[go: up one dir, main page]

WO2025031471A1 - Nouveau composé hétérocyclique pour réguler une fonction p53 - Google Patents

Nouveau composé hétérocyclique pour réguler une fonction p53 Download PDF

Info

Publication number
WO2025031471A1
WO2025031471A1 PCT/CN2024/110919 CN2024110919W WO2025031471A1 WO 2025031471 A1 WO2025031471 A1 WO 2025031471A1 CN 2024110919 W CN2024110919 W CN 2024110919W WO 2025031471 A1 WO2025031471 A1 WO 2025031471A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
saturated
cycloalkyl
hydrogen
partially saturated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/110919
Other languages
English (en)
Chinese (zh)
Inventor
张龙
牛张明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mindrank Therapeutics Suzhou New Drug Research And Development Co Ltd
Original Assignee
Mindrank Therapeutics Suzhou New Drug Research And Development Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mindrank Therapeutics Suzhou New Drug Research And Development Co Ltd filed Critical Mindrank Therapeutics Suzhou New Drug Research And Development Co Ltd
Publication of WO2025031471A1 publication Critical patent/WO2025031471A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and specifically includes novel aromatic ring compounds capable of regulating P53 function, compositions containing such compounds, and methods for applying such compounds to prepare drugs for treating or preventing diseases associated with abnormal P53 genes/proteins or signal pathways (such as tumors, autoimmune diseases, etc.).
  • the P53 tumor suppressor gene is a gene in the body that inhibits cells from transforming into cancer cells.
  • the human P53 gene is located on chromosome 17 P13, with a total length of 16-20kb, containing 11 exons, transcribing 2.8kb of mRNA, encoding the protein P53, which is a nuclear phosphorylated protein.
  • P53 is the gene with the highest correlation with human tumors discovered so far.
  • the P53 protein, the expression product of the P53 gene is composed of 393 amino acid residues and exists in the body as a tetramer with a half-life of 20-30 minutes.
  • the content of P53 protein in cells is very low, and it is difficult to detect due to its short half-life. However, in growing and proliferating cells, it can increase by 5-100 times or more.
  • the P53 gene constantly monitors the integrity of the cell chromosome DNA. Once the cell chromosome DNA is damaged, the P53 protein binds to the corresponding binding site of the gene DNA, acting as a special transcription factor, activating the transcription of the P21 gene, causing the cell to stagnate in the G1 phase; inhibiting the activity of the helicase; and interacting with the replication factor A to participate in the replication and repair of DNA. If the repair fails, the P53 protein will initiate the programmed death (apoptosis) process to induce cell suicide, prevent the generation of mutant cells with a tendency to cancer, and thus prevent the cell from becoming malignant.
  • programmed death apoptosis
  • the mutant P53 was the oncogene. It was not until 1989 that it was known that the mutant P53 was the oncogene. Later, it was confirmed that the wild-type P53 was a tumor suppressor gene.
  • the wild-type P53 protein plays an important role in maintaining normal cell growth and inhibiting malignant proliferation, so it is called the "gene guardian". When the P53 gene mutates, the spatial conformation affects the transcriptional activation function and the phosphorylation process of the P53 protein, which not only loses the wild-type P53's ability to inhibit tumor proliferation, but also the mutation itself makes the gene have the function of an oncogene.
  • the mutant P53 protein combines with the wild-type P53 protein to form an oligomeric protein that cannot bind to DNA, causing some cancer gene transcription to go out of control and lead to tumor occurrence.
  • the P53 gene is associated with 50% of human tumors, including liver cancer, breast cancer, bladder cancer, gastric cancer, colon cancer, prostate cancer, soft tissue sarcoma, ovarian cancer, brain tumors, lymphocytic tumors, esophageal cancer, lung cancer, osteogenic sarcoma, etc.
  • P53 mutations in human tumors are mainly in highly conserved areas, and different types of tumors are different. For example, colon cancer and breast cancer have similar epidemiology, but the P53 mutation spectrum is not consistent. Therefore, there is an urgent need to develop inhibitors against P53 mutations.
  • novel heterocyclic compounds containing phosphorus oxygen or sulfur oxygen groups of the structure of formula (I) of the present invention not only have significant binding ability to the mutant P53 protein, but also can restore the mutant's DNA binding function after binding.
  • they also have higher tumor cell proliferation inhibition activity, better pharmacokinetic properties (including better permeability, lower clearance rate, longer T1/2 and higher exposure) and bioavailability, etc., and are expected to have better human PK properties.
  • Some representative compounds also have excellent brain penetration ability and are more suitable for development as candidate drugs for the prevention or treatment of diseases related to the P53 mutation target and its signaling pathway.
  • the object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product thereof.
  • Ring B arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X 1 and X 2 are independently selected from N or CR;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH, amide or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 al
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfur, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl , C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • ring B When any two R and/or R1 are connected, they form a 7-30 membered macrocyclic structure or a condensed ring structure together with the atoms on the ring.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IA):
  • Ring B arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, sulfamoyl, aminesulfonamido, methanesulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfur, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IB):
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, sulfamoyl, aminesulfonamido, methanesulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10
  • R 1 is optionally preferably replaced by 1 to at most is substituted with a group selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfur, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 C1-10 alkylsulfonyl, C2-10 heteroalkyl,
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IC):
  • X is independently selected from N or -CR-;
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, sulfamoyl, aminesulfonamido, methanesulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (ID),
  • X is independently selected from N or -CR-;
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, sulfamoyl, aminesulfonamido, methanesulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10
  • the hydrogen on R 1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, pentafluoride sulfur, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IE):
  • X is independently selected from N or -CR-;
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, amide, aminesulfonamido, methanesulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10
  • the hydrogen on R 1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, pentafluoride sulfur, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IF),
  • Ring C represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • X is independently selected from N or -CR-;
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkyl acyl, C1-10 alkyl sulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl; wherein the C1-10 alkyl , C2-10 alkynyl or C1-10 Alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IG):
  • Ring C represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IH):
  • X is independently selected from N or -CR-;
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, amide, aminoacyl, alkylsulfinyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl,
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl , C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (II):
  • X1 is independently selected from N or CR
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C3-10 cycloalkyl substituted with C3-10 cycloalkyl C1-10 alkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkyl acyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocyclyl, C1-10 alkyl
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IJ):
  • X 1 and X 2 are independently selected from N or CR;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, acyl, carboxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl ) amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfur, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IK):
  • X 1 and X 2 are independently selected from N or CR;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, acyl, carboxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl ) amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfur, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IM):
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl , C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2 and 3;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IN):
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C 1-10 alkane alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfonamide, N,N-di(C 1-10 alkyl )amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 heterocycloalkyloxy, C 3-10 cycloal
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2 and 3;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IO):
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl , C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2 and 3;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IP),
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, amide, aminoacyl, sulfamoyl, aminesulfonamido, methylsulfonylamino 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, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, sulfur pentafluoride, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl,
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl , C1-10 alkyl substituted by C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 and R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; wherein the C 1-10 alkyl , C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 R d1 , R d2 , R d3 , R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2 and 3;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the formula (III): structure,
  • X is selected from N or CR;
  • R is selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • E is selected from O, S, NR e ;
  • R e is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl;
  • Each R 1 is the same or different and is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, S(O) 2 C 1-6 alkyl, P(O)(C 1-6 alkyl) 2 ;
  • Each R 2 is the same or different and is independently selected from H, P(O)(C 1-6 alkyl) 2 , -NH-Q;
  • Q is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R q : 5-6 membered heterocyclyl;
  • each R q is the same or different and is independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • R d1 and R d2 are the same or different and are independently selected from H, C 1-6 alkyl, and C 1-6 alkoxy;
  • R y1 and R y2 are the same or different and are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy; or, R y1 and R y2 and the atoms to which they are attached form a 5-12 membered heterocyclic group or a 5-10 membered heteroaryl group;
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4.
  • R is selected from H, C 1-3 alkyl, halogenated C 1-3 alkyl;
  • R is selected from H, CH 2 CF 3 .
  • R e is selected from H, C 3-6 cycloalkyl, halogenated C 1-3 alkyl;
  • Re is selected from cyclopropyl, CH 2 CF 3 .
  • each R 1 is the same or different and is independently selected from H, S(O) 2 C 1-3 alkyl, P(O)(C 1-3 alkyl) 2 ;
  • each R 1 is the same or different and is independently selected from H, S(O) 2 CH 3 , P(O)(CH 3 ) 2 .
  • each R 2 is the same or different and is independently selected from H, P(O)(C 1-3 alkyl) 2 , -NH-Q; for example, H, P(O)(C 1-3 alkyl) 2 , (like ), (like ).
  • Q is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R q : 6-membered heterocyclyl; for example piperidinyl.
  • each R q is the same or different and is independently selected from H, halogen, C 1-6 alkyl; for example H, F, methyl.
  • each R 2 is the same or different and is independently selected from H, P(O)(CH 3 ) 2 , (For example ), (For example ), (For example ).
  • R y1 and R y2 are the same or different and are independently selected from H and C 1-3 alkoxy; for example, H and methoxy.
  • R y1 , R y2 and the atoms to which they are attached form a 5-7 membered heterocyclic group, a 12 membered heterocyclic group or a 5-6 membered heteroaryl group; for example, a furan ring, a dihydrofuran ring,
  • the above-mentioned compound or its pharmaceutically acceptable salt, or its corresponding isomer, isotope substitution is a new compound selected from the structures disclosed in the examples in the text.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution.
  • the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, 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 known in the art may be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art.
  • the duration of administration of the pharmaceutical composition according to the present invention may depend on the severity of the disease, and is preferably at least 1 month, for example 1, 2, 3, 4, 5 or 6 months, and may be lifelong medication as required by the disease.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient, which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator.
  • a pharmaceutically acceptable excipient which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator.
  • excipients including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • Another object of the present invention is to provide the use of the above compound in the preparation of a drug for preventing and/or treating diseases related to abnormal P53 signaling pathway.
  • the diseases related to the P53 signaling pathway include but are not limited to various tumors such as lung cancer, intestinal cancer, pancreatic cancer, liver cancer, breast cancer, etc. and autoimmune diseases such as inflammatory bowel disease, key inflammatory or proliferative diseases such as psoriasis.
  • the present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, and the use of the pharmaceutical composition in preventing and/or treating diseases related to the P53 signaling pathway.
  • the diseases related to the P53 signaling pathway have the definitions described above.
  • the present invention also provides a method for preventing and/or treating a disease related to the P53 signaling pathway, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, or administering to a patient a preventive or therapeutically effective amount of the above-mentioned pharmaceutical composition.
  • the disease related to the P53 signaling pathway has the definition described above.
  • the patient is a mammal, preferably a human.
  • C1-10 is selected from the group consisting of C1 , C2 , C3 , C4 , C5, C6, C7, C8, C9 and C10;
  • C2-10 is selected from the group consisting of C2, C3, C4, C5 , C6 , C7 , C8 , C9 and C10 ;
  • C3-10 is selected from the group consisting of C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ;
  • alkyl is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, also referred to as a "C 1-10 alkyl group".
  • a "C 1-8 alkyl group” means a straight or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms
  • a "C 1-6 alkyl group” means a straight or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.
  • alkylene as used herein refers to a straight or branched divalent hydro
  • the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.
  • aliphatic ring refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group
  • the carbocycle can contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms.
  • the carbocycle can be monocyclic or polycyclic, it can be a saturated cycloalkyl or can optionally contain one, two or more double bonds and/or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl.
  • non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.
  • aryl or "aromatic ring” means: it should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) or tricyclic hydrocarbon ring with 6 to 20 carbon atoms, which can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl”.
  • C 6-14 aryl is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring (“C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl or biphenyl, or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl When the C 6-20 aryl is substituted, it may be monosub
  • spirocyclic ring refers to a ring system in which two rings share one ring-forming atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • paracyclic refers to a ring system in which two rings share two ring atoms, and it may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • bridged ring refers to a ring system in which two rings share three or more ring atoms, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms or groups selected from N, O, NH, S, S(O) or S(O) 2 , but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, 1-4 of which are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6).
  • the heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present) or oxygen or sulfur atom (especially in the case of forming an onium salt).
  • the heterocyclic group can include fused or bridged rings and/or spirocyclic rings.
  • the non-limiting examples of monocyclic heterocyclic radicals include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl.
  • Polycyclic heterocyclic radicals include spirocyclic, condensed ring and bridged heterocyclic radicals, and can also be benzo-fused heterocyclic radicals such as dihydro Isoquinolinyl.
  • the heterocyclic group may be bicyclic, non-limiting examples of which include hexahydrocyclopenta[c]pyrrol-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl.
  • the heterocyclic group may also be partially unsaturated, i.e., it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, pentafluoride sulfur, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heteroaryl/heteroaromatic ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus.
  • Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan.
  • heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc.
  • the heteroaryl/heteroaromatic ring may be optionally substituted or unsubstituted.
  • the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, pentafluoride sulfur, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • heterocyclic groups, heteroaryls or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridin-2-yl may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene;
  • thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino 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 a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science
  • 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 the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • pharmaceutically acceptable salts are derivatives of the compounds of the present invention, wherein the parent compound is modified by salification with an acid or alkali.
  • 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 salts, potassium salts, amine salts, quaternary ammonium salts of parent compounds, and the like.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic and organic bases, wherein the inorganic or organic acid is selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene
  • the inorganic base and organic base described in the following examples are selected from sodium, potassium, magnesium, calcium, etc. or amines, diethylamine, triethylamine, ethanolamine, etc.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods.
  • the preparation method of such salts is: in water or an organic solvent or a mixture of the two, by reacting these compounds in free acid or base form with stoichiometric amounts of The reaction can be prepared by reacting with an appropriate base or acid.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • compounds provided by the present invention also exist in prodrug forms.
  • Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention.
  • prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Some compounds of the present invention may exist in non-solvated form or solvated form, including hydrate form. Generally speaking, solvated form is suitable with non-solvated form, all included in the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous form.
  • solvate refers to an association formed by one or more solvent molecules and the compounds of the present 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 formed by a solvent molecule that is water.
  • Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present 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, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically 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. All of these isomers and their mixtures are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers and 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 present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds.
  • radioactive isotope labeled compounds may be used, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present 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 bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to technicians in the field of cosmetics or topical drugs. For additional information about the carrier, 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 at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents When a substituent's bond can cross-link to two atoms on a ring, such substituent can be bonded to any atom on the ring.
  • substituent When a substituent is listed without indicating the atom through which it is bonded to a compound included in the chemical structure but not specifically mentioned, such substituent can be bonded through any atom thereof. Combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • the present invention is now further described by examples.
  • the examples given below are for illustrative purposes only and are not intended to limit the scope of this invention.
  • the compounds of the present invention can be prepared using many known methods in the field of organic synthesis.
  • the embodiments of the present invention can be synthesized using the methods described below, as well as known synthetic methods in the field of organic synthetic chemistry, or by improved methods based thereon.
  • Preferred methods include, but are not limited to, the following description methods.
  • aq is aqueous solution
  • TLC thin layer chromatography
  • RT room temperature
  • MeOH is methanol
  • EtOH is ethanol
  • EtOAc is ethyl acetate
  • THF is tetrahydrofuran
  • equivalent is eq
  • CDI carbonyldiimidazole
  • DCM dichloromethane
  • PE petroleum ether
  • DIAD is diisopropyl azodicarboxylate
  • DMF is N,N-dimethylformamide
  • DMSO is dimethyl sulfoxide
  • CBz is benzyloxycarbonyl
  • BOC is tert-butyl ester.
  • lithium diisopropylamide (9 mL, 17.85 mmol, 2.0 M tetrahydrofuran solution) was added dropwise to a solution of 4-bromo-1-(phenylsulfonyl)-1H-indole (2.00 g, 5.95 mmol) in tetrahydrofuran (20 mL). The addition was complete and stirred at -78 ° C for 30 minutes. Then iodine (2.27 g, 8.93 mmol) was added to the above reaction solution. The resulting reaction solution was stirred at room temperature for 16 hours.
  • reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 40 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 40% B-95% B in 20 minutes; detector: 214 nm).
  • diethylamine (876 mg, 12.00 mmol), cuprous iodide (46 mg, 0.24 mmol) and palladium tetratriphenylphosphine (139 mg, 0.12 mmol) were added to a solution of 4-bromo-2-iodo-1-(2,2,2,2-trifluoroethyl)-1H indole (485 mg, 1.20 mmol) and 2-methyl-4-(methylsulfinyl)-N-(prop-2-yn-1-yl) aniline (574 mg, 2.40 mmol) in dimethyl sulfoxide (10 mL). The resulting reaction solution was stirred at 25 ° C for 4 hours under nitrogen protection.
  • reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated.
  • potassium phosphate 54 mg, 0.25 mmol
  • palladium acetate 4 mg, 0.024 mmol
  • 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.021 mmol) were added to a solution of N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline (100 mg, 0.19 mmol) and dimethylphosphine oxide (20 mg, 0.25 mmol) in N,N-dimethylformamide (10 mL).
  • reaction solution was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (50 mL ⁇ 5). The combined organic layers were washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 ⁇ m, 330 g; mobile phase A: pure water containing 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 120 mL/min; gradient: 5% B-95% B in 40 minutes; detector: 254 nm).
  • iron powder (2.02 g, 36.00 mmol) and ammonium chloride (1.91 g, 36.00 mmol) were added to a mixed solution of ethanol (20 mL) and water (2 mL) containing 1-cyclopropyl-2-iodo-4-nitro-1H-indole (1.18 g, 3.60 mmol).
  • the resulting reaction was heated to 80°C and stirred for 1 hour.
  • LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure.
  • tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (3.28 g, 15.10 mmol) and sodium triacetoxyborohydride (1.60 g, 7.55 mmol) were added to a mixed solution of 1,2-dichloroethane (5 mL) and acetic acid (15 mL) containing 1-cyclopropyl-2-iodo-1H-indol-4-amine (900 mg, 3.02 mmol) and the reaction mixture was heated to 40 ° C and stirred for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure.
  • 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline 774 mg, 3.24 mmol
  • diethylamine 1.18 g, 16.20 mmol
  • cuprous iodide 61 mg, 0.32 mmol
  • tetrakistriphenylphosphine palladium 185 mg, 0.16 mmol
  • tert-butyl 4-((1-cyclopropyl-2-iodo-1H-indol-4-yl)amino)-3-fluoropiperidine-1-carboxylate 810 mg, 1.62 mmol) in dimethyl sulfoxide (10 mL).
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 120g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5% B-95% B in 40 minutes; detector: 254nm) to obtain a crude product (136mg).
  • lithium diisopropylamide (35.21mmol, 18mL, 2M) solution was added dropwise to a tetrahydrofuran (50mL) solution containing 4-bromobenzo[b]thiophene (5.00g, 23.47mmol).
  • the reaction solution was stirred at -78°C for 30 minutes, and then iodine (7.15g, 28.16mmol) was added to the mixed solution.
  • the mixed reaction solution was stirred at room temperature for 5 hours.
  • the reaction solution was poured into a saturated ammonium chloride solution (50mL) to quench, and extracted with ethyl acetate (50mL ⁇ 3).
  • diethylamine (431 mg, 5.90 mmol), cuprous iodide (23 mg, 0.12 mmol) and tetrakistriphenylphosphine palladium (69 mg, 0.059 mmol) were added to a solution of 4-bromo-2-iodobenzo[b]thiophene (200 mg, 0.59 mmol) and (2-methoxy-4-(methylsulfonyl)phenyl)(prop-2-yn-1-yl)carbamic acid tert-butyl ester (400 mg, 1.18 mmol) in dimethyl sulfoxide (10 mL).
  • reaction solution was stirred at 25 ° C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 40% B-100% B in 20 minutes; detector: 214 nm).
  • reaction solution was heated to 90°C and stirred for 2 hours under a nitrogen protection line. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 40% B-100% B in 20 minutes; detector: 214 nm).
  • 2,6-Lutidine (225 mg, 2.10 mmol) and iodotrimethylsilane (420 mg, 2.10 mmol) were added to a solution of tert-butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl)(2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)benzo[b]thiophen-4-yl)amino)-3-fluoropiperidine-1-carboxylate (50 mg, 0.072 mmol) in dichloromethane (10 mL). After the addition, the resulting reaction solution was stirred at room temperature for 1 hour.
  • reaction solution was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 40 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 40% B-95% B in 20 minutes; detector: 214 nm).
  • potassium phosphate (6.89 g, 32.18 mmol), palladium acetate (412 mg, 2.48 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (1.44 g, 2.48 mmol) were added to a solution of N,N-dimethylformamide (50 mL) containing 4-bromo-2-methoxyaniline (5.00 g, 24.75 mmol) and dimethylphosphine oxide (2.51 g, 32.18 mmol). After the addition was completed, the resulting reaction solution was stirred at 150 ° C for 5 hours under nitrogen protection.
  • reaction solution was quenched with water (50 mL) and extracted with acetate (50 mL ⁇ 5). The combined organic layer was washed with saturated The mixture was washed with ammonium chloride solution (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 ⁇ m, 330 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 150 mL/min; gradient: 20% B-95% B in 20 minutes; detector: 214 nm).
  • triethylamine (253 mg, 2.50 mmol), cuprous iodide (10 mg, 0.052 mmol) and palladium tetratriphenylphosphine (35 mg, 0.03 mmol) were added to a solution of (4-(dimethylphosphoryl)-2-methoxyphenyl)(prop-2-yn-1-yl)carbamic acid tert-butyl ester (168 mg, 0.50 mmol) and 4-bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole (202 mg, 0.50 mmol) in dimethyl sulfoxide (3 mL).
  • reaction solution was stirred at 25 ° C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched with water (3 mL) and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 120 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 40% B-100% B in 20 minutes; detector: 214 nm).
  • reaction solution was filtered and concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 120g; mobile phase A: pure water containing 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 40% B-100% B in 20 minutes; detector: 214nm).
  • reaction solution was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: pure water containing 0.1% NH3 ⁇ H2O ; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40%B-95%B in 20 minutes; detector: 214nm).
  • the resulting mixed reaction solution was heated at 90°C and stirred for 3 hours under nitrogen protection.
  • the mixed reaction solution was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 120g; mobile phase A: pure water containing 0.1% NH3 ⁇ H2O ; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 30%B-95%B in 20 minutes; detector: 214nm).
  • the resulting mixed reaction solution was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
  • the combined organic phase was washed with saturated ammonium chloride (20 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 120 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 30% B-95% B in 20 minutes; detector: 214 nm).
  • cuprous iodide (4 mg, 0.02 mmol) and bistriphenylphosphine palladium dichloride (8 mg, 0.011 mmol) were added to a solution of (3S, 4R)-3-fluoro-4-((2-iodobenzo[d]oxazol-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (50 mg, 1.11 mmol) and (2-methoxy-4-(methylsulfonyl)phenyl)(prop-2-yn-1-yl)carbamate (75 mg, 0.22 mmol) in triethylamine (10 mL).
  • the resulting mixed reaction solution was stirred at 30 ° C for 3 hours under nitrogen protection.
  • the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 120g; mobile phase A: 0.1% NH3 ⁇ H2O in water; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 30%B-95%B in 20 minutes; detector: 214nm).
  • 2,6-Lutidine (128 mg, 1.20 mmol) and iodotrimethylsilane (240 mg, 1.20 mmol) were added to a solution of tert-butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl)(2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)benzo[d]oxazol-4-yl)amino)-3-fluoropiperidine-1-carboxylate (30 mg, 0.045 mmol) in dichloromethane (7 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure.
  • the mixed reaction liquid was diluted with water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2).
  • the combined organic phase was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 ⁇ m, 120 g; mobile phase A: pure water containing 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 85 mL/min; gradient: 5% B-95% B in 30 minutes; detector: 254 nm).
  • the obtained mixed reaction liquid was heated at 30°C and stirred for 16 hours under nitrogen protection.
  • the mixed reaction was quenched by adding water (50mL) and extracted with ethyl acetate (20mL ⁇ 2).
  • the combined organic phase was concentrated under reduced pressure.
  • the obtained mixed reaction liquid was heated at 90°C and stirred for 4 hours under nitrogen protection.
  • the mixed reaction liquid was concentrated under reduced pressure.
  • trimethylsilyl iodide (156 mg, 0.78 mmol) was added to a solution of (3S, 4R)-4-((2-(3-((tert-butyloxycarbonyl)(4-(dimethylphosphoryl)-2,3-dihydrobenzofuran-7-yl)amino)propyl-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.036 mmol) and 2,6-lutidine (83 mg, 0.78 mmol) in dichloromethane (2 mL).
  • the resulting mixed reaction solution was stirred at room temperature for 1 hour.
  • the resulting mixed reaction solution was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 ⁇ m, 40 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B-95% B in 30 minutes; detector: 214 nm).
  • the fractions containing the product were collected and concentrated under reduced pressure to obtain a crude product.
  • the mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (50 mL ⁇ 3).
  • the combined organic phase was concentrated under reduced pressure.
  • triethylamine (86 mg, 0.855 mmol, 3.0 equivalents) and cuprous iodide (6 mg, 0.03 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mol) were added to a solution of (4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)(prop-2-yn-1-yl)carbamic acid tert-butyl ester (100 mg, 0.285 mmol) and 4-bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole (138 mg, 0.342 mmol) in dimethyl sulfoxide (5 mL).
  • the obtained mixed reaction liquid was heated at 30 ° C and stirred for 5 hours under nitrogen protection.
  • the mixed reaction liquid was quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (20 mL ⁇ 2).
  • the combined organic phase was washed with saturated brine (50 mL ⁇ 3).
  • the combined organic phase was concentrated under reduced pressure.
  • the crude product was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: pure water containing 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 5% B-95% B in 30 minutes; detector: 214nm).
  • the resulting mixed reaction solution was stirred at room temperature for 2 hours.
  • the resulting mixed reaction solution was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 ⁇ m, 40 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B-95% B in 30 minutes; detector: 214 nm).
  • N-bromosuccinimide (191 mg, 1.07 mmol) and azobisisobutyronitrile (3 mg, 0.02 mmol) were added to a solution of tert-butyl 4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)carbamate (280 mg, 0.89 mmol) in carbon tetrachloride (10 mL).
  • the mixed reaction solution was heated to 85°C and stirred for 1 hour.
  • the mixed reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • triethylamine (87 mg, 0.86 mmol), cuprous iodide (5 mg, 0.03 mmol) and tetrakis(triphenylphosphine)palladium (33 mg, 0.03 mmol) were added to a solution of (4-(methylsulfonyl)benzofuran-7-yl)(prop-2-yn-1-yl)carbamic acid tert-butyl ester (100 mg, 0.29 mmol) and 4-bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole (139 mg, 0.34 mmol) in dimethyl sulfoxide (10 mL).
  • the mixed reaction liquid was heated at 30 ° C and stirred for 2 hours under nitrogen protection.
  • the mixed reaction liquid was quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the mixed reaction solution was stirred at room temperature for 1 hour.
  • the obtained mixed reaction solution was concentrated under reduced pressure.
  • the residue was purified by preparative HPLC under the following conditions: column: spherical C18, 20-40um, 80g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 5%B-60%B in 12 minutes; detector: 254nm.
  • NBS 232 mg, 1.30 mmol
  • AIBN 3 mg, 0.02 mmol
  • tert-butyl (4-(dimethylphosphoryl)-2,3-dihydrobenzofuran-7-yl)carbamate 270 mg, 0.87 mmol
  • carbon tetrachloride 30 mL
  • the mixed reaction solution was heated at 85 ° C and stirred for 1 hour.
  • the mixed reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • triethylamine 122 mg, 1.21 mmol
  • cuprous iodide 8 mg, 0.04 mmol
  • tetrakis(triphenylphosphine)palladium 47 mg, 0.04 mmol
  • 4-(dimethylphosphoryl)benzofuran-7-yl)(prop-2-yn-1-yl)benzofuraldehyde-7-yl(prop-2-ethyn-1-yl)carbamate 140 mg, 0.40 mmol
  • 4-bromo-2-iodo-1-(2.2,2-trifluoroethyl)-1H-indole 196 mg, 0.48 mmol
  • dimethyl sulfoxide 10 mL
  • the resulting mixed reaction liquid was heated at 30 ° C and stirred for 2 hours under nitrogen protection.
  • the mixed reaction liquid was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • K 2 CO 3 (208 mg, 1.51 mmol) was added to a DMF (10 mL) solution containing (7-amino-2H-spiro[benzofuran-3,1'-cyclopropane]-4-yl)dimethylphosphine oxide (300 mg, 1.26 mmol) and 3 -bromoprop- 1 -yne (750 mg, 6.30 mmol), and the mixture was heated at 70°C and stirred for 16 hours. LCMS showed that 42% of the product was generated. H 2 O (50 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL ⁇ 3).
  • BBr 3 (65.34 mL, 65.34 mmol, 1 M in DCM) was added to a solution of 1-(2-methoxy-3-nitrophenyl)cyclopropane-1-carboxylic acid methyl ester (8.2 g, 32.67 mmol) in DCM (100 mL). The mixture was stirred at 0°C for 3 hours. LCMS showed that the reaction was complete. The mixed reaction was quenched with water (100 mL) and extracted with DCM (100 mL ⁇ 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 14 14-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecane-11yl)dimethyl Synthesis of phosphine oxide (compound 14):
  • NBS 637.0 mg, 3.58 mmol
  • DMF 10 mL
  • 2H-spiro[benzofuran-3,1'-cyclopropane]-7-amine 550 mg, 3.41 mmol
  • LCMS showed that the reaction was complete.
  • H 2 O 50 mL
  • EA 50 mL ⁇ 3
  • the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • potassium carbonate (875 mg, 6.34 mmol) was added to a solution of 14-(methylsulfonyl)-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecane-11-amine (1 g, 3.15 mmol, 1.0 eq) and 3-bromoprop-1-yne (1.13 g, 9.51 mmol) in N,N-dimethylformamide (10 mL), and the mixture was heated at 70°C and stirred for 16 hours. The mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 3).
  • the mixed reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • 1,7-dibromoheptane (11.23 g, 43.55 mmol) and cesium carbonate (28.31 g, 87.09 mmol) were added to N,N-dimethylformamide (1000 mL) containing 3-nitrobenzene-1,2-diol (4.50 g, 29.03 mmol), and the mixture was heated at 100 °C and stirred for 16 hours under nitrogen protection.
  • the mixed reaction solution was concentrated under reduced pressure, diluted with water (100 mL), and then extracted with ethyl acetate (200 mL ⁇ 3). The combined polar products were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • NBS 336 mg, 1.90 mmol
  • N,N-dimethylformamide 10 mL
  • 3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]dioxacycloundecane-10-amine 400 mg, 1.81 mmol
  • the mixed reaction liquid was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • dimethylphosphine oxide (520 mg, 6.66 mmol), DIEA (1.29 g, 9.99 mmol), Xantphos (771 mg, 1.33 mmol) and Pd(OAc) 2 (297 mg, 1.33 mmol) were added to N,N-methylformamide (30 mL) containing 13-bromo-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]dioxacycloundecane- 10 -amine (1.00 g, 3.33 mmol), and the mixture was heated at 130°C and stirred for 3 hours.
  • Acetic acid (810 mg, 13.5 mmol) was added to a solution of (13-amino-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]dioxacycloundecane-10-yl)dimethylphosphine oxide (400 mg, 1.35 mmol) and (3S,4R)-3-fluoro-4-((2-(3-oxoprop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (629 mg, 1.35 mmol) in methanol (10 mL), and the mixture was stirred at room temperature for 2 hours.
  • the mixed reaction solution was diluted with dichloromethane (20 mL) and concentrated under reduced pressure.
  • the residue was passed through a fast reverse phase flash chromatography column (chromatographic column: column: spherical C18, 20-40 um, 120 g; mobile phase A: water (0.1% NH 3. H2O ); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 20% B-70% B for 25 minutes; detector: 254 nm).
  • the mixed reaction solution was diluted with water (40 mL), extracted with ethyl acetate (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Cuprous iodide (9 mg, 0.047 mmol), Pd(PPh 3 ) 4 (54 mg, 0.047 mmol) and triethylamine (143 mg, 1.41 mmol) were added to a solution of 7-bromo-2-iodo-3-(2,2,2-trifluoroethyl)benzo[b]thiophene (200 mg, 0.47 mmol) and dimethyl(14-(prop-2-yn- 1 -ylamino)-2,3,5,6,8,9-hexahydrobenzo[b1,4,7,10]tetraoxacyclododec-11-yl)phosphine oxide (247 mg, 0.70 mmol) in dimethyl sulfoxide (3 mL), and the mixture was stirred at 25° C.
  • 2,6-Lutidine (272 mg, 2.54 mmol) and iodotrimethylsilane (178 mg, 1.27 mmol) were added to a solution of tert-butyl (3S,4R)-4-((2-(3-((14-(dimethylphosphoryl)-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododec-11-yl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)benzo[b]thiophen-7-yl)amino)-3-fluoropiperidine-1-carboxylate (100 mg, 0.127 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 2 hours.
  • Pd(dppf)Cl 2 (457 mg, 0.625 mmol) was then added to a solution of 4-bromo-2H-spiro[benzofuran-3,1'-cyclopropane]-7-amine (3.0 g, 12.5 mmol) in methanol (15 mL) and TEA (45 mL), and the mixture was heated at 80°C and stirred for 16 hours under a carbon monoxide atmosphere.
  • Methylamine hydrochloride (9.7 g, 146 mmol), HATU (8.3 g, 21.9 mmol) and triethylamine (22 g, 219 mmol) were added to a DMF (100 mL) solution of 7-amino-2H-spiro[benzofuran-1,1'-cyclopropane]-4-carboxylic acid (3.0 g, 14.6 mmol) and stirred at room temperature for 5 hours. The mixed reaction solution was diluted with saturated NH 4 Cl (200 mL) and extracted with EA (100 mL ⁇ 3).
  • TMSOTf (1.65 g, 7.46 mmol) was added to a solution of (3S,4R)-3-fluoro-4-((2-(3-((4-(methylcarbamoyl)-2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)aminopiperidine-1-carboxylic acid tert-butyl ester (2.5 g, 3.73 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 1 hour.
  • the mixed reaction solution was adjusted to pH 8 with NaHCO 3 and extracted with EA (100 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (200 mL) and anhydrous Na 2 SO 4 was dried, filtered, and concentrated under reduced pressure.
  • Formaldehyde 200 mg, 6.66 mmol
  • NaBH 3 CN 234 mg, 3.66 mmol
  • 7-((3-(4-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amine)-N-methyl-2H-spiro[benzofuran-3,1'-cyclopropane] -4-carboxamide (1.9 g, 3.33 mmol) in MeOH (20 mL), and the mixture was stirred at room temperature for 5 minutes.
  • the mixed reaction solution was diluted with saturated NH 4 Cl (200 mL) and extracted with EA (100 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the residue was purified by reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40um, 330g; mobile phase A: H2O ; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%B-100%B, 15min; detector: 254nm).
  • the mixed reaction solution was quenched with water (50 mL), extracted with EA (100 mL ⁇ 3), and the combined organic phases were quenched with saturated Na 2 S 2 O 3 (50 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to a residue.
  • the mixed reaction liquid was quenched by adding water (20 mL) and extracted with EA (50 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was purified by reverse phase silica gel column chromatography (conditions: C18, 20-35um, 80g; mobile phase A: Water ( 10mM NH4HCO3 in water); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 0% B-85% B in 25min; detection wavelength: 214nm).
  • the present invention uses the following biological tests to demonstrate the efficacy and drugability of the fused ring or macrocyclic new compound of the present invention, and compares it with three reference molecules shown in the following structures:
  • Test Example 1 In vitro DNA binding assay
  • the effect of compounds on P53(Y220C) DNA binding was determined by HTRF.
  • the stock solution of the compound to be tested was prepared with DMSO and diluted to 10 concentrations in a 3-fold gradient.
  • 0.1 ⁇ L of compound was added, 2.5 ⁇ L of enzyme working solution was added, centrifuged at 1000 rpm for 1 minute, and incubated for 10 minutes.
  • 2.5 ⁇ L of MAb-Anti-His-T working solution was added and incubated for 60 minutes.
  • 5 ⁇ L of Streptavidin-d2&dsDNA working solution was added and incubated for 60 minutes.
  • the wells containing 50uM 30002 were used as high controls, and the wells containing the same ratio of dimethyl sulfoxide were used as low controls.
  • the HTRF signals at 620nm and 665nm were read on a BMG plate reader.
  • EC50 was fitted using XLfit 5.5.0.
  • Test Example 2 HUH-7 and NUGC-3 cell proliferation assay
  • the inhibitory effect of compounds on the proliferation of P53 Y220C mutant cells was determined by CTG assay.
  • HUH-7 and NUGC-3 cells were cultured in RPMI 1640 medium containing 10% FBS and 1% penicillin-streptomycin, and the cells were collected and counted.
  • Cells (40 ⁇ L/well) were seeded into 384-well microtiter plates and cultured overnight in a cell culture incubator at 37°C.
  • the stock solution of the test compound was prepared with DMSO and diluted 3-fold with cell culture medium to 10 concentrations. The diluted compounds were added to the cell plate and cultured in a 37°C 5% CO2 incubator for 5 days.
  • the cell lines and culture conditions selected for this test example are shown in Table 3-1.
  • DMSO volume actual amount ⁇ purity / (molecular weight ⁇ theoretical concentration), and prepare the compound stock solution.
  • test compound was diluted 3-fold in the corresponding culture medium to prepare 10 concentrations in total, with the initial working concentration being 10 ⁇ M;
  • Cell growth inhibition rate % [(Ac-As)/(Ac-Ab)] ⁇ 100%, the raw data was converted into cell proliferation inhibition rate according to the equation.
  • the software Graphpad Prism 8 was used and the calculation formula XY-analysis/Nonlinear regression (curve fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters) was used to fit the IC50 curve and calculate the IC50 value.
  • Reference compound 3* is literature data (from https://www.pynnaclestudy.com/file.cfm/9/docs/pc14586_aacr%202021_dumble%20et%20al.pdf)
  • # is the actual test data in the laboratory.
  • the representative compound 16 of the present invention is more sensitive to tumor cells with P53 Y220C mutation, has stronger anti-tumor cell proliferation activity, and has an activity increase of about 2 to 5 times on different cell lines.
  • Test Example 4 PK test of representative compounds in mice
  • test compound was dissolved in the dosing vehicle (IV: 5% DMSO + 5% Solutol + 90% saline; PO: 5% DMSO + 5% Solutol + 90% water) to prepare a stock solution.
  • dosing vehicle IV: 5% DMSO + 5% Solutol + 90% saline; PO: 5% DMSO + 5% Solutol + 90% water
  • This experiment used SPF-grade ICR male mice (Beijing Vital River Laboratory Animal Technology Co., Ltd), 6 mice in each group, and the drug was administered at a dose of 1 mg/kg IV and 10 mg/kg PO.
  • Plasma samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after IV administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after PO administration. (Venous blood was collected, and the blood volume was approximately 0.025 mL each time).
  • the blood collection tubes contained K 2 EDTA anticoagulant, and the sample tubes were placed on wet ice after blood collection. Plasma was separated within 1 hour after blood collection (centrifugation conditions: 3200g, 2-8°C centrifugation for 10 minutes). Plasma samples will be stored in a refrigerator at -60°C or lower until analysis.
  • the drug concentration in plasma was detected by LC-MS/MS.
  • mice The average pharmacokinetic parameters of representative compounds in mice are shown in the following table:
  • T max which is the median
  • MPK mg/kg
  • IV intravenous injection
  • PO oral administration.
  • the representative new fused-ring compound 16 of the present invention has better PK properties, including higher exposure and bioavailability, and low clearance rate, and is therefore more suitable for development as an oral drug for the prevention and treatment of diseases in animals or humans.
  • Test Example 5 In vivo efficacy of representative compounds in a nude mouse xenograft tumor model of human gastric cancer NUGC-3 cells
  • NUGC-3 cell line Human gastric cancer NUGC-3 cell line was cultured in 1640 medium + 10% fetal bovine serum + 1% double antibody at 37°C 5% CO2, and subcultured 2-3 times a week. Collect cells, centrifuge at 1000rpm for 5min to remove supernatant, resuspend cells in medium, count using cell counter, calculate total cell amount according to count concentration, centrifuge again to a cell concentration of 1*10 8 /ml, add matrix gel at 1:1, place on ice, and subcutaneously inoculate 0.2mL (1 ⁇ 10 7 ) NUGC-3 cells (with matrix gel, volume ratio of 1:1) into 6-8 week old BALB/c Nude mice to establish tumor-bearing model.
  • the animals were randomly divided into 6 groups according to body weight and tumor volume. Animals were given vehicle or test compound DR-C46 or DR-C90 by oral gavage, once a day, for a total of 18 days. During the administration period, the tumor volume and animal body weight were measured twice a week, and the animal status was observed every day. At the end point, the animals were euthanized with carbon dioxide, and the subcutaneous tumors were removed and weighed.
  • the data calculation formula is as follows:
  • Tumor volume was calculated as follows: 1/2 ⁇ a ⁇ b 2 , where a and b are the measured length and width of the tumor, respectively;
  • the tumor growth inhibition rate (%TGI TV ) was calculated as follows: (1-TV T /TV C ) ⁇ 100%, TV C was the average tumor volume of the negative control group, and TV T was the average tumor volume of the treatment group;
  • the relative tumor volume (RTV) was calculated as follows: Vt/V 0 , where V 0 was the tumor volume at the time of grouping and Vt was the tumor volume at each measurement.
  • the calculation formula of animal body weight change rate is: (BW t -BW 0 )/BW 0 ⁇ 100%, where BW t is the animal weight at each measurement, and BW 0 is the animal weight at grouping.
  • the representative compound 16 of the present invention has excellent in vivo antitumor activity and has higher tumor growth inhibitory activity than the reference compound 1 at the same dose in the human gastric cancer NUGC-3 tumor model.
  • Test Example 6 In vivo efficacy of representative compounds in a nude mouse xenograft tumor model of human pancreatic cancer BXPC-3 cells
  • the human pancreatic cancer BXPC-3 cell line was cultured in 1640 medium + 10% fetal bovine serum + 1% double antibody at 37°C 5% CO2, and subcultured 2-3 times a week.
  • the cells were collected, centrifuged at 1000rpm for 5min to remove the supernatant, resuspended in culture medium, counted using a cell counter, and the total cell volume was calculated based on the count concentration.
  • the cells were centrifuged again to a cell concentration of 5*10 7 /ml, and matrigel was added at a ratio of 1:1.
  • BXPC-3 cells (with matrigel, volume ratio of 1:1) were subcutaneously inoculated into 6-8 week old NOD SCID mice to establish a tumor-bearing model.
  • the tumor volume was monitored and grouped when it reached about 150mm3.
  • the animals were randomly divided into 7 groups according to body weight and tumor volume.
  • the animals were given the vehicle or the test compound (DR-C96, DR-C98 and DR-C90) by oral gavage, once a day, for a total of 18 days.
  • the tumor volume and animal body weight were measured twice a week, and the animal status was observed every day.
  • the animals were euthanized with carbon dioxide, and the subcutaneous tumors were removed and weighed.
  • the data calculation formula is as follows:
  • Tumor volume was calculated as follows: 1/2 ⁇ a ⁇ b 2 , where a and b are the measured length and width of the tumor, respectively;
  • the tumor growth inhibition rate (%TGI TV ) was calculated as follows: (1-TV T /TV C ) ⁇ 100%, TV C was the average tumor volume of the negative control group, and TV T was the average tumor volume of the treatment group;
  • the relative tumor volume (RTV) was calculated as follows: Vt/V 0 , where V 0 was the tumor volume at the time of grouping and Vt was the tumor volume at each measurement.
  • the calculation formula of animal body weight change rate is: (BW t -BW 0 )/BW 0 ⁇ 100%, where BW t is the animal weight at each measurement, and BW 0 is the animal weight at grouping.
  • the representative compound 16 of the present invention has excellent in vivo antitumor activity.
  • it has higher tumor growth inhibitory activity than the reference compound 3 at the same dose, and 50 mg can achieve an activity similar to that of the reference compound 3 at a dose of 100 mg.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Est divulgué dans la présente invention un nouveau composé macrohétérocyclique ou cyclique en fusion présentant un effet de régulation d'anomalies de voie de signalisation P53, et en particulier un composé présentant une structure telle que représentée dans la formule (I) ou un sel pharmaceutiquement acceptable, un solvate, un hydrate, une substitution d'isotope ou un isomère correspondant en tant que régulateur cible de mutation P53.
PCT/CN2024/110919 2023-08-09 2024-08-09 Nouveau composé hétérocyclique pour réguler une fonction p53 Pending WO2025031471A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202310999503 2023-08-09
CN202310999503.3 2023-08-09
CN202410754113.4 2024-06-12
CN202410754113 2024-06-12

Publications (1)

Publication Number Publication Date
WO2025031471A1 true WO2025031471A1 (fr) 2025-02-13

Family

ID=94533658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/110919 Pending WO2025031471A1 (fr) 2023-08-09 2024-08-09 Nouveau composé hétérocyclique pour réguler une fonction p53

Country Status (1)

Country Link
WO (1) WO2025031471A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109069481A (zh) * 2016-02-19 2018-12-21 皮姆维制药公司 用于恢复突变p53功能的方法和化合物
WO2021262483A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Méthodes et composés pour la restauration de la fonction du p53 mutant
WO2022213975A1 (fr) * 2021-04-08 2022-10-13 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant le mutant y220c de p53
WO2023016434A1 (fr) * 2021-08-10 2023-02-16 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant un mutant de p53
CN116096704A (zh) * 2020-06-24 2023-05-09 皮姆维制药公司 用于治疗癌症的组合疗法
CN117986235A (zh) * 2022-11-04 2024-05-07 长春金赛药业有限责任公司 p53-Y220C选择性小分子重激活剂化合物、药物组合物及其用途
WO2024120471A1 (fr) * 2022-12-08 2024-06-13 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant un mutant de p53

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109069481A (zh) * 2016-02-19 2018-12-21 皮姆维制药公司 用于恢复突变p53功能的方法和化合物
WO2021262483A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Méthodes et composés pour la restauration de la fonction du p53 mutant
CN116096704A (zh) * 2020-06-24 2023-05-09 皮姆维制药公司 用于治疗癌症的组合疗法
WO2022213975A1 (fr) * 2021-04-08 2022-10-13 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant le mutant y220c de p53
WO2023016434A1 (fr) * 2021-08-10 2023-02-16 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant un mutant de p53
CN117986235A (zh) * 2022-11-04 2024-05-07 长春金赛药业有限责任公司 p53-Y220C选择性小分子重激活剂化合物、药物组合物及其用途
WO2024120471A1 (fr) * 2022-12-08 2024-06-13 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant un mutant de p53

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 7 March 2023 (2023-03-07), ANONYMOUS: "7-Benzothiazolamine, 4-(dimethylphosphinyl)-N-[3-[7-[[(3S,4R)-3-fluoro-1- methyl-4-piperidinyl]amino]-3-(2,2,2-trifluoroethyl)benzo[b]thien-2-yl]-2- propyn-1-yl]- (CA INDEX NAME)", XP093274645, retrieved from STN Database accession no. 2904684-31-5 *

Similar Documents

Publication Publication Date Title
JP7716110B2 (ja) ピリミジン－４（３ｈ）－オンヘテロ環式化合物、その調製方法、およびその医薬的使用
TWI551595B (zh) 2,4-disubstituted benzene-1,5-diamine derivatives and their use, Its preparation of pharmaceutical compositions and pharmaceutical compositions
TWI697486B (zh) 作為ｈｄａｃ抑制劑之３-芳基-４-醯胺基-雙環［４,５,０］異羥肟酸
TWI624457B (zh) 四環性化合物
CN114787161B (zh) 吡唑并[1,5-a]吡啶类化合物及其制备方法和应用
WO2021063346A1 (fr) Inhibiteur de kras g12c et application associée
WO2021088945A1 (fr) Composé utilisé comme inhibiteur de shp2 et son utilisation
WO2023001123A1 (fr) Nouveau dérivé de pyridopyrimidine
WO2023174175A1 (fr) Inhibiteur de kif18a
CN118019532A (zh) 氮杂环丁烷和吡咯烷parp1抑制剂及其用途
CN114409656B (zh) Pim激酶抑制剂
CN112028870B (zh) 一种具有苄氧基芳环结构的化合物，其制备方法和用途
WO2021190417A1 (fr) Nouvel inhibiteur aminopyrimidine d'egfr
WO2022194269A1 (fr) Nouvel agent de dégradation de l'egfr
CN110461842A (zh) 作为tnf活性调节剂的稠合五环咪唑衍生物
CN106661032A (zh) 治疗或预防糖尿病、肥胖症和炎性肠病的1,3‑取代的2‑氨基吲哚衍生物及类似物
KR20250044780A (ko) Kif18a 억제제 화합물, 약제학적 조성물 및 이의 제조 방법과 적용
WO2025016457A1 (fr) Nouveau composé hétérocyclique substitué utilisé comme régulateur de flux de signal gspt/myc
CN110655520A (zh) 嘧啶并环化合物及其制备方法和应用
CN114127080A (zh) 作为激酶抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法
WO2021197467A1 (fr) Composé antitumoral multicible, son procédé de préparation et son utilisation
CN110072859A (zh) 作为RORγ调节剂的化合物
WO2023227125A1 (fr) Nouveau composé hétérocyclique fusionné en tant qu'inhibiteur de cdk et son utilisation
TWI787857B (zh) 吡唑并[1,5-a]吡啶類化合物及其製備方法和應用
WO2022174765A1 (fr) Composé cyclique fusionné utilisé comme inhibiteur de wee-1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24851115

Country of ref document: EP

Kind code of ref document: A1