WO2023227125A1 - Nouveau composé hétérocyclique fusionné en tant qu'inhibiteur de cdk et son utilisation - Google Patents

Nouveau composé hétérocyclique fusionné en tant qu'inhibiteur de cdk et son utilisation Download PDF

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WO2023227125A1
WO2023227125A1 PCT/CN2023/096666 CN2023096666W WO2023227125A1 WO 2023227125 A1 WO2023227125 A1 WO 2023227125A1 CN 2023096666 W CN2023096666 W CN 2023096666W WO 2023227125 A1 WO2023227125 A1 WO 2023227125A1
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ring
alkyl
group
cycloalkyl
substituted
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PCT/CN2023/096666
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Chinese (zh)
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings

Definitions

  • the present invention requires the following:
  • the invention belongs to the field of medicinal chemistry, and specifically includes the disclosure of novel heterocyclic compounds with CDKs target inhibitory activity, compositions containing such compounds, and the application of such compounds in the preparation of treatments or preventions related to CDKs targets. Methods of medicine for diseases.
  • CDKs Cyclin-dependent kinases
  • CDK1/2/4/6 mainly function by regulating the cell cycle
  • CDK7/8/9/10/11 can also participate in cell cycle and transcriptional regulation to exert biological functions.
  • CDK7 mainly forms the CDK-activated kinase complex (CAK) with cyclin H (cyclin H) and MAT1.
  • CAK CDK-activated kinase complex
  • cyclin H cyclin H
  • MAT1 CDK-activated kinase complex
  • the CAK complex can phosphorylate other cell cycle kinases and promote the normal progression of the cell cycle.
  • the CAK complex can phosphorylate RNA polymerase II and participate in the transcriptional regulation of related genes.
  • CDK7 is overexpressed in many malignant tumors such as liver cancer, gastric cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, neuroblastoma, prostate cancer, non-small cell lung cancer, and acute myeloid leukemia. , and has a certain correlation with aggressive clinical pathology and poor prognosis. Since members of the entire CDK family have high homology, and their mechanisms are also different in different types of tumors, non-selective CDK7 inhibitors have certain adverse effects due to off-target effects in clinical trials. reaction. Currently, there are no selective CDK7 inhibitors on the market. A large number of preclinical and clinical trials have shown that highly selective CDK7 inhibitors have great potential therapeutic value in a variety of refractory tumors.
  • the object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof,
  • Ring A, Ring C and Ring D are each independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, Alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Ring B is arbitrarily independently non-existent or a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring.
  • paracyclic, spirocyclic or bridged ring structure and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from -C(R d1 )– or -N-;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or carboxyl substitute; or any two R 1 and the carbon atoms connected to
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-I),
  • Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Ring B is arbitrarily independently non-existent or a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring.
  • paracyclic, spirocyclic or bridged ring structure and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from -C(R d1 )– or -N-;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IA),
  • Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Ring B is arbitrarily independently a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, Spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any The two R 1s and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure.
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkane Base, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated Or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl
  • the substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optional
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IB),
  • Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Ring B is arbitrarily independently non-existent or a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring.
  • paracyclic, spirocyclic or bridged ring structure and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aromatic
  • the base and heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 and OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IC),
  • X 1 and X 0 are each independently selected from -CH– or -N-;
  • Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring.
  • Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-ID),
  • Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Ring B is arbitrarily independently a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, Spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IE),
  • X 0 is independently selected from -CH– or -N-;
  • X 1 and X 2 are each independently selected from -CH- or -N-; and X 1 and X 2 are not N at the same time;
  • Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring.
  • Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IF),
  • X 0 and X are independently selected from -CH- or -N-;
  • Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring.
  • Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any The two R 1s and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure.
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl , C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carb
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (2-I),
  • X is arbitrarily independently selected from N or CR;
  • Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be any is selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated ethylenic bonds;
  • Ring B is arbitrarily independently selected from monocyclic or polycyclic structures that do not exist or have 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 alkoxy;
  • Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycycl
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atom
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring
  • the alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optional
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IC),
  • X 1 and X 0 are each independently selected from -CR– or -N-;
  • Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring.
  • Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Ring B is arbitrarily independently selected from monocyclic or polycyclic structures that do not exist or have 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycycl
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atom
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring
  • the alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optional
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-ID),
  • X, X 1 and X 0 are each independently selected from -CR– or -N-;
  • Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring.
  • Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 0 may be the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy; and
  • the hydrogen of R 0 is preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN, -N(R d1 )(R d2 );
  • Each R may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycycl
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoroxy, Alkylsulfonyl, -COOH, acrylamide, N,N-dimethylcrotonamide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkyl Oxygen, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 ring Alkyl or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 Alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IE),
  • X 0 is independently selected from -CR– or -N-;
  • Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring.
  • Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 0 may be the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy; and
  • the hydrogen of R 0 is preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN, -N(R d1 )(R d2 );
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 alkoxy;
  • Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycycl
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atom
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring
  • the alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optional
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1, and 2;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IF),
  • X 0 is independently selected from -CR– or -N-;
  • Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring.
  • Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Each R 0 may be the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy; and
  • the hydrogen of R 0 is preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN, -N(R d1 )(R d2 );
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 alkoxy;
  • Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycycl
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atom
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring
  • the alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optional
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl Oxygen group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkyl group Oxygen, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl,
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (II),
  • Ring A' is arbitrarily independently selected from
  • Ring B' is arbitrarily independently selected from
  • Q, L and Z are arbitrarily independently selected from S, O, NR d3 or C(R 2 ) 2 ;
  • Each X, X 0 , X 1 or X 2 may be the same or different and independently selected from N or CR 2 ;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each Ra, Rb , Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-bis (C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl , C 1-10 alkyloxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3 -10 cycloalkoxy, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Aryl, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (3-I),
  • X when When it is a double bond, X is independently selected from N or CR; when When it is a single bond, X is independently selected from NR d3 or C(R) 2 ;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-bis (C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycle Alkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkyl Sulfinyl, aryl, heteroaryl; and the alkyl, al
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Base, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IA),
  • X is arbitrarily independently selected from NR d3 or C(R) 2 ;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl 1-10 Alkyl, C 2-10 heteroalkyl substituted by C 3-10 cyclo
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, and Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably Substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IB),
  • X is arbitrarily independently selected from N or CR;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated Or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1- substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl 10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 'Together with the carbon atoms connected to the ring, they form a 3-18 membered monocyclic or polycyclic structure.
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, and Ring, spiro ring or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1 -10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3 -10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 The cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute
  • R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IC),
  • X is arbitrarily independently selected from N or CR;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-ID),
  • X is arbitrarily independently selected from N or CR;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • Each R a and R b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 Cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1- 10 alkyl-substituted carboxyl or carboxyl substitute; or R a and R b together with the carbon atoms connected
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxygen substitution, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups; or any two R d1 , R d2 or R d3 may be attached to it
  • the carbons together form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure.
  • the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aromatic
  • the base and heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 and OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IE),
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • R a and R b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2- 10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy Base, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl base or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute; or R a and R b together with the carbon atoms connected to the
  • R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 Saturated or partially filled and cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl base, C 2-10 heteroalkyl substituted by C 3
  • the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, and a paracyclic ring. , spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably 1 Substituted with multiple substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IF),
  • X is independently selected from -CR– or -N-;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • Each R a and R b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 Cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1- 10 alkyl-substituted carboxyl or carboxyl substitute; or R a and R b together with the carbon atoms connected
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IG),
  • X is independently selected from -CR– or -N-;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • R a and R b are independently selected from C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1- 10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl , aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3 -10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or the carbon to which R a and R b are attached to the ring
  • the atoms together form a 3-18 membered monocyclic or polycyclic structure.
  • the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure. ; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably 1 to more selected from H, deuterium , halogen, OCH 3 , carboxyl, OH, CN substituent substitution;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 6-20 spirocyclyl, C 7-20 bridged cyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic
  • the ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic rings, Heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3. Group substitution of OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IH),
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, hetero
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-II),
  • X and X 1 are arbitrarily independently selected from N or CR;
  • X 2 , X 3 and X 4 are arbitrarily independently selected from N, N(R d3 ), C(R d1 )(R d2 ) or CR;
  • Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • Ring B is arbitrarily independently selected from monocyclic or polycyclic structures that do not exist or have 3 to 18 carbon atoms.
  • the monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 alkoxy;
  • Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycycl
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atom
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring
  • the alkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1
  • Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • p is arbitrarily chosen from an integer among 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (4-I),
  • Ring A' is arbitrarily independently selected from
  • Ring B' is arbitrarily independently selected from
  • Q and Z are arbitrarily independently selected from S, O, NR d3 or C(R 2 ) 2 ;
  • Each X, X 0 , X 1 or X 2 may be the same or different and independently selected from N or CR 2 ;
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutylene amide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group base, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C C 1-10 alkyl substituted by 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substitute
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each Ra, Rb , Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-bis (C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl , C 1-10 alkyloxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3 -10 cycloalkoxy, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl
  • the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Base, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IA),
  • Q is arbitrarily independently selected from S, O, NR d3 or C(R 2 ') 2 ;
  • X, X 0 and X 1 are independently selected from N or CR 2 ';
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together they form a 3-18 membered monocyclic or polycyclic structure, which
  • Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 Alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl base, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycle Alkyl-substituted C 1-10 alkyl, C 2-10 heteroalky
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IB),
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated and cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl base, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 '
  • the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, Spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, on R 1 ' Hydrogen is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 Alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl base, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycle Alkyl-substituted C 1-10 alkyl, C 2-10 heteroalky
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IC),
  • Q is arbitrarily independently selected from S, O, NR d3 or C(R 2 ') 2 ;
  • X, X 0 , X 1 and X 2 are independently selected from N or CR 2 ';
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 Alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl base, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycle Alkyl-substituted C 1-10 alkyl, C 2-10 heteroalky
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-ID),
  • X 0 and X 1 are independently selected from N or CR 2 ';
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • Each R 2 ' or R 3 ' may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl , -COOH, acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IE),
  • Each X 0 and X 1 may be the same or different and independently selected from N or CR 2 ';
  • Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure,
  • Each R 2 ' or R 3 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl , -COOH, acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2
  • R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;
  • Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl,
  • C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached.
  • the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring
  • the ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;
  • the halogen is independently selected from F, Cl, Br, I and its isotopes;
  • n is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.
  • R 2 or R 2 ' is preferably selected from hydrogen, deuterium, halogen, -CN, dialkylphosphoroxy, alkylsulfonyl, -COOH, C 1-10 alkyl, C 1- 10 haloalkyl, C 1-10 deuterated alkyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy; further, R 2 or R 2 ' Hydrogen is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, CN.
  • the above-mentioned compound or its pharmaceutically acceptable salt, solvate, hydrate, isotopic substitution or isomer thereof is selected from compounds with structures as listed in the embodiments of the present invention.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution. kind.
  • the pharmaceutical composition is formulated for administration by a route selected from: oral, injectable, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, Intramuscular, intravenous, intradermal, intrathecal and epidural.
  • the pharmaceutical composition is preferably administered orally.
  • the oral dosage form is not particularly limited, and any oral dosage form well known in the art can be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art.
  • the dosage standard used is, for example, 1-1500 mg/day.
  • the pharmaceutical composition may further include pharmaceutically acceptable auxiliary materials, which are selected from at least one of the following auxiliary materials including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, and osmotic pressure regulators.
  • auxiliary materials including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, and osmotic pressure regulators.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • Another object of the present invention is to provide the above compounds in the preparation of drugs for preventing and/or treating diseases related to CDKs targets, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and other diseases. use.
  • diseases related to CDKs targets including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and other diseases. use.
  • the present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions, as well as the pharmaceutical composition for preventing and/or treating CDKs.
  • the diseases related to the CDKs signaling pathway have the definitions described above.
  • the present invention also provides a method for preventing and/or treating diseases related to the CDKs signaling pathway, which includes administering to the patient a preventive or therapeutically effective amount of the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, At least one of enantiomers and isotopic substitutions, or a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition is administered to the patient.
  • the diseases related to the CDKs signaling pathway have the definitions described above.
  • the patient is a mammal, preferably a human.
  • C 1-10 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10
  • C 2-10 is selected from C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10
  • C 3-10 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 ;
  • alkyl refers to a straight or branched chain monovalent hydrocarbon group. Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl and hexyl.
  • alkylene refers to a straight or branched chain divalent hydrocarbon group of the formula -( CH2 ) n- .
  • Non-limiting examples include ethylene and propylene.
  • aliphatic ring refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group.
  • the carbocyclic ring may contain 3 to 20 carbon atoms, preferably 3 to 20 carbon atoms. 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms.
  • the carbocycle may be monocyclic or polycyclic, it may be a saturated cycloalkyl group or it may optionally contain one, two or more double and/or triple bonds on its ring, thereby forming a so-called Cycloalkenyl or cycloalkynyl.
  • a carbocyclic ring When a carbocyclic ring has multiple rings, these rings can form spiro, fused, and bridged ring structures.
  • monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl, cyclooctyl, cyclooctatetraenyl, etc.
  • non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.
  • aryl or "aromatic ring” refers to: It should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic or bicyclic ring (such as fused ring, bridged ring, spiro ring) with 6 to 20 carbon atoms. ) or a tricyclic hydrocarbon ring, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl".
  • C 6-14 aryl is understood to mean preferably a monovalent or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon rings (“C 6-14 aryl”), especially rings with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or with 9 carbon atoms a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring with 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl group When the C 6-20 aryl group is substituted, it may be mono- or poly-substituted. Moreover, there is no restriction on the substitution
  • spiro ring refers to a ring system in which two rings share one ring atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • cyclic ring refers to a ring system in which two rings share two ring-forming atoms, which may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as mentioned above.
  • bridged ring refers to a ring system in which two rings share more than three ring-forming atoms, which may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as mentioned above.
  • heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which Ring atoms are heteroatoms or atomic groups selected from N, O, NH, S, S(O) or S(O) 2 , but do not include the ring part of -OO-, -OS- or -SS-, and the remaining rings
  • the atom is carbon.
  • it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms (eg 1, 2, 3 and 4); more preferably it contains 3 to 6 ring atoms (eg 3, 4, 5, 6).
  • the heterocyclyl group may be attached to the remainder of the molecule through any one of the carbon atoms or nitrogen atom, if present, or oxygen or sulfur atom (particularly in the case of an onium salt).
  • the heterocyclyl group may include fused or bridged rings and/or spirocyclic rings.
  • Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl , dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithiophenyl Alkyl group, trithialkyl group, homopiperazinyl group, diazepanyl group, etc., preferably piperidinyl group and pyrrolidinyl group.
  • Polycyclic heterocyclyl groups include spirocyclic, fused-ring and bridged-ring heterocyclyl groups, and may also be benzo-fused heterocyclyl groups such as dihydroisoquinolinyl groups.
  • the heterocyclyl group may be bicyclic, and non-limiting examples thereof include hexahydrocyclopenta[c]pyrrole-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazine-2(1H) )-base.
  • Heterocyclyl may also be partially unsaturated, i.e.
  • it may contain one or more double bonds, non-limiting examples of which include dihydrofuryl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl , 4H-[1,3,4]thiadiazinyl, 4,5-dihydroxazolyl or 4H-[1,4]thiazinyl.
  • the heterocyclyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • heteroaryl/heteroaryl ring refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus.
  • the heteroaryl group is preferably 5 to 10 yuan (for example, 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, tris Azolyl, thiadiazolyl, thi-4H-pyrazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzo Imidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives , such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolinyl, purinyl, etc.
  • the heteroaryl/heteroaryl ring may be optionally substituted or unsubstituted.
  • the substituent is preferably one, two or more groups independently selected from the group consisting of: alkyl, alkenyl Base, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.
  • heterocyclyl, heteroaryl or heteroaromatic ring includes all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12 may be included Forms in which -, if present, are substituted at one, two or more positions or bonded to other groups, including pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, Pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3 - base; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl;
  • 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.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention prepared from a compound having specific substituents found in the present invention and a relatively non-toxic acid or base.
  • 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.
  • examples of 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 non-toxic salts such as Na salt, potassium salt, amine salt, quaternary ammonium salt of the parent compound, etc.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic bases and organic bases, the inorganic acid or organic acid being selected from 2-acetoxybenzoic acid, 2-hydroxyethyl sulfonate Acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, Carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucose heptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, Hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid, pamoic acid
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • 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.
  • 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.
  • solvate refers to an association of one or more solvent molecules with a compound of the invention.
  • Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Therefore, the term “hydrate” refers to an association of solvent molecules that is water.
  • 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.
  • 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.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • 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.
  • reaction solution was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 3-acrylamide-N-(3-( (2-((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazine- Trifluoroacetate of 4-yl)amino)methyl)phenyl)benzamide (26.5 mg, 0.038 mmol, yield: 42%).
  • LC-MS: m/z 584[M+H] + .
  • reaction solution was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain 3-acrylamido-N-(3-(( 3R, 4R)-3-hydroxypiperidin-4-yl)methylamino)-8-isopropylpyrazole[1,5-a][1,3,5]triazin-4-yl)amino) Phenyl)benzamide (compound 2) (40 mg, 0.07 mmol, yield: 78%).
  • the reaction solution was filtered and purified by C18 column chromatography (mobile phase: acetonitrile and 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7-((3-(3- Acrylamide benzamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine -1-tert-butylcarboxylate (30 mg, 0.039 mmol, yield: 78%).
  • LC-MS: m/z 783[M+H] + .
  • reaction solution was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 3-acrylamide-N-(3-( (5-((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-7-yl)amino)methyl )phenyl)benzamide (compound 3) (15.08 mg, 0.026 mmol, yield: 66%).
  • LC-MS: m/z 583[M+H] + .
  • reaction solution was filtered and purified through C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (R)-3-((7-((3-(3-acrylamide benzene) Carboxamido)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester ( 30 mg, 0.04 mmol, yield: 23%).
  • LC-MS: m/z 740[M+H] + .
  • the resulting mixed reaction liquid was stirred under the protection of nitrogen gas and room temperature under 455nm blue LED light irradiation for 16 hours.
  • the obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the mixed reaction mixture was heated to 90°C and stirred for 4 hours. After cooling, the obtained mixed reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the mixed reaction solution was directly passed through C18 column chromatography (acetonitrile: containing 0.1% formic acid (3R, 4R)-4-(((7-((3-((1s,4s))-4-acrylamidocyclohexane-1-carboxamide)) yl)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1- Tert-butyl carboxylate (25 mg, yield: 38.6%), LC-MS m/z: 789 [M+H] + ;
  • the resulting mixed reaction liquid was heated to 90°C and stirred for 4 hours under the protection of nitrogen gas. After cooling, the obtained mixed reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained mixed reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was heated to 50°C and stirred for 2 hours. After cooling, water (50 mL) was added to the obtained mixed reaction liquid, and the mixture was extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic phases were washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • N 1 -(8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)benzene- A solution of 1,3-diamine (200mg, 0.637mmol) and triethylamine (193mg, 1.91mmol) in acetonitrile (2mL) was added with 2,4,6-tripropyl-1,3,5,2,4, 6-trioxytriphosphate-2,4,6-trioxide (486 mg, 0.764 mmol, 50% mass fraction in ethyl acetate solution). The resulting mixed reaction solution was stirred at room temperature for 2 hours.
  • the mixed reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (3 ⁇ 100 mL). The combined organic phases were washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • N-(3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)benzene A solution of acrylamide (25.0 mg, 0.063 mmol) in tetrahydrofuran (1 mL) was added dropwise to the above mixed reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic phases were washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained mixed reaction solution was diluted with water (30 mL) and mixed with Extract with ethyl acetate (3 ⁇ 30 mL). The combined organic phases were washed with saturated brine (1 ⁇ 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the mixed reaction solution was added to aqueous sodium hydroxide solution (content: 30%, 200 mL), filtered, and the aqueous phase was extracted with ethyl acetate (3 ⁇ 200 mL).
  • the combined organic phases were washed with saturated brine (1 ⁇ 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was heated in microwave at 140°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phases were washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic phases were washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • tert-butyl (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate 50 mg , 0.11mmol
  • 4-aminopiperidine-1-tert-butyl ester 26.44mg, 0.13mmol
  • cesium carbonate 108mg, 0.33mmol
  • 1,4-dioxane 1,4-dioxane (1mL)
  • add (SP -4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2- Yethylene]dichloro(2-methylpyridine)palladium 9.24 mg, 0.011 mmol).
  • the resulting mixed reaction liquid was heated to 90°C and stirred for 4 hours under the protection of nitrogen gas.
  • the obtained mixed reaction liquid was concentrated under reduced pressure.
  • the obtained mixed reaction liquid was heated to 90°C and stirred for 4 hours under nitrogen protection. After cooling, the mixed reaction liquid was diluted with water (5 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixed reaction solution was stirred at room temperature for 2 hours.
  • the mixed reaction solution was diluted with water (50 mL) and ethyl acetate (3 ⁇ 50 mL).
  • the combined organic phases were washed with saturated brine (1 ⁇ 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the mixed reaction was diluted with water (30 mL) and extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic phases were washed with saturated brine (1 ⁇ 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3 ⁇ 10 mL). The combined organic phases were washed with saturated brine (1 ⁇ 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

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Abstract

La présente invention concerne un nouveau composé hétérocyclique fusionné ayant une activité inhibitrice cible pour des CDKs, et spécifiquement décrit un composé ayant une structure telle que représentée par la formule (I) en tant qu'inhibiteur cible pour des CDKs ou un sel pharmaceutiquement acceptable, un solvate, un hydrate, un substitut d'isotope ou un isomère de celui-ci.
PCT/CN2023/096666 2022-05-26 2023-05-26 Nouveau composé hétérocyclique fusionné en tant qu'inhibiteur de cdk et son utilisation WO2023227125A1 (fr)

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CN113880772A (zh) * 2021-10-23 2022-01-04 重庆医科大学 一类cdk激酶抑制剂及其应用
CN114133394A (zh) * 2020-08-12 2022-03-04 赛诺哈勃药业（成都）有限公司 一种选择性针对细胞周期依赖性激酶12活性的化合物、制备方法及医药用途

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CN106458990A (zh) * 2014-04-04 2017-02-22 希洛斯医药品股份有限公司 细胞周期蛋白依赖性激酶7(cdk7)的抑制剂
WO2015154022A1 (fr) * 2014-04-05 2015-10-08 Syros Pharmaceuticals, Inc. Inhibiteurs de kinase cycline-dépendante 7 (cdk7)
WO2016105528A2 (fr) * 2014-12-23 2016-06-30 Dana-Farber Cancer Institute, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
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CN113880772A (zh) * 2021-10-23 2022-01-04 重庆医科大学 一类cdk激酶抑制剂及其应用

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