WO2024037608A1 - Inhibiteur de prmt5 - Google Patents

Inhibiteur de prmt5 Download PDF

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WO2024037608A1
WO2024037608A1 PCT/CN2023/113653 CN2023113653W WO2024037608A1 WO 2024037608 A1 WO2024037608 A1 WO 2024037608A1 CN 2023113653 W CN2023113653 W CN 2023113653W WO 2024037608 A1 WO2024037608 A1 WO 2024037608A1
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alkyl
haloalkyl
halogen
cycloalkyl
atom
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PCT/CN2023/113653
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Chinese (zh)
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杨旭
孟庆华
刘磊
王虎庭
石磊
杜豪林
高蓓蓉
王建浩
孔德升
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北京望实智慧科技有限公司
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Publication of WO2024037608A1 publication Critical patent/WO2024037608A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new class of PRMT5 inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.
  • the present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in preventing and treating PRMT5-mediated diseases such as cancer.
  • Protein arginine methyltransferase 5 belongs to type II PRMT. It is a type of S-adenosylmethionine (SAM)-dependent methyltransferase and is mainly responsible for converting the methyl group of SAM. Symmetrically transferred to the guanidine nitrogen atom at the end of an arginine residue in histones or other proteins.
  • SAM S-adenosylmethionine
  • PRMT5 forms a complex with MEP50 (methylosome protein 50) to recognize the substrate and localize it. At the same time, the complex morphology is also required for PRMT5 to catalyze the methyl transfer activity of histone 2A and histone 4.
  • PRMT5 is a general transcriptional repressor that can regulate the process of gene transcription and protein modification. At the same time, PRMT5 plays an important role in the proliferation, differentiation, and apoptosis of tumor cells and is a highly potential tumor treatment target. However, PRMT5 is also an essential gene for normal cells. PRMT5 knockout and siRNA knockdown studies have shown that inhibiting the activity of PRMT5 in normal tissues may cause many toxic side effects such as thrombocytopenia, infertility, skeletal muscle loss, and cardiac hypertrophy.
  • MTAP methylthioadenosine phosphorylase
  • PRMT5 inhibitors under investigation include SAM competitive inhibitors, substrate competitive inhibitors, SAM and substrate dual competitive inhibitors, and MTA synergistic inhibitors.
  • Non-MTA synergistic PRMT5 inhibitors indiscriminately inhibit the activity of PRMT5, and dose-limiting toxic side effects such as thrombocytopenia, anemia, and neutropenia have been found.
  • MTA synergistic inhibitors target the PRMT5/MTA complex and are expected to inhibit MTAP-deficient tumor cells while eliminating the impact on MTAP WT cells, which can improve the treatment window.
  • the present invention uses the PRMT5/MTA complex as a target and develops a new class of small molecule inhibitors that can be used to treat various cancers.
  • the compound of the present invention targets the PRMT5/MTA complex, is an MTA synergistic PRMT5 inhibitor, has excellent PRMT5/MTA inhibitory activity, and has obvious selectivity for the PRMT5/SAM complex.
  • the compounds of the present invention have good ADMET (absorption-distribution-metabolism-excretion-toxicity) properties.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof Object:
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a or C(O)NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • L 1 is NH or CHR x ;
  • L 2 is a chemical bond or CR x R y ;
  • L 3 is -C(O)-, -S(O)- or -S(O) 2 -;
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • Y 1 is a chemical bond or (CR 3 R 3 ) q ;
  • Y 2 is a chemical bond, O, S, NR', S(O) or S(O) 2 ;
  • Z 1 is N or CR
  • Z 2 is N or CR
  • Z 3 is N or CR
  • R 3 and R are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • CR 3 R 3 together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene
  • R' is selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • p 0, 1, 2, 3 or 4;
  • Ar 1 and Ar 2 are phenyl or 5-6 membered heteroaryl, which is substituted by n R 1 ; the other is H or D; or Ar 1 and Ar 2 are independently H or D;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 halo
  • n 0, 1, 2, 3, 4 or 5;
  • R 1s is selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C(O)R a , C(O)OR a , C(O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 cycloalkyl, -L-3-10-membered hetero Ring group, -LC 6-10 aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl base substitution;
  • L is selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 selected from H, D, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms they are connected together form a 3-10 membered heterocyclyl group ;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.
  • the invention provides a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable excipient, which also contains other therapeutic agents, such as selected from the following target drugs/cell activity modulators, including CDK4/ 6 inhibitors, MAT2A inhibitors, MAPK1/MAPK3 inhibitors, Type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl -2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1/ 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1/2 inhibitors, chemotherapy drugs, radiotherapy, STING agonists or immune checkpoint inhibitors/modul
  • 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-mediated diseases.
  • the invention provides a method of treating and/or preventing a PRMT5-mediated disease in a subject, comprising administering to said subject a compound of the invention or a pharmaceutical composition of the invention.
  • the invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the treatment and/or prevention of PRMT5-mediated diseases.
  • the present invention is used to treat and/or prevent cancer.
  • the present invention is used for the treatment and/or prevention of the following cancers: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratomas.
  • bronchial carcinoma squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma
  • alveolar (bronchiolar) carcinoma bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelial carcinoma Tumors
  • gastrointestinal tract esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastric Secretinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor), Kaposi's sarcoma, leiomyoma, hemangioma
  • the PRMT5-mediated disease of the invention is selected from the following cancers: malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, Breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung squamous cell carcinoma , lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer and thyroid cancer, and sarcoma.
  • cancers malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, Breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colore
  • the PRMT5-mediated disease of the invention is selected from MTAP-related cancers, such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.
  • MTAP-related cancers such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.
  • 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, C 1-3 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 ), i-Bu(-CH 2 CH(CH 3 ) 2 ) or t-Bu(-C(CH 3 ) 3 ).
  • 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 Among them, 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.
  • C 0-6 alkylene means a chemical bond and the above-mentioned “C 1-6 alkylene”
  • C 0-4 alkylene means a chemical bond and the above-mentioned "C 1-4 alkylene”.
  • 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.
  • a C 1-4 haloalkyl group is particularly preferred, a C 1-3 haloalkyl group is more preferred, and a C 1-2 haloalkyl group is more preferred.
  • 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 , -CH 2 CH 2 CF 3 , -C(CH 3 ) 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 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1, 2 or 3 double or triple bonds. In some embodiments, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, with C 5-7 cycloalkyl and C 5-6 cycloalkyl being more preferred base.
  • 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. Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which the substituents on any non-adjacent carbon atoms are connected to form a bridged ring, which together form a polycyclic alkane sharing two or more carbon atoms.
  • Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which substituents on the same carbon atom are connected to form a ring, and together form a polycyclic alkane sharing one carbon atom.
  • 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 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), etc.
  • a cycloalkyl group may be optional
  • C 3-10 cycloalkylene refers to a divalent group formed by removing another hydrogen of C 3-10 cycloalkyl, and may be substituted or unsubstituted.
  • C 3-6 cycloalkylene, C 3-5 cycloalkylene and C 3-4 cycloalkylene are particularly preferred, with cyclopentylene being preferred and cyclopropylene being particularly preferred.
  • 3-10 membered heterocyclyl refers to a saturated or unsaturated group of 3 to 10 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, optionally containing 1, 2 or 3 double or triple bonds.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered is preferred Heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably 5-7-membered heterocyclyl, which is a 3- to 7-membered non-aromatic 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 heterocyclyl 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.
  • Heterocyclyl also includes the above-mentioned heterocyclyl rings, in which the substituents on any non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, which together form a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms.
  • Heterocyclyl also includes the above-mentioned heterocyclyl A ring in which substituents on the same carbon atom are linked together to form a polycyclic heteroalkane that shares one carbon atom.
  • 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: pyrazolidinyl, dioxolyl, oxasulfuranyl, dithiolyl (disulfuranyl) and oxazolidin-2-one.
  • 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: piperidyl, dihydropyranyl, 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 C 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 also includes the above-mentioned heterocyclyl sharing one or two atoms with a cycloalkyl, heterocyclyl, aryl or heteroaryl to form a bridged ring or spiro ring. As long as the valency allows, the shared atoms can be carbon or Nitrogen atom. Heterocyclyl also includes the above-mentioned heterocyclyl and heterocyclyl groups may be optionally substituted by one or more substituents, for example, by 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 (e.g., having 6-10 ring carbon atoms and zero heteroatoms arranged in a cyclic 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.
  • 5-10 membered heteroaryl refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having a 6 or 10 ⁇ electrons), in which each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups containing one or more nitrogen atoms 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 or heterocyclyl groups fused ring systems, 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.
  • 5-6 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.
  • 5-membered heteroaryl groups are particularly preferred.
  • 6-membered heteroaryl groups are particularly preferred.
  • 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 or pyridonyl.
  • 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 thiepeptatrienyl.
  • 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.
  • the divalent groups formed by removing another hydrogen from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups defined above are collectively referred to as "subunits".
  • Ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl are collectively referred to as "cyclic groups”.
  • 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 Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two Rcc groups are combined to form a heterocycle 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;
  • cancer includes, but is not limited to, the following cancers: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratomas; Lung: bronchial carcinoma (squamous cell carcinoma) cystic cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma) cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (duct
  • cancer includes, but is not limited to, the following cancers: malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, breast cancer, brain cancer , skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung squamous cell carcinoma, lung adenocarcinoma, Oral, ovarian, renal and thyroid cancers and sarcomas.
  • cancer includes, but is not limited to, the following cancers: hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.
  • treatment refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • noun “treat” refers to the action of the verb treat, as just defined.
  • 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.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, etc.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • Base addition salts of acidic compounds may be prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base to form the salt.
  • the free acid can be regenerated by contacting the salt form with the acid and isolating the free acid in the usual manner.
  • the free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention the salts are nevertheless equivalent to their respective free acids.
  • the salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salt, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate Acid, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Methanesulfonate, glucoheptonate, lactobionate, lauryl sulfonate and isethionate, etc.
  • Salts may also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate Lenate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylbenzoate Acid, citrate, lactate, maleate, tartrate, methanesulfonate, etc.
  • Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also covered are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1- 19, incorporated by reference).
  • 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.
  • treatment includes an action in a subject suffering from a specific disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a condition ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a specific disease, disorder or condition ("preventive treatment").
  • 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.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition The amount to delay or minimize. treatment of compounds
  • a therapeutically effective amount is that amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition.
  • the term "therapeutically effective amount” may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of a disorder or condition.
  • a prophylactically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in preventing a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the 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.
  • the "compounds of the present invention” refer to the following compounds of formula (I), formula (II), formula (III), and their pharmaceutically acceptable salts, isotopic variants, tautomers, and stereoisomers. Conforms, prodrugs, polymorphs, hydrates or solvates.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a or C(O)NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • L 1 is NH or CHR x ;
  • L 2 is a chemical bond or CR x R y ;
  • L 3 is -C(O)-, -S(O)- or -S(O) 2 -;
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • Y 1 is a chemical bond or (CR 3 R 3 ) q ;
  • Y 2 is a chemical bond, O, S, NR', S(O) or S(O) 2 ;
  • Z 1 is N or CR
  • Z 2 is N or CR
  • Z 3 is N or CR
  • R 3 and R are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • CR 3 R 3 together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene
  • R' is selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • p 0, 1, 2, 3 or 4;
  • Ar 1 and Ar 2 are phenyl or 5-6 membered heteroaryl, which is substituted by n R 1 ; the other is H or D; or Ar 1 and Ar 2 are independently H or D;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 halo
  • n 0, 1, 2, 3, 4 or 5;
  • R 1s is selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C(O)R a , C(O)OR a , C(O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 cycloalkyl, -L-3-10-membered hetero Ring group, -LC 6-10 aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl base substitution;
  • L is selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 selected from H, D, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms they are connected together form a 3-10 membered heterocyclyl group ;
  • X 1 is a C atom; in another embodiment, X 1 is an N atom; in another embodiment, X 1 is CR 2b ; in another embodiment, X 1 is NR 2b ; In one embodiment, X 2 is a C atom; in another embodiment, X 2 is an N atom; in another embodiment, X 2 is CR 2c ; in another embodiment, X 2 is NR 2c ; In one embodiment, X 3 is a C atom; in another embodiment, X 3 is an N atom; in another embodiment, X 3 is CR 2d ; in another embodiment, X 3 is NR 2d .
  • X 1 , X 2 and their substituents together form a C 5-10 cycloalkyl group; in another more specific embodiment, X 1 , X 2 and their substituents together form Forming a 5-10 membered heterocyclyl group, preferably a 5-7 membered heterocyclyl group, preferably a 5-membered heterocyclyl group; in another more specific embodiment, X 1 , X 2 and their substituents together form C 6-10 aryl; in another more specific embodiment, X 1 , X 2 and their substituents together form a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl, preferably a 5-membered Heteroaryl; in another more specific embodiment, X 1 , X 2 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl Aryl; in another more specific embodiment, X 1 ,
  • R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a is CN; in another embodiment, R 2a is OR a ; in another In one embodiment, R 2a is NR b R c ; in another embodiment, R 2a is C(O)OR a ; in another embodiment, R 2a is C(O)NR b R c .
  • R 2a is selected from H, D, CN, OR a or NR b R c ; in another more specific embodiment, R 2a is selected from OR a or NR b R c , preferably It is OMe or NH 2 , preferably OMe, preferably NH 2 .
  • R 2b is H; in another embodiment, R 2b is D; in another embodiment, R 2b is halogen; in another embodiment, R 2b is C(O)OR a ; In another embodiment, R 2b is C(O)NR b R c , such as C(O)NH 2 ; In another embodiment, R 2b is C 1-6 alkyl; In another embodiment, R 2b is a C 1-6 haloalkyl group; in another embodiment, R 2b is a C 3-10 cycloalkyl group; in another embodiment, R 2b is a 3-10 membered heterocyclyl group.
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 2b is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in In another more specific embodiment, R 2b is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably Me; in another more specific embodiment, R 2b is selected from H, D, halogen , C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2b is selected from C(O)NR b R c , C 1- 6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2b is C(O)OR a , C
  • R 2c is H; in another embodiment, R 2c is D; in another embodiment, R 2c is halogen; in another embodiment, R 2c is C 1-6 alkane group; in another embodiment, R 2c is C 1-6 haloalkyl.
  • R 2c is selected from H, D or halogen, preferably H or D, preferably H.
  • R 2d is H; in another embodiment, R 2d is D; in another embodiment, R 2d is halogen; in another embodiment, R 2d is CN; in another In an embodiment, R 2d is NO 2 ; in another embodiment, R 2d is OR a ; in another embodiment, R 2d is NR b R c ; in another embodiment, R 2d is C 1 -6 alkyl; in another embodiment, R 2d is C 1-6 haloalkyl; in another embodiment, R 2d is C 3-10 cycloalkyl, such as C 3-7 cycloalkyl, such as C 5-10 cycloalkyl ; in another embodiment, R 2d is 3-10 membered heterocyclyl, such as 3-7 membered heterocyclyl, such as 5-10 membered heterocyclyl; in another embodiment , R 2d is C 6-10 aryl; in another embodiment, R 2d is 5-10 membered heteroaryl; in another embodiment, R 2d is C 5-7 cycloalky
  • R 2d is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl; in In a more specific embodiment, R 2d is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2d is H or D, preferably H .
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; in a more specific embodiment, R 2d is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in a more specific embodiment, R 2d is selected from H, D, halogen, C 1-6 alkyl group or C 1-6 haloalkyl group.
  • L 1 is NH; in another embodiment, L 1 is CHR x ; in another embodiment, L 1 is NH and L 2 is CR x R y , L 1 -L 2 is preferred for In another embodiment, L 1 -L 2 is preferably In another embodiment, L 1 -L 2 is preferably In another embodiment, L 1 -L 2 is preferably In another embodiment, L 1 -L 2 is preferably In another embodiment, L 1 is NH and L 2 is a chemical bond; in another embodiment, L 1 is CHR x and L 2 is CR x R y , preferably In another embodiment, L 3 is -C(O)-; in another embodiment, L 3 is -S(O)-; in another embodiment, L 3 is -S(O) 2 -.
  • L 1 -L 2 -L 3 are
  • Rx and Ry are H; in another embodiment, Rx and Ry are D; in another embodiment, Rx and Ry are C 1-6 alkyl; in another embodiment, R x and R y are C 1-6 haloalkyl, preferably CF 3 ; in another embodiment, one of R x and Ry is H or D, and the other is C 1-6 alkyl. base; in another embodiment, one of R x and Ry is H or D, and the other It is C 1-6 haloalkyl, preferably CF 3 .
  • Ring A is In one embodiment, Ring A is In another embodiment, Ring A is
  • Y 1 is a chemical bond; in another embodiment, Y 1 is CR 3 R 3 ; in another embodiment, Y 1 is (CR 3 R 3 ) q , such as (CR 3 R 3 ) 2 , such as (CH 2 ) 2 ; in one embodiment, Y 2 is a chemical bond; in another embodiment, Y 2 is O; in another embodiment, Y 2 is S; in another embodiment , Y 2 is NR', preferably NH, preferably NMe; in another embodiment, Y 2 is S(O); in another embodiment, Y 2 is S(O) 2 .
  • Y 1 is a chemical bond or CR 3 R 3
  • Y 2 is selected from a chemical bond, O, S or NH
  • Y 1 is a chemical bond or CR 3 R 3
  • Y 2 is a chemical bond or O
  • Y 1 is CR 3 R 3
  • Y 2 is selected from O, S or NH
  • Y 1 is CR 3 R 3
  • Y 2 is O.
  • Y 1 is (CR 3 R 3 ) q , preferably -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, Preferably -CH 2 -, -CH(CH 3 )- or More preferably -CH 2 - or -CH(CH 3 )-; in a more specific embodiment, Y 1 is
  • Y 2 is selected from O, S, NR', S(O) or S(O) 2 ; in another more specific embodiment, Y 2 is selected from O, S, NR ' or S(O) 2 ; in another more specific embodiment, Y 2 is selected from O, NR' or S(O) 2 , preferably O.
  • Selected from In another embodiment, Selected from Preferably In another embodiment, for Preferably
  • Z 1 is a N atom; in another embodiment, Z 1 is CR; in one embodiment, Z 2 is an N atom; in another embodiment, Z 2 is CR; in another In one embodiment, Z 3 is a N atom; in another embodiment, Z 3 is CR.
  • Z 1 , Z 2 and Z 3 are all CR.
  • R is H; in another embodiment, R is D; in another embodiment, R is halogen; in another embodiment, R is C 1-6 alkyl; in another 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; in another embodiment In another embodiment, R is C 3-10 cycloalkyl; in another embodiment, R is 3-10 membered heterocyclyl; in another embodiment, R is C 6-10 aryl; in another embodiment In the mode, R is a 5-10 membered heteroaryl group.
  • R is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; In a more specific embodiment, R is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, preferably H or D.
  • R 3 is H; in another embodiment, R 3 is D; in another embodiment, R 3 is halogen; in another embodiment, R 3 is C 1-6 alkane group; in another embodiment, R 3 is C 1-6 haloalkyl; in another embodiment, R 3 is C 2-6 alkenyl; in another embodiment, R 3 is C 2-6 Alkynyl; in another embodiment, R 3 is C 3-10 cycloalkyl, such as C 3-6 cycloalkyl; in another embodiment, R 3 is 3-10 membered heterocyclyl, such as 3 -6-membered heterocyclyl; in another embodiment, R 3 is C 6-10 aryl, such as phenyl; in another embodiment, R 3 is 5-10 membered heteroaryl, such as 5-6 Metaheteroaryl; in another embodiment, at least one of the two R 3 in the gem position is H or D, preferably at least one is H.
  • R 3 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl ; In another more specific embodiment, R 3 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; In another more specific embodiment, R 3 is independently selected is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3 is independent is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, preferably selected from H, Me, Et, CF 3 or cyclopropyl; in another more specific In the embodiment, R 3 is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably H,
  • CR 3 R 3 together form a C 3-10 cycloalkylene; in another embodiment, CR 3 R 3 together form a 3-10 membered heterocyclylene; in another embodiment, CR 3 R 3 together form a C 3-6 cycloalkylene; in another embodiment, CR 3 R 3 - Together, they form a 3-6 membered heterocyclylene group; in another embodiment, CR 3 R 3 together form a cyclopropylene group; in another embodiment, with CR 3 R 3 adjacent to the N atom in does not form a ring; in another embodiment, CR 3 R 3 does not form a ring.
  • CR 3 R 3 together form a C 3-6 cycloalkylene or 3-6 membered heterocyclylene; in another more specific embodiment, CR 3 R 3 together form Preferably form Preferably form
  • R 3a is H; in another embodiment, R 3a is D; in another embodiment, R 3a is halogen; in another embodiment, R 3a is C 1-6 alkane group; in another embodiment, R 3a is C 1-6 haloalkyl; in another embodiment, R 3a is C 3-6 cycloalkyl; in another embodiment, R 3a is 3-6 Heterocyclic group.
  • R 3b is H; in another embodiment, R 3b is D; in another embodiment, R 3b is halogen; in another embodiment, R 3b is C 1-6 alkane group; in another embodiment, R 3b is C 1-6 haloalkyl; in another embodiment, R 3b is C 3-6 cycloalkyl; in another embodiment, R 3b is 3-6 Heterocyclic group.
  • R 3c is H; in another embodiment, R 3c is D; in another embodiment, R 3c is halogen; in another embodiment, R 3c is C 1-6 alkane group; in another embodiment, R 3c is C 1-6 haloalkyl; in another embodiment, R 3c is C 3-6 cycloalkyl; in another embodiment, R 3c is 3-6 Heterocyclic group.
  • R 3d is H; in another embodiment, R 3d is D; in another embodiment, R 3d is halogen; in another embodiment, R 3d is C 1-6 alkane group; in another embodiment, R 3d is C 1-6 haloalkyl; in another embodiment, R 3d is C 3-6 cycloalkyl; in another embodiment, R 3d is 3-6 Heterocyclic group.
  • CR 3a R 3b together form a C 3-6 cycloalkylene; in another embodiment, CR 3a R 3b together form a 3-6 membered heterocyclylene; in another embodiment, CR 3a R 3b does not form a ring.
  • CR 3c R 3d together form a C 3-6 cycloalkylene; in another embodiment CR 3c R 3d together form a 3-6 membered heterocyclylene; in another embodiment, CR 3c R 3d does not form a ring.
  • R 3a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3a is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; in another In a more specific embodiment, R 3a is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; in another more specific embodiment, R 3a is selected from From H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably H, Me, Et, CF 3 or cyclopropyl, preferably H, Me or Et; in another more specific embodiment In, R 3a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cyclo
  • R 3b is H or D; in another more specific embodiment, R 3b is H.
  • R 3c is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3c is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; in another In a more specific embodiment, R 3c is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; in another more specific embodiment, R 3c is selected from From H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably H or Me; in another more specific embodiment, R 3c is H or D.
  • R 3d is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; in another more specific embodiment, R 3d is H or D, preferably H.
  • At least one of R 3a and R 3c is H or D; in another more specific embodiment, at least one of R 3a and R 3c is H.
  • R 3a is other than H and D
  • R 3c is H or D.
  • CR 3a R 3b together form a C 3-6 cycloalkylene or a 3-6 membered heterocyclylene, preferably a C 3-6 cycloalkylene, preferably a cyclopropylene
  • CR 3c R 3d together form a C 3-6 cycloalkylene or a 3-6 membered heterocyclylene, preferably a C 3-6 cycloalkylene, preferably a cyclopropylene and cyclopentylene
  • cyclopropylene is formed
  • cyclopentylene is formed
  • R' is H; in another embodiment, R' is D; in another embodiment, R' is C 1-6 alkyl; in another 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; in another embodiment, R' is C 3-10 cycloalkyl; in another embodiment, R' is 3-10 membered heterocyclyl; in another embodiment, R' is C 6-10 aryl; in another embodiment , R' is a 5-10 membered heteroaryl group.
  • R' is selected from H, D, C(O) Ra , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered Heterocyclyl; in a more specific embodiment, R' is selected from H, D, C(O) Ra , C 1-6 alkyl, C 1-6 haloalkyl, preferably H; in a more specific In an embodiment, R' is selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl; in a more specific embodiment, R' is selected from H, C 1-3 alkyl or C 1-3 haloalkyl; in a more specific embodiment, R' is C 1-3 alkyl, preferably Me.
  • Ar 1 is phenyl, and Ar 2 is H or D; in another embodiment, Ar 2 is phenyl, and Ar 1 is H or D; in another embodiment, Ar 1 is 5 -6-membered heteroaryl, Ar 2 is H or D; in another embodiment, Ar 2 is 5-6 membered heteroaryl Aryl, Ar 1 is H or D; in another embodiment, one of rings Ar 1 and Ar 2 is phenyl, pyridyl or pyridazinyl, and the other is H or D.
  • Ar 1 or Ar 2 is replaced by n R 1 s .
  • Ar 1 and Ar 2 are independently H or D.
  • Ar 1 is pyridyl, and Ar 2 is H or D; in another more specific embodiment, Ar 2 is pyridyl, and Ar 1 is H or D; in a more specific embodiment In an embodiment, Ar 1 is pyridazinyl, and Ar 2 is H or D; in another more specific embodiment, Ar 2 is pyridazinyl, and Ar 1 is H or D.
  • Ar 1 is phenyl or 5-6 membered heteroaryl; in another more specific embodiment, Ar 1 is phenyl or 6-membered azaaryl; in another more specific embodiment, Ar 1 is phenyl or 6-membered heteroaryl; In a specific embodiment, Ar 1 is phenyl, pyridyl, pyrimidinyl or pyridazinyl, preferably phenyl, pyridyl or pyridazinyl, preferably phenyl or pyridinyl.
  • the two adjacent ring atoms on Ar 1 or Ar 2 and their substituents together form a C 5-7 cycloalkyl group; in another embodiment, the adjacent two ring atoms on Ar 1 or Ar 2 Two ring atoms and their substituents together form a 5-7 membered heterocyclyl; in another embodiment, two adjacent ring atoms on Ar 1 or Ar 2 and their substituents together form a phenyl group; in another In one embodiment, the two adjacent ring atoms on Ar 1 or Ar 2 and their substituents together form a 5-6 membered heteroaryl group; in another embodiment, the two adjacent rings on Ar 1 or Ar 2 The ring formed by atoms and their substituents is optionally substituted by 1, 2 or 3 R 1s ; in another embodiment, the ring formed by two adjacent ring atoms and their substituents on Ar 1 or Ar 2 is not Substituted; in another embodiment, the two adjacent ring atoms on Ar 1 or Ar 2 and their substituents do not form
  • the two adjacent ring atoms on Ar 1 and their substituents together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl group, preferably forming a 5-7-membered heterocyclyl group or a 5-6-membered heteroaryl group, preferably forming a 5-membered heterocyclyl group or a 5-membered heteroaryl group; in another more specific embodiment, the adjacent ones on Ar 1 The two ring atoms and their substituents together form a 5-7 membered heterocyclyl group, preferably a 5-membered heterocyclyl group, for example In another more specific embodiment, two adjacent ring atoms on Ar 1 and their substituents together form a 5-6 membered heteroaryl group, preferably a 5-membered heteroaryl group, for example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example
  • Ar 1 is
  • Ar 1 is Z 4 , Z 5 , Z 7 and Z 8 are independently CR 1b or N.
  • Ar 2 is
  • Z 4 is CR 1b , such as CH; In a more specific embodiment, Z 4 is N; In a more specific embodiment, Z 5 is CR 1b , such as CH; In a more specific embodiment, Z5 is N.
  • Z 6 is CR 1a ; in a more specific embodiment, Z 6 is N; in a more specific embodiment, Z 7 is CR 1b , such as CH; in a more specific embodiment, Z 6 is CR 1b, such as CH; In a specific embodiment, Z 7 is N; in a more specific embodiment, Z 8 is CR 1b , such as CH; in a more specific embodiment, Z 8 is N.
  • At most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.
  • Z 6 , Z 5 and their substituents together form a C 5-7 cycloalkyl group; in a more specific embodiment, Z 6 , Z 5 and their substituents together form 5-7 membered heterocyclyl, preferably 5-membered heterocyclyl, for example In a more specific embodiment, Z 6 , Z 5 and their substituents together form a phenyl group; in a more specific embodiment, Z 6 , Z 5 and their substituents together form a 5-6 membered heterogeneous Aryl, preferably 5-membered heteroaryl, for example For example For example For example For example For example For example, In a more specific embodiment, when Z 6 , Z 5 and their substituents together form a heteroaryl group, Z 5 is CR 1b ; in a more specific embodiment, Z 6 , Z 5 and their substituents The ring formed by the substituents is optionally substituted by 1, 2 or 3 R 1s ; in a more specific embodiment, the ring formed by Z 6 , Z 5
  • Z 6 , Z 5 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in a In a more specific embodiment, Z 6 , Z 5 and their substituents together form a 5-7-membered heterocyclyl group or a 5-6-membered heteroaryl group, preferably a 5-membered heterocyclyl group or a 5-membered heteroaryl group; in In a more specific embodiment, Z 6 , Z 5 and their substituents together form: Preferably form Preferably form Preferably form Preferably form Preferably form Preferably form
  • Z 4 and Z 5 are not N at the same time.
  • Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is
  • Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is
  • Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In a more specific embodiment, Ar 1 is In
  • Ar 1 is selected from: In a more specific embodiment, Ar 1 is selected from:
  • Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In a more specific embodiment, Ar 2 is In
  • R 1 is H; in another embodiment, R 1 is D; in another embodiment, R 1 is halogen, such as F, such as Cl, such as Br; in another embodiment, R 1 is halogen, such as F, such as Cl, such as Br; in another embodiment, , R 1 is CN; in another embodiment, R 1 is NO 2 ; in another embodiment, R 1 is -L-OR a , such as -OR a ; in another embodiment, R 1 is -L-SR a , such as SR a ; in another embodiment, R 1 is -L-NR b R c , such as NR b R c ; in another embodiment, R 1 is SF 5 ; in another In one embodiment, R 1 is C(O)R a ; in another embodiment, R 1 is C(O)OR a ; in another embodiment, R 1 is C(O)NR b R c ; In another embodiment, R 1 is OC(O) Ra ; in another embodiment, R 1 is NR
  • R 1 is independently selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl , C 5-7 cycloalkyl or 5-7 membered heterocyclyl; in another more specific embodiment, R 1 is independently selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 1 is independently selected from H, D, halogen, SF 5 , OR a , C 1-6 alkyl Or C 1-6 haloalkyl.
  • R 1 is independently selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C (O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(R a ) 2 , P(O ) 2 R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered hetero
  • R 1 is independently selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C(O)R a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O ) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; in another update
  • R 1 is independently selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C(O)R a , S(O)R
  • R 1 is independently selected from H, D, halogen, CN , OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1 is independently selected from H, Cl, Br, CN, CF 3 , CF 2 CF 3 , SF 5 , OCH 3 , OCF 3 , OCHF 2 , OCH 2 CH 3 , OCH 2 CH 2 CF 3 , cyclopropyl, Preferably selected from H, Br, Cl, CN, CF 3 , OCF 3 , cyclopropyl, CF 3 is preferred.
  • R1 is independently selected from H, D, halogen, CN, ORa , SRa , NRbRc , SF5 , C( O )Ra, C (O) ORa ,C(O)NR b R c ,S(O)R a ,S(O) 2 R a ,S(O)OR a ,S(O) 2 OR a ,S(O)NR b R c ,S (O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C
  • R 1 is F; in another more specific embodiment, R 1 is CF 3 ; in another more specific embodiment, R 1 is CF 2 CF 3 ; in another more specific embodiment, R 1 is CF 2 CF 3 ; in another more specific embodiment, R 1 is CF 3
  • R 1 is SF 5 ; in another more specific embodiment, R 1 is OCH 3 ; in another more specific embodiment, R 1 is OCF 3 ; in another more specific embodiment, R 1 is OCF 3 ; in another more specific embodiment, R 1 is OCF 3
  • R 1 is OCF 3
  • R 1 is OCHF 2 ; in another more specific embodiment, R 1 is OCH 2 CH 3 ; in another more specific embodiment, R 1 is OCH 2 CH 2 CF 3 .
  • two adjacent R 1 and the atoms to which they are connected together form a C 3-6 cycloalkyl group; in another embodiment, two adjacent R 1 and the atoms to which they are connected together form 3 -7-membered heterocyclyl; in another embodiment, two adjacent R 1s and the atoms to which they are connected together form a C 6-10 aryl group; in another embodiment, two adjacent R 1s and The atoms they are connected together form a 5-10 membered heteroaryl group; in another embodiment, two adjacent R 1 and the atoms they are connected together form a C 5-6 cycloalkyl group; in another embodiment, Two adjacent R 1 and the atoms to which they are connected together form a 5-6 membered heterocyclic group; in another embodiment, two adjacent R 1 and the atoms to which they are connected together form a thiazolyl group.
  • R 1a is H; in another embodiment, R 1a is D; in another embodiment, R 1a is halogen, such as F, such as Cl, such as Br; in another embodiment, R 1a is halogen, such as F, such as Cl, such as Br; in another embodiment, , R 1a is CN; in another embodiment, R 1a is NO 2 ; in another embodiment, R 1a is -L-OR a , such as OR a , such as OCH 3 , such as OCH 2 CH 3 , such as OCF 3 , such as OCHF 2 , such as OCH 2 CH 2 CF 3 ; in another embodiment, R 1a is -L-SR a , such as SR a ; in another embodiment, R 1a is -L-NR b R c , such as NR b R c ; in another embodiment, R 1a is SF 5 ; in another embodiment, R 1a is C(O)R a ; in another embodiment, R 1a is C
  • R 1a is S(O)OR a ; in another embodiment, R 1a is S(O) 2 OR a ; in another embodiment, R 1a is S(O)NR b R c ; in another embodiment, R 1a is S(O) 2 NR b R c ; in another embodiment, R 1a is P(O)(OR a ) 2 ; in another embodiment, R 1a is P(OR a ) 2 ; in another embodiment, R 1a is P(O)(R a ) 2 , for example In another embodiment, R 1a is C 1-6 alkyl, such as in another In one embodiment, R 1a is C 1-6 haloalkyl, such as CF 3 , such as CF 2 CF 3 , such as In another embodiment, R 1a is C 2-6 alkenyl; in another embodiment, R 1a is C 2-6 alkynyl, for example In another embodiment, R 1a is C 3-7 cycloalkyl, such as C 3-6 cycloalky
  • R 1a is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl; in another more specific embodiment, R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C 1 -6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 1a is selected from H, D, SF 5 , OR a , C 1-6 alkyl or C 1-6 haloalkyl.
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C(O)R a , S(O)R a , S(O) 2 R a , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 Metaheteroaryl; in another more specific embodiment, R 1a is selected from H, D, halogen, CN, SF 5 , OR a , S(O) 2 R a , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1a is selected from H, D, halogen, CN,
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C(O)R a , S(O)R a , S(O) 2 R a , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; in another more specific embodiment, R 1a is selected from H, D, halogen, CN, SF 5 , OR a , S(O ) 2 R a , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl,
  • R 1a is selected from H, Cl, Br, CN, SF 5 , CF 3 , CF 2 CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 , OCHF 2 , OCH 2 CH 2 CF 3 , cyclopropyl, In another more specific embodiment, R 1a is not In another more specific embodiment, R 1a is selected from H, Br, Cl, CN, SF 5 , CF 3 , CF 2 CF 3 , OCF 3 , OCHF 2 , cyclopropyl, In another more specific embodiment, R 1a is selected from SF 5 , Cl, CN, CF 3 , OCF 3 , cyclopropyl,
  • R 1a is CF 3 ; in another more specific embodiment, R 1a is CF 2 CF 3 ; in another more specific embodiment, R 1a is SF 5 ; in In another more specific embodiment, R 1a is OCH 3 ; in another more specific embodiment, R 1a is OCF 3 ; in another more specific embodiment, R 1a is OCHF 2 ; in another more specific embodiment, R 1a is OCF 3 In a more specific embodiment, R 1a is OCH 2 CH 3 ; in another more specific embodiment, R 1a is OCH 2 CH 2 CF 3 .
  • R 1b is H; in another embodiment, R 1b is D; in another embodiment, R 1b is halogen, such as F, such as Cl; in another embodiment, R 1b is CN; in another embodiment, R 1b is OR a ; in another embodiment, R 1b is SR a ; in another embodiment, R 1b is NR b R c ; in another embodiment , R 1b is SF 5 ; in another embodiment, R 1b is C 1-6 alkyl; in another embodiment, R 1b is C 1-6 haloalkyl, such as CF 3 ; in another embodiment , R 1b is as defined as R 1a .
  • R 1b is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in a more specific embodiment, R 1b is independently selected from H, D and halogen, preferably H, F or Cl, preferably H or F; in a more specific embodiment, R 1b is independently selected from H, D, C 1-6 alkyl and C 1-6 Haloalkyl, more preferably H or D; in a more specific embodiment, R 1b is independently selected from H, F, Cl or CF 3 , preferably H or CF 3 , preferably H.
  • R 1b is independently selected from H, D, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkene group, C 2-6 alkynyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl; in a more specific embodiment, R 1b is independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl.
  • R 1s is H; in another embodiment, R 1s is D; in another embodiment, R 1s is halogen, such as F; in another embodiment, R 1s is CN; In another embodiment, R 1s is -L-OR a ; in another embodiment, R 1s is -L-SR a ; in another embodiment, R 1s is -L-NR b R c ; In another embodiment, R 1s is C(O) Ra ; in another embodiment, R 1s is C(O)OR a ; in another embodiment, R 1s is C(O)NR b R c ; in another embodiment, R 1s is C 1-6 alkyl, such as Me; in another embodiment, R 1s is C 1-6 haloalkyl, such as CF 3 ; in another embodiment , R 1s is C 2-6 alkenyl; in another embodiment, R 1s is C 2-6 alkynyl; in another embodiment, R 1s is -LC 3-10 cycloalkyl, such as C 3
  • R 1s is selected from H, D, halogen, -L-OR a , -L-NR b R c , C(O)R a , C(O)OR a , C(O )NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in a more specific embodiment, R 1s is selected from H , D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl; in a more specific embodiment, R 1s is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 5-6
  • R 1s is independently selected from H, D, halogen, CN, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1s is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1s Independently selected from H, D, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl; in another more specific embodiment, R 1s is independently selected from H, D, CN, C 1 -6 alkyl and C 1-6 haloalkyl, preferably selected from H, D,
  • R 1s is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl and C 3-7 cycloalkyl; in another more specific embodiment, R 1s is independently selected from H, D, F, CN, Me, CF 3 and cyclopropyl.
  • L is a chemical bond; in another embodiment, L is C 1-6 alkylene; in another embodiment, L is C 2-6 alkenylene; in another embodiment , L is C 2-6 alkynylene; in another embodiment, L is optionally replaced by 1, 2 or 3 H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2 -6 alkenyl or C 2-6 alkynyl group substitution.
  • Ra , Rb , and Rc are independently H; in another embodiment, Ra , Rb, and Rc are independently D; in another embodiment, Ra , R b and R c are independently C 1-6 alkyl; in another embodiment, R a , R b and R c are independently C 1-6 haloalkyl; in another embodiment, R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group, preferably 5-7 Membered heterocyclyl; in another embodiment, R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclyl, preferably a 3-7 membered heterocyclyl.
  • any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments.
  • any technical solution of ring A or any combination thereof can be combined with X 1 , x , R y , Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , R 3 , R, R ' , Ar 1 , Ar 2 , R 1 , R 1a , R 1b , R 1s , L, n, Any technical solutions of m, p, R a , R b and R c 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 (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a or C(O)NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • L 1 is NH or CHR x ;
  • L 2 is a chemical bond or CR x R y ;
  • L 3 is -C(O)-, -S(O)- or -S(O) 2 -;
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • Y 1 is a chemical bond or (CR 3 R 3 ) q ;
  • Y 2 is a chemical bond, O, S, NR', S(O) or S(O) 2 ;
  • Z 1 is N or CR
  • Z 2 is N or CR
  • Z 3 is N or CR
  • R 3 and R are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • CR 3 R 3 together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene
  • R' is selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • p 0, 1, 2, 3 or 4;
  • Ar 1 and Ar 2 are phenyl or 5-6 membered heteroaryl, which is substituted by n R 1 ; the other is H or D; or Ar 1 and Ar 2 are independently H or D;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 halo
  • n 0, 1, 2, 3, 4 or 5;
  • R 1s is selected from H, D, halogen, CN, -L-OR a , -L-SR a , -L-NR b R c , C(O)R a , C(O)OR a , C(O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 cycloalkyl, -L-3-10-membered hetero Ring group, -LC 6-10 aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl base substitution;
  • L is selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 selected from H, D, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms they are connected together form a 3-10 membered heterocyclyl group ;
  • the invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a or C(O)NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • L 1 is NH or CHR x ;
  • L 2 is a chemical bond or CR x R y ;
  • L 3 is -C(O)-, -S(O)- or -S(O) 2 -;
  • L 1 is CHR x and L 2 is CR x R y , the two R x groups can be combined to form a chemical bond or a C 1-4 alkylene group;
  • Y 1 is a chemical bond or CR 3 R 3 ;
  • Y 2 is a chemical bond, O, S, NR', S(O) or S(O) 2 ;
  • Z 1 is N or CR
  • Z 2 is N or CR
  • Z 3 is N or CR
  • R 3 and R are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • CR 3 R 3 together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene
  • R' is selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • p 0, 1, 2, 3 or 4;
  • Ar 1 and Ar 2 is phenyl or 5-6 membered heteroaryl, which is substituted by n R 1 ; the other is H or D;
  • R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O) 2 R a , S(O)OR a , S (O) 2 OR a , S(O)NR b R c , S(O) 2 NR b R c , P(O)(R a ) 2 , P(O) 2 R a , C 1-6 alkyl , C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10
  • n 0, 1, 2, 3, 4 or 5;
  • R 1s is selected from H, D, halogen, -L-OR a , -L-SR a , -L-NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-10 cycloalkyl, -L- 3-10 membered heterocyclyl , -LC 6-10 aryl or -L-5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;
  • L is selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 selected from H, D, halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group substitution;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-10 membered heterocyclyl group ;
  • 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 R 2a is selected from H, D, CN, OR a or NR b R c ; preferably OR a or NR b R c ; preferably NH 2 .
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably C 1-6 alkyl or C 1- 6 Haloalkyl; preferably Me.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein R 2c is selected from H, D or halogen; preferably H or D.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 2d is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl; preferably Selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably H or D.
  • 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 , X 2 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, any of which optionally substituted by 1, 2 or 3 R 2s ; preferably forming
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein L 1 is NH; L 2 is a chemical bond or CR x R y ; L 3 is -C(O)- or -S(O) 2 -;
  • L 1 -L 2 are selected from L 3 is -C(O)-; or L 1 -L 2 -L 3 is
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein Y 1 is a chemical bond or CR 3 R 3 ; Y 2 is selected from chemical bonds, O, S, NR';
  • Y 1 is a chemical bond or CR 3 R 3 ;
  • Y 2 is selected from a chemical bond, O, S or NH, preferably a chemical bond or O;
  • Y 1 is CR 3 R 3 ;
  • Y 2 is selected from O, S or NH, preferably O;
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein, for Preferably
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein Z 1 , Z 2 and Z 3 are all CR.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; It is preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl; more preferably H or D.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 3 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl , or CR 3 R 3 together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene; preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, or CR 3 R 3 together form C 3-6 cycloalkylene; preferably selected from H or Me, or CR 3 R 3 together form cyclopropylene.
  • R 3 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R' is selected from H, D, C(O) Ra , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 yuan Heterocyclyl; preferably selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, more preferably H or D.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein one of Ar 1 and Ar 2 is phenyl, pyridyl or pyridazinyl, which is substituted by n R 1 ; the other is H or D;
  • Ar 1 is phenyl, pyridyl or pyridazinyl, which is substituted by n R 1 ;
  • Ar 2 is H or D; or
  • Ar 2 is phenyl, which is substituted by n R 1 ;
  • Ar 1 is H or D;
  • one of Ar 1 and Ar 2 is selected from The other is H or D; more preferably one of Ar 1 and Ar 2 is selected from The other is H or D.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 1 is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5- 10-membered heteroaryl, optionally substituted by 1, 2 or 3 R 1s ;
  • F Preferably selected from F, CF 3 , CF 2 CF 3 , SF 5 , OCH 3 , OCF 3 , OCHF 2 , OCH 2 CH 3 or OCH 2 CH 2 CF 3 , preferably F or CF 3 ;
  • R 1 and the atoms they are connected together form a C 5-6 cycloalkyl group, a 5-6 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group or a 5-6 membered heteroaryl group.
  • a heteroaryl group, more preferably forming a thiazolyl group, is optionally substituted by 1, 2 or 3 R 1s .
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 1a is selected from H, D, halogen, CN, NO 2 , -L-OR a , -L-SR a , -L-NR b R c , SF 5 , C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5- 10-membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s ; preferably selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkane base, C 1-6 halo
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 1b is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D or halogen; preferably H or F.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 1s is selected from H, D, halogen, -L-OR a , -L-NR b R c , C(O)R a , C(O)OR a , C(O )NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally replaced by 1, 2 or 3 H, D, Halogen, C 1-6 alkyl or C 1-6 haloalkyl substitution; preferably selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C( O) NR b R c , C
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein L is a chemical bond or C 1-6 alkylene group, which is optionally replaced by 1, 2 or 3 selected from H, D, halogen, C 1-6 alkyl or C 1-6 Substitution of haloalkyl groups; preferably chemical bonds.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, which has the following structural formula:
  • R 3a , R 3b , R 3c and R 3d are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or CR 3a R 3b together form C 3-6 cycloalkylene or 3- 6-membered heterocyclylene; or CR 3c R 3d together form C 3-6 cycloalkylene or 3-6-membered heterocyclylene;
  • R 3a , R 3b , R 3c and R 3d are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 yuan Heterocyclyl; or CR 3a R 3b together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • R 3a , R 3b , R 3c and R 3d are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, or CR 3a R 3b together form C 3-6 subgroups.
  • R 3a , R 3b , R 3c and R 3d are independently H or Me, or CR 3a R 3b together form a cyclopropylene group;
  • the present invention provides the above-mentioned compound of formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, the same Isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, wherein,
  • L 1 is NH
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a or NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3- 6-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5 -7-membered heterocyclyl;
  • Y 1 is selected from chemical bond or CR 3 R 3 ;
  • Y 2 is selected from chemical bond, O, S, NR', S(O) or S(O) 2 ;
  • R 3 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, or CR 3 R 3 together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • R' is selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • Ar 1 and Ar 2 are independently phenyl or 5-6 membered heteroaryl, preferably phenyl, pyridyl or pyridazinyl, which is substituted by n R 1 ;
  • R 1 is independently selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • R 1s is independently selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 5-6 Cycloalkyl or 5-6 membered heterocyclyl;
  • p 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group ;
  • the present invention provides compounds of the above formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein,
  • L 1 is NH
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is OR a or NR b R c ;
  • R 2b , R 2c and R 2d are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y 1 is selected from chemical bond or CR 3 R 3 ;
  • Y 2 is selected from chemical bonds, O, S or NR', preferably selected from chemical bonds, O, S or NH;
  • R 3 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, or CR 3 R 3 together form C 3-6 cycloalkylene;
  • R' is selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl;
  • Ar 1 and Ar 2 are independently
  • Z 4 is CR 1b or N
  • Z 5 is CR 1b or N
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • p 0, 1, 2, 3 or 4;
  • R a , R b and R c are independently selected from H, D, 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,
  • Y 1 is CR 3 R 3 ;
  • Y 2 is selected from O, S or NH, preferably O.
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2b is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 2c is selected from H, D or halogen; preferably H or D;
  • R 2d is H or D
  • R 2s is independently selected from H, D or Me
  • R 3 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, or CR 3 R 3 together form C 3-6 cycloalkylene;
  • Z 4 is CR 1b or N
  • Z 5 is CR 1b or N
  • R 1a is selected from H, D, SF 5 , OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is independently selected from H, D or halogen
  • R a is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CH
  • R 2a is NH 2 ;
  • R 2b is Me
  • R 2c is H
  • R 3 is independently selected from H or Me, or CR 3 R 3 together form cyclopropylene;
  • Ar 1 is Preferably selected from More preferably selected from
  • Z 4 is CR 1b or N
  • Z 5 is CR 1b or N
  • R 1a is selected from CF 3 , CF 2 CF 3 , SF 5 , OCH 3 , OCF 3 , OCHF 2 , OCH 2 CH 3 or OCH 2 CH 2 CF 3 , preferably CF 3 ;
  • R 1b is selected from H or F
  • the present invention provides compounds of the above formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein,
  • L 1 is NH
  • L 2 is CR x R y ;
  • R x and R y are independently H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 -L 2 is Preferably
  • the present invention provides compounds of the above formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein,
  • X 1 is CR 2b ;
  • X 2 is CR 2c ;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2b is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 2c is selected from H, D or halogen; preferably H or D;
  • R 2d is selected from H or D
  • Y 1 is selected from chemical bond or CR 3 R 3 ;
  • Y 2 is selected from chemical bond, O, S or NH, preferably chemical bond or O;
  • R 3 is independently selected from H, D or Me, or CR 3 R 3 together form a cyclopropylene group; preferably H or D;
  • Ar 1 and Ar 2 are independently
  • Z 4 is CR 1b ;
  • Z 5 is CR 1b ;
  • R 1a is selected from H, D, SF 5 , OR a , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is independently selected from H, D or halogen; preferably H or D;
  • R a is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides compounds of the above formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein,
  • X 1 is CR 2b ;
  • X 2 is CH
  • X 3 is CH
  • R 2a is NH 2 ;
  • R 2b is C 1-6 alkyl or C 1-6 haloalkyl, preferably Me;
  • Y 1 is selected from chemical bond or CR 3 R 3 , preferably CR 3 R 3 ;
  • Y 2 is a chemical bond or O
  • R 3 is H
  • Ar 1 and Ar 2 are independently
  • R 1a is C 1-6 alkyl or C 1-6 haloalkyl, preferably CF 3 ;
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 5-10 membered hetero Ring group, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5 -7-membered heterocyclyl;
  • R 3a , R 3b , R 3c and R 3d are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • CR 3a R 3b together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Ar 1 is phenyl or 5-6 membered heteroaryl, preferably phenyl, pyridyl or pyridazinyl, which is substituted by n R 1 ;
  • R 1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 5-7 cycloalkyl or 5- 7-membered heterocyclyl, optionally substituted by 1, 2 or 3 R 1s ;
  • R 1s is selected from H, D, halogen, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 5-7 cycloalkyl or 5-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 5-6 cycloalkyl base or 5-6 membered heterocyclic group;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group ;
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 1 , X 2 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which optionally substituted by 1, 2 or 3 R 2s ;
  • R 2s is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • X 3 is CR 2d ;
  • R 2a is OR a or NR b R c ;
  • R 2d is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3a , R 3b , R 3c and R 3d are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • CR 3a R 3b together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Z 4 is CR 1b or N
  • Z 5 is CR 1b or N
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1 or 2;
  • R a , R b and R c are independently selected from H, D, 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • R 2s is selected from H, D or Me
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is H or D
  • R 3a , R 3b and R 3c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3d is selected from H or D
  • Z 4 is CR 1b or N
  • Z 5 is CR 1b or N
  • R 1a is selected from H, D, SF 5 , OR a , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is selected from H, D or halogen
  • R a is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CH
  • R 2a is NH 2 ;
  • R 3a is H or Me
  • R 3b is H or Me
  • R 3c is H or Me
  • R 3d is H
  • Ar 1 is Preferably selected from More preferably selected from
  • Z 4 is CR 1b or N
  • Z 5 is CR 1b or N
  • R 1a is selected from CF 3 , CF 2 CF 3 , SF 5 , OCH 3 , OCF 3 , OCHF 2 , OCH 2 CH 3 or OCH 2 CH 2 CF 3 , preferably CF 3 ;
  • R 1b is H or F
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
  • L 1 -L 2 is
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a or NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3- 6-membered heterocyclyl;
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Ring group, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3 -7-membered heterocyclyl;
  • Y 1 is selected from (CR 3 R 3 ) q ;
  • Y 2 is selected from O, S, NR', S(O) or S(O) 2 ;
  • R' is selected from H, D, C(O)R a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3 is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, and the two R 3 in the gem position At least one of them is H or D; or CR 3 R 3 together form a C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Ar 1 is phenyl or 5-6 membered heteroaryl, preferably phenyl or 6-membered azaaryl, preferably phenyl, pyridyl, pyrimidinyl or pyridazinyl, which is substituted by n R 1 , or Ar 1 is H or D;
  • R 1 is independently selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C(O)R a , C(O) OR a , C(O)NR b R c ,S(O)R a ,S(O) 2 R a ,S(O)OR a ,S(O) 2 OR a ,S(O)NR b R c ,S(O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3 -10-membered heterocyclyl,
  • R 1s is independently selected from H, D, halogen, CN, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkane base, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably selected from H, D, halogen , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
  • p 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 3-7 membered heterocyclyl group ;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is OR a or NR b R c ;
  • R 2b is selected from H, D, halogen, C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2c and R 2d are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • Y 1 is selected from (CR 3 R 3 ) q ;
  • Y 2 is selected from O, S, NR' or S(O) 2 ;
  • R' is selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl
  • R 3 is independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, and at least one of the two R 3 in the gem position One of them is H or D; or CR 3 R 3 together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Ar 1 is Or Ar 1 is H or D;
  • Z 4 , Z 5 , Z 7 and Z 8 are independently CR 1b or N;
  • Z 6 is CR 1a or N
  • Z 6 , Z 5 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 1s replaced;
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C(O)R a , S(O)R a , S(O) 2 R a , P(O)( R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 1s ;
  • R 1s is independently selected from H, D, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 1b is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • At most 3 are N, preferably at most 2 are N, preferably at most 1 is N.
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d ;
  • R 2a is OMe or NH 2 , preferably OMe, preferably NH 2 ;
  • R 2b is selected from C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl, preferably C(O)NR b R c or C 1-3 alkyl, preferably C(O )NH 2 or Me, preferably C(O)NH 2 ;
  • R 2c is selected from H, D or halogen; preferably H or D;
  • R 2d is H or D
  • One-membered heteroaryl more preferably forming a 5-membered heterocyclyl or 5-membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s ;
  • R 2s is independently selected from H, D and C 1-3 alkyl, preferably selected from H, D and Me;
  • Y 1 is (CR 3 R 3 ) q , preferably -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, Preferably -CH 2 -, -CH(CH 3 )- or More preferably -CH 2 - or -CH(CH 3 )-;
  • Y 2 is selected from O, NR' or S(O) 2 , preferably O;
  • q 1 or 2, preferably 1;
  • R' is H, C 1-3 alkyl or C 1-3 haloalkyl, preferably C 1-3 alkyl, preferably Me;
  • R 3 is independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, preferably H, D, C 1-6 alkyl or C 1-6 haloalkyl , and at least one of the two R 3 in the gem position is H or D; preferably, R 3 is independently selected from H, Me, Et, CF 3 or cyclopropyl, preferably H, Me or Et;
  • CR 3 R 3 together form C 3-6 cycloalkylene, preferably forming Preferably form Preferably CR 3 R 3 does not form a ring;
  • Ar 1 is Or Ar 1 is H; preferably Ar 1 is
  • Z 4 , Z 5 and Z 7 are independently CR 1b or N, preferably Z 7 is CR 1b ;
  • Z 6 is CR 1a or N, preferably CR 1a ;
  • Z 8 is CR 1b ;
  • Z 6 , Z 5 and their substituents together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, more preferably a 5-membered heterocyclyl group or a 5-membered heteroaryl group, which is optionally replaced by 1 , 2 or 3 R 1s substituted;
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , S(O) 2 R a , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, preferably selected from H, D, halogen, CN, OR a , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-7 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, which are optionally substituted by 1 , 2 or 3 R 1s ;
  • R 1s is independently selected from H, D, CN, C 1-6 alkyl and C 1-6 haloalkyl, preferably selected from H, D, CN, Me and CF 3 , preferably selected from H, D and Me;
  • R 1b is independently selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, preferably selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Ring group, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3 -7-membered heterocyclyl;
  • R 3a , R 3c and R 3d are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • R 3b is H or D
  • CR 3a R 3b together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Ar 1 is phenyl or 5-6 membered heteroaryl, preferably phenyl or 6-membered azaaryl, which is substituted by n R 1 ;
  • R 1 is independently selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C(O)R a , C(O) OR a , C(O)NR b R c ,S(O)R a ,S(O) 2 R a ,S(O)OR a ,S(O) 2 OR a ,S(O)NR b R c ,S(O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3 -10-membered heterocyclyl,
  • R 1s is independently selected from H, D, halogen, CN, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkane base, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably selected from H, D, halogen , CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 3-7 membered heterocyclyl group ;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • R 2s is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • X 3 is CR 2d ;
  • R 2a is OR a or NR b R c , preferably OMe or NH 2 ;
  • R 2d is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3a and R 3c are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • R 3b and R 3d are independently H or D;
  • CR 3a R 3b together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Z 4 , Z 5 , Z 7 and Z 8 are independently CR 1b or N;
  • Z 6 is CR 1a or N
  • Z 6 , Z 5 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 1s replaced;
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C(O)R a , S(O)R a , S(O) 2 R a , P(O)( R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 1s ;
  • R 1s is independently selected from H, D, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 1b is independently selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • At most 3 are N, preferably at most 2 are N, preferably at most 1 is N.
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • One-membered heteroaryl preferably forming a 5-6 membered heteroaryl, preferably forming a 5-membered heterocyclyl or a 5-membered heteroaryl, more preferably forming a 5-membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s replaced;
  • R 2s is selected from H, D and C 1-3 alkyl, preferably selected from H, D and Me;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is H or D
  • R 3a and R 3c are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, preferably H, D, C 1-6 alkyl or C 1- 6 haloalkyl;
  • R 3b and R 3d are independently H or D;
  • CR 3a R 3b together form a C 3-6 cycloalkylene group; or CR 3c R 3d together form a C 3-6 cycloalkylene group;
  • Z 4 , Z 5 and Z 7 are independently CR 1b or N, preferably Z 7 is CR 1b ;
  • Z 6 is CR 1a or N, preferably CR 1a ;
  • Z 8 is CR 1b ;
  • Z 6 , Z 5 and their substituents together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, preferably a 5-membered heterocyclyl group or a 5-membered heteroaryl group, which is optionally replaced by 1, 2 or 3 R 1s substituted;
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , S(O) 2 R a , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, preferably selected from H, D, halogen, CN, OR a , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-7 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, which are optionally substituted by 1 , 2 or 3 R 1s ;
  • R 1s is independently selected from H, D, CN, C 1-6 alkyl and C 1-6 haloalkyl, preferably selected from H, D, CN, Me and CF 3 , preferably selected from H, D and Me;
  • R 1b is independently selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, preferably selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl, more preferably H or D;
  • R a is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
  • At least one of R 3a and R 3c is H or D.
  • R 3a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl; R 3c is H or D.
  • X 1 , X 2 and their substituents together form a cycloalkyl group (e.g. For example ) or heterocyclyl (e.g. For example ), Z 6 , Z 5 and their substituents do not together form phenyl or heteroaryl (for example For example For example For example For example For example For example ).
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CH
  • R 2a is NH 2 ;
  • R 3a is H, Me, Et, CF 3 or cyclopropyl, preferably H, Me or Et;
  • R 3b is H
  • R 3c is H or Me
  • R 3d is H
  • Z 4 , Z 5 and Z 7 are independently CR 1b or N, preferably Z 7 is CH or N, preferably Z 7 is CH;
  • Z 6 is CR 1a or N, preferably CR 1a ;
  • Z 8 is CH
  • R 1a is selected from H, Cl, Br, CN, CF 3 , CF 2 CF 3 , SF 5 , OCH 3 , OCF 3 , OCHF 2 , OCH 2 CH 3 , OCH 2 CH 2 CF 3 , cyclopropyl, Preferably selected from H, Br, Cl, CN, CF 3 , OCF 3 , cyclopropyl, Preferably CF 3 ;
  • R 1b is independently H, F, Cl or CF 3 , preferably H or CF 3 , preferably H.
  • At least one of R 3a and R 3c is H.
  • R 3a is Me, Et, CF 3 or cyclopropyl, preferably Me or Et; R 3c is H.
  • Ar 1 is selected from:
  • Ar 1 is selected from:
  • the present invention provides the compound of formula (IV) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
  • X 1 is a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CR 2d or N
  • R 2a is selected from H, D, CN, OR a or NR b R c ;
  • R 2d is selected from H, D, halogen, CN, NO 2 , OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Ring group, C 6-10 aryl or 5-10 membered heteroaryl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3 -7-membered heterocyclyl;
  • R 3a , R 3c and R 3d are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • R 3b is H or D
  • CR 3a R 3b together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Ar 1 is phenyl or 5-6 membered heteroaryl, preferably phenyl or 6-membered azaaryl, which is substituted by n R 1 ;
  • R 1 is independently selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF 5 , C(O)R a , C(O) OR a , C(O)NR b R c ,S(O)R a ,S(O) 2 R a ,S(O)OR a ,S(O) 2 OR a ,S(O)NR b R c ,S(O) 2 NR b R c , P(O)(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(OR a ) 2 , P(O)(R a ) 2 , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-10
  • R 1s is independently selected from H, D, halogen, CN, OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C 1-6 alkane base, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl ;
  • n 0, 1, 2, 3, 4 or 5;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl; or R b , R c and the atoms to which they are connected together form a 3-7 membered heterocyclyl group ;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • R 2s is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • X 3 is CR 2d ;
  • R 2a is OR a or NR b R c , preferably OMe or NH 2 ;
  • R 2d is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3a and R 3c are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • R 3b and R 3d are independently H or D;
  • CR 3a R 3b together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene; or CR 3c R 3d together form C 3-6 cycloalkylene or 3-6 membered heterocyclylene;
  • Z 4 , Z 5 , Z 7 and Z 8 are independently CR 1b or N;
  • Z 6 is CR 1a or N
  • Z 6 , Z 5 and their substituents together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 1s replaced;
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , NR b R c , C(O)R a , S(O)R a , S(O) 2 R a , P(O)( R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, benzene radical and 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1s ;
  • R 1s is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl;
  • R 1b is independently selected from H, D, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl and 3-7 membered heterocyclyl, preferably selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-7 One-membered heterocyclyl;
  • R a , R b and R c are independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • At most 3 are N, preferably at most 2 are N, and preferably at most 1 is N.
  • 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • Aryl more preferably forms a 5-membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 2s ; preferably, X 1 , X 2 and their substituents together form
  • R 2s is selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl, preferably selected from H, D and Me;
  • X 3 is CR 2d ;
  • R 2a is NH 2 ;
  • R 2d is H or D
  • R 3a and R 3c are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl, preferably H, D, C 1-6 alkyl or C 1- 6 haloalkyl; preferably, at least one of R 3a and R 3c is H or D, preferably R 3a is not H and D, and R 3c is H or D;
  • R 3b and R 3d are independently H or D;
  • CR 3a R 3b together form a C 3-6 cycloalkylene group, preferably CR 3a R 3b does not form a ring; or CR 3c R 3d together form a C 3-6 cycloalkylene group, preferably CR 3c R 3d does not form a ring;
  • Z 4 , Z 5 and Z 7 are independently CR 1b or N;
  • Z 6 is CR 1a or N, preferably CR 1a ;
  • Z 8 is CR 1b ;
  • Z 6 , Z 5 and their substituents together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, preferably a 5-7 membered heterocyclyl group, preferably a 5-membered heterocyclyl group or a 5-membered heteroaryl group.
  • Aryl preferably forms a 5-membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1s ; preferably, when Z 6 , Z 5 and their substituents together form a heteroaryl, Z 5 is CR 1b ;
  • Z 4 and Z 5 are not N at the same time;
  • Z 6 , Z 5 and their substituents do not form a ring;
  • R 1a is selected from H, D, halogen, CN, SF 5 , OR a , S(O) 2 R a , P(O)(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, preferably not P(O)(R a ) 2 , preferably selected from SF 5 , Cl, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, -OC 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocycle base, phenyl, It is optionally substituted by 1, 2 or 3 R 1s ;
  • R 1s is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl and C 3-7 cycloalkyl, preferably selected from H, D, F, CN, Me, CF 3 and cyclopropyl;
  • R 1b is independently selected from H, D, halogen, C 1-6 alkyl and C 1-6 haloalkyl, preferably selected from H, D and halogen, more preferably H or D;
  • R a is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl, preferably 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 a C atom or N atom, which is optionally substituted by R 2b ;
  • X 2 is a C atom or N atom, which is optionally substituted by R 2c ;
  • X 3 is CH
  • R 2a is NH 2 ;
  • R 3a is H, Me, Et, CF 3 or cyclopropyl, preferably Me, Et, CF 3 or cyclopropyl, preferably Me;
  • R 3b is H
  • R 3c is H or Me, preferably H
  • R 3d is H
  • Z 4 , Z 5 and Z 7 are independently CR 1b or N, preferably Z 7 is CH or N;
  • Z 6 is CR 1a or N, preferably CR 1a ;
  • Z 8 is CH
  • R 1a is selected from H, Cl, Br, CN, SF 5 , CF 3 , CF 2 CF 3 , OCH 3 , OCH 2 CH 3 , OCF 3 , OCHF 2 , OCH 2 CH 2 CF 3 , cyclopropyl, Prefer not to Preferably selected from H, Br, Cl, CN, SF 5 , CF 3 , CF 2 CF 3 , OCF 3 , OCHF 2 , cyclopropyl, Preferably selected from SF 5 , Cl, CN, CF 3 , OCF 3 , cyclopropyl, Preferably CF 3 ;
  • R 1b is independently H, F, Cl or CF 3 , preferably H, F or Cl, preferably H;
  • At least one of R 3a and R 3c is H;
  • R 3a is Me, Et, CF 3 or cyclopropyl, preferably Me or Et;
  • R 3c is H.
  • Ar 1 is selected from:
  • Ar 1 is other than
  • Ar 1 is selected from:
  • Ar 1 is selected from:
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
  • L 1 , L 2 , R 3 , Y 1 , Y 2 and p are each as defined in the present invention.
  • X 1 , X 2 , X 3 , R 2a and Ar 1 are each as defined in any one of the invention.
  • the present invention provides the compound of the above formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • X 1 , X 2 , R 2a , R 3a and Ar 1 are each as defined in the present invention.
  • 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 compound is selected from the following:
  • 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
  • Tautomers are functional group isomers produced by the rapid movement of an atom in a molecule between two positions.
  • a tautomer is a special functional group isomer.
  • a pair of tautomers can interact with each other. conversion, but usually one of the more stable isomers is its main form of existence. The most important examples are the enol and keto tautomers.
  • 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 (I), except that one or more atoms are surrounded 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 (I) 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” as used herein refers to a compound that is converted in the body to its active form having a medical effect, for example, by hydrolysis in the blood.
  • 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 incorporated herein by reference.
  • a prodrug is any covalently bonded compound of the invention that releases the parent compound in the body when administered to a patient.
  • Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved by conventional manipulations or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention in which a hydroxyl, amino or thiol group is bonded to any group that can be cleaved to form a hydroxyl, amino or thiol group when administered to a patient.
  • representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxyl, thiol and amino functionality of compounds of formula (I).
  • esters such as methyl ester, ethyl ester, etc. can be used.
  • the ester itself may be reactive and/or hydrolyzable under human body conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily break down in the human body to release the parent acid or salt thereof.
  • the present invention also provides pharmaceutical preparations, comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the invention.
  • 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
  • Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions (especially injections (subcutaneous, intravenous solution for intramuscular administration) and infusion (injection)), elixir, syrup, cachet, emulsion, inhalation or dispersible powder.
  • the content of one or more pharmaceutically active compounds should range from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight of the composition as a whole, ie an amount sufficient to achieve the dosage ranges specified below. If necessary, the specified dose may be administered several times per day.
  • 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 separables) containing the compounds of the invention, other therapeutic agents. bulk packaging or other 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 of liquid compositions or in solid Pills, tablets, capsules, etc. in the case of body 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%).
  • MTA-synergistic PRMT5 inhibitors can provide therapeutic benefits to a large number of tumor patients.
  • the compounds of the present invention exert therapeutic effects by negatively regulating the activity of MTA-bound PRMT5 in tumor cells, especially against MTAP-deficient cells or various MTAP-related tumor cells.
  • MTA synergistic PRMT5 inhibitors of the invention can treat a variety of cancers, including but not limited to tumor types, such as malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, Pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, stomach cancer, thymoma, head and neck cancer, liver Cell carcinoma, laryngeal cancer, lung squamous cell carcinoma, lung adenocarcinoma, oral cancer, ovarian cancer, renal cancer and thyroid cancer, and sarcoma.
  • tumor types such as malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, Pancreatic cancer, bile duct cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer,
  • these compounds are useful in the treatment of: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyomas, fibromas, lipomas and teratomas; Lung: bronchial carcinoma ( Squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, etc.), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (Squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), stomach (tumor, lymphoma, leiomyosarcoma, etc.), pancreas (ductal adenodeno
  • the MTA synergistic PRMT5 inhibitor of the present invention can be combined with other drugs to treat cancer, and contains at least one target drug/cell activity regulator, including CDK4/6 inhibitors, MAT2A inhibitors, MAPK1/MAPK3 inhibitors, Type I PRMT inhibitor, EGFR inhibitor, SHP2 inhibitor, pan-KRAS inhibitor, KRASG12C inhibitor, RAF inhibitor, MEK inhibitor, ERK inhibitor, Bcl-2 inhibitor, SOS1 inhibitor, PARP inhibitor, MALT1 inhibitor Agent, MALT2 inhibitor, BTK inhibitor, PI3K inhibitor, AKT inhibitor, FGFR inhibitor, DNA methyltransferase (DNMT) inhibitor, EZH1/2 inhibitor, EZH2 inhibitor, Menin-MLL inhibitor, IDH1 Inhibitors, IDH2 inhibitors, IDH1/2 inhibitors, chemotherapy drugs, radiotherapy, STING agonists or immune checkpoint inhibitors/modulators, etc.
  • target drug/cell activity regulator including CDK4/6 inhibitors, MAT2A inhibitors, MAPK1/MAPK3 inhibitor
  • Lithium hydroxide (240.0 mg) was added to a solution of 1-3 (3.0 g) in methanol (10 mL) and water (10 mL), and the mixture was stirred at room temperature for 2 hours. Concentrate under reduced pressure, add water (20 mL) to dilute, add 1M hydrochloric acid dropwise until the pH is 5-6, filter, and dry the filter cake to obtain white solid 1-4 (1.0 g), which is directly used in the next reaction.
  • Trifluoroacetic acid (3 mL) was added to a solution of 2-4 (80.0 mg) in dichloromethane (3 mL) under ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: Xbridge-C18 150x 19mm, 5um; mobile phase: ACN--H 2 O (0.05% NH 3 ); B%: 2%-10 %, 20 min) to obtain white solid 2 (2.2 mg, yield 8.1%).
  • Trifluoroacetic acid (1 mL) was added to a solution of 3-1 (50.0 mg) in dichloromethane (3 mL) under ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: Xbridge-C18 150x 19mm, 5um; mobile phase: ACN--H 2 O (0.05% NH 3 ); B%: 2%-10 %, 20 min) to obtain white solid 3 (8.6 mg, yield 26.1%).
  • phosphorus oxychloride 58.0 mg was added dropwise to 1-4 (50.0 mg) and 3-(4-(trifluoromethyl)phenyl)azetidine hydrochloride ( 30.0 mg) in a pyridine (2 mL) solution, stir for 1 hour, add water (50 mL), extract with ethyl acetate (10 mL ⁇ 3), wash the organic phase with saturated sodium chloride solution (20 mL), and dry over anhydrous sodium sulfate.
  • Trimethyltin hydroxide (342.0 mg) was added to a solution of 5-2 (300.0 mg) in 1,2-dichloroethane (10 mL). Under nitrogen protection, Stir at 50°C for 3 hours. Add water (10mL) to dilute, extract with dichloromethane (10mL mg). LC-MS m/z(ESI):450.0[M+H] + .
  • Trimethylaluminum (0.2 mL, 2 M in hexanes) was added to 3-(4-(trifluoromethyl)phenyl)azetidine hydrochloride (30.0 mg) in toluene at 0°C under nitrogen atmosphere. (5 mL) solution, stir for 30 minutes, add 5-2 (50.0 mg), and stir at 80°C for 5 hours.
  • Add water (5 mL) to dilute, extract with ethyl acetate (10 mL ⁇ 3), wash the organic phase with saturated sodium chloride (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Trifluoroacetic acid (3 mL) was added to a solution of 7-5 (15.0 mg) in dichloromethane (3 mL) under ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: Xbridge-C18 150x 19mm, 5um; mobile phase: ACN--H 2 O (0.05% NH 3 ); B%: 2%-10 %, 20 min) to obtain white solid 7 (5.0 mg, yield 49.0%).
  • Trifluoroacetic acid (3 mL) was added to a solution of 8-3 (15.0 mg) in dichloromethane (3 mL) under ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: Xbridge-C18 150x 19mm, 5um; mobile phase: ACN--H 2 O (0.05% NH 3 ); B%: 2%-10 %, 20 min) to obtain brown solid 8 (1.5 mg, yield 12.5%).
  • Trifluoroacetic acid (3 mL) was added to a solution of 9-3 (80.0 mg) in dichloromethane (3 mL) under ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: Xbridge-C18 150 ⁇ 19mm, 5um; mobile phase: ACN--H 2 O (0.1% FA); B%: 5%-10 %, 20 min) to obtain the formate salt of 9 as a white solid (6.6 mg, yield 12.2%).
  • HATU (83.2mg) was added to N,N'-diisopropylethylamine (37.7mg), 10-2 (40.0mg) and 7-2 (56.2mg) of N,N'-dimethylformamide ( 2mL) solution.
  • stir at room temperature for 1 hour add water (6mL), extract with ethyl acetate (5mL ⁇ 3), wash the organic phase with saturated sodium chloride solution (5mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a brown solid 10 -3 (80.0 mg, yield 72.1%).

Abstract

L'invention concerne un inhibiteur de PRMT5 représenté par la formule (I), ou un sel pharmaceutiquement acceptable, un variant isotopique, un tautomère, un stéréoisomère, un promédicament, un polymorphe, un hydrate ou un solvate de celui-ci. L'invention concerne également un procédé de préparation du composé, une composition pharmaceutique comprenant le composé, et l'utilisation du composé dans la prévention et le traitement d'un cancer.
PCT/CN2023/113653 2022-08-19 2023-08-18 Inhibiteur de prmt5 WO2024037608A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014100716A1 (fr) * 2012-12-21 2014-06-26 Epizyme, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2022026892A1 (fr) * 2020-07-31 2022-02-03 Tango Therapeutics, Inc. Dérivés de pipéridin-1-yl-n-pyrydine-3-yl-2-oxo-acétamide utiles pour le traitement de cancers déficients en mtap et/ou accumulant mta
WO2023146991A1 (fr) * 2022-01-26 2023-08-03 Tango Therapeutics, Inc. Composés et procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014100716A1 (fr) * 2012-12-21 2014-06-26 Epizyme, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2022026892A1 (fr) * 2020-07-31 2022-02-03 Tango Therapeutics, Inc. Dérivés de pipéridin-1-yl-n-pyrydine-3-yl-2-oxo-acétamide utiles pour le traitement de cancers déficients en mtap et/ou accumulant mta
WO2023146991A1 (fr) * 2022-01-26 2023-08-03 Tango Therapeutics, Inc. Composés et procédés d'utilisation

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