WO2023179600A1 - Nouveaux composés macrohétérocycliques substitués et leur utilisation - Google Patents

Nouveaux composés macrohétérocycliques substitués et leur utilisation Download PDF

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WO2023179600A1
WO2023179600A1 PCT/CN2023/082758 CN2023082758W WO2023179600A1 WO 2023179600 A1 WO2023179600 A1 WO 2023179600A1 CN 2023082758 W CN2023082758 W CN 2023082758W WO 2023179600 A1 WO2023179600 A1 WO 2023179600A1
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alkyl
alkoxy
deuterated
alkenyl
amino
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张龙
牛张明
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杭州德睿智药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D497/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention requires the following:
  • the invention belongs to the field of medicinal chemistry and discloses novel substituted macroheterocyclic compounds, which can be used as ALK mutation target inhibitors. Specifically disclosed are the compounds represented by the formula (I) or their pharmaceutically acceptable salts, solvates, hydrates, isotope substitutions or isomers thereof.
  • the structural compound of formula (I) has a strong inhibitory effect on the ALK mutation target, ROS target, and NTRK target, especially on the ALK compound mutant protein (such as L1196M/G1202R, etc.), and can be used To prepare drugs for preventing or treating diseases related to ALK mutations (especially compound mutations) or ROS and NTRK signaling pathways (such as cancer, immune diseases, etc.).
  • Lung cancer is a malignant tumor with the highest morbidity and mortality in the world, among which non-small cell lung cancer accounts for about 80% of all lung cancers.
  • the main driver genes of lung adenocarcinoma include EGFR, ALK, ROS, NTRKs, etc.
  • ALK was first discovered in a subtype of anaplastic large cell lymphoma (ALCL), so it was named anaplastic lymphoma kinase (ALK). Subsequently, before the discovery of ALK gene rearrangements in non-small cell lung cancer, multiple types of ALK gene rearrangements were discovered in diffuse large B-cell lymphoma and inflammatory myofibroblastic tumor (IMT). ALK is a powerful oncogenic driver gene.
  • the ALK gene is located on the short arm of chromosome 2 of somatic cells. It is usually actively expressed in specific tissues during the human embryonic stage. ALK protein is synthesized through intracellular transcription and translation. After receiving tissue signals and extracellular ligands, it activates intracellular downstream signaling pathways. Promote cell division and proliferation. ALK is shut down after it has completed its functions in specific tissues at a specific period. In adults, ALK is in a dormant state and does not express protein. When cells are damaged or induced by external conditions, gene mutations occur, and the local EML4 gene is broken and inverted and inserted into the position of exon 20 of ALK, generating a new EML4-ALK fusion gene.
  • the EML4-ALK protein synthesized by this gene can be used in tissues that do not accept it. In the absence of signals and ligands, downstream signaling pathways are abnormally activated, and while tumor suppressor genes are inactivated, cells are continuously proliferated and cancer occurs in the human body. For the ALK gene, fusion gene mutations are a very important form of oncogene mutations. It is currently known that the mutated ALK protein participates in a wide range of activated downstream signaling pathways. It is now known that the signaling pathways it participates in include: RAS-MAPK pathway, PI3K-AKT pathway, PLC ⁇ pathway, JAK-STAT pathway and multiple other pathways. These signaling pathways ultimately lead to: cell proliferation, resistance to apoptosis, Promote angiogenesis and ultimately induce cancer.
  • the objective response rate to chemotherapy is only 45%.
  • the first-generation ALK inhibitor crizotinib was the first ALK inhibitor approved for the treatment of ALK+ metastatic NSCLC, increasing the objective response rate to 74%.
  • the second-generation ALK inhibitors alectinib, ceritinib and brigatinib can overcome most of the resistance mutations of first-generation crizotinib (such as G1269A and F1174L), but for Mutations in the soluble region of the kinase, such as G1202R, will cause widespread resistance to first- and second-generation ALK inhibitors; the third-generation ALK inhibitor lorlatinib is more sensitive to G1202R, but not to complex resistance mutations (such as G1202R/L1196M) is not sensitive.
  • ROS1 fusion is a driver gene for a variety of malignant tumors.
  • ROS1 inhibitors such as crizotinib and ceritinib have brought significant benefits to lung cancer patients with ROS1 mutations.
  • ROS1 resistance also occurs.
  • TRK gene fusion is a chromosomal change. When the three genes NTRK1/2/3 are fused with other genes, it will lead to the production of conformationally abnormal TRK proteins (TRKA, TRKB, TKRC) and activate the proliferation of specific types of tumor cells. signaling pathway, thereby inducing malignant tumors with NTRK gene fusion.
  • TRKA, TRKB, TKRC conformationally abnormal TRK proteins
  • the occurrence of NTRK gene fusion has nothing to do with the location of the tumor or age. It can be found in a variety of solid tumor types (accounting for about 0.4%, accounting for a higher proportion in rare tumors), including pancreatic cancer, thyroid cancer, salivary gland cancer Cancer, breast cancer, colorectal cancer, lung cancer, etc.
  • NTRK fusion mutations exceed 1.5% in salivary gland cancer, thyroid cancer, and soft tissue sarcoma, while in non-small cell lung cancer and colorectal cancer The proportion is as low as 0.2%. Overall, the positive rate of NTRK fusion mutations is approximately 0.3% globally and approximately 0.4% in East Asian populations. Among all NTRK fusion-positive tumors, the top five tumors with the highest number of patients are non-small cell lung cancer (16.4%), breast cancer (14.1%), soft tissue sarcoma (9.6%), colorectal cancer (9.3%), and ovarian cancer ( 6.2%), accounting for 55.6% in total.
  • NTRK-specific inhibitors including LOXO-195, PLX7486, and ONO-7579, which have shown good clinical efficacy, complex drug resistance mechanisms and central nervous system metastasis make it difficult for patients to obtain The benefits are limited.
  • the inventor unexpectedly discovered that some of the new macrocyclic compounds of the formula (I) of the present invention show extremely high inhibitory activity against ALK mutations, especially compound mutations, and have a strong proliferation inhibitory effect on ALK, ROS1 or NTRKs mutated tumor cells.
  • some of the compounds of the present invention also have higher oral bioavailability and exposure, as well as better metabolic stability, membrane permeability, brain penetration or Broad-spectrum inhibition of ALK, ROS1 or NTRKs mutations is expected to be useful in the treatment of tumors with ALK, ROS1 or NTRKs mutations.
  • the object of the present invention is to provide new compounds represented by formula (I) or pharmaceutically acceptable salts, solvates, isomers and isotopic substitutions thereof:
  • rings A, B, C, and D are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, etc. containing 0 to more unsaturated bonds.
  • Tricyclic, bridged or spirocyclic; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be selected from O, S or N;
  • L 2 ' is not present or selected from bond, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC(R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(R 0 ) 2 - , -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -,
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphoryl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphoryl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl, amino,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphoryl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino,
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n, u, and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (1-I):
  • Rings A and B are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, tricyclic ring, bridged ring or ring containing 0 to more unsaturated bonds. Spirocycle; and the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X, X 0 , X 1 and X 4 are each independently selected from C(R 0 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphoryl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphoryl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl, amino,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphoryl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino,
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n, and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (1-IA):
  • Rings A and B are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, tricyclic ring, bridged ring or ring containing 0 to more unsaturated bonds. Spirocycle; and the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 0 , X 1 and X 4 are each independently selected from C(R 0 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphoryl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphoryl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl, amino,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphoryl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino,
  • Each R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R b and R a together with the carbon directly connected to form a 3-10 membered ring structure
  • the cyclic structure can be any single ring, bicyclic, bridged ring or spiro ring containing 0 to more unsaturated bonds; and the cyclic structure can be any 0 to more heteroatoms, and the hetero Atoms are arbitrarily selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R a and R b are not H, or at least one of R 8 and R 9 is not hydrogen, or at least one of R 0 , R 1 , R 2 and R 3
  • One is a dialkylphosphono group
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2 or 3;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (1-IB):
  • Rings A and B are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, tricyclic ring, bridged ring or ring containing 0 to more unsaturated bonds. Spirocycle; and the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 0 , X 1 and X 4 are each independently selected from C(R 0 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphonoyl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphonyl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R b and R a together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R a and R b are not H, or at least one of R 8 and R 9 is not hydrogen, or at least one of R 0 , R 1 , R 2 and R 3
  • One is a dialkylphosphono group
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n, and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (1-IC):
  • Rings A and B are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, tricyclic ring, bridged ring or ring containing 0 to more unsaturated bonds. Spirocycle; and the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 0 , X 1 and X 4 are each independently selected from C(R 0 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphonoyl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphonyl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R b and R a together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2 or 3;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (1-ID):
  • Rings A and B are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, tricyclic ring, bridged ring or ring containing 0 to more unsaturated bonds. Spirocycle; and the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 0 , X 1 and X 4 are each independently selected from C(R 0 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphonoyl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphonyl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R b and R a together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2 or 3;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (1-IE):
  • Rings A and B are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, tricyclic ring, bridged ring or ring containing 0 to more unsaturated bonds. Spirocycle; and the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 0 and X 1 are each independently selected from C(R 0 ) or N;
  • Y is independently selected from -O-, -S- or -NR 0 -;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphonoyl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphonyl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R b and R a together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n, and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-I):
  • A, B and D are independently absent, single bond or 3-20 membered non-aromatic or aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic or bicyclic ring containing 0 to more unsaturated bonds. , tricyclic ring, bridged ring or spiro ring; and the non-aromatic or aromatic cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from C(R 1 ) or N, and at least one of X 4 and X 5 is C and connected to an L group.
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphonoyl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl,
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphonyl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • u, n, and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IA-1) or formula (2-IA-2):
  • Rings A and B are independently 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any single ring, bicyclic ring, tricyclic ring, bridged ring or ring containing 0 to more unsaturated bonds. Spirocycle; and the non-aromatic or aromatic cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 0 , X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from C(R 1 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 may be the same or different, and may be independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, Alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy base, dialkylphosphono group; and the hydroxyl group, amino group, C1-6 alkyl group, alkenyl group, alkynyl group, C1-6 alkoxy group, halogenated C1-6 alkoxy group, deuterated C1-6 alkyl group
  • the hydrogen on the oxygen group, cycloalkyl group, heterocycloalkyl group, heterocycloalkoxy group, and cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, and tri
  • Aromatic cyclic structure the cyclic structure may contain 0- to multiple heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 2 or R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl, dialkylphosphonyl; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono
  • the hydrogen on can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino
  • Each R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, Heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R b and R a together with the carbon directly connected to form a 3-10 membered ring structure
  • the cyclic structure can be any single ring, bicyclic, bridged ring or spiro ring containing 0 to more unsaturated bonds; and the cyclic structure can be any 0 to more heteroatoms, and the hetero Atoms are arbitrarily selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • p, n and t are each independently 0, 1, 2 or 3;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IB-1) or formula (2-IB-2):
  • Rings A and D are independently non-existent or 3-20 membered non-aromatic or aromatic cyclic structures.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic or tricyclic ring containing 0 to more unsaturated bonds. Bridged ring or spiro ring; and the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from C(R 1 ) or N;
  • Z 0 is independently selected from -O-, -S- or -NR 0 -;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 may be the same or different, and may be independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, Alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy base, dialkylphosphono group; and the hydroxyl group, amino group, C1-6 alkyl group, alkenyl group, alkynyl group, C1-6 alkoxy group, halogenated C1-6 alkoxy group, deuterated C1-6 alkyl group
  • the hydrogen on the oxygen group, cycloalkyl group, heterocycloalkyl group, heterocycloalkoxy group, and cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, and tri
  • Aromatic cyclic structure the cyclic structure may contain 0- to multiple heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 3 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl base, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono, dialkylphosphono; and the C1-6 alkyl, halogenated C1-6 Hydrogen on alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphonyl It can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6
  • R 6 and R 7 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 7 and R 6 together with the directly connected carbons form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 6 , R 7 , R 8 and R 9 can also form a monocyclic, bicyclic, spirocyclic or bridged ring structure together with the carbons they are connected to.
  • the monocyclic, bicyclic, spirocyclic or bridged ring can be aromatic or non-aromatic. , and can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • t and u are each independently 0, 1, 2 or 3;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IC-1) or formula (2-IC-2):
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are each independently selected from C(R 1 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 may be the same or different, and may be independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, Alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy base, dialkylphosphono group; and the hydroxyl group, amino group, C1-6 alkyl group, alkenyl group, alkynyl group, C1-6 alkoxy group, halogenated C1-6 alkoxy group, deuterated C1-6 alkyl group
  • the hydrogen on the oxygen group, cycloalkyl group, heterocycloalkyl group, heterocycloalkoxy group, and cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, and tri
  • Aromatic cyclic structure the cyclic structure may contain 0- to multiple heteroatoms, and the heteroatoms are selected from O, S or N;
  • R 6 and R 7 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 7 and R 6 together with the directly connected carbons form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 8 and R 9 may be the same or different, and are any independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycle Alkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 8 and R 9 together with the carbon directly connected to them form a 3-10 membered cyclic structure,
  • the cyclic structure may be a monocyclic ring, a bicyclic ring, a bridged ring or a spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms may be any Selected from O, S or N;
  • R 6 , R 7 , R 8 and R 9 can also form a monocyclic, bicyclic, spirocyclic or bridged ring structure together with the carbons they are connected to.
  • the monocyclic, bicyclic, spirocyclic or bridged ring can be aromatic or non-aromatic. , and can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-ID-1) or formula (2-ID-2):
  • Ring B is independently a 3-20 membered non-aromatic or aromatic cyclic structure, and the non-aromatic cyclic structure can be any monocyclic, bicyclic, tricyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; And the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are each independently selected from C(R 1 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphonoyl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl,
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl Base, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, dialkylphosphono;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • u and n are independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IE-1) or formula (2-IE-2):
  • Ring B is independently a 3-20 membered non-aromatic or aromatic cyclic structure, and the non-aromatic cyclic structure can be any monocyclic, bicyclic, tricyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; And the cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are each independently selected from C(R 1 ) or N;
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro, dialkylphosphonoyl; wherein the "hetero" represents 1, 2, or 3 heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R 1 can be the same or different, and is any independently selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy, dialkylphosphonoyl; and the Hydroxy, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl , the hydrogen on the heterocycloalkoxy group and the cycloalkoxy group can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl,
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl Base, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, dialkylphosphono;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • u and n are independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-I):
  • A, B and C are independently absent, single bond or 3-20 membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic or bicyclic ring containing 0 to more unsaturated bonds. , tricyclic, bridged ring or spiro ring structure; and the non-aromatic or aromatic cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • X is each independently selected from C(R 0 ) or N;
  • L 1 , L 2 and L 3 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC (R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C( R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, - C(R 0 ) 2 C(R 0 ) 2 -, - C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro, dialkylphosphono; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic ring structure with the carbons they are connected to, so
  • the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R may be the same or different, and any R may be independently selected from H, deuterium, tritium, hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxyalkyl, halogenated C1-6 Alkoxyalkyl, deuterated C1-6 alkoxyalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, dialkylphosphonoyl; and the hydroxyl, amino, C1-6 alkyl,
  • the hydrogen on the alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, and cycloalkoxy groups can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, Deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, de
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl base, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, Amino, alkenyl, hydroxyl, cyano, nitro; or R a and R b can also form a 3-20 member saturated or unsaturated, aromatic cyclic structure together with the carbon they are connected to, and the cyclic structure can be Monocyclic, bicyclic, tricyclic, bridged or spirocyclic structures containing 0 to more heteroatoms; or R a or R b can also be combined with the carbon on the C ring to form a 4-20 membered saturated or unsaturated aromatic ring like
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyl baseoxy group, heterocycloalkoxy group, amino group, alkenyl group, cyano group, alkynyl group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, dialkylphosphono group; and the C1-6 Alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, The hydrogen on
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n, and t are each independently 0, 1, 2, or 3.
  • R and R0 are hydrogen
  • Y is O
  • L 1 and L 3 are single bonds
  • L 2 is CH 2
  • the C ring is When , R a and R b are not hydrogen.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IA):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • Each X may be the same or different, and each X may be independently selected from C(R 0 ) or N;
  • L 1 , L 2 and L 3 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC (R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C( R 0 ) 2 -, -CH 2 C(R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic cyclic structure with the carbons they are connected to, and the cyclic structure can Contains 0 to more heteroatoms selected from O, S or N;
  • Each R may be the same or different, and any R may be independently selected from H, deuterium, tritium, hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxyalkyl, halogenated C1-6 Alkoxyalkyl, deuterated C1-6 alkoxyalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl; and the hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl,
  • the hydrogen on the cycloalkyl, heterocycloalkyl, heterocycloalkoxy, and cycloalkoxy groups may be optionally further substituted by 1 to more substituents, and the substituents may be selected from the group consisting of H, deuterium, tritium, halogen, Hydroxy, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl base, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, Amino, alkenyl, hydroxyl, cyano, nitro; or R a and R b can also form a 3-20 member saturated or unsaturated, aromatic cyclic structure together with the carbon they are connected to, and the cyclic structure can be Monocyclic, bicyclic, tricyclic, bridged or spirocyclic structures containing 0- to multiple heteroatoms; or R a or R b can also be combined with the carbon on the R 0 ring to form a 4-20-membered saturated or unsaturated,
  • the cyclic structure can be optimally further selected from deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, Amino, alkenyl, cyano, alkynyl, cyanoalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyl Oxygen, heterocycloalkoxy, nitro, acyl, sulfonyl, phosphonyl substitution; hetero refers to heteroatom, and the heteroatom is preferably selected from O, S or N;
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1- 6
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1 or 2;
  • n and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IB):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • Each X may be the same or different, and each X may be independently selected from C(R 0 ) or N;
  • L 1 , L 2 and L 3 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC (R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C( R 0 ) 2 -, -CH 2 C(R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro, dialkylphosphono; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic ring structure with the carbons they are connected to, so
  • the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R may be the same or different, and any R may be independently selected from H, deuterium, tritium, hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxyalkyl, halogenated C1-6 Alkoxyalkyl, deuterated C1-6 alkoxyalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, dialkylphosphonoyl; and the hydroxyl, amino, C1-6 alkyl,
  • the hydrogen on the alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, and cycloalkoxy groups can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, Deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, de
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl base, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, Amino, alkenyl, hydroxyl, cyano, nitro; or R a and R b can also form a 3-20 member saturated or unsaturated, aromatic cyclic structure together with the carbon they are connected to, and the cyclic structure can be Monocyclic, bicyclic, tricyclic, bridged or spirocyclic structures containing 0- to multiple heteroatoms; or R a or R b can also be combined with the carbon on the R 0 ring to form a 4-20-membered saturated or unsaturated,
  • the cyclic structure can be optimally further selected from deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, Amino, alkenyl, cyano, alkynyl, cyanoalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyl Oxygen, heterocycloalkoxy, nitro, acyl, sulfonyl, phosphonyl substitution; hetero refers to heteroatom, and the heteroatom is preferably selected from O, S or N;
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono, dialkylphosphono; and the C1-6 alkyl, halogenated C1-6 alkyl
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n, and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IC):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • Each X may be the same or different, and each X may be independently selected from C(R 0 ) or N;
  • L 1 , L 2 and L 3 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC (R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C( R 0 ) 2 -, -CH 2 C(R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro, dialkylphosphono; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic ring structure with the carbons they are connected to, so
  • the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R may be the same or different, and any R may be independently selected from H, deuterium, tritium, hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxyalkyl, halogenated C1-6 Alkoxyalkyl, deuterated C1-6 alkoxyalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, dialkylphosphonoyl; and the hydroxyl, amino, C1-6 alkyl,
  • the hydrogen on the alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, and cycloalkoxy groups can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, Deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, de
  • R a is any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, C1- 6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino, alkenyl, hydroxyl, cyano , nitro; or when X is CR 0 , R a can also be connected with R 0 to form a 4-20-membered saturated or unsaturated aromatic cyclic structure.
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono, dialkylphosphono; and the C1-6 alkyl, halogenated C1-6 alkyl
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1 or 2;
  • n and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-ID):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • X is independently selected from C(R 0 ) or N;
  • Y and Z are arbitrarily independently selected from absence, single bond, O, S, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(R 0 ) 2 -, -CH 2 C(R 0 ) 2 -, -OC(R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 C(R
  • L 1 , L 2 and L 3 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC (R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C( R 0 ) 2 -, -CH 2 C(R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro, dialkylphosphono; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic ring structure with the carbons they are connected to, so
  • the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R may be the same or different, and any R may be independently selected from H, deuterium, tritium, hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxyalkyl, halogenated C1-6 Alkoxyalkyl, deuterated C1-6 alkoxyalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, dialkylphosphonoyl; and the hydroxyl, amino, C1-6 alkyl,
  • the hydrogen on the alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, and cycloalkoxy groups can be optionally further substituted by 1 to more substituents, and the substituents are optionally selected from H, Deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, de
  • R a is any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, C1- 6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino, alkenyl, hydroxyl, cyano , nitro; or R a can also be connected with R 0 to form a 4-20-membered saturated or unsaturated, aromatic cyclic structure.
  • the cyclic structure can be a single ring, a bicyclic ring containing 0 to multiple heteroatoms, Tricyclic, bridged ring or spirocyclic structure; and the cyclic structure can be further selected from the group consisting of deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, Cycloalkyl, heterocycloalkyl, amino, alkenyl, Substituted by cyano group, alkynyl group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, and phosphono group; hetero refers to a heteroatom, and the heteroatom is preferably selected from O, S or N;
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono, dialkylphosphono; and the C1-6 alkyl, halogenated C1-6 alkyl
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1 or 2;
  • n and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IE):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • Each X may be the same or different, and is independently selected from C(R 0 ) or N;
  • L 1 , L 2 and L 3 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC (R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C( R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, - C(R 0 ) 2 C(R 0 ) 2 -, - C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro, dialkylphosphono; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic ring structure with the carbons they are connected to, so
  • the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms are selected from O, S or N;
  • Each R may be the same or different, and may be independently selected from H, deuterium, tritium, hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxyalkyl, halo C1-6 alkoxyalkyl, deuterated C1-6 alkoxyalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, dialkylphosphonoyl; and said The hydrogen on the hydroxyl, amino, C1-6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy groups may be optionally further substituted by 1 to more substituents , the substituents are optionally selected from H, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy Base, deuterated C1-6 al
  • R a and R b may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl base, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, Amino, alkenyl, hydroxyl, cyano, nitro; or R a and R b can also form a 3-20 member saturated or unsaturated, aromatic cyclic structure together with the carbon they are connected to, and the cyclic structure can be A monocyclic, bicyclic, tricyclic, bridged or spirocyclic structure containing 0- to multiple heteroatoms; or R a can also be connected with R 0 to form a 4-20-membered saturated or unsaturated, aromatic cyclic structure, the The
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono, dialkylphosphono; and the C1-6 alkyl, halogenated C1-6 alkyl
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1 or 2;
  • n and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IF):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • Each X may be the same or different, and is independently selected from C(R 0 ) or N;
  • L 1 , L 2 and L 3 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC (R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic cyclic structure with the carbons they are connected to, and the cyclic structure can Contains 0 to more heteroatoms selected from O, S or N;
  • R b is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, C1- 6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino, alkenyl, hydroxyl, cyano , nitro; or R b can also be connected with R 0 to form a 4-20-membered saturated or unsaturated, aromatic cyclic structure.
  • the cyclic structure can be a single ring, a bicyclic ring containing 0- to multiple heteroatoms, Tricyclic, bridged ring or spirocyclic structure; and the cyclic structure can be further selected from the group consisting of deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, Cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonoyl substitution; hetero refers to a heteroatom, and the heteroatom is preferably selected from O, S or N;
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1- 6
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1 or 2;
  • n and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IF):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or NR;
  • Each X may be the same or different, and is independently selected from C(R 0 ) or N;
  • L 1 and L 2 are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC(R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -,
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino , alkenyl, hydroxyl, cyano, nitro, dialkylphosphono; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, aromatic ring structure with the carbons they are connected to, so
  • the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms are selected from O, S or N;
  • R a and R b are independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino, alkenyl, hydroxyl , cyano group, nitro group; or R b can also be connected with R b to form a 4-20-membered saturated or unsaturated, aromatic cyclic structure.
  • the cyclic structure can be a single ring containing 0- to multiple heteroatoms.
  • cyclic structure can be further selected from deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 Alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonoyl substitution; hetero refers to heteroatom, the heteroatom Preferably selected from O, S or N;
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono, dialkylphosphono; and the C1-6 alkyl, halogenated C1-6 alkyl
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1 or 2;
  • n and t are each independently 0, 1, 2, or 3.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (5-I):
  • a and B are independently absent, have a single bond, or have a 3-20-membered aromatic or non-aromatic cyclic structure.
  • the non-aromatic cyclic structure can be any monocyclic, bicyclic, or tricyclic structure containing 0 to more unsaturated bonds. Ring, bridged ring or spiro ring structure; and the non-aromatic or aromatic ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally selected from O, S or N;
  • X and X 1 may be the same or different and are independently selected from C(R 0 ) or N;
  • L 1 , L 2 and L 2 ' are each independently selected from absence, single bond, -O-, -S-, -C(R 0 ) 2 OC(R 0 ) 2 -, -C(R 0 ) 2 SC(R 0 ) 2 -, -C(R 0 ) 2 N(R)C(R 0 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C (R 0 ) 2 -, -CH 2 CH 2 C(R 0 ) 2 -, -CH 2 CH 2 CH 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0 ) 2 -, -C(R 0 ) 2 C(R 0
  • Each R 0 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl , Heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, ring Alkyloxy, heterocycloalkoxy, amino, alkenyl, hydroxyl, cyano, nitro; and any two adjacent R 0 can also form a 3-20-membered saturated or unsaturated, Aromatic cyclic structure, the cyclic structure may contain 0 to more heteroatoms, and the heteroatoms are selected from O, S or N;
  • R a and R b are independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy, amino, alkenyl, hydroxyl , cyano group, nitro group; or R b can also be connected with R b to form a 4-20-membered saturated or unsaturated, aromatic cyclic structure.
  • the cyclic structure can be a single ring containing 0- to multiple heteroatoms.
  • cyclic structure can be further selected from deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 Alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphonoyl substitution; hetero refers to heteroatom, the heteroatom Preferably selected from O, S or N;
  • Each R 1 , R 2 and R 3 may be the same or different, and may be independently selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, cyclo Alkyl, heterocycloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, heterocyclyloxy, cycloalkyloxy, heterocycloalkoxy , amino, alkenyl, cyano, alkynyl, cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1- 6
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n is independently 0, 1 or 2;
  • n and t are each independently 0, 1, 2, or 3.
  • rings A and B are any independently aryl or heteroaryl, and are preferably selected from The following structure:
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or isomer thereof wherein ring A is any independently cycloalkyl, heterocycloalkyl, aryl or hetero Aryl, and is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridine, pyrimidine, pyrazole, oxazole, thiazole, imidazole, thiophene, furan, tetrahydrofuran, tetrahydropyrrole, Pyrrole, piperazine, morpholine, N-hetetane, piperidine, thiomorpholine, pyridazine or benzene.
  • ring A is any independently cycloalkyl, heterocycloalkyl, aryl or hetero Aryl, and is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl,
  • the above-mentioned compound or its pharmaceutically acceptable salt, or its isomer or isotope substitution is selected from compounds with structures as listed in the examples of the present invention.
  • a pharmaceutical composition comprising the compound, a pharmaceutically acceptable salt, solvate or hydrate thereof and isotopes or isomers thereof.
  • Another object of the present invention is to provide the use of the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers in the preparation of drugs for preventing or treating diseases caused by ALK mutations. .
  • Another object of the present invention is to provide the use of the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers in the preparation of drugs for preventing or treating diseases caused by ALK mutations. .
  • Another object of the present invention is to provide the above compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers for preparation and use in the prevention or treatment of ALK mutations, especially those caused by ALK compound mutations.
  • Another object of the present invention is to provide the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers for preparation and use in the prevention or treatment of ALK mutations, ROS mutations, and NTRK signaling pathways. Application in medicines for diseases.
  • Another object of the present invention is to provide the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers for preparation and use in preventing or treating ALK mutations or signaling pathways related to ALK mutations, such as Inhibitors of NTRK, ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR, PI3K, CDKs, PARP, etc., or with cytotoxins, immune target modulator PD-1 /PD-L1 and other combination therapeutic drugs.
  • the combination therapeutic drug at least contains one or more compounds of the present invention, their pharmaceutically acceptable salts, solvates or hydrates and isotopes or isomers thereof.
  • Another object of the present invention is to provide the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers for preparation and use in preventing or treating ALK mutations or signaling pathways related to ALK mutations, such as Inhibitors of ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR, PI3K, CDKs, PARP, NTRKs, etc., or with cytotoxic and immune target modulator PD-1 /PD-L1 and other combination therapeutic drugs.
  • the combination therapeutic drug at least contains one or more compounds of the present invention, their pharmaceutically acceptable salts, solvates or hydrates and isotopes or isomers thereof.
  • the present invention also provides a method for treating diseases, which includes administering to a patient a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer, or the pharmaceutical combination. things.
  • the disease is selected from the group consisting of diseases related to ALK mutations, ROS mutations, and NTRK signaling pathways.
  • C1-6 is selected from the group consisting of C 1 , C 2 , C 3 , C 4 , C 5 or C 6 , the number indicating the number of carbon atoms in the group.
  • C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 1-6 alkyl is replaced by C 3-6 cycloalkyl or C 3- 6 heterocycloalkyl substituted, and C 1-6 heteroalkyl substituted by C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, including but not limited to: methyl, ethyl, n-propyl, iso Propyl, -CH 2 C(CH 3 )(CH 3 )(OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropylacyl, benzyloxy, cyclopropylalkenyl, trifluoro Methyl, aminomethyl, hydroxymethyl
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , as well as salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutic
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • “Pharmaceutically acceptable salts” as used herein belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by salt formation with an acid or salt with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound, such as salts formed with nontoxic inorganic or organic acids.
  • nontoxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid,
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. Normally, this Such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided by the invention also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
  • prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomeric salts are formed by step-by-step procedures well known in the art. Diastereomers are resolved by crystallization or chromatography, and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on vectors, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to a carrier, diluent and/or medium required for formulating an effective pharmaceutical composition.
  • the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
  • the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable .
  • two hydrogen atoms are substituted.
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • Alkyl and heteroalkyl radicals (including those commonly known as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, Substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (for example, aryl substituted by 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkyl Oxy group or aralkyl group.
  • each R group is independently selected, as when there are more than one R', R", R '', R'''' and R'''' groups for each of these groups.
  • R' and R'' are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 5-, 6- or 7- -Metal rings.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon Groups composed of atoms bonded to non-hydrogen groups, such as haloalkyl groups (such as -CF 3 , -CH 2 CF 3 ) and acyl groups (such as -C(O)CH 3 , -C(O)CF 3 , - C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the general formula -TC(O)-(CRR')qU-, where T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the general formula -A(CH2)rB-, where A and B are independently selected.
  • r is 1 to 4 integer.
  • one single bond in the new ring thus formed can be replaced by a double bond.
  • substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by substituents of the general formula -A(CH2)rB-, where s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl groups.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like wait.
  • haloalkyl groups include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above-mentioned alkyl group having the specified number of carbon atoms connected through an oxygen bridge.
  • C 1-6 alkoxy groups include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration in which one or more carbon-carbon double bonds are present at any stable point on the chain, such as vinyl and propenyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • heteroatom as used herein includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum ( Al) and boron (B), etc.
  • Cycle means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the so-called rings include fused rings.
  • the number of atoms in a ring is usually defined as the ring membership.
  • a "5- to 7-membered ring” means 5 to 7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridinyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which independently meets the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic or bicyclic or bicyclic heterocycle which may be saturated, partially unsaturated or unsaturated and (aromatic), which contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring .
  • Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p).
  • Nitrogen atoms may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein).
  • the heterocycle can be attached to any pendant heteroatom or carbon atom to form a stable structure.
  • the heterocycles described herein may be substituted at the carbon or nitrogen position if the resulting compound is stable.
  • the nitrogen atoms in the heterocycle are optionally quaternized.
  • a preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed 1.
  • aromatic heterocyclic group or “heteroaryl” means a stable 5, 6, 7-membered monocyclic or bicyclic aromatic ring or a 7, 8, 9 or 10-membered bicyclic heterocyclyl, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • Nitrogen atoms may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein).
  • Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed 1.
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring is formed when one or more atoms (i.e., C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and a carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also appear on the bridge.
  • heterocyclic compounds include, but are not limited to: acridinyl, anovanyl, benzimidazolyl, benzofuryl, benzmercaptofuryl, benzmercaptophenyl, benzoxazolyl, benzox Zozolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, Carboline, chromanyl, chromene, cinnolinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofura[2,3-b] Tetrahydrofuryl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indo
  • hydrocarbyl or its sub-concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic.
  • Hydrocarbon radicals or combinations thereof may be fully saturated, mono- or polyunsaturated, may be mono-, disubstituted or poly-substituted, may include divalent or polyvalent radicals, have a specified number of carbon atoms (such as C 1 -C 10 means 1 to 10 carbons).
  • “Hydrocarbon groups” include but are not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups.
  • the aliphatic hydrocarbon groups include chain and cyclic ones, specifically including but not limited to alkyl, alkenyl, and alkynyl groups.
  • the aromatic hydrocarbon groups include but are not limited to 6-12 membered ones.
  • the term "alkyl” refers to a linear or branched chain radical or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) Methyl, cyclopropylmethyl, and homologues or isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups.
  • Unsaturated alkyl groups have one or more double or triple bonds, examples of which include but are not limited to vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers conformation.
  • heteroalkyl or its sub-concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means stable linear, branched chain A cyclic or cyclic hydrocarbon group or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in combination with another term refers to a stable linear, branched chain hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized.
  • Heteroatoms B, O, N, and S can be located at any internal position of the heteroalkyl group (except where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms can be consecutive, for example -CH2- NH- OCH3 .
  • alkoxy alkylamino
  • alkylthio thioalkoxy
  • cycloalkyl Unless otherwise specified, the terms “cycloalkyl”, “heterocycloalkyl”, “cycloalkyl” or their subtitles (such as aryl, heteroaryl, arylheteroyl, cycloalkyl, heterocycloalkyl, cycloalkyl, etc.) Alkheteroyl, cycloalkenyl, heterocycloalkenyl, cycloalkene heteroyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl heteroyl, etc.) By itself or in combination with other terms, it represents a cyclized “hydrocarbyl", “heterohydrocarbyl” or “hydrocarbyl” respectively.
  • heteroalkyl or heterocycloalkyl groups eg, heteroalkyl, heterocycloalkyl
  • the heteroatom may occupy the position where the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclyl examples include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofurindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl refers to a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing one to four heteroatoms. In an exemplary example, the heteroatoms are selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. A heteroaryl group can be attached to the rest of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrrolyl Azolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl Azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indo
  • aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including where a carbon atom (e.g., methylene) has been replaced by, e.g., oxygen
  • alkyl groups replaced by atoms such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as an affinity substitution reaction.
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.
  • the invention is now further described by way of examples.
  • the examples given below are for illustrative purposes only and do not limit the scope of the invention.
  • the compounds of the present invention can be prepared by many methods known in the art of organic synthesis.
  • Embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by improved methods based on them.
  • Preferred methods include, but are not limited to, the methods described below.
  • isopropyl magnesium chloride was added dropwise to a solution of 1-(cyclopropylmethyl)-4-iodo-1H-pyrazole (182.58 mg, 0.97 mmol) in tetrahydrofuran (5 mL). Lithium chloride (400mg, 1.61mmol) was added dropwise within 30 minutes. Then, a solution of 3-bromo-1-methyl-1H-pyrazole-4-carbaldehyde (110 mg, 0.582 mmol) dissolved in tetrahydrofuran (0.5 mL) was added to the above reaction solution. After the addition was completed, the resulting reaction mixture was stirred and reacted at 0° C. for 30 minutes.
  • reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was then concentrated under reduced pressure to obtain 5-fluoro-2- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester (1.02g, crude product) was used directly in the next step without purification. step.
  • LC-MS m/z:369[M+H] + .
  • the resulting reaction was stirred at 25°C for 2 hours. At the end of the reaction, the mixed reaction solution was diluted with saturated ammonium chloride, and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was stirred at 25°C for 2 hours under nitrogen protection. Dilute the reaction solution with water (20 mL) and extract with ethyl acetate (20 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure. Concentrate.
  • the resulting mixture is heated to 120°C and stirred for 12 hours under nitrogen protection. After the reaction was completed, the resulting reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was diluted with saturated ammonium chloride solution (5 mL), and extracted with ethyl acetate (15 mL ⁇ 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the resulting mixed reaction solution was diluted with saturated ammonium chloride (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phases were washed with saturated brine, sodium chloride was added, filtered, and filtered under reduced pressure.
  • the mixed reaction solution was diluted with saturated ammonium chloride (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction liquid is heated to 120°C and stirred for 12 hours under nitrogen protection. After the reaction was completed, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Tetraisopropyl titanate (1.56g, 5.44mmol) was directly added to the dissolved 2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-
  • 2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1- A solution of methyl-1H-pyrazol-3-yl)-5-fluorobenzoate (500 mg, 1.36 mmol) in tetrahydrofuran (10 mL). After the addition is completed, the resulting mixed reaction liquid is stirred at 0°C for 0.5 hours under the protection of nitrogen gas. Ethyl magnesium bromide (10.88 mL, 10.88 mmol, 1 M) was then added to the above solution. After the addition was completed, the resulting mixture was stirred at 0°C for 16 hours under nitrogen protection.
  • Triethylsilyl hydrogen (7.47g, 64.25mmol) was added to (3-bromo-1-methyl-1H-pyrazol-4-yl)(1-(cyclopropylmethyl)-1H-pyrazole-4 -) in a mixed solution of methanol (447 mg, 1.37 mmol) and 2,2,2-trifluoroacetic acid (20 mL). After the addition was completed, the resulting mixed reaction solution was stirred at 70°C for 1 hour. LCMS showed that the starting materials were completely consumed and the product was produced. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (50 mL), and extracted with ethyl acetate (30 mL ⁇ 3).
  • reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (3 ⁇ 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction liquid After the addition is completed, the resulting mixed reaction liquid is heated to 100°C and stirred for 12 hours under nitrogen protection. LCMS showed that the starting material of the compound was completely consumed and the product was formed.
  • the reaction solution was diluted with water (15 mL), and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was quenched by adding saturated ammonium chloride (10 mL), and quenched with ethyl acetate (3 ⁇ 10 mL ) extraction.
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction liquid After the addition is completed, the resulting reaction liquid is protected with nitrogen and stirred at 25°C for 1 hour. LCMS showed that the starting material of the compound was completely consumed and the product was formed.
  • the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (3 ⁇ 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was quenched with saturated ammonium chloride (10 mL), diluted with water (10 mL), and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • phosphorus oxychloride (10687 mg, 69.70 mmol) was added dropwise to a flask containing N,N-dimethylformamide (10 mL). After the addition was completed, the resulting reaction solution was stirred at 0°C for 30 minutes. Then, 3-iodo-1-(prop-2-yl)-1H-pyrazole (1300 mg, 5.51 mmol) was added to the above reaction solution. After the addition is completed, the reaction liquid obtained is heated to 75°C and stirred for 16 hours under the protection of nitrogen gas. LCMS showed that the starting material of the compound was completely consumed and the product was formed.
  • reaction solution was quenched by adding water (20 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1-(cyclopropylmethyl)-1H-pyrazol-4-yl)(3-iodo-1-isopropyl-1H- Pyrazol-4-yl)methanol (2.48 g, crude), LCMS m/z: 387 [M+H] + .
  • reaction solution was quenched with saturated ammonium chloride (10 mL), diluted with water (10 mL), and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was stirred at 0°C for 20 hours. LCMS showed that the starting material of the compound was completely consumed and the product was formed.
  • the reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • isopropyl magnesium chloride was added dropwise to a solution of 1-(cyclopropylmethyl)-4-iodo-1H-pyrazole (3g, 12.09mmol) in tetrahydrofuran (20mL). Lithium (11.16 mL, 1.3 M), stir at 0°C for 30 minutes. Then 1-(cyclopropylmethyl)-3-iodo-1H-pyrazole-4-carbaldehyde (2.00 g, 7.25 mmol) was added. The resulting mixed reaction was stirred at 0°C for 2 hours.
  • reaction solution was added to saturated sodium carbonate solution (20 mL) to quench, diluted with water (30 mL), and extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was stirred at 0°C for 16 hours. After the reaction was completed, the reaction solution was quenched by adding water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction liquid obtained is heated to 100°C and stirred for 16 hours under the protection of nitrogen gas. LCMS detection showed that the reaction was complete.
  • the mixed reaction solution was diluted with water (35 mL), and extracted with ethyl acetate (35 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained mixed reaction solution was quenched with saturated ammonium chloride (10 mL), diluted with water (15 mL), and extracted with ethyl acetate (15 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained mixed reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phases were washed with unsaturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was filtered, and the filter cake was washed with ethyl acetate.
  • the filtrate was concentrated under reduced pressure. Dilute with water (6 mL), and extract with ethyl acetate (6 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction liquid After the addition is completed, the resulting reaction liquid is heated to 100°C and stirred for 16 hours under nitrogen protection. LCMS detection showed that the reaction was complete.
  • reaction solution was poured into saturated ammonium chloride aqueous solution (30 mL) to quench the reaction solution, and ethyl acetate (30 mL ⁇ 3) was used.
  • ethyl acetate (30 mL ⁇ 3) was used.
  • the combined organic phases were washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was stirred at -10°C for 30 minutes. LCMS detection showed that the reaction was complete.
  • the reaction solution was quenched with saturated aqueous ammonium chloride solution (14 mL), and then extracted with ethyl acetate (3 ⁇ 15 mL).
  • reaction liquid was stirred at 25°C for 12 hours under nitrogen protection.
  • LCMS detection reaction completed Complete.
  • the reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (5 mL ⁇ 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was quenched with saturated aqueous ammonium chloride (5 mL), and extracted with ethyl acetate (3 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was diluted with water (3 mL), and extracted with ethyl acetate (3 mL ⁇ 3). The combined organic phases were washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction liquid is heated to 100°C and stirred for 16 hours under nitrogen protection.
  • LCMS detection reaction was complete.
  • the obtained mixed reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (5 mL ⁇ 3). The combined organic phases were washed with unsaturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • NBS (168.6 mg, 0.94 mmol) was added to (R)-5-bromo-3-((1-(2-(4-((5-(cyclopropylmethyl))-1-methyl-1H- Pyrazol-3-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethyl)mercapto)pyridin-2-amine (521 mg, 0.94 mmol) in DMF (15mL) solution. The reaction mixture was stirred at room temperature for 3 hours, then poured into water (80 mL) and extracted with EA (80 mL ⁇ 3).
  • reaction mixture was heated to 80°C and stirred for 5 h, then poured into water (80 mL) and extracted with EtOAc (80 mL x 3). The organic layer was back-extracted with saturated NaCl (60 mL x 2) solution, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • reaction mixture was diluted with DCM (50 mL) and aqueous NaOH (2M, 50 mL) was added. After stirring vigorously for 12 hours, the liquid was separated. The aqueous layer was further extracted with DCM (3x 15 mL). The combined organic phases were back-extracted once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the target inhibitory and anti-tumor activities of the compounds of the present invention are tested by the following enzymatic or cellular assays.
  • ROS1/ROS1-G2032R target inhibitory activity assay
  • ROS1 (0.2ng/ ⁇ L): x ⁇ L 1xKB and x ⁇ L ALK stock (500ng/ ⁇ L)
  • ROS1-G2032R (0.75ng/ ⁇ L): x ⁇ L 1xKB and x ⁇ L ALK stock (100ng/ ⁇ L)
  • the ER of the compound well is marked as ER compound
  • the ER of the vehicle control well is marked as ER vehicle
  • the ER of the blank control well is marked as ER blank .
  • the inhibition rate is calculated using the following formula:
  • Inhibition rate (ER vehicle -ER compound )/(ER vehicle -ER blank ) ⁇ 100%
  • the inhibition rate was analyzed using the software GraphPad Prism, a dose-response curve was fitted, and the IC 50 value was calculated.
  • ALK-G1202R (0.75ng/ ⁇ L): x ⁇ L 1xKB and x ⁇ L ALK stock (200ng/ ⁇ L)
  • ALK-G1202R/L1196M (1.6ng/ ⁇ L): x ⁇ L 1xKB and x ⁇ L ALK stock (100ng/ ⁇ L)
  • the ER of the compound well is marked as ER compound
  • the ER of the vehicle control well is marked as ER vehicle
  • the ER of the blank control well is marked as ER blank .
  • Inhibition rate (ER vehicle -ER compound )/(ER vehicle -ER blank ) ⁇ 100%
  • the inhibition rate was analyzed using the software GraphPad Prism, a dose-response curve was fitted, and the IC 50 value was calculated.
  • the new macrocyclic compound of the present invention shows extremely high inhibitory activity against ALK and its mutations, especially compound mutations, and also has a strong inhibitory effect on ROS1 and its mutations. Further research is still in progress.
  • Test 3 Pharmacokinetic study of the test substance in mice:
  • the pharmacokinetic properties of some compounds of the present invention were evaluated through mouse pharmacokinetic experiments: SPF male CD-1 mice were used, and a single intravenous administration was performed at a dose of 2 mg/kg. For single intragastric administration, the dose is 10 mg/kg. The animals were fasted overnight before the experiment and resumed food intake 4 hours after administration. Blood samples were collected after administration. Plasma sample analysis uses the acetonitrile protein precipitation method to extract the test compounds and internal standards (Labetalol & tolbutamide & Verapamil & dexamethasone & glyburide & Celecoxib) in the plasma, and the extract is analyzed by LC/MS/MS.
  • the measured plasma concentration-time data of individual animals were analyzed using the non-compartmental model of Phoenix WinNonlin 7.0 (Pharsight, USA) software.
  • the mouse pharmacokinetic parameters were obtained in the following table: maximum (peak) plasma drug concentration Cmax; half-life T1/2 and the area under the plasma concentration-time curve extrapolated to infinite time AUC0-inf.
  • the representative compound 1 of the present invention not only has very good medicinal efficacy, but also has very high oral bioavailability and exposure.

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Abstract

La présente invention concerne de nouveaux composés macrohétérocycliques substitués, qui peuvent être utilisés en tant qu'inhibiteurs pour des cibles telles que des mutations ALK, ou des voies de signalisation associées à une mutation ALK, par exemple des NTRK, ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 et/ou VEGFR, PI3K, CDK et PARP. L'invention concerne en particulier des composés représentés par la formule (I), ou des sels, solvates, hydrates, substituts d'isotopes ou isomères pharmaceutiquement acceptables de ceux-ci. Les composés ayant des structures de formule (I) ont un effet d'inhibition sur des cibles telles que des mutations ALK, des NTRK et ROS1, et ont en particulier un fort effet d'inhibition sur une protéine de mutant composite ALK (telle que L1196M/G1202R), et peuvent par conséquent être utilisés pour préparer des médicaments ou des sondes moléculaires utilisés pour prévenir ou traiter des maladies (telles que le cancer et des maladies immunitaires) qui sont associées à des mutations ALK (en particulier des mutations composites), et des voies de signalisation NTRK, ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 et/ou VEGFR, PI3K, CDK et PARP.
PCT/CN2023/082758 2022-03-21 2023-03-21 Nouveaux composés macrohétérocycliques substitués et leur utilisation WO2023179600A1 (fr)

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