula (III-7) or formula (III-8)
  • Ring B is independently a 5-10-membered heterocyclic group, preferably a nitrogen-containing 5-10-membered heterocyclic group, more preferably a 5-7-membered heterocyclic group containing one nitrogen atom, and further preferably
  • Ring C is a 5-10-membered heterocyclic group, preferably a nitrogen-containing 5-10-membered heterocyclic group, more preferably a 3-6-membered heterocyclic group containing one nitrogen atom, and further preferably
  • L 1 is selected from -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CR aa R bb ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH 2 ) n1 -;
  • L 4 is selected from -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CR aa R bb ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 - or -(CR aa R bb ) n O(CH 2 ) n1 -, preferably -C(O)-;
  • R aa and R bb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy , C 1-6 hydroxyalkyl;
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , Deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 ring Alkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, the amino group, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkyne base, deuterated C 1-3 alkyl, halo C 1-3 alkyl , C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 member
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3 -6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, the amino group, C 1-3 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocycle group, C 6
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3- 6- cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl or 5-6-membered heteroaryl, the amino group, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3 -6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 ary
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 31 , R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1- 6 alkyl, C 3-8 cycloalkyl substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl base, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-12 membered heterocyclyl group, C 6-14 aryl group , 5-14 membered heteroaryl, -C 1-6 alkyl -R c , -NHR c , -OR c , -C(O)R c , -SR c , S(O)R c or S(O ) 2 R
  • R 31 , R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 3-8 cycloalkyl substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , deuterated C 1-6 alkyl, halogenated C 1 -6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6- 14 aryl, 5-14 membered heteroaryl, -OR c , -C(O)R c , -SR c , S(O)R c or S(O) 2 R c ; preferably, R 31 , R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen,
  • R c is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , C 1- 6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 4 , R 10 , R 11 and R 12 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3- 8- cycloalkyl, 3-12-membered heterocyclyl, C 6-14 aryl or 5-14-membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3 -8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 ary
  • u 0, 1, 2, 3, 4, 5 or 6;
  • v 0, 1, 2, 3, 4, 5 or 6;
  • w 0, 1, 2, 3, 4, 5 or 6;
  • x 0, 1, 2, 3, 4, 5 or 6;
  • z 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2 or 3;
  • n1 0, 1, 2 or 3;
  • n2 is 0, 1, 2 or 3.
  • the compound is represented by formula (IV):
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , Deuterated C 1-6 alkyl, Halogenated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 ring Alkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heterocyclic group Aryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, deuterated C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1- 6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 32 is selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 3-8 ring Alkyl-substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halosubstituted C 1-6 alkyl, C 1-6 alkoxy , Halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -C 1-6 alkyl -R c , -NHR c , -OR c , -C(O)R c , -SR c , S(O)R c or S(O) 2 R c ;
  • R c is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , C 1- 6 -hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R 4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3- 8- cycloalkyl, 3-12-membered heterocyclyl, C 6-14- membered aryl or 5-14-membered heteroaryl;
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl base, 3-12 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group , Deuterated C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 ring Alkyl, 3-12-membered heterocyclyl, C 6-14
  • x 0, 1, 2, 3, 4, 5 or 6;
  • z 0, 1, 2, 3, 4, 5 or 6.
  • the compound is represented by formula (V):
  • R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl , halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy , C 1- 3 -hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino group, C 1-3 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1 -3- hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy , halo C 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 32 is selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 3-6 ring Alkyl-substituted C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halosubstituted C 1-3 alkyl, C 1-3 alkoxy , Halogenated C 1-3 alkoxy group, C 1-3 hydroxyalkyl group, C 3-6 cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 aryl group, 5-10 membered heteroaryl group, -C 1-6 alkyl -R c , -NHR c , -OR c , -C(O)R c , -SR c , S(O)R c or S(O) 2 R c ;
  • R c is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl , deuterated C 1-3 alkyl , halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1- 3 -hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3- 6- cycloalkyl, 3-8-membered heterocyclyl, C 6-10- membered aryl or 5-10-membered heteroaryl;
  • R 6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl base, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; the amino group, C 1-3 alkyl, C 2-4 alkene Base, C 2-4 alkynyl group, deuterated C 1-3 alkyl group, halogenated C 1-3 alkyl group , C 1-3 alkoxy group, halogenated C 1-3 alkoxy group, C 1-3 hydroxyl group Alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroary
  • the compound is represented by formula (VI):
  • R 11 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , Deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 ring Alkyl or 3-8 membered heterocyclyl;
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy , halo C 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclyl;
  • R 32 is selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 3-6 ring Alkyl-substituted C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halosubstituted C 1-3 alkyl, C 1-3 alkoxy , halogenated C 1-3 alkoxy group, C 1-3 hydroxyalkyl group, C 3-6 cycloalkyl group or 3-8 membered heterocyclyl group;
  • R 4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3- 6- cycloalkyl or 3-8 membered heterocyclyl;
  • R 6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclyl ;
  • q 1, 2, 3 or 4.
  • R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano Base, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl base, C 1-3 alkoxy group, halogenated C 1-3 alkoxy group, C 1-3 hydroxyalkyl group, C 3-6 cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 aryl group Or 5-6 membered heteroaryl, the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 Alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membere
  • R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkene Base, C 2-4 alkynyl group, deuterated C 1-3 alkyl group, halogenated C 1-3 alkyl group, C 1-3 alkoxy group, halogenated C 1-3 alkoxy group, C 1-3 hydroxyl group Alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, the amino group, C 1-3 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy , C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocycly
  • R 1 is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 3-6 cycloalkyl , 3-8 membered heterocyclic group, C 6-10 aryl group or 5-6 membered heteroaryl group, the C 1-3 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1 -3 alkoxy, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl may optionally be further substituted by hydrogen, deuterium, halogen, amino, Hydroxy, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1 -Substituted with one or more of -3 alkyl, C 1-3 alkyl, C 1-3 al
  • R 1 is selected from C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, and said C 3 -6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl may optionally be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, Oxo group, thio group, C 1-3 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, deuterated C 1-3 alkyl group, halogenated C 1-3 alkyl group, C 1- Substituted with one or more of 3 alkoxy, halogenated C 1-3 alkoxy and C 1-3 hydroxyalkyl.
  • R1 is selected from
  • R1 is selected from
  • R1 is selected from or cyclobutyl, the Or cyclobutyl optionally may be further substituted by hydrogen or methyl.
  • L 1 is -O-, -C(O)NHCH 2 -, or -C(O)NH-.
  • L 1 is -O- or -C(O)NHCH 2 -.
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • R2 is independently selected from hydrogen, fluorine, methoxy, or deuterated methoxy.
  • R2 is independently selected from hydrogen, fluorine, or methoxy.
  • L2 is a bond
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 3-6 cycloalkyl substituted C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1 -3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl group, 5-6 membered heteroaryl group, -OR c , -C(O)R c , -SR c , S(O)R c or S(O) 2 R c .
  • Rc is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • R3 is independently selected from hydrogen, methyl, -C(O) NH2 , ethyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, methoxy , amino, oxo, cyclopropyl-methyl-, -NHCH 3 , -NH-tert-butyl or
  • R3 is independently selected from methyl, -C(O) NH2 , ethyl, ethynyl, cyclopropyl, trifluoromethyl, methoxy, amino, oxo base, cyclopropyl-methyl-, -NHCH 3 or
  • R 4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • R4 is independently selected from hydrogen, fluoro, methyl, or methoxy.
  • R4 is independently selected from hydrogen, fluorine, and methyl.
  • R 10 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • R 11 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • R 12 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • L3 is a bond
  • one of R 2 and one of R 3 are connected to adjacent atoms to form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5 -8-membered heteroaryl
  • the C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl and 5-8-membered heteroaryl may optionally be further replaced by hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl , one or more substitutions among halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy and C 1-3 hydroxyalkyl.
  • one of R 3 and one of R 4 are connected to adjacent atoms to form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5 -8-membered heteroaryl
  • the C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl and 5-8-membered heteroaryl may optionally be further replaced by hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterium Substituted with one or more of C 1-3 alkyl halo, C 1-3 alkyl halo, C 1-3 alkoxy, C 1-3 alkoxy halo and C 1-3 hydroxyalkyl.
  • one of R 3 and one of R 4 are connected to adjacent atoms to form
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl; the amino group, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, deuterium Substituted C 1-3 alkyl, halo substituted C 1-3 alkyl, C 1-3 alkoxy or halo substituted C 1-3 alkoxy; the said C 1-3 alkyl, deuterated C 1- 3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkoxy may optionally be further substituted by hydrogen, deuterium, halogen, amino, C 1-3 alkyl Substituted one or more of amino, hydroxyl, cyano, nitro, oxo, thio and C 1-3 alkyl.
  • R 3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl group, 5-14 membered heteroaryl group, -OR c , -C(O)R c , -SR c , S(O) R c or S(O) 2 R c , so
  • R 31 is hydrogen, deuterium, C 1-3 alkyl.
  • R 32 is C 1-3 alkyl, C 2-4 alkenyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkyl Oxygen group, halogenated C 1-3 alkoxy group, C 1-3 hydroxyalkyl group.
  • R 33 is -C(O)R c .
  • Rc is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;
  • Optionally can be further hydrogen, deuterium, halogen, amino, hydroxyl, cyano,
  • one of R 3 and one of R 4 are connected to adjacent atoms to form a C 3-8 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-14 aryl group or a 5 -14-membered heteroaryl
  • the C 3-8 cycloalkyl, 3-12-membered heterocyclyl, C 6-14- membered aryl and 5-14-membered heteroaryl may optionally be further replaced by hydrogen, deuterium, Halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, deuterated C 1-3 alkyl, Halogenated C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 3-6 cycloalkyl, 3-8 membered heterocyclyl , C 6-10 aryl group, 5-6
  • R 1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl group, 5-14 membered heteroaryl group, -OR a , -C(O)R a , -SR a , S(O)R a or S(O) 2 R a , so
  • R is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;
  • Optionally can be further hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro,
  • Ring B is C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aromatic group or 5-14-membered heteroaryl; preferably, ring B is C 3-6 cycloalkyl or 5-6-membered heteroaryl.
  • Ring B is Or cyclobutyl.
  • R 8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl group, 5-14 membered heteroaryl group, -OR h , -C(O)R h , -SR h , S(O ) R h or S(O) 2 R h , so
  • Rh is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;
  • Optionally can be further hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro
  • R8 is independently hydrogen or methyl.
  • L 1 is selected from the group consisting of bonds, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CR aa R bb ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 (CH 2 ) n NR cc -, -(CH 2 ) n NR aa (CR bb R cc ) n -, -(CH 2 ) n NR aa C(O)- .
  • R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, the amino group, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1- 6- hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclyl,
  • L 1 is -O- or -C(O)NHCH 2 -.
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl group, 5-14 membered heteroaryl group, -OR b , -C(O)R b , -SR b , S(O ) R b or S(O) 2 R b , so
  • R b is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;
  • Optionally can be further hydrogen, deuterium, halogen, amino, hydroxyl, cyano,
  • R2 is independently hydrogen, fluoro, or methoxy.
  • R2 is independently hydrogen, fluoro, methoxy, or deuterated methoxy.
  • R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl group, 5-14 membered heteroaryl group, -OR f , -C(O)R f , -SR f , S(O)R f or S(O) 2 R f , so
  • Rf is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;
  • Optionally can be further hydrogen, deuterium, halogen, amino, hydroxyl, cyano,
  • R6 is hydrogen, fluorine or methyl, preferably fluorine.
  • R6 is hydrogen or fluorine.
  • R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl group, 5-14 membered heteroaryl group, -OR g , -C(O)R g , -SR g , S(O)R g or S(O) 2 R g , so
  • Rg is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;
  • Optionally can be further hydrogen, deuterium, halogen, amino, hydroxyl, cyano,
  • R7 is hydrogen or fluorine.
  • L3 is a bond
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyanide Base, nitro, oxo, thio , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl Base, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -OR d , -C(O) R d , -SR d , S(O)R d or S(O) 2 R d , the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12
  • Rd is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl or 5-14 membered heteroaryl; the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl;
  • Optionally can be further hydrogen, deuterium, halogen, amino, hydroxyl, cyano,
  • R4 is independently selected from hydrogen, fluoro, methyl, or methoxy.
  • R4 is independently selected from hydrogen, fluorine, and methyl.
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12-membered hetero Ring group, C 6-14 aryl group, 5-14 membered heteroaryl group, -OR e , -C(O)R e , -SR e , S(O)R e or S(O) 2 R e , so
  • R5 is vinyl
  • L 1 is selected from -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CR aa R bb ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 - or -(CR aa R bb ) n O(CH 2 ) n1 -;
  • R aa and R bb are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, thio, C 1-3 alkyl, deuterated C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • base C 1-3 alkoxy group, halogenated C 1-3 alkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, oxo group, thio group, methyl, ethyl, propyl group base, isopropyl, methoxy, ethoxy or propoxy;
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , Deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 ring Alkyl group, 3-6 membered heterocyclyl group containing 1-3 N, O or S atoms, C 6-10 aryl group or 5-6 membered heteroaryl group containing 1-3 N, O or S atoms, Described amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy base, halogenated C 1-3 alkoxy group, C 1-3 hydroxyal
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkyne base, deuterated C 1-3 alkyl, halo C 1-3 alkyl , C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, C 6-10 aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms , the described amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkyl Oxygen group , halogenated C 1-3 alkoxy group, C 1-3 hydroxyalkyl group,
  • R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, methyl, ethyl, propyl, isopropyl, vinyl, propenyl , allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, containing 1-3 fluorine, chlorine or bromine Substituted methyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine , methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, deuterated C 1-3 alkoxy or C 1-3 hydroxyalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl , ethyl, propyl, isopropyl, hydroxyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy Base, deuterated ethoxy group, deuterated propoxy group, methyl group containing 1-3 fluorine, chlorine or bromine substitutions, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, 1-3 fluorine groups , chlorine or
  • R 31 , R 32 and R 33 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxyl, cyano, nitro , oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterium Propyl group, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions, Methoxy, ethoxy, propoxy, containing 1-3 fluorine, chlorine or bromine substituted ethoxy, containing 1-3 fluorine, chlorine or
  • R c is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 alkyl substituted amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl , deuterated C 1-3 alkyl , halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1- 3 -hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, the amino group, C 1-3 alkyl substituted amino group , hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, Halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6
  • R c is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxyl, cyano, nitro, oxo, sulfide Substitute, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, including 1 - 3 fluorine, chlorine or bromine substituted ethyl groups, 1 to 3 fluorine, chlorine or bromine substituted propyl groups, 1 to 3 fluorine, chlorine or bromine substituted isopropyl groups, methoxy, ethoxy base, propoxy group, ethoxy group containing 1-3 fluorine, chlorine or bromine substitutions, propoxy group containing 1-3 fluorine, chlorine
  • R 4 , R 10 , R 11 and R 12 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy , C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, Nitro, methyl, B base, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl containing 1-3 fluorine, chlorine or bromine substitutions, ethyl containing 1-3 fluor
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3- 6- cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl or 5-10-membered heteroaryl; the amino group, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3 -6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy , C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; the amino group, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10
  • u 0, 1, 2, 3, 4, 5 or 6;
  • v 0, 1, 2, 3, 4, 5 or 6;
  • w 0, 1, 2, 3, 4, 5 or 6;
  • x 0, 1, 2, 3, 4, 5 or 6;
  • z 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2 or 3;
  • n1 0, 1, 2 or 3;
  • n2 is 0, 1, 2 or 3.
  • L 1 is selected from -O-, -C(O)-, -C(O) NHCH2- or -C(O)NH-.
  • R1 is selected from
  • R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy base, deuterated methoxy group, deuterated ethoxy group, deuterated propoxy group, cyano group, ethoxy group, difluoromethoxy group.
  • R 31 is hydrogen, deuterium, methyl, ethyl, propyl.
  • R 32 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH 2 CH 3 , -COCH 3 , vinyl, cyclopropyl, Isopropyl, or -CD 3 .
  • R 33 is -C(O)NH 2 .
  • R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl Methyl, ethyl, propyl, methoxy or cyclopropyl.
  • R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl Methyl, ethyl, propyl or methoxy.
  • R 10 is independently selected from hydrogen, deuterium, fluorine, chlorine or bromine.
  • R 11 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or hydroxyl.
  • R 12 is independently selected from hydrogen or cyano.
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano , -CH 2 OH, -CH 2 OCH 3 , -CF 3 , -CH 2 N(CH 3 ) 2 ,
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH 2 OH, -CH 2 OCH 3 , -CF 3 , -CH 2 N(CH 3 ) 2
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.
  • R6 is independently selected from hydrogen, fluoro, methyl, -CH2OH , -CH2OCH3 , -CF3 .
  • R7 is independently selected from hydrogen.
  • R 8 is independently selected from hydrogen, -CH 2 N(CH 3 ) 2 or
  • R 9 is methyl
  • L 1 is selected from -O-, -C(O)-, -C(O)NHCH 2 - or -C(O)NH-;
  • R 1 is selected from
  • R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethyl Oxygen or deuterated propoxy; preferably fluorine, methoxy, -OCD 3 ;
  • R 31 is hydrogen, deuterium, methyl, ethyl, propyl
  • R 32 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH 2 CH 3 , -COCH 3 , vinyl, cyclopropyl ,
  • R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl group, methoxy group, -COCH 2 CH 3 , -COCH 3 , vinyl group, cyclopropyl group
  • R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl;
  • R 33 is -C(O)NH 2 ;
  • R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy group or cyclopropyl; preferably, R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl , propyl or methoxy; more preferably, R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;
  • R 10 is independently selected from hydrogen, deuterium, fluorine, chlorine or bromine;
  • R 11 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or hydroxyl
  • R 12 is independently selected from hydrogen or cyano
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH 2 OH, -CH 2 OCH 3 , -CF 3 , -CH 2 N(CH 3 ) 2 ,
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH 2 OH, -CH 2 OCH 3 , -CF 3 , -CH 2 N(CH 3 ) 2
  • R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH 2 OH, -CH 2 OCH 3 , -CF 3 , -CH 2
  • R 6 is independently selected from hydrogen, fluorine, methyl, -CH 2 OH, -CH 2 OCH 3 , -CF 3 ;
  • R 7 is independently selected from hydrogen;
  • R 8 is independently selected from is selected from hydrogen, -CH 2 N(CH 3 ) 2 or R 9 is methyl.
  • L 1 is selected from -O-, -C(O)-, -C(O)NHCH 2 - or -C(O)NH-;
  • R 1 is selected from
  • R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethyl Oxygen or deuterated propoxy;
  • R 31 is hydrogen, deuterium, methyl, ethyl, propyl
  • R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl;
  • R 33 is -C(O)NH 2 ;
  • R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.
  • L 1 is selected from -O-, -C(O)NHCH 2 - or -C(O)NH-;
  • R 1 is selected from
  • R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethyl Oxygen or deuterated propoxy;
  • R 31 is hydrogen, deuterium, methyl, ethyl, propyl
  • R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl;
  • R 33 is -C(O)NH 2 ;
  • R 4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.
  • the present invention also provides a method for preparing the compound represented by formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof as described above, which includes the following steps: compound represented by formula (V) Just react with the compound represented by formula (VI) under the action of a condensing agent,
  • R 1 , L 1 , R 2 , x, R 31 , R 32 , R 33 , R 4 , z, R 6 , R 7 and R 8 are the same as mentioned above.
  • the present invention also provides a method for preparing the compound represented by formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof as described above, which includes the following steps: compound represented by formula (VII) Just react with the compound represented by formula (VI) under the action of a condensing agent,
  • R 1 , R 2 , x, R 32 , R 4 , z, R 6 , R 7 and R 8 are the same as mentioned above.
  • the present invention also provides a compound represented by formula (V) or its stereoisomer, or a compound represented by formula (VII) or its stereoisomer:
  • R 1 , L 1 , R 2 , x, R 31 , R 32 , R 33 , R 4 and z are the same as mentioned above.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the compound of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition has a weight percentage of the compound, its stereoisomer or its pharmaceutically acceptable salt, calculated as free base, of 0.1% to 95%, preferably 90% %, 85%, 80%, 75%, 70%, 60%, 50%.
  • the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably, also contains fillers, optionally also contains disintegrants, or further contains flow aids.
  • fillers optionally also contains disintegrants, or further contains flow aids.
  • flow aids one or more of the agents or lubricants.
  • the pharmaceutical composition is an immediate release formulation or a sustained release formulation.
  • the pharmaceutical composition has a unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, calculated as free base, of 1-1000 mg, preferably 1-500 mg. , or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.
  • the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof may be administered by any convenient method, e.g., orally, parenterally, bucally, sublingually, nasally, Rectal, intrathecal or transdermal administration, and pharmaceutical compositions adjusted accordingly.
  • the compounds, stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules , powder, granules, or lozenges.
  • the present invention further relates to the compound of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition in the preparation of FGFR1-4 inhibitor drugs.
  • the FGFR1-4 inhibitor is an FGFR2/3 inhibitor.
  • the object of the present invention is to provide a pharmaceutical composition containing the compound described in general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the preparation of treatment and/or prevention.
  • a pharmaceutical composition containing the compound described in general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the preparation of treatment and/or prevention.
  • the present invention also relates to a method for treating and/or preventing related diseases such as cancer and achondroplasia.
  • the object of the present invention is also to provide a pharmaceutical composition containing the compound described in general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment and/or prevention of cancer and cartilage. Use in developmental dysplasia and other related diseases.
  • the cancer-related diseases are selected from solid tumors, colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocyte cancer cancer, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, or lymphoma.
  • the mother core is modified into a single ring structure, which not only improves the FGFR2 enzyme level inhibitory activity, but also has FGFR3 enzyme and Inhibits activity at the cellular level while maintaining selectivity for FGFR1.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms an alkyl group, most preferably an alkyl group having 1 to 3 carbon atoms.
  • Non-limiting examples include 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- Methylpropyl, 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-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when taken When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl is preferred. and hydroxyl-substituted alkyl groups.
  • alkylene refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 -, etc.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl etc. Alkenyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and preferably 3 to 8 carbon atoms. carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetralin base, benzocycloheptyl, etc. Cycloalkyl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalky
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the one-membered heterocyclyl group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, and oxo groups, including nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, or nitrogen-containing fused heterocyclyl groups.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably Pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazacycloheptyl and piperazinyl.
  • Polycyclic heterocyclyl groups include spirocyclic, fused-cyclic and bridged-cyclic heterocyclyl groups; the involved spirocyclic, fused-cyclic and bridged-cyclic heterocyclyl groups are optionally connected to other groups through a single bond, or through a ring. Any two or more atoms on are further connected to other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
  • Non-limiting examples of monocyclic heterocyclyl groups include:
  • heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6 to 12 members, such as benzene base and naphthyl. More preferred is phenyl.
  • the aryl ring can be condensed on a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group containing a sulfur atom; or a three-membered nitrogen-containing fused ring containing a benzene ring.
  • the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following A group independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably a monocyclic heteroaryl group, and the monocyclic heteroaryl group is 5 to 12 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl , pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or Thiazolyl; more preferred are pyrazolyl, pyrrolyl and oxazolyl.
  • the heteroaryl group can be a polycyclic heteroaryl group.
  • the polycyclic heteroaryl group is the monocyclic heteroaryl group condensed on an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, and is connected to the parent structure at Formed together, the polycyclic heteroaryl group can be bicyclic, tricyclic or more.
  • Non-limiting examples include:
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, carboxyl group or carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, carboxyl group or carboxylate group.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , hetero
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted by hydroxyl, wherein alkyl is as defined above.
  • Alkenyl refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), wherein the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxyl or carboxylate group.
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur.
  • a heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • “Pharmaceutically acceptable salts” or “pharmaceutically acceptable salts” refer to salts of the compounds of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm) units. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ) and deuterated methanol. (CD 3 OD) and deuterated chloroform (CDCl 3 ), with the internal standard being tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • Agilent 1200 Infinity Series mass spectrometer was used for LC-MS measurement. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150 ⁇ 4.6mm column).
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for thin layer chromatography 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 embodiments of the present invention are known and can be purchased on the market, or can be synthesized using or according to methods known in the art.
  • the residue was dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with ethyl acetate to obtain the target compound (5.6g, 64%). .
  • the reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was separated by silica gel column chromatography to obtain the target compound (1.6 g, 76%).
  • Step 7 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxo)phenyl)-5-methyl-4-(4-nitrophenyl)-1H- Preparation of pyrrole-2-carboxylic acid
  • Step 8 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxo)phenyl)-5-methyl-4-(4-nitrophenyl)-1H- Preparation of pyrrole-2-carboxamide
  • Step 9 4-(4-aminophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxo)phenyl)-5-methyl-1H-pyrrole -Preparation of 2-carboxamide
  • Step 10 4-(4-acryloamidophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxo)phenyl)-5-methyl- Preparation of 1H-pyrrole-2-carboxamide
  • reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was dissolved in dichloromethane (10 mL). ), add trifluoroacetic acid (10 mL), stir the reaction at room temperature for 30 minutes, concentrate under reduced pressure to remove the solvent, dissolve the residue in methylene chloride, wash with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and remove the solvent with anhydrous sodium sulfate. Dry, filter and concentrate, and the residue is separated by silica gel column chromatography to obtain the title compound (710 mg, 6%).
  • Step 3 Preparation of 4-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-5-methyl-1H-pyrrole-2-carboxylic acid
  • Methyl 4-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-5-methyl-1H-pyrrole-2-carboxylate 710 mg , 1.69mmol was dissolved in a mixed solvent of tetrahydrofuran (10mL) and methanol (10mL). A solution of sodium hydroxide (68mg, 1.69mmol) in water (10mL) was added with stirring at room temperature.
  • the resulting reaction solution was transferred to 90°C for stirring reaction 1 hour, concentrate under reduced pressure to remove the solvent, disperse the residue in water, add acetic acid to adjust the pH to acidity, extract with dichloromethane, combine the dichloromethane extracts, wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and filter. Concentrate, and the residue is directly used in the next reaction.
  • Step 4 N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl -Preparation of prop-2-enamide
  • the reaction solution was diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and anhydrous sulfuric acid Dried over sodium, filtered, and concentrated, the residue was separated by silica gel column chromatography to obtain the target compound (1.2 g, 89%).
  • Step 5 tert-Butyl 4-bromo-2-carbamoyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-5-methyl- Preparation of pyrrole-1-carboxylate
  • reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was dissolved in acetonitrile (50 mL) , tert-butoxycarbonyl tert-butyl carbonate (1.11g, 5.07mmol) and 4-dimethylaminopyridine (207mg, 1.69mmol) were added in sequence while stirring at room temperature, and the resulting reaction solution was stirred and reacted at room temperature for 2 hours.
  • the solvent was removed by concentration under pressure, and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound (390 mg, 46%).
  • Step 6 4-(2-fluoro-4-(2-methylprop-2-enoylamino)phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl) Preparation of oxo-phenyl)-5-methyl-1H-pyrrole-2-carboxamide
  • Step 1 Preparation of methyl 5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate
  • Step 2 O1-tert-butyl O2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate preparation
  • the reaction solution was diluted with ethyl acetate and washed with saturated sodium chloride aqueous solution. , dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound (3.65g, 52%).
  • the reaction solution was replaced once with nitrogen, transferred to 90°C and stirred for 2 hours.
  • the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue
  • the target compound (922 mg, 88%) was isolated by silica gel column chromatography.
  • Step 5 4-(4-amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-5-methyl Preparation of base-1H-pyrrole-2-carboxamide
  • reaction solution was diluted with ethyl acetate and treated with saturated sodium bicarbonate and saturated sodium chloride aqueous solution. Wash, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is dissolved in a mixed solvent of dioxane (25 mL) and ethanol (25 mL). Iron powder (5.40 g, 96.66 mmol) and ammonium chloride (3.10) are added in sequence.
  • Step 6 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxo)phenyl)-4-(4-methacryloylamido-2-methylphenyl) Preparation of -5-methyl-1H-pyrrole-2-carboxamide
  • reaction solution was diluted with ethyl acetate and saturated with Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate.
  • the residue is separated by preparative TLC and prep-HPLC in sequence to obtain the target compound (26.5 mg, 22%).
  • the residue is dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is The target compound (4.65g, 74%) was obtained by beating with ethyl acetate.
  • Step 4 Methyl 5-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-4-(4-nitrophenyl)-1H- Preparation of pyrrole-2-carboxylate
  • Step 5 Methyl 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H -Preparation of pyrrole-2-carboxylate
  • the resulting reaction solution was replaced with nitrogen, transferred to a microwave synthesizer, heated to 100°C, stirred and reacted for 4 hours, and the pressure was reduced.
  • the solvent was concentrated to remove the residue, and the residue was dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the residue was separated by silica gel column chromatography to obtain the target compound (355 mg, 39%).
  • Step 7 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole -Preparation of 2-carboxamide
  • Step 8 4-(4-aminophenyl)-5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-1H-pyrrole- Preparation of 2-carboxamide
  • Step 9 5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-4-(4-(2-fluoroprop-2-ene) Preparation of amido)phenyl)-1H-pyrrole-2-carboxamide
  • the reaction solution was diluted with ethyl acetate, and washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. , dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by prep-HPLC to obtain the target compound (2.7 mg, 4%).
  • Step 1 4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-5-vinyl-1H-pyrrole- Preparation of 2-carboxamide
  • Step 2 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxo-phenyl)-4-(4-(prop-2-enoylamido)phenyl)-5 -Preparation of vinyl-1H-pyrrole-2-carboxamide
  • 2-Fluoroacrylic acid (12 mg, 129.24 ⁇ mol), HOBt (17 mg, 129.24 ⁇ mol), triethylamine (44 mg, 430.79 ⁇ mol, 60.08 ⁇ L) and HATU (49 mg, 129.24 ⁇ mol) were added to DMF (1 mL) in sequence.
  • the reaction solution was diluted with methylene chloride, washed with saturated sodium chloride aqueous solution and saturated ammonium chloride aqueous solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was separated by silica gel column chromatography to obtain the target compound (1 g, 79%).
  • Step 2 Preparation of methyl 3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate
  • Step 3 Preparation of 3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylic acid
  • Step 4 Preparation of 4-(4-aminophenyl)-3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide
  • the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the residue was dissolved in a mixed solvent of ethanol (10 mL) and dioxane (10 mL), and a solution of iron powder (6.58 g, 117.5 mmol) and ammonium chloride (3.77 g, 70.5 mmol) in water (10 mL) was added successively.
  • the resulting reaction solution was transferred to 90°C and heated for 2 hours, filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was collected and dried under reduced pressure.
  • the residue was dissolved in methylene chloride and treated with saturated aqueous sodium bicarbonate solution and saturated chlorine. Wash with sodium aqueous solution, dry over anhydrous sodium sulfate, filter, and shrink. The residue is separated by silica gel column chromatography to obtain the target compound (947 mg, 100%).
  • Step 5 3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-(prop-2-enoylamino)phenyl)-1H- Preparation of pyrrole-2-carboxamide
  • the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was passed through
  • the target compound (2.4 mg, 1%) was separated by preparative TLC and prep-HPLC.
  • Step 3 Methyl 3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl) )-1H-pyrrole-2-carboxylic acid ester preparation
  • the reaction liquid was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was separated by silica gel column chromatography to obtain the target compound (980 mg, 88%).
  • Step 4 3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)- Preparation of 1H-pyrrole-2-carboxylic acid
  • reaction solution transfer the reaction solution to an oil bath, heat to 50°C and stir for 16 hours, concentrate under reduced pressure to remove the organic solvent, dilute the residue with water, add acetic acid to adjust the pH to neutral while stirring at room temperature, add ethyl acetate for extraction, and the organic phase is saturated in turn Wash with sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate, and the residue will be used directly for the next reaction.
  • Step 5 4-(4-amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-1H -Preparation of pyrrole-2-carboxamide
  • reaction solution was diluted with ethyl acetate and washed with saturated sodium chloride aqueous solution. Dry over anhydrous sodium sulfate, filter, and concentrate. The residue is dissolved in a mixed solvent of dioxane (25 mL) and ethanol (25 mL).
  • Step 6 3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-(prop-2-enoyl) Preparation of amino)phenyl)-1H-pyrrole-2-carboxamide
  • Step 1 Preparation of ethyl-2-(4-bromo-3-methoxy-benzoyl)-3-(dimethylamino)prop-2-enoate
  • Step 2 Preparation of ethyl 5-(4-bromo-3-methoxy-phenyl)isoxazole-4-carboxylate
  • Step 3 Preparation of 5-(4-bromo-3-methoxyphenyl)-2-tert-butyl-4-ethoxyformylisoxazole perchlorate
  • Step 4 Ethyl 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyridine Preparation of azole-4-carboxylate
  • Step 5 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyrazole- Preparation of 4-carboxylic acid
  • the resulting reaction solution was transferred to 70°C and stirred for 5 hours, concentrated under reduced pressure to remove the organic solvent, the residue was diluted with water, cooled to 0°C in an ice-water bath, and the pH was adjusted to weak acidity with dilute hydrochloric acid under stirring conditions, and extracted with ethyl acetate. The phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained the title compound (1.18 g, 100%), which was directly used in the next reaction.
  • the resulting reaction solution continues to stir at room temperature for 16 hours. Transfer to an oil bath, heat to 60°C and stir for 8 hours.
  • the reaction solution is diluted with ethyl acetate, washed successively with saturated sodium chloride aqueous solution, saturated sodium carbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated. , the residue was separated by silica gel column chromatography to obtain the title compound (590 mg, 50%).
  • Step 7 1-(4-amino-2-methyl-phenyl)-3-(tert-butylamino)-5-(4-(isobutylcarbamoyl)-3-methoxy- Preparation of phenyl)pyrazole-4-carboxamide
  • Step 8 3-amino-1-(4-amino-2-methyl-phenyl)-5-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)pyrazole- Preparation of 4-carboxamide
  • Step 9 3-amino-1-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-(4-(isobutylcarbamoyl)-3
  • Step 9 3-amino-1-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-(4-(isobutylcarbamoyl)-3
  • Step 4 Methyl 4-(2-carbamoyl-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole Preparation of -3-yl)-2-methoxybenzoate
  • Step 5 Methyl 4-(4-(4-amino-2-methylphenyl)-2-carbamoyl-1-(4-methoxybenzyl)-5-methyl-1H-pyrrole- Preparation of 3-yl)-2-methoxybenzoate
  • Step 7 Methyl 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrole-3-yl )-2-Methoxybenzoic acid ester preparation
  • Step 1 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrole-3-yl)- Preparation of 2-methoxybenzoic acid
  • Step 2 3-(4-((cyclopropylmethyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamido)-2-methylbenzene Preparation of methyl)-5-methyl-1H-pyrrole-2-carboxamide
  • Methyl 4-bromo-2-(methoxy-d 3 ) benzoate (2.10g, 8.35mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5 -Tetramethyl-1,3,2-dioxaboropent-2-yl)-1,3,2-dioxaboropentane (2.79g, 11mmol), Pd(dppf)Cl 2 .
  • Dichloromethane The complex (0.68g, 0.84mmol) and anhydrous potassium acetate (1.64g, 16.7mmol) were added to dioxane (30mL). The reaction solution was heated to 90°C and stirred for 14 hours. The solvent was concentrated under reduced pressure.
  • Step 3 Methyl 3-(methoxy-d 3 )-4-(methoxycarbonyl)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl) Preparation of -1H-pyrrole-2-carboxylate
  • Step 4 2-(methoxy-d 3 )-4-(2-(methoxycarbonyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H- Preparation of pyrrol-3-yl)benzoic acid
  • the reaction was stirred for 8 hours, concentrated under reduced pressure to remove the organic solvent, the residue was diluted with water, the pH was adjusted to weak acidity with 1N hydrochloric acid aqueous solution, the aqueous solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was directly used in the next step One step reaction.
  • Step 5 Methyl 3-(4-(isobutylcarbamoyl)-3-(methoxy-d 3 )phenyl)-5-methyl-4-(2-methyl-4-nitro Preparation of phenyl)-1H-pyrrole-2-carboxylate
  • Step 6 3-(4-(isobutylcarbamoyl)-3-(methoxy-d 3 )phenyl)-5-methyl-4-(2-methyl-4-nitro- Preparation of phenyl)-1H-pyrrole-2-carboxylic acid
  • Step 7 3-(4-(isobutylcarbamoyl)-3-(methoxy-d 3 )phenyl)-5-methyl-4-(2-methyl-4-nitro- Preparation of phenyl)-1H-pyrrole-2-carboxamide
  • reaction solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was directly used in the following step One step reaction.
  • Step 8 4-(4-amino-2-methyl-phenyl)-3-(4-(isobutylcarbamoyl)-3-(methoxy-d 3 )phenyl)-5- Preparation of methyl-1H-pyrrole-2-carboxamide
  • Step 9 4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-3-(4-(isobutylcarbamoyl)-3-(methoxy Preparation of base-d 3 )phenyl)-5-methyl-1H-pyrrole-2-carboxamide
  • Step 1 Preparation of tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
  • Step 2 O1-tert-butylO2-methyl3-(4-tert-butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4-nitro Preparation of phenyl)pyrrole-1,2-dicarboxylate
  • Step 4 tert-Butyl 4-(2-carbamoyl-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrol-3-yl)-2- Fluoro-benzoate
  • reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was passed through a silica gel column. Chromatography isolated the title compound (1.61g, 100%).
  • Step 5 tert-Butyl 4-(4-(4-amino-2-methyl-phenyl)-2-carbamoyl-5-methyl-1H-pyrrol-3-yl)-2-fluoro -Preparation of benzoate esters
  • Step 6 tert-Butyl 4-(2-carbamoyl-4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-methyl-1H Preparation of -pyrrol-3-yl)-2-fluoro-benzoate
  • 2-Fluoroacrylic acid (365 mg, 4.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (777 mg, 4.05 mmol), 1-hydroxybenzotriazole ( 183 mg, 1.35 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 4-dimethylaminopyridine (83 mg, 676 ⁇ mol) was added with stirring at room temperature.
  • Step 7 4-(2-carbamoyl-4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-methyl-1H-pyrrole-3 -Preparation of -2-fluoro-benzoic acid
  • Step 8 3-(4-((cyclopropylmethyl)carbamoyl)-3-fluorophenyl)-4-(4-(2-fluoroacryloylamido)-2-methylphenyl )-5-Methyl-1H-pyrrole-2-carboxamide preparation
  • HATU (26 mg, 69 ⁇ mol) was added to 4-(4-amino-2-methyl-phenyl)-3-[4-(isobutylcarbamoyl)-3-methoxy-phenyl]-5 -Methyl-1H-pyrrole-2-carboxamide (20 mg, 46 ⁇ mol, preparation refers to step 8 of Example 78), but-2-ynoic acid (3.9 mg, 46 ⁇ mol) and DIPEA (17.8 mg, 138 ⁇ mol) in DMF ( 2.5 ml) solution, the reaction solution was stirred for 2 hours. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (9.1 mg, 39%).
  • HATU (26 mg, 69 ⁇ mol) was added to 4-(4-amino-2-methyl-phenyl)-3-[4-(isobutylcarbamoyl)-3-methoxy-phenyl]-5 -Methyl-1H-pyrrole-2-carboxamide (20 mg, 46 ⁇ mol, preparation refers to step 8 of Example 78), (Z)-4-(dimethylamino)but-2-enoic acid (5.9 mg, 46 ⁇ mol) and DIPEA (18 mg, 138 ⁇ mol) in DMF solution, and the reaction solution was stirred for 2 hours. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (6.0 mg, 22%).
  • the solvent was concentrated under reduced pressure, and the remaining The product was dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with ethyl acetate to obtain the target compound (5.5 g, 80%).
  • reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound (2.0g, 37%). .
  • Step 4 Methyl 3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl Preparation of -1H-pyrrole-2-carboxylate
  • Step 5 3-(4-(isobutycarbamoyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1H -Preparation of pyrrole-2-carboxylic acid
  • Step 6 3-(4-(isobutycarbamoyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1H -Preparation of pyrrole-2-carboxamide
  • Step 7 4-(4-amino-2-methyl-phenyl)-5-ethyl-3-(4-(isobutycarbamoyl)-3-methoxy-phenyl)-1H- Preparation of pyrrole-2-carboxamide
  • Step 8 5-ethyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-3-(4-(isobutylcarbamoyl)-3-methoxy Preparation of phenyl)-1H-pyrrole-2-carboxamide
  • Step 2 N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3- Preparation of methylbutanamide
  • Step 4 3-(3-methoxy-4-(3-methylbutyrylamido)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H -Preparation of pyrrole-2-carboxylic acid
  • Step 5 3-(3-methoxy-4-(3-methylbutyrylamido)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H -Preparation of pyrrole-2-carboxamide
  • Step 6 4-(4-amino-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutyrylamido)phenyl)-5-methyl-1H- Preparation of pyrrole-2-carboxamide
  • Step 7 4-(4-acrylamido-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutyrylamido)phenyl)-5-methyl -Preparation of 1H-pyrrole-2-carboxamide
  • Example 6 For the preparation of Examples 6, 7, 8, 9, 60, and 64, refer to Example 1; for the preparation of Examples 11, 27, 94, and 96, refer to Example 10; for the preparation of Examples 20, 21, 22, 23, and 24, refer to Example 15; the preparation of Examples 25, 49, 50, 51, 65, 66, and 97 refers to Example 3; the preparation of Example 26 refers to Example 12; Examples 36, 40, 41, 42, 43, 44, For the preparation of 45, 46, 47, and 48, refer to Example 30; for the preparation of Example 37, refer to Example 34; for the preparation of Example 38, refer to Example 32; for the preparation of Example 39, refer to Example 33; Examples 53, 54, For the preparation of 55, 56, 57, 58, 59, and 63, refer to Example 52; for the preparation of Examples 61 and 98, refer to Example 2; for the preparation of Examples 62, 93, 95, 99, 100, 101, 103, and 104, refer to Example 13; Examples 69, 70, 71, 72, 73, 74,
  • Examples 226-355 were synthesized with reference to the preparation method of Example 78, and Examples 356-411 were synthesized with reference to the preparation method of Example 78 or 249:
  • Example 159 For the preparation of Examples 227, 228, 229, and 230, please refer to Example 159.
  • Example 164 For the preparation of Examples 259 and 260, reference may also be made to Example 164.
  • Example 108 For the preparation of Examples 325 and 328-330, reference may also be made to Example 108.
  • Example 231 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 234 refers to Example 78, and can also be synthesized according to the following steps.
  • Step 1 Methyl 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl- Preparation of 4-nitrophenyl)-1H-pyrrole-2-carboxylate
  • reaction solution is diluted with water, extracted with ethyl acetate, and the organic phase is washed with saturated sodium chloride aqueous solution. Dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the title compound (250 mg, 55%).
  • Step 2 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4- Preparation of nitrophenyl)-1H-pyrrole-2-carboxylic acid
  • Step 3 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4- Preparation of nitrophenyl)-1H-pyrrole-2-carboxamide
  • Step 4 4-(4-amino-2-methylphenyl)-5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methyl Preparation of oxyphenyl)-1H-pyrrole-2-carboxamide
  • Step 5 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoropropene) Preparation of acylamino)-2-methylphenyl)-1H-pyrrole-2-carboxamide
  • Example 244 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 245 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 247 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 249 refers to Example 78, and can also be synthesized according to the following steps:
  • Step 1 Preparation of methyl 5-chloro-3-iodo-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate
  • Step 3 Methyl 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4 Preparation of -nitrophenyl)-1H-pyrrole-2-carboxylate
  • Step 4 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro Preparation of phenyl)-1H-pyrrole-2-carboxylic acid
  • Methyl 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro Phenyl)-1H-pyrrole-2-carboxylate (600 mg, 1.16 mmol) was dissolved in a mixed solvent of methanol (6 mL) and tetrahydrofuran (6 mL), and sodium hydroxide (928 mg, 23.2 mmol) in water (6 mL) was added with stirring.
  • reaction solution was heated to 60°C and stirred for 14 hours, concentrated under reduced pressure to remove the organic solvent, the residue was acidified with hydrochloric acid, extracted with ethyl acetate, the organic phases were combined, condensed under reduced pressure, and the crude product was directly used in the next reaction.
  • Step 5 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro Preparation of phenyl)-1H-pyrrole-2-carboxamide
  • reaction solution was stirred for 4 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in ethyl acetate, and washed with saturated sodium chloride aqueous solution , dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was directly used in the next reaction.
  • Step 6 4-(4-amino-2-methylphenyl)-5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxy Preparation of phenyl)-1H-pyrrole-2-carboxamide
  • Step 7 5-chloro-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)amino Preparation of formyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide
  • Example 261 refers to Example 78, and can also be synthesized according to the following steps.
  • HATU (50.14 mg, 132.91 ⁇ mol) was added to 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H- Pyrrol-3-yl)-2-methoxybenzoic acid (40 mg, 88.60 ⁇ mol), [1-(trifluoromethyl)cyclopropyl]methanamine hydrochloride (17.11 mg, 97.46 ⁇ mol) and DIPEA (57.26 mg, 443.02 ⁇ mol) in DMF (2.5 mL), and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (19.6 mg, 38.55%).
  • Example 270 The preparation of Example 270 refers to Example 78, and can also be synthesized according to the following steps.
  • HATU 50.14 mg, 132.91 ⁇ mol
  • 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H- Pyrrol-3-yl)-2-methoxybenzoic acid 40 mg, 88.60 ⁇ mol
  • (1-fluorocyclobutyl)methanamine hydrochloride 13.61 mg, 97.46 ⁇ mol
  • DIPEA 57.26 mg, 443.02 ⁇ mol
  • the reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (20.1 mg, 42.02%).
  • Example 273 refers to Example 78, and can also be synthesized according to the following steps.
  • HATU 50.14 mg, 132.91 ⁇ mol
  • 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H- Pyrrol-3-yl)-2-methoxybenzoic acid 40 mg, 88.60 ⁇ mol
  • 1-(aminomethyl)cyclopropanecarbonitrile 12.92 mg, 97.46 ⁇ mol
  • DIPEA 57.26 mg, 443.02 ⁇ mol
  • the reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (26.3 mg, 55.38%).
  • Example 274 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 276 refers to Example 78, and can also be synthesized according to the following steps.
  • HATU 107 mg, 283 ⁇ mol
  • Example 277 refers to Example 78, and can also be synthesized according to the following steps.
  • HATU (42 mg, 111 ⁇ mol) was added to 4-[2-carbamoyl-4-[2-chloro-4-(2-fluoroprop-2-enoylamino)phenyl]-5-methyl-1H- Pyrrol-3-yl]-2-methoxy-benzoic acid (35 mg, 74 ⁇ mol, preparation refers to the first step of Example 68), 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride (11 mg, 82 ⁇ mol) and In a solution of DIPEA (48 mg, 371 ⁇ mol) in DMF (2.5 mL), the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (11 mg, 27%).
  • Example 279 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 280 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 282 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 283 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 284 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 287 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 352 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 354 refers to Example 78, and can also be synthesized according to the following steps.
  • Example 355 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 364 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 365 For the preparation of Example 365, refer to Example 78 or 249. It can also be synthesized according to the following steps.
  • Example 366 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 367 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 368 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 369 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by reverse-phase column chromatography to obtain the title compound (167.2 mg, 24% ).
  • Example 372 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by reverse-phase column chromatography to obtain the title compound (320.4 mg, 28 %).
  • Example 373 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 374 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • HATU (48 mg, 126 ⁇ mol) was added to 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrole- 3-yl)-2-methoxybenzoic acid (38 mg, 84 ⁇ mol), 1-[1-(aminomethyl)cyclopropyl]ethanone hydrochloride (15 mg, 101 ⁇ mol) and DIPEA (54 mg, 421 ⁇ mol) In DMF (2.5 mL) solution, the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (18.5 mg, 40%).
  • Example 375 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 376 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 381 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 383 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 384 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 387 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 389 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Example 398 refers to Example 78 or 249, and can also be synthesized according to the following steps.
  • Embodiment 399 refers to Embodiment 78 or 249, and can also be synthesized according to the following steps.

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Abstract

La présente invention concerne un dérivé hétérocyclique utilisé comme inhibiteur, son procédé de préparation et son utilisation. En particulier, la présente invention concerne un composé représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique comprenant le composé, et son utilisation comme inhibiteur dans la préparation d'un médicament pour le traitement et/ou la prévention de cancers et de maladies associées à l'achondroplasie.
PCT/CN2023/103743 2022-06-29 2023-06-29 Dérivé hétérocyclique utilisé comme inhibiteur, son procédé de préparation et son utilisation WO2024002223A1 (fr)

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