WO2023207556A1 - Prmt5-mta抑制剂 - Google Patents

Prmt5-mta抑制剂 Download PDF

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WO2023207556A1
WO2023207556A1 PCT/CN2023/087001 CN2023087001W WO2023207556A1 WO 2023207556 A1 WO2023207556 A1 WO 2023207556A1 CN 2023087001 W CN2023087001 W CN 2023087001W WO 2023207556 A1 WO2023207556 A1 WO 2023207556A1
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alkyl
haloalkyl
halogen
cycloalkyl
membered heterocyclyl
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PCT/CN2023/087001
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English (en)
French (fr)
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刘彬
高峰
郭永起
吴勇勇
景连栋
李治中
高宇
吴卓
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苏州浦合医药科技有限公司
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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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the invention belongs to the field of medicine, and specifically relates to PRMT5-MTA inhibitors.
  • PRMT Protein arginine methyltransferase
  • PRMT family members have been discovered, which can be divided into types I, II, and III according to the different ways of catalyzing arginine methylation.
  • PRMT5 belongs to type II, and its catalytic form is symmetrical dimethylation.
  • PRMT5 As an epigenetic enzyme, PRMT5 is involved in a variety of biological processes, including transcriptional regulation, RNA metabolism, ribosome biogenesis, and cell cycle regulation. PRMT5 protein is overexpressed in a variety of cancer types, including B and T cell lymphoma, metastatic melanoma, neuroblastoma, glioblastoma, ovarian cancer, breast cancer, etc., and there is increasing evidence that it Plays an important role in tumor occurrence and development (Cell Stress. 2020 Aug; 4(8):199–215) (Cancer Gene Ther. 2022 Mar; 29(3-4): 264-276.). On this basis, PRMT5 inhibitors have become a hot spot in the research and development of tumor treatment drugs.
  • PRMT5 inhibitors can be divided into two categories, one is a substrate competitive inhibitor, the representative drug is GSK3326595; the other is a SAM competitive inhibitor, the representative drug is JNJ64619178. Both types of drugs have strong inhibitory activity against PRMT5 and show strong anti-tumor activity. However, because they have strong inhibitory activity against PRMT5 in both normal cells and tumor cells, strong hematological toxicity has been observed, limiting their clinical application.
  • MTAP has a high deletion rate in a variety of solid tumors, including pancreatic cancer, glioma, etc.
  • MTAP is an intracellular MTA-degrading enzyme. The lack of MTAP can lead to intracellular accumulation of MTA, and MTA can compete with PRMT5's functional substrate methylation donor SAM for binding to PRMT5, thereby inhibiting the function of PRMT5.
  • MTA specifically accumulates in MTAP-deficient tumor cells, by strengthening the binding inhibition between MTA and PRMT5, specific inhibition of PRMT5 activity in tumor cells can be achieved, while the inhibitory effect on PRMT5 activity in normal cells is weak, thus providing a safe window for treatment.
  • Reduce toxicity while ensuring anti-tumor efficacy (Nat Rev Drug Discov.2020 Jan; 19(1):23-38)(Cell Rep.2016 Apr 19;15(3):574-587).
  • MTA synergistic PRMT5 inhibitors have obtained preclinical validation data (J Med Chem. 2022 Feb 10;65(3):1749-1766). The development of MTA-synergistic PRMT5 inhibitors has great potential in the treatment of MTAP-deficient tumors.
  • the invention provides a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof Object:
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • L is selected from C(O), C(O)NH, C(O)-C(O) or C(O)-C(O)NH;
  • Ring S is selected from C 6-10 aryl, 6-10 membered heteroaryl, C 5-10 cycloalkyl or 5-10 membered heterocyclyl;
  • R 1 and R 2 are independently selected from H, halogen, SF 5 , OR a , NR b R c , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1 -6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, S(O) 2 -R d or S(O)-R d ; the R 1 and R 2 may be optionally further substituted by halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.
  • the R 1 and R 2 may be optionally further substituted by halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 , R 2 and the carbon atoms to which they are connected together form a C 4-10 cycloalkyl group, a 4-10 membered heterocyclyl group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 4 -10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be optionally substituted by 1, 2, 3, 4 or 5 Rx;
  • Rx is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, or is optionally substituted by one or more groups of halogen, C 1-6 alkyl, C 1-6 haloalkyl C 4-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heterocyclyl;
  • R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 aryl, R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is selected from C 4-10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 aryl;
  • Ring B is C 5-10 cycloalkyl or 5-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, OR a , C 1-6 alkylene-OR a , NR b R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy ;
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 and R 9 are independently selected from OR a , C 1-6 alkylene-OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 Alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 metaheteroaryl;
  • R 7 and R 8 are independently selected from OR a , NR b R c ;
  • R 10 is selected from H, halogen, OR a , NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 11 is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n is selected from 1, 2 or 3;
  • R a , R b , R c and R d are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 is not C 1-6 alkyl, halogen, C 1-6 haloalkyl and C 2-6 alkynyl;
  • the above groups may optionally be substituted with 1, 2, 3, 4, 5 or more deuteriums until completely deuterated.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
  • X 1 is N or CR 2 ;
  • L is selected from C(O), C(O)NH, C(O)-C(O) or C(O)-C(O)NH;
  • Ring S is selected from C 6-10 aryl, 6-10 membered heteroaryl, C 5-10 cycloalkyl or 5-10 membered heterocyclyl;
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -S(O) 2 C 1-6 alkyl, -S(O) 2 haloC 1 -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 3 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which may be optionally replaced by 1, 2 or 3 R #replace;
  • R 4 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-4 alkylene-OR a or C 1-4 alkylene-NR b R c , It may optionally be replaced by 1, 2 or 3 R#;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group or a C 6-10 aryl group
  • Ring B is C 4-10 cycloalkyl or 4-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3 or 4 R#;
  • R 5 , R 5 ' and R 6 ' are selected from H, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 6 and R 9 are independently selected from OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 heteroaryl;
  • R 5 ' and R 6 ' are connected to form a bond, or R 5 ', R 6 ' and the carbon atoms they are connected together form a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group;
  • R 7 and R 8 are independently selected from OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R# is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 is not C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkynyl;
  • the above groups may optionally be substituted with 1, 2, 3, 4, 5 or more deuteriums until completely deuterated.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
  • the invention provides pharmaceutical compositions containing a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prevention of PRMT5 methyltransferase-mediated diseases.
  • the invention provides a method of treating and/or preventing a PRMT5 methyltransferase-mediated disease in a subject, comprising administering to said subject a compound of the invention or a composition of the invention.
  • the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of PRMT5 methyltransferase-mediated diseases.
  • the diseases treated by the present invention include cancers selected from the group consisting of: acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphatic endothelial sarcoma, hemangioma), appendiceal cancer , benign monoclonal gamma disease, cholangiocarcinoma, bladder cancer, brain cancer (such as meningiomas, gliomas such as astrocytoma, oligodendroglioma, medulloblastoma), bronchial cancer, Carcinoid tumor, cervical cancer (such as cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (such as colon cancer, rectal cancer, large intestine adenocarcinoma), epithelial cancer, ependymoma tumor
  • 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 refers to a straight or branched chain 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 ), tert-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-pentyl (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) substitution.
  • Alkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).
  • C 2-6 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 groups include: vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc.
  • C 2-6 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) substitution.
  • Alkenyl groups 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 groups 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 ), etc.
  • C 2-6 alkynyl 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) substitution.
  • 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 is not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), ethylene Base (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,etc.
  • alkylene groups substituted by one or more alkyl (methyl) include, but are not limited to: substituted methylene (-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 -), etc.
  • C 2-6 alkynylene refers to a divalent group formed by removing the other hydrogen of the C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene is particularly preferred. Exemplary 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 by one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, with C 1-2 haloalkyl being more preferred.
  • 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, etc.
  • Haloalkyl groups may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkoxy refers to the group -OR, where R is C 1-6 alkyl as defined above. C 1-4 alkoxy is preferred.
  • C 1-6 haloalkoxy refers to "C 1-6 alkoxy” which is substituted by one or more halogen groups. In some embodiments, C 1-4 haloalkoxyalkyl is particularly preferred, with C 1-2 haloalkoxyalkyl being more preferred.
  • C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms.
  • C 4-10 cycloalkyl, C 5-10 cycloalkyl, C 4-7 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 Cycloalkyl and C 3-4 cycloalkyl are particularly preferred, with C 5-6 cycloalkyl being more preferred.
  • Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring is fused with 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 as indicated The number of carbons in a cycloalkyl system.
  • Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene group (C 7 ), cycloheptadienyl (C 7 ), cycloheptadienyl (C 7 ), etc.
  • a cycloalkyl group 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 refers to a group of 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 may be a carbon or nitrogen atom as long as the valency permits.
  • 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 4-10 membered is preferred Heterocyclyl, which is a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 5-10 membered heterocyclyl is preferred, which is a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms.
  • 4 to 7 membered non-aromatic ring system of atoms preferably 4 to 6 membered heterocyclyl, which is a 4 to 6 membered nonaromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably 5 to 6 membered Heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, a 3-5-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
  • a 3- to 5-membered nonaromatic ring system of heteroatoms preferably 4 to 6 membered heterocyclyl, which is a 4 to 6 membered nonaromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
  • Heterocyclyl also includes ring systems in which the above-described heterocyclyl ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or in which the above-described heterocyclyl ring is fused with one or more aryl groups 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 represent the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxirinyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-diketone.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolyl, oxasulfuranyl, disulfuranyl, and oxalanyl.
  • Exemplary 5-membered heterocyclyl 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, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl).
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl, oxpanyl, and thipanyl.
  • Exemplary 5-membered heterocyclyl fused to a C6 aryl ring include, but are not limited to: indolyl, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc.
  • Exemplary 6-membered heterocyclyl fused to a C6 aryl ring include, but are not limited to: tetrahydroquinolyl, tetrahydroisoquinolyl, etc.
  • Heterocyclyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 aryl refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having a Shared 6 or 10 ⁇ electrons) group.
  • an aryl group has six ring carbon atoms ("C 6 aryl”; e.g., 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 in which the aryl ring described above 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.
  • Aryl groups 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 refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having a 6, 10 or 14 ⁇ electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes those in which the heteroaryl ring described above is combined with one or more cycloalkyl groups or a heterocyclyl fused ring system, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system.
  • 5-10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-10 membered heteroaryl groups are preferred, which are 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-9 membered heteroaryl groups are preferred, which are 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems 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: azepantrienyl, oxetapyltrienyl, and thioheptantrienyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indazinyl and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pyridinyl, quinolinyl, isoquinolinyl, quinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • “Cycloalkylene”, “heterocyclylene”, “arylene” or “heteroaryl” is the “cycloalkyl", “heterocyclyl”, “aryl” or “heteroaryl” defined above.
  • “Basic group” is a divalent group formed by removing another hydrogen, and may be substituted or unsubstituted.
  • C 5-7 cycloalkylene refers to a divalent group formed by removing another hydrogen of C 5-7 cycloalkyl
  • 5-8 membered heterocyclylene refers to removing 5-8 A divalent group formed by removing another hydrogen of a C 6-10 aryl group
  • C 6-10 arylene refers to a divalent group formed by removing another hydrogen of a C 6-10 aryl group
  • 5-6 Metal-heteroaryl refers to a divalent group formed by removing another hydrogen of a 5- to 6-membered heteroaryl group.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc. are defined herein as optionally substituted groups.
  • Each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa groups are combined to form heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups group replacement;
  • Each R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocycle 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;
  • Each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff groups combine 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;
  • the term "pharmaceutically acceptable salts” means those carboxylate salts and amino acid addition salts of the compounds of the present invention which are suitable for contact with patient tissue within the scope of reliable medical judgment and will not produce undue toxicity, Irritation effects, allergic reactions, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the invention.
  • Subjects for administration include, but are not limited to: humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is human.
  • the subject is a non-human animal.
  • the terms "person,” “patient,” and “subject” are used interchangeably herein.
  • an "effective amount" of a compound is an amount sufficient to elicit a target biological response.
  • the effective amount of a compound of the present 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.
  • the effective amount includes a therapeutically effective amount and a preventive effective amount.
  • 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 present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or with other therapeutic agents in a single unit dosage form.
  • compounds of the present invention refer to the following compounds of formula (A) (including sub-general formulas, such as formulas (A-1), (A-2), (I), (II), (III), (IV), (V), (V-1), (V-2), (VI), (VII), (VIII), (IX), (X), (X-1), (X-2 ), (XI), (XII) or (XIII), etc.), their pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, and their mixture.
  • the present invention relates to a compound of formula (A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • L is selected from C(O), C(O)NH, C(O)-C(O) or C(O)-C(O)NH;
  • Ring S is selected from C 6-10 aryl, 6-10 membered heteroaryl, C 5-10 cycloalkyl or 5-10 membered heterocyclyl;
  • R 1 and R 2 are independently selected from H, halogen, SF 5 , OR a , NR b R c , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1 -6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, S(O) 2 -R d or S(O)-R d ; the R 1 and R 2 may be optionally further substituted by halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.
  • the R 1 and R 2 may be optionally further substituted by halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 , R 2 and the carbon atoms to which they are connected together form a C 4-10 cycloalkyl group, a 4-10 membered heterocyclyl group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 4 -10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be optionally substituted by 1, 2, 3, 4 or 5 Rx;
  • Rx is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, or is optionally substituted by one or more groups of halogen, C 1-6 alkyl, C 1-6 haloalkyl C 4-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heterocyclyl;
  • R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 aryl, R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is selected from C 4-10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 aryl;
  • Ring B is C 5-10 cycloalkyl or 5-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, OR a , C 1-6 alkylene-OR a , NR b R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy ;
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 and R 9 are independently selected from OR a , C 1-6 alkylene-OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 Alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 metaheteroaryl;
  • R 7 and R 8 are independently selected from OR a , NR b R c ;
  • R 10 is selected from H, halogen, OR a , NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 11 is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n is selected from 1, 2 or 3;
  • R a , R b , R c and R d are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 is not C 1-6 alkyl, halogen, C 1-6 haloalkyl and C 2-6 alkynyl.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvates:
  • X 1 is N or CR 2 ;
  • L is selected from C(O), C(O)NH, C(O)-C(O) or C(O)-C(O)NH;
  • Ring S is selected from C 6-10 aryl, 6-10 membered heteroaryl, C 5-10 cycloalkyl or 5-10 membered heterocyclyl;
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -S(O) 2 C 1-6 alkyl, -S(O) 2 haloC 1 -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 3 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which may be optionally replaced by 1, 2 or 3 R #replace;
  • R 4 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-4 alkylene-OR a or C 1-4 alkylene-NR b R c , It may optionally be replaced by 1, 2 or 3 R#;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group or a C 6-10 aryl group
  • Ring B is C 4-10 cycloalkyl or 4-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3 or 4 R#;
  • R 5 , R 5 ' and R 6 ' are selected from H, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 6 and R 9 are independently selected from OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 heteroaryl;
  • R 5 ' and R 6 ' are connected to form a bond, or R 5 ', R 6 ' and the carbon atoms they are connected together form a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group;
  • R 7 and R 8 are independently selected from OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R# is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 is not C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkynyl.
  • X 1 is N; in another specific embodiment, X 1 is CR 2 .
  • X2 is N; in another specific embodiment, X2 is CH.
  • X3 is N; in another specific embodiment, X3 is CH.
  • L is C(O); in another specific embodiment, L is C(O)NH; in another specific embodiment, L is C(O)-C(O); In another specific embodiment, L is C(O)-C(O)NH.
  • Ar is in
  • R 5 , R 5 ' and R 6 ' are selected from H, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 6 is selected from OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 heteroaryl;
  • R 5 ' and R 6 ' are connected to form a bond, or R 5 ', R 6 ' and the carbon atoms to which they are connected together form a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group.
  • Ar is In another specific embodiment, Ar is in another In specific embodiments, Ar is In another specific embodiment, Ar is
  • Ar is in
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 is selected from OR a , C 1-6 alkylene-OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;
  • R 7 is selected from OR a or NR b R c ;
  • R 10 is selected from H, halogen, OR a , NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • n is selected from 1, 2 or 3.
  • Ar is in
  • R 8 is selected from OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 9 is selected from OR a , C 1-6 alkylene-OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;
  • Ring S is C 6-10 aryl; in another specific embodiment, Ring S is 6-10 membered heteroaryl; in another specific embodiment, Ring S is C 5- 10 cycloalkyl; in another specific embodiment, Ring S is 5-10 membered heterocyclyl.
  • R 1 is H; in another specific embodiment, R 1 is halogen, such as Cl, Br; in another specific embodiment, R 1 is C 1-6 alkyl; in another specific embodiment, R 1 is C 1-6 alkyl; In one 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.
  • R 1 is -S(O) 2 C 1-6 alkyl, such as S(O) 2 -C 1-4 haloalkyl; In another specific embodiment, R 1 is -S(O) 2 haloC 1-6 alkyl; in another specific embodiment, R 1 is C 2-6 alkenyl; in another specific embodiment in, R 1 is C 2-6 alkynyl; in another specific embodiment, R 1 is SF 5 ; in another specific embodiment, R 1 is OR a ; in another specific embodiment, R 1 is NR b R c ; in another specific embodiment, R 1 is CN; in another specific embodiment, R 1 is C 1-6 alkoxy; in another specific embodiment, R 1 is C 1-4 alkoxy, preferably C 1-2 alkoxy, such as OCF 3 ; in another specific embodiment, R 1 is C 1-6 haloalkoxy, such as C 1-4 haloalkoxy; in In another specific embodiment, R 1 is
  • R 1 is Cl; in another specific embodiment, R 1 is Br; in another specific embodiment, R 1 is SF 5 ; in another specific embodiment, R 1 is CN; In another specific embodiment, R 1 is CF 3 ; In another specific embodiment, R 1 is OCF 3 ; In another specific embodiment, R 1 is cyclopropyl; In another specific implementation In the scheme, R 1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is in another specific embodiment, R1 is in another specific embodiment, R1 is in another specific embodiment, R1 is in another specific embodiment, R1 is in another specific embodiment, R1 is in another specific
  • R 1 is unsubstituted; in another specific embodiment, R 1 is substituted with Ry; in another specific embodiment, R 1 is optionally halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy is further substituted.
  • R 2 is H; in another specific embodiment, R 2 is halogen; 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 -S(O) 2 C 1-6 alkyl; in another specific embodiment, R 2 is -S(O ) 2 halo C 1-6 alkyl; in another embodiment, R 2 is C 2-6 alkenyl; in another embodiment, R 2 is C 2-6 alkynyl; in another In a specific embodiment, R 2 is SF 5 ; in another specific embodiment, R 2 is OR a ; in another specific embodiment, R 2 is NR b R c ; in another specific embodiment, R 2 is CN; in another specific embodiment, R 2 is C 1-6 alkoxy; in another specific embodiment, R 2 is C 1-6 haloalkoxy; in another specific embodiment, R 2 is a 3-7 membered heterocyclyl; in another embodiment, R 2 is a 5
  • R 2 is unsubstituted; in another specific embodiment, R 2 is optionally further substituted by halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
  • R 1 , R 2 and the carbon atoms to which they are attached together form a C 4-10 cycloalkyl group; in another embodiment, R 1 , R 2 and the carbon atoms to which they are attached together form 4 -10-membered heterocyclyl; in another embodiment, R 1 , R 2 and the carbon atoms to which they are attached together form a C 6-10 aryl group; in another embodiment, R 1 , R 2 and they The attached carbon atoms together form a 5-10 membered heteroaryl group; in another specific embodiment, R1 , R2 and the carbon atoms to which they are attached together form a 5-6 membered heteroaryl group.
  • R 1 , R 2 and the carbon atoms to which they are connected together form a C 4-10 cycloalkyl group, a 4-10 membered heterocyclyl group, a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  • a group may be optionally substituted with 1, 2, 3, 4 or 5 Rx.
  • R 1 , R 2 together form In another specific embodiment, R 1 , R 2 taken together form
  • R 3 is C 1-6 alkyl; in one specific embodiment, R 3 is C 1-4 alkyl; in another specific embodiment, R 3 is C 1-6 haloalkyl group; in another specific embodiment, R 3 is C 1-6 alkylene-OR a ; in another specific embodiment, R 3 is C 1-4 alkylene-OR a , preferably C 1 -4 alkylene-OC 1-4 alkyl; in another embodiment, R 3 is C 1-6 alkylene -NR b R c ; in another embodiment, R 3 is C 1 -4 alkylene-NR b R c ; in another embodiment, R 3 is C 6-10 aryl, such as phenyl; in another embodiment, R 3 is 5-10 membered heteroaryl group; in another specific embodiment, R 3 is C 3-10 cycloalkyl; in another specific embodiment, R 3 is C 3-7 cycloalkyl; in another specific embodiment, R 3 is C 3-5 cycloalkyl; in another specific embodiment, R 3 is a 3
  • R 3 is CH 3 ; in another specific embodiment, R 3 is cyclopropyl; in another specific embodiment, R 3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is cyclopropyl; in another specific embodiment, R 3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In
  • R 3 is unsubstituted; in another specific embodiment, R 3 is substituted with 1 R#; in another In a specific embodiment, R 3 is replaced by 2 R#; in another specific embodiment, R 3 is replaced by 3 R#; in another specific embodiment, R 3 is replaced by 4 R#; in another specific embodiment, R 3 is replaced by 4 R#; In a specific embodiment, R3 is replaced by 5 R#.
  • R 4 is H; in another specific embodiment, R 4 is C 1-6 alkyl; in another specific embodiment, R 4 is C 1-4 alkyl, such as CH 3. CH 2 CH 3 ; In another specific embodiment, R 4 is C 3-7 cycloalkyl; in another specific embodiment, R 4 is C 3-6 cycloalkyl, preferably C 3- 5 cycloalkyl, more preferably C 3-4 cycloalkyl, such as cyclopropyl; in another specific embodiment, R 4 is a 3-7 membered heterocyclyl; in another specific embodiment, R 4 is C 1-6 haloalkyl; in another specific embodiment, R 4 is C 1-4 alkylene-OR a , for example In another specific embodiment, R 4 is C 1-4 alkylene-NR b R c .
  • R 4 is unsubstituted; in another embodiment, R 4 is substituted with 1 R#; in another embodiment, R 4 is substituted with 2 R#; in another In specific embodiments, R 4 is replaced by 3 R#.
  • R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form
  • R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form form In another specific embodiment, R 3 , R 4 and the carbon atom to which they are attached together form form In another specific embodiment
  • R 5 is H; in another specific embodiment, R 5 is OR a ; in another specific embodiment, R 5 is NR b R c ; in another specific embodiment, R 5 is C 1-6 alkyl; in another embodiment, R 5 is C 1-4 alkyl, such as CH 3 ; in another embodiment, R 5 is C 1-6 haloalkyl; In another specific embodiment, R 5 is C 2-6 alkenyl; in another specific embodiment, R 5 is C 2-6 alkynyl.
  • R 5 ' is H; in another embodiment, R 5 ' is OR a ; in another embodiment, R 5 ' is NR b R c ; in another embodiment, R 5 ' is H
  • R 5 ' 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 alkene group; in another specific embodiment, R 5 ' is C 2-6 alkynyl.
  • R 6 is OR a ; in another specific embodiment, R 6 is C 1-6 alkylene-OR a ; in another specific embodiment, R 6 is C 1-4 Alkylene-OH; in another embodiment, R 6 is C(O)NR b R c ; in another embodiment, R 6 is C(O)OR a ; in another embodiment In another specific embodiment, R 6 is C(O) Ra ; in another specific embodiment, R 6 is C 1-6 alkyl; in another specific embodiment, R 6 is C 1-6 haloalkyl; in another specific embodiment, R 6 is C 1-6 haloalkyl; In one specific embodiment, R 6 is C 2-6 alkenyl; in another specific embodiment, R 6 is C 2-6 alkynyl; in another specific embodiment, R 6 is C 3-7 ring Alkyl; in another specific embodiment, R 6 is C 3-5 cycloalkyl; in another specific embodiment, R 6 is 3-7 membered heterocyclyl; in another specific embodiment, R 6 is a 3-5 membered
  • R 6 is OCH 3 ; in another specific embodiment, R 6 is CH 2 OH; in another specific embodiment, R 6 is CH 2 OH; In an embodiment, R 6 is C(O) 2 NH 2 ; in another embodiment, R 6 is cyclopropyl; in another embodiment, R 6 is cyclobutyl; in another embodiment In the scheme, R 6 is
  • R 6 ' is H; in another embodiment, R 6 ' is OR a ; in another embodiment, R 6 ' is NR b R c ; in another embodiment, R 6 ' is OR
  • R 6 ' is C 1-6 alkyl; in another specific embodiment, R 6 ' is C 1-6 haloalkyl; in another specific embodiment, R 6 ' is C 2-6 alkene group; in another specific embodiment, R 6 ' is C 2-6 alkynyl.
  • R 5 ' and R 6 ' are connected to form a bond; in another specific embodiment, R 5 ', R 6 ' and the carbon atoms to which they are connected together form a C 3-7 cycloalkyl group; in another specific embodiment, R 5 ', R 6 ' and the carbon atom to which they are attached together form a 3-7 membered heterocyclyl group.
  • R 7 is OR a ; in another specific embodiment, R 7 is OCH 3 ; in another specific embodiment, R 7 is NR b R c ; in another specific embodiment, R 7 is OCH 3 ; in another specific embodiment, R 7 is NR b R c ; in another specific embodiment, R 7 is OCH 3 , R 7 is NH 2 ; in another specific embodiment, R 7 is C 1-6 alkyl; in another specific embodiment, R 7 is C 1-6 haloalkyl.
  • R 8 is OR a ; in another specific embodiment, R 8 is NR b R c ; in another specific embodiment, R 8 is NH 2 ; in another specific embodiment, R 8 is NH 2 ; in another specific embodiment, R 8 is NR b R c , R 8 is C 1-6 alkyl; in another specific embodiment , R 8 is C 1-6 haloalkyl.
  • R 9 is OR a ; in another specific embodiment, R 9 is C 1-6 alkylene-OR a ; in another specific embodiment, R 9 is C 1-4 Alkylene-OH, such as CH 2 OH, C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-5 cycloalkyl, 3-7 membered heterocyclyl, 3-5 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;
  • R 10 is H; in another specific embodiment, R 10 is halogen; in another specific embodiment, R 10 is OR a ; in another specific embodiment, R 10 is NR b R c ; in another specific embodiment, R 10 is CN; in another specific embodiment, R 10 is C 1-6 alkyl; in another specific embodiment, R 10 is C 1- 6 Haloalkyl.
  • R 11 is H; in another specific embodiment, R 11 is halogen; in another specific embodiment, R 11 is OR a ; in another specific embodiment, R 11 is NR b R c ; in another specific embodiment, R 11 is C 1-6 alkyl; in another specific embodiment, R 11 is C 1-6 haloalkyl.
  • Ring A is a 5-10 membered heteroaryl; in another embodiment, Ring A is a 5-6 membered heteroaryl; in another embodiment, Ring A is a five-membered heteroaryl Heteroaryl; in another embodiment, Ring A is C 6-10 aryl; in another embodiment, Ring A is C 4-10 cycloalkyl; in another embodiment, Ring A is a 4-10 membered heterocyclic group.
  • Ring A is unsubstituted; in another specific embodiment, Ring A is substituted with 1 R#; in another specific embodiment, Ring A is substituted with 2 R#; in another In a specific embodiment, Ring A is substituted with 3 R#s; in another specific embodiment, Ring A is substituted with 4 R#s; in another specific embodiment, Ring A is substituted with 5 R#s.
  • Ring B is C 4-10 cycloalkyl; in another specific embodiment, Ring B is C 4-7 cycloalkyl; in another specific embodiment, Ring B is 4- 10-membered heterocyclyl; in another specific embodiment, Ring B is 4-7 membered heterocyclyl.
  • Ring B is unsubstituted; in another embodiment, Ring B is substituted with 1 R#; in another embodiment, Ring B is substituted with 2 R#; in another In a specific embodiment, Ring B is substituted with 3 R#s; in another specific embodiment, Ring B is substituted with 4 R#s; in another specific embodiment, Ring B is substituted with 5 R#s.
  • R a is H; in another specific embodiment, R a is C 1-6 alkyl; in another specific embodiment, R a is C 1-6 haloalkyl.
  • R b is H; in another specific embodiment, R b is C 1-6 alkyl; in another specific embodiment, R b is C 1-6 haloalkyl.
  • R c is H; in another specific embodiment, R c is C 1-6 alkyl; in another specific embodiment, R c is C 1-6 haloalkyl.
  • R d is H; in another specific embodiment, R d is C 1-6 alkyl; in another specific embodiment, R d is C 1-6 haloalkyl.
  • R# is H; in another embodiment, R# is halogen; in another embodiment, R# is C 1-4 alkylene-OR a ; in another In a specific embodiment, R# is OR a ; in another specific embodiment, R# is NR b R c ; in another specific embodiment, R# is C 1-6 alkyl; in another specific implementation In one embodiment, R# is C 1-6 haloalkyl; in another embodiment, R# is C 2-6 alkenyl; in another embodiment, R# is C 2-6 alkynyl.
  • Rx is halogen; in another embodiment, Rx is C 1-6 alkyl; in another embodiment, Rx is C 1-6 haloalkyl; in another embodiment
  • Rx is C 4-10 cycloalkyl optionally substituted by one or more groups of halogen, C 1-6 alkyl, C 1-6 haloalkyl; in another specific embodiment, Rx is a 4-10 membered heterocyclyl optionally substituted by one or more groups of halogen, C 1-6 alkyl, C 1-6 haloalkyl; in another specific embodiment, Rx is any C 6-10 aryl optionally substituted with one or more of halogen, C 1-6 alkyl, C 1-6 haloalkyl; in another specific embodiment, Rx is optionally halogen , C 1-6 alkyl, C 1-6 haloalkyl, a 5-10 membered heterocyclic group substituted by one or more groups.
  • Ry is H; in another embodiment, Ry is halogen; in another embodiment, Ry is C 1-6 alkyl; in another embodiment, Ry is C 1-4 alkyl; in another embodiment, Ry is C 1-6 haloalkyl; in another embodiment, Ry is C 1-4 haloalkyl; in another embodiment, Ry is C 1-6 alkoxy; in another embodiment, Ry is C 1-4 alkoxy; in another embodiment, Ry is C 1-6 haloalkoxy.
  • Ry is H; in another specific embodiment, Ry is F; in another specific embodiment, Ry is Cl; in another specific embodiment, Ry is CH3; in another specific embodiment, Ry is CH3 ; In one specific embodiment, Ry is OCH 3 ; in another specific embodiment, Ry is CF 3 .
  • n is 1; in another specific embodiment, n is 2; in another specific embodiment, n is 3.
  • 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 solution of X 1 or any combination thereof can be combined with X 2 ,
  • Any technical solutions of a , Rb , Rc , Rd , R#, Rx, Ry and n or any combination thereof are combined.
  • the present invention is intended to include combinations of all these technical solutions, and due to space limitations, they will not be listed one by one.
  • the invention provides compounds of formula (A-1) or (A-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, Prodrug, polymorph, hydrate or solvate:
  • each group is as defined above.
  • the present invention provides compounds of the above formula (A), (A-1) or (A-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • L is selected from C(O), C(O)NH, C(O)-C(O) or C(O)-C(O)NH;
  • Ring S is C 6-10 aryl
  • R 1 is selected from halogen, SF 5 , OR a , NR b R c , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, S(O) 2 -R d or S(O)-R d ; the R 1 may optionally be halogenated , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy further substituted, preferably, R 1 can optionally be halogen, C 1-6 alkyl group or C 1-6 haloalkyl group further substituted;
  • R 2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 , R 2 and the carbon atoms to which they are connected together form a C 4-10 cycloalkyl group, a 4-10 membered heterocyclyl group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 4 -10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be optionally substituted by 1, 2 or 3 Rx;
  • Rx is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, or is optionally substituted by one or more groups of halogen, C 1-6 alkyl, C 1-6 haloalkyl C 4-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heterocyclyl;
  • R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-OR a , C 1-4 alkylene-NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 aryl, R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group or a C 6-10 aryl group
  • Ring B is C 5-10 cycloalkyl or 5-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, OR a , C 1-4 alkylene-OR a , NR b R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy ;
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 is selected from OR a , C 1-6 alkylene-OR a , C(O)NR b R c , C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 heteroaryl;
  • R 7 and R 8 are independently selected from OR a or NR b R c ;
  • R 9 is selected from C 1-6 alkyl or C 3-7 cycloalkyl
  • R 10 is selected from H, halogen, OR a , NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 11 is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R a , R b , R c and R d are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (A), (A-1) or (A-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • L is selected from C(O) or C(O)-C(O)NH
  • R 1 is selected from Cl, Br, SF 5 , CN, CF 3 , OCF 3 , cyclopropyl, Preferably, R 1 is selected from Cl, Br, SF 5 , CN, CF 3 , OCF 3 , cyclopropyl,
  • R 2 is selected from H or CH 3 ;
  • R 3 is selected from CH 3 , cyclopropyl
  • R 4 is selected from H, CH 3 , CH 2 CH 3 or cyclopropyl
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • R 5 is selected from H or CH 3 ;
  • R 6 is selected from OCH 3 , CH 2 OH, C(O) 2 NH 2 , cyclopropyl, cyclobutyl or
  • R 7 is selected from NH 2 or OCH 3 ;
  • R 8 is selected from NH 2 ;
  • R 9 is selected from CH 3 , CH 2 CH 3 or cyclopropyl
  • R 10 is selected from H, F, Cl, CN or CH 3 ;
  • R 11 is selected from H or CH 3 .
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate:
  • X 1 is N or CR 2 ;
  • L is selected from C(O), C(O)NH, C(O)-C(O) or C(O)-C(O)NH;
  • Ring S is selected from C 6-10 aryl, 6-10 membered heteroaryl, C 5-10 cycloalkyl or 5-10 membered heterocyclyl;
  • R 1 and R 2 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -S(O) 2 C 1-6 alkyl, -S(O) 2 haloC 1 -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 3 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which may be optionally replaced by 1, 2 or 3 R #replace;
  • R 4 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-4 alkylene-OR a or C 1-4 alkylene-NR b R c , It may optionally be replaced by 1, 2 or 3 R#;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group or a C 6-10 aryl group
  • Ring B is C 4-10 cycloalkyl or 4-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3 or 4 R#;
  • R 5 , R 5 ' and R 6 ' are selected from H, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 6 and R 9 are independently selected from OR a , C(O)NR b R c , C(O)OR a , C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 heteroaryl;
  • R 5 ' and R 6 ' are connected to form a bond, or R 5 ', R 6 ' and the carbon atoms they are connected together form a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group;
  • R 7 and R 8 are independently selected from OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R# is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 is not C 1-6 alkyl, C 1-6 haloalkyl and C 2-6 alkynyl.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein,
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein,
  • X 1 is N or CR 2 ;
  • L is selected from C(O), C(O)NH, C(O)-C(O) or C(O)-C(O)NH;
  • R 1 and R 2 are independently halogen or C 1-6 haloalkyl
  • R 3 is selected from 5-10 membered heteroaryl, phenyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which may be optionally substituted by 1, 2 or 3 R#;
  • R 4 is selected from C 1-6 alkyl, C 1-4 alkylene-OR a or C 1-4 alkylene-NR b R c ;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group or a C 6-10 aryl group
  • Ring B is C 4-10 cycloalkyl or 4-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2 or 3 R#;
  • R 8 is OR a , NR b R c , C 1-4 alkyl or C 1-4 haloalkyl;
  • R 9 is C 1-6 alkyl or C 3-7 cycloalkyl
  • R# is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein,
  • X 1 is N or CH
  • L is selected from C(O) or C(O)-C(O)NH
  • R 1 is selected from halogen or C 1-2 haloalkyl, preferably Br or CF 3 ;
  • R 3 is selected from cyclopropyl or
  • R 4 is selected from CH 3 , cyclopropyl or
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • R 8 is NH 2 ;
  • R 9 is selected from methyl, ethyl or cyclopropyl.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrates or solvates, which have the following structure:
  • each group is as defined above.
  • the invention provides compounds of formula (II), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 1 is N or CH
  • R 1 is selected from halogen or C 1-6 haloalkyl
  • R 3 is selected from 5-10 membered heteroaryl, phenyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 4 is selected from C 1-6 alkyl, C 1-4 alkylene-OR a or C 1-4 alkylene-NR b R c ;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group
  • Ring B is C 4-10 cycloalkyl or 4-10 membered heterocyclyl
  • R 5 , R 5 ' and R 6 ' are H or C 1-6 alkyl
  • R 6 is C 1-6 alkoxy, C 3-7 cycloalkyl or CONH 2 ;
  • R 5 ' and R 6 ' are connected to form a bond, or R 5 ', R 6 ' and the carbon atoms they are connected together form a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group;
  • R 7 is OR a , NR b R c , C 1-4 alkyl or C 1-4 haloalkyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • X 1 is N or CH
  • R 1 is selected from halogen or C 1-4 haloalkyl
  • R 3 is selected from 5-6 membered heteroaryl or C 3-5 cycloalkyl, which may be optionally substituted by 1 or 2 R#;
  • R# is C 1-4 alkyl
  • R 4 is selected from C 1-4 alkyl or C 1-4 alkylene-OR a ;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-6 membered heteroaryl group
  • Ring B is C 4-7 cycloalkyl or 4-7 membered heterocyclyl
  • R 5 is H or C 1-4 alkyl
  • R 6 is C 1-4 alkoxy, C 3-5 cycloalkyl or CONH 2 ;
  • R 5 ' and R 6 ' are connected to form a bond, or R 5 ', R 6 ' and the carbon atoms they are connected together form a C 3-5 cycloalkyl group;
  • R 7 is NH 2 or C 1-4 alkoxy
  • R a is selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant thereof, Tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • X 1 is N or CH
  • R 1 is selected from halogen or C 1-2 haloalkyl, preferably Br or CF 3 ;
  • R 3 is selected from Or cyclopropyl, preferably
  • R 4 is selected from CH 3 and
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • R 5 is H
  • R 6 is OCH 3 , cyclopropyl, CONH 2 ;
  • R 5 ' and R 6 ' are connected to form a bond, or R 5 ', R 6 ' and the carbon atoms they are connected together form cyclopropane;
  • R 7 is NH 2 or OCH 3 .
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 3 is selected from Or cyclopropyl, preferably
  • the invention provides compounds of formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 1 is N or CH
  • R 1 is C 1-6 haloalkyl
  • Ring A is a five-membered heteroaryl group
  • R 6 is selected from C 1-6 alkoxy or C 3-7 cycloalkyl
  • R 7 is NR b R c ;
  • R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the invention provides compounds of formula (IV), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 1 is N or CH
  • R 1 is selected from halogen or C 1-6 haloalkyl
  • R 3 is selected from 5-10 membered heteroaryl, phenyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which may be optionally substituted by 1, 2 or 3 R#;
  • R 4 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkylene-OR a or C 1-4 alkylene-NR b R c ;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group
  • Ring B is C 4-10 cycloalkyl or 4-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 8 is selected from OR a , NR b R c , C 1-4 alkyl or C 1-4 haloalkyl;
  • R 9 is selected from C 1-6 alkyl or C 3-7 cycloalkyl
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (IV), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein,
  • X 1 is N or CH
  • R 1 is selected from halogen or C 1-4 haloalkyl
  • R 3 is selected from 5-6 membered heteroaryl or C 3-5 cycloalkyl, which may be optionally substituted by 1 or 2 R#;
  • R# is selected from halogen, C 1-4 alkyl or C 1-4 alkoxy
  • R 4 is selected from C 1-4 alkyl or C 1-4 alkylene-OR a ;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • ring A is a 5-6 membered heteroaryl group
  • ring B is a C 4-7 cycloalkyl group or a 4-7 membered heterocyclyl group, and they can be optionally substituted by 1 or 2 R#;
  • R 8 is selected from NH 2 or C 1-4 alkoxy
  • R 9 is selected from C 1-4 alkyl or C 3-5 cycloalkyl.
  • the present invention provides the above-mentioned compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof , hydrate or solvate, wherein,
  • X 1 is N or CH
  • R 1 is selected from halogen or C 1-2 haloalkyl, preferably Br or CF 3 ;
  • R 3 is selected from Or cyclopropyl, preferably
  • R 4 is selected from CH 3 or
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • R 8 is NH 2 ;
  • R 9 is selected from C 1-2 alkyl or cyclopropyl.
  • the present invention provides the above-mentioned compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof , hydrate or solvate, wherein,
  • R 3 is selected from cyclopropyl or Preferably
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • the present invention provides compounds of the above formula (A), (A-1) or (A-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, Stereoisomers, prodrugs, polymorphs, hydrates or solvates having the following structure:
  • each group is as defined above.
  • the invention provides compounds of formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers thereof Isomers, prodrugs, polymorphs, hydrates or solvates:
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • R 1 is selected from halogen, SF 5 , OR a , NR b R c , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, S(O) 2 -R d or S(O)-R d , R 1 may be optionally replaced by halogen, C 1-6 alkyl or C 1-6 haloalkyl is further substituted;
  • R 2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 , R 2 and the carbon atoms to which they are connected together form a C 4-10 cycloalkyl group, a 4-10 membered heterocyclyl group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 4 -10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be optionally substituted by 1, 2 or 3 Rx;
  • Rx is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, or is selected from one or more groups optionally substituted by halogen, C 1-6 alkyl, C 1-6 haloalkyl C 4-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heterocyclyl;
  • R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 aryl, R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group or a C 6-10 aryl group
  • Ring B is C 5-10 cycloalkyl or 5-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, OR a , C 1-4 alkylene-OR a , NR b R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy ;
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 is selected from C 1-6 alkylene-OR a , C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-6 heteroaryl;
  • R 7 is selected from OR a or NR b R c ;
  • R 10 is selected from H, halogen, OR a , NR b R c , CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 11 is selected from H, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R a , R b , R c and R d are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, isotopic variants, tautomers thereof, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • R 1 is selected from halogen, SF 5 , OR a , NR b R c , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or S(O) 2 -R d , R 1 may be optionally further substituted by halogen, C 1-4 alkyl or C 1-4 haloalkyl;
  • R 2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 , R 2 and the carbon atoms to which they are connected together form a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group or C 6-10 aryl group may optionally Replaced by 1, 2 or 3 Rx;
  • Rx is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl, or is selected from one or more groups optionally substituted by halogen, C 1-6 alkyl, C 1-6 haloalkyl 5-10 membered heterocyclyl or C 4-10 cycloalkyl;
  • R 3 is selected from C 1-6 alkyl, C 1-4 alkylene-OR a , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 Aryl, R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 4 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group
  • Ring B is C 5-10 cycloalkyl or 5-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, CH 2 OH or C 1-4 alkoxy;
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 is selected from C 1-6 alkylene-OR a , C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 7 is selected from OR a or NR b R c ;
  • R 10 is selected from H, halogen, OR a , NR b R c , CN or C 1-4 alkyl;
  • R 11 is selected from H, halogen or C 1-6 alkyl
  • R a , R b , R c and R d are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, isotopic variants, tautomers thereof, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • R 1 is selected from halogen, SF 5 , NH 2 , OH, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-5 cycloalkyl or S(O) 2 -C 1-4 haloalkyl base;
  • R 2 is selected from H or C 1-4 alkyl
  • R 1 , R 2 and the carbon atoms to which they are connected together form a 5-6 membered heteroaryl group, and the 5-6 membered heteroaryl group may be optionally substituted by 1 or 2 Rx;
  • Rx is a 5-6 membered heterocyclyl optionally substituted by C 1-4 alkyl
  • R 3 is selected from C 1-4 alkyl, C 1-4 alkylene-OC 1-4 alkyl, C 3-5 cycloalkyl or 5-6 membered heteroaryl, R 3 can be optionally replaced by 1 Replaced by one, two or three R#;
  • R 4 is selected from H, C 1-4 alkyl or C 3-5 cycloalkyl
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-6 membered heteroaryl group
  • Ring B is C 5-6 cycloalkyl or 5-6 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, CH 2 OH or C 1-4 alkoxy;
  • R 5 is selected from H or C 1-4 alkyl
  • R 6 is selected from C 1-4 alkylene-OH, C 3-5 cycloalkyl or 3-5 membered heterocyclyl;
  • R 7 is selected from OH or NH 2 ;
  • R 10 is selected from H, halogen, OH, NH 2 , CN or C 1-4 alkyl;
  • R 11 is selected from H or C 1-4 alkyl.
  • the present invention provides compounds of the above formula (V), (V-1) or (V-2), or pharmaceutically acceptable salts, isotopic variants, tautomers thereof , stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • X 1 is selected from CR 2 or N;
  • X 2 is selected from CH or N;
  • X 3 is selected from CH or N;
  • R 1 is selected from Br, SF 5 , CN, CF 3 , OCF 3 , cyclopropyl,
  • R 2 is selected from H or CH 3 ;
  • R 3 is selected from CH 3 , cyclopropyl
  • R 4 is selected from H, CH 3 , CH 2 CH 3 or cyclopropyl
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • R 5 is selected from H or CH 3 ;
  • R 6 is selected from CH 2 OH, cyclopropyl, cyclobutyl or
  • R 7 is NH 2 ;
  • R 10 is selected from H, F, Cl, CN or CH 3 ;
  • R 11 is selected from H or CH 3 .
  • the present invention provides compounds of formula (VI), or pharmaceutically acceptable salts, isotopic variants, tautomers thereof Isomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates:
  • X 1 is selected from CH or N;
  • X 2 is selected from CH or N;
  • R 1 is selected from halogen, SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-7 cycloalkyl;
  • R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl, R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-4 alkylene-OR a , C 2-6 alkenyl or C 2-6 Alkynyl; preferably, R# is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 4 is selected from C 1-6 alkyl or C 3-7 cycloalkyl
  • R 10 is selected from H, halogen, CN or C 1-6 alkyl; preferably, R 10 is selected from H or halogen.
  • the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • X 1 is selected from CH or N;
  • X 2 is selected from CH or N;
  • R 1 is selected from halogen, SF 5 , C 1-4 haloalkyl, C 1-4 haloalkoxy or C 3-5 cycloalkyl;
  • R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl, and R 3 can be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably, R# is selected from halogen or C 1-6 alkyl;
  • R 4 is selected from C 1-4 alkyl or C 3-5 cycloalkyl
  • R 10 is selected from H, halogen, CN or C 1-4 alkyl; preferably, R 10 is selected from H or halogen.
  • the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • X 1 is selected from CH or N;
  • X 2 is selected from CH or N;
  • R 1 is selected from halogen, SF 5 , C 1-2 haloalkyl, C 1-2 haloalkoxy or C 3-4 cycloalkyl;
  • R 3 is a 5-6 membered heteroaryl group, and R 3 can be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen, C 1-4 alkyl or C 1-4 haloalkyl; preferably, R# is selected from halogen or C 1-4 alkyl;
  • R 4 is selected from C 1-4 alkyl or C 3-4 cycloalkyl
  • R 10 is selected from H, halogen, CN or C 1-4 alkyl; preferably, R 10 is selected from H or halogen.
  • the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • X 1 is selected from CH or N;
  • X 2 is selected from CH or N;
  • R 1 is selected from Br, SF 5 , CF 3 , OCF 3 or cyclopropyl
  • R 3 is selected from Preferably
  • R 4 is selected from CH 3 , CH 2 CH 3 or cyclopropyl
  • R 10 is selected from H, F, Cl, CH 3 or CN, preferably H, F or Cl.
  • the invention provides compounds of formula (VII), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • R 1 is selected from halogen, C 1-4 haloalkyl or C 3-5 cycloalkyl;
  • R 3 is selected from
  • R 4 is selected from CH 3 or C 3-4 cycloalkyl.
  • the present invention provides the above-mentioned compound of formula (VII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1 is selected from halogen, C 1-2 haloalkyl or C 3-4 cycloalkyl;
  • R 3 is selected from
  • R 4 is selected from CH 3 or C 3-4 cycloalkyl.
  • the present invention provides the above-mentioned compound of formula (VII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1 is selected from Br, CF 3 or cyclopropyl
  • R 3 is selected from
  • R4 is selected from CH3 or cyclopropyl.
  • the invention provides compounds of formula (VIII), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • R 1 is selected from 5-10 membered heteroaryl or C 1-6 haloalkyl, and R 1 is optionally substituted by Ry;
  • Ry is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 3 is a 5-10 membered heteroaryl group or C 6-10 aryl group, preferably a 5-10 membered heteroaryl group, and R 3 may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen, CH 2 OH or C 1-4 alkyl
  • R 6 is selected from OR a or C 1-6 alkylene-OR a , preferably C 1-6 alkylene-OR a ;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the invention provides compounds of formula (VIII), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • R 1 is C 1-6 haloalkyl, preferably C 1-4 haloalkyl
  • R 3 is a 5-10 membered heteroaryl group or C 6-10 aryl group, preferably a 5-10 membered heteroaryl group, and R 3 may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen, CH 2 OH or C 1-4 alkyl
  • R 6 is selected from OR a or C 1-6 alkylene-OR a , preferably C 1-6 alkylene-OR a ;
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (VIII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1 is C 1-2 haloalkyl, preferably halomethyl
  • R 3 is a 5-6 membered heteroaryl group, and R 3 can be optionally substituted by 1 or 2 R#;
  • R# is C 1-4 alkyl
  • R 6 is C 1-4 alkylene-OH.
  • the present invention provides the above-mentioned compound of formula (VIII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1 is CF 3 ;
  • R 3 is selected from
  • R 6 is CH 2 OH.
  • the invention provides compounds of formula (IX), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • R 1 is C 1-4 haloalkyl
  • R 3 is selected from
  • the present invention provides the compound of formula (IX) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1 is C 1-2 haloalkyl, preferably halomethyl
  • R 3 is selected from
  • the invention provides compounds of formula (X), (X-1) or (X-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers thereof Isomers, prodrugs, polymorphs, hydrates or solvates:
  • R 1 is selected from halogen, SF 5 , OR a , NR b R c , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, S(O) 2 -R d or S(O)-R d , R 1 can optionally be halogen, C 1-6 alkyl or C 1 -6 haloalkyl further substituted;
  • R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 aryl, R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group or a C 6-10 aryl group
  • Ring B is C 5-10 cycloalkyl or 5-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, OR a , C 1-4 alkylene-OR a , NR b R c , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy ;
  • R 8 is selected from OR a or NR b R c ;
  • R 9 is selected from C 1-6 alkylene-OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aromatic base or 5-6 heteroaryl;
  • R a , R b , R c and R d are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (X), (X-1) or (X-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • R 1 is selected from halogen or C 1-6 haloalkyl
  • R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl, and R 3 can be optionally substituted by 1, 2 or 3 R#;
  • R 4 is C 1-6 alkyl
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-10 membered heteroaryl group
  • Ring B is C 5-10 cycloalkyl or 5-10 membered heterocyclyl
  • Ring A and Ring B may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 8 is selected from OR a or NR b R c ;
  • R 9 is selected from C 1-6 alkyl or C 3-7 cycloalkyl
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (X), (X-1) or (X-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • R 1 is selected from halogen or C 1-4 haloalkyl
  • R 3 is a 5-6 membered heteroaryl group, and R 3 can be optionally substituted by 1, 2 or 3 R#;
  • R 4 is C 1-4 alkyl
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • Ring A is a 5-6 membered heteroaryl group
  • Ring B is C 5-6 cycloalkyl
  • Ring A and Ring B may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen or C 1-4 alkyl
  • R 8 is NR b R c ;
  • R 9 is selected from C 1-4 alkyl or C 3-5 cycloalkyl
  • R b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
  • the present invention provides compounds of the above formula (X), (X-1) or (X-2), or pharmaceutically acceptable salts, isotopic variants, tautomers, Stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein
  • R 1 is selected from Br or CF 3 ;
  • R 3 is selected from
  • R 4 is CH 3 ;
  • R 3 , R 4 and the carbon atoms to which they are connected together form
  • R 8 is selected from NH 2 ;
  • R 9 is selected from CH 3 , CH 2 CH 3 or cyclopropyl.
  • the invention provides compounds of formula (XI), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • R 1 is a 5-10 membered heteroaryl group or a C 1-6 haloalkyl group, and the R 1 is optionally substituted by Ry;
  • Ry is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 3 is a 5-10 membered heteroaryl group or a C 6-10 aryl group, preferably a 5-10 membered heteroaryl group, and the R 3 may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen or C 1-6 alkyl
  • R 5 is selected from C 1-6 alkyl or C 1-6 haloalkyl.
  • the invention provides compounds of formula (XI), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • R 1 is C 1-6 haloalkyl
  • R 3 is a 5-10 membered heteroaryl group or C 6-10 aryl group, preferably a 5-10 membered heteroaryl group, and R 3 may be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen or C 1-6 alkyl
  • R 5 is selected from C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (XI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1 is C 1-4 haloalkyl
  • R 3 is a 5-10 membered heteroaryl group, and R 3 can be optionally substituted by 1, 2 or 3 R#;
  • R# is selected from halogen or C 1-4 alkyl
  • R 5 is C 1-6 alkyl, preferably C 1-4 alkyl.
  • the present invention provides the above-mentioned compound of formula (XI), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1 is C 1-2 haloalkyl, preferably halomethyl
  • R 3 is a 5-6 membered heteroaryl group, and R 3 can be optionally substituted by 1 or 2 R#;
  • R# is C 1-4 alkyl
  • R 5 is C 1-2 alkyl, preferably methyl.
  • the invention provides a compound of formula (XII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof, Hydrate or solvate:
  • Ry is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylene-OR a , C 1-6 alkylene-NR b R c , C 3-10 cycloalkyl, 3 -10-membered heterocyclyl, 5-10-membered heteroaryl or C 6-10 aryl, the R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylene-OH, preferably H;
  • R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably C 1-6 alkyl;
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 is selected from C 1-6 alkylene-OH or C 3-7 cycloalkyl, preferably -CH 2 OH or cyclopropyl;
  • R 10 is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (XII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, or polymorph thereof , hydrate or solvate, wherein,
  • Ry is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 3 is selected from 5-10 membered heteroaryl or C 6-10 aryl, and said R 3 may be optionally substituted by 1, 2, 3, 4 or 5 R#;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylene-OH, preferably H;
  • R 4 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl;
  • R 5 is selected from H or C 1-6 alkyl
  • R 6 is selected from C 1-6 alkylene-OH or C 3-7 cycloalkyl, preferably -CH 2 OH or cyclopropyl;
  • R 10 is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (XII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, or polymorph thereof , hydrate or solvate, wherein,
  • Ry is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy, preferably F or CF 3 ;
  • R 3 is The R 3 may be optionally replaced by 1, 2 or 3 R#;
  • R# is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl, preferably H;
  • R 4 is selected from H, C 1-4 alkyl or C 1-4 haloalkyl, preferably C 1-4 alkyl;
  • R 5 is selected from H or C 1-4 alkyl
  • R 6 is selected from C 1-4 alkylene-OH or C 3-7 cycloalkyl, preferably -CH 2 OH or cyclopropyl;
  • R 10 is selected from H, halogen, CN, C 1-4 alkyl or C 1-4 haloalkyl, preferably H or halogen.
  • the present invention provides the above-mentioned compound of formula (XII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, or polymorph thereof , hydrate or solvate, wherein,
  • Ry is selected from H, F, Cl, CH 3 , OCH 3 or CF 3 , preferably F or CF 3 ;
  • R 3 is The R 3 may be optionally replaced by 1, 2 or 3 R#;
  • R# is selected from H, F, CH 3 or CF 3 , preferably H;
  • R 4 is CH 3 ;
  • R 5 is selected from H or CH 3 ;
  • R 6 is selected from -CH 2 OH or cyclopropyl
  • R 10 is selected from H, F, Cl, CN, CH 3 or CF 3 , preferably H or F.
  • the invention provides a compound of formula (XIII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof, Hydrate or solvate:
  • R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably CF 3 ;
  • R 3 is a 5-10-membered heteroaryl group or a C 6-10 aryl group, preferably a 5-10-membered heteroaryl group.
  • the R 3 can be optionally substituted by 1, 2, 3, 4 or 5 Replace with R#;
  • R# is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 is C 1-6 alkyl, preferably CH 3 ;
  • R 5 is C 1-6 alkyl, preferably CH 3 ;
  • R 6 is selected from C 1-6 alkylene-OH or C 3-7 cycloalkyl, preferably CH 2 OH or cyclopropyl, more preferably CH 2 OH;
  • R 10 is selected from H or halogen, preferably H.
  • the present invention provides the above-mentioned compound of formula (XIII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, or polymorph thereof , hydrate or solvate, wherein,
  • R 1 is C 1-6 haloalkyl, preferably CF 3 ;
  • R 3 is The R 3 may be optionally replaced by 1, 2 or 3 R#;
  • R# is selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 4 is C 1-6 alkyl, preferably CH 3 ;
  • R 5 is C 1-6 alkyl, preferably CH 3 ;
  • R 6 is selected from C 1-6 alkylene-OH or C 3-7 cycloalkyl, preferably CH 2 OH or cyclopropyl, more preferably CH 2 OH;
  • R 10 is selected from H or halogen, preferably H.
  • the present invention provides the above-mentioned compound of formula (XIII), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, or polymorph thereof , hydrate or solvate, wherein,
  • R 1 is C 1-4 haloalkyl, preferably CF 3 ;
  • R 3 is The R 3 may be optionally replaced by 1, 2 or 3 R#;
  • R# is selected from H, halogen, C 1-4 alkyl or C 1-4 haloalkyl
  • R 4 is C 1-4 alkyl, preferably CH 3 ;
  • R 5 is C 1-4 alkyl, preferably CH 3 ;
  • R 6 is selected from C 1-4 alkylene-OH or C 3-5 cycloalkyl, preferably CH 2 OH or cyclopropyl, more preferably CH 2 OH;
  • R 10 is selected from H or halogen, such as H, F or Cl, preferably H.
  • the invention provides a compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein said Compounds selected from:
  • the invention provides a compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein said Compounds selected from:
  • the compounds of the present invention may contain one or more asymmetric centers and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, Includes racemic mixtures and mixtures enriched in one or more stereoisomers.
  • the isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers may be separated by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may also exist as tautomers.
  • Compounds exist in different tautomeric forms, and a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.
  • solvate refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolating, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methoxides.
  • hydrate refers to a compound combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound may be represented, for example, by the general formula R.xH2O , where R is the compound and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1), for example, hemihydrate (R ⁇ 0.5H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1
  • hemihydrate R ⁇ 0.5H 2 O
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)
  • the compounds of the invention may be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (A), except that one or more atoms are represented by atoms having an atomic mass or mass number different from that common in nature. replaced.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the isotope-labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by replacing non-isotopes with readily available isotope-labeled reagents when performing the following processes and/or the processes disclosed in the Examples and Preparation Examples. Labeled reagents.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” refers to a substance that is absorbed in the body by, for example, water in the blood. A compound that is decomposed into its active form that has a medical effect.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press , 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduced in this article Reference.
  • the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions comprise an effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a prophylactically effective amount of a compound of the invention.
  • compositions of the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds with which they are formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin) protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols, and
  • kits eg, pharmaceutical packaging.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packaging or other) containing the compounds of the invention, other therapeutic agents. suitable container).
  • provided kits may also optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents.
  • the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal membrane drug administration, intralesional drug administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice of and under the supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or those who have been determined by genetic testing or screening to be particularly susceptible to developing the condition.
  • compositions provided herein can also be administered over a long period of time ("chronic administration").
  • Long-term administration refers to the administration of a compound or pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may be continued indefinitely, For example, the remainder of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.
  • a pharmaceutical composition may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic levels of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, whereas a bolus dose delivered directly into the vein (e.g., via an IV drip) ) can be delivered more quickly, allowing the concentration of active ingredients in the blood to quickly increase to effective levels.
  • the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions may take the form of bulk liquid solutions or suspensions, or bulk powders. More typically, however, the compositions are provided in unit dosage form to facilitate precise dosing.
  • dosage unit form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions.
  • the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.
  • a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injectable dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially from 24 to 96 hours. To achieve adequate steady state levels, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds of similar nature: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricant, for example, magnesium stearate; glidant, for example, colloidal silicon dioxide; sweetener, for example, sucrose or saccharin; or flavoring agent, for example, mint, water Methyl glycolate or orange flavoring.
  • binders for example, microcrystalline cellulose, tragacanth, or gelatin
  • excipients for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As stated previously, in such compositions the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredients.
  • the active ingredients When formulated as an ointment, the active ingredients are typically combined with a paraffin or water-miscible ointment base.
  • the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and often include other ingredients for promoting stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by this invention.
  • transdermal administration may be achieved using reservoir or porous membrane types, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which article is incorporated by reference.
  • the compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation includes water.
  • the formulation contains a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins consisting of 6, 7 and 8 ⁇ -1,4-linked glucose units respectively, optionally including a or multiple substituents including, but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
  • the reagents used in the present invention are commercial reagents purchased directly or synthesized by common methods well known in the art.
  • PE petroleum ether
  • EA ethyl acetate
  • MeOH methanol
  • DCM diichloromethane
  • DCE dichloroethane
  • CH 3 acetonitrile
  • 1,4-dioxane 1,4-dioxane Hexacyclic
  • DMSO dimethyl sulfoxide
  • HFIP hexafluoroisopropanol
  • DMF N,N-dimethylformamide
  • Hex n-hexane
  • IPA isopropyl alcohol
  • NMP N-methylpyrrolidone
  • NMO N-methylmorpholine-N-oxide
  • TEA triethylamine
  • DIEA diisopropylethylamine
  • CuI cuprous iodide
  • CuCN cuprous cyanide
  • triphosgene triphosgene
  • p -TsOH p-toluenesulfonic acid
  • Step 2 Under nitrogen protection, dissolve the intermediate a1-2 (500mg, 1.95mmol) in the previous step in 10 mL anhydrous THF, add NaH (61mg, 2.53mmol) and raw material a1-3 (359mg, 1.95mmol), and keep at room temperature. Reaction takes 3 hours. Stop the reaction, add 50 mL of water to the system, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE/EA, 3/1) to obtain intermediate a1-4 (426 mg, 1.52 mmol). ), yield: 78%.
  • LC-MS: [M+H] + 281.
  • Step 4 Dissolve intermediate a1-5 (100 mg, 0.41 mmol) in the previous step in 1 mL THF, add 0.5 mL water and LiOH (35 mg, 0.82 mmol), react at room temperature for 6 hours, and add 1.5 M dilute hydrochloric acid to the system. The conditional pH is about 7 and filtered. The filter cake was washed with water and dried to obtain compound a1 (40 mg, 0.18 mmol), yield: 43%.
  • LC-MS: [M+H] + 229.
  • Step 5 Under nitrogen protection, dissolve compound a1 (25 mg, 0.11 mmol) in 0.5 mL dichloromethane, add hydrogen chloride in 1,4-dioxane solution (0.04 mL, 0.13 mmol), and react at room temperature for 30 minutes. . The solvent was evaporated under reduced pressure, and the mixture was dissolved in SOCl 2 (195.4 mg, 1.65 mmol). The temperature was raised to 55°C and the reaction was carried out for 1 hour. The solvent was evaporated under reduced pressure to obtain crude product a2 (20 mg), which was directly used in the next reaction.
  • Step 1 In an ice bath, under nitrogen protection, dissolve the raw material 3-ethyl-2-aminopyridine a3-1 (1.0g, 8.19mmol) in 5mL of concentrated sulfuric acid, and add concentrated nitric acid (1.03g, 16.4mmol) dropwise. .
  • the reaction solution was stirred in an ice bath for 1 hour.
  • the reaction solution was slowly added dropwise to 50 mL of ice water and the pH was adjusted to about 8 with a 1M NaOH aqueous solution.
  • the reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • the crude product was passed through a flash reverse column. Chromatographic separation (acetonitrile/water) gave intermediate a3-2 (1.15g, 6.88mmol), yield: 84%.
  • LC-MS: [M+H] + 168.
  • Step 2 In ice bath, dissolve intermediate a3-2 (1.15g, 6.88mmol) from the previous step in 22mL DMF, add NaH (300mg, 7.57mmol), and stir for 30 minutes.
  • (Boc) 2 O (1.65g, 7.57mmol) was added to the system, and the reaction was continued for 2 hours and then stopped.
  • 60 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.
  • the crude product was separated by flash reverse column chromatography (acetonitrile/water) to obtain intermediate a3-3 (920 mg, 3.44 mmol). Yield: 50%.
  • LC-MS: [M+H] + 268.
  • Step 3 Dissolve intermediate a3-3 (920 mg, 3.44 mmol) in 2 mL methanol under hydrogen atmosphere (1 atm), add Pd/C (20%, 184.0 mg), react at room temperature for 12 hours, stop the reaction, and filter. , the solvent was evaporated under reduced pressure to obtain yellow solid a3 (410 mg, 1.73 mmol), yield: 50%.
  • LC-MS: [M+H] + 238.
  • Step 2 Dissolve intermediate a4-1 (60 mg, 0.26 mmol) in the previous step in 1.8 mL of a mixed solution of THF and water (v/v, 2/1), add LiOH (12.4 mg, 0.52 mmol), and react at room temperature. After 10 hours, add 1 M dilute hydrochloric acid to the reaction solution to adjust the pH to about 6. The crude product is separated by flash reverse column chromatography (acetonitrile/water, 0.1% trifluoroacetic acid) to obtain intermediate a4-2 (50 mg, 0.23 mmol). ), yield: 89%.
  • LC-MS: [M+H] + 219.
  • Step 3 Dissolve the intermediate a4-2 (10 mg, 0.05 mmol) in the previous step in 0.1 mL of hydrogen chloride in 1,4-dioxane solution (4M), react at room temperature for 30 minutes, and evaporate the solvent under reduced pressure. Add 0.2 mL of thionyl chloride to the system, raise the temperature to 55°C and react for 30 minutes. The solvent is evaporated under reduced pressure to obtain crude product a4 (10 mg), which is directly used in the next reaction.
  • Step 1 Under nitrogen protection, dissolve raw materials a1-3 (3.5g, 19.5mmol) and propionitrile (2.1g, 39.0mmol) in 35mL DMSO, add tBuOK (4.3g, 39.0mmol), and heat the reaction solution to React at 50°C for 2 hours and cool to room temperature. Add 80 mL of ice water to the system, wash with ethyl acetate, adjust the pH of the water phase to about 7 with 1M dilute hydrochloric acid, filter with suction, and dry the filter cake to obtain yellow solid a5-1 (3.5 g, 17.3 mmol), yield: 89%.
  • LC-MS: [M+H] + 203.
  • Step 2 Dissolve intermediate a5-1 (500mg, 2.4mmol) in the previous step in 10mL dichloromethane, add hydrogen chloride in 1,4-dioxane solution (0.7mL, 4M), react at room temperature for 30 minutes, reduce The solvent was evaporated under pressure.
  • Add SOCl 2 (4412 mg, 37.0 mmol) to the system raise the temperature to 55°C and react for 1 hour, cool to room temperature, dilute with 10 mL of methylene chloride, filter with suction, wash with n-hexane, and dry to obtain intermediate a5 (400 mg). Yield: 73%.
  • Step 2 Dissolve the intermediate a7-2 (3.1g, 20.4mmol) from the previous step in 31 mL acetic anhydride.
  • the reaction solution is heated to 120°C and reacted for 2 hours. Then, it is cooled to room temperature to stop the reaction. 100 mL of ice water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography to obtain yellow solid a7-3 (2.0 g, 10.4 mmol), yield: 51%.
  • LC-MS: [M+H] + 193.
  • Step 3 Dissolve intermediate a7-3 (2.0g, 10.4mmol) from the previous step in a mixed solution of 20mL methanol and 20mL water, add NaOH (900mg, 22.9mmol), and react at room temperature for 12 hours. Stop the reaction. . Add 40 mL of ice water to the system, adjust the pH to about 7 with 1M dilute hydrochloric acid, and concentrate. The crude product is separated by flash reverse column chromatography to obtain yellow solid a7-4 (1.5 g, 10.0 mmol). Yield: 96% .
  • LC-MS: [M+H] + 151.
  • Step 1 Under nitrogen protection, dissolve raw materials a8-1 (2.0g, 9.2mmol), Pd(dppf)Cl 2 (0.7g, 0.92mmol) and cyclopropylboronic acid (1.6g, 18.4mmol) in 33mL 1, To 4-dioxane, add K 2 CO 3 (2.5 g, 18.4 mmol) and 7 mL water, raise the temperature to 100°C and react for 3 hours, then cool to room temperature. Add 100 mL of ice water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and evaporate the solvent under reduced pressure. The mixture was separated by flash reverse column chromatography (acetonitrile/water) to obtain a8-2 as a yellow solid (940 mg, 5.25 mmol). Yield: 57%.
  • LC-MS: [M+H] + 180.
  • Step 5 Dissolve intermediate a9 (650 mg, 2.65 mmol) in 13 mL of thionyl chloride, heat the reaction solution to 70°C and react for 2 hours, stop the reaction, and concentrate the solvent under reduced pressure to obtain yellow solid a10 (650 mg), which can be used directly react in the next step. Yield: 93%.
  • Step 2 Dissolve intermediate a14-2 (50 mg, 0.21 mmol) in 0.5 mL of thionyl chloride, heat the reaction solution to 70°C and react for 2 hours, stop the reaction, and concentrate the solvent under reduced pressure to obtain yellow solid a14 (50 mg) , used directly for the next reaction. Yield: 93%.
  • Step 1 Dissolve raw material 1,4,5,6-tetrahydroindazolone b1-2 (500mg, 3.7mmol) and raw material b1-1 (781mg, 3.7mmol) in 10mL dichloromethane at room temperature, and add Acetic acid (882 mg, 14.7 mmol) and NaBH(OAc) 3 (2.3 g, 11.0 mmol) were reacted at room temperature for 8 hours, then the reaction was stopped. Add 5 mL of methanol to the system, adjust the pH to about 8 with ammonia water, and separate by flash reverse column chromatography (acetonitrile/water) to obtain light yellow solid b1 (300 mg, 1.01 mmol), yield: 28%.
  • LC-MS: [M+H] + 297.
  • Step 2 In ice bath, under nitrogen protection, dissolve intermediate b1 (60 mg, 0.2 mmol) in 1.2 mL dichloromethane, add TEA (25 mg, 0.24 mmol) and oxalyl chloride monomethyl ester (24.8 mg, 0.20 mmol) . The reaction solution was stirred in an ice bath for 1 hour to stop the reaction. The solvent was evaporated under reduced pressure, and the mixture was dissolved in 3 mL of acetonitrile, and separated by flash reverse column chromatography (acetonitrile/water, 10M NH 4 HCO 3 ) to obtain white solid b2 (30 mg, 0.08 mmol), yield: 39%.
  • LC-MS: [M+H] + 369.
  • Step 1 Dissolve raw material b1-2 (100 mg, 0.73 mmol) in 2 mL DMF under ice bath, slowly add NaH (33 mg, 0.81 mmol), stir for 30 minutes, add SEM-Cl (135 mg) dropwise to the reaction solution , 0.81 mmol), raise the temperature to room temperature and continue stirring for 1.5 hours, stop the reaction, add 20 mL of ice water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and evaporate the solvent under reduced pressure. The mixture was separated by flash reverse column chromatography (acetonitrile/water) to obtain oily intermediate b3-1 (45 mg, 0.17 mmol). Yield: 23%.
  • LC-MS: [M+H] + 267.
  • Step 1 Under nitrogen protection, dissolve raw materials b4-1 (2.1g, 13.7mmol) and Zn(CN) 2 (1.93g, 16.41mmol) in 42mL DMF, add Dppf (0.76g, 1.36mmol) and Pd 2 (dba) 3 (0.63g, 0.68mmol), heated to 100°C and reacted for 3 hours, then cooled to room temperature. Add 100 mL of ice water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and evaporate the solvent under reduced pressure. The mixture was separated by flash reverse column chromatography (acetonitrile/water) to obtain b4-2 (900 mg, 6.25 mmol) as a white solid. Yield: 46%.
  • LC-MS: [M+H] + 145.
  • Step 2 Dissolve intermediate b4-2 (900mg, 6.2mmol) and Pd/C (20%wt, 180mg) in 18mL methanol under hydrogen atmosphere (1atm), add HCl (1.5mL, 6M), and react at room temperature After 1 hour, the reaction stopped. After suction filtration, the solvent was evaporated under reduced pressure to obtain white solid b4-3 (1.0g).
  • LC-MS: [M+H] + 149.
  • Step 1 Ice bath, dissolve raw material b5-1 (500mg, 1.79mmol) in 10mL DMF, add NaH (86mg, 2.15mmol), stir for 30 minutes, add SEM-Cl (358mg, 2.15mmol) to the system, The temperature was raised to room temperature and the reaction was stopped for 1.5 hours. Add 50 mL of ice water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and evaporate the solvent under reduced pressure. The mixture was separated by flash reverse column chromatography (acetonitrile/water) to obtain oil b5-2 (700 mg, 1.71 mmol). Yield: 96%.
  • LC-MS: [M+H] + 410.
  • Step 2 Under nitrogen protection, dissolve intermediate b5-2 (800mg, 1.95mmol) and fluorosulfonyldifluoroacetate methyl ester b5-3 (413mg, 2.15mmol) in 16mL DMF, add CuI (186mg, 0.98mmol) ) and hexamethylphosphoric triamide (1.5g, 8.4mmol), heated to 100°C and reacted for 12 hours, then cooled to room temperature. Add 60 mL of ice water to the system, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and evaporate the solvent under reduced pressure. The mixture was separated by flash reverse column chromatography (acetonitrile/water) to obtain oil b5-4 (400 mg, 1.14 mmol). Yield: 58%.
  • LC-MS: [M+H] + 352.
  • Step 4 Under hydrogen atmosphere (30 atm), dissolve intermediate b5-5 (350 mg, 1.02 mmol) and Pd/C (20% wt, 70 mg) in 8 mL methanol, react at room temperature for 1 hour, and stop the reaction. After suction filtration, the solvent was evaporated under reduced pressure to obtain oil b5 (320 mg).
  • LC-MS: [M+H] + 347.
  • Step 1 Under nitrogen protection, dissolve raw material 2-cyano-5-bromopyridine b8-1 (1.10g, 6.01mmol) and raw material b8-2 (1.1g, 9.02mmol) in 22mL DMF, add K 2 CO 3 (1.66g, 12.02mmol), 1,3-bis(2-pyridyl)-1,3-propanedione (0.27g, 1.20mmol) and CuI (0.23g, 1.20mmol), heated to 110°C for reaction After 12 hours, the reaction stopped. Add 80 mL of ice water to the system, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The mixture was separated by flash reverse column chromatography (acetonitrile/water) to obtain b8-3 (1.0 g, 4.48 mmol) as a yellow solid. Yield: 75%.
  • LC-MS: [M+H] + 224.
  • Step 2 Dissolve intermediate b8-3 (1.0g, 4.48mmol) and Pd/C (20%wt, 200mg) in 40mL methanol under hydrogen atmosphere (1atm), add dilute hydrochloric acid (6M, 1.0mL), React at room temperature for 3 hours and then stop the reaction. Suction filtration, and the solvent was evaporated under reduced pressure to obtain yellow Color solid b8 (1.0g).
  • LC-MS: [M+H] + 228.
  • Step 1 Under nitrogen protection, dissolve the raw material 3-chloro-6-trifluoromethylpyridazine c5-1 (2.0g, 10.96mmol) and the raw material Pd(PPh 3 ) 4 (600mg, 0.55mmol) in 60mL 1, Add AlMe 3 (1.6 g, 21.9 mmol) solution dropwise to 4-dioxane, raise the temperature to 100°C and react for 4 hours, cool to room temperature, and add 80 mL of ice-cold methanol to the system to quench the reaction.
  • AlMe 3 1.6 g, 21.9 mmol
  • Step 3 Dissolve the crude product c5-3 (150mg, 0.62mmol) and intermediate c1-1 (84mg, 0.68mmol) in 3mL acetonitrile, add TEA (315mg, 3.11mmol), react at room temperature for 1 hour, and then stop. reaction. Add 30 mL of water to the system, extract with dichloromethane, evaporate the solvent under reduced pressure, and separate by flash reverse column chromatography (acetonitrile/water) to obtain compound c5 (40 mg).
  • LC-MS: [M+H] + 284.
  • Step 1 Under nitrogen protection, combine the raw material 1-methyl-1,2,4-triazole-3-carbaldehyde c6-1 (3.1g, 27.9mmol) and the raw material (R) to configure tert-butylsulfinamide (3.4g, 27.9mmol) was dissolved in 62mL of anhydrous toluene, added KHSO 4 (3.8g, 27.9mmol), heated to 50°C and reacted for 12 hours, cooled to room temperature, and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain oil c6-2 (4.9g), yield: 91%.
  • LC-MS: [M+H] + 215.
  • Step 3 Under nitrogen protection, dissolve the intermediate c6-3 (2.1g, 9.12mmol) in the previous step in 42mL methanol, add hydrogen chloride in dioxane solution (3.7mL, 14.6mmol), and react at room temperature for 1 hour. Stop reacting. Add 30 mL of water to the system, extract with methyl tert-butyl ether, dry with anhydrous sodium sulfate, and concentrate to obtain compound c6 (1.8 g), yield: 95%.
  • LC-MS: [M+H] + 127.
  • Steps: Under nitrogen protection, dissolve raw material c1-1 (332mg, 2.7mmol), raw material c25-1 (510mg, 2.7mmol) and DIEA (522mg, 4.05mmol) in 10mL methanol, add NaBH 3 CN (339mg, 5.4 mmol) and acetic acid (162 mg, 2.70 mmol), stir at room temperature for 10 minutes, then heat to 50°C and react for 12 hours to stop the reaction. The solvent was evaporated under reduced pressure, the mixture was dissolved in 2 mL of methanol, ammonia water was added to the system to adjust the pH to about 8, and the solvent was evaporated under reduced pressure. The mixture was separated by flash reverse column chromatography (acetonitrile/water, 3/5) to obtain a white solid mixture (120 mg), yield: 15%. LC-MS: [M+H] + 297.
  • Step 1 In ice bath, under nitrogen protection, dissolve the raw material methyl propiolate d1-1 (2.1g, 24.9mmol) and the raw material 2,6-dimethylpyridine d1-2 (2.7g, 24.9mmol) in 42mL To methyl chloride, slowly add TsN 3 (4.1g, 20.8mmol) and catalyst CuI (400mg, 2.08mmol), react in an ice bath for 4 hours, and stop the reaction. The solvent was evaporated under reduced pressure, ethyl acetate was dissolved, and a solid precipitated, which was filtered with suction, and the filter cake was dried to obtain white solid d1-3 (2.5g). Yield: 33%.
  • LC-MS: [M+H] + 361.
  • Step 2 Under nitrogen protection, dissolve the intermediate d1-3 (2.5g, 6.94mmol) and 2-amino-4-bromoacetophenone d1-4 (1.5g, 6.94mmol) in 50mL dichloroethane. medium, raise the temperature to 90°C and react for 4 hours to stop the reaction. The solvent was evaporated under reduced pressure to obtain crude product d1-5 (3.0g).
  • LC-MS: [M+H] + 450.
  • Step 4 In ice bath, under nitrogen protection, dissolve intermediate d1-6 (3.0 mL, 2.5 M) in the previous step in 30 mL anhydrous tetrahydrofuran, slowly add LiAlH 4 in tetrahydrofuran solution (1.3 g, 13.4 mmol), and complete the dropwise , react at room temperature for 1 hour, then stop the reaction. The reaction solution was slowly poured into ice water, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow oil d1-7 (1.0g), yield: 74%.
  • LC-MS: [M+H] + 268.
  • Step 1 Under ice bath, dissolve intermediate b3 (20 mg, 0.05 mmol) and TEA (24 mg, 0.24 mmol) in 1 mL of dichloromethane, slowly add crude intermediate a4 (11 mg, 0.05 mmol), and react for 1 hour. , the solvent was evaporated under reduced pressure to obtain crude compound P2-1 (15 mg, 0.01 mmol). Yield: 26%.
  • LC-MS: [M+H] + 627.
  • Step 2 Dissolve the crude product P2-1 (15 mg, 0.01 mmol) in 0.3 mL dichloromethane, add 0.3 mL trifluoroacetic acid dropwise, react at room temperature for 1 hour, evaporate the solvent under reduced pressure, and add 0.5 mL ethanol to the system.
  • the diamine was dissolved in dichloromethane (2 mL), and the crude product was separated by HPLC preparative chromatography (mobile phase: acetonitrile/water, 10 M aqueous ammonium bicarbonate solution) to obtain compound P2 (3.3 mg).
  • LC-MS: [M+H] + 497.
  • LC-MS: [M+H] + 465.
  • Step 1 Dissolve intermediate c1 (50 mg, 0.18 mmol) and TEA (90 mg, 0.89 mmol) in 1 mL of dichloromethane at room temperature, and add intermediate a12 (50 mg, 0.18 mmol, 0.5 mL) in dichloromethane dropwise. solution, and the mixture was reacted at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 4/5) to obtain compound P59-1 (30 mg), yield: 32%.
  • LC-MS: [M+H] + 527.
  • Step 2 Under nitrogen protection, dissolve compound P59-1 (15 mg, 0.03 mmol) and zinc cyanide (4 mg, 0.034 mmol) in 1 mL anhydrous DMF, and add ligand Xphos (1.4 mg, 0.003 mmol) and catalyst Pd. 2 (dba) 3 (1.4 mg, 0.002 mmol), heated to 100°C and reacted for 12 hours, the solvent was evaporated under reduced pressure, and the crude product was separated by HPLC preparative chromatography (mobile phase: acetonitrile/water, 10M ammonium bicarbonate aqueous solution) to obtain Compound P59 (5.0 mg), yield: 33%.
  • LC-MS: [M+H] + 518.
  • LC-MS: [M+H] + 505.
  • Example 8 Chiral resolution of target molecules P4, P7-P8, P12-P13, P15, P20, and P27
  • Step 2 Dissolve compound H1-1 (30 mg, 0.05 mmol) in 0.5 mL of 1,4-dioxane, add hydrogen chloride in dioxane solution (0.3 mL, 4M), react at room temperature for 30 minutes, and reduce the pressure. The solvent was evaporated, and the crude product was separated by HPLC preparative chromatography (mobile phase: acetonitrile/water, 10M aqueous ammonium bicarbonate solution) to obtain compound H1 (7.5 mg, 0.015 mmol), yield: 30%.
  • LC-MS: [M+H] + 488.
  • Step 1 Dissolve intermediate b11 (200 mg, 0.71 mmol) and TEA (143 mg, 1.42 mmol) in 4 mL of methylene chloride, add oxalyl chloride monomethyl ester (134 mg, 1.1 mmol), and react at room temperature for 1 hour under reduced pressure. The solvent is evaporated. Obtain crude compound H4-1. Proceed to the next step of the reaction.
  • Step 2 Dissolve crude compound H4-1 (30 mg, 0.05 mmol) in 6 mL of a mixed solution of tetrahydrofuran and water (v/v, 1/1), add LiOH (65 mg, 1.62 mmol), and react at room temperature for 4 hours. Slowly add 4M dilute hydrochloric acid to the system to adjust the pH to about 7, evaporate the solvent under reduced pressure, and separate the crude product through flash reverse chromatography (acetonitrile/water) to obtain compound H4-2 (110 mg). The total yield of the two steps: 43% .
  • LC-MS: [M+H] + 355.
  • the target compound H4 was separated by chiral preparative chromatography to obtain H4A and H4B.
  • H4A retention time RT1(min):8.083; H4B retention time: RT2(min):12.922;
  • Step 1 Dissolve intermediate b7 (100mg, 0.3mmol), DIEA (173mg, 1.3mmol) and intermediate a5-1 (68mg, 0.3mmol) in 1mL DMF, add EDCI (97mg, 0.5mmol) and HOBT ( 68 mg, 0.5 mmol), react at room temperature for 10 hours, add 10 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The mixture is separated by flash reverse column chromatography (acetonitrile/water) to obtain compound M3-1 (30.0 mg, 0.05 mmol), yield: 55%.
  • LC-MS: [M+H] + 588.
  • Step 2 Under nitrogen protection, dissolve compound M3-1 (78 mg, 0.16 mmol), dimethylphosphorus oxide (25 mg, 0.32 mmol) and K 3 PO 4 (102.9 mg, 0.48 mmol) in 1 mL of 1,4-bis Add Xantphos (19 mg, 0.03 mmol) and Pd 2 (dba) 3 (14.8 mg, 0.016 mmol) to the oxyhexacyclic ring, heat up to 100°C and react for 4 hours, evaporate the solvent under reduced pressure, and the crude product is separated by HPLC preparative chromatography ( Mobile phase: acetonitrile/water, 10M aqueous ammonium bicarbonate solution) to obtain compound M3 (23 mg, 0.05 mmol), yield: 30%.
  • LC-MS: [M+H] + 480.
  • Step 1 Dissolve the raw materials M7-1 (1.6g, 5.6mmol) and sodium methoxide (2.2g, 40.6mmol) in 16mL methanol, raise the temperature to 70°C and react for 10 hours, then stop the reaction. The solvent was evaporated under reduced pressure, 20 mL of ice water was added to the system, and the pH was adjusted to about 7 with 1 M dilute hydrochloric acid. The solid was precipitated, filtered, washed with ice-cold methanol, and dried to obtain compound M7-2 (1.6 g, 6.05 mmol). Yield: 96%.
  • LC-MS: [M+H] + 296.
  • Step 3 Dissolve intermediate M7-3 (220mg, 0.78mmol), intermediate b10 (224mg, 0.78mmol) and DIEA (403mg, 3.12mmol) in the previous step in 5mL DMF, add EDCI (224mg, 1.17mmol) and HOBT (158mg, 1.17mmol). The mixture was allowed to react at room temperature for 10 hours, then the reaction was stopped. 30 mL of ice water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was separated by flash reverse column chromatography (acetonitrile/water) to obtain compound M7-4 (200 mg, 0.36 mmol). , Yield: 47%.
  • LC-MS: [M+H] + 552.
  • Step 4 Under carbon monoxide atmosphere (5atm), dissolve compound M7-4 (50mg, 0.09mmol) and ditrimethylsilylamine (220mg, 1.36mmol) in 1mL DMF, add dppf (11mg, 0.02mmol) and Pd 2 (dba) 3 (8.3 mg, 0.01 mmol), heated to 100°C and reacted for 2 hours, the solvent was evaporated under reduced pressure, and the crude product was separated by HPLC preparative chromatography (mobile phase: acetonitrile/water, 10M ammonium bicarbonate aqueous solution), Compound M7 (21 mg) was obtained, yield: 43%.
  • LC-MS: [M+H] + 516.
  • Step 2 Under nitrogen protection, dissolve the intermediate N1-2 (1.4g, 4.98mmol) in the previous step in 28mL anhydrous tetrahydrofuran, and add LiAlH 4 (4.4mL, 10.7mmol). The mixture reacted at room temperature for 2 hours, and 50 mL of ice water was added to the system to quench the reaction. After suction filtration, the filtrate was separated by flash reverse column chromatography (acetonitrile/water) to obtain compound N1-3 (340 mg, 1.34 mmol), yield: 27%.
  • LC-MS: [M+H] + 253.
  • Step 5 Dissolve the intermediate N1-5 (280 mg, 0.89 mmol) from the previous step in 3 mL of ethanol, and add NaOH aqueous solution (2.8 mL, 50%). The temperature was raised to 80°C and reacted for 4 hours, then cooled to room temperature. Add 1 M dilute hydrochloric acid to the system to adjust the pH to about 3, evaporate the solvent under reduced pressure, and separate the crude product by flash reverse column chromatography (acetonitrile/water) to obtain compound N1-6 (105 mg, 0.48 mmol), yield: 54 %.
  • LC-MS: [M+H] + 219.
  • Steps: Under nitrogen protection, dissolve intermediate d1 (125mg, 0.54mmol), intermediate c1 (152mg, 0.54mmol) and DIEA (209mg, 1.61mmol) in 3mL DMF, add EDCI (155mg, 0.81mmol) and HOBT (109 mg, 0.81 mmol), the mixture was reacted at room temperature for 2 hours, and the reaction was stopped. Add 15 mL of ice water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. The crude product is separated by flash reverse column chromatography (acetonitrile/10M ammonium bicarbonate aqueous solution, 4/5) to obtain compound N2. (5.9mg). LC-MS: [M+H] + 497.
  • Intracellular arginine symmetric dimethylation inhibition assay In cell western ICW assay
  • HCT116 wild-type or MTAP-deficient cells (HTC116-MTAP del) cultured in RPMI1640 medium containing 10% fetal calf serum and 1% penicillin-streptomycin were seeded on a 384-well microplate with a culture volume of 30 ⁇ L at 37 °C and incubate overnight under 5% carbon dioxide.
  • the Li-Cor Odyssey instrument was used to scan the sdme-RG and DRAQ5 signals at 800nm and 700nm respectively and record the signal values.
  • the ratio of sdme-RG/DRAQ5 was used to calculate the inhibition percentage of arginine symmetric dimethylation (SDMA), and IC50 values were calculated using GraphPad Prism software.
  • Table 1 Inhibitory effects of compounds on arginine symmetric methylation in HTC116-MTAP del and wild type colorectal cancer HCT-116 cell lines
  • HCT116 wild-type and MTAP-deficient cells were cultured in MCCOYS 5A medium containing 10% FBS and 1% penicillin-streptomycin, placed in a 37°C, 5% CO2 constant-temperature incubator, and each in a 384-well microplate.
  • Add 40 ⁇ L of CTG solution Promega, Cat No. G7573
  • Use an Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104) to read the luminescence value.
  • the light signal is proportional to the amount of ATP in the system, and the content of ATP directly represents the number of viable cells in the system.
  • Table 2 2D anti-proliferative effects of compounds on HTC116-MTAP del and wild type colorectal cancer HCT-116 cell lines.
  • liver microsome stability test study on the compounds of the present invention.
  • the compounds to be tested are co-incubated with liver microsomes of different species with or without the addition of NADPH.
  • the final concentration of the compounds to be tested in the test system is 1 ⁇ M, and the final concentration of NADPH is 1 ⁇ M. is 1mM, and the final concentration of liver microsomes is 0.5mg/mL.
  • CD1 female mice were used as test animals and administered orally/intravenously (oral dosage was 10 mg/kg, intravenous dosage was 2 mg/kg).
  • mice There are three animals in each group of the oral group and three animals in each group of the intravenous group.
  • LC/MS/MS method was used to measure the blood concentration of plasma after oral and intravenous administration in mice, and the collected data were calculated using AB Sciex QTRAP6500 software.
  • HCT116 (MTAPdel) tumor cells were cultured, and the tumor cells were inoculated into 6-8 week old female BALB/c nude mice (body weight about 20g), and all mice were inoculated subcutaneously. Mice were cultured in an SPF-grade experimental environment, and all mice had free access to a commercially certified standard diet.
  • the dosage was: blank group vehicle (Saline containing 0.1% Tween 80 and 0.5% methyl cellulose).
  • the dosage of the administration group is 100 mg/kg, once a day.
  • Tumor volume was measured three times a week using a two-dimensional caliper, and animals were weighed daily. After 19 days of continuous administration, the inhibition rate (TGI/100%) was calculated based on the final tumor volume.
  • GSK3326595 has obvious hematological side effects, such as anemia, during clinical use.
  • Molecules of the invention were tested for hematological toxicity in C57BL/6J mice. details as follows:
  • mice Female C57BL/6J mice (weight about 20g) were cultured for 8-9 weeks. Mice were cultured in an SPF-grade experimental environment, and all mice had free access to a commercially certified standard diet. The test compound was administered daily orally, and the dosage was: blank group vehicle (Saline containing 0.1% Tween 80 and 0.5% methyl cellulose). The dosage of the administration group is 300mg/kg, once a day. The animals were weighed every day and their status was observed. The results are as follows (Table A). After 10 days of continuous administration, the hematological indicators of the mice were tested. The results are as follows (Table B).
  • Hematological toxicological data show that compared with the clinical molecules GSK3326595 and AMG9747, the compound of the present invention has a higher in vivo exposure, but has a lower impact on blood toxicity (erythrocytes and precursor reticulocytes), reflecting the high selectivity of the molecule of the present invention. It is expected that other similar highly selective molecules of the present invention will have similar safety advantages.

Abstract

本发明提供了一种化合物作为PRMT5-MTA抑制剂，其为式(A)所示化合物或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。本发明还提供了包含所述化合物的药物组合物，及其在治疗癌症中的用途。

Description

PRMT5-MTA抑制剂
本申请要求享受如下优先权：
PCT/CN2022/089516，申请日：2022年4月27日；
CN202211302299.7，申请日：2022年10月24日；
CN202310308964.1，申请日：2023年3月27日。
技术领域
本发明属于医药领域，具体涉及PRMT5-MTA抑制剂。
背景技术
蛋白质精氨酸甲基转移酶(Protein arginine methyltransferase，PRMT)能够对组蛋白和非组蛋白进行甲基化从而参与调控生物学过程例如基因转录、信号转导、蛋白质稳定性、细胞增殖、分化、凋亡和肿瘤的形成等(Nat Rev Mol Cell Biol.2019 Oct；20(10):642-657)(Nat Rev Drug Discov.2021 Jul；20(7):509-530)。当前发现了11种PRMT家族成员，根据催化精氨酸甲基化方式的不同，可分为I、II、III型，其中PRMT5属于II型，其催化的形式为对称双甲基化。
作为一种表观遗传酶，PRMT5参与多种生物学过程，包括转录调控、RNA代谢、核糖体生物合成和细胞周期调控。PRMT5蛋白在多种癌症类型中过表达，包括B和T细胞淋巴瘤、转移性黑色素瘤、神经母细胞瘤、胶质母细胞瘤、卵巢癌、乳腺癌等，越来越多的证据表明其在肿瘤发生和发展中具有重要作用(Cell Stress.2020 Aug；4(8):199–215)(Cancer Gene Ther.2022 Mar；29(3-4):264-276.)。在此基础上，PRMT5抑制剂已经成为肿瘤治疗药物的研发热点。
早期的PRMT5抑制剂可以分为两类，一类为底物竞争型抑制剂，代表药物为GSK3326595；另一类为SAM竞争型抑制剂，代表药物为JNJ64619178。这两类药物均对PRMT5具有强抑制活性，显示了强抗肿瘤活性，但由于对正常细胞和肿瘤细胞的PRMT5均具有强抑制活性，因此观测到了很强的血液毒性，限制了其临床应用，从而影响了其临床治疗效果(Bioorg Med Chem Lett.2019 Jun 1；29(11):1264-1269)(Expert Opin Ther Pat.2019 Feb；29(2):97-114.)(Annals of Oncology(2020)31(suppl_4):S462-S504.10.1016/annonc/annonc271)(Annals of Oncology(2019)30(suppl_5):v159-v193.10.1093/annonc/mdz244)。
2016年，发表在Science上的论文揭示了MTAP缺失与PRMT5具有合成致死作用(Science.2016 Mar 11；351(6278):1214-8.)。MTAP在多种实体肿瘤中具有高缺失率，包括胰腺癌、神经胶质瘤等。MTAP是胞内的MTA降解酶，由于MTAP缺失可以导致MTA的细胞内积聚，而MTA可与PRMT5的功能底物甲基化供体SAM竞争与PRMT5的结合，从而抑制PRMT5的功能。由于MTA在MTAP缺失肿瘤细胞内特异性积聚，通过加强MTA与PRMT5的结合抑制，可以实现在肿瘤细胞内特异性抑制PRMT5活性，而对正常细胞的PRMT5活性抑制作用弱，从而提供治疗安全窗，在保证抗肿瘤药效的同时降低毒性(Nat Rev Drug Discov.2020 Jan；19(1):23-38)(Cell Rep.2016 Apr 19；15(3):574-587)。当前，MTA协同性PRMT5抑制剂已经获得了临床前验证数据(J Med Chem.2022 Feb 10；65(3):1749-1766)。MTA协同性PRMT5抑制剂的研发在MTAP缺失的肿瘤治疗中具有极大的潜力。
目前尽管在PRMT5研究方面取得了进展，但是仍然缺乏有效的和选择性的PRMT5-MTA抑制剂。
发明内容
在一个方面，本发明提供了式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
Ar为
环S选自C6-10芳基、6-10元杂芳基、C5-10环烷基或5-10元杂环基；
R1和R2独立地选自H、卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、5-6元杂芳基、S(O)2-Rd或S(O)-Rd；所述R1和R2可任选地被卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基进一步取代，优选地，所述R1和R2可任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代；
或者，R1、R2和它们连接的碳原子一起形成C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基，所述C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个、3个、4个或5个Rx取代；
Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂环基；
R3选自C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A选自C4-10环烷基、4-10元杂环基、5-10元杂芳基或C6-10芳基；
环B为C5-10环烷基或5-10元杂环基；
所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
R#选自卤素、ORa、C1-6亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
R5选自H或C1-6烷基；
R6和R9独立地选自ORa、C1-6亚烷基-ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6元杂芳基；
R7和R8独立地选自ORa、NRbRc；
R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
R11选自H、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
n选自1、2或3；
Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基；
前提是，当L为C(O)时，R6不为C1-6烷基、卤素、C1-6卤代烷基和C2-6炔基；
上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
在另一个方面，本发明提供了式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1为N或CR2；
L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
Ar为
环S选自C6-10芳基、6-10元杂芳基、C5-10环烷基或5-10元杂环基；
R1和R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、-S(O)2C1-6烷基、-S(O)2卤代C1-6烷基、C2-6烯基或C2-6炔基；
R3选自C6-10芳基、5-10元杂芳基、C3-10环烷基或3-10元杂环基，其可任选地被1个、2个或3个R#取代；
R4选自C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-4亚烷基-ORa或C1-4亚烷基-NRbRc，其可任选地被1个、2个或3个R#取代；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基或C6-10芳基；
环B为C4-10环烷基或4-10元杂环基；
所述环A和环B可任选地被1个、2个、3个或4个R#取代；
R5、R5’和R6’选自H、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R6和R9独立地选自ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
或者R5’和R6’连接形成键，或者R5’、R6’和他们连接的碳原子一起形成C3-7环烷基或3-7元杂环基；
R7和R8独立地选自ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
R#选自H、卤素、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；
前提是，当L为C(O)时，R6不为C1-6烷基、C1-6卤代烷基和C2-6炔基；
上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂。
在另一个方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂。
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防PRMT5甲基转移酶介导的疾病的药物中的用途。
在另一个方面，本发明提供了在受试者中治疗和/或预防PRMT5甲基转移酶介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防PRMT5甲基转移酶介导的疾病。
在具体实施方案中，本发明治疗的疾病包括选自以下的癌症：声神经瘤、腺癌、肾上腺癌、肛门癌、血管肉瘤(例如淋巴管肉瘤、淋巴管内皮肉瘤、血管瘤)、阑尾癌、良性单克隆伽玛病、胆管癌、膀胱癌、脑癌(例如脑膜瘤、神经胶质瘤，例如星形胶质细胞瘤、少突胶质细胞瘤、髓母细胞瘤)、支气管癌、类癌瘤、宫颈癌(例如宫颈腺癌)、绒(毛)膜癌、脊索瘤、颅咽管瘤、结肠直肠癌(例如结肠癌、直肠癌、大肠腺癌)、上皮癌、室管膜瘤、内皮肉瘤(例如卡波西肉瘤、多发性特发性出血肉瘤)、子宫内膜癌(例如子宫癌、子宫肉瘤)、食道癌(如食管腺癌、巴雷特氏腺癌)、尤因氏肉瘤、眼癌(如眼内黑色素瘤、成视网膜细胞瘤)、嗜酸性粒细胞增多症、胆囊癌、胃癌(如胃腺癌)、胃肠道间质瘤(GIST)、头颈癌(如头颈部鳞状细胞癌、口腔癌(如口腔鳞状细胞癌、喉癌(如喉癌、咽癌、鼻咽癌、口咽癌)))、造血系统癌症(例如白血病，如急性淋巴细胞白血病(ALL)(例如，B细胞ALL、T细胞ALL)、急性髓细胞白血病(AML)(例如，B细胞AML、T细胞AML)、慢性髓细胞白血病(CML)(例如，B细胞CML、T细胞CML)、慢性淋巴细胞白血病(CLL)(例如，B细胞CLL、T细胞CLL)、滤泡性淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、边缘区B细胞淋巴瘤(如粘膜相关淋巴组织(MALT)淋巴瘤、淋巴结边缘区B细胞淋巴瘤、脾脏边缘区B细胞淋巴瘤)、原发性纵隔B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B淋巴母细胞淋巴瘤和原发性中枢神经系统(CNS)淋巴瘤；以及T细胞非霍奇金淋巴瘤、如前体T淋巴母细胞淋巴瘤/白血病、外周T细胞淋巴瘤(如皮肤T细胞淋巴瘤(如真菌病、Sezary综合征)、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤性T细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤、间变性大细胞淋巴瘤)；上述一种或多种白血病/淋巴瘤的混合物；多发性骨髓瘤(MM))、重链疾病(如α链疾病、γ链疾病、μ链疾病)、血管母细胞瘤、炎性肌纤维母细胞瘤、免疫细胞性淀粉样变性、肾癌(如肾母细胞瘤、肾细胞癌)、肝癌(如肝细胞癌、恶性肝细胞癌)、肺癌(如支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌、平滑肌肉瘤(LMS)、肥大细胞增多症(如全身肥大细胞增多症)、骨髓增生异常综合征(MDS)、间皮瘤、骨髓增生性疾病(MPD)(如真性红细胞增多症(PV)、原发性血小板增多症(ET)、特发性骨髓外化生(AMM)、慢性特发性骨髓纤维化、慢性粒细胞白血病(CML)、慢性中性粒细胞白血病(CNL)、嗜酸性粒细胞增多综合征(HES)、神经母细胞瘤、神经纤维瘤(如1型或2型神经纤维瘤病、神经鞘 瘤病)、神经内分泌癌(如胃肠胰神经内分泌肿瘤(GEP-NET)，类癌瘤)、骨肉瘤、卵巢癌(如囊腺癌、卵巢胚胎癌、卵巢腺癌)、乳头状腺癌、阴茎癌。
由随后的具体实施方案、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C1-6烷基”包括C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。
“C1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，C1-4烷基和C1-2烷基是优选的。C1-6烷基的例子包括：甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。术语“C1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括：Me(-CH3)、Et(-CH2CH3)、iPr(-CH(CH3)2)、nPr(-CH2CH2CH3)、n-Bu(-CH2CH2CH2CH3)或i-Bu(-CH2CH(CH3)2)。
“C2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C2-4烯基是优选的。C2-6烯基的例子包括：乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁二烯基(C4)、戊烯基(C5)、戊二烯基(C5)、己烯基(C6)，等等。术语“C2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C2-4炔基是优选的。C2-6炔基的例子包括但不限于：乙炔基(C2)、1-丙炔基(C3)、2-丙炔基(C3)、1-丁炔基(C4)、2-丁炔基(C4)，戊炔基(C5)、己炔基(C6)，等等。术语“C2- 6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C1-6亚烷基”是指除去C1-6烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C1-4亚烷基、C2-4亚烷基和C1-3亚烷基是优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)、亚丁基(-CH2CH2CH2CH2-)、亚戊基(-CH2CH2CH2CH2CH2-)、亚己基(-CH2CH2CH2CH2CH2CH2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH3)-、-C(CH3)2-)、取代的亚乙基(-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-)、取代的亚丙基(-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2C(CH3)2-)，等等。
“C2-6亚烯基”是指除去C2-6烯基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C2-4亚烯基是特别优选的。示例性的未取代的所述亚烯基包括但不限于：亚乙烯基(-CH＝CH-)和亚丙烯基(例如，-CH＝CHCH2-、-CH2-CH＝CH-)。示例性的取代的所述亚烯基，例如，被一个或多个烷基(甲基)取代的亚烯基，包括但不限于：取代的亚乙基(-C(CH3)＝CH-、-CH＝C(CH3)-)、取代的亚丙烯基(-C(CH3)＝CHCH2-、-CH＝C(CH3)CH2-、-CH＝CHCH(CH3)-、-CH＝CHC(CH3)2-、-CH(CH3)-CH＝CH-、-C(CH3)2-CH＝CH-、-CH2-C(CH3)＝CH-、-CH2-CH＝C(CH3)-)，等等。
“C2-6亚炔基”是指除去C2-6炔基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C2-4亚炔基是特别优选的。示例性的所述亚炔基包括但不限于：亚乙炔基(-C≡C-)、取代或未取代的亚丙炔基(-C≡CCH2-)，等等。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
因此，“C1-6卤代烷基”是指上述“C1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C1-4卤代烷基是特别优选的，更优选C1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2-三氟-1,1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。
“C1-6烷氧基”是指-OR基团，其中R为上文定义的C1-6烷基。C1-4烷氧基是优选的。
“C1-6卤代烷氧基”是指“C1-6烷氧基”，其被一个或多个卤素基团取代。在一些实施方案中，C1-4卤代烷氧烷基是特别优选的，更优选C1-2卤代烷氧烷基。
“C3-10环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C4-10环烷基、C5-10环烷基、C4-7环烷基、C3-7环烷基、C3-6环烷基、C3-5环烷基和C3-4环烷基是特别优选的，更优选C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“3-12元杂环基”是指具有环碳原子和1至5个环杂原子的3至12元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至3个环杂原子的3至10元非芳香环系；在一些实施方案中，优选4-10元杂环基，其为具有环碳原子和1至4个环杂原子的4至10元非芳香环系；在一些实施方案中，优选5-10元杂环基，其为具有环碳原子和1至5个环杂原子的5至10元非芳香环系；在一些实施方案中，优选5-8元杂环基，其为具有环碳原子和1至5个环杂原子的5至8元非芳香环系；在一些实施方案中，优选3-7元杂环基，其为具有环碳原子和1至4个环杂原子的3至7元非芳香环系；优选3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选4-7元杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系；优选4-6元杂环基，其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系；更优选5-6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系；更优选3-5元杂环基，其为具有环碳原子和1至3个环杂原子的3至5元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“C6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“5-14元杂芳基”是指具有环碳原子和1-4个环杂原子的5-14元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基 或杂环基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中，5-10元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在一些实施方案中，5-10元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的6-10元单环或双环的4n+2芳族环体系。在一些实施方案中，5-9元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-9元单环或双环的4n+2芳族环体系。在另一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基(例如，1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。
“亚环烷基”、“亚杂环基”、“亚芳基”或“亚杂芳基”为上述定义的“环烷基”、“杂环基”、“芳基”或“杂芳基”除去另一个氢而形成的二价基团，并且可以是取代或未取代的。例如，“C5-7亚环烷基”是指去除C5-7环烷基的另一个氢而形成的二价基团，“5-8元亚杂环基”是指去除5-8元杂环基的另一个氢而形成的二价基团，“C6-10亚芳基”是指去除C6-10芳基的另一个氢而形成的二价基团，“5-6元亚杂芳基”是指去除5-6元杂芳基的另一个氢而形成的二价基团。
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)2Raa、-OP(＝O)2Raa、-P(＝O)(Raa)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)2N(Rbb)2、-OP(＝O)2N(Rbb)2、-P(＝O)(NRbb)2、-OP(＝O)(NRbb)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(Rbb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbb或＝NORcc取代；
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Raa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rbb的每个独立地选自：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rbb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rcc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；
Rdd的每个独立地选自：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2,、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)2Ree、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代，或者两个偕Rdd取代基可结合以形成＝O或＝S；
Ree的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代；
Rff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代；
Rgg的每个独立地是：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6烷基、-ON(C1-6烷基)2、-N(C1-6烷基)2、-N(C1-6烷基)3 +X-、-NH(C1-6烷基)2 +X-、-NH2(C1-6烷基)+X-、-NH3 +X-、-N(OC1-6烷基)(C1-6烷基)、-N(OH)(C1-6烷基)、-NH(OH)、-SH、-SC1-6烷基、-SS(C1-6烷基)、-C(＝O)(C1-6烷基)、-CO2H、-CO2(C1-6烷基)、-OC(＝O)(C1-6烷基)、-OCO2(C1-6烷基)、-C(＝O)NH2、-C(＝O)N(C1-6烷基)2、-OC(＝O)NH(C1-6烷基)、-NHC(＝O)(C1-6烷基)、-N(C1-6烷基)C(＝O)(C1-6烷基)、-NHCO2(C1-6烷基)、-NHC(＝O)N(C1-6烷基)2、-NHC(＝O)NH(C1-6烷基)、-NHC(＝O)NH2、-C(＝NH)O(C1-6烷基)、-OC(＝NH)(C1- 6烷基)、-OC(＝NH)OC1-6烷基、-C(＝NH)N(C1-6烷基)2、-C(＝NH)NH(C1-6烷基)、-C(＝NH)NH2、-OC(＝NH)N(C1-6烷基)2、-OC(NH)NH(C1-6烷基)、-OC(NH)NH2、-NHC(NH)N(C1-6烷基)2、-NHC(＝NH)NH2、-NHSO2(C1-6烷基)、-SO2N(C1-6烷基)2、-SO2NH(C1-6烷基)、-SO2NH2、-SO2C1-6烷基、-SO2OC1-6烷基、-OSO2C1-6烷基、-SOC1-6烷基、-Si(C1-6烷基)3、-OSi(C1-6烷基)3、-C(＝S)N(C1-6烷基)2、C(＝S)NH(C1-6烷基)、C(＝S)NH2、-C(＝O)S(C1-6烷基)、-C(＝S)SC1-6烷基、-SC(＝S)SC1-6烷基、-P(＝O)2(C1-6烷基)、-P(＝O)(C1- 6烷基)2、-OP(＝O)(C1-6烷基)2、-OP(＝O)(OC1-6烷基)2、C1-6烷基、C1-6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、C3-C7杂环基、C5-C10杂芳基；或者两个偕Rgg取代基可结合形成＝O或＝S；其中，X-为反离子。
示例性的氮原子上取代基包括但不局限于：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代，且其中Raa、Rbb、Rcc和Rdd如上所述。
其它定义
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。
具体实施方案
本文中，“本发明化合物”指的是以下的式(A)化合物(包括子通式，例如式(A-1)、(A-2)、(I)、(II)、(III)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VIII)、(IX)、(X)、(X-1)、(X-2)、(XI)、(XII)或(XIII)等)、其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，以及它们的混合物。
在一个实施方案中，本发明涉及式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
Ar为
环S选自C6-10芳基、6-10元杂芳基、C5-10环烷基或5-10元杂环基；
R1和R2独立地选自H、卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、5-6元杂芳基、S(O)2-Rd或S(O)-Rd；所述R1和R2可任选地被卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基进一步取代，优选地，所述R1和R2可任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代；
或者，R1、R2和它们连接的碳原子一起形成C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基，所述C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个、3个、4个或5个Rx取代；
Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂环基；
R3选自C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A选自C4-10环烷基、4-10元杂环基、5-10元杂芳基或C6-10芳基；
环B为C5-10环烷基或5-10元杂环基；
所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
R#选自卤素、ORa、C1-6亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
R5选自H或C1-6烷基；
R6和R9独立地选自ORa、C1-6亚烷基-ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6元杂芳基；
R7和R8独立地选自ORa、NRbRc；
R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
R11选自H、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
n选自1、2或3；
Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基；
前提是，当L为C(O)时，R6不为C1-6烷基、卤素、C1-6卤代烷基和C2-6炔基。
在另一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1为N或CR2；
L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
Ar为
环S选自C6-10芳基、6-10元杂芳基、C5-10环烷基或5-10元杂环基；
R1和R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、-S(O)2C1-6烷基、-S(O)2卤代C1-6烷基、C2-6烯基或C2-6炔基；
R3选自C6-10芳基、5-10元杂芳基、C3-10环烷基或3-10元杂环基，其可任选地被1个、2个或3个R#取代；
R4选自C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-4亚烷基-ORa或C1-4亚烷基-NRbRc，其可任选地被1个、2个或3个R#取代；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基或C6-10芳基；
环B为C4-10环烷基或4-10元杂环基；
所述环A和环B可任选地被1个、2个、3个或4个R#取代；
R5、R5’和R6’选自H、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R6和R9独立地选自ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
或者R5’和R6’连接形成键，或者R5’、R6’和他们连接的碳原子一起形成C3-7环烷基或3-7元杂环基；
R7和R8独立地选自ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
R#选自H、卤素、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；
前提是，当L为C(O)时，R6不为C1-6烷基、C1-6卤代烷基和C2-6炔基。
X1、X2和X3
在一个具体实施方案中，X1为N；在另一个具体实施方案中，X1为CR2。
在一个具体实施方案中，X2为N；在另一个具体实施方案中，X2为CH。
在一个具体实施方案中，X3为N；在另一个具体实施方案中，X3为CH。
L
在一个具体实施方案中，L为C(O)；在另一个具体实施方案中，L为C(O)NH；在另一个具体实施方案中，L为C(O)-C(O)；在另一个具体实施方案中，L为C(O)-C(O)NH。
Ar
在一个具体实施方案中，Ar为其中，
R5、R5’和R6’选自H、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R6选自ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
或者R5’和R6’连接形成键，或者R5’、R6’和他们连接的碳原子一起形成C3-7环烷基或3-7元杂环基。
在一个具体实施方案中，Ar为在另一个具体实施方案中，Ar为在另一个 具体实施方案中，Ar为在另一个具体实施方案中，Ar为
在一个具体实施方案中，Ar为其中，
R5选自H或C1-6烷基；
R6选自ORa、C1-6亚烷基-ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6元杂芳基；
R7选自ORa或NRbRc；
R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
n选自1、2或3。
在一个具体实施方案中，Ar为其中，
R8选自ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
R9选自ORa、C1-6亚烷基-ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6元杂芳基；
环S
在一个具体实施方案中，环S为C6-10芳基；在另一个具体实施方案中，环S为6-10元杂芳基；在另一个具体实施方案中，环S为C5-10环烷基；在另一个具体实施方案中，环S为5-10元杂环基。
R1
在一个具体实施方案中，R1为H；在另一个具体实施方案中，R1为卤素，例如Cl、Br；在另一个具体实施方案中，R1为C1-6烷基；在另一个具体实施方案中，R1为C1-6卤代烷基；在另一个具体实施方案中，R1为C1-4卤代烷基；在另一个具体实施方案中，R1为C1-2卤代烷基，优选卤代甲基，例如CF3；在另一个具体实施方案中，R1为-S(O)2C1-6烷基，例如S(O)2-C1-4卤代烷基；在另一个具体实施方案中，R1为-S(O)2卤代C1-6烷基；在另一个具体实施方案中，R1为C2-6烯基；在另一个具体实施方案中，R1为C2-6炔基；在另一个具体实施方案中，R1为SF5；在另一个具体实施方案中，R1为ORa；在另一个具体实施方案中，R1为NRbRc；在另一个具体实施方案中，R1为CN；在另一个具体实施方案中，R1为C1-6烷氧基；在另一个具体实施方案中，R1为C1-4烷氧基，优选为C1-2烷氧基，例如OCF3；在另一个具体实施方案中，R1为C1-6卤代烷氧基，例如C1-4卤代烷氧基；在另一个具体实施方案中，R1为C3-7环烷基；在另一个具体实施方案中，R1为C3-5环烷基，优选为C3-4环烷基，例如环丙基；在另一个具体实施方案中，R1为3-7元杂环基；在另一个具体实施方案中，R1为5-6元杂芳基，例如吡啶；在另一个具体实施方案中，R1为S(O)2-Rd；在另一个具体实施方案中，R1为S(O)-Rd。
在一个具体实施方案中，R1为Cl；在另一个具体实施方案中，R1为Br；在另一个具体实施方案中，R1为SF5；在另一个具体实施方案中，R1为CN；在另一个具体实施方案中，R1为CF3；在另一个具体实施方案中，R1为OCF3；在另一个具体实施方案中，R1为环丙基；在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为在另一个具体实施方案中，R1为
在一个具体实施方案中，R1未被取代；在另一个具体实施方案中，R1被Ry取代；在另一个具体实施方案中，R1任选地被卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基进一步取代。
R2
在一个具体实施方案中，R2为H；在另一个具体实施方案中，R2为卤素；在另一个具体实施方案中，R2为C1-6烷基；在另一个具体实施方案中，R2为C1-6卤代烷基；在另一个具体实施方案中，R2为-S(O)2C1-6烷基；在另一个具体实施方案中，R2为-S(O)2卤代C1-6烷基；在另一个具体实施方案中，R2为C2-6烯基；在另一个具体实施方案中，R2为C2-6炔基；在另一个具体实施方案中，R2为SF5；在另一个具体实施方案中，R2为ORa；在另一个具体实施方案中，R2为NRbRc；在另一个具体实施方案中，R2为CN；在另一个具体实施方案中，R2为C1-6烷氧基；在另一个具体实施方案中，R2为C1-6卤代烷氧基；在另一个具体实施方案中，R2为3-7元杂环基；在另一个具体实施方案中，R2为5-6元杂芳基；在另一个具体实施方案中，R2为S(O)2-Rd；在另一个具体实施方案中，R2为S(O)-Rd。
在一个具体实施方案中，R2未被取代；在另一个具体实施方案中，R2任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代。
在一个具体实施方案中，R1、R2和它们连接的碳原子一起形成C4-10环烷基；在另一个具体实施方案中，R1、R2和它们连接的碳原子一起形成4-10元杂环基；在另一个具体实施方案中，R1、R2和它们连接的碳原子一起形成C6-10芳基；在另一个具体实施方案中，R1、R2和它们连接的碳原子一起形成5-10元杂芳基；在另一个具体实施方案中，R1、R2和它们连接的碳原子一起形成5-6元杂芳基。
在一个具体实施方案中，R1、R2和它们连接的碳原子一起形成的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个、3个、4个或5个Rx取代。
在一个具体实施方案中，R1、R2一起形成在另一个具体实施方案中，R1、R2一起形成
R3和R4
在一个具体实施方案中，R3为C1-6烷基；在一个具体实施方案中，R3为C1-4烷基；在另一个具体实施方案中，R3为C1-6卤代烷基；在另一个具体实施方案中，R3为C1-6亚烷基-ORa；在另一个具体实施方案中，R3为C1-4亚烷基-ORa，优选为C1-4亚烷基-OC1-4烷基；在另一个具体实施方案中，R3为C1- 6亚烷基-NRbRc；在另一个具体实施方案中，R3为C1-4亚烷基-NRbRc；在另一个具体实施方案中，R3为C6-10芳基，例如苯基；在另一个具体实施方案中，R3为5-10元杂芳基；在另一个具体实施方案中，R3为C3-10环烷基；在另一个具体实施方案中，R3为C3-7环烷基；在另一个具体实施方案中，R3为C3- 5环烷基；在另一个具体实施方案中，R3为3-10元杂环基；在另一个具体实施方案中，R3为5-10元杂芳基，例如5-6元杂芳基。
在一个具体实施方案中，R3为CH3；在另一个具体实施方案中，R3为环丙基；在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为环丙基；在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为在另一个具体实施方案中，R3为
在一个具体实施方案中，R3未被取代；在另一个具体实施方案中，R3被1个R#取代；在另一个 具体实施方案中，R3被2个R#取代；在另一个具体实施方案中，R3被3个R#取代；在另一个具体实施方案中，R3被4个R#取代；在另一个具体实施方案中，R3被5个R#取代。
在一个具体实施方案中，R4为H；在另一个具体实施方案中，R4为C1-6烷基；在另一个具体实施方案中，R4为C1-4烷基，例如CH3、CH2CH3；在另一个具体实施方案中，R4为C3-7环烷基；在另一个具体实施方案中，R4为C3-6环烷基，优选为C3-5环烷基，更优选为C3-4环烷基，例如环丙基；在另一个具体实施方案中，R4为3-7元杂环基；在另一个具体实施方案中，R4为C1-6卤代烷基；在另一个具体实施方案中，R4为C1-4亚烷基-ORa，例如在另一个具体实施方案中，R4为C1-4亚烷基-NRbRc。
在一个具体实施方案中，R4未被取代；在另一个具体实施方案中，R4被1个R#取代；在另一个具体实施方案中，R4被2个R#取代；在另一个具体实施方案中，R4被3个R#取代。
在一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成
在一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成在另一个具体实施方案中，R3、R4和它们连接的碳原子一起形成
R5和R5’
在一个具体实施方案中，R5为H；在另一个具体实施方案中，R5为ORa；在另一个具体实施方案中，R5为NRbRc；在另一个具体实施方案中，R5为C1-6烷基；在另一个具体实施方案中，R5为C1-4烷基，例如CH3；在另一个具体实施方案中，R5为C1-6卤代烷基；在另一个具体实施方案中，R5为C2- 6烯基；在另一个具体实施方案中，R5为C2-6炔基。
在一个具体实施方案中，R5’为H；在另一个具体实施方案中，R5’为ORa；在另一个具体实施方案中，R5’为NRbRc；在另一个具体实施方案中，R5’为C1-6烷基；在另一个具体实施方案中，R5’为C1- 6卤代烷基；在另一个具体实施方案中，R5’为C2-6烯基；在另一个具体实施方案中，R5’为C2-6炔基。
R6
在一个具体实施方案中，R6为ORa；在另一个具体实施方案中，R6为C1-6亚烷基-ORa；在另一个具体实施方案中，R6为C1-4亚烷基-OH；在另一个具体实施方案中，R6为C(O)NRbRc；在另一个具体实施方案中，R6为C(O)ORa；在另一个具体实施方案中，R6为C(O)Ra；在另一个具体实施方案中，R6为C1-6烷基；在另一个具体实施方案中，R6为C1-6卤代烷基；在另一个具体实施方案中，R6为C2- 6烯基；在另一个具体实施方案中，R6为C2-6炔基；在另一个具体实施方案中，R6为C3-7环烷基；在另一个具体实施方案中，R6为C3-5环烷基；在另一个具体实施方案中，R6为3-7元杂环基；在另一个具体实施方案中，R6为3-5元杂环基；在另一个具体实施方案中，R6为C6-10芳基；在另一个具体实施方案中，R6为5-6元杂芳基。
在一个具体实施方案中，R6为OCH3；在另一个具体实施方案中，R6为CH2OH；在另一个具体 实施方案中，R6为C(O)2NH2；在另一个具体实施方案中，R6为环丙基；在另一个具体实施方案中，R6为环丁基；在另一个具体实施方案中，R6为
在一个具体实施方案中，R6’为H；在另一个具体实施方案中，R6’为ORa；在另一个具体实施方案中，R6’为NRbRc；在另一个具体实施方案中，R6’为C1-6烷基；在另一个具体实施方案中，R6’为C1- 6卤代烷基；在另一个具体实施方案中，R6’为C2-6烯基；在另一个具体实施方案中，R6’为C2-6炔基。
在一个具体实施方案中，R5’和R6’连接形成键；在另一个具体实施方案中，R5’、R6’和他们连接的碳原子一起形成C3-7环烷基；在另一个具体实施方案中，R5’、R6’和他们连接的碳原子一起形成3-7元杂环基。
R7
在一个具体实施方案中，R7为ORa；在另一个具体实施方案中，R7为OCH3；在另一个具体实施方案中，R7为NRbRc；在另一个具体实施方案中，R7为NH2；在另一个具体实施方案中，R7为C1-6烷基；在另一个具体实施方案中，R7为C1-6卤代烷基。
R8
在一个具体实施方案中，R8为ORa；在另一个具体实施方案中，R8为NRbRc；在另一个具体实施方案中，R8为NH2；在另一个具体实施方案中，R8为C1-6烷基；在另一个具体实施方案中，R8为C1- 6卤代烷基。
R9
在一个具体实施方案中，R9为ORa；在另一个具体实施方案中，R9为C1-6亚烷基-ORa；在另一个具体实施方案中，R9为C1-4亚烷基-OH，例如CH2OH、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C3-5环烷基、3-7元杂环基、3-5元杂环基、C6-10芳基或5-6元杂芳基；
R10
在一个具体实施方案中，R10为H；在另一个具体实施方案中，R10为卤素；在另一个具体实施方案中，R10为ORa；在另一个具体实施方案中，R10为NRbRc；在另一个具体实施方案中，R10为CN；在另一个具体实施方案中，R10为C1-6烷基；在另一个具体实施方案中，R10为C1-6卤代烷基。
R11
在一个具体实施方案中，R11为H；在另一个具体实施方案中，R11为卤素；在另一个具体实施方案中，R11为ORa；在另一个具体实施方案中，R11为NRbRc；在另一个具体实施方案中，R11为C1-6烷基；在另一个具体实施方案中，R11为C1-6卤代烷基。
环A
在一个具体实施方案中，环A为5-10元杂芳基；在另一个具体实施方案中，环A为5-6元杂芳基；在另一个具体实施方案中，环A为五元杂芳基；在另一个具体实施方案中，环A为C6-10芳基；在另一个具体实施方案中，环A为C4-10环烷基；在另一个具体实施方案中，环A为4-10元杂环基。
在一个具体实施方案中，环A未被取代；在另一个具体实施方案中，环A被1个R#取代；在另一个具体实施方案中，环A被2个R#取代；在另一个具体实施方案中，环A被3个R#取代；在另一个具体实施方案中，环A被4个R#取代；在另一个具体实施方案中，环A被5个R#取代。
环B
在一个具体实施方案中，环B为C4-10环烷基；在另一个具体实施方案中，环B为C4-7环烷基；在另一个具体实施方案中，环B为4-10元杂环基；在另一个具体实施方案中，环B为4-7元杂环基。
在一个具体实施方案中，环B未被取代；在另一个具体实施方案中，环B被1个R#取代；在另一个具体实施方案中，环B被2个R#取代；在另一个具体实施方案中，环B被3个R#取代；在另一个具体实施方案中，环B被4个R#取代；在另一个具体实施方案中，环B被5个R#取代。
Ra、Rb、Rc和Rd
在一个具体实施方案中，Ra为H；在另一个具体实施方案中，Ra为C1-6烷基；在另一个具体实施方案中，Ra为C1-6卤代烷基。
在一个具体实施方案中，Rb为H；在另一个具体实施方案中，Rb为C1-6烷基；在另一个具体实施方案中，Rb为C1-6卤代烷基。
在一个具体实施方案中，Rc为H；在另一个具体实施方案中，Rc为C1-6烷基；在另一个具体实施方案中，Rc为C1-6卤代烷基。
在一个具体实施方案中，Rd为H；在另一个具体实施方案中，Rd为C1-6烷基；在另一个具体实施方案中，Rd为C1-6卤代烷基。
R#
在一个具体实施方案中，R#为H；在另一个具体实施方案中，R#为卤素；在另一个具体实施方案中，R#为C1-4亚烷基-ORa；在另一个具体实施方案中，R#为ORa；在另一个具体实施方案中，R#为NRbRc；在另一个具体实施方案中，R#为C1-6烷基；在另一个具体实施方案中，R#为C1-6卤代烷基；在另一个具体实施方案中，R#为C2-6烯基；在另一个具体实施方案中，R#为C2-6炔基。
Rx
在一个具体实施方案中，Rx为卤素；在另一个具体实施方案中，Rx为C1-6烷基；在另一个具体实施方案中，Rx为C1-6卤代烷基；在另一个具体实施方案中，Rx为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基；在另一个具体实施方案中，Rx为任选地被卤素、C1- 6烷基、C1-6卤代烷基中的一个或多个基团取代的4-10元杂环基；在另一个具体实施方案中，Rx为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C6-10芳基；在另一个具体实施方案中，Rx为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的5-10元杂环基。
Ry
在一个具体实施方案中，Ry为H；在另一个具体实施方案中，Ry为卤素；在另一个具体实施方案中，Ry为C1-6烷基；在另一个具体实施方案中，Ry为C1-4烷基；在另一个具体实施方案中，Ry为C1-6卤代烷基；在另一个具体实施方案中，Ry为C1-4卤代烷基；在另一个具体实施方案中，Ry为C1- 6烷氧基；在另一个具体实施方案中，Ry为C1-4烷氧基；在另一个具体实施方案中，Ry为C1-6卤代烷氧基。
在一个具体实施方案中，Ry为H；在另一个具体实施方案中，Ry为F；在另一个具体实施方案中，Ry为Cl；在另一个具体实施方案中，Ry为CH3；在另一个具体实施方案中，Ry为OCH3；在另一个具体实施方案中，Ry为CF3。
n
在一个具体实施方案中，n为1；在另一个具体实施方案中，n为2；在另一个具体实施方案中，n为3。
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，X1的任一技术方案或其任意组合，可以与X2、X3、L、Ar、环S、环A、环B、R1-R11、R5’、R6’、Ra、Rb、Rc、Rd、R#、Rx、Ry和n等的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。
在更具体的实施方案中，本发明提供了式(A-1)或(A-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，各基团如上文所定义。
在更具体的实施方案中，本发明提供了上述式(A)、(A-1)或(A-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
Ar为
环S为C6-10芳基；
R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、5-6元杂芳基、S(O)2-Rd或S(O)-Rd；所述R1可任选地被卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基进一步取代，优选地，R1可任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代；
R2选自H、C1-6烷基或C1-6卤代烷基；
或者，R1、R2和它们连接的碳原子一起形成C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基，所述C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个或3个Rx取代；
Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂环基；
R3选自C1-6烷基、C1-6卤代烷基、C1-4亚烷基-ORa、C1-4亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基或C6-10芳基；
环B为C5-10环烷基或5-10元杂环基；
所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
R#选自卤素、ORa、C1-4亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
R5选自H或C1-6烷基；
R6选自ORa、C1-6亚烷基-ORa、C(O)NRbRc、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
R7和R8独立地选自ORa或NRbRc；
R9选自C1-6烷基或C3-7环烷基；
R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
R11选自H、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(A)、(A-1)或(A-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
L选自C(O)或C(O)-C(O)NH；
Ar为
R1选自Cl、Br、SF5、CN、CF3、OCF3、环丙基、 优选地，R1选自Cl、Br、SF5、CN、CF3、OCF3、环丙基、
R2选自H或CH3；
或者，R1、R2一起形成
R3选自CH3、环丙基、
R4选自H、CH3、CH2CH3或环丙基；
或者，R3、R4和它们连接的碳原子一起形成
R5选自H或CH3；
R6选自OCH3、CH2OH、C(O)2NH2、环丙基、环丁基或
R7选自NH2或OCH3；
R8选自NH2；
R9选自CH3、CH2CH3或环丙基；
R10选自H、F、Cl、CN或CH3；
R11选自H或CH3。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1为N或CR2；
L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
Ar为
环S选自C6-10芳基、6-10元杂芳基、C5-10环烷基或5-10元杂环基；
R1和R2独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、-S(O)2C1-6烷基、-S(O)2卤代C1-6烷基、C2-6烯基或C2-6炔基；
R3选自C6-10芳基、5-10元杂芳基、C3-10环烷基或3-10元杂环基，其可任选地被1个、2个或3个R#取代；
R4选自C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-4亚烷基-ORa或C1-4亚烷基-NRbRc，其可任选地被1个、2个或3个R#取代；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基或C6-10芳基；
环B为C4-10环烷基或4-10元杂环基；
所述环A和环B可任选地被1个、2个、3个或4个R#取代；
R5、R5’和R6’选自H、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R6和R9独立地选自ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
或者R5’和R6’连接形成键，或者R5’、R6’和他们连接的碳原子一起形成C3-7环烷基或3-7元杂环基；
R7和R8独立地选自ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
R#选自H、卤素、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；
前提是，当L为C(O)时，R6不为C1-6烷基、C1-6卤代烷基和C2-6炔基。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
当L为C(O)时，Ar为
当L为C(O)NH、C(O)-C(O)或C(O)-C(O)NH时，Ar为
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1为N或CR2；
L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
当L为C(O)时，Ar为
当L为C(O)NH、C(O)-C(O)或C(O)-C(O)NH时，Ar为
R1和R2独立地为卤素或C1-6卤代烷基；
R3选自5-10元杂芳基、苯基、C3-7环烷基或3-7元杂环基，其可任选地被1个、2个或3个R#取代；
R4选自C1-6烷基、C1-4亚烷基-ORa或C1-4亚烷基-NRbRc；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基或C6-10芳基；
环B为C4-10环烷基或4-10元杂环基；
所述环A和环B可任选地被1个、2个或3个R#取代；
R8为ORa、NRbRc、C1-4烷基或C1-4卤代烷基；
R9为C1-6烷基或C3-7环烷基；
R#选自H、卤素、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1为N或CH；
L选自C(O)或C(O)-C(O)NH；
当L为C(O)时，Ar为
当L为C(O)-C(O)NH时，Ar为
R1选自卤素或C1-2卤代烷基，优选为Br或CF3；
R3选自环丙基或
R4选自CH3、环丙基或
或者，R3、R4和它们连接的碳原子一起形成
R8为NH2；
R9选自甲基、乙基或环丙基。
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下结构：
其中，各基团如上文所定义。
在更具体的实施方案中，本发明提供了式(II)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1为N或CH；
R1选自卤素或C1-6卤代烷基；
R3选自5-10元杂芳基、苯基、C3-7环烷基或3-7元杂环基，其可任选地被1个、2个或3个R#取代；
R#选自卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R4选自C1-6烷基、C1-4亚烷基-ORa或C1-4亚烷基-NRbRc；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基；
环B为C4-10环烷基或4-10元杂环基；
R5、R5’和R6’为H或C1-6烷基；
R6为C1-6烷氧基、C3-7环烷基或CONH2；
或者R5’和R6’连接形成键，或者R5’、R6’和他们连接的碳原子一起形成C3-7环烷基或3-7元杂环基；
R7为ORa、NRbRc、C1-4烷基或C1-4卤代烷基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(II)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1为N或CH；
R1选自卤素或C1-4卤代烷基；
R3选自5-6元杂芳基或C3-5环烷基，其可任选地被1个或2个R#取代；
R#为C1-4烷基；
R4选自C1-4烷基或C1-4亚烷基-ORa；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-6元杂芳基；
环B为C4-7环烷基或4-7元杂环基；
R5为H或C1-4烷基；
R6为C1-4烷氧基、C3-5环烷基或CONH2；
R5’和R6’连接形成键，或者R5’、R6’和他们连接的碳原子一起形成C3-5环烷基；
R7为NH2或C1-4烷氧基；
Ra选自H、C1-4烷基或C1-4卤代烷基。
在更具体的实施方案中，本发明提供了上述式(II)化合物，或其药学上可接受的盐、同位素变体、 互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1为N或CH；
R1选自卤素或C1-2卤代烷基，优选为Br或CF3；
R3选自或环丙基，优选为
R4选自CH3和
或者，R3、R4和它们连接的碳原子一起形成
R5为H；
R6为OCH3、环丙基、CONH2；
R5’和R6’连接形成键，或者R5’、R6’和他们连接的碳原子一起形成环丙烷；
R7为NH2或OCH3。
在更具体的实施方案中，本发明提供了上述式(II)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R3选自或环丙基，优选为
在更具体的实施方案中，本发明提供了式(III)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1为N或CH；
R1为C1-6卤代烷基；
R3、R4和它们连接的碳原子一起形成
其中，环A为五元杂芳基；
R6选自C1-6烷氧基或C3-7环烷基；
R7为NRbRc；
Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了式(IV)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1为N或CH；
R1选自卤素或C1-6卤代烷基；
R3选自5-10元杂芳基、苯基、C3-7环烷基或3-7元杂环基，其可任选地被1个、2个或3个R#取代；
R4选自C1-6烷基、C3-6环烷基、C1-4亚烷基-ORa或C1-4亚烷基-NRbRc；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基；
环B为C4-10环烷基或4-10元杂环基；
所述环A和环B可任选地被1个、2个或3个R#取代；
R#选自H、卤素、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；
R8选自ORa、NRbRc、C1-4烷基或C1-4卤代烷基；
R9选自C1-6烷基或C3-7环烷基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(IV)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1为N或CH；
R1选自卤素或C1-4卤代烷基；
R3选自5-6元杂芳基或C3-5环烷基，其可任选地被1个或2个R#取代；
R#选自卤素、C1-4烷基或C1-4烷氧基；
R4选自C1-4烷基或C1-4亚烷基-ORa；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-6元杂芳基，环B为C4-7环烷基或4-7元杂环基，它们可任选地被1个或2个R#取代；
R8选自NH2或C1-4烷氧基；
R9选自C1-4烷基或C3-5环烷基。
在更具体的实施方案中，本发明提供了上述式(IV)化合物，，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1为N或CH；
R1选自卤素或C1-2卤代烷基，优选为Br或CF3；
R3选自或环丙基，优选为
R4选自CH3或
或者，R3、R4和它们连接的碳原子一起形成
R8为NH2；
R9选自C1-2烷基或环丙基。
在更具体的实施方案中，本发明提供了上述式(IV)化合物，，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R3选自环丙基或优选为
或者，R3、R4和它们连接的碳原子一起形成
在更具体的实施方案中，本发明提供了上述式(A)、(A-1)或(A-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下结构：
其中，各基团如上文中所定义。
在更具体的实施方案中，本发明提供了式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、5-6元杂芳基、S(O)2-Rd或S(O)-Rd，R1可任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代；
R2选自H、C1-6烷基或C1-6卤代烷基；
或者，R1、R2和它们连接的碳原子一起形成C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基，所述C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个或3个Rx取代；
Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者选自任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂环基；
R3选自C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基或C6-10芳基；
环B为C5-10环烷基或5-10元杂环基；
所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
R#选自卤素、ORa、C1-4亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
R5选自H或C1-6烷基；
R6选自C1-6亚烷基-ORa、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
R7选自ORa或NRbRc；
R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
R11选自H、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或S(O)2-Rd，R1可任选地被卤素、C1-4烷基或C1-4卤代烷基进一步取代；
R2选自H、C1-6烷基或C1-6卤代烷基；
或者，R1、R2和它们连接的碳原子一起形成C6-10芳基或5-10元杂芳基，所述5-10元杂芳基或C6-10芳基可任选地被1个、2个或3个Rx取代；
Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者选自任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的5-10元杂环基或C4-10环烷基；
R3选自C1-6烷基、C1-4亚烷基-ORa、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
R4选自H、C1-6烷基或C3-6环烷基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基；
环B为C5-10环烷基或5-10元杂环基；
所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
R#选自卤素、C1-4烷基、C1-4卤代烷基、CH2OH或C1-4烷氧基；
R5选自H或C1-6烷基；
R6选自C1-6亚烷基-ORa、C3-7环烷基或3-7元杂环基；
R7选自ORa或NRbRc；
R10选自H、卤素、ORa、NRbRc、CN或C1-4烷基；
R11选自H、卤素或C1-6烷基；
Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
R1选自卤素、SF5、NH2、OH、CN、C1-4卤代烷基、C1-4卤代烷氧基、C3-5环烷基或S(O)2-C1-4卤代烷基；
R2选自H或C1-4烷基；
或者，R1、R2和它们连接的碳原子一起形成5-6元杂芳基，所述5-6元杂芳基可任选地被1个或2个Rx取代；
Rx为任选地被C1-4烷基取代的5-6元杂环基；
R3选自C1-4烷基、C1-4亚烷基-OC1-4烷基、C3-5环烷基或5-6元杂芳基，R3可任选地被1个、2个或3个R#取代；
R4选自H、C1-4烷基或C3-5环烷基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-6元杂芳基；
环B为C5-6环烷基或5-6元杂环基；
所述环A和环B可任选地被1个、2个或3个R#取代；
R#选自卤素、C1-4烷基、C1-4卤代烷基、CH2OH或C1-4烷氧基；
R5选自H或C1-4烷基；
R6选自C1-4亚烷基-OH、C3-5环烷基或3-5元杂环基；
R7选自OH或NH2；
R10选自H、卤素、OH、NH2、CN或C1-4烷基；
R11选自H或C1-4烷基。
在更具体的实施方案中，本发明提供了上述式(V)、(V-1)或(V-2)化合物，，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CR2或N；
X2选自CH或N；
X3选自CH或N；
R1选自Br、SF5、CN、CF3、OCF3、环丙基、
R2选自H或CH3；
或者，R1、R2一起形成
R3选自CH3、环丙基、
R4选自H、CH3、CH2CH3或环丙基；
或者，R3、R4和它们连接的碳原子一起形成
R5选自H或CH3；
R6选自CH2OH、环丙基、环丁基或
R7为NH2；
R10选自H、F、Cl、CN或CH3；
R11选自H或CH3。
在更具体的实施方案中，本发明提供了式(VI)化合物，或其药学上可接受的盐、同位素变体、互 变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
X1选自CH或N；
X2选自CH或N；
R1选自卤素、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C3-7环烷基；
R3选自C6-10芳基或5-10元杂芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
R#选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-4亚烷基-ORa、C2-6烯基或C2-6炔基；优选地，R#选自卤素、C1-6烷基、C1-6烷氧基、C2-6烯基或C2-6炔基；
R4选自C1-6烷基或C3-7环烷基；
R10选自H、卤素、CN或C1-6烷基；优选地，R10选自H或卤素。
在更具体的实施方案中，本发明提供了上述式(VI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CH或N；
X2选自CH或N；
R1选自卤素、SF5、C1-4卤代烷基、C1-4卤代烷氧基或C3-5环烷基；
R3选自C6-10芳基或5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
R#选自卤素、C1-6烷基或C1-6卤代烷基；优选地，R#选自卤素或C1-6烷基；
R4选自C1-4烷基或C3-5环烷基；
R10选自H、卤素、CN或C1-4烷基；优选地，R10选自H或卤素。
在更具体的实施方案中，本发明提供了上述式(VI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CH或N；
X2选自CH或N；
R1选自卤素、SF5、C1-2卤代烷基、C1-2卤代烷氧基或C3-4环烷基；
R3为5-6元杂芳基，R3可任选地被1个、2个或3个R#取代；
R#选自卤素、C1-4烷基或C1-4卤代烷基；优选地，R#选自卤素或C1-4烷基；
R4选自C1-4烷基或C3-4环烷基；
R10选自H、卤素、CN或C1-4烷基；优选地，R10选自H或卤素。
在更具体的实施方案中，本发明提供了上述式(VI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
X1选自CH或N；
X2选自CH或N；
R1选自Br、SF5、CF3、OCF3或环丙基；
R3选自优选为
R4选自CH3、CH2CH3或环丙基；
R10选自H、F、Cl、CH3或CN，优选为H、F或Cl。
在更具体的实施方案中，本发明提供了式(VII)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
R1选自卤素、C1-4卤代烷基或C3-5环烷基；
R3选自
R4选自CH3或C3-4环烷基。
在更具体的实施方案中，本发明提供了上述式(VII)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1选自卤素、C1-2卤代烷基或C3-4环烷基；
R3选自
R4选自CH3或C3-4环烷基。
在更具体的实施方案中，本发明提供了上述式(VII)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1选自Br、CF3或环丙基；
R3选自
R4选自CH3或环丙基。
在更具体的实施方案中，本发明提供了式(VIII)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
R1选自5-10元杂芳基或C1-6卤代烷基，所述R1任选地被Ry取代；
Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
R#选自卤素、CH2OH或C1-4烷基；
R6选自ORa或C1-6亚烷基-ORa，优选为C1-6亚烷基-ORa；
Ra选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了式(VIII)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
R1为C1-6卤代烷基，优选为C1-4卤代烷基；
R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
R#选自卤素、CH2OH或C1-4烷基；
R6选自ORa或C1-6亚烷基-ORa，优选为C1-6亚烷基-ORa；
Ra选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(VIII)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1为C1-2卤代烷基，优选为卤代甲基；
R3为5-6元杂芳基，R3可任选地被1个或2个R#取代；
R#为C1-4烷基；
R6为C1-4亚烷基-OH。
在更具体的实施方案中，本发明提供了上述式(VIII)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1为CF3；
R3选自
R6为CH2OH。
在更具体的实施方案中，本发明提供了式(IX)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
R1为C1-4卤代烷基；
R3选自
在更具体的实施方案中，本发明提供了上述式(IX)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1为C1-2卤代烷基，优选为卤代甲基；
R3选自
在更具体的实施方案中，本发明提供了式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、S(O)2-Rd或S(O)-Rd，R1可任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代；
R3选自C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基或C6-10芳基；
环B为C5-10环烷基或5-10元杂环基；
所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
R#选自卤素、ORa、C1-4亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
R8选自ORa或NRbRc；
R9选自C1-6亚烷基-ORa、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1选自卤素或C1-6卤代烷基；
R3选自C6-10芳基或5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
R4为C1-6烷基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-10元杂芳基；
环B为C5-10环烷基或5-10元杂环基；
所述环A和环B可任选地被1个、2个、3个、4个或5个R#取代；
R#选自卤素、C1-6烷基或C1-6卤代烷基；
R8选自ORa或NRbRc；
R9选自C1-6烷基或C3-7环烷基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1选自卤素或C1-4卤代烷基；
R3为5-6元杂芳基，R3可任选地被1个、2个或3个R#取代；
R4为C1-4烷基；
或者，R3、R4和它们连接的碳原子一起形成
其中，环A为5-6元杂芳基；
环B为C5-6环烷基；
所述环A和环B可任选地被1个、2个或3个R#取代；
R#选自卤素或C1-4烷基；
R8为NRbRc；
R9选自C1-4烷基或C3-5环烷基；
Rb和Rc独立地选自H、C1-4烷基或C1-4卤代烷基。
在更具体的实施方案中，本发明提供了上述式(X)、(X-1)或(X-2)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1选自Br或CF3；
R3选自
R4为CH3；
或者，R3、R4和它们连接的碳原子一起形成
R8选自NH2；
R9选自CH3、CH2CH3或环丙基。
在更具体的实施方案中，本发明提供了式(XI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
R1为5-10元杂芳基或C1-6卤代烷基，所述R1任选地被Ry取代；
Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，所述R3可任选地被1个、2个或3个R#取代；
R#选自卤素或C1-6烷基；
R5选自C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了式(XI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，R1为C1-6卤代烷基；
R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
R#选自卤素或C1-6烷基；
R5选自C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(XI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1为C1-4卤代烷基；
R3为5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
R#选自卤素或C1-4烷基；
R5为C1-6烷基，优选为C1-4烷基。
在更具体的实施方案中，本发明提供了上述式(XI)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1为C1-2卤代烷基，优选为卤代甲基；
R3为5-6元杂芳基，R3可任选地被1个或2个R#取代；
R#为C1-4烷基；
R5为C1-2烷基，优选为甲基。
在更具体的实施方案中，本发明提供了式(XII)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
R3为C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，所述R3可任选地被1个、2个、3个、4个或5个R#取代；
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C1-6亚烷基-OH，优选为H；
R4选自H、C1-6烷基或C1-6卤代烷基、C3-7环烷基或3-7元杂环基，优选为C1-6烷基；
R5选自H或C1-6烷基；
R6选自C1-6亚烷基-OH或C3-7环烷基，优选为-CH2OH或环丙基；
R10选自H、卤素、CN、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(XII)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
R3选自5-10元杂芳基或C6-10芳基，所述R3可任选地被1个、2个、3个、4个或5个R#取代；
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C1-6亚烷基-OH，优选为H；
R4选自H、C1-6烷基或C1-6卤代烷基，优选为C1-6烷基；
R5选自H或C1-6烷基；
R6选自C1-6亚烷基-OH或C3-7环烷基，优选为-CH2OH或环丙基；
R10选自H、卤素、CN、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基。
在更具体的实施方案中，本发明提供了上述式(XII)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
Ry选自H、卤素、C1-4烷基、C1-4卤代烷基或C1-4烷氧基，优选为F或CF3；
R3为所述R3可任选地被1个、2个或3个R#取代；
R#选自H、卤素、C1-4烷基或C1-4卤代烷基，优选为H；
R4选自H、C1-4烷基或C1-4卤代烷基，优选为C1-4烷基；
R5选自H或C1-4烷基；
R6选自C1-4亚烷基-OH或C3-7环烷基，优选为-CH2OH或环丙基；
R10选自H、卤素、CN、C1-4烷基或C1-4卤代烷基，优选为H或卤素。
在更具体的实施方案中，本发明提供了上述式(XII)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
Ry选自H、F、Cl、CH3、OCH3或CF3，优选为F或CF3；
R3为所述R3可任选地被1个、2个或3个R#取代；
R#选自H、F、CH3或CF3，优选为H；
R4为CH3；
R5选自H或CH3；
R6选自-CH2OH或环丙基；
R10选自H、F、Cl、CN、CH3或CF3，优选为H或F。
在更具体的实施方案中，本发明提供了式(XIII)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
其中，
R1选自C1-6烷基或C1-6卤代烷基，优选为CF3；
R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R#取代；
R#选自H、卤素、C1-6烷基或C1-6卤代烷基；
R4为C1-6烷基，优选为CH3；
R5为C1-6烷基，优选为CH3；
R6选自C1-6亚烷基-OH或C3-7环烷基，优选为CH2OH或环丙基，更优选为CH2OH；
R10选自H或卤素，优选为H。
在更具体的实施方案中，本发明提供了上述式(XIII)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1为C1-6卤代烷基，优选为CF3；
R3为所述R3可任选地被1个、2个或3个R#取代；
R#选自H、卤素、C1-6烷基或C1-6卤代烷基；
R4为C1-6烷基，优选为CH3；
R5为C1-6烷基，优选为CH3；
R6选自C1-6亚烷基-OH或C3-7环烷基，优选为CH2OH或环丙基，更优选为CH2OH；
R10选自H或卤素，优选为H。
在更具体的实施方案中，本发明提供了上述式(XIII)化合物化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
R1为C1-4卤代烷基，优选为CF3；
R3为所述R3可任选地被1个、2个或3个R#取代；
R#选自H、卤素、C1-4烷基或C1-4卤代烷基；
R4为C1-4烷基，优选为CH3；
R5为C1-4烷基，优选为CH3；
R6选自C1-4亚烷基-OH或C3-5环烷基，优选为CH2OH或环丙基，更优选为CH2OH；
R10选自H或卤素，例如H、F或Cl，优选为H。在更具体的实施方案中，本发明提供了化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：

在更具体的实施方案中，本发明提供了化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：



本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本发明化合物还可能以互变异构体存在。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H2O))和多水合物(x为大于1的数，例如，二水合物(R·2H2O)和六水合物(R·6H2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(A)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(A)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水 解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
药物组合物和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
实施例
本发明所采用的试剂为直接购买的商业化试剂或经本领域熟知的常用方法合成。
缩略词：PE＝石油醚；EA＝乙酸乙酯；MeOH＝甲醇；DCM＝二氯甲烷；DCE＝二氯乙烷；CH3CN＝乙腈；1,4-dioxane＝1,4-二氧六环；DMSO＝二甲基亚砜；HFIP＝六氟异丙醇；DMF＝N,N-二甲基甲酰胺；Hex＝正己烷；IPA＝异丙醇；NMP＝N-甲基吡咯烷酮；NMO＝N-甲基吗啉-N-氧化物；TEA＝三乙胺；DIEA＝二异丙基乙基胺；CuI＝碘化亚铜；CuCN＝氰化亚铜；triphosgene＝三光气；p-TsOH＝对甲苯磺酸；T3P＝1-丙基磷酸环酐；TsN3＝对甲苯磺酰基叠氮。
如下示例的具体反应路线或步骤为本发明所用，具体如下：
实施例1
关键中间体a1-a17的制备
中间体a1,a2的合成
步骤1：冰浴，氮气保护下，将原料a1-1(7.0g,39.5mmol)溶于210mL无水THF中，逐滴加入LiHMDS(43.4mL,1M)和N-溴代琥珀酰亚胺NBS(8.4g,47.4mmol)。反应液在冰浴下搅拌3小时，向体系中加入1M浓度稀盐酸淬灭反应，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(PE/EA,1/1)，得到中间体a1-2(2.1g,8.24mmol)，收率：21％。LC-MS:[M+H]+＝256。
步骤2：氮气保护下，将上步中间体a1-2(500mg,1.95mmol)溶于10mL无水THF中，加入NaH(61mg,2.53mmol)和原料a1-3(359mg,1.95mmol)，室温反应3小时。停止反应，向体系中加入50mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离(PE/EA,3/1)，得到中间体a1-4(426mg,1.52mmol)，收率：78％。LC-MS:[M+H]+＝281。
步骤3：氮气保护下，将中间体a1-4(150mg,0.53mmol)和碳酸钾(221mg,1.6mmol)溶于2mL1,4-二氧六环和水的混合溶液中(v/v,4/1)，加入环丙基硼酸(138mg,1.6mmol)和Pd(Dppp)Cl2(31.4mg,0.05mmol)，混合液于100℃下反应10小时，停止反应。粗品直接经flash反向柱层析分离，得到化合物a1-5(100mg,0.41mmol)，收率：77％。LC-MS:[M+H]+＝243。
步骤4：将上步中间体a1-5(100mg,0.41mmol)溶于1mL THF中，加入0.5mL水和LiOH(35mg,0.82mmol)，室温反应6小时，向体系中加入1.5M浓度稀盐酸条件pH到7左右，抽滤。滤饼经水洗涤，干燥，得到化合物a1(40mg,0.18mmol)，收率：43％。LC-MS:[M+H]+＝229。
步骤5：氮气保护下，将化合物a1(25mg,0.11mmol)溶于0.5mL二氯甲烷中，加入氯化氢的1,4-二氧六环溶液(0.04mL,0.13mmol)，室温下反应30分钟。减压蒸除溶剂，将该混合物溶于SOCl2(195.4mg,1.65mmol)中，升温至55℃反应1小时，减压蒸除溶剂，得到粗品a2(20mg)直接用于下一步反应。
中间体a3，a6的合成
步骤1：冰浴，氮气保护下，将原料3-乙基-2-氨基吡啶a3-1(1.0g,8.19mmol)溶于5mL浓硫酸中，逐滴加入浓硝酸(1.03g,16.4mmol)。反应液在冰浴下搅拌1小时，将反应液缓慢滴加到50mL冰水中并用1M浓度NaOH水溶液调节pH至8左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水)，得到中间体a3-2(1.15g,6.88mmol)，收率：84％。LC-MS:[M+H]+＝168。
步骤2：冰浴，将上步中间体a3-2(1.15g,6.88mmol)溶于22mL DMF中，加入NaH(300mg,7.57mmol)，搅拌30分钟。向体系加入(Boc)2O(1.65g,7.57mmol)，继续反应2小时后停止反应。向反应液中加入60mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水)，得到中间体a3-3(920mg,3.44mmol)，收率：50％。LC-MS:[M+H]+＝268。
步骤3：氢气氛围下(1atm)，将中间体a3-3(920mg,3.44mmol)溶于2mL甲醇中，加入Pd/C(20％,184.0mg)，室温下反应12小时，停止反应，过滤，减压蒸除溶剂，得到黄色固体a3(410mg,1.73mmol)，收率：50％。LC-MS:[M+H]+＝238。
参照中间体a3的合成路线，合成如下中间体。
中间体a4的合成
步骤1：氮气保护下，将中间体a1-4(350mg,1.25mmol)和甲醇钠(135mg,2.49mmol)溶于7mL DMF中，加入CuI(237mg,1.25mmol)，反应液升温至130℃下反应12小时，冷却至室温。向体系中加入20mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，粗品经flash反向柱层析分离(乙腈/水)，得到中间体a4-1(60mg,0.26mmol)，收率：21％。LC-MS:[M+H]+＝233。
步骤2：将上步中间体a4-1(60mg,0.26mmol)溶于1.8mL THF和水的混合溶液中(v/v,2/1)，加入LiOH(12.4mg,0.52mmol)，室温反应10小时，向反应液中加入1M浓度稀盐酸调节pH至6左右，粗品经flash反向柱层析分离(乙腈/水,0.1％三氟乙酸)，得到中间体a4-2(50mg,0.23mmol)，收率：89％。LC-MS:[M+H]+＝219。
步骤3：将上步中间体a4-2(10mg,0.05mmol)溶于0.1mL氯化氢的1,4-二氧六环溶液中(4M)，室温下反应30分钟，减压蒸除溶剂。向体系中加入0.2mL二氯亚砜，升温至55℃下反应30分钟，减压蒸除溶剂，得到粗品a4(10mg)，直接用于下一步反应。
中间体a5的合成
步骤1：氮气保护下，将原料a1-3(3.5g,19.5mmol)和丙腈(2.1g,39.0mmol)溶于35mL DMSO中，加入tBuOK(4.3g,39.0mmol)，反应液升温至50℃下反应2小时，冷却至室温。向体系中加入80mL冰水，乙酸乙酯洗涤，水相用1M浓度稀盐酸调节pH至7左右，抽滤，滤饼干燥，得到黄色固体a5-1(3.5g,17.3mmol)，收率：89％。LC-MS:[M+H]+＝203。
步骤2：将上步中间体a5-1(500mg,2.4mmol)溶于10mL二氯甲烷中，加入氯化氢的1,4-二氧六环溶液(0.7mL,4M)，室温反应30分钟，减压蒸除溶剂。向体系中加入SOCl2(4412mg,37.0mmol)，升温至55℃下反应1小时，冷却至室温，用10mL二氯甲烷稀释，抽滤，正己烷洗涤，干燥，得到中间体a5(400mg)，收率：73％。
中间体a7的合成
步骤1：氮气保护下，将原料a7-1(5.0g,37.3mmol)溶于100mL二氯甲烷中，加入m-CPBA(6.4g,37.3mmol)，反应液在室温下反应2小时，停止反应。向体系中加入80mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离，得到黄色固体a7-2(3.1g,20.4mmol)，收率：55％。LC-MS:[M+H]+＝151。
步骤2：将上步中间体a7-2(3.1g,20.4mmol)溶于31mL醋酸酐中，反应液升温至120℃下反应2小时，冷却至室温，停止反应。向体系中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离，得到黄色固体a7-3(2.0g,10.4mmol)，收率：51％。LC-MS:[M+H]+＝193。
步骤3：将上步中间体a7-3(2.0g,10.4mmol)溶于20mL甲醇和20mL水的混合溶液中，加入NaOH(900mg,22.9mmol)，反应液在室温下反应12小时，停止反应。向体系中加入40mL冰水，用1M浓度稀盐酸调节pH至7左右，浓缩，粗品经flash反向柱层析分离，得到黄色固体a7-4(1.5g,10.0mmol)，收率：96％。LC-MS:[M+H]+＝151。
步骤4：氮气保护下，将上步中间体a7-4(1.5g,10.0mmol)溶于30mL无水二氯甲烷中，加入氧化剂Dess-Martin(4.7g,11.0mmol)，反应液在室温下反应1小时，向体系中加入30mL饱和硫代硫酸钠水溶液淬灭反应。二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离，得到黄色固体a7(500mg)，收率：34％。LC-MS:[M+H]+＝149。
中间体a8的合成
步骤1：氮气保护下，将原料a8-1(2.0g,9.2mmol)、Pd(dppf)Cl2(0.7g,0.92mmol)和环丙基硼酸(1.6g,18.4mmol)溶于33mL 1,4-二氧六环中，加入K2CO3(2.5g,18.4mmol)和7mL水，升温至100℃下反应3小时，冷却至室温。向体系加入冰水100mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水)，得到黄色固体a8-2(940mg,5.25mmol)。收率：57％。LC-MS:[M+H]+＝180。
步骤2：冰浴，将上步中间体a8-2(940mg,5.3mmol)和NaH(273mg,6.8mmol)溶于20mL无水DMF中，搅拌30分钟后，向体系加入Boc2O(1.49g,6.82mmol)。升温至室温，继续反应2小时。向体系中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离，得到黄色固体a8-3(920mg,3.3mmol)，收率：63％。LC-MS:[M+H]+＝280。
步骤3：将上步中间体a8-3(920mg,3.3mmol)溶于10mL乙醇和10mL水的混合溶液中，加入还原铁粉(920mg,16.5mmol)和氯化铵(1.15g,32.9mmol)，反应液升温至回流反应2小时，停止反应，过滤。向体系中加入40mL冰水，乙酸乙酯萃取，浓缩，粗品经flash反向柱层析分离，得到黄色固体a8(513mg)，收率：63％。LC-MS:[M+H]+＝250。
中间体a9-a13,a15-a17的合成
步骤1：将化合物a9-1(7.0g,28.2mmol)溶于70mL乙醇和70mL水的混合溶液中，加入还原铁粉(7.9g,141mmol)和氯化铵(15.1g,282mmol)，反应液升温至回流反应3小时，停止反应，过滤。向体系中加入400mL冰水，乙酸乙酯萃取，浓缩，粗品经柱层析分离，得到黄色固体a9-2(5.3g,24.3mmol)，收率：86％。LC-MS:[M+H]+＝218。
步骤2：将上步中间体a9-2(5.3g,24.3mmol)和化合物a9-3(3.9g,48.6mmol)溶于55mL DMSO中，搅拌5分钟后，向体系加入叔丁醇钾(5.5g,48.6mmol)，升温至50℃下反应2小时。向体系中加入150mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离，得到黄色固体a9-4(3.3g,11.7mmol)，收率：48％。LC-MS:[M+H]+＝281。
步骤3：氮气保护下，将上步中间体a9-4(3.3g,11.7mmol)、Pd2(dba)3(0.5g,0.59mmol)和dppf(0.7g,1.2mmol)溶于66mL DMF中，加入Zn(CN)2(1.7g,14.1mmol)，升温至100℃下反应2小时，冷却至室温，过滤。向体系加入冰水200mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，减压蒸除溶剂。该混合物经柱层析分离，得到黄色固体a9-5(1.1g,4.84mmol)。收率：41％。LC-MS:[M+H]+＝228。
步骤4：将上步中间体a9-5(1.1g,4.84mmol)溶于22mL浓盐酸中，升温至100℃反应2小时。向体系中加入100mL冰水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离，得到白色固体a9(650mg,2.64mmol)，收率：55％。LC-MS:[M-H]-＝245。
步骤5：将中间体a9(650mg,2.65mmol)溶于13mL二氯亚砜中，反应液升温至70℃反应2小时，停止反应，减压浓缩溶剂，得到黄色固体a10(650mg)，直接用于下一步反应。收率：93％。
参照中间体a10的合成路线，合成如下中间体。

中间体a14的合成
步骤1：将原料a14-1(1.2g,6.2mmol)和化合物a9-3(1.0g,12.3mmol)溶于24mL DMSO中，搅拌5分钟后，向体系加入叔丁醇钾(1.4g,12.4mmol)，升温至50℃下反应2小时。向体系中加入80mL冰水，用稀盐酸调节pH至5左右，乙酸乙酯萃取，浓缩，粗品经flash反向柱层析分离(乙腈/水)，得到黄色固体a14-2(50mg)，收率：4％。LC-MS:[M+H]+＝243。
步骤2：将中间体a14-2(50mg,0.21mmol)溶于0.5mL二氯亚砜中，反应液升温至70℃反应2小时，停止反应，减压浓缩溶剂，得到黄色固体a14(50mg)，直接用于下一步反应。收率：93％。
关键中间体b1-b35的制备
中间体b1,b2,b9的合成
步骤1：室温下，将原料1,4,5,6-四氢吲唑酮b1-2(500mg,3.7mmol)和原料b1-1(781mg,3.7mmol)溶于10mL二氯甲烷中，加入醋酸(882mg,14.7mmol)和NaBH(OAc)3(2.3g,11.0mmol)，室温反应8小时，停止反应。向体系加入5mL甲醇，用氨水调节pH至8左右，flash反向柱层析分离(乙腈/水)，得到淡黄色固体b1(300mg,1.01mmol)，收率：28％。LC-MS:[M+H]+＝297。
步骤2：冰浴，氮气保护下，将中间体b1(60mg,0.2mmol)溶于1.2mL二氯甲烷中，加入TEA(25mg,0.24mmol)和草酰氯单甲酯(24.8mg,0.20mmol)。反应液在冰浴下搅拌1小时，停止反应。减压蒸除溶剂，混合物溶解于3mL乙腈中，经flash反向柱层析分离(乙腈/水，10M NH4HCO3)，得到白色固体b2(30mg,0.08mmol)，收率：39％。LC-MS:[M+H]+＝369。
参照中间体b1的合成路线，合成如下中间体。

中间体b3的合成
步骤1：冰浴下，将原料b1-2(100mg,0.73mmol)溶于2mL DMF中，缓慢加入NaH(33mg,0.81mmol)，搅拌30分钟后，向反应液中滴加SEM-Cl(135mg,0.81mmol)，升温至室温继续搅拌1.5小时，停止反应，加入冰水20mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水)，得到油状中间体b3-1(45mg,0.17mmol)。收率：23％。LC-MS:[M+H]+＝267。
步骤2：将中间体b3-1(45mg,0.17mmol)和原料b1-1(36mg,0.17mmol)溶于1mL无水二氯甲烷中，缓慢加入醋酸(41mg,0.68mmol)和NaBH(OAc)3(107.4mg,0.51mmol)，室温反应12小时，停止反应。缓慢向反应液倒入冰水10mL，氨水调节pH至8左右，减压蒸除有机溶剂后，粗品经flash反向柱层析分离(乙腈/水)，得到油状中间体b3(20mg,0.05mmol)。收率：28％。LC-MS:[M+H]+＝427。
中间体b4,b6的合成
步骤1：氮气保护下，将原料b4-1(2.1g,13.7mmol)和Zn(CN)2(1.93g,16.41mmol)溶于42mL DMF中，加入Dppf(0.76g,1.36mmol)和Pd2(dba)3(0.63g,0.68mmol)，升温至100℃下反应3小时，冷却至室温。向体系加入冰水100mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水)，得到白色固体b4-2(900mg,6.25mmol)。收率：46％。LC-MS:[M+H]+＝145。
步骤2：氢气氛围下(1atm)，将中间体b4-2(900mg,6.2mmol)和Pd/C(20％w.t.,180mg)溶于18mL甲醇中，加入HCl(1.5mL,6M)，室温反应1小时，停止反应。抽滤，减压蒸除溶剂，得到白色固体b4-3(1.0g)。LC-MS:[M+H]+＝149。
步骤3：将中间体b4-3(100mg,0.6mmol)和原料b1-2(92mg,0.6mmol)溶于1mL二氯甲烷中，加入醋酸(162mg,2.7mmol)和NaBH(OAc)3(429mg,2.0mmol)，室温反应12小时，停止反应。减压蒸除溶剂，向体系加入氨水调节pH至8左右，减压蒸除溶剂，粗品经反应flash柱层析分离(乙腈/水)，得到白色固体b4(100mg,0.37mmol)，收率：55％。LC-MS:[M+H]+＝269。
参照中间体b4的合成路线，合成如下中间体。
中间体b5的合成
步骤1：冰浴，将原料b5-1(500mg,1.79mmol)溶于10mL DMF中，加入NaH(86mg,2.15mmol)，搅拌30分钟后，向体系加入SEM-Cl(358mg,2.15mmol)，升温至室温反应1.5小时，停止反应。向体系加入冰水50mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水)，得到油状物b5-2(700mg,1.71mmol)。收率：96％。LC-MS:[M+H]+＝410。
步骤2：氮气保护下，将中间体b5-2(800mg,1.95mmol)和氟磺酰基二氟乙酸甲酯b5-3(413mg,2.15mmol)溶于16mL DMF中，加入CuI(186mg,0.98mmol)和六甲基磷酰三胺(1.5g,8.4mmol)，升温至100℃下反应12小时，冷却至室温。向体系加入冰水60mL，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水)，得到油状物b5-4(400mg,1.14mmol)。收率：58％。LC-MS:[M+H]+＝352。
步骤3：氮气保护下，将原料b5-4(400mg,1.14mmol)和Zn(CN)2(160mg,1.36mmol)溶于8mL DMF中，加入Dppf(63mg,0.11mmol)和Pd2(dba)3(52mg,0.06mmol)，升温至100℃下反应2小时，冷却至室温。向体系加入冰水40mL，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水)，得到棕色油状物b5-5(350mg,1.02mmol)。收率：90％。LC-MS:[M+H]+＝343。
步骤4：氢气氛围下(30atm)，将中间体b5-5(350mg,1.02mmol)和Pd/C(20％w.t.,70mg)溶于8mL甲醇中，室温反应1小时，停止反应。抽滤，减压蒸除溶剂，得到油状物b5(320mg)。LC-MS:[M+H]+＝347。
中间体b7，b10-b35的合成
将原料5-溴-氨甲基吡啶b7-1(1.7g,9.0mmol)和4-乙酰基噻唑b7-2(1.1g,9.0mmol)溶于17mL二氯甲烷中，加入醋酸(2.1g,36.3mmol)和NaBH(OAc)3(5.7g,27.2mmol)，室温反应12小时。向体系加入饱和NaHCO3水溶液调节pH至8左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，柱层析分离(DCM/MeOH,10/1)，得到棕色固体b7(1.1g,3.70mmol)，收率：41％。LC-MS:[M+H]+＝298。
参照化合物b7的合成路线，采用类似的原料/中间体，合成如下目标分子中间体。


中间体b8的合成
步骤1：氮气保护下，将原料2-氰基-5-溴吡啶b8-1(1.10g,6.01mmol)和原料b8-2(1.1g,9.02mmol)溶于22mL DMF中，加入K2CO3(1.66g,12.02mmol)、1,3-二(2-吡啶基)-1,3-丙二酮(0.27g,1.20mmol)和CuI(0.23g,1.20mmol)，升温至110℃反应12小时，停止反应。向体系加入冰水80mL，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩。该混合物经flash反向柱层析分离(乙腈/水)，得到黄色固体b8-3(1.0g,4.48mmol)。收率：75％。LC-MS:[M+H]+＝224。
步骤2：氢气氛围下(1atm)，将中间体b8-3(1.0g,4.48mmol)和Pd/C(20％w.t.,200mg)溶于40mL甲醇中，加入稀盐酸(6M,1.0mL)，室温反应3小时，停止反应。抽滤，减压蒸除溶剂，得到黄 色固体b8(1.0g)。LC-MS:[M+H]+＝228。
关键中间体c1-c28的制备
中间体c1-c4,c10-c13,c15-c16,c18-c21,c23-c24的合成
步骤：氮气保护下，将原料c1-1(558mg,3.53mmol)和原料c1-2(618mg,3.53mmol)溶于13mL二氯甲烷中，加入NaBH(OAc)3(2.25g,10.6mmol)，室温下反应1小时，停止反应。减压蒸除溶剂，将混合物溶于2mL甲醇中，向体系加入氨水调节pH至8左右，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水)，得到绿色油状物c1(320mg)。收率：29％。LC-MS:[M+H]+＝283。
参照化合物c1的合成路线，采用类似的原料/中间体，合成如下目标分子中间体。

中间体c5的合成
步骤1：氮气保护下，将原料3-氯-6-三氟甲基哒嗪c5-1(2.0g,10.96mmol)和原料Pd(PPh3)4(600mg,0.55mmol)溶于60mL 1,4-二氧六环中，逐滴加入AlMe3(1.6g,21.9mmol)溶液，升温至100℃反应4小时，冷却至室温，向体系加入冰甲醇80mL淬灭反应。减压蒸除溶剂，向体系加入200mL水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩。该混合物经flash反向柱层析分离(乙腈/水)，得到油状物c5-2(1.3g)。收率：73％。LC-MS:[M+H]+＝163。
步骤2：氮气保护下，将上步中间体c5-2(1.3g,8.02mmol)和AIBN(2.6g,16.0mmol)溶于26mL DMF中，加入NBS(1.4g,8.02mmol)，升温至70℃下反应1小时，停止反应。向体系加入100mL水，甲基叔丁基醚萃取，减压蒸除溶剂，得到粗品c5-3(696mg)。LC-MS:[M+H]+＝241。
步骤3：将上步粗品c5-3(150mg,0.62mmol)和中间体c1-1(84mg,0.68mmol)溶于3mL乙腈中，加入TEA(315mg,3.11mmol)，室温下反应1小时，停止反应。向体系加入30mL水，二氯甲烷萃取，减压蒸除溶剂，flash反向柱层析分离(乙腈/水)，得到化合物c5(40mg)。LC-MS:[M+H]+＝284。
中间体c6-c9,c14,c17,c22的合成
步骤1：氮气保护下，将原料1-甲基-1,2,4-三氮唑-3-甲醛c6-1(3.1g,27.9mmol)和原料(R)构型叔丁基亚磺酰胺(3.4g,27.9mmol)溶于62mL无水甲苯中，加入KHSO4(3.8g,27.9mmol)，升温至50℃反应12小时，冷却至室温，过滤。滤液减压蒸除溶剂，得到油状物c6-2(4.9g)，收率：91％。LC-MS: [M+H]+＝215。
步骤2：-78℃，氮气保护下，将上步油状物c6-2(4.9g,22.87mmol)溶于98mL无水四氢呋喃中，加入格氏试剂甲基溴镁(45.8mL,45.73mmol)的己烷溶液，滴毕，继续在该温度下反应45分钟。缓慢升温至室温，向体系加入100mL饱和碳酸氢钠水溶液淬灭反应，减压蒸除有机溶剂，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水)，得到油状物c6-3(1.1g)，收率：21％。LC-MS:[M+H]+＝231。
步骤3：氮气保护下，将上步中间体c6-3(2.1g,9.12mmol)溶于42mL甲醇中，加入氯化氢的二氧六环溶液(3.7mL,14.6mmol)，室温下反应1小时，停止反应。向体系加入30mL水，甲基叔丁基醚萃取，无水硫酸钠干燥，浓缩，得到化合物c6(1.8g)，收率：95％。LC-MS:[M+H]+＝127。
参照化合物c6的合成路线，采用类似的原料/中间体，合成如下目标分子中间体。
中间体c25-c28的合成
步骤：氮气保护下，将原料c1-1(332mg,2.7mmol)、原料c25-1(510mg,2.7mmol)和DIEA(522mg,4.05mmol)溶于10mL甲醇中，加入NaBH3CN(339mg,5.4mmol)和醋酸(162mg,2.70mmol)，室温下搅拌10分钟后，升温至50℃下反应12小时，停止反应。减压蒸除溶剂，将混合物溶于2mL甲醇中，向体系加入氨水调节pH至8左右，减压蒸除溶剂。该混合物经flash反向柱层析分离(乙腈/水,3/5)，得到白色固体混合物(120mg)，收率：15％。LC-MS:[M+H]+＝297。
混合物(120mg)经HPLC色谱分离，得到非对映异构体前峰c25(50mg)和后峰c26(40mg)。色谱柱:XSelect Prep OBD C18 Column,30*150mm,5μm；流动相A:water(10M NH4HCO3),流动相B:乙腈；流速:60mL/min；梯度:5％B(2分钟),5％B to 21％B(0.2分钟),21％B to 23％B(10分 钟)。
参照化合物c25的合成路线，采用类似的原料/中间体，合成如下目标分子中间体。
关键中间体d1-d12的制备
中间体d1-d3的合成
步骤1：冰浴，氮气保护下，将原料丙炔酸甲酯d1-1(2.1g,24.9mmol)和原料2,6-二甲基吡啶d1-2(2.7g,24.9mmol)溶于42mL氯甲烷中，缓慢加入TsN3(4.1g,20.8mmol)和催化剂CuI(400mg,2.08mmol)，冰浴下反应4小时，停止反应。减压蒸除溶剂，乙酸乙酯溶解，析出固体，抽滤，滤饼干燥，得到白色固体d1-3(2.5g)。收率：33％。LC-MS:[M+H]+＝361。
步骤2：氮气保护下，将上步中间体d1-3(2.5g,6.94mmol)和2-氨基-4-溴苯乙酮d1-4(1.5g,6.94mmol)溶于50mL二氯乙烷中，升温至90℃下反应4小时，停止反应。减压蒸除溶剂，得到粗品d1-5(3.0g)。LC-MS:[M+H]+＝450。
步骤3：冰浴，将上步粗品d1-5(3.0g,6.68mmol)溶于63mL二氯甲烷中，逐滴加入浓硫酸(1.3g,13.4mmol)，滴毕，室温下反应1小时，停止反应。将反应液缓慢倒入冰水中，并用饱和碳酸氢钠水溶液调节pH至9左右，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水,4/5)，得到黄色固体d1-6(1.5g)，收率：76％。LC-MS:[M+H]+＝297。
步骤4：冰浴，氮气保护下，将上步中间体d1-6(3.0mL,2.5M)溶于30mL无水四氢呋喃中，缓慢加入LiAlH4的四氢呋喃溶液(1.3g,13.4mmol)，滴毕，室温下反应1小时，停止反应。将反应液缓慢倒入冰水中，过滤，滤液减压浓缩，得到黄色油状物d1-7(1.0g)，收率：74％。LC-MS:[M+H]+＝268。
步骤5：氮气保护下，将上步中间体d1-7(1.0g,3.74mmol)和氰化锌(500mg,4.49mmol)溶于20mL无水DMF中，加入配体dppf(200mg,0.37mmol)和催化剂Pd2(dba)3(200mg,0.19mmol)，升温至100℃下反应2小时，停止反应。向反应液中加入100mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析色谱分离(乙腈/10M碳酸氢铵水溶液,4/5)，得到黄色油状物d1-8(400mg)，收率：50％。LC-MS:[M+H]+＝214。
步骤6：将上步中间体d1-8(400mg,1.88mmol)溶于8mL乙醇中，缓慢加入NaOH水溶液(8.0mL,50％)，升温至80℃下反应4小时，停止反应。将反应液缓慢倒入冰水中，并用稀盐酸调节pH至3左右，乙酸乙酯萃取，粗品经flash反向柱层析分离(乙腈/水,3/5)，得到灰色固体d1(300mg)，收率：69％。LC-MS:[M+H]+＝233。
参照化合物d1的合成路线，采用类似的原料/中间体，合成如下目标分子中间体。

中间体d4-d6的合成
步骤：氮气保护下，将中间体d1(320mg,1.37mmol)溶于3.2mL二氯亚砜中，升温至70℃下反应1小时，停止反应。减压蒸除溶剂，得到黄色固体d4(320mg)，收率：86％。直接用于下一步反应。
参照化合物d4的合成路线，采用类似的原料/中间体，合成如下目标分子中间体。
中间体d7-d12的合成
步骤1：氮气保护下，将原料5-溴-2-吡啶c3-1(2.9g,15.7mmol)、碳酸钾(4.4g,31.5mmol)和原料5-氯-吡啶-3-硼酸d7-1(22.5g,15.7mmol)溶于58mL 1,4-二氧六环和水的混合溶液中(v/v,2/1)，加入催化剂Pd(dppf)Cl2(929mg,1.57mmol)，升温至100℃下反应1小时，过滤，减压蒸除溶剂。向混合物中加入100mL水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash柱层析色谱分离(PE/EA,5/1)，得到黄色固体d7-2(2.5g)，收率：73％。LC-MS:[M+H]+＝219。
步骤2：冰浴，氮气保护下，将上步中间体d7-2(1.0g,4.5mmol)、三乙胺(0.9g,9.15mmol)和原料c1-1(700mg,5.03mmol)溶于20mL二氯甲烷中，加入还原剂NaBH3(1.1g,5.48mmol)和醋酸(0.3g,5.03mmol)，冰浴下反应2小时，停止反应。向混合物中加入氨水调节pH至8左右，减压蒸除溶剂，粗品经flash反向柱层析色谱分离(乙腈/水,3/5)，得到黄色油状物d7(612mg)，收率：41％。LC-MS:[M+H]+＝326。
参照化合物d7的合成路线，采用类似的原料/中间体，合成如下目标分子中间体。

实施例2：目标分子P1，P3-P19，P22-P58，P70-P71的合成
室温下，将中间体b1(24mg,0.08mmol)和TEA(41mg,0.40mmol)溶于1mL二氯甲烷中，滴加中间体a2(20mg,0.08mmol,0.5mL)的二氯甲烷溶液，混合物于室温下反应2小时。减压蒸除溶剂，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物P1(7.9mg)。LC-MS:[M+H]+＝507。
1H NMR(400MHz,DMSO-d6,ppm):δ12.64(s,1H),8.88(s,1H),8.18(d,J＝8.4Hz,1H),7.92(s,1H),7.75(d,J＝7.2Hz,2H),7.68(s,1H),7.49(dd,J＝10.3,5.1Hz,2H),6.65(s,2H),5.16–5.08(m,1H),4.77(d,J＝17.1Hz,1H),4.13(d,J＝17.0Hz,1H),2.40(s,2H),2.08(d,J＝12.3Hz,1H),1.85–1.79(m,3H),1.66(s,1H),1.38(s,1H),0.97(d,J＝8.2Hz,2H),0.67(s,2H).
参照化合物P1的合成路线，采用类似的原料/中间体，合成如下目标分子。
*代表手性中心，未进行拆分







实施例3：目标分子P2的合成
步骤1：冰浴下，将中间体b3(20mg,0.05mmol)和TEA(24mg,0.24mmol)溶于1mL二氯甲烷中，缓慢加入粗品中间体a4(11mg,0.05mmol)，反应1小时后，减压蒸除溶剂，得到粗品化合物P2-1(15mg,0.01mmol)。收率：26％。LC-MS:[M+H]+＝627。
步骤2：将上步粗品P2-1(15mg,0.01mmol)溶于0.3mL二氯甲烷中，滴加0.3mL三氟乙酸，室温反应1小时，减压蒸除溶剂，向体系加入0.5mL乙二胺的二氯甲烷溶液(2mL)，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物P2(3.3mg)。LC-MS:[M+H]+＝497。
1H NMR(300MHz,DMSO-d6,ppm)δ12.64(s,1H),8.88(s,1H),8.19(d,J＝8.4Hz,1H),7.91(s,1H),7.77(d,J＝8.6Hz,1H),7.67(d,J＝8.6Hz,1H),7.49(d,J＝8.3Hz,2H),7.40(s,1H),6.61(s,2H),2.42(s,2H),2.08(s,1H),1.79(d,J＝14.4Hz,1H),1.69(d,J＝12.6Hz,1H),1.38(s,1H).
实施例4：目标分子P20的合成
步骤：氮气保护下，将化合物P12(25mg,0.05mmol)、环丙基硼酸(21mg,0.25mmol)和K3PO4(32mg,0.15mmol)溶于1mL甲苯和水的混合溶液中(v/v,1/1)，加入三环己基磷(1.5mg,0.01mmol) 和Pd(OAc)2(0.56mg,0.003mmol)，升温至90℃下反应2小时，减压蒸除溶剂，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物P20(3.4mg)，收率：15％。LC-MS:[M+H]+＝465。
1H NMR(400MHz,DMSO-d6,ppm)δ8.78(d,J＝4.9Hz,2H),8.27(s,1H),7.83(s,1H),7.69(s,1H),7.57(s,2H),7.49(s,1H),7.39(t,J＝4.9Hz,1H),7.33(d,J＝8.2Hz,1H),7.20(d,J＝8.2Hz,2H),6.59(s,1H),5.39(s,1H),4.84(d,J＝16.7Hz,1H),1.98–1.74(m,2H),1.57(d,J＝7.0Hz,3H),1.24(s,1H),1.02–0.89(m,4H),0.85(d,J＝7.2Hz,1H),0.73–0.60(m,4H).
实施例5：目标分子P21的合成
步骤：氮气保护下，将化合物P12(50mg,0.09mmol)和氰化锌(14mg,0.12mmol)溶于1mL无水DMF中，加入dppf(5.5mg,0.01mmol)和Pd2(dba)3(1.4mg,0.002mmol)，升温至100℃下反应12小时，减压蒸除溶剂，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物P21(27.1mg)，收率：60％。LC-MS:[M+H]+＝450。
1H NMR(300MHz,DMSO-d6,ppm)δ8.90(d,J＝2.1Hz,1H),8.78(d,J＝4.9Hz,2H),8.21(d,J＝8.2Hz,1H),7.85(s,1H),7.69–7.34(m,5H),6.62(s,2H),5.43(s,1H),4.89(d,J＝17.2Hz,1H),4.49(d,J＝17.1Hz,1H),1.84(d,J＝8.4Hz,1H),1.62(d,J＝7.0Hz,3H),0.97(dq,J＝5.8,3.6Hz,2H),0.67(s,2H).
实施例6：目标分子P59的合成
步骤1：室温下，将中间体c1(50mg,0.18mmol)和TEA(90mg,0.89mmol)溶于1mL二氯甲烷中，滴加中间体a12(50mg,0.18mmol,0.5mL)的二氯甲烷溶液，混合物于室温下反应1小时。减压蒸除溶剂，粗品经flash反向柱层析色谱分离(乙腈/水，4/5)，得到化合物P59-1(30mg)，收率：32％。LC-MS:[M+H]+＝527。
步骤2：氮气保护下，将化合物P59-1(15mg,0.03mmol)和氰化锌(4mg,0.034mmol)溶于1mL无水DMF中，加入配体Xphos(1.4mg,0.003mmol)和催化剂Pd2(dba)3(1.4mg,0.002mmol)，升温至100℃下反应12小时，减压蒸除溶剂，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物P59(5.0mg)，收率：33％。LC-MS:[M+H]+＝518。
1H NMR(300MHz,DMSO-d6,ppm)δ8.85(s,1H),8.78(dd,J＝11.5,5.1Hz,2H),8.11(dd,J＝8.7,2.3Hz,1H),7.96(d,J＝1.8Hz,2H),7.76(s,1H),7.66(d,J＝8.5Hz,1H),7.40(t,J＝4.9Hz,1H),7.04(s,2H),5.24(d,J＝7.1Hz,1H),5.03(d,J＝16.8Hz,1H),4.60(d,J＝16.8Hz,1H),1.94–1.80(m,1H),1.63(d,J＝7.0Hz,3H),1.07–0.97(m,2H),0.72(s,2H).
实施例7：目标分子P60-P69的合成
步骤：氮气保护下，将目标分子P12A(45mg,0.08mmol)、碳酸钾(25mg,0.17mmol)和原料N-甲基-4-吡唑硼酸频哪醇酯P60-1(28mg,0.13mmol)溶于1mL 1,4-二氧六环和水的混合溶液中(v/v, 9/1)，加入催化剂Pd(dppf)Cl2(6.5mg,0.01mmol)，升温至100℃下反应2小时，减压蒸除溶剂，粗品经flash反向柱层析色谱分离(乙腈/水,4/5)，得到化合物P60(24mg)，收率：53％。LC-MS:[M+H]+＝505。
1H NMR(400MHz,DMSO-d6,ppm)δ8.79(d,J＝4.9Hz,2H),8.68(s,1H),8.21(s,1H),7.93(s,1H),7.86(dd,J＝8.1,2.4Hz,2H),7.72–7.30(m,5H),6.62(s,2H),5.41(s,1H),4.87(d,J＝16.6Hz,1H),4.29(d,J＝16.4Hz,1H),3.88(s,3H),1.87(d,J＝36.8Hz,1H),1.61(d,J＝6.9Hz,3H),0.96(s,2H),0.67(s,2H).
参照化合物P60的合成路线，采用类似的原料/中间体，合成如下目标分子。

实施例8：目标分子P4，P7-P8，P12-P13，P15，P20，P27的手性拆分
化合物P4拆分条件：
色谱柱:CHIRALPAK ID,2*25cm,5μm；流动相A:Hex:DCM＝3:1(0.5％2M NH3-MeOH)--HPLC,流动相B:IPA--HPLC；流速:20mL/min；Gradient:20％B to 20％B in 22min；
保留时间P4A:10.022min；P4B:15.675min；
P4A：1H NMR(300MHz,DMSO-d6,ppm)δ8.84(d,J＝2.1Hz,1H),8.79(d,J＝4.9Hz,2H),8.12(d,J＝8.4Hz,1H),7.86(s,1H),7.69(s,1H),7.58(d,J＝7.7Hz,1H),7.54(s,1H),7.49(d,J＝8.4Hz,1H),7.40(t,J＝4.9Hz,1H),6.65(s,2H),5.44(s,1H),4.91(d,J＝17.0Hz,1H),4.49(d,J＝16.9Hz,1H),1.82(s,1H),1.63(d,J＝6.9Hz,3H),0.97(d,J＝7.9Hz,2H),0.67(s,2H).
P4B:1H NMR(300MHz,DMSO-d6,ppm)δ8.87–8.82(m,1H),8.79(d,J＝4.9Hz,2H),8.12(d,J＝8.1Hz,1H),7.86(s,1H),7.69(s,1H),7.60(s,1H),7.56(d,J＝8.3Hz,1H),7.49(d,J＝7.7Hz,1H),7.40(t,J＝4.9Hz,1H),6.65(s,2H),5.44(s,1H),4.91(d,J＝17.0Hz,1H),4.49(d,J＝16.8Hz,1H),1.82(s,1H),1.63(d,J＝7.0Hz,3H),0.97(d,J＝8.0Hz,2H),0.67(s,2H).
化合物P7拆分条件：
色谱柱:CHIRALPAK IE-3,4.6*50mm,3μm；流动相A:MtBA(0.1％DEA):(MeOH:DCM＝1:1)＝90:10,流动相B:IPA--HPLC；流速:1mL/min；Gradient:0％B to 0％；
保留时间P7A:10.022min；P7B:15.675min；
P7A:1H NMR(400MHz,DMSO-d6,ppm)δ8.87(s,1H),8.39(s,1H),8.13(d,J＝8.2Hz,1H),7.91(s,1H),7.69(d,J＝11.1Hz,2H),7.52(d,J＝8.3Hz,2H),6.66(s,2H),5.32(s,1H),4.81(d,J＝16.8Hz,1H),4.50(d,J＝16.9Hz,1H),3.79(s,3H),3.45(s,1H),1.84(s,1H),1.53(d,J＝6.9Hz,3H),0.98(d,J＝7.7Hz,2H),0.70–0.65(m,3H).
P7B:1H NMR(400MHz,DMSO-d6,ppm)δ8.87(s,1H),8.39(s,1H),8.13(d,J＝8.2Hz,1H),7.91(s,1H),7.69(d,J＝11.1Hz,2H),7.52(d,J＝8.3Hz,2H),6.66(s,2H),5.32(s,1H),4.81(d,J＝16.8Hz,1H),4.50(d,J＝16.9Hz,1H),3.79(s,3H),3.45(s,1H),1.84(s,1H),1.53(d,J＝6.9Hz,3H),0.98(d,J＝7.7Hz,2H),0.70–0.65(m,3H).
化合物P8拆分条件：
色谱柱:CHIRALPAK IF,2*25cm,5μm；流动相A:MtBE(0.5％2M NH3-MeOH)--HPLC,流动相B:MeOH:DCM＝1:1--HPLC；流速:20mL/min；Gradient:7％B to 7％B in 14min；
保留时间P8A:9.869min；P8B:11.642min；
P8A:1H NMR(400MHz,DMSO-d6,ppm)δ9.59(s,1H),8.91-8.86(m,1H),8.14(d,J＝8.2Hz,1H),8.06-7.21(m,5H),6.66(s,2H),5.49(s,1H),4.88(d,J＝17.1Hz,1H),4.50(s,1H),1.82(s,1H),1.62(d,J＝6.9Hz,3H),0.97(d,J＝3.8Hz,2H),0.66(s,2H).
P8B:1H NMR(400MHz,DMSO-d6,ppm)δ9.59(s,1H),8.91-8.86(m,1H),8.14(d,J＝7.5Hz,1H),7.73(d,J＝108.3Hz,5H),6.66(s,2H),5.49(s,1H),4.88(d,J＝17.0Hz,1H),4.50(s,1H),1.82(s,1H),1.62(d,J＝7.0Hz,3H),0.97(d,J＝4.0Hz,2H),0.66(s,2H).
化合物P12拆分条件：
色谱柱:CHIRALPAK ID,2*25cm,5μm；流动相A:Hex(0.5％2M NH3-MeOH)--HPLC,流动相B:EtOH--HPLC；流速:17mL/min；Gradient:50％B to 50％B in 45min；
保留时间P12A:16.477min；P12B:15.675min；
P12A:1H NMR(400MHz,DMSO-d6,ppm)δ8.79(d,J＝4.9Hz,2H),8.57(s,1H),7.95(d,J＝8.5Hz,1H),7.84(s,1H),7.69(s,1H),7.59(s,1H),7.49(s,1H),7.40(t,J＝4.9Hz,1H),7.31(d,J＝8.4Hz,1H),6.63(s,2H),5.40(s,1H),4.81(d,J＝16.7Hz,1H),4.33(d,J＝16.6Hz,1H),1.82(s,1H),1.60(d,J＝7.0Hz,3H),0.97(d,J＝8.1Hz,2H),0.67(s,2H).
P12B:1H NMR(400MHz,DMSO-d6,ppm)δ8.79(d,J＝4.9Hz,2H),8.57(s,1H),7.98–7.91(m,1H),7.84(s,1H),7.69(s,1H),7.59(s,1H),7.49(s,1H),7.40(t,J＝4.9Hz,1H),7.31(d,J＝8.4Hz,1H),6.63(s,2H),5.40(s,1H),4.81(d,J＝16.8Hz,1H),4.33(d,J＝16.8Hz,1H),1.82(s,1H),1.60(d,J＝6.8Hz,3H),0.97(d,J＝8.1Hz,2H),0.67(s,2H).
化合物P13拆分条件：
色谱柱:CHIRALPAK IG,2*25cm,5μm；流动相A:HEX:DCM＝3:1--HPLC,流动相B:EtOH--HPLC；流速:20mL/min；Gradient:30％B to 30％B in 25min；
保留时间P13A:15.537min；P13B:22.156min；
P13A:1H NMR(400MHz,DMSO-d6,ppm)δ8.79(d,J＝4.9Hz,2H),7.93(d,J＝8.9Hz,1H),7.82(s,1H),7.68–7.59(m,2H),7.56-7.41(s,3H),6.63(s,2H),5.41(s,1H),4.94(d,J＝16.4Hz,1H),4.64(d,J＝16.2Hz,1H),1.65(d,J＝7.0Hz,3H),1.00–0.93(m,2H),0.66(s,2H).
P13B:1H NMR(400MHz,DMSO-d6,ppm)δ8.79(d,J＝4.9Hz,2H),7.94-7.75(d,J＝8.9Hz,3H),7.63-7.42(d,J＝9.0Hz,3H),6.97(s,1H),5.39(s,2H),4.94(d,J＝16.3Hz,1H),4.63(d,J＝16.4Hz,1H),1.87–1.80(m,1H),1.66(d,J＝7.0Hz,3H),1.02–0.95(m,2H),0.69(s,2H).
化合物P15拆分条件：
色谱柱:CHIRALPAK AD-3,4.6*50mm 3um；流动相A:Hex(0.1％DEA):IPA＝85:15；流速:1mL/min；Gradient:0％B to 0％B；
保留时间P15A:4.267min；P15B:5.746min；
P15A:1H NMR(400MHz,DMSO-d6,ppm)δ8.77(d,J＝4.9Hz,2H),8.52(d,J＝2.8Hz,1H),8.00–7.25(m,7H),6.66(s,2H),5.42(s,1H),4.85(d,J＝16.7Hz,1H),4.55–4.31(m,1H),1.87(d,J＝36.0Hz,1H),1.62(d,J＝7.0Hz,3H),1.09–0.91(m,2H),0.67(s,2H).
P15B:1H NMR(400MHz,DMSO-d6,ppm)δ8.77(d,J＝4.9Hz,2H),8.52(d,J＝2.8Hz,1H),8.00–7.25(m,7H),6.66(s,2H),5.42(s,1H),4.85(d,J＝16.7Hz,1H),4.55–4.31(m,1H),1.87(d,J＝36.0Hz,1H),1.62(d,J＝7.0Hz,3H),1.09–0.91(m,2H),0.67(s,2H).
化合物P20拆分条件：
色谱柱:CHIRALPAK IG,2*25cm,5μm；流动相A:Hex:DCM＝3:1(0.5％2M NH3-MeOH)--HPLC,流动相B:EtOH--HPLC；流速:20mL/min；Gradient:30％B to 30％B in 22min；
保留时间P20A:13.289min；P20B:17.147min；
P20A:1H NMR(400MHz,DMSO-d6,ppm)δ8.78(d,J＝4.9Hz,2H),8.26(s,1H),7.84-7.39(s,6H),7.32(d,J＝8.3Hz,1H),6.61(s,2H),5.39(s,1H),4.84(d,J＝15.9Hz,1H),4.23(d,J＝16.3Hz,1H),1.94–1.82(m,2H),1.57(s,3H),0.97(d,J＝8.3Hz,4H),0.72–0.64(m,4H).
P20B:1H NMR(400MHz,DMSO-d6,ppm)δ8.78(d,J＝4.8Hz,2H),8.29–8.24(m,1H),7.84-7.32(s,7H),6.61(s,2H),5.39(s,1H),4.84(d,J＝16.7Hz,1H),4.23(d,J＝16.2Hz,1H),1.92-1.82(d,J＝8.6Hz,2H),1.57(s,3H),0.97(d,J＝8.0Hz,4H),0.72–0.65(m,4H).
化合物P27拆分条件：
色谱柱:CHIRALPAK IE,2*25cm,5μm；流动相A:MtBE(0.5％2M NH3-MeOH)--HPLC,流动相B:MeOH:DCM＝1:1--HPLC；流速:13mL/min；Gradient:50％B to 50％B in 27min；W
保留时间P27A:17.993min；P27B:22.143min；
P27A:1H NMR(400MHz,DMSO-d6,ppm)δ9.03(d,J＝1.9Hz,1H),8.88–8.83(m,1H),8.15(d,J＝8.4Hz,1H),7.87(d,J＝7.8Hz,1H),7.62–7.56(m,1H),7.45(d,J＝8.2Hz,2H),7.27(d,J＝11.8Hz,1H),6.78(s,2H),5.19(q,J＝6.8Hz,1H),4.85(d,J＝16.9Hz,1H),4.51(s,1H),1.59(dd,J＝12.0,7.0Hz,4H),1.01–0.90(m,2H),0.71–0.63(m,2H).
P27B:1H NMR(400MHz,DMSO-d6,ppm)δ9.03(d,J＝1.9Hz,1H),8.95–8.81(m,1H),8.15(d,J＝8.5Hz,1H),7.87(d,J＝7.7Hz,1H),7.70(d,J＝17.5Hz,1H),7.66–7.56(m,1H),7.45(d,J＝8.1Hz,1H),7.27(d,J＝11.7Hz,1H),6.73(d,J＝39.5Hz,2H),5.19(d,J＝7.0Hz,1H),4.85(d,J＝16.8Hz,1H),4.77–4.46(m,1H),1.90–1.71(m,1H),1.60(dd,J＝12.0,6.9Hz,3H),1.11–0.91(m,2H),0.89–0.47(m,2H).
实施例9：目标分子H1-H3的合成
步骤1：氮气保护下，将中间体a3(22mg,0.09mmol)、DMAP(1.1mg,0.01mmol)和DIEA(36mg,0.28mmol)溶于0.5mL二氯甲烷中，加入提前配置的中间体b2(34mg,0.09mmol)和丙基磷酸酐T3P(44mg,0.14mmol)，室温下反应10小时，减压蒸除溶剂。将混合物溶解于5mL甲醇中，混合液经flash反向柱层析分离(乙腈/水)，得到化合物H1-1(30.0mg,0.05mmol)，收率：55％。LC-MS:[M+H]+＝588。
步骤2：将化合物H1-1(30mg,0.05mmol)溶于0.5mL 1,4-二氧六环中，加入氯化氢的二氧六环溶液(0.3mL,4M)，室温反应30分钟，减压蒸除溶剂，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物H1(7.5mg,0.015mmol)，收率：30％。LC-MS:[M+H]+＝488。
1H NMR(300MHz,DMSO-d6,ppm)δ12.62(d,J＝19.7Hz,1H),10.45(d,J＝92.5Hz,1H),8.83(d,J＝22.0Hz,1H),8.27–7.80(m,2H),7.75–7.18(m,3H),5.80–5.32(m,3H),4.67(d,J＝17.2Hz,1H),4.13(d,J＝16.9Hz,1H),2.48–2.14(m,4H),1.80(d,J＝20.6Hz,2H),1.67(d,J＝33.9Hz,2H),1.09(dt,J＝21.1,7.4Hz,3H).
参照化合物H1的合成路线，采用类似的原料/中间体，合成如下目标分子。
*代表手性中心，未进行拆分
实施例10：目标分子H4-H9的合成
步骤1：将中间体b11(200mg,0.71mmol)和TEA(143mg,1.42mmol)溶于4mL二氯甲烷中，加入草酰氯单甲酯(134mg,1.1mmol)，室温下反应1小时，减压蒸除溶剂。得到粗品化合物H4-1，直 接进行下一步反应。
步骤2：将粗品化合物H4-1(30mg,0.05mmol)溶于6mL四氢呋喃和水的混合溶液中(v/v,1/1)，加入LiOH(65mg,1.62mmol)，室温反应4小时。向体系缓慢加入4M浓度稀盐酸调节pH至7左右，减压蒸除溶剂，粗品经flash反向色谱分离(乙腈/水)，得到化合物H4-2(110mg)，两步总收率：43％。LC-MS:[M+H]+＝355。
步骤3：-20℃，氮气保护下，将化合物H4-2(100mg,0.28mmol)和中间体a6(63mg,0.28mmol)溶于2mL吡啶中，逐滴加入三氯氧磷(87mg,0.56mmol)，滴毕，在该温度下反应15分钟。向体系缓慢加入20mL冰甲醇淬灭反应，减压蒸除溶剂，粗品经flash反向色谱分离(乙腈/水)，得到化合物H4-3(20mg)，收率：13％。LC-MS:[M+H]+＝560。
步骤4：氮气保护下，将化合物H4-3(20mg,0.04mmol)溶于1mL氯化氢的1,4-二氧六环溶液中(浓度1M)，室温下反应30分钟。向体系缓慢加入5mL氨水淬灭反应，减压蒸除溶剂，粗品经HPLC制备色谱分离(乙腈/水)，得到白色固体H4(8.5mg)，收率：52％。LC-MS:[M+H]+＝460。
1H NMR(400MHz,DMSO-d6,ppm)δ10.45(d,J＝67.3Hz,1H),8.85–8.79(m,1H),8.76(dd,J＝8.3,4.9Hz,2H),8.12(ddd,J＝11.8,8.4,2.4Hz,1H),7.97(dd,J＝65.6,2.5Hz,1H),7.71–7.53(m,1H),7.49–7.31(m,2H),5.72(dd,J＝7.1,1.8Hz,1H),5.64(d,J＝22.1Hz,2H),5.21–4.97(m,1H),4.62(s,1H),2.00(d,J＝27.8Hz,3H),1.59(dd,J＝47.9,7.0Hz,3H).
目标化合物H4经手性制备色谱分离，得到H4A和H4B。
手性柱:CHIRAL ART Amylose-SA,2*25cm,5μm；流动相A:Hex:DCM＝3:1(0.5％2M NH3-MeOH)--HPLC,流动相B:IPA--HPLC；Flow rate:20mL/min；Gradient:40％B to 40％B in 15min；
H4A保留时间：RT1(min):8.083；H4B保留时间：RT2(min):12.922；
参照化合物H4的合成路线，采用类似的原料/中间体，合成如下目标分子。

实施例11：目标分子M1-M2，M4的合成
氮气保护下，将中间体a5(105mg,0.4mmol)溶于4mL二氯乙烷中，加入吡啶(376mg,4.7mmol)和提前配置的中间体b4(128mg,0.4mmol)，室温下反应10小时，减压蒸除溶剂。将混合物溶解于5mL甲醇中，混合液经flash反向柱层析分离(乙腈/水)，得到化合物M1(4.0mg)。LC-MS:[M+H]+＝453。
1H NMR(300MHz,DMSO-d6,ppm):δ12.65(s,1H),8.21(s,1H),8.00(d,J＝8.6Hz,1H),7.92(s,1H),7.80(s,1H),7.74(d,J＝8.5Hz,1H),7.51(d,J＝9.6Hz,1H),6.50(s,2H),5.12(s,1H),5.00(d,J＝15.8Hz,1H),4.05(d,J＝16.2Hz,1H),2.37(s,3H),2.22(s,4H),1.97(s,1H),1.73(s,2H),1.64(s,1H),1.32(s,2H).
参照化合物M1的合成路线，采用类似的原料/中间体，合成如下目标分子。
*代表手性中心，未进行拆分
实施例12：目标分子M3，M5-M6的合成
步骤1：将中间体b7(100mg,0.3mmol)、DIEA(173mg,1.3mmol)和中间体a5-1(68mg,0.3mmol)溶于1mL DMF中，加入EDCI(97mg,0.5mmol)和HOBT(68mg,0.5mmol)，室温下反应10小时，向体系加水10mL，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，混合物经flash反向柱层析分离(乙腈/水)，得到化合物M3-1(30.0mg,0.05mmol)，收率：55％。LC-MS:[M+H]+＝588。
步骤2：氮气保护下，将化合物M3-1(78mg,0.16mmol)、二甲基氧化磷(25mg,0.32mmol)和K3PO4(102.9mg,0.48mmol)溶于1mL 1,4-二氧六环中，加入Xantphos(19mg,0.03mmol)和Pd2(dba)3(14.8mg,0.016mmol)，升温至100℃下反应4小时，减压蒸除溶剂，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物M3(23mg,0.05mmol)，收率：30％。LC-MS:[M+H]+＝480。
1H NMR(400MHz,DMSO-d6):δ9.08(s,1H),8.78(s,1H),8.05(s,1H),7.93(s,1H),7.84(s,1H),7.71(s,1H),7.65(d,J＝1.9Hz,1H),7.54(d,J＝8.5Hz,1H),7.42(d,J＝7.4Hz,1H),6.52(s,2H),5.42(s,1H),4.73(d,J＝16.8Hz,1H),4.36(d,J＝16.8Hz,1H),2.23(s,3H),1.70(d,J＝13.5Hz,7H),1.59(d,J＝6.9Hz,3H).
参照化合物M3的合成路线，采用类似的原料/中间体，合成如下目标分子。
*代表手性中心，未进行拆分
实施例13：目标分子M7的合成
步骤1：将原料M7-1(1.6g,5.6mmol)和甲醇钠(2.2g,40.6mmol)溶于16mL甲醇中，升温至70℃下反应10小时，停止反应。减压蒸除溶剂，向体系加入20mL冰水，用1M浓度稀盐酸调节pH至7左右，析出固体，抽滤，用冰甲醇洗涤，干燥，得到化合物M7-2(1.6g,6.05mmol)，收率：96％。LC-MS:[M+H]+＝296。
步骤2：将上步中间体M7-2(1.6g,6.05mmol)和LiOH(0.3g,12.1mmol)溶于21mL四氢呋喃中，加入11mL水。该混合物在室温下反应10小时，停止反应。减压蒸除溶剂，向体系加入20mL冰水，用1M浓度稀盐酸调节pH至7左右，减压蒸除溶剂，粗品经flash反向柱层析分离(乙腈/水)，得到化合物M7-3(1.0g,3.57mmol)，收率：59％。LC-MS:[M+H]+＝282。
步骤3：将上步中间体M7-3(220mg,0.78mmol)、中间体b10(224mg,0.78mmol)和DIEA(403mg,3.12mmol)溶于5mL DMF中，加入EDCI(224mg,1.17mmol)和HOBT(158mg,1.17mmol)。该混合物在室温下反应10小时，停止反应。向体系加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，减压蒸除溶剂，粗品经flash反向柱层析分离(乙腈/水)，得到化合物M7-4(200mg,0.36mmol)，收率：47％。LC-MS:[M+H]+＝552。
步骤4：一氧化碳氛围下(5atm)，将化合物M7-4(50mg,0.09mmol)和二三甲基硅基胺(220mg,1.36mmol)溶于1mL DMF中，加入dppf(11mg,0.02mmol)和Pd2(dba)3(8.3mg,0.01mmol)，升温至100℃下反应2小时，减压蒸除溶剂，粗品经HPLC制备色谱分离(流动相：乙腈/水，10M碳酸氢铵水溶液)，得到化合物M7(21mg)，收率：43％。LC-MS:[M+H]+＝516。
1H NMR(300MHz,DMSO-d6,ppm)δ9.09(s,1H),8.87(s,1H),8.79(s,1H),8.37(s,1H),8.12(d,J＝8.4Hz,1H),8.05–7.42(m,6H),5.33(d,J＝7.0Hz,1H),4.80(d,J＝17.2Hz,1H),4.47(d,J＝16.9Hz,1H),4.10(s,3H),1.62(d,J＝6.9Hz,3H).
实施例14：目标分子N1的合成
步骤1：将原料N1-1(5.5g,27.5mmol)、氰基乙酸甲酯(5.5g,55.0mmol)和叔丁醇钾(6.2g,55.0mmol)溶于55mL DMSO中，升温至50℃下反应2小时，停止反应。向体系加入320mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经柱层析分离得到化合物N1-2(1.4g,4.98mmol)，收率：18％。LC-MS:[M+H]+＝281。
步骤2：氮气保护下，将上步中间体N1-2(1.4g,4.98mmol)溶于28mL无水四氢呋喃中，加入LiAlH4(4.4mL,10.7mmol)。该混合物在室温下反应2小时，向体系加入50mL冰水淬灭反应。抽滤，滤液经flash反向柱层析分离(乙腈/水)，得到化合物N1-3(340mg,1.34mmol)，收率：27％。LC-MS: [M+H]+＝253。
步骤3：氮气保护下，将上步中间体N1-3(340mg,1.34mmol)、Zn(CN)2(189mg,1.61mmol)和Dppf(75mg,0.13mmol)溶于7mL DMF中，加入Pd2(dba)3(62mg,0.07mmol)。该混合物升温至100℃下反应2小时，停止反应。向体系加入30mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水)，得到化合物N1-4(215mg,1.08mmol)，收率：80％。LC-MS:[M+H]+＝200。
步骤4：氮气保护下，将上步中间体N1-4(215mg,1.08mmol)和咪唑(184mg,2.70mmol)溶于5mL DMF中，加入叔丁基二甲基氯硅烷TBDMS-Cl(179mg,1.19mmol)。该混合物在室温下反应2小时，停止反应。向体系加入80mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水)，得到化合物N1-5(295mg)，收率：87％。LC-MS:[M+H]+＝314。
步骤5：将上步中间体N1-5(280mg,0.89mmol)溶于3mL乙醇中，加入NaOH水溶液(2.8mL,50％)。升温至80℃下反应4小时，冷却至室温。向体系加入1M浓度稀盐酸调节pH至3左右，减压蒸除溶剂，粗品经flash反向柱层析分离(乙腈/水)，得到化合物N1-6(105mg,0.48mmol)，收率：54％。LC-MS:[M+H]+＝219。
步骤6：氮气保护下，将上步中间体N1-6(55mg,0.25mmol)、中间体c1(71mg,0.25mmol)和DIEA(98mg,0.76mmol)溶于1.5mL DMF中，加入EDCI(47mg,0.3mmol)和HOBT(41mg,0.3mmol)。该混合物在室温下反应10小时，停止反应。向体系加入10mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，减压蒸除溶剂，粗品经flash反向柱层析分离(乙腈/水)，得到化合物N1(7.8mg)，收率：7％。LC-MS:[M+H]+＝483。
1H NMR(400MHz,DMSO-d6,ppm)δ8.82(dd,J＝21.8,3.6Hz,2H),8.15–8.08(m,1H),7.95(d,J＝12.8Hz,1H),7.59(q,J＝12.9,11.4Hz,2H),7.49–7.20(m,4H),6.44(s,2H),5.56–5.39(m,1H),5.05–4.87(m,2H),4.49(s,2H),3.67–3.57(m,1H),1.63(d,J＝6.8Hz,3H).
实施例15：目标分子N2-N4的合成
步骤：氮气保护下，将中间体d1(125mg,0.54mmol)、中间体c1(152mg,0.54mmol)和DIEA(209mg,1.61mmol)溶于3mL DMF中，加入EDCI(155mg,0.81mmol)和HOBT(109mg,0.81mmol)，该混合物在室温下反应2小时，停止反应。向体系加入15mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，减压蒸除溶剂，粗品经flash反向柱层析分离(乙腈/10M碳酸氢铵水溶液,4/5)，得到化合物N2(5.9mg)。LC-MS:[M+H]+＝497。
1H NMR(400MHz,DMSO-d6,ppm)δ8.80(d,J＝4.9Hz,3H),8.12(d,J＝7.6Hz,1H),8.06(s,1H),7.74–7.32(m,4H),6.36(s,2H),5.45(s,1H),5.13(s,1H),4.93(d,J＝17.1Hz,1H),4.60(s,2H),2.37–2.04(m,1H),1.60(d,J＝7.0Hz,3H).
参照化合物N2的合成路线，采用类似的原料/中间体，合成如下目标分子。
实施例16：目标分子N5-N9的合成
步骤1：-10℃，氮气保护下，将中间体d4(60mg,0.22mmol)、中间体d7(71mg,0.22mmol)和TEA(113mg,0.93mmol)溶于1mL无水二氯甲烷中，该混合物在-10℃下反应1小时，停止反应。向体系加入15mL冰水，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水,3/5)，得到黄色固体N5-1(105mg)，收率：86％。LC-MS:[M+H]+＝558。
步骤2：氮气保护下，将上步化合物N5-1(105mg,0.18mmol)和碳酸钾(208mg,1.50mmol)溶于5mL四氢呋喃和水的混合溶液中(v/v,3/2)，该混合物升温至60℃下反应12小时，停止反应。向体系加入15mL冰水，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经flash反向柱层析分离(乙腈/水,2/5)，得到白色固体N5(5.0mg)，收率：5％。LC-MS:[M+H]+＝540。
1H NMR(300MHz,DMSO-d6,ppm)δ9.00–8.75(m,4H),8.68(d,J＝2.3Hz,1H),8.35(t,J＝2.2Hz,1H),8.24–7.91(m,2H),7.58(d,J＝49.4Hz,4H),6.36(s,2H),5.46(s,1H),5.14(s,1H),4.60(s,3H),2.51(p,J＝1.9Hz,3H),2.25(d,J＝18.5Hz,1H),1.62(d,J＝7.0Hz,3H).
参照化合物N5的合成路线，采用类似的原料/中间体，合成如下目标分子。
实施例17：
细胞内精氨酸对称二甲基化抑制分析(In cell western ICW实验)
将培养在包含10％胎牛血清和1％青链霉素的RPMI1640培养基中的HCT116野生型或MTAP缺失型细胞(HTC116-MTAP del)接种在384孔微板上，培养体积30μL，在37℃,5％二氧化碳条件下温育过夜。使用ECHO在各孔中加入60nL不同浓度化合物，并在37℃,5％二氧化碳条件下温育96小时。
然后，每孔中加入50μL的4％多聚甲醛溶液，室温孵育20分钟固定细胞。移除孔中溶液，每孔中加入包含0.1％吐温20的PBS溶液(PBST)清洗4次，每孔中加入30μL冰浴预冷的甲醇，放置 于-20℃孵育10分钟；移除甲醇并使用PBST清洗4次。每孔中加入30μL包含0.5％吐温20的Odyssey阻断液，室温震荡孵育2小时；移除阻断液，每孔中加入30μL以1:500在包含0.5％吐温20的Odyssey阻断液中稀释的一抗(Symmetric Di-Methyl Arginine Motif[sdme-RG]MultiMabTM Rabbit mAb mix)4℃温孵过夜；移除一抗，每孔中使用PBST清洗四次，每次5分钟；每孔中加入在包含0.5％吐温20的Odyssey阻断液中稀释的二抗(羊抗兔IRDye 800CW，1:800)和核染色(DRAQ5，1:10000)，避光室温孵育2小时。移除二抗并使用PBST清洗4次。
使用Li-Cor Odyssey仪器分别在800nm和700nm扫描sdme-RG和DRAQ5信号并记录信号值，sdme-RG/DRAQ5的比值被用于计算精氨酸对称二甲基化(SDMA)的抑制百分率，并使用GraphPad Prism软件计算IC50值。
表1：化合物对于HTC116-MTAP del和野生型wild type的结直肠癌HCT-116细胞系精氨酸对称甲基化抑制效果

N.D.＝未测试
以上实验结果表明，本发明的优异化合物通过抑制PRMT5，对于MTAP缺失的肿瘤细胞具有明显抑制精氨酸对称甲基的效果，而对于野生型抑制较弱。
实施例14：
将HCT116野生型和MTAP缺失型细胞培养于包含10％FBS和1％青链霉素的MCCOYS 5A培养基中，置于37℃，5％CO2恒温培养箱培养，在384孔微板中每孔加入40μL细胞悬液。使用Echo在每孔中加入40nL不同浓度的化合物，置于37℃，5％CO2恒温培养箱培养7-10天。在每孔中加入40μL的CTG溶液(Promega，Cat No.G7573)，置于37℃，5％CO2恒温培养箱避光温孵30分钟。用Envision多功能酶标仪(Perkin Elmer，目录号Envision 2104)读取发光值，光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数。
IC50值计算：
Y＝下平台信号+(上平台信号-下平台信号)/(1+10^((LogIC50-X)×希尔斜率))
X:化合物浓度log值
Y:抑制率(％)
表2：化合物对于HTC116-MTAP del和野生型wild type的结直肠癌HCT-116细胞系的2D抗增殖效果。

N.D.＝未测试
以上实验结果表明，本发明的优异化合物通过抑制PRMT5，对于MTAP缺失的肿瘤细胞具有明显抗增殖的效果，而对于野生型抑制较弱。部分分子选择性非常高(大于50倍)，从而有望带来更高的安全性。
实施例15：
化合物的肝微粒体稳定性实验。具体如下：
对本发明化合物进行肝微粒体稳定性试验研究，将待测化合物在加入或不加入NADPH情况下与不同种属的肝微粒体进行共孵育，试验体系中待测化合物终浓度为1μM，NADPH终浓度为1mM，肝微粒体终浓度为0.5mg/mL。检测60分钟内不同时间点孵育上清中的化合物浓度并计算药代动力 学参数(例如清除率Clint)。
该结果表明本发明分子具有较好的代谢稳定性(尤其在人体中，具有较好的代谢稳定性)。部分分子如P4A，P7A，N1，H4,P30,P69和P70等分子在人的肝微粒代谢中，相比AMG9747具有更低的清除速率，从而人体代谢更慢。
N.D.＝未测试
AMG9747结构：
实施例16：
小鼠药代动力学评价实验
以CD1雌性小鼠为受试动物，口服/静脉给药(口服给药量为10mg/kg，静脉为2mg/kg)。
实验方案：口服组每组3只，静脉组每组三只。口服：收集给药前(0h)和给药后(0.25,0.5,1,2,4,8,24h)的血浆样品；静脉：收集给药前(0h)和给药后(0.083,0.25,0.5,1,2,4,8,24h)的血浆样品；用LC/MS/MS法分别测定小鼠口服和静脉给药后的血浆的血液浓度，采集的数据用AB Sciex QTRAP6500软件计算，实验结果如下：
以上实验结果表明，本发明化合物具有良好的口服吸收效果。部分分子相比AMG9747具有更低的体内清除速率与更高的体内暴露量，有望带来更高的治疗效果。
实施例17：
BALB/c裸鼠体内药效实验。具体如下：
培养HCT116(MTAPdel)的肿瘤细胞，将该肿瘤细胞接种到6-8周的雌性BALB/c裸鼠中(体重约20g左右)，所有小鼠皮下接种。小鼠培养于SPF级实验环境中，所有小鼠可自由获取商业认证的标准饮食。当小鼠平均肿瘤体积成长到160mm3左右时，将试验化合物开始每日口服给药。给药剂量为：空白组溶媒(Saline containing 0.1％Tween 80 and 0.5％methyl cellulose)。给药组剂量为100mg/kg，每日1次。肿瘤体积一周三次用二维卡尺测量，每天动物称重。连续给药19天后，根据最终肿瘤体积计算抑制率(TGI/100％)。体积计算公式为：V＝1/2a*b2，a代表肿瘤长径，b代表肿瘤短径。
该结果表明本发明分子具有较好体内药效，优于已经在临床开发的药物GSK3326595。
GSK3326595结构：
实施例18：
有临床数据报道，GSK3326595在临床使用中，具有明显的血液学毒副作用，例如贫血。
本发明的分子测试其在C57BL/6J小鼠血液学毒性。具体如下：
培养8-9周的雌性C57BL/6J小鼠(体重约20g左右)。小鼠培养于SPF级实验环境中，所有小鼠可自由获取商业认证的标准饮食。将试验化合物开始每日口服给药，给药剂量为：空白组溶媒(Saline containing 0.1％Tween 80and 0.5％methyl cellulose)。给药组剂量为300mg/kg，每日1次。每天动物称重，观察动物状态，结果如下(表A)。连续给药10天后，测试小鼠的血液学指标，结果如下(表B)。
表A：动物体重数据
体重数据表明，本发明的化合物相比临床分子GSK3326595和AMG9747，对于小鼠体重影响小，毒副作用低。
表B：动物血液学数据
血液学毒理数据表明，本发明的化合物相比临床分子GSK3326595和AMG9747，体内暴露量高，但是对于血液毒性(红细胞和前体网织红细胞)影响较低，体现了本发明的分子高选择性带来的安全性获益，预期本发明其他类似高选择性分子具有类似的安全性优势。

Claims (27)

  1. 式(A)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
    其中，
    X1选自CR2或N；
    X2选自CH或N；
    X3选自CH或N；
    L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
    Ar为
    环S选自C6-10芳基、6-10元杂芳基、C5-10环烷基或5-10元杂环基；
    R1和R2独立地选自H、卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、5-6元杂芳基、S(O)2-Rd或S(O)-Rd，所述R1和R2可任选地被卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基进一步取代；
    或者，R1、R2和它们连接的碳原子一起形成C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基，所述C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个、3个、4个或5个Rx取代；
    Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂环基；
    R3选自C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
    R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
    或者，R3、R4和它们连接的碳原子一起形成
    其中，环A选自C4-10环烷基、4-10元杂环基、5-10元杂芳基或C6-10芳基；
    环B为C5-10环烷基或5-10元杂环基；
    所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
    R#选自卤素、ORa、C1-6亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
    R5选自H或C1-6烷基；
    R6和R9独立地选自ORa、C1-6亚烷基-ORa、C(O)NRbRc、C(O)ORa、C(O)Ra、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6元杂芳基；
    R7和R8独立地选自ORa、NRbRc；
    R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
    R11选自H、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
    n选自1、2或3；
    Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基；
    前提是，当L为C(O)时，R6不为C1-6烷基、卤素、C1-6卤代烷基和C2-6炔基；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  2. 权利要求1的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下结构：
    其中，各基团如权利要求1中所定义。
  3. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CR2或N；
    X2选自CH或N；
    X3选自CH或N；
    L选自C(O)、C(O)NH、C(O)-C(O)或C(O)-C(O)NH；
    Ar为
    环S为C6-10芳基；
    R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、5-6元杂芳基、S(O)2-Rd或S(O)-Rd，R1可任选地被卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基进一步取代；
    R2选自H、C1-6烷基或C1-6卤代烷基；
    或者，R1、R2和它们连接的碳原子一起形成C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基，所述C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个或3个Rx取代；
    Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者为任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂环基；
    R3选自C1-6烷基、C1-6卤代烷基、C1-4亚烷基-ORa、C1-4亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
    R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
    或者，R3、R4和它们连接的碳原子一起形成
    其中，环A为5-10元杂芳基或C6-10芳基；
    环B为C5-10环烷基或5-10元杂环基；
    所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
    R#选自卤素、ORa、C1-4亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
    R5选自H或C1-6烷基；
    R6选自ORa、C1-6亚烷基-ORa、C(O)NRbRc、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
    R7和R8独立地选自ORa或NRbRc；
    R9选自C1-6烷基或C3-7环烷基；
    R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
    R11选自H、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
    Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基。
  4. 权利要求1-3中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CR2或N；
    X2选自CH或N；
    X3选自CH或N；
    L选自C(O)或C(O)-C(O)NH；
    Ar为
    R1选自Cl、Br、SF5、CN、CF3、OCF3、环丙基、
    R2选自H或CH3；
    或者，R1、R2一起形成
    R3选自CH3、环丙基、
    R4选自H、CH3、CH2CH3或环丙基；
    或者，R3、R4和它们连接的碳原子一起形成
    R5选自H或CH3；
    R6选自OCH3、CH2OH、C(O)2NH2、环丙基、环丁基或
    R7选自NH2或OCH3；
    R8选自NH2；
    R9选自CH3、CH2CH3或环丙基；
    R10选自H、F、Cl、CN或CH3；
    R11选自H或CH3。
  5. 权利要求1-4中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其具有以下结构：

    其中，各基团如权利要求1-4中任一项所定义；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  6. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(V)、(V-1)或(V-2)化合物：
    其中，
    X1选自CR2或N；
    X2选自CH或N；
    X3选自CH或N；
    R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、5-6元杂芳基、S(O)2-Rd或S(O)-Rd，R1可任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代；
    R2选自H、C1-6烷基或C1-6卤代烷基；
    或者，R1、R2和它们连接的碳原子一起形成C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基，所述C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基可任选地被1个、2个或3个Rx取代；
    Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者选自任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的C4-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂环基；
    R3选自C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
    R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
    或者，R3、R4和它们连接的碳原子一起形成
    其中，环A为5-10元杂芳基或C6-10芳基；
    环B为C5-10环烷基或5-10元杂环基；
    所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
    R#选自卤素、ORa、C1-4亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
    R5选自H或C1-6烷基；
    R6选自C1-6亚烷基-ORa、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
    R7选自ORa或NRbRc；
    R10选自H、卤素、ORa、NRbRc、CN、C1-6烷基或C1-6卤代烷基；
    R11选自H、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
    Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  7. 权利要求6的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CR2或N；
    X2选自CH或N；
    X3选自CH或N；
    R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或S(O)2-Rd，R1可任选地被卤素、C1-4烷基或C1-4卤代烷基进一步取代；
    R2选自H、C1-6烷基或C1-6卤代烷基；
    或者，R1、R2和它们连接的碳原子一起形成C6-10芳基或5-10元杂芳基，所述5-10元杂芳基或C6-10芳基可任选地被1个、2个或3个Rx取代；
    Rx选自卤素、C1-6烷基或C1-6卤代烷基，或者选自任选地被卤素、C1-6烷基、C1-6卤代烷基中的一个或多个基团取代的5-10元杂环基或C4-10环烷基；
    R3选自C1-6烷基、C1-4亚烷基-ORa、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
    R4选自H、C1-6烷基或C3-6环烷基；
    或者，R3、R4和它们连接的碳原子一起形成
    其中，环A为5-10元杂芳基；
    环B为C5-10环烷基或5-10元杂环基；
    所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
    R#选自卤素、C1-4烷基、C1-4卤代烷基、CH2OH或C1-4烷氧基；
    R5选自H或C1-6烷基；
    R6选自C1-6亚烷基-ORa、C3-7环烷基或3-7元杂环基；
    R7选自ORa或NRbRc；
    R10选自H、卤素、ORa、NRbRc、CN或C1-4烷基；
    R11选自H、卤素或C1-6烷基；
    Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基。
  8. 权利要求6或7的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CR2或N；
    X2选自CH或N；
    X3选自CH或N；
    R1选自卤素、SF5、NH2、OH、CN、C1-4卤代烷基、C1-4卤代烷氧基、C3-5环烷基或S(O)2-C1-4卤代烷基；
    R2选自H或C1-4烷基；
    或者，R1、R2和它们连接的碳原子一起形成5-6元杂芳基，所述5-6元杂芳基可任选地被1个或2个Rx取代；
    Rx为任选地被C1-4烷基取代的5-6元杂环基；
    R3选自C1-4烷基、C1-4亚烷基-OC1-4烷基、C3-5环烷基或5-6元杂芳基，R3可任选地被1个、2个或3个R#取代；
    R4选自H、C1-4烷基或C3-5环烷基；
    或者，R3、R4和它们连接的碳原子一起形成
    其中，环A为5-6元杂芳基；
    环B为C5-6环烷基或5-6元杂环基；
    所述环A和环B可任选地被1个、2个或3个R#取代；
    R#选自卤素、C1-4烷基、C1-4卤代烷基、CH2OH或C1-4烷氧基；
    R5选自H或C1-4烷基；
    R6选自C1-4亚烷基-OH、C3-5环烷基或3-5元杂环基；
    R7选自OH或NH2；
    R10选自H、卤素、OH、NH2、CN或C1-4烷基；
    R11选自H或C1-4烷基。
  9. 权利要求6-8中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CR2或N；
    X2选自CH或N；
    X3选自CH或N；
    R1选自Br、SF5、CN、CF3、OCF3、环丙基、
    R2选自H或CH3；
    或者，R1、R2一起形成
    R3选自CH3、环丙基、
    R4选自H、CH3、CH2CH3或环丙基；
    或者，R3、R4和它们连接的碳原子一起形成
    R5选自H或CH3；
    R6选自CH2OH、环丙基、环丁基或
    R7为NH2；
    R10选自H、F、Cl、CN或CH3；
    R11选自H或CH3。
  10. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(VI)化合物：
    其中，
    X1选自CH或N；
    X2选自CH或N；
    R1选自卤素、SF5、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C3-7环烷基；
    R3选自C6-10芳基或5-10元杂芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
    R#选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-4亚烷基-ORa、C2-6烯基或C2-6炔基；优选地，R#选自卤素、C1-6烷基、C1-6烷氧基、C2-6烯基或C2-6炔基；
    R4选自C1-6烷基或C3-7环烷基；
    R10选自H、卤素、CN或C1-6烷基；优选地，R10选自H或卤素；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  11. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CH或N；
    X2选自CH或N；
    R1选自卤素、SF5、C1-4卤代烷基、C1-4卤代烷氧基或C3-5环烷基；
    R3选自C6-10芳基或5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
    R#选自卤素、C1-6烷基或C1-6卤代烷基；优选地，R#选自卤素或C1-6烷基；
    R4选自C1-4烷基或C3-5环烷基；
    R10选自H、卤素、CN或C1-4烷基；优选地，R10选自H或卤素。
  12. 权利要求10或11的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CH或N；
    X2选自CH或N；
    R1选自卤素、SF5、C1-2卤代烷基、C1-2卤代烷氧基或C3-4环烷基；
    R3为5-6元杂芳基，R3可任选地被1个、2个或3个R#取代；
    R#选自卤素、C1-4烷基或C1-4卤代烷基；优选地，R#选自卤素或C1-4烷基；
    R4选自C1-4烷基或C3-4环烷基；
    R10选自H、卤素、CN或C1-4烷基；优选地，R10选自H或卤素。
  13. 权利要求10-12中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    X1选自CH或N；
    X2选自CH或N；
    R1选自Br、SF5、CF3、OCF3或环丙基；
    R3选自优选为
    R4选自CH3、CH2CH3或环丙基；
    R10选自H、F、Cl、CH3或CN，优选为H、F或Cl。
  14. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(VIII)化合物：
    其中，
    R1选自5-10元杂芳基或C1-6卤代烷基，所述R1任选地被Ry取代；
    Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
    R#选自卤素、CH2OH或C1-4烷基；
    R6选自ORa或C1-6亚烷基-ORa，优选为C1-6亚烷基-ORa；
    Ra选自H、C1-6烷基或C1-6卤代烷基；
    优选地，
    R1为C1-6卤代烷基，优选为C1-4卤代烷基；
    R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，R3可任选地被1个、2个或3个R#取代；
    R#选自卤素、CH2OH或C1-4烷基；
    R6选自ORa或C1-6亚烷基-ORa，优选为C1-6亚烷基-ORa；
    Ra选自H、C1-6烷基或C1-6卤代烷基；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  15. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IX)化合物：
    其中，
    R1为C1-4卤代烷基；
    R3选自
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  16. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(X)、(X-1)或(X-2)化合物：
    其中，
    R1选自卤素、SF5、ORa、NRbRc、CN、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、S(O)2-Rd或S(O)-Rd，R1可任选地被卤素、C1-6烷基或C1-6卤代烷基进一步取代；
    R3选自C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，R3可任选地被1个、2个、3个、4个或5个R#取代；
    R4选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；
    或者，R3、R4和它们连接的碳原子一起形成
    其中，环A为5-10元杂芳基或C6-10芳基；
    环B为C5-10环烷基或5-10元杂环基；
    所述环A和环B可任选地被1个、2个、3个4个或5个R#取代；
    R#选自卤素、ORa、C1-4亚烷基-ORa、NRbRc、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1- 6烷氧基或C1-6卤代烷氧基；
    R8选自ORa或NRbRc；
    R9选自C1-6亚烷基-ORa、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C6-10芳基或5-6杂芳基；
    Ra、Rb、Rc和Rd独立地选自H、C1-6烷基或C1-6卤代烷基；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  17. 权利要求16的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，
    R1选自Br或CF3；
    R3选自
    R4为CH3；
    或者，R3、R4和它们连接的碳原子一起形成
    R8选自NH2；
    R9选自CH3、CH2CH3或环丙基。
  18. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(XI)化合物：
    其中，
    R1为5-10元杂芳基或C1-6卤代烷基，所述R1任选地被Ry取代；
    Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，所述R3可任选地被1个、2个或3个R#取代；
    R#选自卤素或C1-6烷基；
    R5选自C1-6烷基或C1-6卤代烷基；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  19. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(XII)化合物：
    其中，
    Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    R3为C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C1-6亚烷基-NRbRc、C3-10环烷基、3-10元杂环基、5-10元杂芳基或C6-10芳基，所述R3可任选地被1个、2个、3个、4个或5个R#取代；
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C1-6亚烷基-OH，优选为H；
    R4选自H、C1-6烷基或C1-6卤代烷基、C3-7环烷基或3-7元杂环基，优选为C1-6烷基；
    R5选自H或C1-6烷基；
    R6选自C1-6亚烷基-OH或C3-7环烷基，优选为-CH2OH或环丙基；
    R10选自H、卤素、CN、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；
    优选地，
    Ry选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；
    R3选自5-10元杂芳基或C6-10芳基，所述R3可任选地被1个、2个、3个、4个或5个R#取代；
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C1-6亚烷基-OH，优选为H；
    R4选自H、C1-6烷基或C1-6卤代烷基，优选为C1-6烷基；
    R5选自H或C1-6烷基；
    R6选自C1-6亚烷基-OH或C3-7环烷基，优选为-CH2OH或环丙基；
    R10选自H、卤素、CN、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；
    优选地，
    Ry选自H、卤素、C1-4烷基、C1-4卤代烷基或C1-4烷氧基，优选为F或CF3；
    R3为所述R3可任选地被1个、2个或3个R#取代；
    R#选自H、卤素、C1-4烷基或C1-4卤代烷基，优选为H；
    R4选自H、C1-4烷基或C1-4卤代烷基，优选为C1-4烷基；
    R5选自H或C1-4烷基；
    R6选自C1-4亚烷基-OH或C3-7环烷基，优选为-CH2OH或环丙基；
    R10选自H、卤素、CN、C1-4烷基或C1-4卤代烷基，优选为H或卤素；
    更优选地，
    Ry选自H、F、Cl、CH3、OCH3或CF3，优选为F或CF3；
    R3为所述R3可任选地被1个、2个或3个R#取代；
    R#选自H、F、CH3或CF3，优选为H；
    R4为CH3；
    R5选自H或CH3；
    R6选自-CH2OH或环丙基；
    R10选自H、F、Cl、CN、CH3或CF3，优选为H或F；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  20. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(XIII)化合物：
    其中，
    R1选自C1-6烷基或C1-6卤代烷基，优选为CF3；
    R3为5-10元杂芳基或C6-10芳基，优选为5-10元杂芳基，所述R3可任选地被1个、2个、3个、4个或5个R#取代；
    R#选自H、卤素、C1-6烷基或C1-6卤代烷基；
    R4为C1-6烷基，优选为CH3；
    R5为C1-6烷基，优选为CH3；
    R6选自C1-6亚烷基-OH或C3-7环烷基，优选为CH2OH或环丙基，更优选为CH2OH；
    R10选自H或卤素，优选为H；
    优选地，
    R1为C1-6卤代烷基，优选为CF3；
    R3为所述R3可任选地被1个、2个或3个R#取代；
    R#选自H、卤素、C1-6烷基或C1-6卤代烷基；
    R4为C1-6烷基，优选为CH3；
    R5为C1-6烷基，优选为CH3；
    R6选自C1-6亚烷基-OH或C3-7环烷基，优选为CH2OH或环丙基，更优选为CH2OH；
    R10选自H或卤素，优选为H；
    更优选地，
    R1为C1-4卤代烷基，优选为CF3；
    R3为所述R3可任选地被1个、2个或3个R#取代；
    R#选自H、卤素、C1-4烷基或C1-4卤代烷基；
    R4为C1-4烷基，优选为CH3；
    R5为C1-4烷基，优选为CH3；
    R6选自C1-4亚烷基-OH或C3-5环烷基，优选为CH2OH或环丙基，更优选为CH2OH；
    R10选自H或卤素，例如H、F或Cl，优选为H；
    上述基团可任选地被1个、2个、3个、4个、5个或更多个氘取代，直至完全氘代。
  21. 化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：

  22. 化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物选自：



  23. 药物组合物，其含有权利要求1-22中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。
  24. 权利要求1-22中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体在制备用于治疗和/或预防PRMT5甲基转移酶介导的疾病的药物中的用途。
  25. 一种在受试者中治疗和/或预防PRMT5甲基转移酶介导的疾病的方法，所述方法包括向所述受试者给药权利要求1-22中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体或权利要求23的药物组合物。
  26. 权利要求1-22中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、溶剂合物、水合物或同位素变体或权利要求23的药物组合物，其用于治疗和/或预防PRMT5甲基转移酶介导的疾病。
  27. 权利要求24的用途或权利要求25的方法或权利要求26的化合物或组合物的用途，其中所述PRMT5甲基转移酶介导的疾病为癌症，所述癌症选自：声神经瘤、腺癌、肾上腺癌、肛门癌、血管肉瘤(例如淋巴管肉瘤、淋巴管内皮肉瘤、血管瘤)、阑尾癌、良性单克隆伽玛病、胆管癌、膀胱癌、脑癌(例如脑膜瘤、神经胶质瘤，例如星形胶质细胞瘤、少突胶质细胞瘤、髓母细胞瘤)、支气管癌、类癌瘤、宫颈癌(例如宫颈腺癌)、绒(毛)膜癌、脊索瘤、颅咽管瘤、结肠直肠癌(例如结肠癌、直肠癌、大肠腺癌)、上皮癌、室管膜瘤、内皮肉瘤(例如卡波西肉瘤、多发性特发性出血肉瘤)、子宫内膜癌(例如子宫癌、子宫肉瘤)、食道癌(如食管腺癌、巴雷特氏腺癌)、尤因氏肉瘤、眼癌(如眼内黑色素瘤、成视网膜细胞瘤)、嗜酸性粒细胞增多症、胆囊癌、胃癌(如胃腺癌)、胃肠道间质瘤(GIST)、头颈癌(如头颈部鳞状细胞癌、口腔癌(如口腔鳞状细胞癌、喉癌(如喉癌、咽癌、鼻咽癌、口咽癌)))、造血系统癌症(例如白血病，如急性淋巴细胞白血病(ALL)(例如，B细胞ALL、T细胞ALL)、急性髓细胞白血病(AML)(例如，B细胞AML、T细胞AML)、慢性髓细胞白血病(CML)(例如，B细胞CML、T细胞CML)、慢性淋巴细胞白血病(CLL)(例如，B细胞CLL、T细胞CLL)、滤泡性淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、边缘区B细胞淋巴瘤(如粘膜相关淋巴组织(MALT)淋巴瘤、淋巴结边缘区B细胞淋巴瘤、脾脏边缘区B细胞淋巴瘤)、原发性纵隔B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B淋巴母细胞淋巴瘤和原发性中枢神经系统(CNS)淋巴瘤；以及T细胞非霍奇金淋巴瘤、如前体T淋巴母细胞淋巴瘤/白血病、外周T细胞淋巴瘤(如皮肤T细胞淋巴瘤(如 真菌病、Sezary综合征)、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤性T细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤、间变性大细胞淋巴瘤)；上述一种或多种白血病/淋巴瘤的混合物；多发性骨髓瘤(MM))、重链疾病(如α链疾病、γ链疾病、μ链疾病)、血管母细胞瘤、炎性肌纤维母细胞瘤、免疫细胞性淀粉样变性、肾癌(如肾母细胞瘤、肾细胞癌)、肝癌(如肝细胞癌、恶性肝细胞癌)、肺癌(如支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌、平滑肌肉瘤(LMS)、肥大细胞增多症(如全身肥大细胞增多症)、骨髓增生异常综合征(MDS)、间皮瘤、骨髓增生性疾病(MPD)(如真性红细胞增多症(PV)、原发性血小板增多症(ET)、特发性骨髓外化生(AMM)、慢性特发性骨髓纤维化、慢性粒细胞白血病(CML)、慢性中性粒细胞白血病(CNL)、嗜酸性粒细胞增多综合征(HES)、神经母细胞瘤、神经纤维瘤(如1型或2型神经纤维瘤病、神经鞘瘤病)、神经内分泌癌(如胃肠胰神经内分泌肿瘤(GEP-NET)，类癌瘤)、骨肉瘤、卵巢癌(如囊腺癌、卵巢胚胎癌、卵巢腺癌)、乳头状腺癌、阴茎癌。
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