WO2023116902A1 - Sos1 inhibitor - Google Patents

Sos1 inhibitor Download PDF

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Publication number
WO2023116902A1
WO2023116902A1 PCT/CN2022/141536 CN2022141536W WO2023116902A1 WO 2023116902 A1 WO2023116902 A1 WO 2023116902A1 CN 2022141536 W CN2022141536 W CN 2022141536W WO 2023116902 A1 WO2023116902 A1 WO 2023116902A1
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Prior art keywords
alkyl
haloalkyl
optionally substituted
halogen
cycloalkyl
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PCT/CN2022/141536
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French (fr)
Chinese (zh)
Inventor
王虎庭
杨旭
石磊
刘磊
杜豪林
孙广龙
孟庆华
王建浩
王晶晶
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北京望实智慧科技有限公司
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Publication of WO2023116902A1 publication Critical patent/WO2023116902A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to SOS1 inhibitors, specifically compounds represented by formula (A), or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers, prodrugs, polymorphic forms, hydrated substances or solvates.
  • the present invention also relates to the preparation method of the compound, the pharmaceutical composition containing the compound, and the effect of the compound in the prevention and treatment of related cancers, such as lung cancer, colon cancer and pancreatic cancer.
  • KRAS protein V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
  • V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog is a small G protein with GTP hydrolase activity. After binding to GTP, it will activate downstream MAPK and PI3K-AKT signaling pathways, thereby regulating cell proliferation, Differentiation, growth and apoptosis, etc.; however, its mutation will lead to abnormal activation of downstream signaling pathways, which is closely related to the occurrence and development of cancer.
  • SOS1 (Son of Sevenless 1) is the key GEF (Guanine Nucleotide Exchange factor) that regulates KRAS. SOS1 can promote KRAS to release GDP, combine with GTP, and then activate KRAS.
  • GTP-bound KRAS participates in the allosteric regulation of SOS1 and enhances the catalytic activity of SOS1.
  • the signaling pathway downstream of KRAS regulates SOS1 function through a negative feedback mechanism.
  • SOS1 inhibitors to block the protein-protein interaction between SOS1 and KRAS can greatly reduce the KRAS protein bound to the GTP state, thereby effectively inhibiting the abnormal activation of downstream signaling pathways and preventing the occurrence and development of tumors.
  • the present invention uses SOS1 as the target, and develops a new class of compound small molecule inhibitors for the treatment of lung cancer, colon cancer and other cancers.
  • the present invention provides a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof thing:
  • Ring A represents phenyl or 5-6 membered heteroaryl
  • Ring B selected from
  • R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
  • R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
  • R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
  • Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
  • R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
  • R Z3b is selected from H, D, halogen, -NR a R b , -OR a , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , -LC 3-6 cycloalkyl, -L-4-6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, optionally replaced by 1, 2 or 3 R s replaces;
  • L is a chemical bond, O, S or NH
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z3c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  • the present invention provides a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound:
  • Ring A represents phenyl or 5-6 membered heteroaryl
  • Ring B selected from
  • R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
  • R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
  • R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
  • Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
  • R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
  • R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z3c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  • the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound:
  • Ring A represents phenyl or 5-6 membered heteroaryl
  • R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
  • R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
  • Z1 is NR Z1a or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is N or CR Z3b ;
  • R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2. -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkane base;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can be optionally replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH , -C(O)OC 1-6 alkyl substitution;
  • R Z3b is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, or R, R' and their connected nitrogen atom form a 4-8 membered heterocyclic group.
  • the general formula compound of the present invention does not include specific compounds in WO2022251497, such as any one or more of compounds 1-182.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which also comprises other therapeutic agents.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment and/or prevention of SOS1-mediated diseases.
  • the present invention provides a method of treating and/or preventing a SOS1-mediated disease in a subject, comprising administering to said subject a compound of the present invention or a pharmaceutical composition of the present invention.
  • the present invention provides a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment and/or prevention of SOS1 mediated diseases.
  • the invention is used to treat and/or prevent cancer.
  • the present invention is used for the treatment and/or prevention of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer , prostate cancer, glioblastoma, kidney cancer, or sarcoma.
  • the present invention is used for the treatment and/or prevention of RAS disease
  • the RAS disease is selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), multiple Macular Noonan Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Heart-Face-Skin Syndrome (CFC), Legers Syndrome and hereditary gingival fibromatosis.
  • NF1 neurofibromatosis type 1
  • NS Noonan syndrome
  • NSML multiple Macular Noonan Syndrome
  • CM-AVM Capillary Malformation-Arteriovenous Malformation Syndrome
  • CS Costello Syndrome
  • CFC Heart-Face-Skin Syndrome
  • Legers Syndrome and hereditary gingival fibromatosis.
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5, C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl and C 1-2 alkyl are preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), t-butyl Base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • C 1-6 alkyl also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkenyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl include: ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentenyl (C 5 ), hexenyl (C 6 ), and the like.
  • C alkenyl also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl include, but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • C2-6alkynyl also includes heteroalkynyl groups in which one or more (e.g., 1 , 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead.
  • An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkylene refers to a divalent group formed by removing another hydrogen of C 1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene group includes but not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene group (-CH 2 CH 2 CH 2 CH 2 -), pentylene group (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene group (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - ) ,etc.
  • alkylene groups substituted with one or more alkyl (methyl) groups include but are not limited to: substituted methylene groups (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), and the like.
  • C 0-6 alkylene refers to a chemical bond and the above-mentioned “C 1-6 alkylene”
  • C 0-4 alkylene refers to a chemical bond and the above-mentioned “C 1-4 alkylene”.
  • alkenylene groups eg, alkenylene groups substituted with one or more alkyl (methyl) groups
  • C 2-6 alkynylene refers to a divalent group formed by removing another hydrogen of a C 2-6 alkynyl, and may be substituted or unsubstituted. In some embodiments, C2-4 alkynylene is particularly preferred. Exemplary such alkynylene groups include, but are not limited to, ethynylene (-C ⁇ C-), substituted or unsubstituted propynylene (-C ⁇ CCH 2 -), and the like.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-6 haloalkyl refers to the above-mentioned “C 1-6 alkyl", which is substituted with one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl.
  • Exemplary haloalkyl groups include, but are not limited to: -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • a haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-8 cycloalkyl, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, more preferably C 5-6 cycloalkyl. Cycloalkyl also includes ring systems wherein the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in the cycloalkyl system.
  • cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene Cycloheptadienyl (C 7 ), Cycloheptadienyl (C 7 ), Cycloheptatrienyl (C 7 ), and the like. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 3-12 membered heterocyclyl means a saturated or unsaturated group of a 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from Nitrogen, Oxygen, Sulfur, Boron, Phosphorus and Silicon.
  • the point of attachment can be a carbon or nitrogen atom, as valence permits.
  • 4-12 membered heterocyclyl which is a 4 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms
  • 3-10 membered Heterocyclyl which is a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms
  • a 3-8 membered heterocyclyl group having ring carbon atoms and 3 to 8 membered non-aromatic ring systems with 1 to 4 ring heteroatoms
  • preferably 3-6 membered heterocyclyl which is a 3 to 6 membered nonaromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms
  • 4-8 membered heterocyclic groups which are 4 to 8 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms
  • Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl ring is fused to one or more aryl or Heteroaryl-fused ring systems wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxasulfuranyl Oxazolidin-2-ones.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 5-membered heterocyclyls (also referred to herein as 5,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to: indolinyl, isoindolinyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclyls (also referred to herein as 6,6 -bicyclic heterocyclyls) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.
  • the heterocyclic group also includes the above-mentioned heterocyclic group sharing one or two atoms with a cycloalkyl group, heterocyclic group, aryl group or heteroaryl group to form a bridged ring or a spiro ring.
  • the shared atom can be carbon or Nitrogen atom.
  • Heterocyclyl also includes the aforementioned heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 aryl means a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having shared 6 or 10 ⁇ electrons) groups.
  • an aryl group has six ring carbon atoms ("C aryl”; eg, phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems wherein the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • An aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 5-14 membered heteroaryl means a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6, 10 or 14 ⁇ electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment can be a carbon or nitrogen atom, as valence permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said heteroaryl ring, in which case the carbon atoms Numbers continue to indicate the number of carbon atoms in the heteroaryl ring system.
  • 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms .
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 5,6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl , Benzisofuryl, Benzimidazolyl, Benzoxazolyl, Benzisoxazolyl, Benzoxadiazolyl, Benzthiazolyl, Benzisothiazolyl, Benzthiadiazolyl, Indenazinyl and Purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, multiplinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • a heteroaryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined above, divalent groups formed by removing another hydrogen are collectively referred to as "subunits”.
  • Ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl are collectively referred to as "cyclyl”.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, etc. are defined herein as optionally substituted groups.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R groups group replacement;
  • Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle radical or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;
  • R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R groups;
  • Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R gg group substitution;
  • cancer includes, but is not limited to, the following cancers: pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer , urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, colloid Blastoma, renal carcinoma, and sarcoma.
  • treating relates to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition.
  • the noun “treat” as used herein refers to the action of the verb treat, which is as just defined.
  • the term "pharmaceutically acceptable salt” refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention, which are suitable for use in contact with patient tissues within the scope of sound medical judgment without undue toxicity, Irritation, allergic effects, etc., commensurate with a reasonable benefit/risk ratio, are valid for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, for example alkali and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • Base addition salts of acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt, in conventional manner.
  • the free acid may be regenerated by contacting the salt form with the acid and isolating the free acid in a conventional manner.
  • the free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are nevertheless equivalent to their respective free acids for the purposes of the present invention.
  • Salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphoric acids prepared from inorganic acids Salts, chlorides, bromides, iodides, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauryl salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate and isethionate, etc.
  • Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate, Tolate, Mandelate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Naphthoate, Benzenesulfonate, Toluenesulfonate, Phenylethyl salt, citrate, lactate, maleate, tartrate, methanesulfonate, etc.
  • Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.
  • Salts of amino acids are also contemplated, such as arginine salts, gluconate salts, galacturonate salts, etc. (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J.Pharm.Sci., 1977; 66:1- 19, which is incorporated by reference).
  • Subjects for administration include, but are not limited to: human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adult, middle-aged adult or older adult)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • treating includes an effect on a subject suffering from a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a disease, disorder or condition ("therapeutic treatment”) and also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition (“prophylactic treatment").
  • an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response.
  • an effective amount of a compound of the invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age Health conditions and symptoms.
  • An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to induce one or more symptoms associated with the disease, disorder or condition. Amount to delay or minimize.
  • a therapeutically effective amount of a compound refers to that amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of the disorder or condition.
  • a prophylactically effective amount of a compound refers to that amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” may include amounts that improve overall prophylaxis, or that enhance the prophylactic effect of other prophylactic agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the invention may be administered with the other therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together with the other therapeutic agent in a single unit dosage form.
  • the compound of the present invention refers to the following compounds of formula (X), formula (A) (including sub-general formulas, such as formula (I) to formula (VII) etc.), and their pharmaceutically acceptable salts , isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates.
  • the present invention relates to a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound:
  • Ring A represents phenyl or 5-6 membered heteroaryl
  • Ring B selected from
  • R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
  • R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
  • R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
  • Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
  • R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
  • R Z3b is selected from H, D, halogen, -NR a R b , -OR a , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , -LC 3-6 cycloalkyl, -L-4-6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, optionally replaced by 1, 2 or 3 R s replaces;
  • L is a chemical bond, O, S or NH
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group, -C 1-6 alkylene -OC 1-6 haloalkyl, -C 1-6 alkylene - NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z3c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration;
  • the present invention relates to a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvate:
  • Ring A represents phenyl or 5-6 membered heteroaryl
  • Ring B selected from
  • R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
  • R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
  • R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
  • Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
  • R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
  • R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z3c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration;
  • the present invention relates to a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvate:
  • Ring A represents phenyl or 5-6 membered heteroaryl
  • R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
  • R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
  • Z1 is NR Z1a or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is N or CR Z3b ;
  • R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2. -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkane base;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can be optionally replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH , -C(O)OC 1-6 alkyl substitution;
  • R Z3b is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • Ring A represents phenyl or 5-6 membered heteroaryl; In another specific embodiment, Ring A represents phenyl; In another specific embodiment, Ring A represents 5-6 membered Heteroaryl; In another specific embodiment, Ring A represents a 5-membered heteroaryl; In another specific embodiment, Ring A represents a 6-membered heteroaryl.
  • Ring B is In another specific embodiment, Ring B is
  • R 1 is H; In another specific embodiment, R 1 is D; In another specific embodiment, R 1 is halogen; In another specific embodiment, R 1 is - CN; In another specific embodiment, R 1 is C 1-6 alkyl; In another specific embodiment, R 1 is C 1-6 haloalkyl; In another specific embodiment, R 1 is C 1-4 haloalkyl; In another specific embodiment, R 1 is C 1-2 haloalkyl; In another specific embodiment, R 1 is C 1 haloalkyl; In another specific embodiment, R 1 is C 2-6 alkenyl; in another specific embodiment, R 1 is C 2-6 alkynyl; in another specific embodiment, R 1 is -OR; in another specific embodiment, R 1 is -NRR'; in another specific embodiment, R is -C(O)R; in another specific embodiment, R is -C(O)OR; in another specific embodiment, R 1 is -C(O)NRR'; in another specific embodiment, R 1 is -S(O) 1-2 R
  • R 1 is CF 3 ; in another embodiment, R 1 is CHF 2 ; in another embodiment, R 1 is CF 2 CH 2 OH; in another embodiment In another specific embodiment, R 1 is CF 2 CH 3 ; in another specific embodiment, R 1 is CF 2 C(OH)(CH 3 ) 2 ; in another specific embodiment, R 1 is CN; in another specific embodiment In one embodiment, R 1 is OCHF 2 ; in another specific embodiment, R 1 is C(O)NHCH 3 ; in another specific embodiment, R 1 is C(O)N(CH 3 ) 2 ; In another specific embodiment, R 1 is OCF 3 ; in another specific embodiment, R 1 is OMe.
  • R 2 is H; in another specific embodiment, R 2 is halogen; in another specific embodiment, R 2 is -CN; in another specific embodiment, R 2 is C 1-6 alkyl; In another specific embodiment, R 2 is C 1-6 haloalkyl; In another specific embodiment, R 2 is C 1-4 haloalkyl; In another specific embodiment , R 2 is C 1-2 haloalkyl; in another specific embodiment, R 2 is C 1 haloalkyl; in another specific embodiment, R 2 is C 2-6 alkenyl; in another specific embodiment In one embodiment, R 2 is C 2-6 alkynyl; in another specific embodiment, R 2 is -OR; in another specific embodiment, R 2 is -NRR'; in another specific embodiment, R 2 is -C(O)R; in another specific embodiment, R 2 is -C(O)OR; in another specific embodiment, R 2 is -C(O)NRR'; in another specific embodiment, R 2 is -C(O)NRR'; In another specific embodiment, R 2 is
  • R2 is H; in another embodiment, R2 is F; in another embodiment, R2 is CH3 .
  • R 3 is H; In another specific embodiment, R 3 is halogen; In another specific embodiment, R 3 is -CN; In another specific embodiment, R 3 is C 1-6 alkyl; In another specific embodiment, R 3 is C 1-6 haloalkyl; In another specific embodiment, R 3 is -OR; In another specific embodiment, R 3 is -NRR'; In another specific embodiment, R 3 is -C(O)R; In another specific embodiment, R 3 is -C(O)OR; In another specific embodiment, R 3 is -C(O)OR; In another specific embodiment, R 3 is -C(O)OR; In another specific embodiment, R 3 is -C(O)NRR'; in another specific embodiment, R 3 is -S(O) 1-2 R; in another specific embodiment, R 3 is -S(O)(NR)R '; In another specific embodiment, R 3 is -P(O)RR'; In another specific embodiment, R 3 is -S(O) 0-2 R; In another specific embodiment, R 3 is
  • R3 is H; in another embodiment, R3 is NH2 .
  • R 1 and R 2 and the atoms they are connected together form a C 3-7 cycloalkyl; in another specific embodiment, R 1 and R 2 and the atoms they are connected together form 4-8 In another specific embodiment, R 1 and R 2 and their connected atoms together form a 4-7 membered heterocyclic group; in another specific embodiment, R 1 and R 2 and their connected atoms Atoms together form a 5-6 membered heterocyclic group; in another specific embodiment, R and R together form a 5-6 membered heterocyclic group containing a sulfur atom; in another specific embodiment, R and R 2 and the atoms to which they are attached together form phenyl; in another specific embodiment, R and R and the atoms to which they are attached together form a 5-6 membered heteroaryl.
  • R and R and the atoms to which they are attached together form In another specific embodiment, R and R and the atoms to which they are attached are taken together to form In another specific embodiment, R and R and the atoms to which they are attached are taken together to form In another specific embodiment, R and R and the atoms to which they are attached are taken together to form In another specific embodiment, R and R and the atoms to which they are attached are taken together to form
  • R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by one R#; in another specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 2 R#; in another specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection is optionally substituted by 3 R#; in another specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 4 R#; in another In a specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 5 R#;
  • R is H; in another specific embodiment, R is D; in another specific embodiment, R is C 1-6 alkyl; in another specific embodiment , R 5 is C 1-6 haloalkyl; in another specific embodiment, R 5 is C 2-6 alkenyl, such as vinyl; in another specific embodiment, R 5 is C 2-6 alkynyl ; In another specific embodiment, R 5 is —CH 3 ; In another specific embodiment, R 5 is CHF 2 ; In another specific embodiment, R 5 is CF 3 ; In another specific embodiment, R 5 is CF 3 ; In another specific embodiment, R 5 is —CH 3 ; In, R 5 is CH 2 F.
  • R 5 can be optionally substituted by -OH; in another embodiment, R 5 can be optionally substituted by -NH 2 ; in another embodiment, R 5 can be optionally Optionally replaced by --CN.
  • R 6 is H; In another specific embodiment, R 6 is C 1-6 alkyl; In another specific embodiment, R 6 is C 1-4 alkyl; In another In one specific embodiment, R 6 is C 1-2 alkyl; in another specific embodiment, R 6 is -CH 3 ; in another specific embodiment, R 6 is -CD 3 ; in another specific embodiment In one embodiment, R 6 is C 1-6 haloalkyl, such as CHF 2 ; in another specific embodiment, R 6 is 4-7 membered heterocyclyl; in another specific embodiment, R 6 is C 3 -10 cycloalkyl; In another specific embodiment, R 6 is C 3-6 cycloalkyl; In another specific embodiment, R 6 is C 3-4 cycloalkyl, such as cyclopropyl.
  • R can be optionally substituted by D; in another embodiment, R can be optionally substituted by -OH; in another embodiment, R can be optionally is substituted by -NH2 ; in another specific embodiment, R6 can be optionally substituted by -CN.
  • Z 1 in Ring B as In one specific embodiment of Z 1 is NR Z1a ; in another specific embodiment, Z 1 is CR Z1b R Z1c . in Ring B as In one specific embodiment of Z 1 is N; in another specific embodiment, Z 1 is CR Z1b .
  • Z 2 is NR Z2a ; in another specific embodiment, Z 2 is CR Z2b R Z2c .
  • Ring B in Ring B as In one specific embodiment of Z 3 is N; in another specific embodiment, Z 3 is CR Z3b . in Ring B as In one specific embodiment of Z 3 is NR Z3a ; in another specific embodiment, Z 3 is CR Z3b R Z3c .
  • R Z1a is a chemical bond; in another specific embodiment, R Z1a is C 1-6 alkyl; in another specific embodiment, R Z1a is C 1-6 haloalkyl; in another In one specific embodiment, R Z1a is C 1-4 haloalkyl; In another specific embodiment, R Z1a is C 2-6 alkenyl; In another specific embodiment, R Z1a is C 2-6 alkyne In another specific embodiment, R Z1a is a 4-7 membered heterocyclyl; In another specific embodiment, R Z1a is a 5-6 membered heterocyclic group; In another specific embodiment, R Z1a is C 3-10 cycloalkyl; in another specific embodiment, R Z1a is C 3-8 cycloalkyl; in another specific embodiment, R Z1a is C 3-7 cycloalkyl; in another In a specific embodiment, R Z1a is a 5-10 membered heteroaryl group; in another specific embodiment, R Z1a is a 5-6 membered
  • R Z1a is a chemical bond; in another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment, R Z1a is In another specific embodiment
  • R Z2a is a chemical bond; in another embodiment, R Z2a is C 1-6 alkyl; in another embodiment, R Z2a is C 1-6 haloalkyl; in another embodiment In one specific embodiment, R Z2a is C 1-4 haloalkyl; In another specific embodiment, R Z2a is C 2-6 alkenyl; In another specific embodiment, R Z2a is C 2-6 alkyne In another specific embodiment, R Z2a is a 4-7 membered heterocyclyl; In another specific embodiment, R Z2a is a 5-6 membered heterocyclic group; In another specific embodiment, R Z2a is C 3-10 cycloalkyl; in another specific embodiment, R Z2a is C 3-8 cycloalkyl; in another specific embodiment, R Z2a is C 3-7 cycloalkyl; in another In a specific embodiment, R Z2a is a 5-10 membered heteroaryl group; in another specific embodiment, R Z2a is a 5-6 membered heteroary
  • R Z2a is a chemical bond; In another specific embodiment, R Z2a is
  • R Z1a is optionally substituted with 1 R*; in another embodiment, R Z1a is optionally substituted with 2 R*; in another embodiment, R Z1a is optionally is optionally substituted with 3 R*; in another embodiment, R Z1a is optionally substituted with 4 R*; in another embodiment, R Z1a is optionally substituted with 5 R*.
  • R Z2a is optionally substituted with 1 R*; in another embodiment, R Z2a is optionally substituted with 2 R*; in another embodiment, R Z2a is optionally is optionally substituted with 3 R*; in another embodiment, R Z2a is optionally substituted with 4 R*; in another embodiment, R Z2a is optionally substituted with 5 R*.
  • R Z3a is a chemical bond; In another specific embodiment, R Z3a is C 1-6 alkyl; In another specific embodiment, R Z3a is C 1-6 haloalkyl; In another specific embodiment, R Z3a is C 1-6 haloalkyl; In one specific embodiment, R Z3a is C 1-4 haloalkyl; In another specific embodiment, R Z3a is C 2-6 alkenyl; In another specific embodiment, R Z3a is C 2-6 alkyne In another specific embodiment, R Z3a is a 4-7 membered heterocyclyl; In another specific embodiment, R Z3a is a 5-6 membered heterocyclic group; In another specific embodiment, R Z3a is C 3-10 cycloalkyl; in another specific embodiment, R Z3a is C 3-8 cycloalkyl; in another specific embodiment, R Z3a is C 3-7 cycloalkyl; in another In a specific embodiment, R Z3a is a 5-10 membered heteroaryl group
  • R Z1b is -L Z1b -R X1b .
  • R Z2b is -L Z2b -R X2b .
  • L Z1b is a chemical bond; In another specific embodiment, L Z1b is -S-; In another specific embodiment, L Z1b is -O-; In another specific embodiment, L Z1b is -N-; in another specific embodiment, L Z1b is -C(O)-; in another specific embodiment, L Z1b is -C(O)O-; in another specific embodiment In, L Z1b is -OC(O)-; In another specific embodiment, L Z1b is -C(O)NH-; In another specific embodiment, L Z1b is -NHC(O)-; In In another specific embodiment, L Z1b is -S(O) 2 -; in another specific embodiment, L Z1b is -C 1-6 alkylene-; in another specific embodiment, L Z1b is -C 2-6 alkenylene-; In another specific embodiment, L Z1b is -C 2-6 alkynylene-.
  • L Z2b is a chemical bond; In another specific embodiment, L Z2b is -S-; In another specific embodiment, L Z2b is -O-; In another specific embodiment, L Z2b is -N-; In another specific embodiment, L Z2b is -C(O)-; In another specific embodiment, L Z2b is -C(O)O-; In another specific embodiment In, L Z2b is -OC(O)-; In another specific embodiment, L Z2b is -C(O)NH-; In another specific embodiment, L Z2b is -NHC(O)-; In In another specific embodiment, L Z2b is -S(O) 2 -; in another specific embodiment, L Z2b is -C 1-6 alkylene-; in another specific embodiment, L Z2b is -C 2-6 alkenylene-; In another specific embodiment, L Z2b is -C 2-6 alkynylene-.
  • R X1b is H; In another specific embodiment, R X1b is D; In another specific embodiment, R X1b is C 1-6 alkyl; In another specific embodiment, R X1b is a C 1-6 haloalkyl group; in another specific embodiment, R X1b is a 4-7 membered heterocyclic group; in another specific embodiment, R X1b is a 5-6 membered heterocyclic group; In another specific embodiment, R X1b is C 3-7 cycloalkyl; In another specific embodiment, R X1b is 5-10 yuan heteroaryl; In another specific embodiment, R X1b is 5- 6-membered heteroaryl; In another specific embodiment, R X1b is C 6-10 aryl.
  • R X2b is H; In another specific embodiment, R X2b is D; In another specific embodiment, R X2b is C 1-6 alkyl; In another specific embodiment, R X2b is a C 1-6 haloalkyl group; in another specific embodiment, R X2b is a 4-7 membered heterocyclic group; in another specific embodiment, R X2b is a 5-6 membered heterocyclic group; In another specific embodiment, R X2b is C 3-7 cycloalkyl; In another specific embodiment, R X2b is 5-10 yuan heteroaryl; In another specific embodiment, R X2b is 5- 6-membered heteroaryl; In another specific embodiment, R X2b is C 6-10 aryl.
  • R X1b is optionally substituted with halogen; in another embodiment, R X1b is optionally substituted with -OH; in another embodiment, R X1b is optionally In another specific embodiment, R X1b can be optionally substituted by -CN; In another specific embodiment, R X1b can be optionally substituted by C 1-6 alkyl; In another specific embodiment, R X1b can be optionally substituted by C 1-6 alkyl; In one specific embodiment, R X1b may be optionally substituted by C 1-6 haloalkyl; in another specific embodiment, R X1b may be optionally substituted by C 2-6 alkenyl; in another specific embodiment In, R X1b can be optionally substituted by C 2-6 alkynyl; in another specific embodiment, R X1b can be optionally substituted by -C(O)NH 2 ; in another specific embodiment, R X1b can be optionally substituted by -C(O)NH-C 1-6 alky
  • R X2b is optionally substituted with halogen; in another embodiment, R X2b is optionally substituted with -OH; in another embodiment, R X2b is optionally Substituted by -NH 2 ; In another specific embodiment, R X2b can be optionally substituted by -CN; In another specific embodiment, R X2b can be optionally substituted by C 1-6 alkyl; In another specific embodiment, R X2b may be optionally substituted by C 1-6 haloalkyl; in another specific embodiment, R X2b may be optionally substituted by C 2-6 alkenyl; in another specific embodiment In, R X2b can be optionally substituted by C 2-6 alkynyl; in another specific embodiment, R X2b can be optionally substituted by -C(O)NH 2 ; in another specific embodiment, R X2b can be optionally substituted by -C(O)NH-C 1-6 alkyl; in another specific embodiment, R
  • R Z1b is H; In another specific embodiment, R Z1b is OMe; In another specific embodiment, R Z1b is In another specific embodiment, R Z1b is In another specific embodiment, R Z1b is In another specific embodiment, R Z1b is
  • R Z2b is H; In another specific embodiment, R Z2b is OMe; In another specific embodiment, R Z2b is In another specific embodiment, R Z2b is
  • R Z1c is H; in another embodiment, R Z1c is a chemical bond.
  • R Z2c is H; in another embodiment, R Z2c is a chemical bond.
  • R Z3c is H; in another embodiment, R Z3c is a chemical bond.
  • R Z1a and R Z2c can be combined to form a double bond; in another specific embodiment, R Z1a and R Z2a can be combined to form a double bond; in another specific embodiment, R Z2a and R Z1c can be combined to form a double bond; in another specific embodiment, R Z1c and R Z2c can be combined to form a double bond; in another specific embodiment, R Z2a and R Z3a can be combined to form a double bond; in another In a specific embodiment, R Z2a and R Z3c can be combined to form a double bond; in another specific embodiment, R Z2c and R Z3a can be combined to form a double bond; in another specific embodiment, R Z2c and R Z3c can combine to form a double bond.
  • R Z3b is H; In another specific embodiment, R Z3b is D; In another specific embodiment, R Z3b is halogen; In another specific embodiment, R Z3b is - NR a R b ; in another specific embodiment, R Z3b is -OR a ; in another specific embodiment, R Z3b is -OH; in another specific embodiment, R Z3b is -NH 2 ; In another specific embodiment, R Z3b is -CN; in another specific embodiment, R Z3b is C 1-6 alkyl, preferably methyl; in another specific embodiment, R Z3b is C 1-6 Haloalkyl; In another specific embodiment, R Z3b is C 2-6 alkenyl; In another specific embodiment, R Z3b is C 2-6 alkynyl; In another specific embodiment, R Z3b is -LC 3-6 cycloalkyl; In another specific embodiment, R Z3b is -L-4-6 membered heterocyclyl; In another specific embodiment, R Z3b is -
  • R Z3b is Cl; In another specific embodiment, R Z3b is F; In another specific embodiment, R Z3b is Me; In another specific embodiment, R Z3b is CHF 2 ; in another specific embodiment, R Z3b is NH 2 ; in another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific embodiment, R Z3b is In another specific
  • L is a chemical bond; in another specific embodiment, L is O; in another specific embodiment, L is S; in another specific embodiment, L is NH.
  • Ra and R b are H; In another specific embodiment, Ra and R b are C 1-6 alkyl; In another specific embodiment, Ra and R b are C 1-6 haloalkyl; In another specific embodiment, R a and R b are -C 1-6 alkylene-OH; In another specific embodiment, R a and R b are -C 1- 6 alkylene-OC 1-6 alkyl; In another specific embodiment, R a and R b are -C 1-6 alkylene-OC 1-6 haloalkyl; In another specific embodiment, R a and R b are -C 1-6 alkylene-NH 2 ; in another specific embodiment, R a and R b are -C 1-6 alkylene-NHC 1-6 alkyl; in another In one specific embodiment, R a and R b are -C 1-6 alkylene-N(C 1-6 alkyl) 2 ; in another specific embodiment, R a and R b are -C 1- 6 alkylene-NHC 1-6
  • R# is halogen; In another specific embodiment, R# is -CN; In another specific embodiment, R# is -NRR'; In another specific embodiment, R # is -OR; in another specific embodiment, R# is -C(O)R; in another specific embodiment, R# is -C(O)OR; in another specific embodiment, R # is -C(O)NRR'; in another specific embodiment, R# is -OC(O)R'; in another specific embodiment, R# is -NRC(O)R'; in another specific embodiment In one specific embodiment, R# is -OC (O) NRR '; In another specific embodiment, R # is -NRC (O) NRR '; In another specific embodiment, R # is -S ( O) 1-2 R; In another specific embodiment, R# is -S(O)(NR)R'; In another specific embodiment, R# is C 1-6 alkyl; In another specific embodiment In a specific embodiment, R# is C 1-6 haloalkyl; in
  • R is H; In another specific embodiment, R is C 1-6 alkyl; In another specific embodiment, R is C 1-6 haloalkyl; In another specific embodiment, R is C 2-6 alkenyl; in another embodiment, R is C 2-6 alkynyl; in another embodiment, R is C 3-7 cycloalkyl; in another embodiment In a specific embodiment, R is a 3-8 membered heterocyclic group; in another specific embodiment, R is a C 6-10 aryl group; in another specific embodiment, R is a 5-10 membered heteroaryl group.
  • R' is H; In another specific embodiment, R' is C 1-6 alkyl; In another specific embodiment, R' is C 1-6 haloalkyl; In another In one specific embodiment, R' is C 2-6 alkenyl; in another specific embodiment, R' is C 2-6 alkynyl; in another specific embodiment, R' is C 3-7 ring Alkyl; In another specific embodiment, R' is a 3-8 membered heterocyclic group; In another specific embodiment, R' is C 6-10 aryl; In another specific embodiment, R' It is a 5-10 membered heteroaryl group.
  • R, R' and the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group.
  • R* is halogen; In another specific embodiment, R* is -C 0-4 alkylene-OR; In another specific embodiment, R* is -C 0-4 Alkylene-NRR'; In another specific embodiment, R* is -C 0-4 alkylene-CN; In another specific embodiment, R* is -C(O)R; In another specific embodiment, R* is -C(O)R; In a specific embodiment, R* is -C(NH)OR; in another specific embodiment, R* is -C(O)OR; in another specific embodiment, R* is -C(O)NRR '; in another specific embodiment, R* is -NH 2 ; in another specific embodiment, R* is -CN; in another specific embodiment, R* is C 1-6 alkyl; in In another specific embodiment, R* is C 1-6 haloalkyl; in another specific embodiment, R* is C 1-4 haloalkyl; in another specific embodiment, R* is C 2-6 Alkenyl; In another specific specific
  • two R* on the same or different carbon atoms and the atoms to which they are attached together form a C5-6 cycloalkyl, which is optionally substituted by 1, 2 or 3 Rx; in another In one specific embodiment, two R* on the same or different carbon atoms and the atoms they connect together form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 Rx; in another specific In an embodiment, two R* are linked to form a C 1-4 alkylene.
  • Rx is C 1-6 alkyl; In another specific embodiment, Rx is C 1-6 haloalkyl; In another specific embodiment, Rx is -C 0-6 alkylene -OR; In another specific embodiment, Rx is -C 0-6 alkylene-NRR'; In another specific embodiment, Rx is -C(O)R; In another specific embodiment, Rx is -C(O)R; , Rx is -C(NH)OR; in another specific embodiment, Rx is -C(O)OR; in another specific embodiment, Rx is -C(O)NRR'; in another specific embodiment In one embodiment, Rx is C 3-6 cycloalkyl; in another specific embodiment, Rx is 4-6 membered heterocyclyl.
  • any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments.
  • any technical scheme of Ring A or any combination thereof can be combined with any technical scheme of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 , Z 2 and Z 3 etc. Combine in any combination.
  • the present invention intends to include the combination of all these technical solutions, which are not listed one by one due to space limitation.
  • the present invention provides a compound of formula (I), (I-1) or (I-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
  • R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 1 and R 2 together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2, 3, 4 or 5 R# substitutions;
  • R 3 is selected from H, NH 2 , OH or -CN;
  • R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
  • R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
  • Z1 is NR Z1a or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2. -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkane base;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can be optionally replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH , -C(O)OC 1-6 alkyl substitution;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond
  • the present invention provides the above-mentioned (I), (I-1) or (I-2) compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
  • R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 1 and R 2 together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2, 3, 4 or 5 R# substitutions;
  • R 3 is selected from H or NH 2 ;
  • R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-4 cycloalkyl, which is optionally substituted by D;
  • Z1 is NR Z1a or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, optionally substituted by 1, 2, 3, 4 or 5 R*;
  • R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkane Base) 2 , -C(O)OH or -C(O)OC 1-6 alkyl substitution;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond
  • the present invention provides a compound of formula (II), (II-1) or (II-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
  • R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
  • R 3 is selected from H or NH 2 ;
  • R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
  • Z1 is NR Z1a or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, optionally substituted by 1, 2 or 3 R*;
  • R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkane Base) 2 , -C(O)OH or -C(O)OC 1-6 alkyl substitution;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond
  • the present invention provides the above-mentioned (II), (II-1) or (II-2) compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R is selected from C 1-6 alkyl or C 1-6 haloalkyl optionally substituted by -OH;
  • R 2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
  • R 3 is selected from H or NH 2 ;
  • R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
  • Z1 is NR Z1a or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • R Z1a , R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-8 cycloalkyl, the groups can optionally be 1, 2 or 3 R* substitutions;
  • R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b and L Z2b are independently selected from chemical bonds, -O-, -S- or -N-;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl; the C 3-7 cycloalkyl can optionally be replaced by -C (O)OH or -C(O)NH 2 substitution;
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond
  • the present invention provides the above-mentioned (II), (II-1) or (II-2) compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CF 3 , CHF 2 , CF 2 CH 2 OH or CF 2 CH 3 ;
  • R 2 is selected from H, F or CH 3 ;
  • R 3 is selected from H or NH 2 ;
  • R 6 is selected from CH 3 or CD 3 ;
  • Z1 is NR Z1a or CR Z1b R Z1c ;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • R Z1a is selected from chemical bonds
  • R Z2a is selected from a chemical bond or
  • R Z1b is selected from H, OMe,
  • R Z2b is selected from H, OMe,
  • R Z1c is selected from H or a chemical bond
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond
  • the present invention provides a compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is C 1-6 haloalkyl
  • R is selected from H or halogen
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH- or -S(O) 2 -;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl; -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O )OC 1-6 alkyl substitution;
  • the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl
  • R is selected from H or halogen
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b and L Z2b are independently selected from chemical bonds, -O-, -S- or -N-;
  • R X1b and R X2b are independently selected from H, C 1-6 alkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl; the C 3-7 cycloalkyl can optionally be replaced by -C (O)OH or -C(O) NH2 substitution.
  • the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CF 3 or CHF 2 ;
  • R is selected from H or F
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R Z1b is selected from OMe
  • R Z2b is selected from H, OMe or
  • the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl
  • R is selected from H or halogen
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b and L Z2b are independently selected from -O-, -S- or -N-;
  • R X1b and R X2b are independently selected from C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl.
  • the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1 haloalkyl
  • R is selected from H or halogen
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R Z1b is -L Z1b -R X1b ;
  • R Z2b is -L Z2b -R X2b ;
  • L Z1b and L Z2b are independently selected from -O- or -S-;
  • R X1b and R X2b are independently selected from C 1-6 alkyl or 5-6 membered heterocyclic group.
  • the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CF 3 or CHF 2 ;
  • R is selected from H or F
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R Z1b is selected from OMe or
  • R Z2b is selected from OMe or
  • the present invention provides a compound of formula (IV), (IV-1) or (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
  • R 2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
  • Z 2 is CR Z2b R Z2c ;
  • R Z1a is selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , 4-7 membered heterocyclyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2 or 3 R*;
  • R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Z2b is selected from H or 4-7 membered heterocyclyl
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c combine to form a double bond
  • the present invention provides the above-mentioned (IV), (IV-1) or (IV-2) compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-6 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
  • R 2 is selected from H, halogen or C 1-6 alkyl
  • R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
  • Z 2 is CR Z2b R Z2c ;
  • R Z1a is selected from a chemical bond, 4-7 membered heterocyclyl or C 3-8 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
  • R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z2b is selected from H or 5-6 membered heterocyclic groups, preferably H;
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c combine to form a double bond
  • the present invention provides the above-mentioned (IV), (IV-1) or (IV-2) compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CHF 2 , CF 3 , CF 2 CH 2 OH or CF 2 CH 3 ;
  • R 2 is selected from H, F or CH 3 ;
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R 6 is selected from CH 3 or CD 3 ;
  • Z 2 is CR Z2b R Z2c ;
  • R Z1a is selected from chemical bonds
  • R Z2b is selected from H or H is preferred
  • R Z2c is selected from H or a chemical bond
  • R Z1a and R Z2c combine to form a double bond
  • the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is C 1-4 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
  • R is selected from H or halogen
  • R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which is optionally replaced by 1 or 2 R #replace;
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D;
  • R Z1a is selected from 4-7 membered heterocyclyl or C 3-8 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
  • R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl
  • the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CF 3 , CHF 2 , CF 2 CH 2 OH or CF 2 CH 3 ;
  • R is selected from H or F
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R 6 is selected from CH 3 or CD 3 ;
  • R Z1a is selected from
  • the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-2 haloalkyl
  • R is selected from H or halogen
  • R 1 and R 2 together form a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1, 2 or 3 R#;
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R 6 is C 1-2 alkyl, which may be optionally substituted by D;
  • R Z1a is C 3-7 cycloalkyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1 haloalkyl
  • R is selected from H or halogen
  • R 1 and R 2 together form a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R 6 is methyl, which may be optionally substituted by D;
  • R Z1a is C 3-4 cycloalkyl optionally substituted by 1 or 2 R*;
  • R* is selected from C 1-4 alkyl or C 1-4 haloalkyl.
  • the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CHF 2 or CF 3 ;
  • R is selected from H or F
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R 6 is selected from CH 3 or CD 3 ;
  • R Z1a is selected from
  • the present invention provides a compound of formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is C 1-6 haloalkyl
  • R is selected from H or halogen
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • Z1 is CR Z1b R Z1c ;
  • R Z1b is selected from H, 4-7 membered heterocyclyl or C 3-7 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
  • R Z1c is selected from H or a chemical bond
  • R Z2a is selected from a chemical bond, C 3-7 cycloalkyl or 5-6 membered heterocyclyl, which may be optionally substituted by 1, 2 or 3 R*;
  • R* is selected from -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Z2a and R Z1c combine to form a double bond
  • the present invention provides the above-mentioned compound of formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-6 haloalkyl
  • R is selected from H or halogen
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • Z1 is CR Z1b R Z1c ;
  • R Z1b is selected from H or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R*;
  • R Z1c is selected from H or a chemical bond
  • R Z2a is selected from a chemical bond, C 3-7 cycloalkyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R Z2a and R Z1c combine to form a double bond.
  • the present invention provides the above-mentioned compound of formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CHF 2 or CF 3 ;
  • R is selected from H or F
  • R 3 is selected from H or NH 2
  • R 2 and R 3 are not H at the same time
  • Z1 is CR Z1b R Z1c ;
  • R Z1b is selected from H or
  • R Z1c is selected from H or a chemical bond
  • R Z2a is selected from a chemical bond or
  • R Z2a and R Z1c combine to form a double bond.
  • the present invention provides a compound of formula (VII), (VII-1) or (VII-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is C 1-2 haloalkyl
  • R is selected from H or halogen
  • R 3 is selected from H or NH 2
  • R 2 and R 3 are not H at the same time
  • R Z1b is selected from 5-6 membered heterocyclyl, C 3-7 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
  • R* is selected from -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • the present invention provides the above-mentioned compound of formula (VII), (VII-1) or (VII-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from C 1 haloalkyl, preferably CF 3 or CHF 2
  • R is selected from H, halogen, preferably H or F;
  • R 3 is selected from H or NH 2 ;
  • R 2 and R 3 are not H at the same time
  • R Z1b is a 5-6 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R Z1b is preferably
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compound, it has the structure of formula (VIII), (VIII-1) or (VIII-2):
  • R 1 is C 1-4 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
  • R 2 is selected from H, D, halogen or C 1-2 alkyl
  • R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R is selected from H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by D, up to fully deuterium generation;
  • Z 3 is N or CR Z3b ;
  • R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
  • R Z1a is preferably the following group:
  • R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration;
  • the present invention provides the compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
  • R 2 is selected from H, D, halogen or C 1-2 alkyl
  • R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3 or 4 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R is selected from C 1-4 alkyl or C 1-4 haloalkyl
  • R 6 is selected from C 1-4 alkyl or C 1-4 haloalkyl
  • Z 3 is N or CR Z3b ;
  • R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from halogen, OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or the same or different carbon atoms
  • R Z3b is selected from H, D or halogen
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  • the present invention provides the compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CHF 2 , CF 3 , CF 2 CH 3 or CF 2 CH 2 OH;
  • R 2 is selected from H, D, F or CH 3 ;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R 5 is selected from CH 3 or CHF 2 ;
  • R 6 is selected from CH 3 or CD 3 ;
  • Z 3 is N or CR Z3b ;
  • R Z1a is selected from
  • R Z3b is selected from H, D or Cl.
  • the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • R 1 is C 1-4 haloalkyl
  • R 2 is selected from H, D, halogen or C 1-2 alkyl
  • R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1, 2 or 3 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R is selected from C 1-4 alkyl or C 1-4 haloalkyl
  • R 6 is selected from C 1-4 alkyl or C 1-4 haloalkyl
  • Z 3 is N or CR Z3b ;
  • R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from C 1-4 alkyl, C 1-4 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and their connected atoms Together form C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
  • R Z3b is selected from H, D or halogen
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  • the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • R 1 is C 1-2 haloalkyl
  • R 2 is selected from H, D, halogen or C 1-2 alkyl
  • R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R is selected from C 1-2 alkyl or C 1-2 haloalkyl
  • R 6 is C 1-2 alkyl
  • Z 3 is N or CR Z3b ;
  • R Z1a is C 3-6 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from C 1-2 alkyl, C 1-2 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and their connected atoms Together form a 5-6 membered heterocyclic group;
  • R Z3b is selected from H, D or halogen
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  • the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
  • R 2 is selected from H, D, F or CH 3 ;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R 5 is selected from CH 3 or CHF 2 ;
  • R 6 is selected from CH 3 or CD 3 ;
  • Z 3 is N or CR Z3b ;
  • R Z1a is selected from
  • R Z3b is selected from H, D or Cl.
  • the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • R 1 is C 1-4 haloalkyl
  • R 2 is selected from halogen or C 1-4 alkyl, preferably halogen
  • R 1 and R 2 and the atoms to which they are attached together form a C 4-7 cycloalkyl group, which is optionally substituted by 1, 2 or 3 R#;
  • R# is halogen
  • R is selected from H or D
  • R 5 is C 1-2 alkyl
  • R 6 is C 1-2 alkyl
  • Z 3 is N or CR Z3b ;
  • R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group;
  • R Z3b is selected from H or D
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  • the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • R 1 is C 1-2 haloalkyl
  • R 2 is selected from halogen or C 1-2 alkyl, preferably halogen
  • R 1 and R 2 and the atoms they are connected together form a C 5-6 cycloalkyl group, which is optionally substituted by 1 or 2 R#;
  • R# is halogen
  • R is selected from H or D
  • R 5 is C 1-2 alkyl
  • R 6 is C 1-2 alkyl
  • Z 3 is N or CR Z3b ;
  • R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group;
  • R Z3b is selected from H or D
  • each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  • the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
  • R 2 is selected from F or CH 3 ; preferably, when R 1 is CF 2 CH 3 , R 2 is not CH 3 ;
  • R3 is H
  • R 5 is CH 3 ;
  • R 6 is selected from CH 3 or CD 3 ;
  • Z 3 is N or CR Z3b ;
  • R Z1a is selected from
  • R Z3b is H.
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compound, wherein the compound has the general formula:
  • each group is as defined in any one of the compounds of formula (VIII), (VIII-1) or (VIII-2);
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R is selected from -CN, halogen or C1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH2 or -CN, which is also optionally substituted by D, until fully deuterated ;
  • R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
  • R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
  • R Z1a is C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R*, optionally substituted by D, up to fully deuterated;
  • R* is selected from halogen, -C 0-4 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-4 alkylene-OR, -C 0-4 alkylene -NRR', -C(O)R, -C(NH)OR, -C(O)OR, -C(O)NRR', phenyl or 5-6 membered heteroaryl; or the same or different carbon atoms
  • Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
  • R Z1a is preferably the following group:
  • R Z3b is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4 -6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, up to complete Deuterium;
  • L is a chemical bond, O, S or NH
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • R Z3b is preferably the following groups:
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R is selected from CN, halogen or C1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH2 or -CN, which is also optionally substituted by D, up to complete deuteration;
  • R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 3 is selected from H, D or NH 2 ;
  • R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
  • R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
  • R Z1a is C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R*, optionally substituted by D, up to fully deuterated;
  • R* is selected from halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-OC 1-6 alkyl, - C 1-4 alkylene-OC 1-6 haloalkyl, -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, -C(O)NH-C 1-6 Alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(NH)OC 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -C(O)NH- C 1-6 haloalkyl, -C(O)N(C 1-6 haloalkyl) 2 , phenyl or 5-6 membered heteroaryl, which is optionally substituted by D, up to complete deuteration;
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
  • L is a chemical bond, O, S or NH
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R is C 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH or NH , which is also optionally substituted by D, up to complete deuteration;
  • R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 3 is selected from H, D or NH 2 ;
  • R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
  • R is selected from H, C 1-4 alkyl or C 1-4 haloalkyl, which is optionally substituted by D, until fully deuterated;
  • R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
  • R* is selected from halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, -C(O )NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(NH)OC 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -C(O)NH-C 1-6 haloalkyl, -C(O)N(C 1-6 haloalkyl) 2 , phenyl or 5-6 membered heteroaryl optionally substituted by D, up to Fully deuterated;
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
  • L is a chemical bond, O, S or NH
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl, which is optionally substituted by 1 or 2 OH, which is also optionally substituted by D, until fully deuterated;
  • R is selected from H, D, halogen or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
  • R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
  • R* is selected from F, CN, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CHF 3 , -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, Phenyl or 5-6 membered heteroaryl, which is optionally substituted by D, up to fully deuterated;
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
  • L is a chemical bond, O or NH
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane Group, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene - NHC 1-6 alkyl or -C 1-6 alkylene-N(C 1-6 alkyl) 2 , It is optionally substituted by D up to full deuteration;
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CHF 2 , CF 3 , CF 2 CH 3 or CF 2 C(OH)(CH 3 ) 2 , optionally substituted by D, up to full deuteration;
  • R2 is selected from H, D, F or CH3 , which is optionally substituted by D, up to complete deuteration;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • R 5 is CH 3 , which is optionally substituted by D until fully deuterated;
  • R 6 is H or CH 3 , which is optionally substituted by D until fully deuterated;
  • R Z1a is selected from It is optionally substituted by D up to full deuteration;
  • R Z3b is selected from H, D, Cl, F, Me, It is optionally substituted with D until fully deuterated.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
  • R 2 is halogen
  • R is selected from H or D
  • R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
  • R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
  • R* is selected from CH 3 , CH 2 F, CHF 2 , -C(NH)OC 1-6 alkyl or -C(O)OC 1-6 alkyl optionally substituted with D until fully deuterated ;
  • R Z3b is selected from H or D.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-2 haloalkyl, which is optionally substituted by D, up to fully deuterated;
  • R 2 is halogen
  • R is selected from H or D
  • R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
  • R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R Z1a is It is optionally substituted by D up to full deuteration
  • R* is selected from CH 3 , CH 2 F, CHF 2 , -C(NH)OC 1-4 alkyl or -C(O)OC 1-4 alkyl optionally substituted with D up to fully deuterium generation;
  • R Z3b is selected from H or D.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
  • R2 is F
  • R3 is H
  • R 5 is CH 3 ;
  • R 6 is selected from H, CH 3 or CD 3 ;
  • R Z1a is selected from
  • R Z3b is H.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CN, halogen, C 1-6 haloalkyl, OR, C(O)OR or -C(O)NRR', optionally replaced by 1, 2 or 3 OH, -NH 2 or -CN Substituted, which is also optionally substituted by D, up to complete deuteration;
  • R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
  • R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
  • R Z1a is a 4-7 membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5 R*, optionally substituted by D, up to full deuteration;
  • R Z3b is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4 -6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, up to complete Deuterium;
  • L is a chemical bond, O, S or NH
  • R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group, -C 1-6 alkylene -OC 1-6 haloalkyl, -C 1-6 alkylene - NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, or R, R' and their connected nitrogen atom form a 4-8 membered heterocyclic group.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CN, halogen, C 1-6 haloalkyl, OR, C(O)OR or -C(O)NRR', optionally replaced by 1, 2 or 3 OH, -NH 2 or -CN Substituted, which is also optionally substituted by D, up to complete deuteration;
  • R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
  • R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
  • R Z1a is It is optionally substituted by D up to full deuteration
  • X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
  • RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R, C 3-8 cycloalkyl or 4-7 membered heterocyclyl;
  • R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl;
  • R and R' are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
  • R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CN, halogen, C 1-6 haloalkyl or OC 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH 2 or -CN, which is also optionally substituted by D Substitution, until complete deuteration;
  • R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 3 is selected from H, D or NH 2 ;
  • R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
  • R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
  • R Z1a is It is optionally substituted by D up to full deuteration
  • X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
  • RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C(O)R;
  • R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
  • R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CN, halogen, C 1-6 haloalkyl or OC 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH 2 or -CN, which is also optionally substituted by D Substitution, until complete deuteration;
  • R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R 3 is selected from H, D or NH 2 ;
  • R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
  • R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
  • R Z1a is It is optionally substituted by D up to full deuteration
  • R* is selected from H, D or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
  • R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
  • R 2 is halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R is selected from H or D
  • R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
  • R 6 is C 1-4 alkyl, which is optionally substituted by D, until fully deuterated;
  • R Z1a is It is optionally substituted by D up to full deuteration
  • X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
  • RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C(O)R;
  • R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl or C 1-6 haloalkyl;
  • R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
  • R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
  • R 2 is halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R is selected from H or D
  • R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
  • R 6 is C 1-4 alkyl, which is optionally substituted by D, until fully deuterated;
  • R Z1a is It is optionally substituted by D up to full deuteration
  • R* is selected from H, D or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
  • R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-2 haloalkyl, which is optionally substituted by D, up to fully deuterated;
  • R 2 is halogen or C 1-2 alkyl, which is optionally substituted by D, up to fully deuterated;
  • R is selected from H or D
  • R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
  • R 6 is C 1-2 alkyl, which is optionally substituted by D, until fully deuterated;
  • R Z1a is It is optionally substituted by D up to full deuteration
  • R* is selected from H, D or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
  • R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
  • R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  • the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CF 3 or CHF 2 ;
  • R 2 is selected from F or CH 3 ;
  • R3 is H
  • R 5 is CH 3 ;
  • R 6 is selected from CH 3 or CD 3 ;
  • R Z1a is selected from
  • R Z3b is selected from H, Cl,
  • the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compound, it has the structure of formula (X), (X-1) or (X-2):
  • R 1 is C 1-4 haloalkyl
  • R 2 is selected from H, D, halogen or C 1-4 alkyl
  • R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is NR Z3a ;
  • R Z1b is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
  • R Z2a and R Z3a are independently chemical bonds, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z2c is a chemical bond
  • R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond
  • each group in R 1 , R 2 , R Z2a , R Z3a , R Z1b and R Z2b can be optionally substituted by D until complete deuteration;
  • the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-2 haloalkyl
  • R 2 is selected from H, D, halogen or C 1-2 alkyl
  • R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is NR Z3a ;
  • R Z1b is optionally substituted by 1, 2 or 3 R * 5-6 membered heterocyclyl
  • R* is selected from H, D, halogen, -OR, -C(O)R, C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and their connected The atoms together form a 5-6 membered heterocyclic group;
  • R Z2a and R Z3a are independently chemical bonds, C 1-6 alkyl or C 1-6 haloalkyl;
  • R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z2c is a chemical bond
  • R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond
  • R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
  • each group in R 1 , R 2 , R Z2a , R Z3a , R Z1b and R Z2b may be optionally substituted by D until complete deuteration.
  • the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is selected from CHF 2 or CF 3 ;
  • R 2 is selected from H, D, F or CH 3 ;
  • R 3 is selected from H, D or NH 2 ;
  • R 2 and R 3 are not H or D at the same time;
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is NR Z3a ;
  • R Z1b selected from
  • R Z2a and R Z3a are independently a chemical bond or CH 3 ;
  • R Z2b is H or D
  • R Z2c is a chemical bond
  • R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond
  • the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • R 1 is C 1-4 haloalkyl
  • R 2 is selected from halogen or C 1-4 alkyl
  • R 1 and R 2 and the atoms to which they are attached together form a C 4-7 cycloalkyl group, which is optionally substituted by 1, 2 or 3 R#;
  • R# is halogen
  • R is selected from H or D
  • Z 2 is NR Z2a or CR Z2b R Z2c ;
  • Z 3 is NR Z3a ;
  • R Z1b is a 5-6 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
  • R* is selected from H, D, halogen, C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group ;
  • R Z2a and R Z3a are independently chemical bonds
  • R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • R Z2c is a chemical bond
  • R Z2a and R Z3a , R Z2c and R Z3a combine to form double bonds
  • each group in R 1 , R 2 , R Z1b and R Z2b can be optionally substituted by D until complete deuteration.

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Abstract

Disclosed are an SOS1 inhibitor represented by formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. Further disclosed are a preparation method for a compound, a pharmaceutical composition comprising a compound, and a use of a compound in prevention and treatment of related cancers, such as lung cancer, colon cancer, and pancreatic cancer.

Description

SOS1抑制剂SOS1 inhibitor 技术领域technical field
本发明涉及SOS1抑制剂，具体为式(A)所示的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。本发明还涉及所述化合物的制备方法、包含所述化合物的药物组合物，以及所述化合物在预防和治疗相关癌症，例如肺癌、结肠癌和胰腺癌等中的作用。The present invention relates to SOS1 inhibitors, specifically compounds represented by formula (A), or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers, prodrugs, polymorphic forms, hydrated substances or solvates. The present invention also relates to the preparation method of the compound, the pharmaceutical composition containing the compound, and the effect of the compound in the prevention and treatment of related cancers, such as lung cancer, colon cancer and pancreatic cancer.
背景技术Background technique
KRAS蛋白(V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog)是一种具有GTP水解酶活性的小G蛋白，其结合GTP之后会激活下游MAPK以及PI3K-AKT等信号通路，从而调节细胞的增殖、分化、生长与凋亡等；然而其突变会导致下游信号通路的异常激活，这与癌症的发生与发展密切相关。SOS1(Son of Sevenless 1)是调节KRAS的关键GEF(Guanine Nucleotide Exchange factor)，SOS1能够促进KRAS释放GDP，结合GTP，进而激活KRAS。GTP结合的KRAS参与别构调节SOS1，提高SOS1的催化活性。KRAS下游的信号通路通过负反馈机制调节SOS1功能。开发SOS1的抑制剂来阻碍SOS1与KRAS之间的蛋白-蛋白相互作用可使得结合GTP状态的KRAS蛋白大大减少，进而有效抑制下游信号通路的异常激活，阻止肿瘤的发生与发展。KRAS protein (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a small G protein with GTP hydrolase activity. After binding to GTP, it will activate downstream MAPK and PI3K-AKT signaling pathways, thereby regulating cell proliferation, Differentiation, growth and apoptosis, etc.; however, its mutation will lead to abnormal activation of downstream signaling pathways, which is closely related to the occurrence and development of cancer. SOS1 (Son of Sevenless 1) is the key GEF (Guanine Nucleotide Exchange factor) that regulates KRAS. SOS1 can promote KRAS to release GDP, combine with GTP, and then activate KRAS. GTP-bound KRAS participates in the allosteric regulation of SOS1 and enhances the catalytic activity of SOS1. The signaling pathway downstream of KRAS regulates SOS1 function through a negative feedback mechanism. The development of SOS1 inhibitors to block the protein-protein interaction between SOS1 and KRAS can greatly reduce the KRAS protein bound to the GTP state, thereby effectively inhibiting the abnormal activation of downstream signaling pathways and preventing the occurrence and development of tumors.
本领域对SOS1抑制剂存在普遍需求，尤其是除了抑制作用和效力之外，还显示出良好的溶解性、代谢稳定性、安全性、DMPK特性和对人激酶组的激酶具有良好选择性的那些SOS1抑制剂。本发明提供的新化合物解决了上述问题。There is a general need in the art for SOS1 inhibitors, especially those that, in addition to inhibition and potency, exhibit good solubility, metabolic stability, safety, DMPK profile and good selectivity for kinases of the human kinome SOS1 inhibitor. The novel compounds provided by the present invention solve the above problems.
发明内容Contents of the invention
本发明以SOS1作为靶点，研发了一类新的化合物小分子抑制剂，用于治疗肺癌、结肠癌等癌症。The present invention uses SOS1 as the target, and develops a new class of compound small molecule inhibitors for the treatment of lung cancer, colon cancer and other cancers.
在一个方面，本发明提供了式(X)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In one aspect, the present invention provides a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof thing:
Figure PCTCN2022141536-appb-000001
Figure PCTCN2022141536-appb-000001
其中：in:
环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
环B选自
Figure PCTCN2022141536-appb-000002
Ring B selected from
Figure PCTCN2022141536-appb-000002
R 1、R 2、R 3和R 4独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 0-2R、-S(O)(NR)R’、-P(O)RR’或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O) R, -C(O)OR, -C(O)NRR', -S(O) 0-2 R, -S(O)(NR)R', -P(O)RR', or -N=S (O)RR';
或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R# 选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
R 5选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其可任选地被OH、-NH 2或-CN取代； R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
Z 1为N、NR Z1a、CR Z1b或CR Z1bR Z1c； Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为N、NR Z3a、CR Z3b或CR Z3bR Z3c； Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
R Z1a、R Z2a和R Z3a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、5-6元杂芳基或C 6-10芳基；或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 5-6环烷基或5-6元杂环基，其任选地被1、2或3个Rx取代；或者两个R*连接形成C 1-4亚烷基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 Heteroaryl or C 6-10 aryl; or two R* on the same or different carbon atoms and the atoms they connect together form C=O, C=S, C 5-6 cycloalkyl or 5-6 A membered heterocyclic group, which is optionally substituted by 1, 2 or 3 Rx; or two R* are connected to form C 1-4 alkylene;
Rx选自C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR、-C 0-6亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 3-6环烷基或4-6元杂环基； Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
R Z3b选自H、D、卤素、-NR aR b、-OR a、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代； R Z3b is selected from H, D, halogen, -NR a R b , -OR a , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , -LC 3-6 cycloalkyl, -L-4-6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, optionally replaced by 1, 2 or 3 R s replaces;
L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
R s选自CN、OR、C 1-6烷基、C 1-6卤代烷基、S(O)R或S(O) 2R，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R s is selected from CN, OR, C 1-6 alkyl, C 1-6 haloalkyl, S(O)R or S(O) 2 R, or two adjacent R s on the same carbon atom together form C =O or C=S, optionally substituted by D, up to complete deuteration;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
R Z3c选自H或化学键； R Z3c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z1a和R Z2a、R Z2a和R Z1c、R Z1c和R Z2c、R Z2a和R Z3a、R Z2a和R Z3c、R Z2c和R Z3a、R Z2c和R Z3c可以结合形成双键； Or R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
在另一个方面，本发明提供了式(X)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In another aspect, the present invention provides a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound:
Figure PCTCN2022141536-appb-000003
Figure PCTCN2022141536-appb-000003
其中：in:
环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
环B选自
Figure PCTCN2022141536-appb-000004
Ring B selected from
Figure PCTCN2022141536-appb-000004
R 1、R 2、R 3和R 4独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、-P(O)RR’、-S(O) 0-2R或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O) R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) ) 0-2 R or -N=S(O)RR';
或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R#选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring groups formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
R 5选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其可任选地被OH、-NH 2或-CN取代； R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
Z 1为N、NR Z1a、CR Z1b或CR Z1bR Z1c； Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为N、NR Z3a、CR Z3b或CR Z3bR Z3c； Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
R Z1a、R Z2a和R Z3a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 1-4亚烷基、C 5-6环烷基或5-6元杂环基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C( O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkyl, 5-6 membered heteroaryl or C 6-10 aryl, or the same Or two R* on different carbon atoms and the atoms they connect together form C=O, C=S, C 1-4 alkylene, C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
R Z3b选自H、D、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
R Z3c选自H或化学键； R Z3c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z1a和R Z2a、R Z2a和R Z1c、R Z1c和R Z2c、R Z2a和R Z3a、R Z2a和R Z3c、R Z2c和R Z3a、R Z2c和R Z3c可以结合形成双键； Or R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
在另一个方面，本发明提供了式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In another aspect, the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound:
Figure PCTCN2022141536-appb-000005
Figure PCTCN2022141536-appb-000005
其中：in:
环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
R 1、R 2、R 3和R 4独立地选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、-P(O)RR’、-S(O) 0-2R或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) 0 -2 R or -N=S(O)RR';
或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R#选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring groups formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
R 5选自H、C 1-6烷基或C 1-6卤代烷基，其可任选地被OH、-NH 2或-CN取代； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2. -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkane base;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2- 6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can be optionally replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH , -C(O)OC 1-6 alkyl substitution;
R Z3b选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基； R Z3b is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基。 R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, or R, R' and their connected nitrogen atom form a 4-8 membered heterocyclic group.
本发明的通式化合物不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。The general formula compound of the present invention does not include specific compounds in WO2022251497, such as any one or more of compounds 1-182.
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂，例如载体、佐剂或媒介物。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.
在另一个方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which also comprises other therapeutic agents.
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防SOS1介导的疾病的药物中的用途。In another aspect, the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment and/or prevention of SOS1-mediated diseases.
在另一个方面，本发明提供了在受试者中治疗和/或预防SOS1介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明药物组合物。In another aspect, the present invention provides a method of treating and/or preventing a SOS1-mediated disease in a subject, comprising administering to said subject a compound of the present invention or a pharmaceutical composition of the present invention.
在另一个方面，本发明提供了本发明化合物或本发明药物组合物，其用于治疗和/或预防SOS1介导的疾病。In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition of the present invention for use in the treatment and/or prevention of SOS1 mediated diseases.
在具体实施方案中，本发明用于治疗和/或预防癌症。在另一具体实施方案中，本发明用于治疗和/或预防胰腺癌、肺癌、结直肠癌、胆管癌、多发性骨髓瘤、黑素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、胶质母细胞瘤、肾癌或肉瘤。在另一具体实施方案中，本发明用于治疗和/或预防RAS病，优选地，所述RAS病选自1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病。In a specific embodiment, the invention is used to treat and/or prevent cancer. In another specific embodiment, the present invention is used for the treatment and/or prevention of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer , prostate cancer, glioblastoma, kidney cancer, or sarcoma. In another specific embodiment, the present invention is used for the treatment and/or prevention of RAS disease, preferably, the RAS disease is selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), multiple Macular Noonan Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Heart-Face-Skin Syndrome (CFC), Legers Syndrome and hereditary gingival fibromatosis.
定义definition
化学定义chemical definition
下面更详细地描述具体官能团和化学术语的定义。Definitions of specific functional groups and chemical terms are described in more detail below.
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C 1-6烷基”包括C 1、C 2、C 3、C 4、C 5、C 6、C 1-6、C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-5、C 2-4、C 2-3、C 3-6、C 3-5、C 3-4、C 4-6、C 4-5和C 5-6烷基。 When a numerical range is listed, each value and subranges within that range are intended to be included. For example, "C 1-6 alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5, C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
“C 1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，C 1-4烷基和C 1-2烷基是优选的。C 1-6烷基的例子包括：甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、异丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、叔戊基(C 5)和正己基(C 6)。术语“C 1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括：Me(-CH 3)、Et(-CH 2CH 3)、iPr(-CH(CH 3) 2)、nPr(-CH 2CH 2CH 3)、n-Bu(-CH 2CH 2CH 2CH 3)或i-Bu(-CH 2CH(CH 3) 2)。 "C 1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl and C 1-2 alkyl are preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), t-butyl Base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ). The term "C 1-6 alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. An alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu (—CH 2 CH(CH 3 ) 2 ).
“C 2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C 2-4烯基是优选的。C 2-6烯基的例子包括：乙烯基(C 2)、1-丙烯基(C 3)、2-丙烯基(C 3)、1-丁烯基(C 4)、2-丁烯基(C 4)、丁二烯基(C 4)、戊烯基(C 5)、戊二烯基(C 5)、己烯基(C 6)，等等。术语“C 2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "C 2-6 alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl include: ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentenyl (C 5 ), hexenyl (C 6 ), and the like. The term "C alkenyl " also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C 2-4炔基是优选的。C 2-6炔基的例子包括但不限于：乙炔基(C 2)、1-丙炔基(C 3)、2-丙炔基(C 3)、1-丁炔基(C 4)、2-丁炔基(C 4)，戊炔基(C 5)、己炔基(C 6)，等等。术语“C 2- 6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "C 2-6 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl include, but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and the like. The term " C2-6alkynyl " also includes heteroalkynyl groups in which one or more (e.g., 1 , 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 1-6亚烷基”是指除去C 1-6烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 1-4亚烷基、C 2-4亚烷基和C 1-3亚烷基是优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-)、亚丁基(-CH 2CH 2CH 2CH 2-)、亚戊基(-CH 2CH 2CH 2CH 2CH 2-)、亚己基(-CH 2CH 2CH 2CH 2CH 2CH 2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH 3)-、-C(CH 3) 2-)、取代的亚乙基(-CH(CH 3)CH 2-、-CH 2CH(CH 3)-、-C(CH 3) 2CH 2-、-CH 2C(CH 3) 2-)、取代的亚丙基(-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH 2CH 2CH(CH 3)-、-C(CH 3) 2CH 2CH 2-、-CH 2C(CH 3) 2CH 2-、-CH 2CH 2C(CH 3) 2-)，等等。 "C 1-6 alkylene" refers to a divalent group formed by removing another hydrogen of C 1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred. The unsubstituted alkylene group includes but not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene group (-CH 2 CH 2 CH 2 CH 2 -), pentylene group (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene group (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - ) ,etc. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include but are not limited to: substituted methylene groups (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), and the like.
“C 0-6亚烷基”是指化学键以及上述“C 1-6亚烷基”，“C 0-4亚烷基”是指化学键以及上述“C 1-4亚烷基”。 "C 0-6 alkylene" refers to a chemical bond and the above-mentioned "C 1-6 alkylene", and "C 0-4 alkylene" refers to a chemical bond and the above-mentioned "C 1-4 alkylene".
“C 2-6亚烯基”是指除去C 2-6烯基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 2-4亚烯基是特别优选的。示例性的未取代的所述亚烯基包括但不限于：亚乙烯基(-CH＝CH-)和亚丙烯基(例如，-CH＝CHCH 2-、-CH 2-CH＝CH-)。示例性的取代的所述亚烯基，例如，被一个或多个烷基(甲基)取代的亚烯基，包括但不限于：取代的亚乙基(-C(CH 3)＝CH-、-CH＝C(CH 3)-)、取代的亚丙烯基(-C(CH 3)＝CHCH 2-、-CH＝C(CH 3)CH 2-、-CH＝CHCH(CH 3)-、-CH＝CHC(CH 3) 2-、-CH(CH 3)-CH＝CH-、-C(CH 3) 2-CH＝CH-、-CH 2-C(CH 3)＝CH-、-CH 2-CH＝C(CH 3)-)，等等。 "C 2-6 alkenylene" refers to a divalent group formed by removing another hydrogen of C 2-6 alkenyl, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkenylene is particularly preferred. Exemplary unsubstituted such alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (eg, -CH= CHCH2- , -CH2 -CH=CH-). Exemplary substituted alkenylene groups, eg, alkenylene groups substituted with one or more alkyl (methyl) groups, include but are not limited to: substituted ethylene groups (-C(CH 3 )=CH- , -CH=C(CH 3 )-), substituted propenylene (-C(CH 3 )=CHCH 2 -, -CH=C(CH 3 )CH 2 -, -CH=CHCH(CH 3 )- , -CH=CHC(CH 3 ) 2 -, -CH(CH 3 )-CH=CH-, -C(CH 3 ) 2 -CH=CH-, -CH 2 -C(CH 3 )=CH-, -CH2 -CH=C( CH3 )-), and so on.
“C 2-6亚炔基”是指除去C 2-6炔基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 2-4亚炔基是特别优选的。示例性的所述亚炔基包括但不限于：亚乙炔基(-C≡C-)、取代或未取代的亚丙炔基(-C≡CCH 2-)，等等。 "C 2-6 alkynylene" refers to a divalent group formed by removing another hydrogen of a C 2-6 alkynyl, and may be substituted or unsubstituted. In some embodiments, C2-4 alkynylene is particularly preferred. Exemplary such alkynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH 2 -), and the like.
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
因此，“C 1-6卤代烷基”是指上述“C 1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C 1-4卤代烷基是特别优选的，更优选C 1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF 3、-CH 2F、-CHF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 Accordingly, "C 1-6 haloalkyl" refers to the above-mentioned "C 1-6 alkyl", which is substituted with one or more halogen groups. In some embodiments, C 1-4 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl. Exemplary haloalkyl groups include, but are not limited to: -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. A haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 3-10环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C 3-8环烷基、C 3-7环烷基和C 3-6环烷基是特别优选的，更优选C 5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环已二烯基(C 6)、环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "C 3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-8 cycloalkyl, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, more preferably C 5-6 cycloalkyl. Cycloalkyl also includes ring systems wherein the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene Cycloheptadienyl (C 7 ), Cycloheptadienyl (C 7 ), Cycloheptatrienyl (C 7 ), and the like. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“3-12元杂环基”是指具有环碳原子和1至5个环杂原子的3至12元非芳香环系的饱和或不饱和基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选4-12元杂环基，其为具有环碳原子和1至5个环杂原子的4至12元非芳香环系；在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至5个环杂原子的3至10元非芳香环系；在一些实施方案中，优选3-8元杂环基，其为具有环碳原子和1至4个环杂原子的3至8元非芳香环系；优选3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选4-8元杂环基，其为具有环碳原子和1至3个环杂原子的4至8元非芳香环系；优选4-7元杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系；更优选5-6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C 6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C 6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。杂环基还包括上述杂环基与一个环烷基、杂环基、芳基或杂芳基共享一个或两个原子，形成桥环或螺环，只要化合价允许，共享的 原子可为碳或氮原子。杂环基还包括上述杂环基与杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "3-12 membered heterocyclyl" means a saturated or unsaturated group of a 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from Nitrogen, Oxygen, Sulfur, Boron, Phosphorus and Silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 4-12 membered heterocyclyl, which is a 4 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, is preferred; in some embodiments, 3-10 membered Heterocyclyl, which is a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-8 membered heterocyclyl group having ring carbon atoms and 3 to 8 membered non-aromatic ring systems with 1 to 4 ring heteroatoms; preferably 3-6 membered heterocyclyl, which is a 3 to 6 membered nonaromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; Preferred are 4-8 membered heterocyclic groups, which are 4 to 8 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; preferred 4-7 membered heterocyclic groups, which are ring carbon atoms and 1 A 4 to 7 membered non-aromatic ring system with up to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclyl, which is a 5 to 6 membered nonaromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl ring is fused to one or more aryl or Heteroaryl-fused ring systems wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxasulfuranyl Oxazolidin-2-ones. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyls (also referred to herein as 5,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to: indolinyl, isoindolinyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyls (also referred to herein as 6,6 -bicyclic heterocyclyls) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group also includes the above-mentioned heterocyclic group sharing one or two atoms with a cycloalkyl group, heterocyclic group, aryl group or heteroaryl group to form a bridged ring or a spiro ring. As long as the valence allows, the shared atom can be carbon or Nitrogen atom. Heterocyclyl also includes the aforementioned heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C 6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C 10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "C 6-10 aryl" means a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having shared 6 or 10 π electrons) groups. In some embodiments, an aryl group has six ring carbon atoms ("C aryl"; eg, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 aryl"; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl). Aryl also includes ring systems wherein the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. An aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“5-14元杂芳基”是指具有环碳原子和1-4个环杂原子的5-14元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中，5-10元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在另一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基(例如，1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"5-14 membered heteroaryl" means a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6, 10 or 14 π electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems wherein the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said heteroaryl ring, in which case the carbon atoms Numbers continue to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms . Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl , Benzisofuryl, Benzimidazolyl, Benzoxazolyl, Benzisoxazolyl, Benzoxadiazolyl, Benzthiazolyl, Benzisothiazolyl, Benzthiadiazolyl, Indenazinyl and Purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cincinyl, quinoxalinyl, phthalazinyl, and quinazolinyl . A heteroaryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
上文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等基团除去另一个氢而形成的二价基团统称为“亚基”。环烷基、杂环基、芳基和杂芳基等成环的基团统称为“环基”。Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined above, divalent groups formed by removing another hydrogen are collectively referred to as "subunits". Ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl are collectively referred to as "cyclyl".
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, etc. are defined herein as optionally substituted groups.
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR aa、-ON(R bb) 2、-N(R bb) 2、-N(R bb) 3 +X -、-N(OR cc)R bb、-SH、-SR aa、-SSR cc、-C(＝O)R aa、-CO 2H、-CHO、-C(OR cc) 2、-CO 2R aa、-OC(＝O)R aa、-OCO 2R aa、-C(＝O)N(R bb) 2、-OC(＝O)N(R bb) 2、-NR bbC(＝O)R aa、-NR bbCO 2R aa、-NR bbC(＝O)N(R bb) 2、-C(＝NR bb)R aa、-C(＝NR bb)OR aa、-OC(＝NR bb)R aa、-OC(＝NR bb)OR aa、-C(＝NR bb)N(R bb) 2、-OC(＝NR bb)N(R bb) 2、-NR bbC(＝NR bb)N(R bb) 2、-C(＝O)NR bbSO 2R aa、-NR bbSO 2R aa、-SO 2N(R bb) 2、-SO 2R aa、-SO 2OR aa、-OSO 2R aa、-S(＝O)R aa、-OS(＝O)R aa、-Si(R aa) 3、-OSi(R aa) 3、-C(＝S)N(R bb) 2、-C(＝O)SR aa、-C(＝S)SR aa、-SC(＝S)SR aa、-SC(＝O)SR aa、-OC(＝O)SR aa、-SC(＝O)OR aa、-SC(＝O)R aa、-P(＝O) 2R aa、-OP(＝O) 2R aa、-P(＝O)(R aa) 2、-OP(＝O)(R aa) 2、-OP(＝O)(OR cc) 2、-P(＝O) 2N(R bb) 2、-OP(＝O) 2N(R bb) 2、- P(＝O)(NR bb) 2、-OP(＝O)(NR bb) 2、-NR bbP(＝O)(OR cc) 2、-NR bbP(＝O)(NR bb) 2、-P(R cc) 2、-P(R cc) 3、-OP(R cc) 2、-OP(R cc) 3、-B(R aa) 2、-B(OR cc) 2、-BR aa(OR cc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -C (=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2. -OC(=NR bb )N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb SO 2 R aa , -NR bb SO 2 R aa , -SO 2 N(R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R aa , -S(=O)R aa , -OS(=O)R aa , - Si(R aa ) 3 , -OSi(R aa ) 3 , -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S)SR aa , -SC(= S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O) 2 R aa , -OP(=O) 2 R aa , -P(=O)(R aa ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)(OR cc ) 2 , -P( =O) 2 N(R bb ) 2 , -OP(=O) 2 N(R bb ) 2 , -P(=O)(NR bb ) 2 , -OP(=O)(NR bb ) 2 , - NR bb P(=O)(OR cc ) 2 , -NR bb P(=O)(NR bb ) 2 , -P(R cc ) 2 , -P(R cc ) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups are substituted;
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(R bb) 2、＝NNR bbC(＝O)R aa、＝NNR bbC(＝O)OR aa、＝NNR bbS(＝O) 2R aa、＝NR bb或＝NOR cc取代； Or two geminal hydrogens on a carbon atom are replaced by groups =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , = Substituted by NNR bb S(=O) 2 R aa , =NR bb or =NOR cc ;
R aa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R aa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R groups group replacement;
R bb的每个独立地选自：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R bb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Each of R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2. -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O ) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkene group, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb groups combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R groups;
R cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R cc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle radical or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;
R dd的每个独立地选自：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR ee、-ON(R ff) 2、-N(R ff) 2,、-N(R ff) 3 +X -、-N(OR ee)R ff、-SH、-SR ee、-SSR ee、-C(＝O)R ee、-CO 2H、-CO 2R ee、-OC(＝O)R ee、-OCO 2R ee、-C(＝O)N(R ff) 2、-OC(＝O)N(R ff) 2、-NR ffC(＝O)R ee、-NR ffCO 2R ee、-NR ffC(＝O)N(R ff) 2、-C(＝NR ff)OR ee、-OC(＝NR ff)R ee、-OC(＝NR ff)OR ee、-C(＝NR ff)N(R ff) 2、-OC(＝NR ff)N(R ff) 2、-NR ffC(＝NR ff)N(R ff) 2、-NR ffSO 2R ee、-SO 2N(R ff) 2、-SO 2R ee、-SO 2OR ee、-OSO 2R ee、-S(＝O)R ee、-Si(R ee) 3、-OSi(R ee) 3、-C(＝S)N(R ff) 2、-C(＝O)SR ee、-C(＝S)SR ee、-SC(＝S)SR ee、-P(＝O) 2R ee、-P(＝O)(R ee) 2、-OP(＝O)(R ee) 2、-OP(＝O)(OR ee) 2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代，或者两个偕R dd取代基可结合以形成＝O或＝S； Each of R dd is independently selected from: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N (R ff ) 2 ,, -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , - NR ff C(=O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff ) R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff ) N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , - SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may combine to form =O or =S;
R ee的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代； Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R groups;
R ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R ff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代； Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R gg group substitution;
R gg的每个独立地是：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OC 1-6烷基、-ON(C 1-6烷基) 2、-N(C 1-6烷基) 2、-N(C 1-6烷基) 3 +X -、-NH(C 1-6烷基) 2 +X -、-NH 2(C 1-6烷基) +X -、-NH 3 +X -、-N(OC 1-6烷基)(C 1-6烷基)、-N(OH)(C 1-6烷基)、-NH(OH)、-SH、-SC 1-6烷基、-SS(C 1-6烷基)、-C(＝O)(C 1-6烷基)、-CO 2H、-CO 2(C 1-6烷基)、-OC(＝O)(C 1-6烷基)、-OCO 2(C 1-6烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-OC(＝O)NH(C 1-6烷基)、-NHC(＝O)(C 1-6烷基)、-N(C 1-6烷基)C(＝O)(C 1-6烷基)、-NHCO 2(C 1-6烷基)、-NHC(＝O)N(C 1-6烷基) 2、-NHC(＝O)NH(C 1-6烷基)、-NHC(＝O)NH 2、-C(＝NH)O(C 1-6烷基)、-OC(＝NH)(C 1- 6烷基)、-OC(＝NH)OC 1-6烷基、-C(＝NH)N(C 1-6烷基) 2、-C(＝NH)NH(C 1-6烷基)、-C(＝NH)NH 2、-OC(＝NH)N(C 1-6烷基) 2、-OC(NH)NH(C 1-6烷基)、-OC(NH)NH 2、-NHC(NH)N(C 1-6烷基) 2、-NHC(＝NH)NH 2、 -NHSO 2(C 1-6烷基)、-SO 2N(C 1-6烷基) 2、-SO 2NH(C 1-6烷基)、-SO 2NH 2、-SO 2C 1-6烷基、-SO 2OC 1-6烷基、-OSO 2C 1-6烷基、-SOC 1-6烷基、-Si(C 1-6烷基) 3、-OSi(C 1-6烷基) 3、-C(＝S)N(C 1-6烷基) 2、C(＝S)NH(C 1-6烷基)、C(＝S)NH 2、-C(＝O)S(C 1-6烷基)、-C(＝S)SC 1-6烷基、-SC(＝S)SC 1-6烷基、-P(＝O) 2(C 1-6烷基)、-P(＝O)(C 1- 6烷基) 2、-OP(＝O)(C 1-6烷基) 2、-OP(＝O)(OC 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7环烷基、C 6-C 10芳基、C 3-C 7杂环基、C 5-C 10杂芳基；或者两个偕R gg取代基可结合形成＝O或＝S；其中，X -为反离子。 Each of R gg is independently: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON(C 1-6 Alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 + X - , -NH(C 1-6 alkyl) 2 + X - , -NH 2 (C 1-6 alkyl) + X - , -NH 3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl ), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C (=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl) C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , - NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl) , -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 , -C(=S)N(C 1-6 alkyl) 2 , C (=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl , -SC(=S)SC 1-6 alkyl, -P(=O ) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(= O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 3 -C 7 heterocyclyl, C 5 -C 10 heteroaryl; or two gem R gg substitutions The groups can combine to form =O or =S; where X- is the counterion.
示例性的氮原子上取代基包括但不局限于：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR bb)R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个R cc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代，且其中R aa、R bb、R cc和R dd如上所述。 Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N (R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2. -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O )(NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups attached to a nitrogen atom combine to form a heterocycle radical or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc and R dd are as described above.
其它定义other definitions
术语“癌症”包括但不限于下列癌症：胰腺癌、肺癌、结直肠癌、胆管癌、多发性骨髓瘤、黑素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、胶质母细胞瘤、肾癌和肉瘤。The term "cancer" includes, but is not limited to, the following cancers: pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer , urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, colloid Blastoma, renal carcinoma, and sarcoma.
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者预防之，或者这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作，后者是如刚才所定义的。The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein refers to the action of the verb treat, which is as just defined.
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention, which are suitable for use in contact with patient tissues within the scope of sound medical judgment without undue toxicity, Irritation, allergic effects, etc., commensurate with a reasonable benefit/risk ratio, are valid for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.
药学上可接受的碱加成盐是与金属或胺生成的，例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因。Pharmaceutically acceptable base addition salts are formed with metals or amines, for example alkali and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
酸性化合物的碱加成盐可以这样制备，按照常规方式使游离酸形式与足量所需的碱接触，生成盐。按照常规方式使盐形式与酸接触，再分离游离酸，可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式，例如在极性溶剂中的溶解度，但是出于本发明的目的，盐还是等价于它们各自的游离酸。Base addition salts of acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt, in conventional manner. The free acid may be regenerated by contacting the salt form with the acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the salts are nevertheless equivalent to their respective free acids for the purposes of the present invention.
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物，酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括：氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和羟乙磺酸盐等。盐也可以是从有机酸制备的，例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盆、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、 苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金属的阳离子，例如钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐，例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等(例如参见Berge S.M.et al.，"Pharmaceutical Salts,”J.Pharm.Sci.，1977；66:1-19，引入此作为参考)。Salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphoric acids prepared from inorganic acids Salts, chlorides, bromides, iodides, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauryl salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate and isethionate, etc. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate, Tolate, Mandelate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Naphthoate, Benzenesulfonate, Toluenesulfonate, Phenylethyl salt, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids are also contemplated, such as arginine salts, gluconate salts, galacturonate salts, etc. (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J.Pharm.Sci., 1977; 66:1- 19, which is incorporated by reference).
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。"Subjects" for administration include, but are not limited to: human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adult, middle-aged adult or older adult)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
“疾病”、“障碍”和“病症”在本文中可互换地使用。"Disease", "disorder" and "condition" are used interchangeably herein.
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。As used herein, unless otherwise specified, the term "treating" includes an effect on a subject suffering from a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a disease, disorder or condition ("therapeutic treatment") and also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition ("prophylactic treatment").
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, an effective amount of a compound of the invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age Health conditions and symptoms. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。化合物的治疗有效量是指单独使用或与其它疗法联用时，治疗剂的量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to induce one or more symptoms associated with the disease, disorder or condition. Amount to delay or minimize. A therapeutically effective amount of a compound refers to that amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的量，或足以预防与疾病、障碍或病症有关的一或多种症状的量，或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时，治疗剂的量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量，或增强其它预防药剂的预防效果的量。As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of the disorder or condition. A prophylactically effective amount of a compound refers to that amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" may include amounts that improve overall prophylaxis, or that enhance the prophylactic effect of other prophylactic agents.
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。"Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered with the other therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together with the other therapeutic agent in a single unit dosage form.
具体实施方案specific implementation plan
本文中，“本发明化合物”指的是以下的式(X)、式(A)等化合物(包括子通式，例如式(I)至式(VII)等)、其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。Herein, "the compound of the present invention" refers to the following compounds of formula (X), formula (A) (including sub-general formulas, such as formula (I) to formula (VII) etc.), and their pharmaceutically acceptable salts , isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates.
本文中，化合物使用标准的命名法命名。具有非对称中心的化合物，应该明白(除非另有说明)所有的光学异构体及其混合物均包含在内。此外，除非另有规定，本发明所包括的所有异构体化合物与碳碳双键可能以Z和E的形式出现。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。Herein, compounds are named using standard nomenclature. For compounds having asymmetric centers, it is to be understood that (unless otherwise stated) all optical isomers and mixtures thereof are included. In addition, all isomeric compounds with carbon-carbon double bonds may occur in the Z and E forms unless otherwise specified. For compounds that exist in different tautomeric forms, a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.
在一个实施方案中，本发明涉及式(X)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In one embodiment, the present invention relates to a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound:
Figure PCTCN2022141536-appb-000006
Figure PCTCN2022141536-appb-000006
其中：in:
环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
环B选自
Figure PCTCN2022141536-appb-000007
Ring B selected from
Figure PCTCN2022141536-appb-000007
R 1、R 2、R 3和R 4独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 0-2R、-S(O)(NR)R’、-P(O)RR’或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O) R, -C(O)OR, -C(O)NRR', -S(O) 0-2 R, -S(O)(NR)R', -P(O)RR', or -N=S (O)RR';
或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R#选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring groups formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
R 5选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其可任选地被OH、-NH 2或-CN取代； R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
Z 1为N、NR Z1a、CR Z1b或CR Z1bR Z1c； Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为N、NR Z3a、CR Z3b或CR Z3bR Z3c； Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
R Z1a、R Z2a和R Z3a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、5-6元杂芳基或C 6-10芳基；或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 5-6环烷基或5-6元杂环基，其任选地被1、2或3个Rx取代；或者两个R*连接形成C 1-4亚烷基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 Heteroaryl or C 6-10 aryl; or two R* on the same or different carbon atoms and the atoms they connect together form C=O, C=S, C 5-6 cycloalkyl or 5-6 A membered heterocyclic group, which is optionally substituted by 1, 2 or 3 Rx; or two R* are connected to form C 1-4 alkylene;
Rx选自C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR、-C 0-6亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 3-6环烷基或4-6元杂环基； Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
R Z3b选自H、D、卤素、-NR aR b、-OR a、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代； R Z3b is selected from H, D, halogen, -NR a R b , -OR a , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , -LC 3-6 cycloalkyl, -L-4-6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, optionally replaced by 1, 2 or 3 R s replaces;
L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group, -C 1-6 alkylene -OC 1-6 haloalkyl, -C 1-6 alkylene - NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
R s选自CN、OR、C 1-6烷基、C 1-6卤代烷基、S(O)R或S(O) 2R，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R s is selected from CN, OR, C 1-6 alkyl, C 1-6 haloalkyl, S(O)R or S(O) 2 R, or two adjacent R s on the same carbon atom together form C =O or C=S, optionally substituted by D, up to complete deuteration;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
R Z3c选自H或化学键； R Z3c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z1a和R Z2a、R Z2a和R Z1c、R Z1c和R Z2c、R Z2a和R Z3a、R Z2a和R Z3c、R Z2c和R Z3a、R Z2c和R Z3c可以结合形成双键； Or R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代； Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在另一个实施方案中，本发明涉及式(X)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In another embodiment, the present invention relates to a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvate:
Figure PCTCN2022141536-appb-000008
Figure PCTCN2022141536-appb-000008
其中：in:
环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
环B选自
Figure PCTCN2022141536-appb-000009
Ring B selected from
Figure PCTCN2022141536-appb-000009
R 1、R 2、R 3和R 4独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、-P(O)RR’、-S(O) 0-2R或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O) R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) ) 0-2 R or -N=S(O)RR';
或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R#选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring groups formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
R 5选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其可任选地被OH、-NH 2或-CN 取代； R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
Z 1为N、NR Z1a、CR Z1b或CR Z1bR Z1c； Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为N、NR Z3a、CR Z3b或CR Z3bR Z3c； Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
R Z1a、R Z2a和R Z3a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 1-4亚烷基、C 5-6环烷基或5-6元杂环基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C( O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkyl, 5-6 membered heteroaryl or C 6-10 aryl, or the same Or two R* on different carbon atoms and the atoms they connect together form C=O, C=S, C 1-4 alkylene, C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
R Z3b选自H、D、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
R Z3c选自H或化学键； R Z3c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z1a和R Z2a、R Z2a和R Z1c、R Z1c和R Z2c、R Z2a和R Z3a、R Z2a和R Z3c、R Z2c和R Z3a、R Z2c和R Z3c可以结合形成双键； Or R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代； Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在另一个实施方案中，本发明涉及式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In another embodiment, the present invention relates to a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvate:
Figure PCTCN2022141536-appb-000010
Figure PCTCN2022141536-appb-000010
其中：in:
环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
R 1、R 2、R 3和R 4独立地选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、-P(O)RR’、-S(O) 0-2R或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) 0 -2 R or -N=S(O)RR';
或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R#选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring groups formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
R 5选自H、C 1-6烷基或C 1-6卤代烷基，其可任选地被OH、-NH 2或-CN取代； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2. -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkane base;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2- 6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can be optionally replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH , -C(O)OC 1-6 alkyl substitution;
R Z3b选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基； R Z3b is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
环ARing A
在一个具体实施方式中，环A表示苯基或5-6元杂芳基；在另一个具体实施方式中，环A表示苯基；在另一个具体实施方式中，环A表示5-6元杂芳基；在另一个具体实施方式中，环A表示5元杂芳基；在另一个具体实施方式中，环A表示6元杂芳基。In one specific embodiment, Ring A represents phenyl or 5-6 membered heteroaryl; In another specific embodiment, Ring A represents phenyl; In another specific embodiment, Ring A represents 5-6 membered Heteroaryl; In another specific embodiment, Ring A represents a 5-membered heteroaryl; In another specific embodiment, Ring A represents a 6-membered heteroaryl.
环BRing B
在一个具体实施方式中，环B为
Figure PCTCN2022141536-appb-000011
在另一个具体实施方式中，环B为
Figure PCTCN2022141536-appb-000012
In a specific embodiment, Ring B is
Figure PCTCN2022141536-appb-000011
In another specific embodiment, Ring B is
Figure PCTCN2022141536-appb-000012
R 1、R 2、R 3和R 4 R 1 , R 2 , R 3 and R 4
在一个具体实施方式中，R 1为H；在另一个具体实施方式中，R 1为D；在另一个具体实施方式中，R 1为卤素；在另一个具体实施方式中，R 1为-CN；在另一个具体实施方式中，R 1为C 1-6烷基；在另一个具体实施方式中，R 1为C 1-6卤代烷基；在另一个具体实施方式中，R 1为C 1-4卤代烷基；在另一个具体实施方式中，R 1为C 1-2卤代烷基；在另一个具体实施方式中，R 1为C 1卤代烷基；在另一个具体实施方式中，R 1为C 2-6烯基；在另一个具体实施方式中，R 1为C 2-6炔基；在另一个具体实施方式中，R 1为-OR；在另一个具体实施方式中，R 1为-NRR’；在另一个具体实施方式中，R 1为-C(O)R；在另一个具体实施方式中，R 1为-C(O)OR；在另一个具体实施方式中，R 1为-C(O)NRR’；在另一个具体实施方式中，R 1为-S(O) 1-2R；在另一个具体实施方式中，R 1为-S(O)(NR)R’；在另一个具体实施方式中，R 1为-P(O)RR’；在另一个具体实施方式中，R 1为-S(O) 0-2R；在另一个具体实施方式中，R 1为-N＝S(O)RR’。 In one specific embodiment, R 1 is H; In another specific embodiment, R 1 is D; In another specific embodiment, R 1 is halogen; In another specific embodiment, R 1 is - CN; In another specific embodiment, R 1 is C 1-6 alkyl; In another specific embodiment, R 1 is C 1-6 haloalkyl; In another specific embodiment, R 1 is C 1-4 haloalkyl; In another specific embodiment, R 1 is C 1-2 haloalkyl; In another specific embodiment, R 1 is C 1 haloalkyl; In another specific embodiment, R 1 is C 2-6 alkenyl; in another specific embodiment, R 1 is C 2-6 alkynyl; in another specific embodiment, R 1 is -OR; in another specific embodiment, R 1 is -NRR'; in another specific embodiment, R is -C(O)R; in another specific embodiment, R is -C(O)OR; in another specific embodiment, R 1 is -C(O)NRR'; in another specific embodiment, R 1 is -S(O) 1-2 R; in another specific embodiment, R 1 is -S(O)(NR) R'; In another specific embodiment, R 1 is -P(O)RR'; In another specific embodiment, R 1 is -S(O) 0-2 R; In another specific embodiment, R 1 is -S(O) 0-2 R; In another specific embodiment , R 1 is -N=S(O)RR'.
在一个具体实施方式中，R 1为CF 3；在另一个具体实施方式中，R 1为CHF 2；在另一个具体实施方式中，R 1为CF 2CH 2OH；在另一个具体实施方式中，R 1为CF 2CH 3；在另一个具体实施方式中，R 1为CF 2C(OH)(CH 3) 2；在另一个具体实施方式中，R 1为CN；在另一个具体实施方式中，R 1为OCHF 2；在另一个具体实施方式中，R 1为C(O)NHCH 3；在另一个具体实施方式中，R 1为C(O)N(CH 3) 2；在另一个具体实施方式中，R 1为OCF 3；在另一个具体实施方式中，R 1为OMe。 In one embodiment, R 1 is CF 3 ; in another embodiment, R 1 is CHF 2 ; in another embodiment, R 1 is CF 2 CH 2 OH; in another embodiment In another specific embodiment, R 1 is CF 2 CH 3 ; in another specific embodiment, R 1 is CF 2 C(OH)(CH 3 ) 2 ; in another specific embodiment, R 1 is CN; in another specific embodiment In one embodiment, R 1 is OCHF 2 ; in another specific embodiment, R 1 is C(O)NHCH 3 ; in another specific embodiment, R 1 is C(O)N(CH 3 ) 2 ; In another specific embodiment, R 1 is OCF 3 ; in another specific embodiment, R 1 is OMe.
在一个具体实施方式中，R 2为H；在另一个具体实施方式中，R 2为卤素；在另一个具体实施方式中，R 2为-CN；在另一个具体实施方式中，R 2为C 1-6烷基；在另一个具体实施方式中，R 2为C 1-6卤代烷基；在另一个具体实施方式中，R 2为C 1-4卤代烷基；在另一个具体实施方式中，R 2为C 1-2卤代烷基；在另一个具体实施方式中，R 2为C 1卤代烷基；在另一个具体实施方式中，R 2为C 2-6烯基；在另一个具体实施方式中，R 2为C 2-6炔基；在另一个具体实施方式中，R 2为-OR；在另一个具体实施方式中，R 2为-NRR’；在另一个具体实施方式中，R 2为-C(O)R；在另一个具体实施方式中，R 2为-C(O)OR；在另一个具体实施方式中，R 2为-C(O)NRR’；在另一个具体实施方式中，R 2为-S(O) 1-2R；在另一个具体实施方式中，R 2为-S(O)(NR)R’；在另一个具体实施方式中，R 2为-P(O)RR’；在另一个具体实施方式中，R 2为-S(O) 0-2R；在另一个具体实施方式中，R 2为-N＝S(O)RR’。 In one specific embodiment, R 2 is H; in another specific embodiment, R 2 is halogen; in another specific embodiment, R 2 is -CN; in another specific embodiment, R 2 is C 1-6 alkyl; In another specific embodiment, R 2 is C 1-6 haloalkyl; In another specific embodiment, R 2 is C 1-4 haloalkyl; In another specific embodiment , R 2 is C 1-2 haloalkyl; in another specific embodiment, R 2 is C 1 haloalkyl; in another specific embodiment, R 2 is C 2-6 alkenyl; in another specific embodiment In one embodiment, R 2 is C 2-6 alkynyl; in another specific embodiment, R 2 is -OR; in another specific embodiment, R 2 is -NRR'; in another specific embodiment, R 2 is -C(O)R; in another specific embodiment, R 2 is -C(O)OR; in another specific embodiment, R 2 is -C(O)NRR'; in another specific embodiment, R 2 is -C(O)NRR'; In a specific embodiment, R 2 is -S(O) 1-2 R; in another specific embodiment, R 2 is -S(O)(NR)R'; in another specific embodiment, R 2 is -P(O)RR'; in another specific embodiment, R 2 is -S(O) 0-2 R; in another specific embodiment, R 2 is -N=S(O)RR' .
在一个具体实施方式中，R 2为H；在另一个具体实施方式中，R 2为F；在另一个具体实施方式中，R 2为CH 3。 In one embodiment, R2 is H; in another embodiment, R2 is F; in another embodiment, R2 is CH3 .
在一个具体实施方式中，R 3为H；在另一个具体实施方式中，R 3为卤素；在另一个具体实施方式中，R 3为-CN；在另一个具体实施方式中，R 3为C 1-6烷基；在另一个具体实施方式中，R 3为C 1-6卤代烷基；在另一个具体实施方式中，R 3为-OR；在另一个具体实施方式中，R 3为-NRR’；在另一个具体实施方式中，R 3为-C(O)R；在另一个具体实施方式中，R 3为-C(O)OR；在另一个具体实施方式中，R 3为-C(O)NRR’；在另一个具体实施方式中，R 3为-S(O) 1-2R；在另一个具体实施方式中，R 3为-S(O)(NR)R’；在另一个具体实施方式中，R 3为-P(O)RR’；在另一个具体实施方式中，R 3为-S(O) 0-2R；在另一个具体实施方式中，R 3为-N＝S(O)RR’。 In one specific embodiment, R 3 is H; In another specific embodiment, R 3 is halogen; In another specific embodiment, R 3 is -CN; In another specific embodiment, R 3 is C 1-6 alkyl; In another specific embodiment, R 3 is C 1-6 haloalkyl; In another specific embodiment, R 3 is -OR; In another specific embodiment, R 3 is -NRR'; In another specific embodiment, R 3 is -C(O)R; In another specific embodiment, R 3 is -C(O)OR; In another specific embodiment, R 3 is -C(O)OR; In another specific embodiment, R 3 is -C(O)NRR'; in another specific embodiment, R 3 is -S(O) 1-2 R; in another specific embodiment, R 3 is -S(O)(NR)R '; In another specific embodiment, R 3 is -P(O)RR'; In another specific embodiment, R 3 is -S(O) 0-2 R; In another specific embodiment, R 3 is -N=S(O)RR'.
在一个具体实施方式中，R 3为H；在另一个具体实施方式中，R 3为NH 2。 In one embodiment, R3 is H; in another embodiment, R3 is NH2 .
在一个具体实施方式中，R 4为H；在另一个具体实施方式中，R 4为卤素；在另一个具体实施方式 中，R 4为-CN；在另一个具体实施方式中，R 4为C 1-6烷基；在另一个具体实施方式中，R 4为C 1-6卤代烷基；在另一个具体实施方式中，R 4为-OR；在另一个具体实施方式中，R 4为-NRR’；在另一个具体实施方式中，R 4为-C(O)R；在另一个具体实施方式中，R 4为-C(O)OR；在另一个具体实施方式中，R 4为-C(O)NRR’；在另一个具体实施方式中，R 4为-S(O) 1-2R；在另一个具体实施方式中，R 4为-S(O)(NR)R’；在另一个具体实施方式中，R 2为-P(O)RR’；在另一个具体实施方式中，R 4为-S(O) 0-2R；在另一个具体实施方式中，R 4为-N＝S(O)RR’。 In one specific embodiment, R 4 is H; In another specific embodiment, R 4 is halogen; In another specific embodiment, R 4 is -CN; In another specific embodiment, R 4 is C 1-6 alkyl; In another specific embodiment, R 4 is C 1-6 haloalkyl; In another specific embodiment, R 4 is -OR; In another specific embodiment, R 4 is -NRR'; in another specific embodiment, R 4 is -C(O)R; in another specific embodiment, R 4 is -C(O)OR; in another specific embodiment, R 4 is is -C(O)NRR'; in another specific embodiment, R 4 is -S(O) 1-2 R; in another specific embodiment, R 4 is -S(O)(NR)R '; in another specific embodiment, R 2 is -P(O)RR'; in another specific embodiment, R 4 is -S(O) 0-2 R; in another specific embodiment, R 4 is -N=S(O)RR'.
在一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基；在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成4-8元杂环基；在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成4-7元杂环基；在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成5-6元杂环基；在另一个具体实施方式中，R 1和R 2一起形成含硫原子的5-6元杂环基；在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成苯基；在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成5-6元杂芳基。 In one specific embodiment, R 1 and R 2 and the atoms they are connected together form a C 3-7 cycloalkyl; in another specific embodiment, R 1 and R 2 and the atoms they are connected together form 4-8 In another specific embodiment, R 1 and R 2 and their connected atoms together form a 4-7 membered heterocyclic group; in another specific embodiment, R 1 and R 2 and their connected atoms Atoms together form a 5-6 membered heterocyclic group; in another specific embodiment, R and R together form a 5-6 membered heterocyclic group containing a sulfur atom; in another specific embodiment, R and R 2 and the atoms to which they are attached together form phenyl; in another specific embodiment, R and R and the atoms to which they are attached together form a 5-6 membered heteroaryl.
在一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成
Figure PCTCN2022141536-appb-000013
在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成
Figure PCTCN2022141536-appb-000014
在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成
Figure PCTCN2022141536-appb-000015
在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成
Figure PCTCN2022141536-appb-000016
在另一个具体实施方式中，R 1和R 2以及它们连接的原子一起形成
Figure PCTCN2022141536-appb-000017
In a specific embodiment, R and R and the atoms to which they are attached together form
Figure PCTCN2022141536-appb-000013
In another specific embodiment, R and R and the atoms to which they are attached are taken together to form
Figure PCTCN2022141536-appb-000014
In another specific embodiment, R and R and the atoms to which they are attached are taken together to form
Figure PCTCN2022141536-appb-000015
In another specific embodiment, R and R and the atoms to which they are attached are taken together to form
Figure PCTCN2022141536-appb-000016
In another specific embodiment, R and R and the atoms to which they are attached are taken together to form
Figure PCTCN2022141536-appb-000017
在一个具体实施方式中，R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1个R#取代；在另一个具体实施方式中，R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被2个R#取代；在另一个具体实施方式中，R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被3个R#取代；在另一个具体实施方式中，R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被4个R#取代；在另一个具体实施方式中，R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被5个R#取代； In one specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by one R#; in another specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 2 R#; in another specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection is optionally substituted by 3 R#; in another specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 4 R#; in another In a specific embodiment, R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 5 R#;
R 5 R 5
在一个具体实施方式中，R 5为H；在另一个具体实施方式中，R 5为D；在另一个具体实施方式中，R 5为C 1-6烷基；在另一个具体实施方式中，R 5为C 1-6卤代烷基；在另一个具体实施方式中，R 5为C 2-6烯基，例如乙烯基；在另一个具体实施方式中，R 5为C 2-6炔基；在另一个具体实施方式中，R 5为-CH 3；在另一个具体实施方式中，R 5为CHF 2；在另一个具体实施方式中，R 5为CF 3；在另一个具体实施方式中，R 5为CH 2F。 In one specific embodiment, R is H; in another specific embodiment, R is D; in another specific embodiment, R is C 1-6 alkyl; in another specific embodiment , R 5 is C 1-6 haloalkyl; in another specific embodiment, R 5 is C 2-6 alkenyl, such as vinyl; in another specific embodiment, R 5 is C 2-6 alkynyl ; In another specific embodiment, R 5 is —CH 3 ; In another specific embodiment, R 5 is CHF 2 ; In another specific embodiment, R 5 is CF 3 ; In another specific embodiment, R 5 is CF 3 ; In another specific embodiment, R 5 is —CH 3 ; In, R 5 is CH 2 F.
在一个具体实施方式中，R 5可任选地被-OH取代；在另一个具体实施方式中，R 5可任选地被-NH 2取代；在另一个具体实施方式中，R 5可任选地被--CN取代。 In one embodiment, R 5 can be optionally substituted by -OH; in another embodiment, R 5 can be optionally substituted by -NH 2 ; in another embodiment, R 5 can be optionally Optionally replaced by --CN.
R 6 R 6
在一个具体实施方式中，R 6为H；在另一个具体实施方式中，R 6为C 1-6烷基；在另一个具体实施方式中，R 6为C 1-4烷基；在另一个具体实施方式中，R 6为C 1-2烷基；在另一个具体实施方式中，R 6为-CH 3；在另一个具体实施方式中，R 6为-CD 3；在另一个具体实施方式中，R 6为C 1-6卤代烷基，例如 CHF 2；在另一个具体实施方式中，R 6为4-7元杂环基；在另一个具体实施方式中，R 6为C 3-10环烷基；在另一个具体实施方式中，R 6为C 3-6环烷基；在另一个具体实施方式中，R 6为C 3-4环烷基，例如环丙基。 In one specific embodiment, R 6 is H; In another specific embodiment, R 6 is C 1-6 alkyl; In another specific embodiment, R 6 is C 1-4 alkyl; In another In one specific embodiment, R 6 is C 1-2 alkyl; in another specific embodiment, R 6 is -CH 3 ; in another specific embodiment, R 6 is -CD 3 ; in another specific embodiment In one embodiment, R 6 is C 1-6 haloalkyl, such as CHF 2 ; in another specific embodiment, R 6 is 4-7 membered heterocyclyl; in another specific embodiment, R 6 is C 3 -10 cycloalkyl; In another specific embodiment, R 6 is C 3-6 cycloalkyl; In another specific embodiment, R 6 is C 3-4 cycloalkyl, such as cyclopropyl.
在一个具体实施方式中，R 6可任选地被D取代；在另一个具体实施方式中，R 6可任选地被-OH取代；在另一个具体实施方式中，R 6可任选地被-NH 2取代；在另一个具体实施方式中，R 6可任选地被-CN取代。 In one embodiment, R can be optionally substituted by D; in another embodiment, R can be optionally substituted by -OH; in another embodiment, R can be optionally is substituted by -NH2 ; in another specific embodiment, R6 can be optionally substituted by -CN.
Z 1、Z 2和Z 3 Z 1 , Z 2 and Z 3
在环B为
Figure PCTCN2022141536-appb-000018
的一个具体实施方式中，Z 1为NR Z1a；在另一个具体实施方式中，Z 1为CR Z1bR Z1c。在环B为
Figure PCTCN2022141536-appb-000019
的一个具体实施方式中，Z 1为N；在另一个具体实施方式中，Z 1为CR Z1b。 in Ring B as
Figure PCTCN2022141536-appb-000018
In one specific embodiment of Z 1 is NR Z1a ; in another specific embodiment, Z 1 is CR Z1b R Z1c . in Ring B as
Figure PCTCN2022141536-appb-000019
In one specific embodiment of Z 1 is N; in another specific embodiment, Z 1 is CR Z1b .
在一个具体实施方式中，Z 2为NR Z2a；在另一个具体实施方式中，Z 2为CR Z2bR Z2c。 In one specific embodiment, Z 2 is NR Z2a ; in another specific embodiment, Z 2 is CR Z2b R Z2c .
在环B为
Figure PCTCN2022141536-appb-000020
的一个具体实施方式中，Z 3为N；在另一个具体实施方式中，Z 3为CR Z3b。在环B为
Figure PCTCN2022141536-appb-000021
的一个具体实施方式中，Z 3为NR Z3a；在另一个具体实施方式中，Z 3为CR Z3bR Z3c。 in Ring B as
Figure PCTCN2022141536-appb-000020
In one specific embodiment of Z 3 is N; in another specific embodiment, Z 3 is CR Z3b . in Ring B as
Figure PCTCN2022141536-appb-000021
In one specific embodiment of Z 3 is NR Z3a ; in another specific embodiment, Z 3 is CR Z3b R Z3c .
在更具体的实施方式中，
Figure PCTCN2022141536-appb-000022
为
Figure PCTCN2022141536-appb-000023
In a more specific embodiment,
Figure PCTCN2022141536-appb-000022
for
Figure PCTCN2022141536-appb-000023
R Z1a、R Z2a和R Z3a R Z1a , R Z2a and R Z3a
在一个具体实施方式中，R Z1a为化学键；在另一个具体实施方式中，R Z1a为C 1-6烷基；在另一个具体实施方式中，R Z1a为C 1-6卤代烷基；在另一个具体实施方式中，R Z1a为C 1-4卤代烷基；在另一个具体实施方式中，R Z1a为C 2-6烯基；在另一个具体实施方式中，R Z1a为C 2-6炔基；在另一个具体实施方式中，R Z1a为4-7元杂环基；在另一个具体实施方式中，R Z1a为5-6元杂环基；在另一个具体实施方式中，R Z1a为C 3-10环烷基；在另一个具体实施方式中，R Z1a为C 3-8环烷基；在另一个具体实施方式中，R Z1a为C 3-7环烷基；在另一个具体实施方式中，R Z1a为5-10元杂芳基；在另一个具体实施方式中，R Z1a为5-6元杂芳基；在另一个具体实施方式中，R Z1a为C 6-10芳基。 In one specific embodiment, R Z1a is a chemical bond; in another specific embodiment, R Z1a is C 1-6 alkyl; in another specific embodiment, R Z1a is C 1-6 haloalkyl; in another In one specific embodiment, R Z1a is C 1-4 haloalkyl; In another specific embodiment, R Z1a is C 2-6 alkenyl; In another specific embodiment, R Z1a is C 2-6 alkyne In another specific embodiment, R Z1a is a 4-7 membered heterocyclyl; In another specific embodiment, R Z1a is a 5-6 membered heterocyclic group; In another specific embodiment, R Z1a is C 3-10 cycloalkyl; in another specific embodiment, R Z1a is C 3-8 cycloalkyl; in another specific embodiment, R Z1a is C 3-7 cycloalkyl; in another In a specific embodiment, R Z1a is a 5-10 membered heteroaryl group; in another specific embodiment, R Z1a is a 5-6 membered heteroaryl group; in another specific embodiment, R Z1a is C 6-10 Aryl.
在一个具体实施方式中，R Z1a为化学键；在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000024
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000025
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000026
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000027
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000028
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000029
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000030
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000031
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000032
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000033
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000034
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000035
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000036
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000037
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000038
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000039
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000040
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000041
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000042
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000043
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000044
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000045
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000046
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000047
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000048
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000049
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000050
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000051
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000052
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000053
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000054
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000055
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000056
在另一个具体实施方 式中，R Z1a为
Figure PCTCN2022141536-appb-000057
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000058
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000059
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000060
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000061
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000062
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000063
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000064
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000065
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000066
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000067
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000068
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000069
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000070
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000071
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000072
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000073
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000074
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000075
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000076
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000077
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000078
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000079
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000080
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000081
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000082
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000083
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000084
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000085
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000086
在另一个具体实施方式中，R Z1a为
Figure PCTCN2022141536-appb-000087
In one specific embodiment, R Z1a is a chemical bond; in another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000024
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000025
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000026
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000027
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000028
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000029
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000030
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000031
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000032
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000033
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000034
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000035
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000036
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000037
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000038
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000039
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000040
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000041
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000042
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000043
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000044
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000045
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000046
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000047
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000048
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000049
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000050
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000051
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000052
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000053
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000054
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000055
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000056
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000057
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000058
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000059
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000060
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000061
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000062
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000063
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000064
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000065
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000066
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000067
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000068
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000069
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000070
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000071
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000072
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000073
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000074
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000075
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000076
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000077
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000078
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000079
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000080
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000081
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000082
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000083
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000084
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000085
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000086
In another specific embodiment, R Z1a is
Figure PCTCN2022141536-appb-000087
在一个具体实施方式中，R Z2a为化学键；在另一个具体实施方式中，R Z2a为C 1-6烷基；在另一个具体实施方式中，R Z2a为C 1-6卤代烷基；在另一个具体实施方式中，R Z2a为C 1-4卤代烷基；在另一个具体实施方式中，R Z2a为C 2-6烯基；在另一个具体实施方式中，R Z2a为C 2-6炔基；在另一个具体实施方式中，R Z2a为4-7元杂环基；在另一个具体实施方式中，R Z2a为5-6元杂环基；在另一个具体实施方式中，R Z2a为C 3-10环烷基；在另一个具体实施方式中，R Z2a为C 3-8环烷基；在另一个具体实施方式中，R Z2a为C 3-7环烷基；在另一个具体实施方式中，R Z2a为5-10元杂芳基；在另一个具体实施方式中，R Z2a为5-6元杂芳基；在另一个具体实施方式中，R Z2a为C 6-10芳基。 In one embodiment, R Z2a is a chemical bond; in another embodiment, R Z2a is C 1-6 alkyl; in another embodiment, R Z2a is C 1-6 haloalkyl; in another embodiment In one specific embodiment, R Z2a is C 1-4 haloalkyl; In another specific embodiment, R Z2a is C 2-6 alkenyl; In another specific embodiment, R Z2a is C 2-6 alkyne In another specific embodiment, R Z2a is a 4-7 membered heterocyclyl; In another specific embodiment, R Z2a is a 5-6 membered heterocyclic group; In another specific embodiment, R Z2a is C 3-10 cycloalkyl; in another specific embodiment, R Z2a is C 3-8 cycloalkyl; in another specific embodiment, R Z2a is C 3-7 cycloalkyl; in another In a specific embodiment, R Z2a is a 5-10 membered heteroaryl group; in another specific embodiment, R Z2a is a 5-6 membered heteroaryl group; in another specific embodiment, R Z2a is C 6-10 Aryl.
在一个具体实施方式中，R Z2a为化学键；在另一个具体实施方式中，R Z2a为
Figure PCTCN2022141536-appb-000088
In one specific embodiment, R Z2a is a chemical bond; In another specific embodiment, R Z2a is
Figure PCTCN2022141536-appb-000088
在一个具体实施方式中，R Z1a任选地被1个R*取代；在另一个具体实施方式中，R Z1a任选地被2个R*取代；在另一个具体实施方式中，R Z1a任选地被3个R*取代；在另一个具体实施方式中，R Z1a任选地被4个R*取代；在另一个具体实施方式中，R Z1a任选地被5个R*取代。 In one embodiment, R Z1a is optionally substituted with 1 R*; in another embodiment, R Z1a is optionally substituted with 2 R*; in another embodiment, R Z1a is optionally is optionally substituted with 3 R*; in another embodiment, R Z1a is optionally substituted with 4 R*; in another embodiment, R Z1a is optionally substituted with 5 R*.
在一个具体实施方式中，R Z2a任选地被1个R*取代；在另一个具体实施方式中，R Z2a任选地被2个R*取代；在另一个具体实施方式中，R Z2a任选地被3个R*取代；在另一个具体实施方式中，R Z2a任选地被4个R*取代；在另一个具体实施方式中，R Z2a任选地被5个R*取代。 In one embodiment, R Z2a is optionally substituted with 1 R*; in another embodiment, R Z2a is optionally substituted with 2 R*; in another embodiment, R Z2a is optionally is optionally substituted with 3 R*; in another embodiment, R Z2a is optionally substituted with 4 R*; in another embodiment, R Z2a is optionally substituted with 5 R*.
在一个具体实施方式中，R Z3a为化学键；在另一个具体实施方式中，R Z3a为C 1-6烷基；在另一个具体实施方式中，R Z3a为C 1-6卤代烷基；在另一个具体实施方式中，R Z3a为C 1-4卤代烷基；在另一个具体实施方式中，R Z3a为C 2-6烯基；在另一个具体实施方式中，R Z3a为C 2-6炔基；在另一个具体实施方式中，R Z3a为4-7元杂环基；在另一个具体实施方式中，R Z3a为5-6元杂环基；在另一个具体实施方式中，R Z3a为C 3-10环烷基；在另一个具体实施方式中，R Z3a为C 3-8环烷基；在另一个具体实施方式中，R Z3a为C 3-7环烷基；在另一个具体实施方式中，R Z3a为5-10元杂芳基；在另一个具体实施方式中，R Z3a为5-6元杂芳基；在另一个具体实施方式中，R Z3a为C 6-10芳基。 In one specific embodiment, R Z3a is a chemical bond; In another specific embodiment, R Z3a is C 1-6 alkyl; In another specific embodiment, R Z3a is C 1-6 haloalkyl; In another specific embodiment, R Z3a is C 1-6 haloalkyl; In one specific embodiment, R Z3a is C 1-4 haloalkyl; In another specific embodiment, R Z3a is C 2-6 alkenyl; In another specific embodiment, R Z3a is C 2-6 alkyne In another specific embodiment, R Z3a is a 4-7 membered heterocyclyl; In another specific embodiment, R Z3a is a 5-6 membered heterocyclic group; In another specific embodiment, R Z3a is C 3-10 cycloalkyl; in another specific embodiment, R Z3a is C 3-8 cycloalkyl; in another specific embodiment, R Z3a is C 3-7 cycloalkyl; in another In a specific embodiment, R Z3a is a 5-10 membered heteroaryl group; in another specific embodiment, R Z3a is a 5-6 membered heteroaryl group; in another specific embodiment, R Z3a is C 6-10 Aryl.
R Z1b和R Z2b R Z1b and R Z2b
在一个具体实施方式中，R Z1b为-L Z1b-R X1b。 In a specific embodiment, R Z1b is -L Z1b -R X1b .
在一个具体实施方式中，R Z2b为-L Z2b-R X2b。 In a specific embodiment, R Z2b is -L Z2b -R X2b .
在一个具体实施方式中，L Z1b为化学键；在另一个具体实施方式中，L Z1b为-S-；在另一个具体实施方式中，L Z1b为-O-；在另一个具体实施方式中，L Z1b为-N-；在另一个具体实施方式中，L Z1b为-C(O)-；在另一个具体实施方式中，L Z1b为-C(O)O-；在另一个具体实施方式中，L Z1b为-OC(O)-；在另一个具体实施方式中，L Z1b为-C(O)NH-；在另一个具体实施方式中，L Z1b为-NHC(O)-；在另一个具体实施方式中，L Z1b为-S(O) 2-；在另一个具体实施方式中，L Z1b为-C 1-6亚烷基-；在另一个具体实施方式中，L Z1b为-C 2-6亚烯基-；在另一个具体实施方式中，L Z1b为-C 2-6亚炔基-。 In one specific embodiment, L Z1b is a chemical bond; In another specific embodiment, L Z1b is -S-; In another specific embodiment, L Z1b is -O-; In another specific embodiment, L Z1b is -N-; in another specific embodiment, L Z1b is -C(O)-; in another specific embodiment, L Z1b is -C(O)O-; in another specific embodiment In, L Z1b is -OC(O)-; In another specific embodiment, L Z1b is -C(O)NH-; In another specific embodiment, L Z1b is -NHC(O)-; In In another specific embodiment, L Z1b is -S(O) 2 -; in another specific embodiment, L Z1b is -C 1-6 alkylene-; in another specific embodiment, L Z1b is -C 2-6 alkenylene-; In another specific embodiment, L Z1b is -C 2-6 alkynylene-.
在一个具体实施方式中，L Z2b为化学键；在另一个具体实施方式中，L Z2b为-S-；在另一个具体实施方式中，L Z2b为-O-；在另一个具体实施方式中，L Z2b为-N-；在另一个具体实施方式中，L Z2b为-C(O)-；在另一个具体实施方式中，L Z2b为-C(O)O-；在另一个具体实施方式中，L Z2b为-OC(O)-；在另一个具体实施方式中，L Z2b为-C(O)NH-；在另一个具体实施方式中，L Z2b为-NHC(O)-；在另一个具体实施方式中，L Z2b为-S(O) 2-；在另一个具体实施方式中，L Z2b为-C 1-6亚烷基-；在另一个具体实施方式中，L Z2b为-C 2-6亚烯基-；在另一个具体实施方式中，L Z2b为-C 2-6亚炔基-。 In one specific embodiment, L Z2b is a chemical bond; In another specific embodiment, L Z2b is -S-; In another specific embodiment, L Z2b is -O-; In another specific embodiment, L Z2b is -N-; In another specific embodiment, L Z2b is -C(O)-; In another specific embodiment, L Z2b is -C(O)O-; In another specific embodiment In, L Z2b is -OC(O)-; In another specific embodiment, L Z2b is -C(O)NH-; In another specific embodiment, L Z2b is -NHC(O)-; In In another specific embodiment, L Z2b is -S(O) 2 -; in another specific embodiment, L Z2b is -C 1-6 alkylene-; in another specific embodiment, L Z2b is -C 2-6 alkenylene-; In another specific embodiment, L Z2b is -C 2-6 alkynylene-.
在一个具体实施方式中，R X1b为H；在另一个具体实施方式中，R X1b为D；在另一个具体实施方式中，R X1b为C 1-6烷基；在另一个具体实施方式中，R X1b为C 1-6卤代烷基；在另一个具体实施方式中，R X1b为4-7元杂环基；在另一个具体实施方式中，R X1b为5-6元杂环基；在另一个具体实施方式中，R X1b为C 3-7环烷基；在另一个具体实施方式中，R X1b为5-10元杂芳基；在另一个具体实施方式中，R X1b为5-6元杂芳基；在另一个具体实施方式中，R X1b为C 6-10芳基。 In one specific embodiment, R X1b is H; In another specific embodiment, R X1b is D; In another specific embodiment, R X1b is C 1-6 alkyl; In another specific embodiment , R X1b is a C 1-6 haloalkyl group; in another specific embodiment, R X1b is a 4-7 membered heterocyclic group; in another specific embodiment, R X1b is a 5-6 membered heterocyclic group; In another specific embodiment, R X1b is C 3-7 cycloalkyl; In another specific embodiment, R X1b is 5-10 yuan heteroaryl; In another specific embodiment, R X1b is 5- 6-membered heteroaryl; In another specific embodiment, R X1b is C 6-10 aryl.
在一个具体实施方式中，R X2b为H；在另一个具体实施方式中，R X2b为D；在另一个具体实施方式中，R X2b为C 1-6烷基；在另一个具体实施方式中，R X2b为C 1-6卤代烷基；在另一个具体实施方式中，R X2b为4-7元杂环基；在另一个具体实施方式中，R X2b为5-6元杂环基；在另一个具体实施方式中，R X2b为C 3-7环烷基；在另一个具体实施方式中，R X2b为5-10元杂芳基；在另一个具体实施方式中，R X2b为5-6元杂芳基；在另一个具体实施方式中，R X2b为C 6-10芳基。 In one specific embodiment, R X2b is H; In another specific embodiment, R X2b is D; In another specific embodiment, R X2b is C 1-6 alkyl; In another specific embodiment , R X2b is a C 1-6 haloalkyl group; in another specific embodiment, R X2b is a 4-7 membered heterocyclic group; in another specific embodiment, R X2b is a 5-6 membered heterocyclic group; In another specific embodiment, R X2b is C 3-7 cycloalkyl; In another specific embodiment, R X2b is 5-10 yuan heteroaryl; In another specific embodiment, R X2b is 5- 6-membered heteroaryl; In another specific embodiment, R X2b is C 6-10 aryl.
在一个具体实施方式中，R X1b可任选地被卤素取代；在另一个具体实施方式中，R X1b可任选地被-OH取代；在另一个具体实施方式中，R X1b可任选地被-NH 2取代；在另一个具体实施方式中，R X1b可任选地被-CN取代；在另一个具体实施方式中，R X1b可任选地被C 1-6烷基取代；在另一个具体实施方式中，R X1b可任选地被C 1-6卤代烷基取代；在另一个具体实施方式中，R X1b可任选地被C 2-6烯基取代；在另一个具体实施方式中，R X1b可任选地被C 2-6炔基取代；在另一个具体实施方式中，R X1b可任选地被-C(O)NH 2取代；在另一个具体实施方式中，R X1b可任选地被-C(O)NH-C 1-6烷基取代；在另一个具体实施方式中，R X1b可任选地被-C(O)N-(C 1-6烷基) 2取代；在另一个具体实施方式中，R X1b可任选地被-C(O)OH取代；在另一个具体实施方式中，R X1b可任选地被-C(O)O-C 1-6烷基取代。 In one embodiment, R X1b is optionally substituted with halogen; in another embodiment, R X1b is optionally substituted with -OH; in another embodiment, R X1b is optionally In another specific embodiment, R X1b can be optionally substituted by -CN; In another specific embodiment, R X1b can be optionally substituted by C 1-6 alkyl; In another specific embodiment, R X1b can be optionally substituted by C 1-6 alkyl; In one specific embodiment, R X1b may be optionally substituted by C 1-6 haloalkyl; in another specific embodiment, R X1b may be optionally substituted by C 2-6 alkenyl; in another specific embodiment In, R X1b can be optionally substituted by C 2-6 alkynyl; in another specific embodiment, R X1b can be optionally substituted by -C(O)NH 2 ; in another specific embodiment, R X1b can be optionally substituted by -C(O)NH-C 1-6 alkyl; in another specific embodiment, R X1b can be optionally substituted by -C(O)N-(C 1-6 alkyl ) 2 substituted; in another specific embodiment, R X1b may be optionally substituted by -C(O)OH; in another specific embodiment, R X1b may be optionally substituted by -C(O)OC 1- 6 alkyl substitutions.
在一个具体实施方式中，R X2b可任选地被卤素取代；在另一个具体实施方式中，R X2b可任选地被-OH取代；在另一个具体实施方式中，R X2b可任选地被-NH 2取代；在另一个具体实施方式中，R X2b可任选地被-CN取代；在另一个具体实施方式中，R X2b可任选地被C 1-6烷基取代；在另一个具体实施方式中，R X2b可任选地被C 1-6卤代烷基取代；在另一个具体实施方式中，R X2b可任选地被C 2-6烯基取代；在另一个具体实施方式中，R X2b可任选地被C 2-6炔基取代；在另一个具体实施方式中，R X2b可任选地被-C(O)NH 2取代；在另一个具体实施方式中，R X2b可任选地被-C(O)NH-C 1-6烷基取代；在另一个具体实施方式中，R X2b可任选地被-C(O)N-(C 1-6烷基) 2取代；在另一个具体实施方式中，R X2b可任选地被-C(O)OH取代；在另一个具体实施方式中，R X2b可任选地被-C(O)O-C 1-6烷基取代。 In one embodiment, R X2b is optionally substituted with halogen; in another embodiment, R X2b is optionally substituted with -OH; in another embodiment, R X2b is optionally Substituted by -NH 2 ; In another specific embodiment, R X2b can be optionally substituted by -CN; In another specific embodiment, R X2b can be optionally substituted by C 1-6 alkyl; In another specific embodiment In one specific embodiment, R X2b may be optionally substituted by C 1-6 haloalkyl; in another specific embodiment, R X2b may be optionally substituted by C 2-6 alkenyl; in another specific embodiment In, R X2b can be optionally substituted by C 2-6 alkynyl; in another specific embodiment, R X2b can be optionally substituted by -C(O)NH 2 ; in another specific embodiment, R X2b can be optionally substituted by -C(O)NH-C 1-6 alkyl; in another specific embodiment, R X2b can be optionally substituted by -C(O)N-(C 1-6 alkyl ) 2 substituted; in another specific embodiment, R X2b can be optionally replaced by -C(O)OH; in another specific embodiment, R X2b can be optionally replaced by -C(O)OC 1- 6 alkyl substitutions.
在一个具体实施方式中，R Z1b为H；在另一个具体实施方式中，R Z1b为OMe；在另一个具体实施方式中，R Z1b为
Figure PCTCN2022141536-appb-000089
在另一个具体实施方式中，R Z1b为
Figure PCTCN2022141536-appb-000090
在另一个具体实施方式中，R Z1b为
Figure PCTCN2022141536-appb-000091
In one specific embodiment, R Z1b is H; In another specific embodiment, R Z1b is OMe; In another specific embodiment, R Z1b is
Figure PCTCN2022141536-appb-000089
In another specific embodiment, R Z1b is
Figure PCTCN2022141536-appb-000090
In another specific embodiment, R Z1b is
Figure PCTCN2022141536-appb-000091
在一个具体实施方式中，R Z2b为H；在另一个具体实施方式中，R Z2b为OMe；在另一个具体实施方式中，R Z2b为
Figure PCTCN2022141536-appb-000092
在另一个具体实施方式中，R Z2b为
Figure PCTCN2022141536-appb-000093
In one specific embodiment, R Z2b is H; In another specific embodiment, R Z2b is OMe; In another specific embodiment, R Z2b is
Figure PCTCN2022141536-appb-000092
In another specific embodiment, R Z2b is
Figure PCTCN2022141536-appb-000093
R Z1c、R Z2c和R Z3c R Z1c , R Z2c and R Z3c
在一个具体实施方式中，R Z1c为H；在另一种具体实施方式中，R Z1c为化学键。 In one embodiment, R Z1c is H; in another embodiment, R Z1c is a chemical bond.
在一个具体实施方式中，R Z2c为H；在另一种具体实施方式中，R Z2c为化学键。 In one embodiment, R Z2c is H; in another embodiment, R Z2c is a chemical bond.
在一个具体实施方式中，R Z3c为H；在另一种具体实施方式中，R Z3c为化学键。 In one embodiment, R Z3c is H; in another embodiment, R Z3c is a chemical bond.
在一个具体实施方式中，R Z1a和R Z2c可以结合形成双键；在另一种具体实施方式中，R Z1a和R Z2a 可以结合形成双键；在另一种具体实施方式中，R Z2a和R Z1c可以结合形成双键；在另一种具体实施方式中，R Z1c和R Z2c可以结合形成双键；在另一种具体实施方式中，R Z2a和R Z3a可以结合形成双键；在另一种具体实施方式中，R Z2a和R Z3c可以结合形成双键；在另一种具体实施方式中，R Z2c和R Z3a可以结合形成双键；在另一种具体实施方式中，R Z2c和R Z3c可以结合形成双键。 In a specific embodiment, R Z1a and R Z2c can be combined to form a double bond; in another specific embodiment, R Z1a and R Z2a can be combined to form a double bond; in another specific embodiment, R Z2a and R Z1c can be combined to form a double bond; in another specific embodiment, R Z1c and R Z2c can be combined to form a double bond; in another specific embodiment, R Z2a and R Z3a can be combined to form a double bond; in another In a specific embodiment, R Z2a and R Z3c can be combined to form a double bond; in another specific embodiment, R Z2c and R Z3a can be combined to form a double bond; in another specific embodiment, R Z2c and R Z3c can combine to form a double bond.
在一个具体实施方式中，R Z1b和R Z1c与它们连接的碳原子形成C＝O；在另一个具体实施方式中，R Z1b和R Z1c与它们连接的碳原子形成C＝S。 In one embodiment, R Z1b and R Z1c form C=O with the carbon atom to which they are attached; in another embodiment, R Z1b and R Z1c form C=S with the carbon atom to which they are attached.
在一个具体实施方式中，R Z2b和R Z2c与它们连接的碳原子形成C＝O；在另一个具体实施方式中，R Z2b和R Z2c与它们连接的碳原子形成C＝S。 In one embodiment, R Z2b and R Z2c form C=O with the carbon atom to which they are attached; in another embodiment, R Z2b and R Z2c form C=S with the carbon atom to which they are attached.
R Z3b Z3b
在一个具体实施方式中，R Z3b为H；在另一个具体实施方式中，R Z3b为D；在另一个具体实施方式中，R Z3b为卤素；在另一个具体实施方式中，R Z3b为-NR aR b；在另一个具体实施方式中，R Z3b为-OR a；在另一个具体实施方式中，R Z3b为-OH；在另一个具体实施方式中，R Z3b为-NH 2；在另一个具体实施方式中，R Z3b为-CN；在另一个具体实施方式中，R Z3b为C 1-6烷基，优选甲基；在另一个具体实施方式中，R Z3b为C 1-6卤代烷基；在另一个具体实施方式中，R Z3b为C 2-6烯基；在另一个具体实施方式中，R Z3b为C 2-6炔基；在另一个具体实施方式中，R Z3b为-L-C 3-6环烷基；在另一个具体实施方式中，R Z3b为-L-4-6元杂环基；在另一个具体实施方式中，R Z3b为-L-苯基；在另一个具体实施方式中，R Z3b为-L-5-9元杂芳基；在另一个具体实施方式中，R Z3b任选地被1、2或3个R s取代。 In one specific embodiment, R Z3b is H; In another specific embodiment, R Z3b is D; In another specific embodiment, R Z3b is halogen; In another specific embodiment, R Z3b is - NR a R b ; in another specific embodiment, R Z3b is -OR a ; in another specific embodiment, R Z3b is -OH; in another specific embodiment, R Z3b is -NH 2 ; In another specific embodiment, R Z3b is -CN; in another specific embodiment, R Z3b is C 1-6 alkyl, preferably methyl; in another specific embodiment, R Z3b is C 1-6 Haloalkyl; In another specific embodiment, R Z3b is C 2-6 alkenyl; In another specific embodiment, R Z3b is C 2-6 alkynyl; In another specific embodiment, R Z3b is -LC 3-6 cycloalkyl; In another specific embodiment, R Z3b is -L-4-6 membered heterocyclyl; In another specific embodiment, R Z3b is -L-phenyl; In another specific embodiment In one specific embodiment, R Z3b is -L-5-9 membered heteroaryl; in another specific embodiment, R Z3b is optionally substituted with 1, 2 or 3 R s .
在另一个具体实施方式中，R Z3b为Cl；在另一个具体实施方式中，R Z3b为F；在另一个具体实施方式中，R Z3b为Me；在另一个具体实施方式中，R Z3b为CHF 2；在另一个具体实施方式中，R Z3b为NH 2；在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000094
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000095
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000096
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000097
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000098
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000099
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000100
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000101
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000102
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000103
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000104
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000105
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000106
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000107
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000108
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000109
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000110
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000111
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000112
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000113
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000114
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000115
在另一个具体实施方式中，R Z3b为
Figure PCTCN2022141536-appb-000116
In another specific embodiment, R Z3b is Cl; In another specific embodiment, R Z3b is F; In another specific embodiment, R Z3b is Me; In another specific embodiment, R Z3b is CHF 2 ; in another specific embodiment, R Z3b is NH 2 ; in another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000094
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000095
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000096
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000097
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000098
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000099
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000100
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000101
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000102
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000103
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000104
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000105
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000106
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000107
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000108
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000109
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000110
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000111
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000112
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000113
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000114
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000115
In another specific embodiment, R Z3b is
Figure PCTCN2022141536-appb-000116
LL
在一个具体实施方式中，L为化学键；在另一个具体实施方式中，L为O；在另一个具体实施方式中，L为S；在另一个具体实施方式中，L为NH。In one specific embodiment, L is a chemical bond; in another specific embodiment, L is O; in another specific embodiment, L is S; in another specific embodiment, L is NH.
R a和R b R a and R b
在一个具体实施方式中，R a和R b为H；在另一个具体实施方式中，R a和R b为C 1-6烷基；在另一个具体实施方式中，R a和R b为C 1-6卤代烷基；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-OH；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-OC 1-6烷基；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-OC 1-6卤代烷基；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-NH 2；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-NHC 1-6烷基；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-N(C 1-6烷基) 2；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-NHC 1-6卤代烷基；在另一个具体实施方式中，R a和R b为-C 1-6亚烷基-N(C 1-6卤代烷基) 2。 In one specific embodiment, Ra and R b are H; In another specific embodiment, Ra and R b are C 1-6 alkyl; In another specific embodiment, Ra and R b are C 1-6 haloalkyl; In another specific embodiment, R a and R b are -C 1-6 alkylene-OH; In another specific embodiment, R a and R b are -C 1- 6 alkylene-OC 1-6 alkyl; In another specific embodiment, R a and R b are -C 1-6 alkylene-OC 1-6 haloalkyl; In another specific embodiment, R a and R b are -C 1-6 alkylene-NH 2 ; in another specific embodiment, R a and R b are -C 1-6 alkylene-NHC 1-6 alkyl; in another In one specific embodiment, R a and R b are -C 1-6 alkylene-N(C 1-6 alkyl) 2 ; in another specific embodiment, R a and R b are -C 1- 6 alkylene-NHC 1-6 haloalkyl; In another specific embodiment, R a and R b are —C 1-6 alkylene-N(C 1-6 haloalkyl) 2 .
R s R s
在一个具体实施方式中，R s为CN；在另一个具体实施方式中，R s为OR；在另一个具体实施方式中，R s为C 1-6烷基；在另一个具体实施方式中，R s为C 1-6卤代烷基；在另一个具体实施方式中，R s为S(O)R；在另一个具体实施方式中，R s为S(O) 2R；在另一个具体实施方式中，同一碳原子上的两个相邻R s一起形成C＝O；在另一个具体实施方式中，同一碳原子上的两个相邻R s一起形成C＝S。 In one specific embodiment, R s is CN; In another specific embodiment, R s is OR; In another specific embodiment, R s is C 1-6 alkyl; In another specific embodiment , R s is C 1-6 haloalkyl; in another specific embodiment, R s is S(O)R; in another specific embodiment, R s is S(O) 2 R; in another specific embodiment In one embodiment, two adjacent R s on the same carbon atom together form C=O; in another specific embodiment, two adjacent R s on the same carbon atom together form C=S.
R#R#
在一个具体实施方式中，R#为卤素；在另一个具体实施方式中，R#为-CN；在另一个具体实施方式中，R#为-NRR’；在另一个具体实施方式中，R#为-OR；在另一个具体实施方式中，R#为-C(O)R；在另一个具体实施方式中，R#为-C(O)OR；在另一个具体实施方式中，R#为-C(O)NRR’；在另一个具体实施方式中，R#为-OC(O)R’；在另一个具体实施方式中，R#为-NRC(O)R’；在另一个具体实施方式中，R#为-OC(O)NRR’；在另一个具体实施方式中，R#为-NRC(O)NRR’；在另一个具体实施方式中，R#为-S(O) 1-2R；在另一个具体实施方式中，R#为-S(O)(NR)R’；在另一个具体实施方式中，R#为C 1-6 烷基；在另一个具体实施方式中，R#为C 1-6卤代烷基；在另一个具体实施方式中，R#为C 2-6烯基；在另一个具体实施方式中，R#为C 2-6炔基；在另一个具体实施方式中，R#为C 3-7环烷基；在另一个具体实施方式中，R#为4-8元杂环基；在另一个具体实施方式中，R#为C 6-10芳基；在另一个具体实施方式中，R#为5-10元杂芳基；在另一个具体实施方式中，同一碳原子上的两个相邻R#一起形成C＝O或C＝S。 In one specific embodiment, R# is halogen; In another specific embodiment, R# is -CN; In another specific embodiment, R# is -NRR'; In another specific embodiment, R # is -OR; in another specific embodiment, R# is -C(O)R; in another specific embodiment, R# is -C(O)OR; in another specific embodiment, R # is -C(O)NRR'; in another specific embodiment, R# is -OC(O)R'; in another specific embodiment, R# is -NRC(O)R'; in another specific embodiment In one specific embodiment, R# is -OC (O) NRR '; In another specific embodiment, R # is -NRC (O) NRR '; In another specific embodiment, R # is -S ( O) 1-2 R; In another specific embodiment, R# is -S(O)(NR)R'; In another specific embodiment, R# is C 1-6 alkyl; In another specific embodiment In a specific embodiment, R# is C 1-6 haloalkyl; in another specific embodiment, R# is C 2-6 alkenyl; in another specific embodiment, R# is C 2-6 alkynyl ; In another specific embodiment, R# is C 3-7 cycloalkyl; In another specific embodiment, R# is 4-8 membered heterocyclyl; In another specific embodiment, R# is C 6-10 aryl; In another specific embodiment, R# is 5-10 membered heteroaryl; In another specific embodiment, two adjacent R# on the same carbon atom form C=O together or C=S.
R和R’R and R'
在一个具体实施方式中，R为H；在另一个具体实施方式中，R为C 1-6烷基；在另一个具体实施方式中，R为C 1-6卤代烷基；在另一个具体实施方式中，R为C 2-6烯基；在另一个具体实施方式中，R为C 2-6炔基；在另一个具体实施方式中，R为C 3-7环烷基；在另一个具体实施方式中，R为3-8元杂环基；在另一个具体实施方式中，R为C 6-10芳基；在另一个具体实施方式中，R为5-10元杂芳基。 In one specific embodiment, R is H; In another specific embodiment, R is C 1-6 alkyl; In another specific embodiment, R is C 1-6 haloalkyl; In another specific embodiment In another embodiment, R is C 2-6 alkenyl; in another embodiment, R is C 2-6 alkynyl; in another embodiment, R is C 3-7 cycloalkyl; in another embodiment In a specific embodiment, R is a 3-8 membered heterocyclic group; in another specific embodiment, R is a C 6-10 aryl group; in another specific embodiment, R is a 5-10 membered heteroaryl group.
在一个具体实施方式中，R’为H；在另一个具体实施方式中，R’为C 1-6烷基；在另一个具体实施方式中，R’为C 1-6卤代烷基；在另一个具体实施方式中，R’为C 2-6烯基；在另一个具体实施方式中，R’为C 2-6炔基；在另一个具体实施方式中，R’为C 3-7环烷基；在另一个具体实施方式中，R’为3-8元杂环基；在另一个具体实施方式中，R’为C 6-10芳基；在另一个具体实施方式中，R’为5-10元杂芳基。 In one specific embodiment, R' is H; In another specific embodiment, R' is C 1-6 alkyl; In another specific embodiment, R' is C 1-6 haloalkyl; In another In one specific embodiment, R' is C 2-6 alkenyl; in another specific embodiment, R' is C 2-6 alkynyl; in another specific embodiment, R' is C 3-7 ring Alkyl; In another specific embodiment, R' is a 3-8 membered heterocyclic group; In another specific embodiment, R' is C 6-10 aryl; In another specific embodiment, R' It is a 5-10 membered heteroaryl group.
在另一个具体实施方式中，R、R’与它们连接的氮原子形成4-8元杂环基。In another specific embodiment, R, R' and the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group.
R*R*
在一个具体实施方式中，R*为卤素；在另一个具体实施方式中，R*为-C 0-4亚烷基-OR；在另一个具体实施方式中，R*为-C 0-4亚烷基-NRR’；在另一个具体实施方式中，R*为-C 0-4亚烷基-CN；在另一个具体实施方式中，R*为-C(O)R；在另一个具体实施方式中，R*为-C(NH)OR；在另一个具体实施方式中，R*为-C(O)OR；在另一个具体实施方式中，R*为-C(O)NRR’；在另一个具体实施方式中，R*为-NH 2；在另一个具体实施方式中，R*为-CN；在另一个具体实施方式中，R*为C 1-6烷基；在另一个具体实施方式中，R*为C 1-6卤代烷基；在另一个具体实施方式中，R*为C 1-4卤代烷基；在另一个具体实施方式中，R*为C 2-6烯基；在另一个具体实施方式中，R*为C 2-6炔基；在另一个具体实施方式中，R*为-C(O)NH 2；在另一个具体实施方式中，R*为-C(O)NH-C 1-6烷基；在另一个具体实施方式中，R*为-C(O)N-(C 1-6烷基) 2；在另一个具体实施方式中，R*为-C(O)OH；在另一个具体实施方式中，R*为-C(O)O-C 1-6烷基；在另一个具体实施方式中，R*为5-6元杂芳基；在另一个具体实施方式中，R*为C 6-10芳基；在另一个具体实施方式中，相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O；在另一个具体实施方式中，相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝S；在另一个具体实施方式中，相同或不同碳原子上的两个R*以及它们连接的原子一起形成C 1-4亚烷基；在另一个具体实施方式中，相同或不同碳原子上的两个R*以及它们连接的原子一起形成C 5-6环烷基；在另一个具体实施方式中，相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基。 In one specific embodiment, R* is halogen; In another specific embodiment, R* is -C 0-4 alkylene-OR; In another specific embodiment, R* is -C 0-4 Alkylene-NRR'; In another specific embodiment, R* is -C 0-4 alkylene-CN; In another specific embodiment, R* is -C(O)R; In another specific embodiment, R* is -C(O)R; In a specific embodiment, R* is -C(NH)OR; in another specific embodiment, R* is -C(O)OR; in another specific embodiment, R* is -C(O)NRR '; in another specific embodiment, R* is -NH 2 ; in another specific embodiment, R* is -CN; in another specific embodiment, R* is C 1-6 alkyl; in In another specific embodiment, R* is C 1-6 haloalkyl; in another specific embodiment, R* is C 1-4 haloalkyl; in another specific embodiment, R* is C 2-6 Alkenyl; In another specific embodiment, R* is C 2-6 alkynyl; In another specific embodiment, R* is -C(O)NH 2 ; In another specific embodiment, R* is -C(O)NH-C 1-6 alkyl; in another specific embodiment, R* is -C(O)N-(C 1-6 alkyl) 2 ; in another specific embodiment , R* is -C(O)OH; in another specific embodiment, R* is -C(O)OC 1-6 alkyl; in another specific embodiment, R* is 5-6 membered hetero Aryl; In another specific embodiment, R* is C 6-10 aryl; In another specific embodiment, two R* on the same or different carbon atoms and the atoms they are connected together form C=O ; in another specific embodiment, two R* on the same or different carbon atoms and the atoms to which they are attached together form C=S; in another specific embodiment, two R* on the same or different carbon atoms and the atoms they are connected to form a C 1-4 alkylene group; in another specific embodiment, two R* on the same or different carbon atoms and the atoms they are connected to form a C 5-6 cycloalkyl group together; in In another specific embodiment, two R* on the same or different carbon atoms and the atoms connected to them together form a 5-6 membered heterocyclic group.
在另一个具体实施方式中，相同或不同碳原子上的两个R*以及它们连接的原子一起形成C 5-6环烷基，其任选地被1、2或3个Rx取代；在另一个具体实施方式中，相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基，其任选地被1、2或3个Rx取代；在另一个具体实施方式中，两个R*连接形成C 1-4亚烷基。 In another specific embodiment, two R* on the same or different carbon atoms and the atoms to which they are attached together form a C5-6 cycloalkyl, which is optionally substituted by 1, 2 or 3 Rx; in another In one specific embodiment, two R* on the same or different carbon atoms and the atoms they connect together form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 Rx; in another specific In an embodiment, two R* are linked to form a C 1-4 alkylene.
RxRx
在一个具体实施方式中，Rx为C 1-6烷基；在另一个具体实施方式中，Rx为C 1-6卤代烷基；在另 一个具体实施方式中，Rx为-C 0-6亚烷基-OR；在另一个具体实施方式中，Rx为-C 0-6亚烷基-NRR’；在另一个具体实施方式中，Rx为-C(O)R；在另一个具体实施方式中，Rx为-C(NH)OR；在另一个具体实施方式中，Rx为-C(O)OR；在另一个具体实施方式中，Rx为-C(O)NRR’；在另一个具体实施方式中，Rx为C 3-6环烷基；在另一个具体实施方式中，Rx为4-6元杂环基。 In one specific embodiment, Rx is C 1-6 alkyl; In another specific embodiment, Rx is C 1-6 haloalkyl; In another specific embodiment, Rx is -C 0-6 alkylene -OR; In another specific embodiment, Rx is -C 0-6 alkylene-NRR'; In another specific embodiment, Rx is -C(O)R; In another specific embodiment, Rx is -C(O)R; , Rx is -C(NH)OR; in another specific embodiment, Rx is -C(O)OR; in another specific embodiment, Rx is -C(O)NRR'; in another specific embodiment In one embodiment, Rx is C 3-6 cycloalkyl; in another specific embodiment, Rx is 4-6 membered heterocyclyl.
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，环A的任一技术方案或其任意组合，可以与R 1、R 2、R 3、R 4、R 5、R 6、Z 1、Z 2和Z 3等的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。 Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical scheme of Ring A or any combination thereof can be combined with any technical scheme of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 , Z 2 and Z 3 etc. Combine in any combination. The present invention intends to include the combination of all these technical solutions, which are not listed one by one due to space limitation.
在更具体的实施方案中，本发明提供了式(I)、(I-1)或(I-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In a more specific embodiment, the present invention provides a compound of formula (I), (I-1) or (I-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
Figure PCTCN2022141536-appb-000117
Figure PCTCN2022141536-appb-000117
其中，in,
R 1选自C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2、-CN、C 1-6烷基、C 2-6烯基或C 2-6炔基取代； R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
R 2选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R#取代； Alternatively, R 1 and R 2 together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2, 3, 4 or 5 R# substitutions;
R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
R 3选自H、NH 2、OH或-CN； R 3 is selected from H, NH 2 , OH or -CN;
R 4选自H、C 1-6烷基或C 1-6卤代烷基，其可任选地被OH、-NH 2或-CN取代； R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
R 5选自H、C 1-6烷基或C 1-6卤代烷基，其可任选地被OH、-NH 2或-CN取代； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基，其可任选地被D、OH、-NH 2或-CN取代； R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2. -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkane base;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基 或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2- 6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can be optionally replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH , -C(O)OC 1-6 alkyl substitution;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述(I)、(I-1)或(I-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned (I), (I-1) or (I-2) compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2、-CN、C 1-6烷基、C 2-6烯基或C 2-6炔基取代； R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
R 2选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R#取代； Alternatively, R 1 and R 2 together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2, 3, 4 or 5 R# substitutions;
R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 4选自H、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 5选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基或C 3-4环烷基，其任选地被D取代； R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-4 cycloalkyl, which is optionally substituted by D;
Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 7环烷基、5-10元杂芳基或C 6-10芳基，可任选地被1、2、3、4或5个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, optionally substituted by 1, 2, 3, 4 or 5 R*;
R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-NHC(O)-、-C(O)NH-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkane Base) 2 , -C(O)OH or -C(O)OC 1-6 alkyl substitution;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
在更具体的实施方案中，本发明提供了式(II)、(II-1)或(II-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In a more specific embodiment, the present invention provides a compound of formula (II), (II-1) or (II-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
Figure PCTCN2022141536-appb-000118
Figure PCTCN2022141536-appb-000118
其中，in,
R 1选自C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2、-CN、C 1-6烷基、C 2-6烯基或C 2-6炔基取代； R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
R 2选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 6选自H、D、C 1-6烷基、C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 7环烷基、5-10元杂芳基或C 6-10芳基，可任选地被1、2或3个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, optionally substituted by 1, 2 or 3 R*;
R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-NHC(O)-、-C(O)NH-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkane Base) 2 , -C(O)OH or -C(O)OC 1-6 alkyl substitution;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述(II)、(II-1)或(II-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned (II), (II-1) or (II-2) compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自任选地被-OH取代的C 1-6烷基或C 1-6卤代烷基； R is selected from C 1-6 alkyl or C 1-6 haloalkyl optionally substituted by -OH;
R 2选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R 2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被 1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
R#选自卤素、＝O或＝S；R# is selected from halogen, =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 6选自C 1-6烷基或C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-8环烷基，所述基团可任选地被1、2或3个R*取代； R Z1a , R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-8 cycloalkyl, the groups can optionally be 1, 2 or 3 R* substitutions;
R*选自卤素、-OH、C 1-6烷基或C 1-6卤代烷基； R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-或-N-； Wherein, L Z1b and L Z2b are independently selected from chemical bonds, -O-, -S- or -N-;
R X1b、R X2b独立地选自H、C 1-6烷基、4-7元杂环基或C 3-7环烷基；所述C 3-7环烷基可任选地被-C(O)OH或-C(O)NH 2取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl; the C 3-7 cycloalkyl can optionally be replaced by -C (O)OH or -C(O)NH 2 substitution;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
在更具体的实施方案中，本发明提供了上述(II)、(II-1)或(II-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned (II), (II-1) or (II-2) compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CF 3、CHF 2、CF 2CH 2OH或CF 2CH 3； R 1 is selected from CF 3 , CHF 2 , CF 2 CH 2 OH or CF 2 CH 3 ;
R 2选自H、F或CH 3； R 2 is selected from H, F or CH 3 ;
或者，R 1和R 2一起形成
Figure PCTCN2022141536-appb-000119
Alternatively, R1 and R2 together form
Figure PCTCN2022141536-appb-000119
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
R Z1a选自化学键、
Figure PCTCN2022141536-appb-000120
R Z1a is selected from chemical bonds,
Figure PCTCN2022141536-appb-000120
R Z2a选自化学键或
Figure PCTCN2022141536-appb-000121
R Z2a is selected from a chemical bond or
Figure PCTCN2022141536-appb-000121
R Z1b选自H、OMe、
Figure PCTCN2022141536-appb-000122
R Z1b is selected from H, OMe,
Figure PCTCN2022141536-appb-000122
R Z2b选自H、OMe、
Figure PCTCN2022141536-appb-000123
R Z2b is selected from H, OMe,
Figure PCTCN2022141536-appb-000123
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
在更具体的实施方案中，本发明提供了式(III)、(III-1)或(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In a more specific embodiment, the present invention provides a compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
Figure PCTCN2022141536-appb-000124
Figure PCTCN2022141536-appb-000124
其中，in,
R 1为C 1-6卤代烷基； R 1 is C 1-6 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-NHC(O)-、-C(O)NH-或-S(O) 2-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH- or -S(O) 2 -;
R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基；所述基团可任选地被-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl; -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O )OC 1-6 alkyl substitution;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述式(III)、(III-1)或(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-或-N-； Wherein, L Z1b and L Z2b are independently selected from chemical bonds, -O-, -S- or -N-;
R X1b、R X2b独立地选自H、C 1-6烷基、4-7元杂环基或C 3-7环烷基；所述C 3-7环烷基可任选地被-C(O)OH或-C(O)NH 2取代。 R X1b and R X2b are independently selected from H, C 1-6 alkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl; the C 3-7 cycloalkyl can optionally be replaced by -C (O)OH or -C(O) NH2 substitution.
在更具体的实施方案中，本发明提供了上述式(III)、(III-1)或(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CF 3或CHF 2； R 1 is selected from CF 3 or CHF 2 ;
R 2选自H或F； R is selected from H or F;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b选自OMe、
Figure PCTCN2022141536-appb-000125
R Z1b is selected from OMe,
Figure PCTCN2022141536-appb-000125
R Z2b选自H、OMe或
Figure PCTCN2022141536-appb-000126
R Z2b is selected from H, OMe or
Figure PCTCN2022141536-appb-000126
在更具体的实施方案中，本发明提供了上述式(III)、(III-1)或(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自-O-、-S-或-N-； Wherein, L Z1b and L Z2b are independently selected from -O-, -S- or -N-;
R X1b、R X2b独立地选自C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-7环烷基。 R X1b and R X2b are independently selected from C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl.
在更具体的实施方案中，本发明提供了上述式(III)、(III-1)或(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1卤代烷基； R 1 is C 1 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
其中，L Z1b、L Z2b独立地选自-O-或-S-； Wherein, L Z1b and L Z2b are independently selected from -O- or -S-;
R X1b、R X2b独立地选自C 1-6烷基或5-6元杂环基。 R X1b and R X2b are independently selected from C 1-6 alkyl or 5-6 membered heterocyclic group.
在更具体的实施方案中，本发明提供了上述式(III)、(III-1)或(III-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CF 3或CHF 2； R 1 is selected from CF 3 or CHF 2 ;
R 2选自H或F； R is selected from H or F;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b选自OMe或
Figure PCTCN2022141536-appb-000127
R Z1b is selected from OMe or
Figure PCTCN2022141536-appb-000127
R Z2b选自OMe或
Figure PCTCN2022141536-appb-000128
R Z2b is selected from OMe or
Figure PCTCN2022141536-appb-000128
在更具体的实施方案中，本发明提供了式(IV)、(IV-1)或(IV-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In a more specific embodiment, the present invention provides a compound of formula (IV), (IV-1) or (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
Figure PCTCN2022141536-appb-000129
Figure PCTCN2022141536-appb-000129
其中，in,
R 1为C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2或-CN取代； R 1 is C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
R 2选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R 2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-6元杂芳基或C 6-10芳基，其可任选地被1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6选自H、D、C 1-6烷基或C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
Z 2为CR Z2bR Z2c； Z 2 is CR Z2b R Z2c ;
R Z1a选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-8环烷基、5-6元杂芳基或C 6-10芳基，其可任选地被1、2或3个R*取代； R Z1a is selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , 4-7 membered heterocyclyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2 or 3 R*;
R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基或C 1-6卤代烷基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2b选自H或4-7元杂环基； R Z2b is selected from H or 4-7 membered heterocyclyl;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c结合形成双键； Or R Z1a and R Z2c combine to form a double bond;
R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述(IV)、(IV-1)或(IV-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned (IV), (IV-1) or (IV-2) compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-6卤代烷基，其可任选地被-OH、-NH 2或-CN取代； R 1 is C 1-6 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
R 2选自H、卤素或C 1-6烷基； R 2 is selected from H, halogen or C 1-6 alkyl;
或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-6元杂芳基或C 6-10芳基，其可任选地被1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
R#选自卤素、＝O或＝S；R# is selected from halogen, =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6选自C 1-6烷基或C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
Z 2为CR Z2bR Z2c； Z 2 is CR Z2b R Z2c ;
R Z1a选自化学键、4-7元杂环基或C 3-8环烷基，其可任选地被1、2或3个R*取代； R Z1a is selected from a chemical bond, 4-7 membered heterocyclyl or C 3-8 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
R*选自卤素、-OH、C 1-6烷基或C 1-6卤代烷基； R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2b选自H或5-6元杂环基，优选H； R Z2b is selected from H or 5-6 membered heterocyclic groups, preferably H;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c结合形成双键； Or R Z1a and R Z2c combine to form a double bond;
R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
在更具体的实施方案中，本发明提供了上述(IV)、(IV-1)或(IV-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned (IV), (IV-1) or (IV-2) compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CHF 2、CF 3、CF 2CH 2OH或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 , CF 2 CH 2 OH or CF 2 CH 3 ;
R 2选自H、F或CH 3； R 2 is selected from H, F or CH 3 ;
或者，R 1和R 2一起形成
Figure PCTCN2022141536-appb-000130
Alternatively, R1 and R2 together form
Figure PCTCN2022141536-appb-000130
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
Z 2为CR Z2bR Z2c； Z 2 is CR Z2b R Z2c ;
R Z1a选自化学键、
Figure PCTCN2022141536-appb-000131
R Z1a is selected from chemical bonds,
Figure PCTCN2022141536-appb-000131
R Z2b选自H或
Figure PCTCN2022141536-appb-000132
优选H； R Z2b is selected from H or
Figure PCTCN2022141536-appb-000132
H is preferred;
R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
或者R Z1a和R Z2c结合形成双键； Or R Z1a and R Z2c combine to form a double bond;
R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
在更具体的实施方案中，本发明提供了式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
Figure PCTCN2022141536-appb-000133
Figure PCTCN2022141536-appb-000133
其中，in,
R 1为C 1-4卤代烷基，其可任选地被-OH、-NH 2或-CN取代； R 1 is C 1-4 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
R 2选自H或卤素； R is selected from H or halogen;
或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-6元杂芳基或C 6-10芳基，其任选地被1或2个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which is optionally replaced by 1 or 2 R #replace;
R#选自卤素、＝O或＝S；R# is selected from halogen, =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6选自C 1-6烷基或C 1-6卤代烷基，其可任选地被D取代； R is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D;
R Z1a选自4-7元杂环基或C 3-8环烷基，其可任选地被1、2或3个R*取代； R Z1a is selected from 4-7 membered heterocyclyl or C 3-8 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
R*选自卤素、-OH、C 1-6烷基或C 1-6卤代烷基； R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CF 3、CHF 2、CF 2CH 2OH或CF 2CH 3； R 1 is selected from CF 3 , CHF 2 , CF 2 CH 2 OH or CF 2 CH 3 ;
R 2选自H或F； R is selected from H or F;
或者，R 1和R 2一起形成
Figure PCTCN2022141536-appb-000134
Alternatively, R1 and R2 together form
Figure PCTCN2022141536-appb-000134
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
R Z1a选自
Figure PCTCN2022141536-appb-000135
R Z1a is selected from
Figure PCTCN2022141536-appb-000135
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
或者R 1和R 2一起形成含硫原子的5-6元杂环基，其任选地被1、2或3个R#取代； Or R 1 and R 2 together form a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1, 2 or 3 R#;
R#选自-OH、-NH 2、-CN、＝O或＝S； R# is selected from -OH, -NH 2 , -CN, =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6为C 1-2烷基，其可任选地被D取代； R 6 is C 1-2 alkyl, which may be optionally substituted by D;
R Z1a为任选地被1、2或3个R*取代的C 3-7环烷基； R Z1a is C 3-7 cycloalkyl optionally substituted by 1, 2 or 3 R*;
R*选自C 1-6烷基或C 1-6卤代烷基。 R* is selected from C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1卤代烷基； R 1 is C 1 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
或者R 1和R 2一起形成含硫原子的5-6元杂环基，其任选地被1或2个R#取代； Or R 1 and R 2 together form a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
R#选自＝O或＝S；R# is selected from =O or =S;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6为甲基，其可任选地被D取代； R 6 is methyl, which may be optionally substituted by D;
R Z1a为任选地被1或2个R*取代的C 3-4环烷基； R Z1a is C 3-4 cycloalkyl optionally substituted by 1 or 2 R*;
R*选自C 1-4烷基或C 1-4卤代烷基。 R* is selected from C 1-4 alkyl or C 1-4 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CHF 2或CF 3； R 1 is selected from CHF 2 or CF 3 ;
R 2选自H或F； R is selected from H or F;
或者R 1和R 2一起形成
Figure PCTCN2022141536-appb-000136
or R1 and R2 together form
Figure PCTCN2022141536-appb-000136
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
R Z1a选自
Figure PCTCN2022141536-appb-000137
R Z1a is selected from
Figure PCTCN2022141536-appb-000137
在更具体的实施方案中，本发明提供了式(VI)、(VI-1)或(VI-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In a more specific embodiment, the present invention provides a compound of formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
Figure PCTCN2022141536-appb-000138
Figure PCTCN2022141536-appb-000138
其中，in,
R 1为C 1-6卤代烷基； R 1 is C 1-6 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
Z 1为CR Z1bR Z1c； Z1 is CR Z1b R Z1c ;
R Z1b选自H、4-7元杂环基或C 3-7环烷基，其可任选地被1、2或3个R*取代； R Z1b is selected from H, 4-7 membered heterocyclyl or C 3-7 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
R Z2a选自化学键、C 3-7环烷基或5-6元杂环基，其可任选地被1、2或3个R*取代； R Z2a is selected from a chemical bond, C 3-7 cycloalkyl or 5-6 membered heterocyclyl, which may be optionally substituted by 1, 2 or 3 R*;
R*选自-OH、-NH 2、-CN、C 1-6烷基或C 1-6卤代烷基； R* is selected from -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
或者R Z2a和R Z1c结合形成双键； Or R Z2a and R Z1c combine to form a double bond;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述式(VI)、(VI-1)或(VI-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-6卤代烷基； R 1 is C 1-6 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
Z 1为CR Z1bR Z1c； Z1 is CR Z1b R Z1c ;
R Z1b选自H或5-6元杂环基，其任选地被1、2或3个R*取代； R Z1b is selected from H or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R*;
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
R Z2a选自化学键、C 3-7环烷基，所述C 3-7环烷基任选地被1、2或3个R*取代； R Z2a is selected from a chemical bond, C 3-7 cycloalkyl optionally substituted by 1, 2 or 3 R*;
R*选自C 1-6烷基或C 1-6卤代烷基； R* is selected from C 1-6 alkyl or C 1-6 haloalkyl;
或者R Z2a和R Z1c结合形成双键。 Or R Z2a and R Z1c combine to form a double bond.
在更具体的实施方案中，本发明提供了上述式(VI)、(VI-1)或(VI-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CHF 2或CF 3； R 1 is selected from CHF 2 or CF 3 ;
R 2选自H或F； R is selected from H or F;
R 3选自H或NH 2 R 3 is selected from H or NH 2
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
Z 1为CR Z1bR Z1c； Z1 is CR Z1b R Z1c ;
R Z1b选自H或
Figure PCTCN2022141536-appb-000139
R Z1b is selected from H or
Figure PCTCN2022141536-appb-000139
R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
R Z2a选自化学键或
Figure PCTCN2022141536-appb-000140
R Z2a is selected from a chemical bond or
Figure PCTCN2022141536-appb-000140
或者R Z2a和R Z1c结合形成双键。 Or R Z2a and R Z1c combine to form a double bond.
在更具体的实施方案中，本发明提供了式(VII)、(VII-1)或(VII-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：In a more specific embodiment, the present invention provides a compound of formula (VII), (VII-1) or (VII-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates:
Figure PCTCN2022141536-appb-000141
Figure PCTCN2022141536-appb-000141
其中，in,
R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
R 2选自H或卤素； R is selected from H or halogen;
R 3选自H或NH 2 R 3 is selected from H or NH 2
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b选自5-6元杂环基、C 3-7环烷基，其可任选地被1、2或3个R*取代； R Z1b is selected from 5-6 membered heterocyclyl, C 3-7 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
R*选自-OH、-NH 2、-CN、C 1-6烷基或C 1-6卤代烷基； R* is selected from -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述式(VII)、(VII-1)或(VII-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VII), (VII-1) or (VII-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自C 1卤代烷基，优选为CF 3或CHF 2 R 1 is selected from C 1 haloalkyl, preferably CF 3 or CHF 2
R 2选自H、卤素，优选为H或F； R is selected from H, halogen, preferably H or F;
R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
R Z1b为5-6元杂环基，其可任选地被1、2或3个R*取代； R Z1b is a 5-6 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
R*选自C 1-6烷基或C 1-6卤代烷基； R* is selected from C 1-6 alkyl or C 1-6 haloalkyl;
R Z1b优选为
Figure PCTCN2022141536-appb-000142
R Z1b is preferably
Figure PCTCN2022141536-appb-000142
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有式(VIII)、(VIII-1)或(VIII-2)的结构：In a more specific embodiment, the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compound, it has the structure of formula (VIII), (VIII-1) or (VIII-2):
Figure PCTCN2022141536-appb-000143
Figure PCTCN2022141536-appb-000143
其中，in,
R 1为C 1-4卤代烷基，其可任选地被OH、-NH 2或-CN取代； R 1 is C 1-4 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-6烯基或C 2-6炔基； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 6选自H、D、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其可任选地被D取代，直至完全氘代； R is selected from H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by D, up to fully deuterium generation;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、C 1-6烷基、C 1-6卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 1-4亚烷基、C 5-6环烷基或5-6元杂环基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, C 1- 6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and the atoms they connect together form C=O, C =S, C 1-4 alkylene, C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
R Z1a优选为以下基团： R Z1a is preferably the following group:
Figure PCTCN2022141536-appb-000144
Figure PCTCN2022141536-appb-000144
Figure PCTCN2022141536-appb-000145
Figure PCTCN2022141536-appb-000145
R Z3b选自H、D、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代； Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基，其可任选地被OH、-NH 2或-CN取代； R 1 is C 1-4 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3或4个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3 or 4 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5选自C 1-4烷基或C 1-4卤代烷基； R is selected from C 1-4 alkyl or C 1-4 haloalkyl;
R 6选自C 1-4烷基或C 1-4卤代烷基； R 6 is selected from C 1-4 alkyl or C 1-4 haloalkyl;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
R*选自卤素、OH、-NH 2、-CN、C 1-4烷基、C 1-4卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基； R* is selected from halogen, OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or the same or different carbon atoms The two R* on and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group;
R Z3b选自H、D或卤素； R Z3b is selected from H, D or halogen;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CHF 2、CF 3、CF 2CH 3或CF 2CH 2OH； R 1 is selected from CHF 2 , CF 3 , CF 2 CH 3 or CF 2 CH 2 OH;
R 2选自H、D、F或CH 3； R 2 is selected from H, D, F or CH 3 ;
或者R 1和R 2一起形成
Figure PCTCN2022141536-appb-000146
or R1 and R2 together form
Figure PCTCN2022141536-appb-000146
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5选自CH 3或CHF 2； R 5 is selected from CH 3 or CHF 2 ;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a选自
Figure PCTCN2022141536-appb-000147
Figure PCTCN2022141536-appb-000148
R Z1a is selected from
Figure PCTCN2022141536-appb-000147
Figure PCTCN2022141536-appb-000148
R Z3b选自H、D或Cl。 R Z3b is selected from H, D or Cl.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或含硫原子的5-6元杂环基，其任选地被1、2或3个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1, 2 or 3 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5选自C 1-4烷基或C 1-4卤代烷基； R is selected from C 1-4 alkyl or C 1-4 haloalkyl;
R 6选自C 1-4烷基或C 1-4卤代烷基； R 6 is selected from C 1-4 alkyl or C 1-4 haloalkyl;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
R*选自C 1-4烷基、C 1-4卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基； R* is selected from C 1-4 alkyl, C 1-4 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and their connected atoms Together form C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
R Z3b选自H、D或卤素； R Z3b is selected from H, D or halogen;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或含硫原子的5-6元杂环基，其任选地被1或2个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5选自C 1-2烷基或C 1-2卤代烷基； R is selected from C 1-2 alkyl or C 1-2 haloalkyl;
R 6为C 1-2烷基； R 6 is C 1-2 alkyl;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a为任选地被1、2或3个R*取代的C 3-6环烷基或4-7元杂环基； R Z1a is C 3-6 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
R*选自C 1-2烷基、C 1-2卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from C 1-2 alkyl, C 1-2 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and their connected atoms Together form a 5-6 membered heterocyclic group;
R Z3b选自H、D或卤素； R Z3b is selected from H, D or halogen;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
R 1选自CHF 2、CF 3或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
R 2选自H、D、F或CH 3； R 2 is selected from H, D, F or CH 3 ;
或者R 1和R 2一起形成
Figure PCTCN2022141536-appb-000149
or R1 and R2 together form
Figure PCTCN2022141536-appb-000149
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5选自CH 3或CHF 2； R 5 is selected from CH 3 or CHF 2 ;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a选自
Figure PCTCN2022141536-appb-000150
R Z1a is selected from
Figure PCTCN2022141536-appb-000150
R Z3b选自H、D或Cl。 R Z3b is selected from H, D or Cl.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
R 2选自卤素或C 1-4烷基，优选为卤素； R 2 is selected from halogen or C 1-4 alkyl, preferably halogen;
或者R 1和R 2以及它们连接的原子一起形成C 4-7环烷基，其任选地被1、2或3个R#取代； or R 1 and R 2 and the atoms to which they are attached together form a C 4-7 cycloalkyl group, which is optionally substituted by 1, 2 or 3 R#;
R#为卤素；R# is halogen;
R 3选自H或D； R is selected from H or D;
R 5为C 1-2烷基； R 5 is C 1-2 alkyl;
R 6为C 1-2烷基； R 6 is C 1-2 alkyl;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a为任选地被1、2或3个R*取代的环丙基； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*;
R*选自C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group;
R Z3b选自H或D； R Z3b is selected from H or D;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物化合物，或其药学 上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
R 2选自卤素或C 1-2烷基，优选为卤素； R 2 is selected from halogen or C 1-2 alkyl, preferably halogen;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基，其任选地被1或2个R#取代； Or R 1 and R 2 and the atoms they are connected together form a C 5-6 cycloalkyl group, which is optionally substituted by 1 or 2 R#;
R#为卤素；R# is halogen;
R 3选自H或D； R is selected from H or D;
R 5为C 1-2烷基； R 5 is C 1-2 alkyl;
R 6为C 1-2烷基； R 6 is C 1-2 alkyl;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a为任选地被1、2或3个R*取代的环丙基； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*;
R*选自C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group;
R Z3b选自H或D； R Z3b is selected from H or D;
其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VIII)、(VIII-1)或(VIII-2)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above compound compound of formula (VIII), (VIII-1) or (VIII-2), or a pharmaceutically acceptable salt, isotopic variant, or tautomer , stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
R 1选自CHF 2、CF 3或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
R 2选自F或CH 3；优选地，当R 1为CF 2CH 3时，R 2不为CH 3； R 2 is selected from F or CH 3 ; preferably, when R 1 is CF 2 CH 3 , R 2 is not CH 3 ;
或者R 1和R 2一起形成
Figure PCTCN2022141536-appb-000151
or R1 and R2 together form
Figure PCTCN2022141536-appb-000151
R 3为H； R3 is H;
R 5为CH 3； R 5 is CH 3 ;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
R Z1a选自
Figure PCTCN2022141536-appb-000152
R Z1a is selected from
Figure PCTCN2022141536-appb-000152
R Z3b为H。 R Z3b is H.
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中所述化合物具有以下通式：In a more specific embodiment, the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compound, wherein the compound has the general formula:
Figure PCTCN2022141536-appb-000153
Figure PCTCN2022141536-appb-000153
其中各基团如上述式(VIII)、(VIII-1)或(VIII-2)化合物中任一项所定义；wherein each group is as defined in any one of the compounds of formula (VIII), (VIII-1) or (VIII-2);
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自-CN、卤素或C 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R is selected from -CN, halogen or C1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH2 or -CN, which is also optionally substituted by D, until fully deuterated ;
R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基，其任选地被D取代，直至完全氘代； R Z1a is C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R*, optionally substituted by D, up to fully deuterated;
R*选自卤素、-C 0-4亚烷基-CN、C 1-6烷基、C 1-6卤代烷基、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、苯基或5-6元杂芳基；或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 5-6环烷基或5-6元杂环基，其任选地被1、2或3个Rx取代；其任选地被D取代，直至完全氘代； R* is selected from halogen, -C 0-4 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-4 alkylene-OR, -C 0-4 alkylene -NRR', -C(O)R, -C(NH)OR, -C(O)OR, -C(O)NRR', phenyl or 5-6 membered heteroaryl; or the same or different carbon atoms The two R* on and the atoms to which they are attached together form C=O, C=S, C5-6cycloalkyl or 5-6 membered heterocyclyl, optionally substituted by 1, 2 or 3 Rx ; it is optionally substituted by D until fully deuterated;
Rx选自C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR、-C 0-6亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
R Z1a优选为以下基团： R Z1a is preferably the following group:
Figure PCTCN2022141536-appb-000154
Figure PCTCN2022141536-appb-000154
R Z3b选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4 -6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, up to complete Deuterium;
L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
R s选自CN、OR、C 1-6烷基、C 1-6卤代烷基、S(O)R或S(O) 2R，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R s is selected from CN, OR, C 1-6 alkyl, C 1-6 haloalkyl, S(O)R or S(O) 2 R, or two adjacent R s on the same carbon atom together form C =O or C=S, optionally substituted by D, up to complete deuteration;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
R Z3b优选为以下基团： R Z3b is preferably the following groups:
H、D、Cl、F、Me、CHF 2、NH 2、
Figure PCTCN2022141536-appb-000155
Figure PCTCN2022141536-appb-000156
H, D, Cl, F, Me, CHF 2 , NH 2 ,
Figure PCTCN2022141536-appb-000155
Figure PCTCN2022141536-appb-000156
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CN、卤素或C 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R is selected from CN, halogen or C1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH2 or -CN, which is also optionally substituted by D, up to complete deuteration;
R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
R Z1a为任选地被1、2或3个R*取代的C 3-6环烷基，其任选地被D取代，直至完全氘代； R Z1a is C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R*, optionally substituted by D, up to fully deuterated;
R*选自卤素、CN、C 1-6烷基、C 1-6卤代烷基、-C 1-4亚烷基-OH、-C 1-4亚烷基-OC 1-6烷基、-C 1-4亚烷基-OC 1-6卤代烷基、-C(NH)O-C 1-6烷基、-C(O)O-C 1-6烷基、-C(O)NH-C 1-6烷基、-C(O)N(C 1-6烷基) 2、-C(NH)O-C 1-6卤代烷基、-C(O)O-C 1-6卤代烷基、-C(O)NH-C 1-6卤代烷基、-C(O)N(C 1-6卤代烷基) 2、苯基或5-6元杂芳基，其任选地被D取代，直至完全氘代； R* is selected from halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-OC 1-6 alkyl, - C 1-4 alkylene-OC 1-6 haloalkyl, -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, -C(O)NH-C 1-6 Alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(NH)OC 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -C(O)NH- C 1-6 haloalkyl, -C(O)N(C 1-6 haloalkyl) 2 , phenyl or 5-6 membered heteroaryl, which is optionally substituted by D, up to complete deuteration;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
R s选自CN、OH、OC 1-6烷基、OC 1-6卤代烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基、S(O) 2C 1- 6烷基、S(O)C 1-6卤代烷基或S(O) 2C 1-6卤代烷基，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代。 R s is selected from CN, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl, S(O ) 2 C 1-6 alkyl, S(O)C 1-6 haloalkyl or S(O) 2 C 1-6 haloalkyl, or two adjacent R s on the same carbon atom together form C=O or C=S, which is optionally substituted by D, up to full deuteration.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、 同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-6卤代烷基，其任选地被1、2或3个OH或NH 2取代，其还任选地被D取代，直至完全氘代； R is C 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH or NH , which is also optionally substituted by D, up to complete deuteration;
R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
R 6选自H、C 1-4烷基或C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl or C 1-4 haloalkyl, which is optionally substituted by D, until fully deuterated;
R Z1a为任选地被1、2或3个R*取代的环丙基，其任选地被D取代，直至完全氘代； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
R*选自卤素、CN、C 1-4烷基、C 1-4卤代烷基、-C(NH)O-C 1-6烷基、-C(O)O-C 1-6烷基、-C(O)NH-C 1- 6烷基、-C(O)N(C 1-6烷基) 2、-C(NH)O-C 1-6卤代烷基、-C(O)O-C 1-6卤代烷基、-C(O)NH-C 1-6卤代烷基、-C(O)N(C 1-6卤代烷基) 2、苯基或5-6元杂芳基，其任选地被D取代，直至完全氘代； R* is selected from halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, -C(O )NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(NH)OC 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -C(O)NH-C 1-6 haloalkyl, -C(O)N(C 1-6 haloalkyl) 2 , phenyl or 5-6 membered heteroaryl optionally substituted by D, up to Fully deuterated;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
R s选自CN、OH、OC 1-6烷基、OC 1-6卤代烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基、S(O) 2C 1- 6烷基、S(O)C 1-6卤代烷基或S(O) 2C 1-6卤代烷基，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代。 R s is selected from CN, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl, S(O ) 2 C 1-6 alkyl, S(O)C 1-6 haloalkyl or S(O) 2 C 1-6 haloalkyl, or two adjacent R s on the same carbon atom together form C=O or C=S, which is optionally substituted by D, up to full deuteration.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基，其任选地被1或2个OH取代，其还任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by 1 or 2 OH, which is also optionally substituted by D, until fully deuterated;
R 2选自H、D、卤素或C 1-2烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5为C 1-2烷基，其任选地被D取代，直至完全氘代； R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
R 6为H或C 1-2烷基，其任选地被D取代，直至完全氘代； R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
R Z1a为任选地被1、2或3个R*取代的环丙基，其任选地被D取代，直至完全氘代； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
R*选自F、CN、CH 3、CH 2CH 3、CH 2F、CHF 2、CHF 3、-C(NH)O-C 1-6烷基、-C(O)O-C 1-6烷基、苯基或5-6元杂芳基，其任选地被D取代，直至完全氘代； R* is selected from F, CN, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CHF 3 , -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, Phenyl or 5-6 membered heteroaryl, which is optionally substituted by D, up to fully deuterated;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
L为化学键、O或NH；L is a chemical bond, O or NH;
R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基或-C 1-6亚烷基-N(C 1-6烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane Group, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene - NHC 1-6 alkyl or -C 1-6 alkylene-N(C 1-6 alkyl) 2 , It is optionally substituted by D up to full deuteration;
R s选自CN、OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，或者同 一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代。 R s is selected from CN, OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkane group, or two adjacent R s on the same carbon atom together form C=O or C=S, which is optionally substituted with D, up to complete deuteration.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CHF 2、CF 3、CF 2CH 3或CF 2C(OH)(CH 3) 2，其任选地被D取代，直至完全氘代； R 1 is selected from CHF 2 , CF 3 , CF 2 CH 3 or CF 2 C(OH)(CH 3 ) 2 , optionally substituted by D, up to full deuteration;
R 2选自H、D、F或CH 3，其任选地被D取代，直至完全氘代； R2 is selected from H, D, F or CH3 , which is optionally substituted by D, up to complete deuteration;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
R 5为CH 3，其任选地被D取代，直至完全氘代； R 5 is CH 3 , which is optionally substituted by D until fully deuterated;
R 6为H或CH 3，其任选地被D取代，直至完全氘代； R 6 is H or CH 3 , which is optionally substituted by D until fully deuterated;
R Z1a选自
Figure PCTCN2022141536-appb-000157
Figure PCTCN2022141536-appb-000158
其任选地被D取代，直至完全氘代； R Z1a is selected from
Figure PCTCN2022141536-appb-000157
Figure PCTCN2022141536-appb-000158
It is optionally substituted by D up to full deuteration;
R Z3b选自H、D、Cl、F、Me、
Figure PCTCN2022141536-appb-000159
Figure PCTCN2022141536-appb-000160
其任选地被D取代，直至完全氘代。 R Z3b is selected from H, D, Cl, F, Me,
Figure PCTCN2022141536-appb-000159
Figure PCTCN2022141536-appb-000160
It is optionally substituted with D until fully deuterated.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
R 2为卤素； R 2 is halogen;
R 3选自H或D； R is selected from H or D;
R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
R 6为H或C 1-2烷基，其任选地被D取代，直至完全氘代； R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
R Z1a为任选地被1、2或3个R*取代的环丙基，其任选地被D取代，直至完全氘代； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
R*选自CH 3、CH 2F、CHF 2、-C(NH)O-C 1-6烷基或-C(O)O-C 1-6烷基，其任选地被D取代，直至完全氘代； R* is selected from CH 3 , CH 2 F, CHF 2 , -C(NH)OC 1-6 alkyl or -C(O)OC 1-6 alkyl optionally substituted with D until fully deuterated ;
R Z3b选自H或D。 R Z3b is selected from H or D.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-2卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-2 haloalkyl, which is optionally substituted by D, up to fully deuterated;
R 2为卤素； R 2 is halogen;
R 3选自H或D； R is selected from H or D;
R 5为C 1-2烷基，其任选地被D取代，直至完全氘代； R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
R 6为H或C 1-2烷基，其任选地被D取代，直至完全氘代； R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
R Z1a为
Figure PCTCN2022141536-appb-000161
其任选地被D取代，直至完全氘代； R Z1a is
Figure PCTCN2022141536-appb-000161
It is optionally substituted by D up to full deuteration;
其中R*选自CH 3、CH 2F、CHF 2、-C(NH)O-C 1-4烷基或-C(O)O-C 1-4烷基，其任选地被D取代，直至完全氘代； where R* is selected from CH 3 , CH 2 F, CHF 2 , -C(NH)OC 1-4 alkyl or -C(O)OC 1-4 alkyl optionally substituted with D up to fully deuterium generation;
R Z3b选自H或D。 R Z3b is selected from H or D.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CHF 2、CF 3或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
R 2为F； R2 is F;
R 3为H； R3 is H;
R 5为CH 3； R 5 is CH 3 ;
R 6选自H、CH 3或CD 3； R 6 is selected from H, CH 3 or CD 3 ;
R Z1a选自
Figure PCTCN2022141536-appb-000162
R Z1a is selected from
Figure PCTCN2022141536-appb-000162
R Z3b为H。 R Z3b is H.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CN、卤素、C 1-6卤代烷基、OR、C(O)OR或-C(O)NRR’，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl, OR, C(O)OR or -C(O)NRR', optionally replaced by 1, 2 or 3 OH, -NH 2 or -CN Substituted, which is also optionally substituted by D, up to complete deuteration;
R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
R Z1a为4-7元杂环基，其可任选地被1、2、3、4或5个R*取代，其任选地被D取代，直至完全氘代； R Z1a is a 4-7 membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5 R*, optionally substituted by D, up to full deuteration;
R*选自H、D、卤素、-C 0-4亚烷基-CN、C 1-6烷基、C 1-6卤代烷基、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 3-8环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者两个R*以及它们连接的原子一起形成C＝O或C＝S，或者两个R*连接形成C 1-4亚烷基；其任选地被D取代，直至完全氘代； R* is selected from H, D, halogen, -C 0-4 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-4 alkylene-OR, -C 0- 4 alkylene-NRR', -C(O)R, -C(NH)OR, -C(O)OR, -C(O)NRR', C 3-8 cycloalkyl, 4-7 membered hetero Cyclic group, phenyl or 5-6 membered heteroaryl; or two R* and the atoms they connect together form C=O or C=S, or two R* connect to form C 1-4 alkylene; its optionally substituted with D, up to full deuteration;
R Z3b选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元 杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4 -6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, up to complete Deuterium;
L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group, -C 1-6 alkylene -OC 1-6 haloalkyl, -C 1-6 alkylene - NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
R s选自CN、OR、C 1-6烷基、C 1-6卤代烷基、S(O)R或S(O) 2R，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R s is selected from CN, OR, C 1-6 alkyl, C 1-6 haloalkyl, S(O)R or S(O) 2 R, or two adjacent R s on the same carbon atom together form C =O or C=S, optionally substituted by D, up to complete deuteration;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基。 R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, or R, R' and their connected nitrogen atom form a 4-8 membered heterocyclic group.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CN、卤素、C 1-6卤代烷基、OR、C(O)OR或-C(O)NRR’，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl, OR, C(O)OR or -C(O)NRR', optionally replaced by 1, 2 or 3 OH, -NH 2 or -CN Substituted, which is also optionally substituted by D, up to complete deuteration;
R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
R Z1a为
Figure PCTCN2022141536-appb-000163
其任选地被D取代，直至完全氘代； R Z1a is
Figure PCTCN2022141536-appb-000163
It is optionally substituted by D up to full deuteration;
X为O、S、S(O)、S(O) 2、NR N或C(R C) 2； X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
R*选自H、D或C 1-4烷基，或者两个R*以及它们连接的原子一起形成C＝O或C＝S，或者两个R*连接形成C 1-4亚烷基；其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, or two R* and their connected atoms form C=O or C=S together, or two R* connect to form C 1-4 alkylene; It is optionally substituted by D up to full deuteration;
R N选自H、C 1-6烷基、C 1-6卤代烷基、C(O)R、C 3-8环烷基或4-7元杂环基； RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R, C 3-8 cycloalkyl or 4-7 membered heterocyclyl;
R C独立地选自H、D、卤素、OH、C(O)R、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基或4-7元杂环基； R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl;
R和R’独立地选自H、C 1-6烷基或C 1-6卤代烷基； R and R' are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CN、卤素、C 1-6卤代烷基或OC 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN 取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl or OC 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH 2 or -CN, which is also optionally substituted by D Substitution, until complete deuteration;
R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
R Z1a为
Figure PCTCN2022141536-appb-000164
其任选地被D取代，直至完全氘代； R Z1a is
Figure PCTCN2022141536-appb-000164
It is optionally substituted by D up to full deuteration;
X为O、S、S(O)、S(O) 2、NR N或C(R C) 2； X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
R*选自H、D或C 1-4烷基，或者两个R*以及它们连接的原子一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, or two R* and the atoms to which they are attached together form C=O or C=S, which is optionally substituted by D, up to complete deuteration;
R N选自H、C 1-6烷基、C 1-6卤代烷基或C(O)R； RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C(O)R;
R C独立地选自H、D、卤素、OH、C(O)R、C 1-6烷基或C 1-6卤代烷基； R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl or C 1-6 haloalkyl;
R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CN、卤素、C 1-6卤代烷基或OC 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl or OC 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH 2 or -CN, which is also optionally substituted by D Substitution, until complete deuteration;
R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
R Z1a为
Figure PCTCN2022141536-appb-000165
其任选地被D取代，直至完全氘代； R Z1a is
Figure PCTCN2022141536-appb-000165
It is optionally substituted by D up to full deuteration;
R*选自H、D或C 1-4烷基，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、 同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereo Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
R 2为卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R 2 is halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R 3选自H或D； R is selected from H or D;
R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
R 6为C 1-4烷基，其任选地被D取代，直至完全氘代； R 6 is C 1-4 alkyl, which is optionally substituted by D, until fully deuterated;
R Z1a为
Figure PCTCN2022141536-appb-000166
其任选地被D取代，直至完全氘代； R Z1a is
Figure PCTCN2022141536-appb-000166
It is optionally substituted by D up to full deuteration;
X为O、S、S(O)、S(O) 2、NR N或C(R C) 2； X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
R*选自H、D或C 1-4烷基，或者两个R*以及它们连接的原子一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, or two R* and the atoms to which they are attached together form C=O or C=S, which is optionally substituted by D, up to complete deuteration;
R N选自H、C 1-6烷基、C 1-6卤代烷基或C(O)R； RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C(O)R;
R C独立地选自H、D、卤素、OH、C(O)R、C 1-6烷基或C 1-6卤代烷基； R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl or C 1-6 haloalkyl;
R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
R 2为卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R 2 is halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R 3选自H或D； R is selected from H or D;
R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
R 6为C 1-4烷基，其任选地被D取代，直至完全氘代； R 6 is C 1-4 alkyl, which is optionally substituted by D, until fully deuterated;
R Z1a为
Figure PCTCN2022141536-appb-000167
其任选地被D取代，直至完全氘代； R Z1a is
Figure PCTCN2022141536-appb-000167
It is optionally substituted by D up to full deuteration;
R*选自H、D或C 1-4烷基，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-2卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-2 haloalkyl, which is optionally substituted by D, up to fully deuterated;
R 2为卤素或C 1-2烷基，其任选地被D取代，直至完全氘代； R 2 is halogen or C 1-2 alkyl, which is optionally substituted by D, up to fully deuterated;
R 3选自H或D； R is selected from H or D;
R 5为C 1-2烷基，其任选地被D取代，直至完全氘代； R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
R 6为C 1-2烷基，其任选地被D取代，直至完全氘代； R 6 is C 1-2 alkyl, which is optionally substituted by D, until fully deuterated;
R Z1a为
Figure PCTCN2022141536-appb-000168
其任选地被D取代，直至完全氘代； R Z1a is
Figure PCTCN2022141536-appb-000168
It is optionally substituted by D up to full deuteration;
R*选自H、D或C 1-2烷基，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
在更具体的实施方案中，本发明提供了式(IX)、(IX-1)或(IX-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides a compound of formula (IX), (IX-1) or (IX-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereotype Isomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CF 3或CHF 2； R 1 is selected from CF 3 or CHF 2 ;
R 2选自F或CH 3； R 2 is selected from F or CH 3 ;
R 3为H； R3 is H;
R 5为CH 3； R 5 is CH 3 ;
R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
R Z1a选自
Figure PCTCN2022141536-appb-000169
R Z1a is selected from
Figure PCTCN2022141536-appb-000169
R Z3b选自H、Cl、
Figure PCTCN2022141536-appb-000170
R Z3b is selected from H, Cl,
Figure PCTCN2022141536-appb-000170
在更具体的实施方案中，本发明提供了上述化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有式(X)、(X-1)或(X-2)的结构：In a more specific embodiment, the present invention provides the above compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvents thereof compound, it has the structure of formula (X), (X-1) or (X-2):
Figure PCTCN2022141536-appb-000171
Figure PCTCN2022141536-appb-000171
其中，in,
R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
R 2选自H、D、卤素或C 1-4烷基； R 2 is selected from H, D, halogen or C 1-4 alkyl;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4 或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为NR Z3a； Z 3 is NR Z3a ;
R Z1b为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1b is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、C 1-6烷基、C 1-6卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 1-4亚烷基、C 5-6环烷基或5-6元杂环基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, C 1- 6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and the atoms they connect together form C=O, C =S, C 1-4 alkylene, C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
R Z2a和R Z3a独立地为化学键、C 1-6烷基或C 1-6卤代烷基； R Z2a and R Z3a are independently chemical bonds, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2c为化学键； R Z2c is a chemical bond;
其中R Z2a和R Z3a、R Z2c和R Z3a可以结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
其中R 1、R 2、R Z2a、R Z3a、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代； wherein each group in R 1 , R 2 , R Z2a , R Z3a , R Z1b and R Z2b can be optionally substituted by D until complete deuteration;
优选地，其中不包括WO2022251497中的具体化合物，例如化合物1-182中的任一个或多个。Preferably, specific compounds in WO2022251497, such as any one or more of compounds 1-182, are not included therein.
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或含硫原子的5-6元杂环基，其任选地被1或2个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为NR Z3a； Z 3 is NR Z3a ;
R Z1b任选地被1、2或3个R*取代的5-6元杂环基； R Z1b is optionally substituted by 1, 2 or 3 R * 5-6 membered heterocyclyl;
R*选自H、D、卤素、-OR、-C(O)R、C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from H, D, halogen, -OR, -C(O)R, C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and their connected The atoms together form a 5-6 membered heterocyclic group;
R Z2a和R Z3a独立地为化学键、C 1-6烷基或C 1-6卤代烷基； R Z2a and R Z3a are independently chemical bonds, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2c为化学键； R Z2c is a chemical bond;
其中R Z2a和R Z3a、R Z2c和R Z3a可以结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
其中R 1、R 2、R Z2a、R Z3a、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R Z2a , R Z3a , R Z1b and R Z2b may be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1选自CHF 2或CF 3； R 1 is selected from CHF 2 or CF 3 ;
R 2选自H、D、F或CH 3； R 2 is selected from H, D, F or CH 3 ;
R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为NR Z3a； Z 3 is NR Z3a ;
R Z1b选自
Figure PCTCN2022141536-appb-000172
R Z1b selected from
Figure PCTCN2022141536-appb-000172
R Z2a和R Z3a独立地为化学键或CH 3； R Z2a and R Z3a are independently a chemical bond or CH 3 ;
R Z2b为H或D； R Z2b is H or D;
R Z2c为化学键； R Z2c is a chemical bond;
其中R Z2a和R Z3a、R Z2c和R Z3a可以结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond;
或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
R 2选自卤素或C 1-4烷基； R 2 is selected from halogen or C 1-4 alkyl;
或者R 1和R 2以及它们连接的原子一起形成C 4-7环烷基，其任选地被1、2或3个R#取代； or R 1 and R 2 and the atoms to which they are attached together form a C 4-7 cycloalkyl group, which is optionally substituted by 1, 2 or 3 R#;
R#为卤素；R# is halogen;
R 3选自H或D； R is selected from H or D;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为NR Z3a； Z 3 is NR Z3a ;
R Z1b为任选地被1、2或3个R*取代的5-6元杂环基； R Z1b is a 5-6 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
R*选自H、D、卤素、C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from H, D, halogen, C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group ;
R Z2a和R Z3a独立地为化学键； R Z2a and R Z3a are independently chemical bonds;
R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2c为化学键； R Z2c is a chemical bond;
其中R Z2a和R Z3a、R Z2c和R Z3a结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a combine to form double bonds;
其中R 1、R 2、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R Z1b and R Z2b can be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
R 2选自卤素或C 1-2烷基； R 2 is selected from halogen or C 1-2 alkyl;
R 3选自H或D； R is selected from H or D;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为NR Z3a； Z 3 is NR Z3a ;
R Z1b为5-6元杂环基； R Z1b is a 5-6 membered heterocyclic group;
R Z2a和R Z3a独立地为化学键； R Z2a and R Z3a are independently chemical bonds;
R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R Z2c为化学键； R Z2c is a chemical bond;
其中R Z2a和R Z3a、R Z2c和R Z3a结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a combine to form double bonds;
其中R 1、R 2、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R Z1b and R Z2b can be optionally substituted by D until complete deuteration.
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (X), (X-1) or (X-2), or a pharmaceutically acceptable salt, isotope variant, tautomer, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
R 1为CHF 2； R 1 is CHF 2 ;
R 2为F； R2 is F;
R 3为H； R3 is H;
Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
Z 3为NR Z3a； Z 3 is NR Z3a ;
R Z1b为
Figure PCTCN2022141536-appb-000173
R Z1b is
Figure PCTCN2022141536-appb-000173
R Z2a和R Z3a独立地为化学键； R Z2a and R Z3a are independently chemical bonds;
R Z2b为H或D； R Z2b is H or D;
R Z2c为化学键； R Z2c is a chemical bond;
其中R Z2a和R Z3a、R Z2c和R Z3a结合形成双键。 Wherein R Z2a and R Z3a , R Z2c and R Z3a combine to form double bonds.
在更具体的实施方案中，本发明提供了化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中所述化合物选自：In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof substances, wherein the compound is selected from:
Figure PCTCN2022141536-appb-000174
Figure PCTCN2022141536-appb-000174
Figure PCTCN2022141536-appb-000175
Figure PCTCN2022141536-appb-000175
Figure PCTCN2022141536-appb-000176
Figure PCTCN2022141536-appb-000176
Figure PCTCN2022141536-appb-000177
Figure PCTCN2022141536-appb-000177
Figure PCTCN2022141536-appb-000178
Figure PCTCN2022141536-appb-000178
Figure PCTCN2022141536-appb-000179
Figure PCTCN2022141536-appb-000179
Figure PCTCN2022141536-appb-000180
Figure PCTCN2022141536-appb-000180
Figure PCTCN2022141536-appb-000181
Figure PCTCN2022141536-appb-000181
Figure PCTCN2022141536-appb-000182
Figure PCTCN2022141536-appb-000182
Figure PCTCN2022141536-appb-000183
Figure PCTCN2022141536-appb-000183
Figure PCTCN2022141536-appb-000184
Figure PCTCN2022141536-appb-000184
Figure PCTCN2022141536-appb-000185
Figure PCTCN2022141536-appb-000185
在更具体的实施方案中，本发明提供了化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中所述化合物选自：In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof substances, wherein the compound is selected from:
Figure PCTCN2022141536-appb-000186
Figure PCTCN2022141536-appb-000186
Figure PCTCN2022141536-appb-000187
Figure PCTCN2022141536-appb-000187
Figure PCTCN2022141536-appb-000188
Figure PCTCN2022141536-appb-000188
Figure PCTCN2022141536-appb-000189
Figure PCTCN2022141536-appb-000189
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。The compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, eg, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereoisomers or geometric isomers (eg cis and trans isomers), or may be in the form of a mixture of stereoisomers, Racemic mixtures and mixtures enriched in one or more stereoisomers are included. Isomers can be separated from mixtures by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by prepared by asymmetric synthesis.
本发明化合物可以互变异构体形式存在。互变异构体为因分子中某一原子在两个位置迅速移动而 产生的官能团异构体，互变异构体是一种特殊的官能团异构体，一对互变异构体可以互相转换，但通常以比较稳定的一种异构体为其主要的存在形式。最主要的例子为烯醇式和酮式互变异构体。The compounds of the present invention may exist in tautomeric forms. Tautomers are functional group isomers produced by the rapid movement of an atom in a molecule at two positions. Tautomers are special functional group isomers. A pair of tautomers can interact with each other. Conversion, but usually a relatively stable isomer is the main form of existence. The most prominent examples are enol and keto tautomers.
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。Those skilled in the art will appreciate that organic compounds may form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as "solvates". When the solvent is water, the complex is called a "hydrate". The invention covers all solvates of the compounds of the invention.
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。The term "solvate" refers to a form of a compound, or a salt thereof, which is associated with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution state solvates and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5 H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2 H 2O)和六水合物(R·6 H 2O))。 The term "hydrate" refers to a compound that combines with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R.x H 2 O, where R is the compound, and x is a number greater than zero. A given compound may form more than one hydrate type, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R 0.5 H2 O)) and polyhydrates (x is a number greater than 1, eg, dihydrate (R·2 H 2 O) and hexahydrate (R·6 H 2 O)).
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。The compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(A)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。 The invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I), but with one or more atoms represented by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replaced. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The compounds of the present invention, their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms all belong to the scope of the present invention. Certain isotopically-labeled compounds of the invention, eg, those incorporating radioactive isotopes (eg, 3H and14C ), are useful in drug and/or substrate tissue distribution assays. Tritium, ie3H , and carbon-14, ie14C isotopes are particularly preferred because of their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium, ie2H , may be preferred in some circumstances since greater metabolic stability may afford therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. The isotope-labeled compound of formula (A) of the present invention and its prodrug can generally be prepared in this way, when carrying out the processes disclosed in the following schemes and/or examples and preparation examples, replace the non-isotope with easily available isotope-labeled reagents Labeled reagents.
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。Furthermore, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo to its active form having a medical effect, for example by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, per intro This article is for reference.
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通 常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(A)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。A prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo. Prodrugs are generally prepared by modifying functional groups in such a way that the modification can be cleaved by routine manipulation or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or thiol group is bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amino, or thiol group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxy, sulfhydryl and amino functional groups of the compounds of formula (A). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester and the like can be used. The esters themselves may be reactive and/or hydrolyzable under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those which break down readily in the human body to release the parent acid or a salt thereof.
本发明还提供药物制剂，包含治疗有效量的式(A)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。The present invention also provides a pharmaceutical preparation, comprising a therapeutically effective amount of a compound of formula (A) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are included in the present invention.
药物组合物和试剂盒Pharmaceutical compositions and kits
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。A pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols and lanolin.
用于给予本发明化合物的合适制剂将对于本领域普通技术人员而言是显而易见的，并且包括例如片剂、丸剂、胶囊、栓剂、锭剂、糖锭剂、溶液(特别是注射(皮下、静脉内、肌内)和输注(注射剂)用溶液)、酏剂、糖浆、扁囊剂、乳液、吸入剂或可分散粉剂。一种或多种药物活性化合物的含量的范围应该是作为整体的组合物的0.1至90wt％、优选0.5至50wt％，即，其量足以实现以下指定的剂量范围。如有必要，指定的剂量可每天给药若干次。Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions (especially for injection (subcutaneous, intravenous intramuscular) and infusion (injection) solutions), elixirs, syrups, cachets, emulsions, inhalants or dispersible powders. The content of one or more pharmaceutically active compounds should range from 0.1 to 90 wt%, preferably 0.5 to 50 wt%, of the composition as a whole, ie in an amount sufficient to achieve the dosage ranges specified below. The indicated dose may be administered several times a day, if necessary.
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。The invention also includes kits (eg, pharmaceutical packs). Provided kits can include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container). In some embodiments, provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent. In some embodiments, a compound of the invention and other therapeutic agent provided in a first container and a second container are combined to form a unit dosage form.
给药medication
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal cavity administration, buccal administration, vaginal administration Drugs, by implants, or by other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal administration, intralesional administration, and intracranial injection or infusion techniques.
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered can be determined by the physician according to the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受 试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。When used to prevent a condition described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically on the advice and supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition generally include those with a family history of the condition, or those determined by genetic testing or screening to be particularly susceptible to developing the condition.
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。Long-term administration of the pharmaceutical compositions provided herein ("chronic administration") can also be used. Long-term administration refers to administering a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, For example, the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within the therapeutic window.
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, pharmaceutical compositions may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to effective levels. The bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose provides slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV intravenous infusion) ) can be delivered more rapidly, so that the concentration of the active ingredient in the blood rises rapidly to effective levels. In other embodiments, the pharmaceutical compositions may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More usually, however, the compositions will be presented in unit dosage form for ease of precise dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions. In such compositions, the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful for forming the desired administration form. Carriers or excipients and processing aids.
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。For oral dosages, a typical regimen is one to five oral dosages per day, especially two to four oral dosages, typically three oral dosages. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。In order to provide blood levels similar to, or lower than, the injected dose, the transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。Injection dosage levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially 24 to 96 hours. A preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given in order to achieve adequate steady state levels. For a human patient of 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid form may comprise, for example, any of the following components, or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl sylate or orange flavoring.
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. In such compositions, as previously mentioned, the active compound is typically a minor component, often from about 0.05 to 10% by weight, the remainder being injectable excipients and the like.
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的 其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated in an ointment, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream, with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art, and generally include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。The compounds of the invention may also be administered by transdermal devices. Thus, transdermal administration can be achieved using patches of the reservoir or porous membrane type, or various solid matrices.
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。The foregoing components of compositions for oral administration, injection or topical administration are representative only. Other materials and processing techniques, etc. are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。The compounds of the invention may also be administered in sustained release form, or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins composed of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally including a or multiple substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, eg, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (eg, 10-50% in water).
药物联用drug combination
目前本领域中已知的许多化学治疗剂可与本发明化合物组合使用。Many chemotherapeutic agents currently known in the art can be used in combination with the compounds of the present invention.
有待与本发明式(I)的化合物(包括化合物(I)的所有单独实施方案或通用子集)一起/组合使用或在如本文(上文和下文)所定义的医学用途、用途、治疗和/或预防方法中使用的药理学活性物质可选自以下中的任何一种或多种(优选在所有这些实施方案中仅使用一种另外的药理学活性物质)：to be used together/in combination with the compounds of formula (I) of the present invention (including all individual embodiments or general subsets of compounds (I)) or as defined herein (above and below) in medical use, use, treatment and / or the pharmacologically active substance used in the prophylactic method may be selected from any one or more of the following (preferably in all these embodiments only one additional pharmacologically active substance is used):
1.EGFR和/或其突变体的抑制剂1. Inhibitors of EGFR and/or its mutants
a.例如，阿法替尼、厄洛替尼、吉非替尼、拉帕替尼、西妥昔单抗、帕尼单抗、奥希替尼、奥莫替尼、EGF-816；a. For example, afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, ommotinib, EGF-816;
b.优选的是阿法替尼、奥希替尼和西妥昔单抗；b. Preferred are afatinib, osimertinib and cetuximab;
c.最优选的是阿法替尼；c. The most preferred is afatinib;
2.ErbB2(Her2)和/或其突变体的抑制剂2. Inhibitors of ErbB2 (Her2) and/or its mutants
a.例如，阿法替尼、拉帕替尼、曲妥珠单抗、帕妥珠单抗；a. For example, afatinib, lapatinib, trastuzumab, pertuzumab;
b.优选的是阿法替尼和曲妥珠单抗；b. preferably afatinib and trastuzumab;
c.最优选的是曲妥珠单抗；c. The most preferred is trastuzumab;
3.ALK和/或其突变体的抑制剂3. Inhibitors of ALK and/or its mutants
a.例如，克唑替尼、阿来替尼、恩曲替尼、布加替尼；a. For example, crizotinib, alectinib, entrectinib, brigatinib;
b.优选的是克唑替尼和阿来替尼；b. Crizotinib and Alectinib are preferred;
c.最优选的是克唑替尼；c. The most preferred is crizotinib;
4.MEK和/或其突变体的抑制剂4. Inhibitors of MEK and/or its mutants
a.例如，曲美替尼、考比替尼、比美替尼(binimetinib)、舍美替尼、瑞美替尼(refametinib)；a. For example, trametinib, cobimetinib, binimetinib, sermetinib, refametinib;
b.优选的是曲美替尼和考比替尼；b. Trametinib and cobimetinib are preferred;
c.最优选的是曲美替尼；c. The most preferred is trametinib;
5.KRAS G12C的抑制剂5. Inhibitors of KRAS G12C
a.例如，ARS-853(WO 2014/152588中的化合物V-64)、WO2016/044772中的实施例I-272；a. For example, ARS-853 (compound V-64 in WO 2014/152588), Example 1-272 in WO 2016/044772;
6.BCR-ABL和/或其突变体的抑制剂6. Inhibitors of BCR-ABL and/or its mutants
a.例如，伊马替尼、达沙替尼、尼洛替尼；a. For example, imatinib, dasatinib, nilotinib;
b.优选的是伊马替尼和尼洛替尼；b. preferably imatinib and nilotinib;
c.最优选的是伊马替尼；c. The most preferred is imatinib;
7.FGFR1和/或FGFR2和/或FGFR3和/或其突变体的抑制剂7. Inhibitors of FGFR1 and/or FGFR2 and/or FGFR3 and/or mutants thereof
a.例如，尼达尼布；a. For example, nintedanib;
8.ROS1和/或其突变体的抑制剂8. Inhibitors of ROS1 and/or mutants thereof
a.例如，克唑替尼、恩曲替尼、洛拉替尼、色瑞替尼(ceritinib)、美瑞替尼(merestinib)；a. For example, crizotinib, entrectinib, lorlatinib, ceritinib, meretinib;
b.优选的是克唑替尼和恩曲替尼；b. Preferred are crizotinib and entrectinib;
c.最优选的是克唑替尼；c. The most preferred is crizotinib;
9.c-MET和/或其突变体的抑制剂9. Inhibitors of c-MET and/or its mutants
10.AXL和/或其突变体的抑制剂10. Inhibitors of AXL and/or mutants thereof
11.NTRK1和/或其突变体的抑制剂11. Inhibitors of NTRK1 and/or mutants thereof
12.RET和/或其突变体的抑制剂12. Inhibitors of RET and/or mutants thereof
13.紫杉烷13. Taxanes
a.例如，紫杉醇、白蛋白结合型紫杉醇(nab-paclitaxel)、多西他赛；a. For example, paclitaxel, nab-paclitaxel, docetaxel;
b.优选的是紫杉醇；b. Paclitaxel is preferred;
14.含铂化合物14. Platinum-containing compounds
a.例如，顺铂、卡铂、奥沙利铂；a. For example, cisplatin, carboplatin, oxaliplatin;
15.抗代谢药15. Antimetabolites
a.例如，5-氟尿嘧啶、卡培他滨、氟尿苷、阿糖胞苷、吉西他滨、三氟尿苷和替吡嘧啶(tipiracil)的组合(＝TAS102)；a. For example, combinations of 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, trifluridine and tipiracil (=TAS102);
b.优选的是吉西他滨；b. Gemcitabine is preferred;
16.有丝分裂激酶抑制剂16. Mitotic Kinase Inhibitors
a.例如，CDK4/6抑制剂a. For example, CDK4/6 inhibitors
i.例如，帕博西尼、瑞博西尼、阿贝西利(abemaciclib)；i. For example, palbociclib, ribociclib, abemaciclib;
ii.优选的是帕博西尼和阿贝西利；ii. Preferred are palbociclib and abeciclib;
iii.最优选的是阿贝西利；iii. The most preferred is Abecicil;
17.免疫治疗剂17. Immunotherapeutics
a.例如，免疫检查点抑制剂a. For example, immune checkpoint inhibitors
i.例如，抗-CTLA4mAb、抗-PD1mAb、抗-PD-L1mAb、抗-PD-L2mAb、抗-LAG3mAb、抗-TIM3mAb；i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb;
ii.优选的是抗-PD1mAb；ii. preferably anti-PD1 mAb;
iii.例如，易普利姆玛、纳武单抗、派姆单抗、阿特利珠单抗、阿维鲁单抗(avelumab)、度伐鲁单抗、匹地利珠单抗(pidilizumab)、PDR-001(WO 2017/019896中公开且使用的BAP049-克隆-E)；iii. For example, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab , PDR-001 (BAP049-clone-E disclosed and used in WO 2017/019896);
iv.优选的是纳武单抗、派姆单抗和PDR-001；iv. Nivolumab, pembrolizumab and PDR-001 are preferred;
v.最优选的是派姆单抗；v. The most preferred is pembrolizumab;
18.抗血管生成药18. Anti-angiogenic drugs
a.例如，贝伐珠单抗、尼达尼布；a. For example, bevacizumab, nintedanib;
b.最优选的是贝伐珠单抗；b. Most preferably bevacizumab;
19.拓扑异构酶抑制剂19. Topoisomerase inhibitors
a.例如，伊立替康、脂质体伊立替康、拓扑替康；a. For example, irinotecan, liposomal irinotecan, topotecan;
b.最优选的是伊立替康；b. Most preferably irinotecan;
20.A-Raf和/或B-Raf和/或C-Raf和/或其突变体的抑制剂20. Inhibitors of A-Raf and/or B-Raf and/or C-Raf and/or mutants thereof
a.例如，RAF-709(＝WO 2014/151616中的实施例131)、LY-3009120(＝WO 2013/134243中的实施例1)；a. For example, RAF-709 (=Example 131 in WO 2014/151616), LY-3009120 (=Example 1 in WO 2013/134243);
21.ERK和/或其突变体的抑制剂21. Inhibitors of ERK and/or mutants thereof
a.例如，乌利替尼(ulixertinib)；a. For example, ulixertinib;
22.细胞凋亡调节剂22. Apoptosis regulator
a.例如，对p53(优选功能性p53、最优选wt p53)与MDM2之间的相互作用的抑制剂(“MDM2抑制剂”)；a. For example, inhibitors of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 ("MDM2 inhibitors");
i.例如，HDM-201、NVP-CGM097、RG-7112、MK-8242、RG-7388、SAR405838、AMG-232、DS-3032、RG-7775、APG-115；i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115;
ii.优选的是HDM-201、RG-7388和AMG-232ii. Preferred are HDM-201, RG-7388 and AMG-232
b.例如，PARP抑制剂；b. For example, PARP inhibitors;
c.例如，MCL-1抑制剂；c. For example, MCL-1 inhibitors;
23.mTOR抑制剂23. mTOR inhibitors
a.例如，雷帕霉素、替西罗莫司、依维莫司、地磷莫司；a. For example, rapamycin, temsirolimus, everolimus, defafolimus;
24.表观遗传调节剂24. Epigenetic Modulators
a.例如，BET抑制剂a. For example, BET inhibitors
i.例如，JQ-1、GSK 525762、OTX 015(＝MK8628)、CPI 0610、TEN-010(＝RO6870810)；i. For example, JQ-1, GSK 525762, OTX 015(=MK8628), CPI 0610, TEN-010(=RO6870810);
b.例如，CDK9抑制剂；b. For example, a CDK9 inhibitor;
25.IGF1/2和/或IGF1-R的抑制剂25. Inhibitors of IGF1/2 and/or IGF1-R
a.例如，珍妥珠单抗(xentuzumab)(WO 2010/066868中的抗体60833)、MEDI-573(＝度司妥单抗(dusigitumab))。a. For example, xentuzumab (antibody 60833 in WO 2010/066868), MEDI-573 (= dusigitumab).
在本发明中，应理解，根据本发明的组合、组合物、试剂盒、方法、用途或用于所述用途的化合物可设想活性成分或组分的同时、并行、依次、相继、交替或单独给予。应当理解，SOS1抑制剂化合物(例如，式(I)的化合物)和至少一种其他药理学活性物质可以依赖性地或独立地配制给予，例如像SOS1抑制剂化合物(例如，式(I)的化合物)和至少一种其他药理学活性物质可以作为同一药物组合物/剂型的一部分给予或者优选以单独的药物组合物/剂型给予。In the present invention, it is to be understood that a combination, composition, kit, method, use or compound for said use according to the present invention envisages simultaneous, parallel, sequential, sequential, alternate or separate active ingredients or components give. It will be appreciated that the SOS1 inhibitor compound (e.g., a compound of formula (I)) and at least one other pharmacologically active substance may be formulated for administration dependently or independently, e.g., as an SOS1 inhibitor compound (e.g., a compound of formula (I) compound) and at least one other pharmacologically active substance may be administered as part of the same pharmaceutical composition/dosage form or preferably in separate pharmaceutical compositions/dosage forms.
实施例Example
本文所用的原料或试剂为可购买到的或由本领域通常已知的合成方法制备。The starting materials or reagents used herein are commercially available or prepared by synthetic methods generally known in the art.
合成方法：resolve resolution:
中间体A1的合成Synthesis of Intermediate A1
Figure PCTCN2022141536-appb-000190
Figure PCTCN2022141536-appb-000190
中间体A1-1的合成Synthesis of Intermediate A1-1
Figure PCTCN2022141536-appb-000191
Figure PCTCN2022141536-appb-000191
将化合物2-甲基-3-三氟甲基苯乙酮(1g)溶解在四氢呋喃(10mL)中，将(R)-(+)-2-甲基-2-丙亚磺酰胺(700mg)和钛酸四乙酯(1.6g)加入反应液中，反应液升温至回流搅拌4小时。降至室温，向反应液中加入水(10mL)，过滤，用乙酸乙酯(60mL)淋洗滤饼，干燥得橙色油状物A1-1(980mg,65.3％)。The compound 2-methyl-3-trifluoromethylacetophenone (1g) was dissolved in tetrahydrofuran (10mL), and (R)-(+)-2-methyl-2-propanesulfinamide (700mg) and tetraethyl titanate (1.6 g) were added to the reaction solution, and the reaction solution was heated to reflux and stirred for 4 hours. Cool down to room temperature, add water (10 mL) to the reaction solution, filter, rinse the filter cake with ethyl acetate (60 mL), and dry to obtain orange oil A1-1 (980 mg, 65.3%).
MS：M+H +＝310。 MS: M+H + =310.
化合物A1-2的合成Synthesis of compound A1-2
Figure PCTCN2022141536-appb-000192
Figure PCTCN2022141536-appb-000192
将化合物A1-1(980mg)溶解在四氢呋喃(10mL)中，0℃分批加入硼氢化钠(120mg)，反应液回温至25℃搅拌6小时。降至0℃，在反应液中加入饱和氯化铵溶液，使反应液的pH为7，向反应液中加入乙酸乙酯(30mL×2)萃取，合并有机相，用饱和氯化钠溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残渣通过柱层析(SiO 2，石油醚/乙酸乙酯＝100/0-0/1)纯化，得黄色油状物A1-2(300mg,30.5％)。 Compound A1-1 (980 mg) was dissolved in tetrahydrofuran (10 mL), sodium borohydride (120 mg) was added in batches at 0°C, and the reaction solution was warmed to 25°C and stirred for 6 hours. Drop to 0°C, add saturated ammonium chloride solution to the reaction solution, make the pH of the reaction solution 7, add ethyl acetate (30mL × 2) to the reaction solution for extraction, combine the organic phases, wash with saturated sodium chloride solution ( 10 mL×2), washed with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/0-0/1) to obtain yellow oil A1- 2 (300 mg, 30.5%).
MS：M+H +＝308。 MS: M+H + =308.
化合物A1的合成Synthesis of Compound A1
Figure PCTCN2022141536-appb-000193
Figure PCTCN2022141536-appb-000193
将化合物A1-2(300mg)溶解在乙酸乙酯(5mL)中，加入盐酸/乙酸乙酯(4N，10mL)溶液，25℃下搅拌4小时。减压浓缩，得白色固体A1(200mg,85.1％)。Compound A1-2 (300 mg) was dissolved in ethyl acetate (5 mL), hydrochloric acid/ethyl acetate (4N, 10 mL) solution was added, and stirred at 25°C for 4 hours. Concentration under reduced pressure gave white solid A1 (200 mg, 85.1%).
MS：M+H +＝204； MS: M+H + =204;
1H NMR(400MHz,DMSO-d6)δ8.02(t,J＝7.2Hz,1H),7.86-7.80(m,1H),7.50-7.57(m,1H),4.72(q,J＝6.4Hz,1H),1.55(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.02(t, J=7.2Hz, 1H), 7.86-7.80(m, 1H), 7.50-7.57(m, 1H), 4.72(q, J=6.4Hz , 1H), 1.55 (d, J=6.8Hz, 3H).
化合物A2的合成Synthesis of Compound A2
Figure PCTCN2022141536-appb-000194
Figure PCTCN2022141536-appb-000194
中间体A2-1的合成Synthesis of Intermediate A2-1
Figure PCTCN2022141536-appb-000195
Figure PCTCN2022141536-appb-000195
将化合物2-氟-3-溴苯甲醛(40g)加入到二氯甲烷(280mL)中，在0℃下滴加三氟化二乙氨基硫(63.5g)，混合物回温至25℃，搅拌1小时。反应液用饱和碳酸氢钠(100mL)淬灭，用乙酸乙酯(200mL，100mL)萃取。合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥，过滤，减压浓缩，残渣通过柱层析(SiO 2，石油醚/乙酸乙酯＝100/0-0/1)纯化，得无色油化合物A2-1(30g,68％)。 The compound 2-fluoro-3-bromobenzaldehyde (40g) was added to dichloromethane (280mL), and diethylaminosulfur trifluoride (63.5g) was added dropwise at 0°C, and the mixture was warmed to 25°C and stirred 1 hour. The reaction solution was quenched with saturated sodium bicarbonate (100 mL), extracted with ethyl acetate (200 mL, 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/0-0/1) to obtain Colorless oil compound A2-1 (30 g, 68%).
中间体A2-2的合成Synthesis of Intermediate A2-2
Figure PCTCN2022141536-appb-000196
Figure PCTCN2022141536-appb-000196
将化合物A2-1(30g)溶于二氧六环(210mL)中，加入三乙胺(33.7g)、三丁基(1-乙氧基乙烯)锡(57.8g)和二(三苯基膦)二氯化钯(9.36g)，氮气保护下100℃搅拌反应12小时。将反应液降温至0℃左右，盐酸(6M，56.0mL)滴加到反应液中，25℃下反应1小时。反应体系用乙酸乙酯(200mL×2)萃取，合并有机相，用饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩，得残渣。残渣通过柱层析(SiO 2，石油醚/乙酸乙酯＝100/0-0/1)纯化，得无色油状物A2-2(20g,80％)。 Compound A2-1 (30g) was dissolved in dioxane (210mL), triethylamine (33.7g), tributyl(1-ethoxyethylene)tin (57.8g) and bis(triphenyl Phosphine)palladium dichloride (9.36g), stirred and reacted at 100°C for 12 hours under the protection of nitrogen. The temperature of the reaction solution was lowered to about 0°C, hydrochloric acid (6M, 56.0 mL) was added dropwise to the reaction solution, and the reaction was carried out at 25°C for 1 hour. The reaction system was extracted with ethyl acetate (200 mL×2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/0-0/1) to obtain a colorless oil A2-2 (20 g, 80%).
中间体A2-3的合成Synthesis of Intermediate A2-3
Figure PCTCN2022141536-appb-000197
Figure PCTCN2022141536-appb-000197
化合物A2-2(20g)溶于四氢呋喃(150mL)中，加入钛酸四乙酯(36.3g)、(R)-2-甲基-2-丙亚磺酰胺(23.2g)，回流反应4小时。将反应液降温至0℃左右。加入乙醇(20mL)，控温0℃，缓慢加入NaBH 4(3.6g)，反应在25℃搅拌1小时。反应液用HCl(1M)调节pH值至5～6，用乙酸乙酯(200mL×2)萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得残渣。残渣通过柱层析(SiO 2,石油醚/乙酸乙酯＝100/0-0/1)纯化，得黄色固体A2-3(8g,25％)。 Compound A2-2 (20g) was dissolved in tetrahydrofuran (150mL), tetraethyl titanate (36.3g) and (R)-2-methyl-2-propanesulfinamide (23.2g) were added, and refluxed for 4 hours . The temperature of the reaction solution was lowered to about 0°C. Ethanol (20 mL) was added, the temperature was controlled at 0°C, NaBH 4 (3.6 g) was added slowly, and the reaction was stirred at 25°C for 1 hour. The reaction solution was adjusted to pH 5-6 with HCl (1M), extracted with ethyl acetate (200mL×2), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/0-0/1) to obtain yellow solid A2-3 (8 g, 25%).
中间体A2的合成Synthesis of Intermediate A2
Figure PCTCN2022141536-appb-000198
Figure PCTCN2022141536-appb-000198
化合物A2-3(8g)溶于盐酸/乙酸乙酯(4N,20mL)中，25℃下搅拌反应1小时。反应液直接浓缩得残渣，粗品用甲基叔丁基醚(20mL)打浆，过滤，干燥得白色固体A2(6g,98％)。Compound A2-3 (8 g) was dissolved in hydrochloric acid/ethyl acetate (4N, 20 mL), and stirred at 25° C. for 1 hour. The reaction solution was directly concentrated to obtain a residue, and the crude product was slurried with methyl tert-butyl ether (20 mL), filtered, and dried to obtain a white solid A2 (6 g, 98%).
1H NMR(400MHz,CD 3OD)δ7.71(br d,J＝6.4Hz,2H),7.41-7.48(m,1H),6.89–7.19(m,1H),4.76-4.84(m,1H),1.68(d，J＝7.2Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ7.71 (br d, J = 6.4Hz, 2H), 7.41-7.48 (m, 1H), 6.89–7.19 (m, 1H), 4.76-4.84 (m, 1H ), 1.68 (d, J=7.2Hz, 3H).
中间体A3的合成Synthesis of Intermediate A3
Figure PCTCN2022141536-appb-000199
Figure PCTCN2022141536-appb-000199
化合物A3-1的合成Synthesis of Compound A3-1
Figure PCTCN2022141536-appb-000200
Figure PCTCN2022141536-appb-000200
将化合物3-溴-5-硝基三氟甲苯(60g)溶解在二氧六环(420mL)中，反应混合物中加入三乙胺(44.9g)，三丁基(1-乙氧基乙烯)锡(107g)和二(三苯基膦)二氯化钯(15.6g)，氮气置换3次，80℃搅拌12小时。冷却至室温，向反应液中滴加HCl(4M，149mL)，混合物在20～25℃反应1小时。反应液用乙酸乙酯(200mL×3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，得残渣。残渣通过柱层析(SiO 2，石油醚/乙酸乙酯＝100/0-0/1)纯化，得黄色液体A3-1(50g,粗品)。 Compound 3-bromo-5-nitrobenzotrifluoride (60g) was dissolved in dioxane (420mL), triethylamine (44.9g) was added in the reaction mixture, tributyl (1-ethoxyethylene) Tin (107g) and bis(triphenylphosphine)palladium dichloride (15.6g) were replaced with nitrogen three times, and stirred at 80°C for 12 hours. After cooling to room temperature, HCl (4M, 149 mL) was added dropwise to the reaction solution, and the mixture was reacted at 20-25°C for 1 hour. The reaction solution was extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/0-0/1) to obtain yellow liquid A3-1 (50 g, crude product).
化合物A3-2的合成Synthesis of Compound A3-2
Figure PCTCN2022141536-appb-000201
Figure PCTCN2022141536-appb-000201
将化合物A3-1(50g)溶解在四氢呋喃(350mL)中，反应混合物中加入(R)-甲基-2-丙亚磺酰胺(33.8)和钛酸四乙酯(122g)，混合物在65℃反应3小时。将反应液降温至20～25℃，加入乙醇(50mL)，控温20～30℃，缓慢加入NaBH 4(22.4g)，反应在25℃搅拌1小时。反应液用HCl(1M)调节pH值至5～6，用乙酸乙酯(200mL×2)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得残渣。残渣通过柱层析(SiO 2，石油醚/乙酸乙酯＝100/0-0/1)纯化。得黄色液体A3-2(12g,16％)。 Compound A3-1 (50g) was dissolved in tetrahydrofuran (350mL), (R)-methyl-2-propanesulfinamide (33.8) and tetraethyl titanate (122g) were added to the reaction mixture, and the mixture was heated at 65°C React for 3 hours. The temperature of the reaction solution was lowered to 20-25°C, ethanol (50 mL) was added, the temperature was controlled at 20-30°C, NaBH 4 (22.4 g) was added slowly, and the reaction was stirred at 25°C for 1 hour. The reaction solution was adjusted to pH 5-6 with HCl (1M), extracted with ethyl acetate (200 mL×2), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/0-0/1). A yellow liquid A3-2 (12 g, 16%) was obtained.
化合物A3-3的合成Synthesis of compound A3-3
Figure PCTCN2022141536-appb-000202
Figure PCTCN2022141536-appb-000202
化合物A3-2(12g)加入到盐酸/乙酸乙酯(4N,50mL)中，20℃下搅拌1小时。固体过滤，减压浓缩得白色固体A3-3(8g,83％)。Compound A3-2 (12 g) was added to hydrochloric acid/ethyl acetate (4N, 50 mL), and stirred at 20° C. for 1 hour. The solid was filtered and concentrated under reduced pressure to obtain white solid A3-3 (8 g, 83%).
中间体A3的合成Synthesis of Intermediate A3
Figure PCTCN2022141536-appb-000203
Figure PCTCN2022141536-appb-000203
化合物A3-3(4g)加入到MeOH(80mL)中，在Ar气氛下加入Pd/C(1g，20％纯度)，溶液用H 2置换3次。混合物在H 2(40psi)条件下，在25℃下搅拌24小时。反应液直接过滤，滤液减压浓缩，得 黄色固体A3(3.8g,98％)。 Compound A3-3 (4 g) was added into MeOH (80 mL), Pd/C (1 g, 20% purity) was added under Ar atmosphere, and the solution was replaced with H 2 three times. The mixture was stirred at 25° C. under H 2 (40 psi) for 24 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid A3 (3.8 g, 98%).
中间体A4的合成Synthesis of Intermediate A4
Figure PCTCN2022141536-appb-000204
Figure PCTCN2022141536-appb-000204
中间体A4-1的合成Synthesis of Intermediate A4-1
Figure PCTCN2022141536-appb-000205
Figure PCTCN2022141536-appb-000205
将化合物2-氟-3-三氟甲基苯乙酮(1g)溶解在四氢呋喃(3mL)中，将(R)-(+)-2-甲基-2-丙亚磺酰胺(706mg)和钛酸四乙酯(1.6g)加入反应液中，反应液升温至回流搅拌4小时。冷却至室温，向反应液中加入水(10mL)，过滤，用乙酸乙酯(60mL)淋洗滤饼，干燥得橙色油状物A4-1(980mg,65.3％)。The compound 2-fluoro-3-trifluoromethylacetophenone (1g) was dissolved in tetrahydrofuran (3mL), and (R)-(+)-2-methyl-2-propanesulfinamide (706mg) and Tetraethyl titanate (1.6 g) was added to the reaction solution, and the reaction solution was heated to reflux and stirred for 4 hours. Cool to room temperature, add water (10 mL) to the reaction solution, filter, rinse the filter cake with ethyl acetate (60 mL), and dry to obtain orange oil A4-1 (980 mg, 65.3%).
MS：M+H +＝310。 MS: M+H + =310.
化合物A4-2的合成Synthesis of Compound A4-2
Figure PCTCN2022141536-appb-000206
Figure PCTCN2022141536-appb-000206
将化合物A4-1(980mg)溶解在四氢呋喃(6mL)中，0℃分批加入硼氢化钠(120mg)，反应液回温至25℃搅拌6小时。冷却至0℃，在反应液中加入饱和氯化铵溶液，调反应液的pH为7，向反应液中加入乙酸乙酯(30mL×2)萃取，合并有机相，用饱和氯化钠溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残渣通过柱层析(SiO 2，石油醚/乙酸乙酯＝100/0-0/1)纯化，得黄色油状物A4-2(300mg,30.4％)。 Compound A4-1 (980 mg) was dissolved in tetrahydrofuran (6 mL), sodium borohydride (120 mg) was added in batches at 0°C, and the reaction solution was warmed to 25°C and stirred for 6 hours. Cool to 0°C, add saturated ammonium chloride solution to the reaction solution, adjust the pH of the reaction solution to 7, add ethyl acetate (30mL×2) to the reaction solution for extraction, combine the organic phases, and wash with saturated sodium chloride solution ( 10 mL×2), washed with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/0-0/1) to obtain yellow oil A4 -2 (300mg, 30.4%).
MS：M+H +＝312。 MS: M+H + =312.
化合物A4的合成Synthesis of compound A4
Figure PCTCN2022141536-appb-000207
Figure PCTCN2022141536-appb-000207
将化合物A4-2(300mg)溶解在乙酸乙酯(5mL)中，加入盐酸/乙酸乙酯溶液(4N,10mL)，25℃下搅拌4小时。减压浓缩，得白色固体A4(200mg,85.1％)。Compound A4-2 (300 mg) was dissolved in ethyl acetate (5 mL), hydrochloric acid/ethyl acetate solution (4N, 10 mL) was added, and stirred at 25° C. for 4 hours. Concentration under reduced pressure gave white solid A4 (200 mg, 85.1%).
MS：M+H +＝208； MS: M+H + =208;
1H NMR(400MHz,DMSO-d6)δ8.02(t,J＝7.2Hz,1H),7.86-7.80(m,1H),7.50-7.57(m,1H),4.72(q,J＝6.4Hz,1H),1.55(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.02(t, J=7.2Hz, 1H), 7.86-7.80(m, 1H), 7.50-7.57(m, 1H), 4.72(q, J=6.4Hz , 1H), 1.55 (d, J=6.8Hz, 3H).
终产物的制备Preparation of the final product
反应式1Reaction 1
Figure PCTCN2022141536-appb-000208
Figure PCTCN2022141536-appb-000208
反应式2Reaction 2
Figure PCTCN2022141536-appb-000209
Figure PCTCN2022141536-appb-000209
反应式3Reaction 3
Figure PCTCN2022141536-appb-000210
Figure PCTCN2022141536-appb-000210
实施例1的合成Synthesis of Example 1
Figure PCTCN2022141536-appb-000211
Figure PCTCN2022141536-appb-000211
中间体1-1的合成Synthesis of Intermediate 1-1
Figure PCTCN2022141536-appb-000212
Figure PCTCN2022141536-appb-000212
将高锰酸钾(1.83g)和氢氧化钠(638mg)溶解在水(5mL)中，加入5,6-二甲氧基异苯并呋喃-1(3H)-酮(1g)。混合物在25℃下搅拌24小时。过滤，滤饼用水(5mL×2)淋洗，10-20℃下滤液用浓盐酸调pH至2，过滤，滤饼用水(5mL×3)淋洗，收集滤饼，干燥得到白色固体1-1(730mg，62.6％)。Potassium permanganate (1.83 g) and sodium hydroxide (638 mg) were dissolved in water (5 mL), and 5,6-dimethoxyisobenzofuran-1(3H)-one (1 g) was added. The mixture was stirred at 25°C for 24 hours. Filter, rinse the filter cake with water (5mL×2), adjust the pH of the filtrate to 2 with concentrated hydrochloric acid at 10-20°C, filter, rinse the filter cake with water (5mL×3), collect the filter cake, and dry to obtain a white solid 1- 1 (730 mg, 62.6%).
MS：M+H +＝227。 MS: M+H + =227.
中间体1-2的合成Synthesis of Intermediate 1-2
Figure PCTCN2022141536-appb-000213
Figure PCTCN2022141536-appb-000213
将1-1(730mg)加到乙酸酐(7mL)中,混合物在130℃下搅拌1小时后，直接减压浓缩得到白色固体1-2(520mg,77.4％)。1-1 (730mg) was added to acetic anhydride (7mL), and the mixture was stirred at 130°C for 1 hour, then directly concentrated under reduced pressure to obtain white solid 1-2 (520mg, 77.4%).
MS：M+H +＝209。 MS: M+H + =209.
中间体1-3的合成Synthesis of Intermediates 1-3
Figure PCTCN2022141536-appb-000214
Figure PCTCN2022141536-appb-000214
将1-2(520mg)溶解在无水乙醇(5mL)中，加入甲基肼(417mg,40％水溶液)，混合物在80℃下搅拌1.5小时。混合物降至室温，有白色固体析出，过滤，滤饼用乙醇(5mL×2)洗涤，收集滤饼，减压浓缩得到白色固体1-3(500mg,84.7％)。1-2 (520 mg) was dissolved in absolute ethanol (5 mL), methylhydrazine (417 mg, 40% aqueous solution) was added, and the mixture was stirred at 80° C. for 1.5 hours. The mixture was cooled to room temperature, a white solid precipitated, filtered, the filter cake was washed with ethanol (5mL×2), the filter cake was collected, and concentrated under reduced pressure to obtain white solid 1-3 (500mg, 84.7%).
MS：M+H +＝237。 MS: M+H + =237.
中间体1-4的合成Synthesis of Intermediates 1-4
Figure PCTCN2022141536-appb-000215
Figure PCTCN2022141536-appb-000215
将1-3(200mg)溶解在三氯氧磷(2mL)溶液中，混合物在110℃下搅拌2小时。减压浓缩，加入 乙酸乙酯(2mL)稀释，然后倒入冰水(10mL)中，用饱和的碳酸钠溶液调pH至8，析出固体，过滤，收集滤饼烘干得白色固体1-4(180mg,83.4％)。1-3 (200 mg) was dissolved in phosphorus oxychloride (2 mL) solution, and the mixture was stirred at 110°C for 2 hr. Concentrate under reduced pressure, add ethyl acetate (2 mL) to dilute, then pour into ice water (10 mL), adjust pH to 8 with saturated sodium carbonate solution, precipitate solid, filter, collect filter cake and dry to obtain white solid 1-4 (180 mg, 83.4%).
MS：M+H +＝225。 MS: M+H + =225.
中间体1-5的合成Synthesis of Intermediates 1-5
Figure PCTCN2022141536-appb-000216
Figure PCTCN2022141536-appb-000216
将1-4(100mg)和A3-3(106mg)溶解在甲苯(2mL)中，然后加入叔丁醇钠(151mg)，(2-二环己基膦基-2,6-二异丙氧基-1,1-联苯基)[2-(2-氨基-1,1-联苯基)]钯(II)(16.4mg)，氮气置换三次，110℃下搅拌12小时。过滤，滤液减压浓缩。粗品经柱层析(SiO 2，石油醚/乙酸乙酯＝30/1-0/1)纯化得黄色固体1-5(80mg,45％)。 Dissolve 1-4 (100 mg) and A3-3 (106 mg) in toluene (2 mL), then add sodium tert-butoxide (151 mg), (2-dicyclohexylphosphino-2,6-diisopropoxy -1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (16.4 mg), replaced with nitrogen three times, and stirred at 110°C for 12 hours. Filter and concentrate the filtrate under reduced pressure. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=30/1-0/1) to obtain yellow solid 1-5 (80 mg, 45%).
MS：M+H +＝453。 MS: M+H + =453.
1的合成Synthesis of 1
Figure PCTCN2022141536-appb-000217
Figure PCTCN2022141536-appb-000217
将化合物1-5(30mg)溶于甲醇(1mL)和水(0.1mL)中，加入氯化铵(35.5mg)，铁粉(26mg)，混合物60℃搅拌2小时。冷却到室温，过滤，滤液减压浓缩。粗品经高效液相色谱法(色谱柱：Waters Xbridge BEH C18 100*30mm*10um；流动相：[水(氨水+碳酸氢胺溶液)-乙腈]；B％：20％-60％，8min)纯化得黄色固体1(4.6mg,16.5％)。Compound 1-5 (30 mg) was dissolved in methanol (1 mL) and water (0.1 mL), ammonium chloride (35.5 mg), iron powder (26 mg) were added, and the mixture was stirred at 60° C. for 2 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonia water + ammonium bicarbonate solution)-acetonitrile]; B%: 20%-60%, 8min) A yellow solid 1 (4.6 mg, 16.5%) was obtained.
MS：M+H +＝423； MS: M+H + =423;
1H NMR(400MHz,CD 3OD)δ7.65(s,1H),7.61(s,1H),6.99(s,2H),6.78(s,1H),4.96-5.01(m,1H),4.57(s,1H),4.04(s,3H),3.94(s,3H),3.56(s,3H),1.58(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ7.65(s,1H),7.61(s,1H),6.99(s,2H),6.78(s,1H),4.96-5.01(m,1H),4.57 (s, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 3.56 (s, 3H), 1.58 (d, J=6.8Hz, 3H).
实施例2的合成Synthesis of Example 2
Figure PCTCN2022141536-appb-000218
Figure PCTCN2022141536-appb-000218
将1-4(20mg)和A2(17mg)溶解在甲苯(1mL)中，加入叔丁醇钠(30mg)，(2-二环己基膦基-2,6-二异丙氧基-1,1-联苯基)[2-(2-氨基-1,1-联苯基)]钯(II)(3.3mg)，氮气保护下110℃搅拌12小时。过滤，滤液减压浓缩。粗品经高效液相色谱法(色谱柱：Waters Xbridge BEH C18 100*30mm*10um；流动相：[水(氨水+碳酸氢胺溶液)-乙腈]；B％：20％-60％，8min)纯化得黄色固体2(1.33mg,4.1％)。Dissolve 1-4 (20 mg) and A2 (17 mg) in toluene (1 mL), add sodium tert-butoxide (30 mg), (2-dicyclohexylphosphino-2,6-diisopropoxy-1, 1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (3.3 mg), stirred at 110°C for 12 hours under nitrogen protection. Filter and concentrate the filtrate under reduced pressure. The crude product was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonia water + ammonium bicarbonate solution)-acetonitrile]; B%: 20%-60%, 8min) A yellow solid 2 (1.33 mg, 4.1%) was obtained.
MS：M+H +＝408； MS: M+H + =408;
1H NMR(400MHz,CD 3OD)δ7.57-7.63(m,3H),7.42(t,J＝6.8Hz,1H),7.14-7.20(m,1H),7.86-7.00(m,1H),5.29-5.35(m,1H),4.58(s,1H),4.05(s,3H),3.94(s,3H),3.49(s,3H),1.62(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ7.57-7.63 (m, 3H), 7.42 (t, J = 6.8Hz, 1H), 7.14-7.20 (m, 1H), 7.86-7.00 (m, 1H) , 5.29-5.35 (m, 1H), 4.58 (s, 1H), 4.05 (s, 3H), 3.94 (s, 3H), 3.49 (s, 3H), 1.62 (d, J=6.8Hz, 3H).
实施例3和4的合成Synthesis of Examples 3 and 4
Figure PCTCN2022141536-appb-000219
Figure PCTCN2022141536-appb-000219
中间体3-1和4-1的合成Synthesis of Intermediates 3-1 and 4-1
Figure PCTCN2022141536-appb-000220
Figure PCTCN2022141536-appb-000220
将化合物1-4(1.7g)溶解在浓硫酸(10mL)中，100℃下搅拌18小时。冷却至室温，缓慢倒入冰水中(30mL)，然后用氢氧化钠溶液调pH到8，减压浓缩得到白色固体。固体加入60mL的N,N-二甲基甲酰胺，室温搅拌1小时，过滤，滤液减压浓缩得到粗品。粗品用高效液相色谱法(色谱柱：Phenomenex luna C18(250*70mm，15um)；流动相：[水(三氟乙酸)-乙腈]；B％：5％-40％，30min)纯化，馏分冻干得白色固体混合物3-1和4-1(600mg,37.3％)。Compound 1-4 (1.7 g) was dissolved in concentrated sulfuric acid (10 mL), and stirred at 100° C. for 18 hours. Cool to room temperature, slowly pour into ice water (30 mL), then adjust the pH to 8 with sodium hydroxide solution, and concentrate under reduced pressure to obtain a white solid. Add 60 mL of N,N-dimethylformamide to the solid, stir at room temperature for 1 hour, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 (250*70mm, 15um); mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 5%-40%, 30min), and the fraction Freeze-drying gave white solid mixtures 3-1 and 4-1 (600 mg, 37.3%).
MS：M+H +＝241。 MS: M+H + =241.
中间体3-2和4-2的合成Synthesis of Intermediates 3-2 and 4-2
Figure PCTCN2022141536-appb-000221
Figure PCTCN2022141536-appb-000221
将混合物3-1和4-1(600mg)，甲磺酸四氢呋喃-3-醇酯(621mg)溶解在N,N-二甲基甲酰胺(20mL)溶液中，然后加入碳酸钾(1.03g)，混合物在90℃搅拌12小时。冷却至室温，加入100mL水，用乙 酸乙酯萃取(50mL×3)，合并的有机相用饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩得到白色固体混合物3-2和4-2(800mg,粗品)。Mixtures 3-1 and 4-1 (600 mg), tetrahydrofuran-3-ol methanesulfonate (621 mg) were dissolved in N,N-dimethylformamide (20 mL) solution, and potassium carbonate (1.03 g) was added , and the mixture was stirred at 90°C for 12 hours. Cool to room temperature, add 100 mL of water, extract with ethyl acetate (50 mL×3), wash the combined organic phase once with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a white solid mixture 3 -2 and 4-2 (800mg, crude product).
MS：M+H +＝311。 MS: M+H + =311.
中间体3-3和4-3的合成Synthesis of intermediates 3-3 and 4-3
Figure PCTCN2022141536-appb-000222
Figure PCTCN2022141536-appb-000222
将混合物3-2和4-2(200mg)和化合物A3-3(174mg)溶解在甲苯(2mL)中，加入(2-二环己基膦基-2,6-二异丙氧基-1,1-联苯基)[2-(2-氨基-1,1-联苯基)]钯(II)(26.9mg)，叔丁醇钠(247mg)，110℃搅拌12小时。冷却至室温，过滤，滤液减压浓缩得到粗品。粗品用高效液相色谱法(色谱柱：Phenomenex C18 80*40mm*3um；流动相：[水(碳酸氢胺)-乙腈]；B％：45％-65％，8min)纯化。得白色固体混合物3-3和4-3(85mg,24.7％)。Mixtures 3-2 and 4-2 (200 mg) and compound A3-3 (174 mg) were dissolved in toluene (2 mL), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1, 1-Biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (26.9 mg), sodium tert-butoxide (247 mg), stirred at 110°C for 12 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Phenomenex C18 80*40mm*3um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 45%-65%, 8min). The white solid mixture 3-3 and 4-3 (85 mg, 24.7%) was obtained.
MS：M+H +＝509。 MS: M+H + =509.
3和4的合成Synthesis of 3 and 4
将混合物3-3和4-3(75mg)溶解在甲醇(2mL)和水(0.2mL)中，然后加入氯化铵(118mg)和铁粉(82.4mg)，混合物在65℃下搅拌12小时。冷却至室温，过滤，滤液减压浓缩得到粗品。粗品用高效液相色谱法(色谱柱：Phenomenex Luna 80*30mm*3um；流动相：[水(三氟乙酸)-乙腈]；B％：30％-60％，8min)纯化，得混合物3和4。混合物经超临界液相色谱(色谱柱：DAICEL CHIRALPAK IC(250mm*30mm，10um)；流动相：[0.1％氨水-异丙醇]；B％：45％-45％，12min)分离得类白色固体3(3.58mg)和类白色固体4(2.64mg)。Mixtures 3-3 and 4-3 (75 mg) were dissolved in methanol (2 mL) and water (0.2 mL), then ammonium chloride (118 mg) and iron powder (82.4 mg) were added, and the mixture was stirred at 65° C. for 12 hours . Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; B%: 30%-60%, 8min) to obtain mixture 3 and 4. The mixture was separated by supercritical liquid chromatography (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: [0.1% ammonia water-isopropanol]; B%: 45%-45%, 12min) to obtain off-white Solid 3 (3.58 mg) and off-white solid 4 (2.64 mg).
MS：M+H +＝479； MS: M+H + =479;
3： 1H NMR(400MHz,CD 3OD)δ7.73(s,1H),7.61(s,1H),6.98(s,2H),6.79(s,1H),5.29-5.35(m,1H),4.97-5.03(m,1H),4.03-4.10(m,3H),3.99-4.03(m,3H),3.91-3.96(m,1H),3.57(s,3H),2.29-2.40(m,1H),2.14-2.26(m,1H),1.59(d,J＝6.8Hz,3H)； 3: 1 H NMR (400MHz, CD 3 OD) δ7.73(s,1H),7.61(s,1H),6.98(s,2H),6.79(s,1H),5.29-5.35(m,1H) ,4.97-5.03(m,1H),4.03-4.10(m,3H),3.99-4.03(m,3H),3.91-3.96(m,1H),3.57(s,3H),2.29-2.40(m, 1H), 2.14-2.26(m, 1H), 1.59(d, J=6.8Hz, 3H);
4： 1H NMR(400MHz,CD 3OD)δ7.65(d,J＝3.4Hz,2H),6.99(s,2H),6.79(s,1H),5.16-5.18(m,1H),4.97-5.02(m,1H),3.98-4.04(m,3H),3.89-3.93(m,4H),3.57(s,3H),2.33-2.37(m,1H),2.18-2.21(m,1H),1.59(d,J＝6.8Hz,3H)。 4: 1 H NMR (400MHz, CD 3 OD) δ7.65 (d, J = 3.4Hz, 2H), 6.99 (s, 2H), 6.79 (s, 1H), 5.16-5.18 (m, 1H), 4.97 -5.02(m,1H),3.98-4.04(m,3H),3.89-3.93(m,4H),3.57(s,3H),2.33-2.37(m,1H),2.18-2.21(m,1H) , 1.59 (d, J=6.8Hz, 3H).
实施例5和6的合成Synthesis of Examples 5 and 6
Figure PCTCN2022141536-appb-000223
Figure PCTCN2022141536-appb-000223
将混合物3-2和4-2(100mg)和化合物A2(72.6mg)溶于甲苯(2mL)中，然后加入(2-二环己基膦基-2,6-二异丙氧基-1,1-联苯基)[2-(2-氨基-1,1-联苯基)]钯(II)(13.5mg)，叔丁醇钠(124mg)，混合物用氮气置换三次，然后在110℃下搅拌12小时。冷却至室温，过滤，滤液减压浓缩得到粗品。粗品用高效液相色谱法(色谱柱：Phenomenex C18 75*30mm*3um；流动相：[水(碳酸氢胺)-乙腈]；B％：30％-60％，8min)纯化，得混合物5和6。混合物经超临界液相色谱(色谱柱:DAICEL CHIRALPAK IC(250mm*30mm，10um)；流动相：[0.1％氨水-乙醇]；B％：50％-50％，10min)分离得类白色固体5(6.95mg)和类白色固体6(9.31mg)。Mixtures 3-2 and 4-2 (100 mg) and compound A2 (72.6 mg) were dissolved in toluene (2 mL), and then (2-dicyclohexylphosphino-2,6-diisopropoxy-1, 1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (13.5mg), sodium tert-butoxide (124mg), the mixture was replaced with nitrogen three times, and then at 110°C Stirring was continued for 12 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 75*30mm*3um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 30%-60%, 8min) to obtain mixture 5 and 6. The mixture was separated by supercritical liquid chromatography (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: [0.1% ammonia water-ethanol]; B%: 50%-50%, 10min) to obtain off-white solid 5 (6.95 mg) and 6 (9.31 mg) as an off-white solid.
MS：M+H +＝464； MS: M+H + =464;
5： 1H NMR(400MHz,CD 3OD)δ7.67(s,1H),7.57-7.64(m,2H),7.43(t,J＝6.8Hz,1H),7.19(t,J＝7.4Hz,1H),6.86-7.16(m,1H),5.33(q,J＝6.8Hz,1H),5.15-5.17(m,1H),3.99-4.05(m,3H),3.86-3.99(m,4H),3.50(s,3H)2.29-2.41(m,1H),2.11-2.22(m,1H),1.63(d,J＝6.8Hz,3H)； 5: 1 H NMR (400MHz, CD 3 OD) δ7.67(s, 1H), 7.57-7.64(m, 2H), 7.43(t, J＝6.8Hz, 1H), 7.19(t, J＝7.4Hz ,1H),6.86-7.16(m,1H),5.33(q,J＝6.8Hz,1H),5.15-5.17(m,1H),3.99-4.05(m,3H),3.86-3.99(m,4H ),3.50(s,3H)2.29-2.41(m,1H),2.11-2.22(m,1H),1.63(d,J=6.8Hz,3H);
6： 1H NMR(400MHz,CD 3OD)δ7.71(s,1H),7.56-7.64(m,2H),7.44(t,J＝6.8Hz,1H),7.20(t,J＝7.6Hz,1H),6.86-7.16(m,1H),5.27-5.38(m,2H),4.05-4.07(m,3H),3.93-4.02(m,4H),3.50(s,3H),2.35-2.40(m,1H),2.21-2.24(m,1H),1.63(d,J＝6.8Hz,3H)。 6: 1 H NMR (400MHz, CD 3 OD) δ7.71(s, 1H), 7.56-7.64(m, 2H), 7.44(t, J＝6.8Hz, 1H), 7.20(t, J＝7.6Hz ,1H),6.86-7.16(m,1H),5.27-5.38(m,2H),4.05-4.07(m,3H),3.93-4.02(m,4H),3.50(s,3H),2.35-2.40 (m, 1H), 2.21-2.24 (m, 1H), 1.63 (d, J=6.8Hz, 3H).
实施例7的合成Synthesis of Example 7
Figure PCTCN2022141536-appb-000224
Figure PCTCN2022141536-appb-000224
中间体7-1的合成Synthesis of Intermediate 7-1
Figure PCTCN2022141536-appb-000225
Figure PCTCN2022141536-appb-000225
将化合物3-氧代戊二酸二甲酯(10g)溶于2-甲基四氢呋喃(75mL)，0℃，滴加N,N-二甲基甲酰胺二甲基缩醛(6.84g)，混合物在0℃下搅拌3小时，直接用于下一步反应。The compound 3-oxoglutaric acid dimethyl ester (10g) was dissolved in 2-methyltetrahydrofuran (75mL), at 0°C, N,N-dimethylformamide dimethyl acetal (6.84g) was added dropwise, The mixture was stirred at 0°C for 3 hours and used directly in the next reaction.
中间体7-2的合成Synthesis of Intermediate 7-2
Figure PCTCN2022141536-appb-000226
Figure PCTCN2022141536-appb-000226
向上一步反应液中加入盐酸(4M,26mL)，室温下搅拌3小时。分液，有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到中间体7-2(12g,粗品)。Hydrochloric acid (4M, 26 mL) was added to the reaction solution in the previous step, and stirred at room temperature for 3 hours. The liquid was separated, the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7-2 (12 g, crude product).
中间体7-3的合成Synthesis of Intermediate 7-3
Figure PCTCN2022141536-appb-000227
Figure PCTCN2022141536-appb-000227
将1-甲基-1-环丙基胺盐酸盐(5g)溶于甲醇(35mL)中，室温下滴加7-2(10.8g)的甲醇(9mL)溶液。混合物于室温下搅拌12小时。将30％甲醇钠甲醇溶液(9.62g)滴入上述混合物中，室温搅拌2小时。反应体系用水(50mL)淬灭，接着加入浓盐酸(10mL)，室温搅拌2小时，过滤，滤饼用水(20mL×3)淋洗。滤饼真空干燥后得到黄色固体7-3(5g,48.2％)。1-Methyl-1-cyclopropylamine hydrochloride (5 g) was dissolved in methanol (35 mL), and a solution of 7-2 (10.8 g) in methanol (9 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 12 hours. A 30% sodium methoxide methanol solution (9.62 g) was dropped into the above mixture, and stirred at room temperature for 2 hours. The reaction system was quenched with water (50 mL), then concentrated hydrochloric acid (10 mL) was added, stirred at room temperature for 2 hours, filtered, and the filter cake was rinsed with water (20 mL×3). The filter cake was dried in vacuo to give 7-3 (5 g, 48.2%) as a yellow solid.
MS：M+H +＝224。 MS: M+H + =224.
中间体7-4的合成Synthesis of Intermediate 7-4
Figure PCTCN2022141536-appb-000228
Figure PCTCN2022141536-appb-000228
将对甲苯磺酰氯(4.48g)加入至7-3(5g)和三乙胺的乙腈(35mL)溶液中，室温搅拌2小时。反应体系用水(50mL)淬灭，过滤，滤饼用水(10mL×2)淋洗，将滤饼烘干得到黄色固体7-4(5g,59.2％)。p-Toluenesulfonyl chloride (4.48 g) was added to a solution of 7-3 (5 g) and triethylamine in acetonitrile (35 mL), and stirred at room temperature for 2 hours. The reaction system was quenched with water (50 mL), filtered, the filter cake was rinsed with water (10 mL×2), and the filter cake was dried to obtain a yellow solid 7-4 (5 g, 59.2%).
MS：M+H +＝378。 MS: M+H + =378.
中间体7-5的合成Synthesis of Intermediate 7-5
Figure PCTCN2022141536-appb-000229
Figure PCTCN2022141536-appb-000229
在甲苯(70mL)和甲醇(13.5mL)混合溶剂中加入中间体7-4(4.5g)，醋酸钯(401mg)，1,3-双(二环己基膦)丙烷双(四氟硼酸盐)(2.19g)和碳酸钾(3.3g)。混合物在80℃(一氧化碳:50psi)下反应12小时。将反应液浓缩，加入水(50mL)。混合物用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，真空干燥得粗品。粗品过柱层析纯化(SiO 2，石油醚/乙酸乙酯＝10/1-1/1)得到黄色固体7-5(2.5g,79％)。 Intermediate 7-4 (4.5g), palladium acetate (401mg), 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate) were added to a mixed solvent of toluene (70mL) and methanol (13.5mL) ) (2.19g) and potassium carbonate (3.3g). The mixture was reacted at 80°C (carbon monoxide: 50 psi) for 12 hours. The reaction solution was concentrated, and water (50 mL) was added. The mixture was extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried in vacuo to obtain a crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=10/1-1/1) to obtain 7-5 as a yellow solid (2.5 g, 79%).
MS：M+H +＝266。 MS: M+H + =266.
中间体7-6和7-7的合成Synthesis of intermediates 7-6 and 7-7
Figure PCTCN2022141536-appb-000230
Figure PCTCN2022141536-appb-000230
7-5(0.3g)和40％甲基肼水溶液(0.59g)的甲醇(2mL)溶液于65℃反应24小时。将反应体系减压浓缩得到粗品。粗品用高效液相质谱法(色谱柱:Phenomenex Luna 80*30mm*3um；流动相:[水+盐酸溶液-乙腈]；B％:1％-20％，8min)纯化得到淡黄色固体7-6(65mg,23.2％)和淡黄色固体7-7(100mg,35.8％)。7-5 (0.3 g) and 40% methylhydrazine aqueous solution (0.59 g) in methanol (2 mL) were reacted at 65°C for 24 hours. The reaction system was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid mass spectrometry (chromatographic column: Phenomenex Luna 80*30mm*3um; mobile phase: [water+hydrochloric acid solution-acetonitrile]; B%: 1%-20%, 8min) to obtain light yellow solid 7-6 (65mg, 23.2%) and pale yellow solid 7-7 (100mg, 35.8%).
MS：M+H +＝248。 MS: M+H + =248.
中间体7-8的合成Synthesis of intermediates 7-8
Figure PCTCN2022141536-appb-000231
Figure PCTCN2022141536-appb-000231
0℃下，三氟甲磺酸酐(86mg)加入7-6(65mg)和三乙胺(61.4mg)的二氯甲烷(1mL)溶液中。0℃搅拌30分钟，回温至室温搅拌12小时。反应液用薄层色谱法(石油醚/乙酸乙酯＝1/1,Rf＝0.43)分离得到黄色固体7-8(35mg,45.6％)。Trifluoromethanesulfonic anhydride (86 mg) was added to a solution of 7-6 (65 mg) and triethylamine (61.4 mg) in dichloromethane (1 mL) at 0°C. Stir at 0°C for 30 minutes, return to room temperature and stir for 12 hours. The reaction solution was separated by thin layer chromatography (petroleum ether/ethyl acetate=1/1, Rf=0.43) to obtain yellow solid 7-8 (35 mg, 45.6%).
MS：M+H +＝380。 MS: M+H + =380.
7的合成Synthesis of 7
Figure PCTCN2022141536-appb-000232
Figure PCTCN2022141536-appb-000232
在二氧六环(1mL)中加入7-8(20mg)，A2(14mg)，三(二亚苄基丙酮)二钯(5mg)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(6mg)和碳酸铯(52mg)，100℃反应6小时。冷却至室温，过滤，用乙腈(5mL)淋洗滤饼，滤液减压浓缩后得到粗品。粗品用高效液相色谱法(色谱柱:Waters Xbridge BEH C18 100*30mm*10um；流动相:水(碳酸氢胺溶液)-乙腈；B％:35％-55％，8min)纯化得到黄色固体7(1.17mg,5.2％)。To dioxane (1 mL) was added 7-8 (20 mg), A2 (14 mg), tris(dibenzylideneacetone) dipalladium (5 mg), 4,5-bisdiphenylphosphine-9,9- Dimethylxanthene (6mg) and cesium carbonate (52mg) were reacted at 100°C for 6 hours. Cool to room temperature, filter, rinse the filter cake with acetonitrile (5 mL), and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: water (ammonium bicarbonate solution)-acetonitrile; B%: 35%-55%, 8min) to obtain a yellow solid 7 (1.17 mg, 5.2%).
MS：M+H +＝419。 MS: M+H + =419.
实施例8的合成Synthesis of Example 8
Figure PCTCN2022141536-appb-000233
Figure PCTCN2022141536-appb-000233
中间体8-1的合成Synthesis of Intermediate 8-1
Figure PCTCN2022141536-appb-000234
Figure PCTCN2022141536-appb-000234
0℃下将三氟甲磺酸酐(85.6mg)加入到7-7(50mg)和三乙胺(61.4mg)的二氯甲烷(1mL)溶液中，搅拌30分钟后回温至室温反应12小时。反应液用薄层色谱法(石油醚/乙酸乙酯＝1/1,Rf＝0.43)分离得到8-1(35mg,45.6％)。Add trifluoromethanesulfonic anhydride (85.6mg) to a solution of 7-7 (50mg) and triethylamine (61.4mg) in dichloromethane (1mL) at 0°C, stir for 30 minutes and return to room temperature for 12 hours . The reaction solution was separated by thin layer chromatography (petroleum ether/ethyl acetate=1/1, Rf=0.43) to obtain 8-1 (35 mg, 45.6%).
MS：M+H +＝380。 MS: M+H + =380.
8的合成Synthesis of 8
Figure PCTCN2022141536-appb-000235
Figure PCTCN2022141536-appb-000235
在二氧六环(1mL)中加入中间体8-1(20mg)，A2(14mg)，三(二亚苄基丙酮)二钯(5mg)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(6mg)和碳酸铯(52mg)。100℃反应16小时。冷却至室温，过滤，乙腈(5mL)淋洗滤饼，将滤液减压浓缩后得到粗品。粗品用高效液相色谱法(色谱柱:Waters Xbridge BEH C18 100*30mm*10um；流动相:水(碳酸氢胺溶液)-乙腈；B％:40％-70％，10min)分离得到黄色固体8(3.84mg,17.3％)。Intermediate 8-1 (20 mg), A2 (14 mg), tris(dibenzylideneacetone)dipalladium (5 mg), 4,5-bisdiphenylphosphine-9, 9-Dimethylxanthene (6 mg) and cesium carbonate (52 mg). React at 100°C for 16 hours. Cool to room temperature, filter, rinse the filter cake with acetonitrile (5 mL), and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: water (ammonium bicarbonate solution)-acetonitrile; B%: 40%-70%, 10min) to obtain a yellow solid 8 (3.84mg, 17.3%).
MS：M+H +＝419； MS: M+H + =419;
1H NMR(400MHz,CD 3OD)δ8.73(s,1H),7.56-7.59(m,1H),7.44-7.48(m,1H),7.21-7.25(m,1H),6.87-7.15(m,2H),5.26(q,J＝6.8Hz,1H),3.50(s,3H),1.60(d,J＝7.6Hz,3H),1.59(s,3H),1.11-1.20(m,4H)。 1 H NMR (400MHz, CD 3 OD) δ8.73(s, 1H), 7.56-7.59(m, 1H), 7.44-7.48(m, 1H), 7.21-7.25(m, 1H), 6.87-7.15( m,2H),5.26(q,J=6.8Hz,1H),3.50(s,3H),1.60(d,J=7.6Hz,3H),1.59(s,3H),1.11-1.20(m,4H ).
实施例9的合成Synthesis of Example 9
Figure PCTCN2022141536-appb-000236
Figure PCTCN2022141536-appb-000236
中间体9-1的合成Synthesis of Intermediate 9-1
Figure PCTCN2022141536-appb-000237
Figure PCTCN2022141536-appb-000237
氮气保护下将丁基锂(2.5M,40.6mL)在-50℃加入到2,2,6,6-四甲基哌啶(10.7g)的四氢呋喃(50mL)溶液中。体系搅拌5分钟之后，将6-氯烟酸(4g)的四氢呋喃(50mL)溶液在氮气保护下，在-50℃下加 入上述溶液中。反应体系在-50℃反应10分钟，后回温至-25℃反应30分钟。将反应液倾入干冰(100g)中，将淬灭后的反应液浓缩得到粗品，将粗品在正庚烷(100mL)中搅拌30分钟后过滤，滤饼用正庚烷(15mL)淋洗。随后滤饼用2.5M稀盐酸调pH至4，将该体系用二氯甲烷(50mL×3)萃取。水相继续用2.5M稀盐酸调pH至1后，将水相浓缩到约30mL时，有固体析出，将固体过滤，滤饼用水(5mL)淋洗，干燥后得到黄色固体9-1(1.2g,23.4％)。Under nitrogen protection, butyl lithium (2.5M, 40.6 mL) was added to a solution of 2,2,6,6-tetramethylpiperidine (10.7 g) in tetrahydrofuran (50 mL) at -50°C. After the system was stirred for 5 minutes, a solution of 6-chloronicotinic acid (4 g) in tetrahydrofuran (50 mL) was added to the above solution at -50°C under nitrogen protection. The reaction system was reacted at -50°C for 10 minutes, and then returned to -25°C for 30 minutes. The reaction solution was poured into dry ice (100 g), and the quenched reaction solution was concentrated to obtain a crude product, which was stirred in n-heptane (100 mL) for 30 minutes and then filtered, and the filter cake was rinsed with n-heptane (15 mL). Then the filter cake was adjusted to pH 4 with 2.5M dilute hydrochloric acid, and the system was extracted with dichloromethane (50 mL×3). After the aqueous phase was adjusted to pH 1 with 2.5M dilute hydrochloric acid, when the aqueous phase was concentrated to about 30 mL, a solid precipitated, the solid was filtered, and the filter cake was rinsed with water (5 mL). After drying, a yellow solid 9-1 (1.2 g, 23.4%).
MS：M+H +＝202。 MS: M+H + =202.
中间体9-2的合成Synthesis of Intermediate 9-2
Figure PCTCN2022141536-appb-000238
Figure PCTCN2022141536-appb-000238
9-1(1.2g)和吗啡啉(2.59g)混合物在100℃搅拌2小时。反应液直接浓缩得到化合物9-2(1.5g,粗品)。A mixture of 9-1 (1.2 g) and morpholine (2.59 g) was stirred at 100°C for 2 hours. The reaction solution was directly concentrated to obtain compound 9-2 (1.5 g, crude product).
MS：M+H +＝253。 MS: M+H + =253.
中间体9-3的合成Synthesis of Intermediate 9-3
Figure PCTCN2022141536-appb-000239
Figure PCTCN2022141536-appb-000239
化合物9-2(1.5g)在乙酸酐(10mL)中在130℃搅拌3小时。将反应液直接浓缩得到化合物9-3(1.39g,粗品)。Compound 9-2 (1.5 g) was stirred in acetic anhydride (10 mL) at 130°C for 3 hours. The reaction solution was directly concentrated to obtain compound 9-3 (1.39 g, crude product).
MS：M+MeOH+H +＝267。 MS: M+MeOH+H + =267.
中间体9-4的合成Synthesis of Intermediate 9-4
Figure PCTCN2022141536-appb-000240
Figure PCTCN2022141536-appb-000240
化合物9-3(1.39g)和甲醇(30mL)在65℃下回流搅拌3小时。反应液直接浓缩得到粗品。采用柱层析(SiO 2，石油醚乙酸乙酯＝1:1)对粗品进行纯化，得到黄色固体9-4(700mg,44.3％)。 Compound 9-3 (1.39 g) and methanol (30 mL) were stirred under reflux at 65° C. for 3 hours. The reaction solution was directly concentrated to obtain the crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether ethyl acetate=1:1) to obtain yellow solid 9-4 (700 mg, 44.3%).
MS：M+H +＝267。 MS: M+H + =267.
中间体9-5的合成Synthesis of Intermediate 9-5
Figure PCTCN2022141536-appb-000241
Figure PCTCN2022141536-appb-000241
0℃下将O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(1.2g)加入9-4(700mg)，2-甲基肼甲酸叔丁酯(403mg)和N,N-二异丙基乙胺(1.02g)的N,N-二甲基甲酰胺(10mL)溶液中，室温搅拌2小时。将反应液用水(30mL)淬灭，用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤， 滤液减压浓缩得到粗品。采用柱层析(SiO 2，石油醚：乙酸乙酯＝1:1)对粗品进行纯化，得到黄色固体9-5(630mg,60.7％)。 O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (1.2g) was added to 9-4 (700mg) at 0°C, A solution of tert-butyl 2-methylhydrazinecarboxylate (403 mg) and N,N-diisopropylethylamine (1.02 g) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=1:1) to obtain a yellow solid 9-5 (630 mg, 60.7%).
MS：M+H +＝395。 MS: M+H + =395.
中间体9-6的合成Synthesis of Intermediate 9-6
Figure PCTCN2022141536-appb-000242
Figure PCTCN2022141536-appb-000242
0℃下将三氟乙酸(7mL)加入到粗品9-5(630mg)的二氯甲烷(5mL)溶液中，回温至室温后反应12小时。减压浓缩，将10mL水加入反应体系中，搅拌30分钟，有淡黄色固体析出，过滤，滤饼用水淋洗。滤饼干燥后得到淡黄色固体9-6(0.25g,60％)。Trifluoroacetic acid (7 mL) was added to a dichloromethane (5 mL) solution of the crude product 9-5 (630 mg) at 0° C., and the reaction was carried out after returning to room temperature for 12 hours. Concentrate under reduced pressure, add 10 mL of water into the reaction system, stir for 30 minutes, a light yellow solid precipitates, filter, and rinse the filter cake with water. The filter cake was dried to obtain pale yellow solid 9-6 (0.25 g, 60%).
MS：M+H +＝263。 MS: M+H + =263.
中间体9-7的合成Synthesis of Intermediate 9-7
Figure PCTCN2022141536-appb-000243
Figure PCTCN2022141536-appb-000243
将化合物9-6(100mg)加入三氯氧磷(1.46g)中，90℃下反应4小时。冷却至室温，将反应液缓慢倒入饱和碳酸钠溶液(80mL)中，搅拌10分钟，有黄色固体析出，过滤，滤饼用水淋洗，滤饼干燥得到黄色固体9-7(60mg,56.1％)。Compound 9-6 (100 mg) was added to phosphorus oxychloride (1.46 g), and reacted at 90° C. for 4 hours. Cool to room temperature, slowly pour the reaction solution into saturated sodium carbonate solution (80mL), stir for 10 minutes, a yellow solid precipitates, filter, rinse the filter cake with water, and dry the filter cake to obtain a yellow solid 9-7 (60mg, 56.1% ).
MS：M+H +＝281。 MS: M+H + =281.
中间体9-8的合成Synthesis of Intermediate 9-8
Figure PCTCN2022141536-appb-000244
Figure PCTCN2022141536-appb-000244
在甲苯(1mL)中加入化合物9-7(50mg)，化合物A3-3(58mg)，叔丁醇钠(69mg)和(2-二环己基膦基-2,6-二异丙氧基-1,1-联苯基)[2-(2-氨基-1,1-联苯基)]钯(II)(15mg)，氮气保护下110℃反应4小时。冷却至室温，过滤，滤饼用二氯甲烷(10mL)淋洗，将滤液直接浓缩得到粗品。粗品用薄层色谱法(石油醚：乙酸乙酯＝1：1，Rf＝0.25)纯化得到类白色固体9-8(40mg,46.9％)。Add compound 9-7 (50 mg), compound A3-3 (58 mg), sodium tert-butoxide (69 mg) and (2-dicyclohexylphosphino-2,6-diisopropoxy- 1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (15mg), react at 110°C for 4 hours under nitrogen protection. Cool to room temperature, filter, rinse the filter cake with dichloromethane (10 mL), and directly concentrate the filtrate to obtain the crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate=1:1, Rf=0.25) to obtain off-white solid 9-8 (40 mg, 46.9%).
MS：M+H +＝479。 MS: M+H + =479.
9的合成Synthesis of 9
Figure PCTCN2022141536-appb-000245
Figure PCTCN2022141536-appb-000245
将化合物9-8(35mg)溶于乙醇(3mL)和水(0.3mL)后加入铁粉(29mg)和氯化铵(39mg)，混合物在60℃搅拌12小时。冷却至室温，过滤，将滤饼用甲醇(5mL)淋洗，将滤液浓缩得到粗品。粗品经高效液相色谱法(色谱柱：Phenomenex C18 75*30mm*3um；流动相：水(10mM碳酸氢铵溶液)；B％：20％-70％，8min)纯化得到白色固体9(20mg,61.6％)。Compound 9-8 (35 mg) was dissolved in ethanol (3 mL) and water (0.3 mL), iron powder (29 mg) and ammonium chloride (39 mg) were added, and the mixture was stirred at 60° C. for 12 hours. Cool to room temperature, filter, rinse the filter cake with methanol (5 mL), and concentrate the filtrate to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Phenomenex C18 75*30mm*3um; mobile phase: water (10mM ammonium bicarbonate solution); B%: 20%-70%, 8min) to obtain white solid 9 (20mg, 61.6%).
MS：M+H +＝449； MS: M+H + =449;
1H NMR(400MHz,CD 3OD)δ9.05(s,1H),7.19(s,1H),6.93(d,J＝2.4Hz,2H),6.78(s,1H),4.93-4.96(q,J＝6.8Hz,1H),3.75-3.83(m,8H),3.48(s,3H),1.56(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ9.05(s, 1H), 7.19(s, 1H), 6.93(d, J=2.4Hz, 2H), 6.78(s, 1H), 4.93-4.96(q , J=6.8Hz, 1H), 3.75-3.83(m, 8H), 3.48(s, 3H), 1.56(d, J=6.8Hz, 3H).
实施例10的合成Synthesis of Example 10
Figure PCTCN2022141536-appb-000246
Figure PCTCN2022141536-appb-000246
中间体10-1的合成Synthesis of intermediate 10-1
Figure PCTCN2022141536-appb-000247
Figure PCTCN2022141536-appb-000247
将1-氨基-环丙基甲醇(15g)溶于二氯甲烷(150mL)后加入咪唑(24.8g)，再缓慢加入叔丁基氯二苯基硅烷(83.4g)，混合物在室温下搅拌3小时。向反应液中加入饱和氯化铵溶液(100mL)，用二氯甲烷(150mL×2)萃取，合并的有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。粗品通过柱层析(石油醚/乙酸乙酯＝30/1-1/1)纯化得到无色油状物10-1(33.6g,84.9％)。1-Amino-cyclopropylmethanol (15g) was dissolved in dichloromethane (150mL) and imidazole (24.8g) was added, then tert-butylchlorodiphenylsilane (83.4g) was added slowly, and the mixture was stirred at room temperature for 3 Hour. Add saturated ammonium chloride solution (100mL) to the reaction solution, extract with dichloromethane (150mL×2), wash the combined organic phase with saturated sodium chloride solution (100mL), dry over anhydrous sodium sulfate, filter, and reduce pressure concentrate. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=30/1-1/1) to obtain colorless oil 10-1 (33.6 g, 84.9%).
MS：M+H +＝326。 MS: M+H + =326.
中间体10-2的合成Synthesis of Intermediate 10-2
Figure PCTCN2022141536-appb-000248
Figure PCTCN2022141536-appb-000248
将化合物10-1(23.5g)和丙炔酸乙酯(7.08g)溶于乙醇(230mL)，室温下搅拌40小时，得到黄色溶液直接用于下一步反应。Compound 10-1 (23.5 g) and ethyl propiolate (7.08 g) were dissolved in ethanol (230 mL), and stirred at room temperature for 40 hours to obtain a yellow solution that was directly used in the next reaction.
MS：M+H +＝424。 MS: M+H + =424.
中间体10-3的合成Synthesis of Intermediate 10-3
Figure PCTCN2022141536-appb-000249
Figure PCTCN2022141536-appb-000249
向上步溶液中加入丁炔二酸二甲酯(10.3g)，在80℃下回流搅拌16小时，得到黄色溶液直接用于下一步反应。Dimethyl butynedioate (10.3 g) was added to the solution in the previous step, and stirred under reflux at 80° C. for 16 hours to obtain a yellow solution that was directly used in the next reaction.
MS：M+H +＝566。 MS: M+H + =566.
中间体10-4的合成Synthesis of Intermediate 10-4
Figure PCTCN2022141536-appb-000250
Figure PCTCN2022141536-appb-000250
室温下将乙醇钠(23.39g)加入到上步溶液中，升至80℃回流搅拌16小时。反应液真空浓缩并通过柱层析(石油醚/乙酸乙酯＝30/1-3/1)纯化得到棕黑色油状物10-4(16g,40.4％)。Sodium ethoxide (23.39 g) was added to the solution in the previous step at room temperature, raised to 80°C and stirred under reflux for 16 hours. The reaction solution was concentrated in vacuo and purified by column chromatography (petroleum ether/ethyl acetate=30/1-3/1) to obtain brown-black oil 10-4 (16 g, 40.4%).
MS：M+H +＝548。 MS: M+H + =548.
中间体10-5的合成Synthesis of Intermediate 10-5
Figure PCTCN2022141536-appb-000251
Figure PCTCN2022141536-appb-000251
将化合物10-4(6g)溶于四氢呋喃(60mL)中，加入四丁基氟化铵(1M,16.43mL)，70℃回流反应3小时。反应液真空浓缩并通过柱层析(石油醚/乙酸乙酯＝30/1-0/1)纯化得到黑棕色油状物10-5(2g,59％)。Compound 10-4 (6 g) was dissolved in tetrahydrofuran (60 mL), tetrabutylammonium fluoride (1M, 16.43 mL) was added, and the mixture was refluxed at 70° C. for 3 hours. The reaction solution was concentrated in vacuo and purified by column chromatography (petroleum ether/ethyl acetate=30/1-0/1) to obtain dark brown oil 10-5 (2 g, 59%).
MS：M+H +＝310。 MS: M+H + =310.
中间体10-6的合成Synthesis of intermediate 10-6
Figure PCTCN2022141536-appb-000252
Figure PCTCN2022141536-appb-000252
将化合物10-5(2g)溶解在二氯甲烷(20mL)中，加入氯铬酸吡啶(5.58g)，反应液在25℃下反应16小时。反应液过滤，滤液真空浓缩并通过柱层析(石油醚/乙酸乙酯＝30/1-1/1)纯化得到黑棕色油状物10-6(1.26g,63.4％)。Compound 10-5 (2 g) was dissolved in dichloromethane (20 mL), pyridinium chlorochromate (5.58 g) was added, and the reaction solution was reacted at 25° C. for 16 hours. The reaction solution was filtered, and the filtrate was concentrated in vacuo and purified by column chromatography (petroleum ether/ethyl acetate=30/1-1/1) to obtain dark brown oil 10-6 (1.26 g, 63.4%).
MS：M+H +＝308。 MS: M+H + =308.
中间体10-7的合成Synthesis of Intermediate 10-7
Figure PCTCN2022141536-appb-000253
Figure PCTCN2022141536-appb-000253
将化合物将10-6(1.26g)溶解在二氯甲烷(15mL)中，在0℃下缓慢滴入三氟化二乙氨基硫(1.98g)，室温下反应3小时。将反应液加入冰水(20mL)中，搅拌30min，加入二氯甲烷(20mL×2)萃取，合并的有机相用饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到类白色固体10-7(1.28g,粗品)。Compound 10-6 (1.26g) was dissolved in dichloromethane (15mL), and diethylaminosulfur trifluoride (1.98g) was slowly added dropwise at 0°C, and reacted at room temperature for 3 hours. The reaction solution was added to ice water (20 mL), stirred for 30 min, added dichloromethane (20 mL × 2) for extraction, the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to Concentration under reduced pressure gave off-white solid 10-7 (1.28 g, crude product).
MS：M+H +＝330。 MS: M+H + =330.
中间体10-8的合成Synthesis of intermediate 10-8
Figure PCTCN2022141536-appb-000254
Figure PCTCN2022141536-appb-000254
将氢氧化钠(213mg)溶于水(10mL)后加入至化合物10-7(1.17g)的乙醇(50mL)溶液中，室温下反应3小时。反应液减压浓缩，加入水(5mL)，二氯甲烷(10mL×2)萃取，合并有机相，用饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到白色固体10-8(0.4g,粗品)。Sodium hydroxide (213 mg) was dissolved in water (10 mL), and added to a solution of compound 10-7 (1.17 g) in ethanol (50 mL), and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, added water (5 mL), extracted with dichloromethane (10 mL×2), combined the organic phases, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain White solid 10-8 (0.4g, crude).
MS：M+H +＝302。 MS: M+H + =302.
中间体10-9的合成Synthesis of Intermediate 10-9
Figure PCTCN2022141536-appb-000255
Figure PCTCN2022141536-appb-000255
将化合物10-8(400mg)和N-(甲基氨基)氨基甲酸叔丁酯(291mg)溶于二氯甲烷(10mL)，然后加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(606mg)和N,N-二异丙基乙胺(343mg)，室温搅拌1.5小时。反应液减压浓缩并通过柱层析(石油醚/乙酸乙酯＝30/1-1/1)纯化得到黄色油状物10-9(490mg,85.9％)。Compound 10-8 (400mg) and tert-butyl N-(methylamino)carbamate (291mg) were dissolved in dichloromethane (10mL), then 2-(7-azobenzotriazole)-N , N,N,N-tetramethylurea hexafluorophosphate (606mg) and N,N-diisopropylethylamine (343mg), stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate=30/1-1/1) to obtain yellow oil 10-9 (490 mg, 85.9%).
MS：M+H +＝430。 MS: M+H + =430.
中间体10-10的合成Synthesis of intermediate 10-10
Figure PCTCN2022141536-appb-000256
Figure PCTCN2022141536-appb-000256
将化合物10-9(20mg)溶于二氯甲烷(1mL)后加入盐酸二氧六环(4M,1mL)，室温搅拌16小时。反应液减压浓缩得到黄色固体10-10(10mg,粗品)。Compound 10-9 (20 mg) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride (4M, 1 mL) was added, and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain yellow solid 10-10 (10 mg, crude product).
MS：M+H +＝284。 MS: M+H + =284.
中间体10-11的合成Synthesis of intermediates 10-11
Figure PCTCN2022141536-appb-000257
Figure PCTCN2022141536-appb-000257
将化合物10-10(10mg)溶于二氯甲烷(1mL)后加入吡啶(6mg)，0℃下将三氟甲磺酸酐(15mg)的二氯甲烷(1mL)溶液缓慢滴入上述溶液中，35℃下搅拌16小时。将反应液中加入水(2mL)中，乙酸乙酯(2mL×2)萃取，合并的有机相用饱和氯化钠溶液(2mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，薄层色谱法(石油醚/乙酸乙酯＝1/1)纯化得到黄色固体10-11(10mg,68.2％)。Compound 10-10 (10 mg) was dissolved in dichloromethane (1 mL) and pyridine (6 mg) was added, and a solution of trifluoromethanesulfonic anhydride (15 mg) in dichloromethane (1 mL) was slowly dropped into the above solution at 0°C, Stir at 35°C for 16 hours. The reaction solution was added to water (2 mL), extracted with ethyl acetate (2 mL×2), the combined organic phases were washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to thin Purification by layer chromatography (petroleum ether/ethyl acetate=1/1) gave yellow solid 10-11 (10 mg, 68.2%).
MS：M+H +＝416。 MS: M+H + =416.
化合物10的合成Synthesis of Compound 10
Figure PCTCN2022141536-appb-000258
Figure PCTCN2022141536-appb-000258
将化合物10-11(10mg)和化合物A2(5.47mg)溶于二氧六环(1mL)后加入4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(2.79mg)，三(二亚苄基丙酮)二钯(2.2mg)和碳酸铯(23.54mg)，80℃搅拌16小时。冷却至室温，过滤，滤液减压浓缩，高效液相色谱法(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[水(碳酸氢铵)-乙腈]；B％：35％-65％，8min)纯化得到黄色固体10(2mg,18.2％)。Dissolve compound 10-11 (10 mg) and compound A2 (5.47 mg) in dioxane (1 mL) and add 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (2.79 mg), tris(dibenzylideneacetone) dipalladium (2.2 mg) and cesium carbonate (23.54 mg), stirred at 80°C for 16 hours. Cool to room temperature, filter, filtrate is concentrated under reduced pressure, high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; Mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 35% -65%, 8 min) purification gave yellow solid 10 (2 mg, 18.2%).
MS：M+H +＝455。 MS: M+H + =455.
实施例11的合成Synthesis of Example 11
Figure PCTCN2022141536-appb-000259
Figure PCTCN2022141536-appb-000259
中间体11-1的合成Synthesis of Intermediate 11-1
Figure PCTCN2022141536-appb-000260
Figure PCTCN2022141536-appb-000260
将氢氧化钠(730mg)溶于水(100mL)后加入至化合物10-4(10g)的乙醇(500mL)溶液中，室温反应16小时。反应液减压浓缩，然后加入1M的稀盐酸至pH值5～6，乙酸乙酯(200mL×3)萃取，合并有机相，用饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经柱层析(石油醚/乙 酸乙酯＝30/1-0/1)纯化得到棕色固体11-1(7.5g,79％)。Sodium hydroxide (730 mg) was dissolved in water (100 mL), and added to a solution of compound 10-4 (10 g) in ethanol (500 mL), and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, then 1M dilute hydrochloric acid was added to pH 5-6, extracted with ethyl acetate (200mL×3), the organic phases were combined, washed with saturated sodium chloride solution (200mL), dried over anhydrous sodium sulfate, After filtration and concentration under reduced pressure, the crude product was purified by column chromatography (petroleum ether/ethyl acetate=30/1-0/1) to obtain brown solid 11-1 (7.5 g, 79%).
MS：M+H +＝520。 MS: M+H + =520.
中间体11-2的合成Synthesis of Intermediate 11-2
Figure PCTCN2022141536-appb-000261
Figure PCTCN2022141536-appb-000261
将化合物11-1(3g)溶于二氯甲烷(90mL)，然后加入硫酸甲基肼(1.66g)，三正丙基环磷酸酐50％乙酸乙酯溶液(1.84g)和N,N-二异丙基乙胺(2.24g)，室温反应16小时。反应液减压浓缩，加入水(50mL)，乙酸乙酯(50mL×3)萃取，合并有机相，饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品通过柱层析(石油醚/乙酸乙酯＝1/1-0/1)纯化得到黄色固体11-2(1.4g,48.3％)。Compound 11-1 (3g) was dissolved in dichloromethane (90mL), then methylhydrazine sulfate (1.66g), tri-n-propyl cyclic phosphoric anhydride 50% ethyl acetate solution (1.84g) and N,N- Diisopropylethylamine (2.24g) was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, water (50 mL) was added, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/1-0/1) to obtain yellow solid 11-2 (1.4 g, 48.3%).
MS：M+H +＝502。 MS: M+H + =502.
中间体11-3的合成Synthesis of intermediate 11-3
Figure PCTCN2022141536-appb-000262
Figure PCTCN2022141536-appb-000262
将四丁基氟化铵(1M,782mg)加入11-2(1g)的四氢呋喃(10mL)溶液中，70℃回流反应16小时。反应液减压浓缩，粗品用酸性树酯纯化得到黄色固体11-3(350mg,66.7％)。Tetrabutylammonium fluoride (1M, 782mg) was added into a solution of 11-2 (1g) in tetrahydrofuran (10mL), and reacted under reflux at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified with acidic resin to obtain yellow solid 11-3 (350 mg, 66.7%).
MS：M+H +＝264。 MS: M+H + =264.
中间体11-4的合成Synthesis of Intermediate 11-4
Figure PCTCN2022141536-appb-000263
Figure PCTCN2022141536-appb-000263
-60℃，将二乙氨基三氟化硫(367mg)的二氯甲烷(6mL)溶液缓慢滴入11-3(240mg)的二氯甲烷(15mL)溶液中，缓慢回温至0℃，反应1小时。减压浓缩，薄层色谱法(二氯甲烷/甲醇＝10/1)纯化得到黄色固体11-4(70mg,28.9％)。-60°C, slowly drop a solution of diethylaminosulfur trifluoride (367mg) in dichloromethane (6mL) into a solution of 11-3 (240mg) in dichloromethane (15mL), slowly return to 0°C, and react 1 hour. Concentrate under reduced pressure, and purify by thin layer chromatography (dichloromethane/methanol=10/1) to obtain yellow solid 11-4 (70 mg, 28.9%).
MS：M+H +＝266。 MS: M+H + =266.
中间体11-5的合成Synthesis of Intermediate 11-5
Figure PCTCN2022141536-appb-000264
Figure PCTCN2022141536-appb-000264
将化合物11-4(55mg)和吡啶(33mg)溶于二氯甲烷(2mL)，然后在0℃下缓慢滴入三氟甲磺酸酐(88mg)，室温下反应2小时。反应液减压浓缩，薄层色谱法(石油醚/乙酸乙酯＝1/1)纯化得到黄色油状物11-5(40mg,48.5％)。Compound 11-4 (55 mg) and pyridine (33 mg) were dissolved in dichloromethane (2 mL), and trifluoromethanesulfonic anhydride (88 mg) was slowly added dropwise at 0° C., and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by thin layer chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow oil 11-5 (40 mg, 48.5%).
MS：M+H +＝398。 MS: M+H + =398.
化合物11的合成Synthesis of compound 11
Figure PCTCN2022141536-appb-000265
Figure PCTCN2022141536-appb-000265
将化合物11-5(25mg)和化合物A2(14mg)溶于二氧六环(1mL)后加入碳酸铯(62mg)，三(二亚苄基丙酮)二钯(6mg)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(7mg)，60℃下反应16小时。冷却至室温，过滤，滤液减压浓缩，高效液相色谱法(色谱柱：Phenomenex C18 75*30mm*3um；流动相[水(碳酸氢铵)-乙腈]；B％:30％-60％,8min)纯化得到黄色固体11(1.92mg,7％)。Compound 11-5 (25 mg) and compound A2 (14 mg) were dissolved in dioxane (1 mL) and cesium carbonate (62 mg), tris(dibenzylideneacetone) dipalladium (6 mg) and 4,5-bis (Diphenylphosphine)-9,9-dimethylxanthene (7mg), react at 60°C for 16 hours. Cool to room temperature, filter, filtrate is concentrated under reduced pressure, high performance liquid chromatography (chromatographic column: Phenomenex C18 75*30mm*3um; Mobile phase [water (ammonium bicarbonate)-acetonitrile]; B%: 30%-60%, 8 min) and purified to give yellow solid 11 (1.92 mg, 7%).
MS：M+H +＝437； MS: M+H + =437;
1H NMR(400MHz,CD 3CN)δ8.41(s,1H),7.61(br t,J＝7.2Hz,1H),7.47(t,J＝7.2Hz,1H),7.27-7.21(m,1H),7.17-6.85(m,2H),5.66(br d,J＝5.8Hz,1H),5.22(q,J＝6.8Hz,1H),4.76-4.43(m,2H),3.28(s,3H),1.56(d,J＝7.0Hz,3H),1.36-1.27(m,4H)。 1 H NMR (400MHz, CD 3 CN) δ8.41(s, 1H), 7.61(br t, J=7.2Hz, 1H), 7.47(t, J=7.2Hz, 1H), 7.27-7.21(m, 1H), 7.17-6.85(m, 2H), 5.66(br d, J=5.8Hz, 1H), 5.22(q, J=6.8Hz, 1H), 4.76-4.43(m, 2H), 3.28(s, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.36-1.27 (m, 4H).
实施例12的合成Synthesis of Example 12
Figure PCTCN2022141536-appb-000266
Figure PCTCN2022141536-appb-000266
将10-11(20mg)、A1(12mg)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(6mg)、三(二亚苄基丙酮)二钯(5mg)和碳酸铯(47mg)加入二氧六环(5mL)中，80℃反应16小时。冷却至室温，过滤，滤液减压浓缩，高效液相色谱法(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[水(碳酸氢铵)-乙腈]；B％：35％-65％，8min)纯化得到黄色固体12(4mg,17.7％)。10-11 (20 mg), A1 (12 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (6 mg), tris(dibenzylideneacetone)dipalladium ( 5 mg) and cesium carbonate (47 mg) were added to dioxane (5 mL), and reacted at 80° C. for 16 hours. Cool to room temperature, filter, filtrate is concentrated under reduced pressure, high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; Mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 35% -65%, 8 min) purification gave yellow solid 12 (4mg, 17.7%).
MS：M+H +＝469； MS: M+H + =469;
1H NMR(400MHz,CD 3CN)δ8.37(s,1H),7.75-7.65(m,1H),7.54(br d,J＝7.6Hz,1H),7.35-7.23(m,1H),7.02-6.70(m,1H),6.35-5.94(m,1H),5.80-5.67(m,1H),5.28-5.12(m,1H),3.29-3.19(m,3H),2.57(br s,3H),1.49(br d,J＝6.9Hz,3H),1.36(br s,2H),1.27(br s,2H)。 1 H NMR (400MHz, CD 3 CN) δ8.37(s, 1H), 7.75-7.65(m, 1H), 7.54(br d, J=7.6Hz, 1H), 7.35-7.23(m, 1H), 7.02-6.70(m,1H),6.35-5.94(m,1H),5.80-5.67(m,1H),5.28-5.12(m,1H),3.29-3.19(m,3H),2.57(br s, 3H), 1.49 (br d, J=6.9Hz, 3H), 1.36 (br s, 2H), 1.27 (br s, 2H).
实施例50的合成Synthesis of Example 50
Figure PCTCN2022141536-appb-000267
Figure PCTCN2022141536-appb-000267
中间体50-1的合成Synthesis of Intermediate 50-1
Figure PCTCN2022141536-appb-000268
Figure PCTCN2022141536-appb-000268
乙醇钠(4.7g)的乙醇(20mL)溶液中加入乙二酸二乙酯(13g)和丁二酸二乙酯(10g)。混合物在20℃下搅拌12小时。减压浓缩，残渣用盐酸溶液(2N)调节pH＝2-3，乙酸乙酯(200mL×3)萃取，合并有机相饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到黄色油状化合物50-1(18g，粗品)，直接用于下一步反应。Diethyl oxalate (13 g) and diethyl succinate (10 g) were added to a solution of sodium ethoxide (4.7 g) in ethanol (20 mL). The mixture was stirred at 20°C for 12 hours. Concentrate under reduced pressure, adjust the residue to pH=2-3 with hydrochloric acid solution (2N), extract with ethyl acetate (200mL×3), combine the organic phases and wash with saturated sodium chloride solution (100mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentration under reduced pressure gave yellow oily compound 50-1 (18 g, crude product), which was directly used in the next reaction.
中间体50-2的合成Synthesis of Intermediate 50-2
Figure PCTCN2022141536-appb-000269
Figure PCTCN2022141536-appb-000269
化合物50-1(20g)的乙醇(2mL)溶液中加入水合肼(7mL)，混合物20℃下搅拌1小时。反应液减压浓缩得到黄色油状化合物50-2(10g，粗品)，直接用于下一步反应。To a solution of compound 50-1 (20 g) in ethanol (2 mL) was added hydrazine hydrate (7 mL), and the mixture was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain yellow oily compound 50-2 (10 g, crude product), which was directly used in the next reaction.
中间体50-3的合成Synthesis of intermediate 50-3
Figure PCTCN2022141536-appb-000270
Figure PCTCN2022141536-appb-000270
向50-2(10g)的醋酸(70mL)溶液中加入溴素(2mL)，混合物在100℃下搅拌4小时。减压浓缩，粗产物经柱层析(石油醚/乙酸乙酯＝50/1-0/1)纯化得到化合物50-3(2.3g)。To a solution of 50-2 (10 g) in acetic acid (70 mL) was added bromine (2 mL), and the mixture was stirred at 100°C for 4 hr. Concentrated under reduced pressure, the crude product was purified by column chromatography (petroleum ether/ethyl acetate=50/1-0/1) to obtain compound 50-3 (2.3 g).
MS：M+H +＝240。 MS: M+H + =240.
中间体50-4的合成Synthesis of Intermediate 50-4
Figure PCTCN2022141536-appb-000271
Figure PCTCN2022141536-appb-000271
50-3(2g)、四甲基氯化铵(2.7g)、三氯氧磷(2.3mL)和乙腈(14mL)的混合物在85℃下搅拌2小时。冷却至室温，减压浓缩，残渣用饱和碳酸氢钠溶液(100mL)稀释，二氯甲烷(200mL×3)萃取，合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物 50-4(2.15g，粗品)，直接用于下一步反应。A mixture of 50-3 (2 g), tetramethylammonium chloride (2.7 g), phosphorus oxychloride (2.3 mL) and acetonitrile (14 mL) was stirred at 85°C for 2 hr. Cool to room temperature, concentrate under reduced pressure, dilute the residue with saturated sodium bicarbonate solution (100 mL), extract with dichloromethane (200 mL×3), wash the combined organic phase with saturated sodium chloride solution (50 mL), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 50-4 (2.15 g, crude product), which was directly used in the next reaction.
MS：M+H +＝259。 MS: M+H + =259.
中间体50-5的合成Synthesis of Intermediate 50-5
Figure PCTCN2022141536-appb-000272
Figure PCTCN2022141536-appb-000272
50-4(2g)、吗啡啉(1g)和1,4-二氧六环(14mL)的混合物在50℃下搅拌6小时。混合物减压浓缩，残渣用水(100mL)稀释，乙酸乙酯(100mL×3)萃取，合并有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，残渣经柱层析(石油醚/乙酸乙酯＝50/1-0/1)纯化得到黄色固体50-5(1.8g，收率75％)。A mixture of 50-4 (2 g), morpholine (1 g) and 1,4-dioxane (14 mL) was stirred at 50° C. for 6 hours. The mixture was concentrated under reduced pressure, the residue was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), the combined organic phases were washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50/1-0/1) to obtain a yellow solid 50-5 (1.8 g, yield 75%).
MS：M+H +＝310。 MS: M+H + =310.
中间体50-6的合成Synthesis of Intermediate 50-6
Figure PCTCN2022141536-appb-000273
Figure PCTCN2022141536-appb-000273
将氢氧化锂(808uL,2M)加入到50-5(1g)、乙醇(2.5mL)和水(0.5mL)的溶液中。混合物在25℃下搅拌2小时。反应液减压浓缩得到化合物50-6(900mg，粗品)，直接用于下一步反应。Lithium hydroxide (808 uL, 2M) was added to a solution of 50-5 (1 g), ethanol (2.5 mL) and water (0.5 mL). The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 50-6 (900 mg, crude product), which was directly used in the next reaction.
MS:M+H +＝282。 MS: M+H + =282.
中间体50-7的合成Synthesis of Intermediate 50-7
Figure PCTCN2022141536-appb-000274
Figure PCTCN2022141536-appb-000274
50-6(900mg)、1-叔丁氧羰基-1-甲基肼(491mg)、O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(1.3g)、N,N-二异丙基乙胺(1.7g)和N,N-二甲基甲酰胺(5mL)的混合溶液在25℃下搅拌12小时。混合物用水(50mL)淬灭，乙酸乙酯(50mL×3)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩得到黄色固体50-7(800mg)。50-6 (900mg), 1-tert-butoxycarbonyl-1-methylhydrazine (491mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetra A mixed solution of methylurea hexafluorophosphine salt (1.3 g), N,N-diisopropylethylamine (1.7 g) and N,N-dimethylformamide (5 mL) was stirred at 25° C. for 12 hours. The mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a yellow solid 50-7 (800 mg).
MS:M+H +＝410。 MS: M+H + =410.
中间体50-8的合成Synthesis of Intermediate 50-8
Figure PCTCN2022141536-appb-000275
Figure PCTCN2022141536-appb-000275
50-7(1.2g)和三氟乙酸/二氯甲烷(14mL，1/1)混合物在20℃下搅拌12小时。混合物减压浓缩，粗品溶于1,4-二氧六环(2mL)中，50℃下搅拌12小时，减压浓缩得到黄色固体50-8(600mg， 收率77％)。A mixture of 50-7 (1.2 g) and trifluoroacetic acid/dichloromethane (14 mL, 1/1) was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure, and the crude product was dissolved in 1,4-dioxane (2 mL), stirred at 50° C. for 12 hours, and concentrated under reduced pressure to obtain yellow solid 50-8 (600 mg, yield 77%).
MS:M+H +＝264。 MS: M+H + =264.
中间体50-9的合成Synthesis of intermediate 50-9
Figure PCTCN2022141536-appb-000276
Figure PCTCN2022141536-appb-000276
50-8(100mg)、对甲苯磺酰氯(108mg)、4-二甲氨基吡啶(4.6mg)、三乙胺(77mg)和二氯甲烷(3mL)的混合物在25℃下搅拌12小时。混合物减压浓缩，残渣用水(50mL)稀释，乙酸乙酯(50mL×3)萃取，合并有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到黄色固体50-9(100mg)，直接用于下一步反应。A mixture of 50-8 (100 mg), p-toluenesulfonyl chloride (108 mg), 4-dimethylaminopyridine (4.6 mg), triethylamine (77 mg) and dichloromethane (3 mL) was stirred at 25°C for 12 hr. The mixture was concentrated under reduced pressure, the residue was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow The solid 50-9 (100 mg) was directly used in the next reaction.
MS:M+H +＝418。 MS: M+H + =418.
化合物50的合成Synthesis of Compound 50
Figure PCTCN2022141536-appb-000277
Figure PCTCN2022141536-appb-000277
氮气保护下，50-9(60mg)、A2(40mg)、三(二亚苄基丙酮)二钯(26mg)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(33mg)、碳酸铯(117mg)和1,4-二氧六环(2mL)的混合物在100℃下搅拌12小时。冷却至室温，加入水(10mL)，乙酸乙酯(10mL×3)萃取，合并有机相用饱和氯化钠溶液(3mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，粗品经高效液相色谱法(色谱柱:Waters Xbridge Prep OBD C18 150*40mm*10um；流动相:[水(氨水+碳酸氢铵)-乙腈]；B％:25％-65％，8min)纯化得到黄色固体50(34.7mg，收率：55％)。Under nitrogen protection, 50-9 (60mg), A2 (40mg), tris(dibenzylideneacetone)dipalladium (26mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxy A mixture of xanthene (33 mg), cesium carbonate (117 mg) and 1,4-dioxane (2 mL) was stirred at 100°C for 12 hours. Cool to room temperature, add water (10 mL), extract with ethyl acetate (10 mL×3), combine organic phases, wash with saturated sodium chloride solution (3 mL), and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the crude product was subjected to high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (ammonium water+ammonium bicarbonate)-acetonitrile]; B%: 25% -65%, 8 min) was purified to give yellow solid 50 (34.7 mg, yield: 55%).
MS:M+H +＝435； MS: M+H + =435;
1H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.59(br t,J＝7.2Hz,1H),7.46(t,J＝6.8Hz,1H),7.21(t,J＝7.6Hz,1H),7.00(t,J＝54.8Hz,1H),5.29(q,J＝7.2Hz,1H),3.88(s,8H),3.48(s,3H),1.63(d,J＝7.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ7.63(s, 1H), 7.59(br t, J=7.2Hz, 1H), 7.46(t, J=6.8Hz, 1H), 7.21(t, J= 7.6Hz, 1H), 7.00(t, J=54.8Hz, 1H), 5.29(q, J=7.2Hz, 1H), 3.88(s, 8H), 3.48(s, 3H), 1.63(d, J= 7.2Hz, 3H).
实施例56的合成Synthesis of Example 56
Figure PCTCN2022141536-appb-000278
Figure PCTCN2022141536-appb-000278
中间体56-1的合成Synthesis of Intermediate 56-1
Figure PCTCN2022141536-appb-000279
Figure PCTCN2022141536-appb-000279
将化合物5-溴吡啶-2,3-二羧酸(6.7g)溶解在甲醇(100mL)中加入二氯亚砜(3.89g)，混合物在70℃搅拌48小时。将反应液减压浓缩得到粗品。粗品经柱层析(SiO 2，石油醚/乙酸乙酯＝100/1-5/1)纯化得到白色固体56-1(5g,收率：66.99％)。 Compound 5-bromopyridine-2,3-dicarboxylic acid (6.7 g) was dissolved in methanol (100 mL) and thionyl chloride (3.89 g) was added, and the mixture was stirred at 70° C. for 48 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/1-5/1) to obtain white solid 56-1 (5 g, yield: 66.99%).
MS:M+H +＝276。 MS: M+H + =276.
中间体56-2的合成Synthesis of Intermediate 56-2
Figure PCTCN2022141536-appb-000280
Figure PCTCN2022141536-appb-000280
氮气保护下，56-2(2g)、吗啡啉(1.27g)、三(二亚苄基丙酮)二钯(200.5mg)、二环己基(2,6-二异丙氧基-[1,1-二联苯]-2-基)膦(681.05mg)、碳酸铯(4.76g)和二氧六环(20mL)在80℃搅拌16小时。冷却至室温，过滤，滤液减压浓缩。粗品使用柱层析(SiO 2，石油醚/乙酸乙酯＝100/1-0/1)纯化得到黄色固体56-2(1.5g,收率：61.6％)。 Under nitrogen protection, 56-2 (2g), morpholine (1.27g), tris(dibenzylideneacetone) dipalladium (200.5mg), dicyclohexyl (2,6-diisopropoxy-[1, 1-Diphenyl]-2-yl)phosphine (681.05 mg), cesium carbonate (4.76 g) and dioxane (20 mL) were stirred at 80° C. for 16 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=100/1-0/1) to obtain yellow solid 56-2 (1.5 g, yield: 61.6%).
MS：M+H +＝281。 MS: M+H + =281.
中间体56-3的合成Synthesis of intermediate 56-3
Figure PCTCN2022141536-appb-000281
Figure PCTCN2022141536-appb-000281
56-2(2g)、氢氧化钠(571mg)、乙醇(20mL)和水(2mL)在20℃搅拌16小时。向反应液中加入3N盐酸，调pH＝3，过滤，滤饼干燥得到淡黄色固体56-3(1g)，直接用于下一步反应。56-2 (2 g), sodium hydroxide (571 mg), ethanol (20 mL) and water (2 mL) were stirred at 20°C for 16 hours. 3N hydrochloric acid was added to the reaction solution to adjust the pH to 3, filtered, and the filter cake was dried to obtain a light yellow solid 56-3 (1 g), which was directly used in the next reaction.
MS:M+H +＝253。 MS: M+H + =253.
化合物56的合成Synthesis of compound 56
Figure PCTCN2022141536-appb-000282
Figure PCTCN2022141536-appb-000282
参考实施例1的方法制得化合物56。Compound 56 was prepared by referring to the method of Example 1.
MS:M+H +＝434； MS: M+H + =434;
1H NMR(400MHz,CD 3OD)δ8.80(s,1H),8.33(d,J＝2.6Hz,1H),7.64(br t,J＝7.2Hz,1H),7.48(br t,J＝7.0Hz,1H),7.24(t,J＝7.8Hz,1H),7.19-6.86(m,1H),5.35(q,J＝7.0Hz,1H),3.96-3.91(m,4H),3.69-3.63(m,4H),3.57(s,3H),1.68(d,J＝7.0Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ8.80(s, 1H), 8.33(d, J=2.6Hz, 1H), 7.64(br t, J=7.2Hz, 1H), 7.48(br t, J =7.0Hz,1H),7.24(t,J=7.8Hz,1H),7.19-6.86(m,1H),5.35(q,J=7.0Hz,1H),3.96-3.91(m,4H),3.69 -3.63 (m, 4H), 3.57 (s, 3H), 1.68 (d, J=7.0Hz, 3H).
实施例63的合成Synthesis of Example 63
Figure PCTCN2022141536-appb-000283
Figure PCTCN2022141536-appb-000283
参考实施例10的方法制得化合物63。Compound 63 was prepared by referring to the method of Example 10.
MS:M+H +＝468； MS: M+H + = 468;
1H NMR(400MHz,CD 3OD)δ8.97(s,1H),7.73(t,J＝7.0Hz,1H),7.55(t,J＝6.8Hz,1H),7.28(t,J＝7.6Hz,1H),7.16(s,1H),5.28(m,1H),3.33-4.02(m,12H),1.61(d,J＝7.2Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ8.97(s, 1H), 7.73(t, J=7.0Hz, 1H), 7.55(t, J=6.8Hz, 1H), 7.28(t, J=7.6 Hz, 1H), 7.16(s, 1H), 5.28(m, 1H), 3.33-4.02(m, 12H), 1.61(d, J=7.2Hz, 3H).
实施例148的合成Synthesis of Example 148
Figure PCTCN2022141536-appb-000284
Figure PCTCN2022141536-appb-000284
将N-氯代丁二酰亚胺(158mg)加入63(500mg)和乙腈(10mL)中，混合物在25℃下搅拌12小时。反应液减压浓缩，粗品经高效液相色谱法(色谱柱Phenomenex luna C18(250*70mm,15um)；水相(氨水+碳酸氢钠)-乙腈]；B％:20％-50％，8分钟)纯化得到类白色固体148(5.5mg，产率41％)。N-Chlorosuccinimide (158 mg) was added to 63 (500 mg) and acetonitrile (10 mL), and the mixture was stirred at 25°C for 12 hr. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to high performance liquid chromatography (chromatographic column Phenomenex luna C18 (250*70mm, 15um); aqueous phase (ammonia+sodium bicarbonate)-acetonitrile]; B%: 20%-50%, 8 min) purification afforded 148 (5.5 mg, 41% yield) as an off-white solid.
MS:M+H +＝502； MS: M+H + = 502;
1H NMR(400MHz,CD 3OD)δ8.85(s,1H),7.71(t,J＝7.0Hz,1H),7.54(t,J＝7.2Hz,1H),7.26(t,J＝7.8Hz,1H),5.18-5.34(m,1H),3.33-3.96(m,11H),1.59(d,J＝7.0Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ8.85(s, 1H), 7.71(t, J=7.0Hz, 1H), 7.54(t, J=7.2Hz, 1H), 7.26(t, J=7.8 Hz, 1H), 5.18-5.34 (m, 1H), 3.33-3.96 (m, 11H), 1.59 (d, J=7.0Hz, 3H).
实施例150的合成Synthesis of Example 150
Figure PCTCN2022141536-appb-000285
Figure PCTCN2022141536-appb-000285
氮气保护下，148(30mg)、6-三氟甲基吡啶-3-硼酸频哪醇酯(24mg)、1,1-双(二苯基磷)二茂铁氯化钯(4mg)、乙酸钾(42mg)、二氧六环(5mL)和水(1mL)在100℃反应12小时。冷却至室温，过滤，滤液减压浓缩。粗品经高效液相色谱(色谱柱：column:Phenomenex C18 75x 30mm x 3um；流动相：水(氨水+碳酸氢铵)-乙腈；B％:40％-70％，8分钟)纯化得黄色固体150(22.8mg，收率：62.24％)。Under nitrogen protection, 148 (30mg), 6-trifluoromethylpyridine-3-boronic acid pinacol ester (24mg), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (4mg), acetic acid Potassium (42 mg), dioxane (5 mL) and water (1 mL) were reacted at 100° C. for 12 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by high performance liquid chromatography (column: Phenomenex C18 75x 30mm x 3um; mobile phase: water (ammonium bicarbonate)-acetonitrile; B%: 40%-70%, 8 minutes) to obtain a yellow solid 150 (22.8 mg, yield: 62.24%).
MS:M+H +＝613； MS: M+H + = 613;
1H NMR(400MHz,CD 3OD)δ9.04(s,1H),8.43-8.51(m,1H),7.78-7.88(m,2H),7.74(t,J＝7.2Hz, 1H),7.54(t,J＝6.8Hz,1H),7.28(t,J＝7.8Hz,1H),5.28(m,1H),3.88(br s,4H),3.32-3.34(m,2H),3.30(br s,2H),3.22(s,3H),1.61(d,J＝7.2Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ9.04(s, 1H), 8.43-8.51(m, 1H), 7.78-7.88(m, 2H), 7.74(t, J=7.2Hz, 1H), 7.54 (t,J=6.8Hz,1H),7.28(t,J=7.8Hz,1H),5.28(m,1H),3.88(br s,4H),3.32-3.34(m,2H),3.30(br s, 2H), 3.22 (s, 3H), 1.61 (d, J=7.2Hz, 3H).
实施例205的合成Synthesis of Example 205
Figure PCTCN2022141536-appb-000286
Figure PCTCN2022141536-appb-000286
中间体205-1的合成Synthesis of Intermediate 205-1
Figure PCTCN2022141536-appb-000287
Figure PCTCN2022141536-appb-000287
苄氧羰基肼(5g)、4-甲氧基苯甲醛(4.1g)和四氢呋喃(50mL)在25℃下搅拌16小时。反应液减压浓缩得到白色固体205-1(8.55g)。直接用于下一步反应。Benzyloxycarbonylhydrazine (5 g), 4-methoxybenzaldehyde (4.1 g) and tetrahydrofuran (50 mL) were stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain white solid 205-1 (8.55 g). used directly in the next reaction.
MS:M+H +＝285。 MS: M+H + =285.
中间体205-2的合成Synthesis of Intermediate 205-2
Figure PCTCN2022141536-appb-000288
Figure PCTCN2022141536-appb-000288
化合物205-1(8.55g)溶于甲醇(45mL)中，再加入氰基硼氢化钠(3.21g)和盐酸(5.01mL,12M)。混合物在25℃下搅拌16小时。用氢氧化钠溶液(6M)将反应液调至pH＝9，减压浓缩，残渣用水(50mL)稀释，二氯甲烷(50mL×3)萃取，合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，粗品采用柱层析(石油醚/乙酸乙酯＝1/0-100/1)纯化得白色固体205-2(6g)。Compound 205-1 (8.55g) was dissolved in methanol (45mL), and sodium cyanoborohydride (3.21g) and hydrochloric acid (5.01mL, 12M) were added. The mixture was stirred at 25°C for 16 hours. The reaction solution was adjusted to pH=9 with sodium hydroxide solution (6M), concentrated under reduced pressure, the residue was diluted with water (50mL), extracted with dichloromethane (50mL×3), and the organic phases were combined with saturated sodium chloride solution (50mL) Washed and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/0-100/1) to obtain 205-2 (6 g) as a white solid.
MS:M+H +＝287。 MS: M+H + =287.
中间体205-3的合成Synthesis of intermediate 205-3
Figure PCTCN2022141536-appb-000289
Figure PCTCN2022141536-appb-000289
参考实施例10的方法制得205-3。205-3 was prepared by referring to the method of Example 10.
MS:M+H +＝574。 MS: M+H + =574.
化合物205的合成Synthesis of Compound 205
Figure PCTCN2022141536-appb-000290
Figure PCTCN2022141536-appb-000290
205-3(35mg)和三氟乙酸(1mL)在80℃下搅拌12小时。冷却至室温，用氨水将反应液调至pH＝8，减压浓缩。粗品采用高效液相色谱法(色谱柱:Phenomenex C18 75*30mm*3um；流动相:水(氨水+碳酸氢铵)-乙腈；B％：30％-50％，8分钟)纯化得到黄色固体205(7.8mg，收率：28.1％)。205-3 (35 mg) and trifluoroacetic acid (1 mL) were stirred at 80°C for 12 hours. After cooling to room temperature, the reaction solution was adjusted to pH = 8 with aqueous ammonia, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 75*30mm*3um; mobile phase: water (ammonia+ammonium bicarbonate)-acetonitrile; B%: 30%-50%, 8 minutes) to obtain a yellow solid 205 (7.8 mg, yield: 28.1%).
MS:M+H +＝454； MS: M+H + =454;
1H NMR(400MHz,CD 3OD)δ8.98(s,1H),7.69(t,J＝7.2Hz,1H),7.52(t,J＝7.2Hz,1H),7.22-7.29(m,2H),5.27(q,J＝6.8Hz,1H),3.96-3.42(m,8H),1.57(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ8.98(s, 1H), 7.69(t, J=7.2Hz, 1H), 7.52(t, J=7.2Hz, 1H), 7.22-7.29(m, 2H ), 5.27 (q, J = 6.8Hz, 1H), 3.96-3.42 (m, 8H), 1.57 (d, J = 6.8Hz, 3H).
实施例219的合成Synthesis of Example 219
Figure PCTCN2022141536-appb-000291
Figure PCTCN2022141536-appb-000291
中间体219-1的合成Synthesis of Intermediate 219-1
Figure PCTCN2022141536-appb-000292
Figure PCTCN2022141536-appb-000292
将氘代碘甲烷(27.64g)加入N-Boc氨基邻苯二甲酰亚胺(10g)、苯甲基(三乙基)氯化铵(1.82g)、碳酸钾(21.08g)和无水乙腈(100mL)中，混合物在50℃下搅拌16小时。冷却至室温，过滤，滤液减压浓缩，加入200mL水，二氯甲烷(200mL×3)萃取，合并有机相，饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，粗品通过柱层析法(石油醚/乙酸乙酯＝3/1 to 1/1)纯化得到类白色固体219-1(9.3g,收率：87.3％)。Deuteroiodomethane (27.64 g) was added to N-Boc aminophthalimide (10 g), benzyl (triethyl) ammonium chloride (1.82 g), potassium carbonate (21.08 g) and anhydrous In acetonitrile (100 mL), the mixture was stirred at 50°C for 16 hours. Cool to room temperature, filter, concentrate the filtrate under reduced pressure, add 200 mL of water, extract with dichloromethane (200 mL×3), combine organic phases, wash with saturated sodium chloride solution (200 mL), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to 1/1) to obtain off-white solid 219-1 (9.3g, yield: 87.3%).
1H NMR(400MHz,DMSO-d6)δ7.91-8.00(m,4H)，1.24-1.47(m,9H)。 1 H NMR (400 MHz, DMSO-d6) δ 7.91-8.00 (m, 4H), 1.24-1.47 (m, 9H).
中间体219-2的合成Synthesis of Intermediate 219-2
Figure PCTCN2022141536-appb-000293
Figure PCTCN2022141536-appb-000293
化合物219-1(9.3g)、水合肼(2.55g)和四氢呋喃(100mL)在25℃下搅拌2小时。过滤，滤饼用乙酸乙酯(100mL)冲洗，滤液用饱和氯化钠溶液(20mL)洗涤，有机相无水硫酸钠干燥。过滤，滤液减压浓缩，粗品通过柱层析法(石油醚/乙酸乙酯＝1/1)纯化得到黄色油状物219-2(3.33g，收率：67.03％)。Compound 219-1 (9.3 g), hydrazine hydrate (2.55 g) and tetrahydrofuran (100 mL) were stirred at 25°C for 2 hours. After filtering, the filter cake was washed with ethyl acetate (100 mL), the filtrate was washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/1) to obtain yellow oil 219-2 (3.33 g, yield: 67.03%).
中间体219-3的合成Synthesis of Intermediate 219-3
Figure PCTCN2022141536-appb-000294
Figure PCTCN2022141536-appb-000294
将氯甲酸苄酯(3.81g)加入化合物219-2(3.33g)、氢氧化钠(1.18g)和无水二氯甲烷(33mL)中，混合物在20℃搅拌1小时。反应液中加入水(20mL)，二氯甲烷(20mL×3)萃取，合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，得到白色固体219-3(4.52g)，直接用于下一步反应。Benzyl chloroformate (3.81 g) was added to compound 219-2 (3.33 g), sodium hydroxide (1.18 g) and anhydrous dichloromethane (33 mL), and the mixture was stirred at 20° C. for 1 hr. Water (20 mL) was added to the reaction solution, extracted with dichloromethane (20 mL×3), the combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain white solid 219-3 (4.52 g), which was directly used in the next reaction.
中间体219-4的合成Synthesis of Intermediate 219-4
Figure PCTCN2022141536-appb-000295
Figure PCTCN2022141536-appb-000295
化合物219-3(4.52g)、氯化氢-1,4-二氧六环溶液(24.7mL)和二氯甲烷(45mL)在20℃下反应2小时。减压浓缩得到白色固体219-4(3.5g)。Compound 219-3 (4.52 g), hydrogen chloride-1,4-dioxane solution (24.7 mL) and dichloromethane (45 mL) were reacted at 20° C. for 2 hours. Concentration under reduced pressure gave white solid 219-4 (3.5 g).
MS:M+H +＝184。 MS: M+H + =184.
化合物219的合成Synthesis of compound 219
Figure PCTCN2022141536-appb-000296
Figure PCTCN2022141536-appb-000296
参考实施例10的合成方法制得219。Referring to the synthetic method of Example 10, 219 was prepared.
MS:M+H +＝471； MS: M+H + =471;
1H NMR(400MHz,CD 3OD)δ8.97(s,1H),7.73(t,J＝7.0Hz,1H),7.55(br t,J＝7.0Hz,1H),7.28(t,J＝7.8Hz,1H),7.17(s,1H),5.28(q,J＝7.2Hz,1H),3.90(br s,8H),1.61(d,J＝7.0Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ8.97(s, 1H), 7.73(t, J=7.0Hz, 1H), 7.55(br t, J=7.0Hz, 1H), 7.28(t, J= 7.8Hz, 1H), 7.17(s, 1H), 5.28(q, J=7.2Hz, 1H), 3.90(br s, 8H), 1.61(d, J=7.0Hz, 3H).
以上述同样方法合成如下实施例。The following examples were synthesized in the same manner as above.
Figure PCTCN2022141536-appb-000297
Figure PCTCN2022141536-appb-000297
Figure PCTCN2022141536-appb-000298
Figure PCTCN2022141536-appb-000298
Figure PCTCN2022141536-appb-000299
Figure PCTCN2022141536-appb-000299
Figure PCTCN2022141536-appb-000300
Figure PCTCN2022141536-appb-000300
Figure PCTCN2022141536-appb-000301
Figure PCTCN2022141536-appb-000301
Figure PCTCN2022141536-appb-000302
Figure PCTCN2022141536-appb-000302
Figure PCTCN2022141536-appb-000303
Figure PCTCN2022141536-appb-000303
Figure PCTCN2022141536-appb-000304
Figure PCTCN2022141536-appb-000304
Figure PCTCN2022141536-appb-000305
Figure PCTCN2022141536-appb-000305
Figure PCTCN2022141536-appb-000306
Figure PCTCN2022141536-appb-000306
Figure PCTCN2022141536-appb-000307
Figure PCTCN2022141536-appb-000307
Figure PCTCN2022141536-appb-000308
Figure PCTCN2022141536-appb-000308
Figure PCTCN2022141536-appb-000309
Figure PCTCN2022141536-appb-000309
Figure PCTCN2022141536-appb-000310
Figure PCTCN2022141536-appb-000310
Figure PCTCN2022141536-appb-000311
Figure PCTCN2022141536-appb-000311
Figure PCTCN2022141536-appb-000312
Figure PCTCN2022141536-appb-000312
Figure PCTCN2022141536-appb-000313
Figure PCTCN2022141536-appb-000313
Figure PCTCN2022141536-appb-000314
Figure PCTCN2022141536-appb-000314
Figure PCTCN2022141536-appb-000315
Figure PCTCN2022141536-appb-000315
Figure PCTCN2022141536-appb-000316
Figure PCTCN2022141536-appb-000316
Figure PCTCN2022141536-appb-000317
Figure PCTCN2022141536-appb-000317
Figure PCTCN2022141536-appb-000318
Figure PCTCN2022141536-appb-000318
Figure PCTCN2022141536-appb-000319
Figure PCTCN2022141536-appb-000319
Figure PCTCN2022141536-appb-000320
Figure PCTCN2022141536-appb-000320
Figure PCTCN2022141536-appb-000321
Figure PCTCN2022141536-appb-000321
Figure PCTCN2022141536-appb-000322
Figure PCTCN2022141536-appb-000322
Figure PCTCN2022141536-appb-000323
Figure PCTCN2022141536-appb-000323
Figure PCTCN2022141536-appb-000324
Figure PCTCN2022141536-appb-000324
Figure PCTCN2022141536-appb-000325
Figure PCTCN2022141536-appb-000325
Figure PCTCN2022141536-appb-000326
Figure PCTCN2022141536-appb-000326
Figure PCTCN2022141536-appb-000327
Figure PCTCN2022141536-appb-000327
Figure PCTCN2022141536-appb-000328
Figure PCTCN2022141536-appb-000328
Figure PCTCN2022141536-appb-000329
Figure PCTCN2022141536-appb-000329
Figure PCTCN2022141536-appb-000330
Figure PCTCN2022141536-appb-000330
Figure PCTCN2022141536-appb-000331
Figure PCTCN2022141536-appb-000331
Figure PCTCN2022141536-appb-000332
Figure PCTCN2022141536-appb-000332
Figure PCTCN2022141536-appb-000333
Figure PCTCN2022141536-appb-000333
Figure PCTCN2022141536-appb-000334
Figure PCTCN2022141536-appb-000334
Figure PCTCN2022141536-appb-000335
Figure PCTCN2022141536-appb-000335
Figure PCTCN2022141536-appb-000336
Figure PCTCN2022141536-appb-000336
Figure PCTCN2022141536-appb-000337
Figure PCTCN2022141536-appb-000337
Figure PCTCN2022141536-appb-000338
Figure PCTCN2022141536-appb-000338
Figure PCTCN2022141536-appb-000339
Figure PCTCN2022141536-appb-000339
Figure PCTCN2022141536-appb-000340
Figure PCTCN2022141536-appb-000340
Figure PCTCN2022141536-appb-000341
Figure PCTCN2022141536-appb-000341
Figure PCTCN2022141536-appb-000342
Figure PCTCN2022141536-appb-000342
Figure PCTCN2022141536-appb-000343
Figure PCTCN2022141536-appb-000343
Figure PCTCN2022141536-appb-000344
Figure PCTCN2022141536-appb-000344
Figure PCTCN2022141536-appb-000345
Figure PCTCN2022141536-appb-000345
生物活性试验Biological activity test
1.KRAS G12C GDP::SOS1均相时间分辨荧光结合实验1. KRAS G12C GDP::SOS1 homogeneous time-resolved fluorescence binding experiment
通过均相时间分辨荧光技术来测定蛋白-蛋白之间的相互作用。在ProxiPlate-384 Plus反应板(PerkinElmer，6008280)中，加入0.1微升的化合物，离心后，加入5微升的GST-KRAS G12C(aa 1-169)蛋白和终浓度10μM的GDP(SIGMA,G7127)混合液。再加入5微升的His-SOS1(aa 564-1049)蛋白溶液，室温反应15分钟。所有的蛋白相互作用均发生在含有50mM HEPES(Life Technologies，15630-080),150mM NaCl(Sigma，S5886),0.05％BSA(sigma，A1933)的缓冲溶液中。加入10微升预混的100X的Ab Anti-6HIS Tb cryptate Gold(Cisbio，61HI2TLA)和25X的MAb Anti GST-XL665(cisbio，61GSTXLA)检测溶液，25℃反应60分钟。通过多功能微孔酶标仪检测反应信号，使用GraphPad Prism数据分析软件中非线性拟合公式方程(四参数)分析数据计算半数抑制浓度IC 50。 Protein-protein interactions are measured by homogeneous time-resolved fluorescence techniques. In the ProxiPlate-384 Plus reaction plate (PerkinElmer, 6008280), add 0.1 μl of the compound, after centrifugation, add 5 μl of GST-KRAS G12C (aa 1-169) protein and a final concentration of 10 μM GDP (SIGMA, G7127 ) mixture. Add 5 microliters of His-SOS1 (aa 564-1049) protein solution and react at room temperature for 15 minutes. All protein interactions occurred in a buffer solution containing 50 mM HEPES (Life Technologies, 15630-080), 150 mM NaCl (Sigma, S5886), 0.05% BSA (sigma, A1933). Add 10 microliters of premixed 100X Ab Anti-6HIS Tb cryptate Gold (Cisbio, 61HI2TLA) and 25X MAb Anti GST-XL665 (cisbio, 61GSTXLA) detection solution, and react at 25°C for 60 minutes. The reaction signal was detected by a multi-functional microplate reader, and the half maximal inhibitory concentration IC 50 was calculated using the nonlinear fitting formula equation (four parameters) in the GraphPad Prism data analysis software to analyze the data.
2.H358细胞的3D增殖实验2. 3D proliferation experiment of H358 cells
BI-3406作为SOS1::KRAS抑制剂，被用来作为阳性化合物。BI-3406, a SOS1::KRAS inhibitor, was used as a positive compound.
Figure PCTCN2022141536-appb-000346
Figure PCTCN2022141536-appb-000346
利用纳升移液系统(LABCYTE,P-0200)将稀释好的待测化合物加入384孔细胞培养板(Corning,LS3830-50EA)中,铺入H358细胞后，将培养板放置于37℃，5％CO 2恒温培养箱。化合物与细胞共孵育7天后，加入
Figure PCTCN2022141536-appb-000347
3D试剂(Promega,9683),用Envision多功能酶标仪读取发光值(光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数)。最后使用XLFIT软件用非线性拟合公式得化合物的IC 50(半数抑制浓度)。 Add the diluted compound to be tested into a 384-well cell culture plate (Corning, LS3830-50EA) using a nanoliter pipetting system (LABCYTE, P-0200). After spreading H358 cells, place the culture plate at 37°C for 5 % CO2 constant temperature incubator. After the compound was co-incubated with the cells for 7 days, the
Figure PCTCN2022141536-appb-000347
3D reagent (Promega, 9683), read the luminescence value with Envision multifunctional microplate reader (the light signal is directly proportional to the amount of ATP in the system, and the content of ATP directly represents the number of living cells in the system). Finally, XLFIT software was used to obtain the IC 50 (half maximal inhibitory concentration) of the compound with a nonlinear fitting formula.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)×HillSlope)) Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)×HillSlope))
X：化合物浓度log值X: log value of compound concentration
Y：抑制率(％)Y: inhibition rate (%)
抑制率(％)＝100×(阴性对照平均值-化合物读值)/(阴性对照平均值-阳性对照平均值)Inhibition rate (%)=100×(negative control average value-compound reading value)/(negative control average value-positive control average value)
阴性对照：DMSONegative control: DMSO
阳性对照：Medium onlyPositive control: Medium only
表1：化合物的体外细胞学活性结果Table 1: In vitro cytological activity results of compounds
Figure PCTCN2022141536-appb-000348
Figure PCTCN2022141536-appb-000348
Figure PCTCN2022141536-appb-000349
Figure PCTCN2022141536-appb-000349
Figure PCTCN2022141536-appb-000350
Figure PCTCN2022141536-appb-000350
Figure PCTCN2022141536-appb-000351
Figure PCTCN2022141536-appb-000351
3.人肝微粒体中代谢稳定性的研究3. Study on metabolic stability in human liver microsomes
微粒体保存于-80℃冰箱，使用之前先于37℃水浴中融化，溶化后放置于冰上待用。其他试剂均通过本地供应商购买。The microsomes were stored in a -80°C refrigerator, and melted in a 37°C water bath before use, and placed on ice after melting. All other reagents were purchased through local suppliers.
将反应体系放在37℃水浴中预孵育10分钟。向反应体系中加入40μL 10mM NADPH溶液，NADPH的最终浓度分别为1mM。用40μL超纯水代替NADPH溶液作为阴性对照。在反应中加入4μL的100μM的待测化合物和对照药启动反应，药物的最终浓度为1μM。在0，15，30，45和60分钟分别取出50μL反应样品，用4倍的含有内标(200nM阿普唑仑、200nM拉贝洛尔、2μM酮洛芬、200nM咖啡因)的冷乙腈淬灭。样品在3,220g转速下离心45分钟。离心完成后取90μL上清液和90μL超纯水混匀用于LC-MS/MS分析检测。The reaction system was pre-incubated in a 37°C water bath for 10 minutes. Add 40 μL of 10 mM NADPH solution to the reaction system, and the final concentration of NADPH is 1 mM respectively. Replace the NADPH solution with 40 μL of ultrapure water as a negative control. Add 4 μL of 100 μM test compound and control drug to the reaction to start the reaction, and the final concentration of the drug is 1 μM. Take 50 μL reaction samples at 0, 15, 30, 45 and 60 minutes respectively, quench with 4 times cold acetonitrile containing internal standard (200nM alprazolam, 200nM labetalol, 2μM ketoprofen, 200nM caffeine) off. Samples were centrifuged at 3,220g for 45 minutes. After centrifugation, take 90 μL of supernatant and 90 μL of ultrapure water and mix well for LC-MS/MS analysis and detection.
所有的数据计算均通过Microsoft Excel软件进行。通过提取离子图谱检测峰面积。通过对母药的消失百分比与时间进行线性拟合，检测母药的体外半衰期(t1/2)。All data calculations were performed by Microsoft Excel software. Peak areas were detected by extracted ion spectra. The in vitro half-life (t1/2) of the parent drug was detected by linear fitting the percent disappearance of the parent drug with time.
体外(t1/2)通过斜率计算：In vitro (t1/2) is calculated by the slope:
体外t 1/2＝-(0.693/k) In vitro t 1/2 = -(0.693/k)
用下列公式把体外(t1/2)转化为体外清除率(单位μL/min/mg)：Use the following formula to convert in vitro (t1/2) into in vitro clearance rate (unit μL/min/mg):
Figure PCTCN2022141536-appb-000352
Figure PCTCN2022141536-appb-000352
以人Scaling Factor 1254.2进行计算Scale-up ClintCalculate Scale-up Clint with Human Scaling Factor 1254.2
测试化合物在混合人肝微粒体中代谢稳定性结果见下表。The metabolic stability results of the test compounds in mixed human liver microsomes are shown in the table below.
实施例编号Example number 体外T 1/2(min) In vitro T 1/2 (min) Scale-up Clint(mL/min/kg)Scale-up Clint(mL/min/kg)
77 411.33411.33 4.234.23
1111 384.61384.61 4.524.52
3939 536.10536.10 3.243.24
4.人肝细胞代谢稳定性的研究4. Study on the metabolic stability of human hepatocytes
将人肝活细胞的混悬液转移到96孔板，预热10分钟。Transfer the suspension of live human liver cells to a 96-well plate and preheat for 10 minutes.
每孔加入2μL 100μM受试物或维拉帕米进行反应起始，孵育样品，分别于0、15、30、60、90和120分钟，取25μL混悬液，加入150μL含内标的乙腈(200nM阿普唑仑、200nM拉贝洛尔、2μM酮洛芬、200nM咖啡因)终止反应。涡旋10分钟，离心30分后取上清液和超纯水混匀用于UPLC-MS/MS分析检测。Add 2 μL of 100 μM test substance or verapamil to each well to initiate the reaction, incubate the samples, and take 25 μL suspension at 0, 15, 30, 60, 90 and 120 minutes, add 150 μL of acetonitrile (200 nM Alprazolam, 200 nM labetalol, 2 μM ketoprofen, 200 nM caffeine) terminate the reaction. Vortex for 10 minutes, centrifuge for 30 minutes, take the supernatant and mix with ultrapure water for UPLC-MS/MS analysis and detection.
所有的数据计算均通过Microsoft Excel软件进行。通过提取离子图谱检测峰面积。通过对母药消除百分比的自然对数与时间进行线性拟合，检测母药的体外半衰期(t 1/2)，计算Scale-up Clint All data calculations were performed by Microsoft Excel software. Peak areas were detected by extracted ion spectra. The in vitro half-life (t 1/2 ) of the parent drug is detected by linear fitting of the natural logarithm of the parent drug elimination percentage and time, and the Scale-up Clint is calculated
测试化合物在混合人肝微粒体中代谢稳定性结果见下表。The metabolic stability results of the test compounds in mixed human liver microsomes are shown in the table below.
实施例编号Example number Scale-up Clint(mL/min/kg)Scale-up Clint(mL/min/kg)
4444 7.07.0
5959 低于检测限below detection limit
6363 5.55.5
219219 低于检测限below detection limit
5.hERG钾离子通道的安全性评估5. Safety assessment of hERG potassium channel
稳定表达hERG离子通道的HEK293细胞株购自Invitrogen公司。该细胞株被培养消化，接种在玻片上以备后续的手动膜片钳的实验。HEK293 cell lines stably expressing hERG ion channels were purchased from Invitrogen. The cell line was cultured and digested, and seeded on glass slides for subsequent manual patch clamp experiments.
待测化合物用DMSO溶解并配制成终浓度为10mM的储备液。将储备液以DMSO为溶剂以1:3比例梯度稀释成其他三个中间浓度溶液，浓度分别为(mM)：3.33，1.11和0.37。实验开始前，用细胞外液将待测化合物梯度中间溶液再次按1：1000的比例稀释成一系列浓度的工作溶液，其终浓度分 别为(M)：10，3.33，1.11和0.37，而30M工作液由10mM储液稀释333.33倍而成。DMSO在工作溶液中的含量为0.1-0.3％(体积比)。5个不同浓度梯度30，10，3.33，1.11和0.37M的工作溶液用于测定化合物对hERG通道的潜在抑制作用并用以拟合量效曲线和计算IC 50。 The compounds to be tested were dissolved in DMSO and prepared as stock solutions with a final concentration of 10 mM. The stock solution was diluted with DMSO as a solvent at a ratio of 1:3 to other three intermediate concentration solutions, the concentrations were (mM): 3.33, 1.11 and 0.37. Before the start of the experiment, dilute the gradient intermediate solution of the compound to be tested into a series of working solutions at a ratio of 1:1000 with extracellular fluid, and the final concentrations are (M): 10, 3.33, 1.11 and 0.37, and 30M working solution The solution was prepared by diluting 10mM stock solution 333.33 times. The content of DMSO in the working solution is 0.1-0.3% (volume ratio). Five working solutions with different concentration gradients of 30, 10, 3.33, 1.11 and 0.37 M were used to determine the potential inhibitory effect of the compound on hERG channel and to fit the dose-effect curve and calculate the IC 50 .
将培养皿中载有HEK293细胞的小玻片放置于显微操作台的灌流槽中。在Olympus IX51，IX71或IX73倒置显微镜下将合适的细胞调置于视野中央，使用×10倍物镜找到玻璃电极的尖端，并置于视野的中央。然后使用微操纵器下移电极，同时调整粗准焦螺旋，使电极慢慢接近细胞。当快接近细胞时，转换为×40倍物镜进行观察，通过微操纵器微调档，使电极逐渐接近细胞的表面。给予负压，使电极尖与细胞膜之间形成电阻高于1G的封接。在电压钳模式下对瞬时电容电流Cfast进行补偿。然后重复给予短促的负压进行破膜，最终形成全细胞记录模式。在膜电位钳制于-60mV的条件下，对缓慢电容电流Cslow，细胞膜电容(Cm)和输入膜电阻(Ra)分别进行补偿。细胞稳定后，将钳制电压改为-90mV，采样频率设置为20kHz，过滤频率为10kHz。漏电流的检测条件为钳制电压转为-80mV，时程500ms。Place the small slides loaded with HEK293 cells in the culture dish in the perfusion tank of the micromanipulator. Place the appropriate cell in the center of the field of view under an Olympus IX51, IX71 or IX73 inverted microscope, use the ×10 objective lens to find the tip of the glass electrode, and place it in the center of the field of view. Then use the micromanipulator to move the electrode down while adjusting the coarse focus helix so that the electrode slowly approaches the cell. When it is close to the cell, switch to a ×40 objective lens for observation, and fine-tune the gear through the micromanipulator to make the electrode gradually approach the surface of the cell. Apply negative pressure to form a seal with a resistance higher than 1G between the electrode tip and the cell membrane. The instantaneous capacitive current Cfast is compensated in voltage clamp mode. Then repeated brief negative pressure was applied to permeate the membrane, and finally the whole-cell recording mode was formed. Under the condition that the membrane potential was clamped at -60mV, the slow capacitive current Cslow, cell membrane capacitance (Cm) and input membrane resistance (Ra) were compensated respectively. After the cells are stable, change the clamping voltage to -90mV, set the sampling frequency to 20kHz, and filter frequency to 10kHz. The detection condition of the leakage current is that the clamping voltage is changed to -80mV, and the duration is 500ms.
hERG电流测试方法如下：施加4.8秒去极化命令电压将膜电位从-80mV去极化至+30mV，然后瞬间施加5.2秒的复极化电压使膜电位降至-50mV以去除通道失活，从而得以观察到hERG尾电流。尾电流的峰值为hERG电流的大小。The hERG current test method is as follows: apply a depolarization command voltage for 4.8 seconds to depolarize the membrane potential from -80mV to +30mV, and then apply a repolarization voltage for 5.2 seconds to reduce the membrane potential to -50mV to remove channel inactivation, Thus, the hERG tail current can be observed. The peak value of the tail current is the magnitude of the hERG current.
用于检测待测化合物的hERG电流在给药前均被持续记录120秒以评估受试细胞产生hERG电流的稳定性。只有在评价标准接受范围以内的稳定细胞才能进入后续化合物检测。The hERG current used to detect the test compound was continuously recorded for 120 seconds before administration to evaluate the stability of the hERG current produced by the test cells. Only stable cells within the acceptance range of the evaluation criteria can enter the subsequent compound detection.
待测化合物对hERG电流抑制作用的测试：首先将在含0.1％DMSO的细胞外液中测定得到的hERG电流作为检测基线。在hERG电流保持稳定至少5分钟后将含有待测化合物的溶液从低浓度到高浓度依次灌注于细胞周围。每次灌流结束后等待约5分钟以使化合物充分作用于细胞并同步记录hERG电流。待记录电流趋于稳定后记录最后5个hERG电流值，并取其平均值作为其最终在特定浓度下的电流值。在测试完化合物后，加入150nM多菲莱德至同一个细胞上，将其电流完全抑制，作为该细胞的阳性对照。同时，阳性化合物多菲莱德在测试药实验结束前后用同一膜片钳系统进行同步检测，以确保整个检测系统的可靠性和灵敏性。Test of the inhibitory effect of the test compound on hERG current: firstly, the hERG current measured in the extracellular fluid containing 0.1% DMSO was used as the detection baseline. After the hERG current remained stable for at least 5 minutes, the solutions containing the compound to be tested were perfused sequentially around the cells from low to high concentrations. Wait about 5 minutes after each perfusion to allow the compound to fully act on the cells and simultaneously record the hERG current. After the recorded current tends to be stable, record the last 5 hERG current values, and take the average value as the final current value at a specific concentration. After testing the compound, add 150nM dofferin to the same cell to completely inhibit the current, which is used as the positive control of the cell. At the same time, the positive compound Dophilaide was detected synchronously with the same patch clamp system before and after the end of the test drug experiment to ensure the reliability and sensitivity of the entire detection system.
灌注空白溶剂或化合物梯度溶液后，稳定得到的5个连续电流值，求取平均值，分别作为“尾电流大小 空白”和“尾电流大小 化合物”。 After perfusing the blank solvent or compound gradient solution, stabilize the obtained 5 continuous current values, calculate the average value, and use them as the "tail current size blank " and "tail current size compound ".
电流抑制百分率通过以下公式进行计算。The percent current inhibition is calculated by the following formula.
Figure PCTCN2022141536-appb-000353
Figure PCTCN2022141536-appb-000353
量效曲线通过Graphpad Prism 8.0软件进行拟合并计算IC 50值。 The dose-response curve was fitted by Graphpad Prism 8.0 software and the IC50 value was calculated.
实施例Example hERG IC 50[μM] hERG IC50 [μM]
4444 26.426.4
5959 21.221.2
6363 17.017.0
6.口服后雄性CD1小鼠体内的药代动力学实验6. Pharmacokinetic experiment in male CD1 mice after oral administration
雄性CD1小鼠在给药前禁食过夜，自由饮水，给药4小时后给予饲料。给药剂量10mg/kg，体积10mL/kg，采用口服给药。样品以5％DMSO/95％“10％HP-β-CD in water”配制。Male CD1 mice were fasted overnight before administration, had free access to water, and were given feed 4 hours after administration. The dosage is 10mg/kg, the volume is 10mL/kg, and it is administered orally. Samples were prepared with 5% DMSO/95% "10% HP-β-CD in water".
采用足背静脉取血，时间点为0.25、0.5、1、2、4、8和24小时。每次取血30μL，置于含有EDTA- K2的抗凝管中颠倒数次充分混匀。全血样品在4℃，4000g条件下离心5分钟分离血浆。血浆样品分装至干净的聚乙烯微量离心管中，然后置于-75±15℃冰箱保存直至分析。Blood was collected from the dorsal foot vein at 0.25, 0.5, 1, 2, 4, 8 and 24 hours. Take 30 μL of blood each time, put it in an anticoagulant tube containing EDTA-K2 and invert several times to mix well. Whole blood samples were centrifuged at 4000g for 5 minutes at 4°C to separate plasma. Plasma samples were dispensed into clean polyethylene microcentrifuge tubes and stored in a -75±15°C refrigerator until analysis.
应用LC-MS/MS检测方法，对血浆测定结果，将用WinNonlin 8.3(PhoenixTM)或其它类似软件进行药代动力学参数计算。Apply the LC-MS/MS detection method, and use WinNonlin 8.3 (PhoenixTM) or other similar software to calculate the pharmacokinetic parameters for the plasma measurement results.
实施例化合物的口服(10mg/kg)药代动力学参数表The oral (10mg/kg) pharmacokinetic parameter table of embodiment compound
Figure PCTCN2022141536-appb-000354
Figure PCTCN2022141536-appb-000354
7.化合物对细胞色素P450酶CYP3A时间依赖性抑制作用研究7. Study on the time-dependent inhibitory effect of compounds on cytochrome P450 enzyme CYP3A
混合人肝微粒体(Cat.452117)从BD(Corning)购买，微粒体储存在-80℃备用，96圆形深井板(P-DW-11-C)从Axygen购买。其他试剂通过当地供应商购买。Mixed human liver microsomes (Cat.452117) were purchased from BD (Corning), and the microsomes were stored at -80°C for future use. 96 round deep well plates (P-DW-11-C) were purchased from Axygen. Other reagents were purchased through local suppliers.
整个孵育过程将于96孔深孔板中进行。先在深孔板中加入169μL孵育体系，之后再加入1μL待测化合物或对照药的不同浓度的工作液或空白对照。先将孵育体系于37℃预热5分钟。The entire incubation process will be carried out in 96-well deep-well plates. First add 169 μL of incubation system to the deep well plate, and then add 1 μL of working solutions of different concentrations of the compound to be tested or control drug or blank control. Preheat the incubation system at 37°C for 5 minutes.
对于0分钟预孵育组，先加入10μL底物工作液，然后通过加入20μL浓度为10mM的NADPH溶液来起始反应。在37℃水浴中进行对应时间的孵育。孵育结束后加入400μL含内标的冷甲醇(500nM拉贝洛尔,100nM阿普唑仑和2μM酮洛芬)终止反应。For the 0 min pre-incubation group, 10 μL of substrate working solution was added first, and then the reaction was initiated by adding 20 μL of 10 mM NADPH solution. Incubate for the corresponding time in a 37°C water bath. After incubation, 400 μL of cold methanol containing internal standard (500 nM labetalol, 100 nM alprazolam and 2 μM ketoprofen) was added to stop the reaction.
对于30分钟预孵育加NADPH组，加入20μL浓度为10mM的NADPH溶液于37℃进行30分钟孵育。孵育结束后加入10μL底物工作液继续进行对应时间的孵育。孵育结束后加入400μL含内标的冷甲醇(500nM拉贝洛尔,100nM阿普唑仑和2μM酮洛芬)终止反应。For the 30-minute pre-incubation plus NADPH group, add 20 μL of 10 mM NADPH solution and incubate at 37°C for 30 minutes. After the incubation, 10 μL of substrate working solution was added to continue the incubation for the corresponding time. After incubation, 400 μL of cold methanol containing internal standard (500 nM labetalol, 100 nM alprazolam and 2 μM ketoprofen) was added to stop the reaction.
对于30分钟预孵育不加NADPH组，将170μL含药的孵育体系于37℃进行30分钟孵育，孵育结束后加入10μL底物工作液和20μL浓度为10mM的NADPH溶液继续进行对应时间的孵育。孵育结束后加入400μL含内标的冷甲醇(500nM拉贝洛尔,100nM阿普唑仑和2μM酮洛芬)终止反应。For the 30-minute pre-incubation without NADPH group, 170 μL of the drug-containing incubation system was incubated at 37°C for 30 minutes. After the incubation, 10 μL of substrate working solution and 20 μL of 10 mM NADPH solution were added to continue incubation for the corresponding time. After incubation, 400 μL of cold methanol containing internal standard (500 nM labetalol, 100 nM alprazolam and 2 μM ketoprofen) was added to stop the reaction.
反应体系终止后涡旋混匀，将深孔板于3220g、4℃离心50分钟。转移100μL上清液到新板子上，加入100μL纯水混匀。After the reaction system was terminated, vortex mixed, and the deep-well plate was centrifuged at 3220g, 4°C for 50 minutes. Transfer 100 μL supernatant to a new plate, add 100 μL pure water and mix well.
生成的代谢产物用LC-MS/MS分析。使用Prism 8.0.2软件(Graphpad)计算三个IC 50值(0分钟预孵育，30分钟预孵育有NADPH,30分钟预孵育无NADPH)，将不同条件下不同抑制剂浓度下的酶活性百分比平均值对抑制剂浓度的对数进行IC 50曲线拟合。IC 50的偏移用于评估抑制机制。 The resulting metabolites were analyzed by LC-MS/MS. Three IC50 values (0 min pre-incubation, 30 min pre-incubation with NADPH, 30 min pre-incubation without NADPH) were calculated using Prism 8.0.2 software (Graphpad), and the percentage of enzyme activity at different inhibitor concentrations under different conditions was averaged Values were fitted to the IC50 curve against the logarithm of the inhibitor concentration. The shift in IC50 was used to assess the mechanism of inhibition.
三个化合物预孵育后，IC 50均大于30μM。 After pre-incubation of the three compounds, the IC 50 was greater than 30 μM.
实施例Example IC 50[μM] IC50 [μM]
4444 40.540.5
5959 38.838.8
6363 50+50+
8.化合物在小鼠Mia Paca-2异种肿瘤移植模型上的研究8. Research of compounds on mouse Mia Paca-2 xenograft tumor transplantation model
BALB/c nude小鼠，于后侧背部皮下接种5×106细胞，接种后定期观察肿瘤生长情况，待肿瘤生长至平均体积约150mm 3时根据肿瘤大小和小鼠体重随机分组给药。 BALB/c nude mice were subcutaneously inoculated with 5×106 cells on the back of the back, and the tumor growth was observed regularly after inoculation. When the tumors grew to an average volume of about 150mm 3 , they were randomly divided into groups according to the tumor size and the weight of the mice.
开始给药后，每周测量两次小鼠的体重和肿瘤的大小。肿瘤体积计算公式：肿瘤体积(mm 3)＝1/2×(a×b 2)(其中a表示长径，b表示短径)。 After the start of dosing, the body weight and tumor size of the mice were measured twice a week. Tumor volume calculation formula: tumor volume (mm 3 )=1/2×(a×b 2 ) (where a represents the long diameter and b represents the short diameter).
以肿瘤抑制率评估药效，TGI(％)，计算公式如下：TGI％＝(1-(T-T0)/(C-C0))×100％。T和C分别为治疗组和对照组在某一特定时间点的平均肿瘤体积。T0与C0分别为开始给药时，治疗组和对照组的平均肿瘤体积。The drug efficacy was evaluated by tumor inhibition rate, TGI (%), and the calculation formula was as follows: TGI%=(1-(T-T0)/(C-C0))×100%. T and C are the mean tumor volumes of the treatment group and the control group at a specific time point, respectively. T0 and C0 are the average tumor volumes of the treatment group and the control group at the beginning of administration, respectively.
对化合物44、59、63进行体内药效研究。在BID 10-30mg/kg的口服剂量下，TGI为40-99％，呈现剂量依赖性关系，且具有统计学差异。Compounds 44, 59, and 63 were studied in vivo. At the oral dose of BID 10-30mg/kg, TGI is 40-99%, presenting a dose-dependent relationship with statistical differences.

Claims (67)

  1. 式(X)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：A compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
    Figure PCTCN2022141536-appb-100001
    Figure PCTCN2022141536-appb-100001
    其中：in:
    环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
    环B选自
    Figure PCTCN2022141536-appb-100002
    Ring B selected from
    Figure PCTCN2022141536-appb-100002
    R 1、R 2、R 3和R 4独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 0-2R、-S(O)(NR)R’、-P(O)RR’或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O) R, -C(O)OR, -C(O)NRR', -S(O) 0-2 R, -S(O)(NR)R', -P(O)RR', or -N=S (O)RR';
    或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
    其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R#选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring groups formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
    R 5选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其可任选地被OH、-NH 2或-CN取代； R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
    R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
    Z 1为N、NR Z1a、CR Z1b或CR Z1bR Z1c； Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为N、NR Z3a、CR Z3b或CR Z3bR Z3c； Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
    R Z1a、R Z2a和R Z3a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
    R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、5-6元杂芳基或C 6-10芳基；或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 5-6环烷基或5-6元杂环基，其任选地被1、2或3个Rx取代；或者两个R*连接形成C 1-4亚烷基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 Heteroaryl or C 6-10 aryl; or two R* on the same or different carbon atoms and the atoms they connect together form C=O, C=S, C 5-6 cycloalkyl or 5-6 A membered heterocyclic group, which is optionally substituted by 1, 2 or 3 Rx; or two R* are connected to form C 1-4 alkylene;
    Rx选自C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR、-C 0-6亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 3-6环烷基或4-6元杂环基； Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
    R X1b、R X2b独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
    R Z3b选自H、D、卤素、-NR aR b、-OR a、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代； R Z3b is selected from H, D, halogen, -NR a R b , -OR a , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , -LC 3-6 cycloalkyl, -L-4-6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, optionally replaced by 1, 2 or 3 R s replaces;
    L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
    R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
    R s选自CN、OR、C 1-6烷基、C 1-6卤代烷基、S(O)R或S(O) 2R，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R s is selected from CN, OR, C 1-6 alkyl, C 1-6 haloalkyl, S(O)R or S(O) 2 R, or two adjacent R s on the same carbon atom together form C =O or C=S, optionally substituted by D, up to complete deuteration;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    R Z3c选自H或化学键； R Z3c is selected from H or a chemical bond;
    或者R Z1a和R Z2c、R Z1a和R Z2a、R Z2a和R Z1c、R Z1c和R Z2c、R Z2a和R Z3a、R Z2a和R Z3c、R Z2c和R Z3a、R Z2c和R Z3c可以结合形成双键； Or R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
    R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  2. 式(X)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：A compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
    Figure PCTCN2022141536-appb-100003
    Figure PCTCN2022141536-appb-100003
    其中：in:
    环A表示苯基或5-6元杂芳基；Ring A represents phenyl or 5-6 membered heteroaryl;
    环B选自
    Figure PCTCN2022141536-appb-100004
    Ring B selected from
    Figure PCTCN2022141536-appb-100004
    R 1、R 2、R 3和R 4独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-OR、-NRR’、-C(O)R、-C(O)OR、-C(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、-P(O)RR’、-S(O) 0-2R或-N＝S(O)RR’； R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -NRR', -C(O) R, -C(O)OR, -C(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', -P(O)RR', -S(O) ) 0-2 R or -N=S(O)RR';
    或者，R 1和R 2以及它们连接的原子一起形成C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R1 and R2 and the atoms they connect together form a C3-7 cycloalkyl group, a 4-8 membered heterocyclic group, a C6-10 aryl group or a 5-10 membered heteroaryl group;
    其中R 1、R 2、R 3和R 4，以及它们连接形成的环基任选地被1、2、3、4或5个R#取代，其中R# 选自卤素、-CN、-NRR’、-OR、-C(O)R、-C(O)OR、-C(O)NRR’、-OC(O)R’、-NRC(O)R’、-OC(O)NRR’、-NRC(O)NRR’、-S(O) 1-2R、-S(O)(NR)R’、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、4-8元杂环基、C 6-10芳基或5-10元杂芳基；或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S； Wherein R 1 , R 2 , R 3 and R 4 , and the ring group formed by their connection are optionally substituted by 1, 2, 3, 4 or 5 R#, wherein R# is selected from halogen, -CN, -NRR ', -OR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR' , -NRC(O)NRR', -S(O) 1-2 R, -S(O)(NR)R', C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or two adjacent R on the same carbon atom #together form C=O or C=S;
    R 5选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，其可任选地被OH、-NH 2或-CN取代； R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, which can optionally be replaced by OH, -NH 2 or -CN replace;
    R 6选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-10环烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-10 cycloalkyl, which can be optionally replaced by D, OH, -NH 2 or -CN substitution;
    Z 1为N、NR Z1a、CR Z1b或CR Z1bR Z1c； Z1 is N, NR Z1a , CR Z1b or CR Z1b R Z1c ;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为N、NR Z3a、CR Z3b或CR Z3bR Z3c； Z 3 is N, NR Z3a , CR Z3b or CR Z3b R Z3c ;
    R Z1a、R Z2a和R Z3a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a , R Z2a and R Z3a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
    R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 1-4亚烷基、C 5-6环烷基或5-6元杂环基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C( O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkyl, 5-6 membered heteroaryl or C 6-10 aryl, or the same Or two R* on different carbon atoms and the atoms they connect together form C=O, C=S, C 1-4 alkylene, C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
    R X1b、R X2b独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O )OH, -C(O)OC 1-6 alkyl substitution;
    R Z3b选自H、D、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    R Z3c选自H或化学键； R Z3c is selected from H or a chemical bond;
    或者R Z1a和R Z2c、R Z1a和R Z2a、R Z2a和R Z1c、R Z1c和R Z2c、R Z2a和R Z3a、R Z2a和R Z3c、R Z2c和R Z3a、R Z2c和R Z3c可以结合形成双键； Or R Z1a and R Z2c , R Z1a and R Z2a , R Z2a and R Z1c , R Z1c and R Z2c , R Z2a and R Z3a , R Z2a and R Z3c , R Z2c and R Z3a , R Z2c and R Z3c can be combined form a double bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
    R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  3. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(I)、(I-1)或(I-2)的结构：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of the formula ( The structure of I), (I-1) or (I-2):
    Figure PCTCN2022141536-appb-100005
    Figure PCTCN2022141536-appb-100005
    其中，in,
    R 1选自C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2、-CN、C 1-6烷基、C 2-6烯基或C 2-6炔基取代； R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
    R 2选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R#取代； Alternatively, R 1 and R 2 together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2, 3, 4 or 5 R# substitutions;
    R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
    R 3选自H、NH 2、OH或-CN； R 3 is selected from H, NH 2 , OH or -CN;
    R 4选自H、C 1-6烷基或C 1-6卤代烷基，其可任选地被OH、-NH 2或-CN取代； R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
    R 5选自H、C 1-6烷基或C 1-6卤代烷基，其可任选地被OH、-NH 2或-CN取代； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
    R 6选自H、D、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基，其可任选地被D、OH、-NH 2或-CN取代； R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
    Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 10环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 10 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2, 3, 4 or 5 R*;
    R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)NH 2. -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O)OC 1-6 alkane base;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -C( O) NH-, -NHC(O)-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
    R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2- 6炔基、-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH、-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can be optionally replaced by halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH , -C(O)OC 1-6 alkyl substitution;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  4. 权利要求3的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2、-CN、C 1-6烷基、C 2-6烯基或C 2-6炔基取代； R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
    R 2选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2、3、4或5个R#取代； Alternatively, R 1 and R 2 together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2, 3, 4 or 5 R# substitutions;
    R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 4选自H、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 5选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R 6选自H、D、C 1-6烷基、C 1-6卤代烷基或C 3-4环烷基，其任选地被D取代； R is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-4 cycloalkyl, which is optionally substituted by D;
    Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 7环烷基、5-10元杂芳基或C 6-10芳基，可任选地被1、2、3、4或5个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, optionally substituted by 1, 2, 3, 4 or 5 R*;
    R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-NHC(O)-、-C(O)NH-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
    R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkane Base) 2 , -C(O)OH or -C(O)OC 1-6 alkyl substitution;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  5. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(II)、(II-1)或(II-2)化合物：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of the formula ( II), (II-1) or (II-2) compound:
    Figure PCTCN2022141536-appb-100006
    Figure PCTCN2022141536-appb-100006
    其中，in,
    R 1选自C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2、-CN、C 1-6烷基、C 2-6烯基或C 2-6炔基取代； R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may optionally be replaced by -OH, -NH 2 , -CN, C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 alkynyl substitution;
    R 2选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R 2 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
    R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 6选自H、D、C 1-6烷基或C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
    Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3- 7环烷基、5-10元杂芳基或C 6-10芳基，可任选地被1、2或3个R*取代； R Z1a and R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-7 membered heterocyclyl, C 3- 7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, optionally substituted by 1, 2 or 3 R*;
    R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-NHC(O)-、-C(O)NH-、-S(O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-或-C 2-6亚炔基-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH-, -S(O) 2 -, -C 1-6 alkylene-, -C 2-6 alkenylene- or -C 2-6 alkynylene-;
    R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基；所述基团可任选地被-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; said group can optionally be replaced by -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkane Base) 2 , -C(O)OH or -C(O)OC 1-6 alkyl substitution;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  6. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自任选地被-OH取代的C 1-6烷基或C 1-6卤代烷基； R is selected from C 1-6 alkyl or C 1-6 haloalkyl optionally substituted by -OH;
    R 2选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R 2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-10元杂芳基或C 6-10芳基，其可任选地被1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
    R#选自卤素、＝O或＝S；R# is selected from halogen, =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 6选自C 1-6烷基或C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
    Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    R Z1a、R Z2a独立地选自化学键、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-8环烷基，所述基团可任选地被1、2或3个R*取代； R Z1a , R Z2a are independently selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-8 cycloalkyl, the groups can optionally be 1, 2 or 3 R* substitutions;
    R*选自卤素、-OH、C 1-6烷基或C 1-6卤代烷基； R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-或-N-； Wherein, L Z1b and L Z2b are independently selected from chemical bonds, -O-, -S- or -N-;
    R X1b、R X2b独立地选自H、C 1-6烷基、4-7元杂环基或C 3-7环烷基；所述C 3-7环烷基可任选地被-C(O)OH或-C(O)NH 2取代； R X1b and R X2b are independently selected from H, C 1-6 alkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl; the C 3-7 cycloalkyl can optionally be replaced by -C (O)OH or -C(O)NH 2 substitution;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  7. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CF 3、CHF 2、CF 2CH 2OH或CF 2CH 3； R 1 is selected from CF 3 , CHF 2 , CF 2 CH 2 OH or CF 2 CH 3 ;
    R 2选自H、F或CH 3； R 2 is selected from H, F or CH 3 ;
    或者，R 1和R 2一起形成
    Figure PCTCN2022141536-appb-100007
    Alternatively, R1 and R2 together form
    Figure PCTCN2022141536-appb-100007
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    Z 1为NR Z1a或CR Z1bR Z1c； Z1 is NR Z1a or CR Z1b R Z1c ;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    R Z1a选自化学键、
    Figure PCTCN2022141536-appb-100008
    R Z1a is selected from chemical bonds,
    Figure PCTCN2022141536-appb-100008
    R Z2a选自化学键或
    Figure PCTCN2022141536-appb-100009
    R Z2a is selected from a chemical bond or
    Figure PCTCN2022141536-appb-100009
    R Z1b选自H、OMe、
    Figure PCTCN2022141536-appb-100010
    R Z1b is selected from H, OMe,
    Figure PCTCN2022141536-appb-100010
    R Z2b选自H、OMe、
    Figure PCTCN2022141536-appb-100011
    R Z2b is selected from H, OMe,
    Figure PCTCN2022141536-appb-100011
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c、R Z2a和R Z1c、R Z1c和R Z2c可以结合形成双键； Or R Z1a and R Z2c , R Z2a and R Z1c , R Z1c and R Z2c can combine to form a double bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  8. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III)、(III-1)或(III-2)化合物：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of the formula ( III), (III-1) or (III-2) compound:
    Figure PCTCN2022141536-appb-100012
    Figure PCTCN2022141536-appb-100012
    其中，in,
    R 1为C 1-6卤代烷基； R 1 is C 1-6 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-、-N-、-C(O)-、-C(O)O-、-OC(O)-、-NHC(O)-、-C(O)NH-或-S(O) 2-； Wherein, L Z1b , L Z2b are independently selected from chemical bond, -O-, -S-, -N-, -C(O)-, -C(O)O-, -OC(O)-, -NHC( O)-, -C(O)NH- or -S(O) 2 -;
    R X1b、R X2b独立地选自H、C 1-6烷基、C 1-6卤代烷基、4-7元杂环基、C 3-7环烷基；所述基团可任选地被-C(O)NH 2、-C(O)NH-C 1-6烷基、-C(O)N-(C 1-6烷基) 2、-C(O)OH或-C(O)O-C 1-6烷基取代。 R X1b and R X2b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl, C 3-7 cycloalkyl; -C(O)NH 2 , -C(O)NH-C 1-6 alkyl, -C(O)N-(C 1-6 alkyl) 2 , -C(O)OH or -C(O )OC 1-6 alkyl substitution.
  9. 权利要求8的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自化学键、-O-、-S-或-N-； Wherein, L Z1b and L Z2b are independently selected from chemical bonds, -O-, -S- or -N-;
    R X1b、R X2b独立地选自H、C 1-6烷基、4-7元杂环基或C 3-7环烷基；所述C 3-7环烷基可任选地被-C(O)OH或-C(O)NH 2取代。 R X1b and R X2b are independently selected from H, C 1-6 alkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl; the C 3-7 cycloalkyl can optionally be replaced by -C (O)OH or -C(O) NH2 substitution.
  10. 权利要求8的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CF 3或CHF 2； R 1 is selected from CF 3 or CHF 2 ;
    R 2选自H或F； R is selected from H or F;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b选自OMe、
    Figure PCTCN2022141536-appb-100013
    R Z1b is selected from OMe,
    Figure PCTCN2022141536-appb-100013
    R Z2b选自H、OMe或
    Figure PCTCN2022141536-appb-100014
    R Z2b is selected from H, OMe or
    Figure PCTCN2022141536-appb-100014
  11. 权利要求8的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自-O-、-S-或-N-； Wherein, L Z1b and L Z2b are independently selected from -O-, -S- or -N-;
    R X1b、R X2b独立地选自C 1-6烷基、C 1-6卤代烷基、4-7元杂环基或C 3-7环烷基。 R X1b and R X2b are independently selected from C 1-6 alkyl, C 1-6 haloalkyl, 4-7 membered heterocyclyl or C 3-7 cycloalkyl.
  12. 权利要求8的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1卤代烷基； R 1 is C 1 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b为-L Z1b-R X1b； R Z1b is -L Z1b -R X1b ;
    R Z2b为-L Z2b-R X2b； R Z2b is -L Z2b -R X2b ;
    其中，L Z1b、L Z2b独立地选自-O-或-S-； Wherein, L Z1b and L Z2b are independently selected from -O- or -S-;
    R X1b、R X2b独立地选自C 1-6烷基或5-6元杂环基。 R X1b and R X2b are independently selected from C 1-6 alkyl or 5-6 membered heterocyclic group.
  13. 权利要求8的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CF 3或CHF 2； R 1 is selected from CF 3 or CHF 2 ;
    R 2选自H或F； R is selected from H or F;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b选自OMe或
    Figure PCTCN2022141536-appb-100015
    R Z1b is selected from OMe or
    Figure PCTCN2022141536-appb-100015
    R Z2b选自OMe或
    Figure PCTCN2022141536-appb-100016
    R Z2b is selected from OMe or
    Figure PCTCN2022141536-appb-100016
  14. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有式(IV)、(IV-1)或(IV-2)的结构：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the formula ( The structure of IV), (IV-1) or (IV-2):
    Figure PCTCN2022141536-appb-100017
    Figure PCTCN2022141536-appb-100017
    其中，in,
    R 1为C 1-6烷基或C 1-6卤代烷基，其可任选地被-OH、-NH 2或-CN取代； R 1 is C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
    R 2选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R 2 is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-6元杂芳基或C 6-10芳基，其可任选地被1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
    R#选自卤素、-OH、-NH 2、-CN、＝O或＝S； R# is selected from halogen, -OH, -NH 2 , -CN, =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R 6选自H、D、C 1-6烷基或C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
    Z 2为CR Z2bR Z2c； Z 2 is CR Z2b R Z2c ;
    R Z1a选自化学键、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、4-7元杂环基、C 3-8环烷基、5-6元杂芳基或C 6-10芳基，其可任选地被1、2或3个R*取代； R Z1a is selected from chemical bonds, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , 4-7 membered heterocyclyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may be optionally substituted by 1, 2 or 3 R*;
    R*选自卤素、-OH、-NH 2、-CN、C 1-6烷基或C 1-6卤代烷基； R* is selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2b选自H或4-7元杂环基； R Z2b is selected from H or 4-7 membered heterocyclyl;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c结合形成双键； Or R Z1a and R Z2c combine to form a double bond;
    R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  15. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-6卤代烷基，其可任选地被-OH、-NH 2或-CN取代； R 1 is C 1-6 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
    R 2选自H、卤素或C 1-6烷基； R 2 is selected from H, halogen or C 1-6 alkyl;
    或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-6元杂芳基或C 6-10芳基，其可任选地被1、2或3个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which may optionally be replaced by 1, 2 or 3 R# replacements;
    R#选自卤素、＝O或＝S；R# is selected from halogen, =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R 6选自C 1-6烷基或C 1-6卤代烷基，其可任选地被D、OH、-NH 2或-CN取代； R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D, OH, -NH 2 or -CN;
    Z 2为CR Z2bR Z2c； Z 2 is CR Z2b R Z2c ;
    R Z1a选自化学键、4-7元杂环基或C 3-8环烷基，其可任选地被1、2或3个R*取代； R Z1a is selected from a chemical bond, 4-7 membered heterocyclyl or C 3-8 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
    R*选自卤素、-OH、C 1-6烷基或C 1-6卤代烷基； R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2b选自H或5-6元杂环基，优选H； R Z2b is selected from H or 5-6 membered heterocyclic groups, preferably H;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c结合形成双键； Or R Z1a and R Z2c combine to form a double bond;
    R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  16. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2、CF 3、CF 2CH 2OH或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 , CF 2 CH 2 OH or CF 2 CH 3 ;
    R 2选自H、F或CH 3； R 2 is selected from H, F or CH 3 ;
    或者，R 1和R 2一起形成
    Figure PCTCN2022141536-appb-100018
    Alternatively, R1 and R2 together form
    Figure PCTCN2022141536-appb-100018
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    Z 2为CR Z2bR Z2c； Z 2 is CR Z2b R Z2c ;
    R Z1a选自化学键、
    Figure PCTCN2022141536-appb-100019
    R Z1a is selected from chemical bonds,
    Figure PCTCN2022141536-appb-100019
    R Z2b选自H或
    Figure PCTCN2022141536-appb-100020
    优选H；     R Z2b is selected from H or
    Figure PCTCN2022141536-appb-100020
    H is preferred;
    R Z2c选自H或化学键； R Z2c is selected from H or a chemical bond;
    或者R Z1a和R Z2c结合形成双键； Or R Z1a and R Z2c combine to form a double bond;
    R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  17. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(V)、(V-1)或(V-2)化合物：The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (V) , (V-1) or (V-2) compound:
    Figure PCTCN2022141536-appb-100021
    Figure PCTCN2022141536-appb-100021
    其中，in,
    R 1为C 1-4卤代烷基，其可任选地被-OH、-NH 2或-CN取代； R 1 is C 1-4 haloalkyl, which may be optionally substituted by -OH, -NH 2 or -CN;
    R 2选自H或卤素； R is selected from H or halogen;
    或者，R 1和R 2一起形成4-7元杂环基、C 3-7环烷基、5-6元杂芳基或C 6-10芳基，其任选地被1或2个R#取代； Alternatively, R and R together form a 4-7 membered heterocyclyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, which is optionally replaced by 1 or 2 R #replace;
    R#选自卤素、＝O或＝S；R# is selected from halogen, =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R2 and R3 are not H at the same time;
    R 6选自C 1-6烷基或C 1-6卤代烷基，其可任选地被D取代； R is selected from C 1-6 alkyl or C 1-6 haloalkyl, which may be optionally substituted by D;
    R Z1a选自4-7元杂环基或C 3-8环烷基，其可任选地被1、2或3个R*取代； R Z1a is selected from 4-7 membered heterocyclyl or C 3-8 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
    R*选自卤素、-OH、C 1-6烷基或C 1-6卤代烷基。 R* is selected from halogen, -OH, C 1-6 alkyl or C 1-6 haloalkyl.
  18. 权利要求17的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CF 3、CHF 2、CF 2CH 2OH或CF 2CH 3； R 1 is selected from CF 3 , CHF 2 , CF 2 CH 2 OH or CF 2 CH 3 ;
    R 2选自H或F； R is selected from H or F;
    或者，R 1和R 2一起形成
    Figure PCTCN2022141536-appb-100022
    Alternatively, R1 and R2 together form
    Figure PCTCN2022141536-appb-100022
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    R Z1a选自
    Figure PCTCN2022141536-appb-100023
    R Z1a is selected from
    Figure PCTCN2022141536-appb-100023
  19. 权利要求17的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    或者R 1和R 2一起形成含硫原子的5-6元杂环基，其任选地被1、2或3个R#取代； Or R 1 and R 2 together form a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1, 2 or 3 R#;
    R#选自-OH、-NH 2、-CN、＝O或＝S； R# is selected from -OH, -NH 2 , -CN, =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R 6为C 1-2烷基，其可任选地被D取代； R 6 is C 1-2 alkyl, which may be optionally substituted by D;
    R Z1a为任选地被1、2或3个R*取代的C 3-7环烷基； R Z1a is C 3-7 cycloalkyl optionally substituted by 1, 2 or 3 R*;
    R*选自C 1-6烷基或C 1-6卤代烷基。 R* is selected from C 1-6 alkyl or C 1-6 haloalkyl.
  20. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1卤代烷基； R 1 is C 1 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    或者R 1和R 2一起形成含硫原子的5-6元杂环基，其任选地被1或2个R#取代； Or R 1 and R 2 together form a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
    R#选自＝O或＝S；R# is selected from =O or =S;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R 6为甲基，其可任选地被D取代； R 6 is methyl, which may be optionally substituted by D;
    R Z1a为任选地被1或2个R*取代的C 3-4环烷基； R Z1a is C 3-4 cycloalkyl optionally substituted by 1 or 2 R*;
    R*选自C 1-4烷基或C 1-4卤代烷基。 R* is selected from C 1-4 alkyl or C 1-4 haloalkyl.
  21. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2或CF 3； R 1 is selected from CHF 2 or CF 3 ;
    R 2选自H或F； R is selected from H or F;
    或者R 1和R 2一起形成
    Figure PCTCN2022141536-appb-100024
    or R1 and R2 together form
    Figure PCTCN2022141536-appb-100024
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    R Z1a选自
    Figure PCTCN2022141536-appb-100025
    R Z1a is selected from
    Figure PCTCN2022141536-appb-100025
  22. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有式(VI)、(VI-1)或(VI-2)的结构：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the formula ( The structure of VI), (VI-1) or (VI-2):
    Figure PCTCN2022141536-appb-100026
    Figure PCTCN2022141536-appb-100026
    其中，in,
    R 1为C 1-6卤代烷基； R 1 is C 1-6 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    Z 1为CR Z1bR Z1c； Z1 is CR Z1b R Z1c ;
    R Z1b选自H、4-7元杂环基或C 3-7环烷基，其可任选地被1、2或3个R*取代； R Z1b is selected from H, 4-7 membered heterocyclyl or C 3-7 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    R Z2a选自化学键、C 3-7环烷基或5-6元杂环基，其可任选地被1、2或3个R*取代； R Z2a is selected from a chemical bond, C 3-7 cycloalkyl or 5-6 membered heterocyclyl, which may be optionally substituted by 1, 2 or 3 R*;
    R*选自-OH、-NH 2、-CN、C 1-6烷基或C 1-6卤代烷基； R* is selected from -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl;
    或者R Z2a和R Z1c结合形成双键。 Or R Z2a and R Z1c combine to form a double bond.
  23. 权利要求22的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-6卤代烷基； R 1 is C 1-6 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    Z 1为CR Z1bR Z1c； Z1 is CR Z1b R Z1c ;
    R Z1b选自H或5-6元杂环基，其任选地被1、2或3个R*取代； R Z1b is selected from H or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R*;
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    R Z2a选自化学键、C 3-7环烷基，所述C 3-7环烷基任选地被1、2或3个R*取代； R Z2a is selected from a chemical bond, C 3-7 cycloalkyl optionally substituted by 1, 2 or 3 R*;
    R*选自C 1-6烷基或C 1-6卤代烷基； R* is selected from C 1-6 alkyl or C 1-6 haloalkyl;
    或者R Z2a和R Z1c结合形成双键。 Or R Z2a and R Z1c combine to form a double bond.
  24. 权利要求22的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2或CF 3； R 1 is selected from CHF 2 or CF 3 ;
    R 2选自H或F； R is selected from H or F;
    R 3选自H或NH 2 R 3 is selected from H or NH 2
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    Z 1为CR Z1bR Z1c； Z1 is CR Z1b R Z1c ;
    R Z1b选自H或
    Figure PCTCN2022141536-appb-100027
    R Z1b is selected from H or
    Figure PCTCN2022141536-appb-100027
    R Z1c选自H或化学键； R Z1c is selected from H or a chemical bond;
    或者R Z1b和R Z1c与它们连接的碳原子形成C＝O或C＝S； or R Z1b and R Z1c form C=O or C=S with the carbon atom to which they are attached;
    R Z2a选自化学键或
    Figure PCTCN2022141536-appb-100028
    R Z2a is selected from a chemical bond or
    Figure PCTCN2022141536-appb-100028
    或者R Z2a和R Z1c结合形成双键。 Or R Z2a and R Z1c combine to form a double bond.
  25. 权利要求22的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有式(VII)、(VII-1)或(VII-2)的结构：The compound of claim 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having formula (VII) , the structure of (VII-1) or (VII-2):
    Figure PCTCN2022141536-appb-100029
    Figure PCTCN2022141536-appb-100029
    其中，in,
    R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
    R 2选自H或卤素； R is selected from H or halogen;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b选自5-6元杂环基、C 3-7环烷基，其可任选地被1、2或3个R*取代； R Z1b is selected from 5-6 membered heterocyclyl, C 3-7 cycloalkyl, which may be optionally substituted by 1, 2 or 3 R*;
    R*选自-OH、-NH 2、-CN、C 1-6烷基或C 1-6卤代烷基。 R* is selected from -OH, -NH 2 , -CN, C 1-6 alkyl or C 1-6 haloalkyl.
  26. 权利要求25的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自C 1卤代烷基，优选为CF 3或CHF 2； R 1 is selected from C 1 haloalkyl, preferably CF 3 or CHF 2 ;
    R 2选自H、卤素，优选为H或F； R is selected from H, halogen, preferably H or F;
    R 3选自H或NH 2； R 3 is selected from H or NH 2 ;
    R 2和R 3不同时为H； R 2 and R 3 are not H at the same time;
    R Z1b为5-6元杂环基，其可任选地被1、2或3个R*取代； R Z1b is a 5-6 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
    R*选自C 1-6烷基或C 1-6卤代烷基； R* is selected from C 1-6 alkyl or C 1-6 haloalkyl;
    R Z1b优选为
    Figure PCTCN2022141536-appb-100030
    R Z1b is preferably
    Figure PCTCN2022141536-appb-100030
  27. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有式(VIII)、(VIII-1)或(VIII-2)的结构：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the formula ( The structure of VIII), (VIII-1) or (VIII-2):
    Figure PCTCN2022141536-appb-100031
    Figure PCTCN2022141536-appb-100031
    其中，in,
    R 1为C 1-4卤代烷基，其可任选地被OH、-NH 2或-CN取代； R 1 is C 1-4 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
    R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-6烯基或C 2-6炔基； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R 6选自H、D、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其可任选地被D取代，直至完全氘代； R is selected from H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by D, up to fully deuterium generation;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
    R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、C 1-6烷基、C 1-6卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 1-4亚烷基、C 5-6环烷基或5-6元杂环基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, C 1- 6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and the atoms they connect together form C=O, C =S, C 1-4 alkylene, C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
    R Z1a优选为以下基团： R Z1a is preferably the following group:
    Figure PCTCN2022141536-appb-100032
    Figure PCTCN2022141536-appb-100032
    R Z3b选自H、D、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R Z3b is selected from H, D, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  28. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基，其可任选地被OH、-NH 2或-CN取代； R 1 is C 1-4 haloalkyl, which may be optionally substituted by OH, -NH 2 or -CN;
    R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3或4个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3 or 4 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5选自C 1-4烷基或C 1-4卤代烷基； R is selected from C 1-4 alkyl or C 1-4 haloalkyl;
    R 6选自C 1-4烷基或C 1-4卤代烷基； R 6 is selected from C 1-4 alkyl or C 1-4 haloalkyl;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
    R*选自卤素、OH、-NH 2、-CN、C 1-4烷基、C 1-4卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基； R* is selected from halogen, OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or the same or different carbon atoms The two R* on and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group;
    R Z3b选自H、D或卤素； R Z3b is selected from H, D or halogen;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  29. 权利要求28的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2、CF 3、CF 2CH 3或CF 2CH 2OH； R 1 is selected from CHF 2 , CF 3 , CF 2 CH 3 or CF 2 CH 2 OH;
    R 2选自H、D、F或CH 3； R 2 is selected from H, D, F or CH 3 ;
    或者R 1和R 2一起形成
    Figure PCTCN2022141536-appb-100033
    or R1 and R2 together form
    Figure PCTCN2022141536-appb-100033
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5选自CH 3或CHF 2； R 5 is selected from CH 3 or CHF 2 ;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a选自
    Figure PCTCN2022141536-appb-100034
    Figure PCTCN2022141536-appb-100035
    R Z1a is selected from
    Figure PCTCN2022141536-appb-100034
    Figure PCTCN2022141536-appb-100035
    R Z3b选自H、D或Cl。 R Z3b is selected from H, D or Cl.
  30. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
    R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或含硫原子的5-6元杂环基，其任选地被1、2或3个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1, 2 or 3 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5选自C 1-4烷基或C 1-4卤代烷基； R is selected from C 1-4 alkyl or C 1-4 haloalkyl;
    R 6选自C 1-4烷基或C 1-4卤代烷基； R 6 is selected from C 1-4 alkyl or C 1-4 haloalkyl;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1a is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
    R*选自C 1-4烷基、C 1-4卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基； R* is selected from C 1-4 alkyl, C 1-4 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and their connected atoms Together form C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
    R Z3b选自H、D或卤素； R Z3b is selected from H, D or halogen;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  31. 权利要求30的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
    R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或含硫原子的5-6元杂环基，其任选地被1或2个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5选自C 1-2烷基或C 1-2卤代烷基； R is selected from C 1-2 alkyl or C 1-2 haloalkyl;
    R 6为C 1-2烷基； R 6 is C 1-2 alkyl;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a为任选地被1、2或3个R*取代的C 3-6环烷基或4-7元杂环基； R Z1a is C 3-6 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
    R*选自C 1-2烷基、C 1-2卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from C 1-2 alkyl, C 1-2 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and their connected atoms Together form a 5-6 membered heterocyclic group;
    R Z3b选自H、D或卤素； R Z3b is selected from H, D or halogen;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  32. 权利要求30的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2、CF 3或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
    R 2选自H、D、F或CH 3； R 2 is selected from H, D, F or CH 3 ;
    或者R 1和R 2一起形成
    Figure PCTCN2022141536-appb-100036
    or R1 and R2 together form
    Figure PCTCN2022141536-appb-100036
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5选自CH 3或CHF 2； R 5 is selected from CH 3 or CHF 2 ;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a选自
    Figure PCTCN2022141536-appb-100037
    R Z1a is selected from
    Figure PCTCN2022141536-appb-100037
    R Z3b选自H、D或Cl。 R Z3b is selected from H, D or Cl.
  33. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
    R 2选自卤素或C 1-4烷基，优选为卤素； R 2 is selected from halogen or C 1-4 alkyl, preferably halogen;
    或者R 1和R 2以及它们连接的原子一起形成C 4-7环烷基，其任选地被1、2或3个R#取代； or R 1 and R 2 and the atoms to which they are attached together form a C 4-7 cycloalkyl group, which is optionally substituted by 1, 2 or 3 R#;
    R#为卤素；R# is halogen;
    R 3选自H或D； R is selected from H or D;
    R 5为C 1-2烷基； R 5 is C 1-2 alkyl;
    R 6为C 1-2烷基； R 6 is C 1-2 alkyl;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a为任选地被1、2或3个R*取代的环丙基； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*;
    R*选自C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group;
    R Z3b选自H或D； R Z3b is selected from H or D;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  34. 权利要求33的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
    R 2选自卤素或C 1-2烷基，优选为卤素； R 2 is selected from halogen or C 1-2 alkyl, preferably halogen;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基，其任选地被1或2个R#取代； Or R 1 and R 2 and the atoms they are connected together form a C 5-6 cycloalkyl group, which is optionally substituted by 1 or 2 R#;
    R#为卤素；R# is halogen;
    R 3选自H或D； R is selected from H or D;
    R 5为C 1-2烷基； R 5 is C 1-2 alkyl;
    R 6为C 1-2烷基； R 6 is C 1-2 alkyl;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a为任选地被1、2或3个R*取代的环丙基； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*;
    R*选自C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group;
    R Z3b选自H或D； R Z3b is selected from H or D;
    其中R 1、R 2、R 3、R 5、R 6、R Z1a和R Z3b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R 3 , R 5 , R 6 , R Z1a and R Z3b can be optionally substituted by D until complete deuteration.
  35. 权利要求33的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2、CF 3或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
    R 2选自F或CH 3；优选地，当R 1为CF 2CH 3时，R 2不为CH 3； R 2 is selected from F or CH 3 ; preferably, when R 1 is CF 2 CH 3 , R 2 is not CH 3 ;
    或者R 1和R 2一起形成
    Figure PCTCN2022141536-appb-100038
    or R1 and R2 together form
    Figure PCTCN2022141536-appb-100038
    R 3为H； R3 is H;
    R 5为CH 3； R 5 is CH 3 ;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    Z 3为N或CR Z3b； Z 3 is N or CR Z3b ;
    R Z1a选自
    Figure PCTCN2022141536-appb-100039
    R Z1a is selected from
    Figure PCTCN2022141536-appb-100039
    R Z3b为H。 R Z3b is H.
  36. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中所述化合物具有式(IX)、(IX-1)或(IX-2)的结构：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound A structure of formula (IX), (IX-1) or (IX-2):
    Figure PCTCN2022141536-appb-100040
    Figure PCTCN2022141536-appb-100040
    其中各基团如权利要求1或2中任一项所定义。Wherein each group is as defined in any one of claim 1 or 2.
  37. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自-CN、卤素或C 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R is selected from -CN, halogen or C1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH2 or -CN, which is also optionally substituted by D, until fully deuterated ;
    R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
    R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
    R Z1a为任选地被1、2或3个R*取代的C 3-8环烷基，其任选地被D取代，直至完全氘代； R Z1a is C 3-8 cycloalkyl optionally substituted by 1, 2 or 3 R*, optionally substituted by D, up to fully deuterated;
    R*选自卤素、-C 0-4亚烷基-CN、C 1-6烷基、C 1-6卤代烷基、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、苯基或5-6元杂芳基；或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 5-6环烷基或5-6元杂环基，其任选地被1、2或3个Rx取代；其任选地被D取代，直至完全氘代； R* is selected from halogen, -C 0-4 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-4 alkylene-OR, -C 0-4 alkylene -NRR', -C(O)R, -C(NH)OR, -C(O)OR, -C(O)NRR', phenyl or 5-6 membered heteroaryl; or the same or different carbon atoms The two R* on and the atoms to which they are attached together form C=O, C=S, C5-6cycloalkyl or 5-6 membered heterocyclyl, optionally substituted by 1, 2 or 3 Rx ; it is optionally substituted by D until fully deuterated;
    Rx选自C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-OR、-C 0-6亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； Rx is selected from C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR, -C 0-6 alkylene-NRR', -C(O)R, -C( NH)OR, -C(O)OR, -C(O)NRR', C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
    R Z1a优选为以下基团： R Z1a is preferably the following group:
    Figure PCTCN2022141536-appb-100041
    Figure PCTCN2022141536-appb-100041
    R Z3b选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4 -6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, up to complete Deuterium;
    L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
    R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
    R s选自CN、OR、C 1-6烷基、C 1-6卤代烷基、S(O)R或S(O) 2R，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R s is selected from CN, OR, C 1-6 alkyl, C 1-6 haloalkyl, S(O)R or S(O) 2 R, or two adjacent R s on the same carbon atom together form C =O or C=S, optionally substituted by D, up to complete deuteration;
    R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
    R Z3b优选为以下基团： R Z3b is preferably the following groups:
    H、D、Cl、F、Me、CHF 2、NH 2、
    Figure PCTCN2022141536-appb-100042
    H, D, Cl, F, Me, CHF 2 , NH 2 ,
    Figure PCTCN2022141536-appb-100042
    Figure PCTCN2022141536-appb-100043
    Figure PCTCN2022141536-appb-100043
  38. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CN、卤素或C 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R is selected from CN, halogen or C1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH2 or -CN, which is also optionally substituted by D, up to complete deuteration;
    R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
    R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
    R Z1a为任选地被1、2或3个R*取代的C 3-6环烷基，其任选地被D取代，直至完全氘代； R Z1a is C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R*, optionally substituted by D, up to fully deuterated;
    R*选自卤素、CN、C 1-6烷基、C 1-6卤代烷基、-C 1-4亚烷基-OH、-C 1-4亚烷基-OC 1-6烷基、-C 1-4亚烷基-OC 1-6卤代烷基、-C(NH)O-C 1-6烷基、-C(O)O-C 1-6烷基、-C(O)NH-C 1-6烷基、-C(O)N(C 1-6烷基) 2、-C(NH)O-C 1-6卤代烷基、-C(O)O-C 1-6卤代烷基、-C(O)NH-C 1-6卤代烷基、-C(O)N(C 1-6卤代烷基) 2、苯基或5-6元杂芳基，其任选地被D取代，直至完全氘代； R* is selected from halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-OC 1-6 alkyl, - C 1-4 alkylene-OC 1-6 haloalkyl, -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, -C(O)NH-C 1-6 Alkyl, -C(O)N(C 1-6 alkyl) 2 , -C(NH)OC 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -C(O)NH- C 1-6 haloalkyl, -C(O)N(C 1-6 haloalkyl) 2 , phenyl or 5-6 membered heteroaryl, which is optionally substituted by D, up to complete deuteration;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
    L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
    R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group, -C 1-6 alkylene -OC 1-6 haloalkyl, -C 1-6 alkylene - NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
    R s选自CN、OH、OC 1-6烷基、OC 1-6卤代烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基、S(O) 2C 1- 6烷基、S(O)C 1-6卤代烷基或S(O) 2C 1-6卤代烷基，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代。 R s is selected from CN, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl, S(O ) 2 C 1-6 alkyl, S(O)C 1-6 haloalkyl or S(O) 2 C 1-6 haloalkyl, or two adjacent R s on the same carbon atom together form C=O or C=S, which is optionally substituted by D, up to full deuteration.
  39. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-6卤代烷基，其任选地被1、2或3个OH或NH 2取代，其还任选地被D取代，直至完全氘代； R is C 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH or NH , which is also optionally substituted by D, up to complete deuteration;
    R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
    R 6选自H、C 1-4烷基或C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl or C 1-4 haloalkyl, which is optionally substituted by D, until fully deuterated;
    R Z1a为任选地被1、2或3个R*取代的环丙基，其任选地被D取代，直至完全氘代； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
    R*选自卤素、CN、C 1-4烷基、C 1-4卤代烷基、-C(NH)O-C 1-6烷基、-C(O)O-C 1-6烷基、-C(O)NH-C 1- 6烷基、-C(O)N(C 1-6烷基) 2、-C(NH)O-C 1-6卤代烷基、-C(O)O-C 1-6卤代烷基、-C(O)NH-C 1-6卤代烷基、-C(O)N(C 1-6卤代烷基) 2、苯基或5-6元杂芳基，其任选地被D取代，直至完全氘代； R* is selected from halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, -C(O )NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl) 2 , -C( NH )OC 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -C(O)NH-C 1-6 haloalkyl, -C(O)N(C 1-6 haloalkyl) 2 , phenyl or 5-6 membered heteroaryl optionally substituted by D, up to Fully deuterated;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
    L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
    R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group , -C 1-6 alkylene-OC 1-6 haloalkyl, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
    R s选自CN、OH、OC 1-6烷基、OC 1-6卤代烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基、S(O) 2C 1- 6烷基、S(O)C 1-6卤代烷基或S(O) 2C 1-6卤代烷基，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代。 R s is selected from CN, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl, S(O ) 2 C 1-6 alkyl, S(O)C 1-6 haloalkyl or S(O) 2 C 1-6 haloalkyl, or two adjacent R s on the same carbon atom together form C=O or C=S, which is optionally substituted by D, up to full deuteration.
  40. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基，其任选地被1或2个OH取代，其还任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by 1 or 2 OH, which is also optionally substituted by D, until fully deuterated;
    R 2选自H、D、卤素或C 1-2烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5为C 1-2烷基，其任选地被D取代，直至完全氘代； R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
    R 6为H或C 1-2烷基，其任选地被D取代，直至完全氘代； R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
    R Z1a为任选地被1、2或3个R*取代的环丙基，其任选地被D取代，直至完全氘代； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
    R*选自F、CN、CH 3、CH 2CH 3、CH 2F、CHF 2、CHF 3、-C(NH)O-C 1-6烷基、-C(O)O-C 1-6烷基、苯基或5-6元杂芳基，其任选地被D取代，直至完全氘代； R* is selected from F, CN, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CHF 3 , -C(NH)OC 1-6 alkyl, -C(O)OC 1-6 alkyl, Phenyl or 5-6 membered heteroaryl, which is optionally substituted by D, up to fully deuterated;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4-6 Heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, until fully deuterated;
    L为化学键、O或NH；L is a chemical bond, O or NH;
    R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基或-C 1-6亚烷基-N(C 1-6烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane Group, -C 1-6 alkylene-NH 2 , -C 1-6 alkylene - NHC 1-6 alkyl or -C 1-6 alkylene-N(C 1-6 alkyl) 2 , It is optionally substituted by D up to full deuteration;
    R s选自CN、OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代。 R s is selected from CN, OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkane group, or two adjacent R s on the same carbon atom together form C=O or C=S, which is optionally substituted with D, up to complete deuteration.
  41. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2、CF 3、CF 2CH 3或CF 2C(OH)(CH 3) 2，其任选地被D取代，直至完全氘代； R 1 is selected from CHF 2 , CF 3 , CF 2 CH 3 or CF 2 C(OH)(CH 3 ) 2 , optionally substituted by D, up to full deuteration;
    R 2选自H、D、F或CH 3，其任选地被D取代，直至完全氘代； R2 is selected from H, D, F or CH3 , which is optionally substituted by D, up to complete deuteration;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    R 5为CH 3，其任选地被D取代，直至完全氘代； R 5 is CH 3 , which is optionally substituted by D until fully deuterated;
    R 6为H或CH 3，其任选地被D取代，直至完全氘代； R 6 is H or CH 3 , which is optionally substituted by D until fully deuterated;
    R Z1a选自
    Figure PCTCN2022141536-appb-100044
    Figure PCTCN2022141536-appb-100045
    其任选地被D取代，直至完全氘代；     R Z1a is selected from
    Figure PCTCN2022141536-appb-100044
    Figure PCTCN2022141536-appb-100045
    It is optionally substituted by D up to full deuteration;
    R Z3b选自H、D、Cl、F、Me、
    Figure PCTCN2022141536-appb-100046
    Figure PCTCN2022141536-appb-100047
    其任选地被D取代，直至完全氘代。     R Z3b is selected from H, D, Cl, F, Me,
    Figure PCTCN2022141536-appb-100046
    Figure PCTCN2022141536-appb-100047
    It is optionally substituted with D until fully deuterated.
  42. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
    R 2为卤素； R 2 is halogen;
    R 3选自H或D； R is selected from H or D;
    R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
    R 6为H或C 1-2烷基，其任选地被D取代，直至完全氘代； R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
    R Z1a为任选地被1、2或3个R*取代的环丙基，其任选地被D取代，直至完全氘代； R Z1a is cyclopropyl optionally substituted by 1, 2 or 3 R*, which is optionally substituted by D, up to full deuteration;
    R*选自CH 3、CH 2F、CHF 2、-C(NH)O-C 1-6烷基或-C(O)O-C 1-6烷基，其任选地被D取代，直至完全氘代； R* is selected from CH 3 , CH 2 F, CHF 2 , -C(NH)OC 1-6 alkyl or -C(O)OC 1-6 alkyl optionally substituted with D until fully deuterated ;
    R Z3b选自H或D。 R Z3b is selected from H or D.
  43. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-2卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-2 haloalkyl, which is optionally substituted by D, up to fully deuterated;
    R 2为卤素； R 2 is halogen;
    R 3选自H或D； R is selected from H or D;
    R 5为C 1-2烷基，其任选地被D取代，直至完全氘代； R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
    R 6为H或C 1-2烷基，其任选地被D取代，直至完全氘代； R is H or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
    R Z1a为
    Figure PCTCN2022141536-appb-100048
    其任选地被D取代，直至完全氘代；     R Z1a is
    Figure PCTCN2022141536-appb-100048
    It is optionally substituted by D up to full deuteration;
    其中R*选自CH 3、CH 2F、CHF 2、-C(NH)O-C 1-4烷基或-C(O)O-C 1-4烷基，其任选地被D取代，直至完全氘代； where R* is selected from CH 3 , CH 2 F, CHF 2 , -C(NH)OC 1-4 alkyl or -C(O)OC 1-4 alkyl optionally substituted with D up to fully deuterium generation;
    R Z3b选自H或D。 R Z3b is selected from H or D.
  44. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2、CF 3或CF 2CH 3； R 1 is selected from CHF 2 , CF 3 or CF 2 CH 3 ;
    R 2为F； R2 is F;
    R 3为H； R3 is H;
    R 5为CH 3； R 5 is CH 3 ;
    R 6选自H、CH 3或CD 3； R 6 is selected from H, CH 3 or CD 3 ;
    R Z1a选自
    Figure PCTCN2022141536-appb-100049
    R Z1a is selected from
    Figure PCTCN2022141536-appb-100049
    R Z3b为H。 R Z3b is H.
  45. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CN、卤素、C 1-6卤代烷基、OR、C(O)OR或-C(O)NRR’，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl, OR, C(O)OR or -C(O)NRR', optionally replaced by 1, 2 or 3 OH, -NH 2 or -CN Substituted, which is also optionally substituted by D, up to complete deuteration;
    R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
    R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
    R Z1a为4-7元杂环基，其可任选地被1、2、3、4或5个R*取代，其任选地被D取代，直至完全氘代； R Z1a is a 4-7 membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5 R*, optionally substituted by D, up to full deuteration;
    R*选自H、D、卤素、-C 0-4亚烷基-CN、C 1-6烷基、C 1-6卤代烷基、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C(O)R、-C(NH)OR、-C(O)OR、-C(O)NRR’、C 3-8环烷基、4-7元杂环基、苯基或5-6元杂芳基；或者两个R*以及它们连接的原子一起形成C＝O或C＝S，或者两个R*连接形成C 1-4亚烷基；其任选地被D取代，直至完全氘代； R* is selected from H, D, halogen, -C 0-4 alkylene-CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-4 alkylene-OR, -C 0- 4 alkylene-NRR', -C(O)R, -C(NH)OR, -C(O)OR, -C(O)NRR', C 3-8 cycloalkyl, 4-7 membered hetero Cyclic group, phenyl or 5-6 membered heteroaryl; or two R* and the atoms they connect together form C=O or C=S, or two R* connect to form C 1-4 alkylene; its optionally substituted with D, up to full deuteration;
    R Z3b选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-NR aR b、-OR a、-L-C 3-6环烷基、-L-4-6元杂环基、-L-苯基或-L-5-9元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -NR a R b , -OR a , -LC 3-6 cycloalkyl, -L-4 -6 membered heterocyclyl, -L-phenyl or -L-5-9 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R s , which is also optionally substituted by D, up to complete Deuterium;
    L为化学键、O、S或NH；L is a chemical bond, O, S or NH;
    R a和R b独立地选自H、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-OH、-C 1-6亚烷基-OC 1-6烷基、-C 1- 6亚烷基-OC 1-6卤代烷基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NHC 1-6烷基、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1- 6亚烷基-NHC 1-6卤代烷基或-C 1-6亚烷基-N(C 1-6卤代烷基) 2，其任选地被D取代，直至完全氘代； R a and R b are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 alkane group, -C 1-6 alkylene -OC 1-6 haloalkyl, -C 1-6 alkylene - NH 2 , -C 1-6 alkylene-NHC 1-6 alkyl, -C 1- 6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NHC 1-6 haloalkyl or -C 1-6 alkylene-N(C 1-6 haloalkyl) 2 , which is optionally substituted by D until fully deuterated;
    R s选自CN、OR、C 1-6烷基、C 1-6卤代烷基、S(O)R或S(O) 2R，或者同一碳原子上的两个相邻R s一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R s is selected from CN, OR, C 1-6 alkyl, C 1-6 haloalkyl, S(O)R or S(O) 2 R, or two adjacent R s on the same carbon atom together form C =O or C=S, optionally substituted by D, up to complete deuteration;
    R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基。 R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, or R, R' and their connected nitrogen atom form a 4-8 membered heterocyclic group.
  46. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CN、卤素、C 1-6卤代烷基、OR、C(O)OR或-C(O)NRR’，其任选地被1、2或3个OH、- NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl, OR, C(O)OR or -C(O)NRR', optionally replaced by 1, 2 or 3 OH, -NH 2 or -CN Substituted, which is also optionally substituted by D, up to complete deuteration;
    R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
    R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-8环烷基或4-7元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
    R Z1a为
    Figure PCTCN2022141536-appb-100050
    其任选地被D取代，直至完全氘代；     R Z1a is
    Figure PCTCN2022141536-appb-100050
    It is optionally substituted by D up to full deuteration;
    X为O、S、S(O)、S(O) 2、NR N或C(R C) 2； X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
    R*选自H、D或C 1-4烷基，或者两个R*以及它们连接的原子一起形成C＝O或C＝S，或者两个R*连接形成C 1-4亚烷基；其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, or two R* and their connected atoms form C=O or C=S together, or two R* connect to form C 1-4 alkylene; It is optionally substituted by D up to full deuteration;
    R N选自H、C 1-6烷基、C 1-6卤代烷基、C(O)R、C 3-8环烷基或4-7元杂环基； RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R, C 3-8 cycloalkyl or 4-7 membered heterocyclyl;
    R C独立地选自H、D、卤素、OH、C(O)R、C 1-6烷基、C 1-6卤代烷基、C 3-8环烷基或4-7元杂环基； R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or 4-7 membered heterocyclyl;
    R和R’独立地选自H、C 1-6烷基或C 1-6卤代烷基； R and R' are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
    R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  47. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CN、卤素、C 1-6卤代烷基或OC 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl or OC 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH 2 or -CN, which is also optionally substituted by D Substitution, until complete deuteration;
    R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
    R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
    R Z1a为
    Figure PCTCN2022141536-appb-100051
    其任选地被D取代，直至完全氘代；     R Z1a is
    Figure PCTCN2022141536-appb-100051
    It is optionally substituted by D up to full deuteration;
    X为O、S、S(O)、S(O) 2、NR N或C(R C) 2； X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
    R*选自H、D或C 1-4烷基，或者两个R*以及它们连接的原子一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, or two R* and the atoms to which they are attached together form C=O or C=S, which is optionally substituted by D, up to complete deuteration;
    R N选自H、C 1-6烷基、C 1-6卤代烷基或C(O)R； RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C(O)R;
    R C独立地选自H、D、卤素、OH、C(O)R、C 1-6烷基或C 1-6卤代烷基； R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl or C 1-6 haloalkyl;
    R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
    R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  48. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CN、卤素、C 1-6卤代烷基或OC 1-6卤代烷基，其任选地被1、2或3个OH、-NH 2或-CN取代，其还任选地被D取代，直至完全氘代； R 1 is selected from CN, halogen, C 1-6 haloalkyl or OC 1-6 haloalkyl, which is optionally substituted by 1, 2 or 3 OH, -NH 2 or -CN, which is also optionally substituted by D Substitution, until complete deuteration;
    R 2选自H、D、卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R is selected from H, D, halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    R 5选自C 1-4烷基、C 1-4卤代烷基、C 2-4烯基或C 2-4炔基，其任选地被D取代，直至完全氘代； R is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl or C 2-4 alkynyl, which is optionally substituted by D until fully deuterated;
    R 6选自H、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基或4-6元杂环基，其任选地被D取代，直至完全氘代； R is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, which is optionally substituted by D until fully deuterated;
    R Z1a为
    Figure PCTCN2022141536-appb-100052
    其任选地被D取代，直至完全氘代；     R Z1a is
    Figure PCTCN2022141536-appb-100052
    It is optionally substituted by D up to full deuteration;
    R*选自H、D或C 1-4烷基，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
    R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  49. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
    R 2为卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R 2 is halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R 3选自H或D； R is selected from H or D;
    R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
    R 6为C 1-4烷基，其任选地被D取代，直至完全氘代； R 6 is C 1-4 alkyl, which is optionally substituted by D, until fully deuterated;
    R Z1a为
    Figure PCTCN2022141536-appb-100053
    其任选地被D取代，直至完全氘代；     R Z1a is
    Figure PCTCN2022141536-appb-100053
    It is optionally substituted by D up to full deuteration;
    X为O、S、S(O)、S(O) 2、NR N或C(R C) 2； X is O, S, S(O), S(O) 2 , NR N or C(R C ) 2 ;
    R*选自H、D或C 1-4烷基，或者两个R*以及它们连接的原子一起形成C＝O或C＝S，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, or two R* and the atoms to which they are attached together form C=O or C=S, which is optionally substituted by D, up to complete deuteration;
    R N选自H、C 1-6烷基、C 1-6卤代烷基或C(O)R； RN is selected from H, C 1-6 alkyl, C 1-6 haloalkyl or C(O)R;
    R C独立地选自H、D、卤素、OH、C(O)R、C 1-6烷基或C 1-6卤代烷基； R C is independently selected from H, D, halogen, OH, C(O)R, C 1-6 alkyl or C 1-6 haloalkyl;
    R选自H、C 1-6烷基或C 1-6卤代烷基； R is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个 R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
    R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  50. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-4 haloalkyl, which is optionally substituted by D, up to complete deuteration;
    R 2为卤素或C 1-4烷基，其任选地被D取代，直至完全氘代； R 2 is halogen or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R 3选自H或D； R is selected from H or D;
    R 5为C 1-4烷基，其任选地被D取代，直至完全氘代； R is C 1-4 alkyl, which is optionally substituted by D until fully deuterated;
    R 6为C 1-4烷基，其任选地被D取代，直至完全氘代； R 6 is C 1-4 alkyl, which is optionally substituted by D, until fully deuterated;
    R Z1a为
    Figure PCTCN2022141536-appb-100054
    其任选地被D取代，直至完全氘代；     R Z1a is
    Figure PCTCN2022141536-appb-100054
    It is optionally substituted by D up to full deuteration;
    R*选自H、D或C 1-4烷基，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-4 alkyl, which is optionally substituted by D, up to complete deuteration;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
    R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  51. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-2卤代烷基，其任选地被D取代，直至完全氘代； R 1 is C 1-2 haloalkyl, which is optionally substituted by D, up to fully deuterated;
    R 2为卤素或C 1-2烷基，其任选地被D取代，直至完全氘代； R 2 is halogen or C 1-2 alkyl, which is optionally substituted by D, up to fully deuterated;
    R 3选自H或D； R is selected from H or D;
    R 5为C 1-2烷基，其任选地被D取代，直至完全氘代； R is C 1-2 alkyl, which is optionally substituted by D until fully deuterated;
    R 6为C 1-2烷基，其任选地被D取代，直至完全氘代； R 6 is C 1-2 alkyl, which is optionally substituted by D, until fully deuterated;
    R Z1a为
    Figure PCTCN2022141536-appb-100055
    其任选地被D取代，直至完全氘代；     R Z1a is
    Figure PCTCN2022141536-appb-100055
    It is optionally substituted by D up to full deuteration;
    R*选自H、D或C 1-2烷基，其任选地被D取代，直至完全氘代； R* is selected from H, D or C 1-2 alkyl, which is optionally substituted by D, up to complete deuteration;
    R Z3b选自H、D、卤素、C 1-6烷基、C 1-6卤代烷基、苯基或5-6元杂芳基，其任选地被1、2或3个R s取代，其还任选地被D取代，直至完全氘代； R Z3b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted by 1, 2 or 3 Rs , It is also optionally substituted with D, up to full deuteration;
    R s选自OH、OC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、S(O)C 1-6烷基或S(O) 2C 1-6烷基，其任选地被D取代，直至完全氘代。 R s is selected from OH, OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, S(O)C 1-6 alkyl or S(O) 2 C 1-6 alkyl, It is optionally substituted with D until fully deuterated.
  52. 权利要求36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CF 3或CHF 2； R 1 is selected from CF 3 or CHF 2 ;
    R 2选自F或CH 3； R 2 is selected from F or CH 3 ;
    R 3为H； R3 is H;
    R 5为CH 3； R 5 is CH 3 ;
    R 6选自CH 3或CD 3； R 6 is selected from CH 3 or CD 3 ;
    R Z1a选自
    Figure PCTCN2022141536-appb-100056
    R Z1a is selected from
    Figure PCTCN2022141536-appb-100056
    R Z3b选自H、Cl、
    Figure PCTCN2022141536-appb-100057
    R Z3b is selected from H, Cl,
    Figure PCTCN2022141536-appb-100057
  53. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有式(X)、(X-1)或(X-2)的结构：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the formula ( Structure of X), (X-1) or (X-2):
    Figure PCTCN2022141536-appb-100058
    Figure PCTCN2022141536-appb-100058
    其中，in,
    R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
    R 2选自H、D、卤素或C 1-4烷基； R 2 is selected from H, D, halogen or C 1-4 alkyl;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或5-6元杂环基，其任选地被1、2、3、4或5个R#取代； Or R 1 and R 2 and the atoms they connect together form C 5-6 cycloalkyl or 5-6 membered heterocyclyl, which is optionally substituted by 1, 2, 3, 4 or 5 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为NR Z3a； Z 3 is NR Z3a ;
    R Z1b为任选地被1、2或3个R*取代的C 3-8环烷基或4-7元杂环基； R Z1b is C 3-8 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
    R*选自卤素、-C 0-4亚烷基-OR、-C 0-4亚烷基-NRR’、-C 0-4亚烷基-CN、-C(O)R、C 1-6烷基、C 1-6卤代烷基、5-6元杂芳基或C 6-10芳基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成C＝O、C＝S、C 1-4亚烷基、C 5-6环烷基或5-6元杂环基； R* is selected from halogen, -C 0-4 alkylene-OR, -C 0-4 alkylene-NRR', -C 0-4 alkylene-CN, -C(O)R, C 1- 6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl or C 6-10 aryl, or two R* on the same or different carbon atoms and the atoms they connect together form C=O, C =S, C 1-4 alkylene, C 5-6 cycloalkyl or 5-6 membered heterocyclic group;
    R Z2a和R Z3a独立地为化学键、C 1-6烷基或C 1-6卤代烷基； R Z2a and R Z3a are independently chemical bonds, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2c为化学键； R Z2c is a chemical bond;
    其中R Z2a和R Z3a、R Z2c和R Z3a可以结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
    其中R 1、R 2、R Z2a、R Z3a、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R Z2a , R Z3a , R Z1b and R Z2b may be optionally substituted by D until complete deuteration.
  54. 权利要求53的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 53, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
    R 2选自H、D、卤素或C 1-2烷基； R 2 is selected from H, D, halogen or C 1-2 alkyl;
    或者R 1和R 2以及它们连接的原子一起形成C 5-6环烷基或含硫原子的5-6元杂环基，其任选地被 1或2个R#取代； Or R 1 and R 2 and the atoms they connect together form a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing a sulfur atom, which is optionally substituted by 1 or 2 R#;
    R#选自卤素，或者同一碳原子上的两个相邻R#一起形成C＝O或C＝S；R# is selected from halogen, or two adjacent R# on the same carbon atom together form C=O or C=S;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为NR Z3a； Z 3 is NR Z3a ;
    R Z1b任选地被1、2或3个R*取代的5-6元杂环基； R Z1b is optionally substituted by 1, 2 or 3 R * 5-6 membered heterocyclyl;
    R*选自H、D、卤素、-OR、-C(O)R、C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from H, D, halogen, -OR, -C(O)R, C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and their connected The atoms together form a 5-6 membered heterocyclic group;
    R Z2a和R Z3a独立地为化学键、C 1-6烷基或C 1-6卤代烷基； R Z2a and R Z3a are independently chemical bonds, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2c为化学键； R Z2c is a chemical bond;
    其中R Z2a和R Z3a、R Z2c和R Z3a可以结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S； or R Z2b and R Z2c form C=O or C=S with the carbon atoms to which they are attached;
    R和R’独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基，或者R、R’与它们连接的氮原子形成4-8元杂环基； R and R' are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-8 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, or R, R' and their connected nitrogen atoms form a 4-8 membered heterocyclic group;
    其中R 1、R 2、R Z2a、R Z3a、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R Z2a , R Z3a , R Z1b and R Z2b may be optionally substituted by D until complete deuteration.
  55. 权利要求54的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1选自CHF 2或CF 3； R 1 is selected from CHF 2 or CF 3 ;
    R 2选自H、D、F或CH 3； R 2 is selected from H, D, F or CH 3 ;
    R 3选自H、D或NH 2； R 3 is selected from H, D or NH 2 ;
    优选地，R 2和R 3不同时为H或D； Preferably, R 2 and R 3 are not H or D at the same time;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为NR Z3a； Z 3 is NR Z3a ;
    R Z1b选自
    Figure PCTCN2022141536-appb-100059
    R Z1b selected from
    Figure PCTCN2022141536-appb-100059
    R Z2a和R Z3a独立地为化学键或CH 3； R Z2a and R Z3a are independently a chemical bond or CH 3 ;
    R Z2b为H或D； R Z2b is H or D;
    R Z2c为化学键； R Z2c is a chemical bond;
    其中R Z2a和R Z3a、R Z2c和R Z3a可以结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a can be combined to form a double bond;
    或者R Z2b和R Z2c与它们连接的碳原子形成C＝O或C＝S。 Alternatively R Z2b and R Z2c form C=O or C=S with the carbon atom to which they are attached.
  56. 权利要求53的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 53, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-4卤代烷基； R 1 is C 1-4 haloalkyl;
    R 2选自卤素或C 1-4烷基； R 2 is selected from halogen or C 1-4 alkyl;
    或者R 1和R 2以及它们连接的原子一起形成C 4-7环烷基，其任选地被1、2或3个R#取代； or R 1 and R 2 and the atoms to which they are attached together form a C 4-7 cycloalkyl group, which is optionally substituted by 1, 2 or 3 R#;
    R#为卤素；R# is halogen;
    R 3选自H或D； R is selected from H or D;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为NR Z3a； Z 3 is NR Z3a ;
    R Z1b为任选地被1、2或3个R*取代的5-6元杂环基； R Z1b is a 5-6 membered heterocyclyl optionally substituted by 1, 2 or 3 R*;
    R*选自H、D、卤素、C 1-2烷基或C 1-2卤代烷基，或者相同或不同碳原子上的两个R*以及它们连接的原子一起形成5-6元杂环基； R* is selected from H, D, halogen, C 1-2 alkyl or C 1-2 haloalkyl, or two R* on the same or different carbon atoms and the atoms they are connected together form a 5-6 membered heterocyclic group ;
    R Z2a和R Z3a独立地为化学键； R Z2a and R Z3a are independently chemical bonds;
    R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2c为化学键； R Z2c is a chemical bond;
    其中R Z2a和R Z3a、R Z2c和R Z3a结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a combine to form double bonds;
    其中R 1、R 2、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R Z1b and R Z2b can be optionally substituted by D until complete deuteration.
  57. 权利要求56的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 56, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为C 1-2卤代烷基； R 1 is C 1-2 haloalkyl;
    R 2选自卤素或C 1-2烷基； R 2 is selected from halogen or C 1-2 alkyl;
    R 3选自H或D； R is selected from H or D;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为NR Z3a； Z 3 is NR Z3a ;
    R Z1b为5-6元杂环基； R Z1b is a 5-6 membered heterocyclic group;
    R Z2a和R Z3a独立地为化学键； R Z2a and R Z3a are independently chemical bonds;
    R Z2b为H、D、C 1-6烷基或C 1-6卤代烷基； R Z2b is H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R Z2c为化学键； R Z2c is a chemical bond;
    其中R Z2a和R Z3a、R Z2c和R Z3a结合形成双键； Wherein R Z2a and R Z3a , R Z2c and R Z3a combine to form double bonds;
    其中R 1、R 2、R Z1b和R Z2b中的各基团可任选地被D取代，直至完全氘代。 Wherein each group in R 1 , R 2 , R Z1b and R Z2b can be optionally substituted by D until complete deuteration.
  58. 权利要求57的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，The compound of claim 57, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    R 1为CHF 2； R 1 is CHF 2 ;
    R 2为F； R2 is F;
    R 3为H； R3 is H;
    Z 2为NR Z2a或CR Z2bR Z2c； Z 2 is NR Z2a or CR Z2b R Z2c ;
    Z 3为NR Z3a； Z 3 is NR Z3a ;
    R Z1b为
    Figure PCTCN2022141536-appb-100060
    R Z1b is
    Figure PCTCN2022141536-appb-100060
    R Z2a和R Z3a独立地为化学键； R Z2a and R Z3a are independently chemical bonds;
    R Z2b为H或D； R Z2b is H or D;
    R Z2c为化学键； R Z2c is a chemical bond;
    其中R Z2a和R Z3a、R Z2c和R Z3a结合形成双键。 Wherein R Z2a and R Z3a , R Z2c and R Z3a combine to form double bonds.
  59. 化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中所述化合物选自：A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from:
    Figure PCTCN2022141536-appb-100061
    Figure PCTCN2022141536-appb-100061
    Figure PCTCN2022141536-appb-100062
    Figure PCTCN2022141536-appb-100062
    Figure PCTCN2022141536-appb-100063
    Figure PCTCN2022141536-appb-100063
    Figure PCTCN2022141536-appb-100064
    Figure PCTCN2022141536-appb-100064
    Figure PCTCN2022141536-appb-100065
    Figure PCTCN2022141536-appb-100065
    Figure PCTCN2022141536-appb-100066
    Figure PCTCN2022141536-appb-100066
    Figure PCTCN2022141536-appb-100067
    Figure PCTCN2022141536-appb-100067
    Figure PCTCN2022141536-appb-100068
    Figure PCTCN2022141536-appb-100068
    Figure PCTCN2022141536-appb-100069
    Figure PCTCN2022141536-appb-100069
    Figure PCTCN2022141536-appb-100070
    Figure PCTCN2022141536-appb-100070
    Figure PCTCN2022141536-appb-100071
    Figure PCTCN2022141536-appb-100071
  60. 化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中所述化合物选自：A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from:
    Figure PCTCN2022141536-appb-100072
    Figure PCTCN2022141536-appb-100072
    Figure PCTCN2022141536-appb-100073
    Figure PCTCN2022141536-appb-100073
    Figure PCTCN2022141536-appb-100074
    Figure PCTCN2022141536-appb-100074
  61. 药物组合物，其包含权利要求1-60中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，和药学上可接受的载体、佐剂或媒介物，任选地其它治疗剂。A pharmaceutical composition comprising a compound according to any one of claims 1-60, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrated compound or solvate, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally other therapeutic agents.
  62. 权利要求1-60中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物在制备用于治疗或预防SOS1介导的疾病的药物中的用途。The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof in Use in the preparation of medicines for treating or preventing SOS1-mediated diseases.
  63. 一种在受试者中治疗或预防SOS1介导的疾病的方法，包括向所述受试者给药权利要求1-60中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，或权利要求61的药物组合物。A method for treating or preventing a disease mediated by SOS1 in a subject, comprising administering to the subject a compound according to any one of claims 1-60, or a pharmaceutically acceptable salt thereof, an isotopically modified isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, or the pharmaceutical composition of claim 61.
  64. 权利要求1-60中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，或权利要求61的药物组合物，其用于治疗或预防SOS1介导的疾病。The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or the pharmaceutical composition of claim 61, which is used for the treatment or prevention of SOS1 mediated diseases.
  65. 权利要求62的用途或权利要求63的方法或权利要求64的化合物或药物组合物的用途，其中所述SOS1介导的疾病为癌症。The use of claim 62 or the method of claim 63 or the use of the compound or pharmaceutical composition of claim 64, wherein the disease mediated by SOS1 is cancer.
  66. 权利要求62的用途或权利要求63的方法或权利要求64的化合物或药物组合物的用途，其中所述SOS1介导的疾病选自胰腺癌、肺癌、结直肠癌、胆管癌、多发性骨髓瘤、黑素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、胶质母细胞瘤、肾癌和肉瘤。The use of claim 62 or the method of claim 63 or the use of the compound or pharmaceutical composition of claim 64, wherein the SOS1-mediated disease is selected from pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma , melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, Esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.
  67. 权利要求62的用途或权利要求63的方法或权利要求64的化合物或药物组合物的用途，其中所述SOS1介导的疾病为RAS病，优选地，所述RAS病选自1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病。The use of claim 62 or the method of claim 63 or the use of the compound or pharmaceutical composition of claim 64, wherein the SOS1-mediated disease is RAS disease, preferably, the RAS disease is selected from neurofibromatosis type 1 Noonan Syndrome (NF1), Noonan Syndrome (NS), Noonan Syndrome with Mottling (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-facial-cutaneous syndrome (CFC), Legers syndrome, and hereditary gingival fibromatosis.
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