WO2023116902A1 - Inhibiteur de sos1 - Google Patents

Inhibiteur de sos1 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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alkyl
haloalkyl
optionally substituted
halogen
cycloalkyl
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PCT/CN2022/141536
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English (en)
Chinese (zh)
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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/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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

L'invention concerne un inhibiteur de SOS1 représenté par la formule (X), ou un sel pharmaceutiquement acceptable, un variant isotopique, un tautomère, un stéréoisomère, un promédicament, un polymorphe, un hydrate ou un solvate de celui-ci. L'invention concerne en outre un procédé de préparation d'un composé, une composition pharmaceutique comprenant un composé, et une utilisation d'un composé dans la prévention et le traitement de cancers associés, tels que le cancer du poumon, le cancer du côlon et le cancer du pancréas.
PCT/CN2022/141536 2021-12-23 2022-12-23 Inhibiteur de sos1 WO2023116902A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016130460A2 (fr) * 2015-02-09 2016-08-18 The Johns Hopkins University Dérivés de phtalazinone pyrazole pour le traitement d'une maladie dégénérative rétinienne
WO2022026465A1 (fr) * 2020-07-28 2022-02-03 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022081912A2 (fr) * 2020-10-15 2022-04-21 Kumquat Biosciences Inc. Hétérocycles et leurs utilisations
CN114621186A (zh) * 2022-05-12 2022-06-14 上海维申医药有限公司 作为ras信号通路调控剂的杂环化合物
WO2022170952A1 (fr) * 2021-02-09 2022-08-18 苏州阿尔脉生物科技有限公司 Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation
CN115043842A (zh) * 2021-03-09 2022-09-13 苏州泽璟生物制药股份有限公司 胺基取代双环类抑制剂及其制备方法和应用
WO2022251497A1 (fr) * 2021-05-27 2022-12-01 Schrödinger, Inc. Composés hétérocycliques et procédés d'utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016130460A2 (fr) * 2015-02-09 2016-08-18 The Johns Hopkins University Dérivés de phtalazinone pyrazole pour le traitement d'une maladie dégénérative rétinienne
WO2022026465A1 (fr) * 2020-07-28 2022-02-03 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022081912A2 (fr) * 2020-10-15 2022-04-21 Kumquat Biosciences Inc. Hétérocycles et leurs utilisations
WO2022170952A1 (fr) * 2021-02-09 2022-08-18 苏州阿尔脉生物科技有限公司 Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation
CN115043842A (zh) * 2021-03-09 2022-09-13 苏州泽璟生物制药股份有限公司 胺基取代双环类抑制剂及其制备方法和应用
WO2022251497A1 (fr) * 2021-05-27 2022-12-01 Schrödinger, Inc. Composés hétérocycliques et procédés d'utilisation
CN114621186A (zh) * 2022-05-12 2022-06-14 上海维申医药有限公司 作为ras信号通路调控剂的杂环化合物

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