WO2022247839A1 - Inhibiteur de parp7 - Google Patents

Inhibiteur de parp7 Download PDF

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Publication number
WO2022247839A1
WO2022247839A1 PCT/CN2022/094808 CN2022094808W WO2022247839A1 WO 2022247839 A1 WO2022247839 A1 WO 2022247839A1 CN 2022094808 W CN2022094808 W CN 2022094808W WO 2022247839 A1 WO2022247839 A1 WO 2022247839A1
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Prior art keywords
alkyl
alkoxy
amino
halogenated
cyano
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PCT/CN2022/094808
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English (en)
Chinese (zh)
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刘斌
陈博
田金龙
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山东轩竹医药科技有限公司
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Priority to CN202280037061.8A priority Critical patent/CN117396485A/zh
Publication of WO2022247839A1 publication Critical patent/WO2022247839A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a class of PARP7 inhibitor compounds, pharmaceutically acceptable salts or isomers thereof, and pharmaceutical compositions containing the compounds, pharmaceutically acceptable salts or isomers thereof and preparations, methods for preparing the compound, its pharmaceutically acceptable salt or its isomer, and the use of the compound, its pharmaceutically acceptable salt or its isomer.
  • the poly-ADP-ribose polymerase (Poly-ADP-ribose polymerases, PARPs) family is responsible for transferring single or multiple ADP-ribose subunits from NAD+ to substrate targets, Change the function of the target protein, perform post-translational modification, regulate basic processes such as cellular gene expression, protein degradation, and cellular stress, and participate in tumor formation. Based on the homology of the catalytic domain in the human genome, the PARP family can be divided into 17 members, each of which is highly expressed in different cancers.
  • the PARPs family can be divided into three categories according to their catalytic activity.
  • the first category belongs to PolyPARPs, including PARP 1, PARP 2, PARP 5a, and PARP 5b, which catalyze the transfer of multiple ADP-ribose subunits to the substrate.
  • the second category belongs to MonoPARPs, including PARP 3, PARP 4, PARP 6, PARP 7, PARP 8, PARP 9, PARP 10, PARP 11, PARP 12, PARP 14, PARP 15, and PARP 16 have a total of 12 members, which catalyze the transfer of a single ADP-ribose subunit to the substrate;
  • the third category includes PARP 13, which has not been found to have catalytic activity so far.
  • TIPARP TCDD-Inducible Poly-ADP-Ribose Polymerase
  • TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), TCDD)
  • Inducible poly ADP-ribose polymerase also known as PARP7 or ARTD14
  • TIPARP PARP7 or ARTD14
  • PARP7 or ARTD14 belongs to monoPARPs, which can transfer a single ADP-ribose subunit to the target protein and change the function of the target protein. It belongs to post-translational modification, participates in the regulation of life activities such as cell proliferation, and has various cellular functions.
  • the transcription factor Aryl hydrocarbon receptor belongs to the bHLH-PAS family of transcription regulators, which mainly regulates the development and physiological functions of the organism, including neurogenesis, trachea and salivary duct formation, toxin metabolism, circadian rhythm, hypoxia response and Hormone receptor function, etc., can be activated by environmental pollutants such as exogenous ligands such as TCDD, endogenous ligands such as toxic metabolites such as kynurenine, and small molecules of ligands from microorganisms and food sources. exert different biological effects.
  • exogenous ligands such as TCDD
  • endogenous ligands such as toxic metabolites such as kynurenine
  • small molecules of ligands from microorganisms and food sources exert different biological effects.
  • AHR The activation of AHR promotes the transcription and expression of downstream genes such as TIPARP (PARP7 or ARTD14), CYP1A1, among which TIPARP can negatively regulate some proteins by transferring a single ADP-ribose subunit. TIPARP can also be regulated by other transcription factors or signaling pathways.
  • TIPARP PARP7 or ARTD14
  • CYP1A1 CYP1A1
  • TIPARP can also be regulated by other transcription factors or signaling pathways.
  • TBK1 kinase In tumors or after cells are infected with viruses, cytoplasmic free RNA or DNA increases, and TBK1 kinase (TANK binding kinase 1) mainly plays a role in activating type I interferon response and antiviral immunity in this way.
  • TIPARP causes ADP-ribosylation of the kinase domain of TBK1, TBK1 changes from a free activated state to an inactive state, inhibits type I interferon response and subsequent innate immune response, and then inhibits T cell-mediated adaptive anti-tumor Immunity, ultimately affecting immune activation throughout the body. Inhibition of TIPARP can restore the type I interferon response and further improve the body's immune response.
  • TIPARP is overexpressed in lung cancer, esophageal cancer, ovarian cancer, head and neck cancer, cervical cancer and other cancers, especially in lung squamous cell carcinoma, and inhibiting TIPARP can inhibit cell proliferation. Therefore, TIPARP inhibitors can not only directly inhibit the growth of tumor cells, but also repair type I interferon signaling, and release the immune escape of tumor cells and the suppression of the immune system.
  • TIPARP inhibitors have great potential in the treatment of cancer or other related diseases, and there is no small-molecule inhibitor of this target on the market, and the development of highly efficient and low-toxic TIPARP inhibitors has important clinical significance.
  • the technical problem to be solved by the present invention is to provide a polycyclic compound with novel structure and good inhibitory effect on PARP7. Furthermore, such compounds can be used for preventing and/or treating diseases related to the overexpression of PARP7. Furthermore, such compounds can be used for the prevention and/or treatment of cancer, including carcinoma in situ and metastatic cancer.
  • the present invention provides a compound represented by the following general formula (I'), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • Ring B is a triple ring structure; the ring B is optionally substituted by 1-3 Q1 and also optionally substituted by one or more R8 ; each Q1 is independently selected from halogen, hydroxyl, amino , nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy; each R 8 is independently Selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy, cyano C 1-6 alkoxy ;
  • X, X 1 , X 2 are independently selected from -CH(R 6 )-, -N(R 7 )-, -O-, -S-, -C(O)-, -S(O)- or -S(O) 2 -;
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio;
  • Each R 4 , each R 4 ', each R 5 , each R 5 ', each R 6 are independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkane Base, halogenated C 1-6 alkyl , hydroxy C 1-6 alkyl , amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy , amino C 1-6 alkoxy, cyano C 1-6 alkoxy, 3-8 Cycloalkyl, 3-8-membered cycloalkyl-C 1-6 alkyl, 3-8-membered heterocyclyl, 3-8-membered heterocyclyl-C 1-6- alkyl, phenyl, phenyl-C 1-6 alkyl, 5-7 heteroaryl or 5-7 heteroaryl-C 1-6 alkyl;
  • Each R 7 is independently selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;
  • n and n are independently selected from 1, 2, 3 or 4;
  • the present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • X, X 1 , X 2 are independently selected from -CH(R 6 )-, -N(R 7 )-, -O-, -S-, -C(O)-, -S(O)- or -S(O) 2 -;
  • X is selected from C, CH or N;
  • X 4 is selected from N or C (R 8 );
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form an 8-11 membered fused ring cycloalkyl group, an 8-11 membered fused ring heterocyclic group, an 8- 11-membered fused-ring aryl or 8-11-membered condensed-ring heteroaryl; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1 -6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • Each R 4 , each R 4 ', each R 5 , each R 5 ', each R 6 are independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkane Base, halogenated C 1-6 alkyl , hydroxy C 1-6 alkyl , amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy , amino C 1-6 alkoxy, cyano C 1-6 alkoxy, 3-8 Cycloalkyl, 3-8-membered cycloalkyl-C 1-6 alkyl, 3-8-membered heterocyclyl, 3-8-membered heterocyclyl-C 1-6- alkyl, phenyl, phenyl-C 1-6 alkyl, 5-7 heteroaryl or 5-7 heteroaryl-C 1-6 alkyl;
  • Each R 7 is independently selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;
  • Each R is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1 -6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy - C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1 -6 alkoxy, amino C 1-6 alkoxy, cyano C 1-6 alkoxy;
  • n and n are independently selected from 1, 2, 3 or 4;
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form an 8-11 membered fused ring heterocyclic group or an 8-11 membered fused ring optionally substituted by 1-3 Q1 Ring heteroaryl; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy Or halogenated C 1-6 alkoxy.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form a 9-10 membered fused ring heterocyclic group or a 9-10 membered ring optionally substituted by 1-3 Q1 Fused ring heteroaryl; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy Base or halogenated C 1-6 alkoxy.
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form a 9-10 membered fused ring heterocyclic group optionally substituted by 1-3 Q1, 9-10 membered A condensed ring heteroaryl group containing at least one nitrogen atom or one oxygen atom; each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1- 6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group optionally substituted by 1-3 Q1:
  • Each X 3 , each X 8 , X 9 is independently selected from CH or N;
  • each X is independently selected from CH, C or N;
  • Each X 6 , each X 7 is independently selected from -CH 2 -, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O) 2- ;
  • Ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclic group, 5-7 membered aryl or 5-7 membered heteroaryl;
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 -6 alkoxy.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • Each X 3 , each X 8 , X 9 is independently selected from CH or N;
  • each X is independently selected from CH, C or N;
  • Each X 6 , X 7 is independently selected from -CH 2 -, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O) 2 - ;
  • Ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclic group, 5-7 membered aryl or 5-7 membered heteroaryl;
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 -6 alkoxy;
  • p is selected from 0, 1, 2 or 3.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • Each X 3 , each X 8 , X 9 is independently selected from CH or N;
  • each X is independently selected from CH, C or N;
  • Each X 6 , X 7 is independently selected from -CH 2 -, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O) 2 - ;
  • Ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, phenyl, pyridine Base, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, thiopyranyl, oxazinyl, azepine or diazepine;
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 -6 alkoxy;
  • p is selected from 0, 1, 2 or 3.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • Ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclic group, 5-7 membered aryl or 5-7 membered heteroaryl;
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 -6 alkoxy;
  • X3 is selected from CH or N;
  • X is selected from CH, C or N;
  • p is selected from 0, 1, 2 or 3.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • Ring A is selected from 5-7 membered aryl or 5-7 membered heteroaryl
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 -6 alkoxy;
  • p is selected from 0, 1, 2 or 3.
  • ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, Azorazolyl, phenyl, pyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, thiopyranyl, oxazinyl, azepinyl or diazepinyl.
  • Ring A is selected from 5-7 membered N-containing heteroaryls.
  • Ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl , pyrimidinyl, dihydropyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, azepine or diazepine.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 -6 alkoxy;
  • p is selected from 0, 1, 2 or 3.
  • each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl , cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 alkyl, 3-6 membered heterocyclyl, 3-6 membered hetero Cyclic group-C 1-6 alkyl, phenyl, phenyl-C 1-6 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C 1-6 alkyl.
  • L is selected from
  • X is selected from -Ch(R 6 )-, -N(R 7 )-, -O-, -S-;
  • Each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group-C 1-6 alkane Base, phenyl, phenyl-C 1-6 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C 1-6 alkyl;
  • Each R 6 and each R 7 are independently selected from H, C 1-6 alkyl or halogenated C 1-6 alkyl;
  • n and n are independently selected from 1, 2 or 3, respectively.
  • L is selected from
  • XX 1 choose X from 2 -C respectively (R alone 6 )-stand, ground-N choose (R from 7 )--C, H-(OR- 6 ,)-,-S--; N( R 7 )-, -O-, -S-, -C(O)-, -S(O)- or -S(O) 2 -;
  • X is selected from C, CH or N;
  • X 4 is selected from N or C (R 8 );
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, fluoro C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy Or fluoro C 1-6 alkoxy;
  • Each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group-C 1-6 alkane Base, phenyl, phenyl-C 1-6 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C 1-6 alkyl;
  • Each R 6 and each R 7 are independently selected from H, C 1-6 alkyl or halogenated C 1-6 alkyl;
  • Each R 8 is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, fluoro C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkane Oxygen or fluoro C 1-6 alkoxy;
  • n and n are independently selected from 1, 2 or 3;
  • q is selected from 1 or 2;
  • L is selected from
  • X is selected from -CH(R 6 )-, -N(R 7 )-, -O-, -S-;
  • Each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1 -6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 alkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group-C 1-6 alkane Base, phenyl, phenyl-C 1-6 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C 1-6 alkyl;
  • Each R 6 and each R 7 is independently selected from H, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl , cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3-6 saturated cycloalkyl, 3-6 saturated cycloalkyl-C 1-6 alkyl, 5-6 saturated heterocyclyl, 5- 6-membered saturated heterocyclic group-C 1-6 alkyl, phenyl, phenyl-C 1-6 alkyl, 5-6-membered heteroaryl or 5-6-membered heteroaryl-C 1-6 alkyl.
  • each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl , cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, 3-6 saturated cycloalkyl, 3-6 saturated cycloalkyl-methyl, 3-6 saturated cycloalkyl-ethyl, 5-6 Membered saturated heterocyclic group, 5-6 membered saturated heterocyclic group-methyl, 5-6 membered saturated heterocyclic group-ethyl, phenyl, phenyl-methyl, phenyl-ethyl, 5-6 membered heterocyclic group Aryl, 5-6 membered heteroaryl-methyl or 5-6 membered heteroaryl-ethyl
  • each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl , cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy.
  • each R 4 , each R 4 ', each R 5 , and each R 5 ' are independently selected from H, hydroxyl, amino, methyl, ethyl, propyl, iso Propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxyisopropyl, Aminomethyl, 1-aminoethyl, 2-aminoethyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, methoxymethyl, methoxyethyl, ethoxy Methyl, ethoxyethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy or 1,1,1- Trifluoroethyl.
  • X 1 and X 2 are independently selected from -CH(R 6 )-, -N(R 7 )-, -O-, -S-, -C(O)-, - S(O)- or -S(O) 2 -;
  • Each R 6 and each R 7 is independently selected from H, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • each R 6 and each R 7 are independently selected from H, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl group, 1,1,1-trifluoroethyl.
  • X 1 and X 2 are independently selected from -CH(R 6 )-, -N(R 7 )-, -O-, -S- or -C(O)-;
  • Each R 6 and each R 7 are independently selected from H or C 1-6 alkyl.
  • each R 6 and each R 7 is independently selected from H, methyl, ethyl, propyl or isopropyl.
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, fluoro C 1-6 alkyl, cyano C 1-6 alkyl , C 1-6 alkoxy or fluoro C 1-6 alkoxy.
  • R is selected from H, halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl methoxy, ethoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • X4 is selected from N or CH.
  • each R 8 is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, fluoro C 1-6 alkyl, cyano C 1-6 Alkyl, C 1-6 alkoxy or fluoro C 1-6 alkoxy.
  • each R is independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoro Methyl, cyanomethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • q is selected from 1 or 2.
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or its isomer wherein,
  • L is X is selected from -CH 2 -, -NH-, -O- or -S-;
  • X 1 is selected from -N(R 7 )-, -O- or -S-;
  • X 2 is selected from -CH(R 6 )- or -C(O)-;
  • X is selected from N or CH
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • X3 is selected from CH or N;
  • X is selected from CH, C or N;
  • X 6 and X 7 are independently selected from -CH 2 -, -NH-, -O-, -S-, -C(O)-, -S(O)- or -S(O) 2 -;
  • X 8 and X 9 are independently selected from C(R 9 ) or N;
  • Ring A is selected from phenyl or 5-6 membered nitrogen-containing heteroaryl
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 4 , R 4 ', R 6 are independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkane group, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy Base, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or cyano C 1-6 alkoxy;
  • R 7 is selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;
  • Each R 8 is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkoxy, amino C 1-6 alkoxy, cyano C 1-6 alkoxy;
  • Each R 9 is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • p is selected from 0, 1 or 2;
  • q is selected from 1 or 2.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or its isomer wherein,
  • L is X is selected from -O- or -S-;
  • X 1 is selected from -N(R 7 )-;
  • X 2 is selected from -CH(R 6 )- or -C(O)-;
  • X is selected from N or CH
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • Ring A is selected from phenyl or 5-6 membered heteroaryl containing 1-3 nitrogens;
  • Q1 is selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 4 , R 4 ', R 6 are independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkane group, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy Base, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy or cyano C 1-6 alkoxy;
  • R 7 is selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;
  • Each R 8 is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkoxy, amino C 1-6 alkoxy, cyano C 1-6 alkoxy;
  • Each R 9 is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or its isomer wherein,
  • L is X is selected from -O- or -S-;
  • X 1 is selected from -N(R 7 )-;
  • X 2 is selected from -CH(R 6 )- or -C(O)-;
  • X is selected from N or CH
  • R is selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkoxy, C 1 -4 alkylthio, halogenated C 1-4 alkoxy or halogenated C 1-4 alkylthio;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • Ring A is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl or triazolyl;
  • Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • R 4 and R 4 ' are independently selected from H, halogen, hydroxyl, amino, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl , C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkoxy or amino C 1-4 alkoxy base;
  • R6 is H
  • R is selected from H, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl or amino C 1-4 alkyl;
  • Each R is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkane group, cyano C 1-4 alkyl, C 1-4 alkoxy - C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkane Oxygen, amino C 1-4 alkoxy, cyano C 1-4 alkoxy;
  • Each R 9 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, or triazolyl.
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or its isomer wherein,
  • L is X is selected from -O- or -S-;
  • X 1 is selected from -N(R 7 )-;
  • X 2 is selected from -CH(R 6 )- or -C(O)-;
  • X is selected from N or CH
  • R is selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkoxy, C 1 -4 alkylthio, halogenated C 1-4 alkoxy or halogenated C 1-4 alkylthio;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • R 4 and R 4 ' are independently selected from H, halogen, hydroxyl, amino, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl , C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkoxy or amino C 1-4 alkoxy base;
  • R6 is H
  • R is selected from H, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl or amino C 1-4 alkyl;
  • Each R is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkane group, cyano C 1-4 alkyl, C 1-4 alkoxy - C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkane Oxygen, amino C 1-4 alkoxy, cyano C 1-4 alkoxy;
  • Each R 9 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or its isomer wherein,
  • L is X is selected from -O- or -S-;
  • X 1 is selected from -N(R 7 )-;
  • X 2 is selected from -CH(R 6 )- or -C(O)-;
  • X is selected from N or CH
  • R is selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, fluoro C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkoxy or fluoro C 1-4 alkoxy;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 alkyl, fluoro C 1-4 alkyl, C 1-4 alkoxy or fluoro C 1-4 alkoxy;
  • R 4 and R 4 ' are independently selected from H, halogen, hydroxyl, amino, C 1-4 alkyl, fluoro C 1-4 alkyl, C 1-4 alkoxy or fluoro C 1-4 alkane Oxygen;
  • R6 is H
  • R 7 is selected from H or C 1-4 alkyl
  • Each R is independently selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, fluoro C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkane Group, cyano C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy or fluoro C 1-4 alkoxy;
  • Each R 9 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, fluoro C 1-4 alkyl, C 1-4 alkoxy or fluoro C 1-4 alkoxy;
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or its isomer wherein,
  • L is X is selected from -O- or -S-;
  • X 1 is selected from -N(R 7 )-;
  • X 2 is selected from -CH(R 6 )- or -C(O)-;
  • X is selected from N or CH
  • R is selected from H, halogen, hydroxyl, amino, cyano, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, methoxy, ethoxy, mono Fluoromethoxy, difluoromethoxy or trifluoromethoxy;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • Q1 is selected from halogen, hydroxy, amino, cyano, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, fluoromethoxy , difluoromethoxy or trifluoromethoxy;
  • R 4 and R 4 ' are independently selected from H, halogen, hydroxyl, amino, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy;
  • R6 is H
  • R is selected from H, methyl, ethyl or isopropyl
  • Each R is independently selected from H, halogen, hydroxyl, amino, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethyl Oxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, aminomethyl, cyanomethyl or methoxymethyl;
  • Each R is independently selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy;
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • the present invention provides a compound represented by the following general formula (II), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • R 1 , R 2 , R 3 , R 7 , R 8 , L, X 3 , X 4 , Q1, X, R 4 , R 4 ' , R 5 , R 5' , m, n, q, imaginary key The definition of is as described in any scheme above.
  • the compound represented by general formula (II), its pharmaceutically acceptable salt or its isomer wherein,
  • L is X is selected from -O- or -S-;
  • X is selected from N or CH
  • R is selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkoxy or halo C 1-4 alkoxy;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • Ring A is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl or 1,2,4-triazolyl;
  • Q1 is selected from halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • R 4 and R 4 ' are independently selected from H, halogen, hydroxyl, amino, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl Or C 1-4 alkoxy-C 1-4 alkyl;
  • R 7 is selected from H or C 1-4 alkyl
  • R is selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkoxy;
  • Each R 9 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 alkyl or halogenated C 1-4 alkyl; p is 1; q is 1.
  • R 2 , R 3 , the carbon atom connected to R 2 , and X 3 together form the following group:
  • the present invention provides a compound represented by the following general formula (III-1) or general formula (III-2), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • R 1 , R 2 , R 3 , R 8 , X 3 , X 4 , R 5 , R 5' , Q1, q, virtual bond The definition of is as described in any scheme above.
  • the present invention provides a compound represented by the following general formula (IV-1) or general formula (IV-2), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • R 1 , R 8 , X 4 , Q1, and q are as described in any scheme above.
  • the present invention provides a compound represented by the following general formula (IV-3), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • R 1 , R 8 , X 4 , Q1, and q are as described in any scheme above.
  • the compound represented by general formula (IV-3), its pharmaceutically acceptable salt or its isomer wherein,
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio;
  • Each R is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1 -6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1 -6 alkoxy, amino C 1-6 alkoxy, cyano C 1-6 alkoxy;
  • X 4 is N
  • Q1 is selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy ;
  • q is selected from 1 or 2.
  • the present invention provides a compound represented by the following general formula (IV-4), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • R 1 , R 8 , R 9 , X 4 , Q1, p, and q are as described in any of the above schemes;
  • Ring A is selected from phenyl, pyridyl, pyrimidinyl or pyrazinyl.
  • the present invention provides a compound represented by the following general formula (IV-5), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • R 1 , R 8 , R 9 , X 4 , Q1, p, and q are as described in any of the above schemes.
  • the compound represented by general formula (IV-5), its pharmaceutically acceptable salt or its isomer wherein,
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio;
  • Each R is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1 -6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy - C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1 -6 alkoxy, amino C 1-6 alkoxy, cyano C 1-6 alkoxy;
  • R is selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group;
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1 -6 alkoxy;
  • X 4 is N
  • p is selected from 1 or 2;
  • q is selected from 1 or 2.
  • the compound represented by general formula (I), its pharmaceutically acceptable salt or its isomer in certain embodiments, its pharmaceutically acceptable salt or its isomer,
  • L is X is selected from -O- or -S-;
  • X 1 is selected from -N(R 7 )-;
  • X2 is -C(O)-
  • X 4 is N
  • R is selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, halogenated C 1-6 alkoxy or halogenated C 1-6 alkylthio;
  • R 2 , R 3 and the carbon atom connected to R 2 and X 3 together form the following group:
  • Each Q1 is independently selected from halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 4 and R 4 ' are independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl , C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkoxy, amino C 1-6 alkoxy or cyano C 1-6 alkoxy;
  • R 7 is selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl or amino C 1-6 alkyl;
  • Each R 8 is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1 -6 alkyl, cyano C 1-6 alkyl, C 1-6 alkoxy - C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1 -6 alkoxy, amino C 1-6 alkoxy, cyano C 1-6 alkoxy;
  • R is selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group;
  • p is selected from 0, 1 or 2;
  • q is selected from 1 or 2.
  • the present invention also provides the following compounds, their pharmaceutically acceptable salts or their isomers,
  • the present invention also provides a pharmaceutical composition containing the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2) ), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5) described compound, its pharmaceutically acceptable salt or its isomer, and one or more pharmaceutically acceptable excipients, the pharmaceutical composition can be in any pharmaceutically acceptable dosage form.
  • a pharmaceutically acceptable excipient is a substance that is nontoxic, compatible with the active ingredient and otherwise biologically suitable for the organism. The choice of a particular excipient will depend on the mode of administration or the type and state of the disease being used to treat the particular patient.
  • the pharmaceutical compositions described above can be administered orally, parenterally, rectally, or pulmonary to a patient or subject in need of such treatment.
  • the pharmaceutical composition can be made into oral preparations, for example, it can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc.
  • the above pharmaceutical composition can also be made into injections, including injections, sterile powders for injections and concentrated solutions for injections.
  • the pharmaceutical composition can be made into suppositories and the like.
  • the pharmaceutical composition can be made into inhalation preparations, aerosols, powder mists or sprays and the like.
  • the present invention also relates to the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV- 1), the compound described in general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5), its pharmaceutically acceptable salt or its isomer Use in the preparation of medicaments for preventing and/or treating diseases associated with PARP7 overactivation.
  • the present invention also relates to the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV- 1), the compound described in general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5), its pharmaceutically acceptable salt or its isomer Use in the preparation of a medicament for preventing and/or treating cancer, including carcinoma in situ and metastatic cancer.
  • the present invention also relates to a compound containing the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV-1) ), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5) described compound, its pharmaceutically acceptable salt or its isomer Use of the pharmaceutical composition in preparing medicines for preventing and/or treating diseases related to PARP7 overactivation.
  • the present invention also relates to a compound containing the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV-1) ), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5) described compound, its pharmaceutically acceptable salt or its isomer
  • a compound containing the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV-1) ), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5) described compound containing the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV-1) ), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5) described compound, its pharmaceutically acceptable salt or its isomer
  • the pharmaceutical composition of the present invention comprises the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2) , general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5) described compound, its pharmaceutically acceptable Salts or isomers thereof may also contain one or more second therapeutically active agents selected from anticancer agents, which may alleviate or reduce the effect of the compounds of the present invention on the A drug that produces one or more side effects during the disease, or a drug that enhances the efficacy of the compound of the present invention.
  • the present invention also provides a method for treating diseases associated with PARP7 overactivation, the method comprising administering to patients in need an effective amount of the aforementioned general formula (I'), general formula (I), general formula Formula (II), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV- 4) or the compound described in general formula (IV-5), its pharmaceutically acceptable salt or its isomer, the aforementioned pharmaceutical composition.
  • the present invention also provides a method for treating cancer, the method comprising administering an effective amount of the aforementioned general formula (I'), general formula (I), general formula (II), general formula ( III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV- 5)
  • the compound, its pharmaceutically acceptable salt or its isomer, the aforementioned pharmaceutical composition comprising administering an effective amount of the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV- 5)
  • the compound, its pharmaceutically acceptable salt or its isomer, the aforementioned pharmaceutical composition comprising administering an effective amount of the aforementioned general formula (I'), general formula (I), general formula (II), general formula ( III-1), general formula (III-2), general formula (IV-1), general formula (
  • the present invention also provides a kit comprising an effective amount of one or more of the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1 ), general formula (III-2), general formula (IV-1) or, formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5)
  • kit comprising an effective amount of one or more of the aforementioned general formula (I'), general formula (I), general formula (II), general formula (III-1 ), general formula (III-2), general formula (IV-1) or, formula (IV-2), general formula (IV-3), general formula (IV-4) or general formula (IV-5)
  • the above-mentioned compound its pharmaceutically acceptable salt or its isomer.
  • the present invention also provides a kit, comprising:
  • the "anti-cancer agent” in the present invention refers to a drug that has a certain therapeutic effect on tumors, including but not limited to mitosis inhibitors, alkylating agents, anti-metabolites, DNA chimeric agents, anti-tumor antibiotics, growth factor inhibitors, Signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor regulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth Inhibitors, targeting antibodies, HMG-CoA reductase inhibitors and protein prenyl transferase inhibitors, etc.
  • the "effective amount” refers to the dose of the drug that can prevent, alleviate, delay, inhibit or cure the subject's symptoms.
  • the dosage is related to the way of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the individual signs (gender, weight, height, age) of the subject.
  • halogen in the present invention refers to fluorine atom, chlorine atom, bromine atom or iodine atom.
  • C 1-6 alkyl in the present invention means a linear or branched alkyl group containing 1-6 carbon atoms, including, for example, “C 1-4 alkyl”, “C 1-3 alkyl” , “C 1-2 alkyl”, “C 2-6 alkyl”, “C 2-5 alkyl”, “C 2-4 alkyl”, “C 2-3 alkyl”, etc.
  • C 1-4 alkyl in the present invention refers to specific examples of C 1-6 alkyl containing 1-4 carbon atoms.
  • C 1-6 alkoxy in the present invention refers to “C 1-6 alkyl-O-", and the “C 1-6 alkyl” is as defined above.
  • C 1-4 alkoxy in the present invention refers to “C 1-4 alkyl-O-”, and the “C 1-4 alkyl” is as defined above.
  • C 1-6 alkylthio in the present invention refers to “C 1-6 alkyl-S-", and the “C 1-6 alkyl” is as defined above.
  • C 1-4 alkylthio in the present invention refers to “C 1-4 alkyl-S-”, and the “C 1-4 alkyl” is as defined above.
  • 6 Alkyl means that one or more hydrogens in a C 1-6 alkyl group are replaced by one or more hydroxyl, amino, halogen, cyano or C 1-6 alkoxy groups.
  • C 1-6 alkyl and C 1-6 alkoxy are as defined above.
  • Hydrochlor C 1-6 alkoxy, amino C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano C 1-6 alkoxy in the present invention means "C 1-6 One or more hydrogens in “alkoxy” are replaced by one or more hydroxyl, amino, halogen or cyano groups.
  • Hydrogens are replaced by one or more hydroxy, amino or halo.
  • fluoro C 1-6 alkyl and fluoro C 1-6 alkoxy in the present invention refer to one or more of “C 1-6 alkyl” and “C 1-6 alkoxy” Multiple hydrogens are replaced by one or more fluorine atoms.
  • the "3-8 membered cycloalkyl group” in the present invention refers to a saturated or partially saturated and non-aromatic monocyclic ring group containing 3-8 ring atoms.
  • the "3-8 membered cycloalkyl group” described in the present invention 8-membered cycloalkyl” includes “3-8-membered saturated cycloalkyl” and “3-8-membered partially saturated cycloalkyl”, such as “3-6-membered cycloalkyl", “3-6-membered saturated cycloalkane ", "5-7 membered cycloalkyl group”, “5-7 membered saturated cycloalkyl group”, “5-6 membered cycloalkyl group”, “5-6 membered saturated cycloalkyl group”, etc.
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl, and the like.
  • the "3-8 membered heterocyclic group” in the present invention refers to a heterocyclic group containing at least one (for example, containing 1, 2, 3, 4 or 5) heteroatoms and the number of ring atoms is 3-8
  • a saturated or partially saturated and non-aromatic monocyclic ring group the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom (such as a carbon atom) in the ring structure , nitrogen atom or sulfur atom) can be oxo.
  • the "3-8 membered heterocyclic group” in the present invention includes "3-8 membered saturated heterocyclic group” and "3-8 membered partially saturated heterocyclic group”.
  • the “3-8 membered heterocyclic group” is, for example, "3-6 membered heterocyclic group", “3-6 membered saturated heterocyclic group", “3-7 membered heterocyclic group”, “3-7 membered saturated "Heterocyclic group”, "5-7 membered heterocyclic group”, “5-7 membered saturated heterocyclic group”, “5-6 membered heterocyclic group”, “5-6 membered saturated heterocyclic group” and the like.
  • the "3-8 membered cycloalkyl-C 1-6 alkyl” and “3-8 membered heterocyclyl-C 1-6 alkyl” in the present invention refer to 3-8 membered cycloalkyl-C 1 -6 alkyl-", “3-8 membered heterocyclyl-C 1-6 alkyl-", among them, "3-8 membered cycloalkyl", “3-8 membered heterocyclyl", "C 1 -6 alkyl” is as defined above.
  • the "8-11 membered fused ring cycloalkyl group" in the present invention refers to a group consisting of two or more ring structures sharing two adjacent atoms, containing 8-11 ring carbon atoms, Saturated or partially saturated, non-aromatic cyclic group, one of the rings in the condensed ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, examples include but are not limited to: Wait.
  • the "8-11 membered condensed ring heterocyclic group" in the present invention refers to a group formed by two or more ring structures that share two adjacent atoms with each other, containing 8-11 ring atoms, and at least One of the ring atoms is a heteroatom, saturated or partially saturated, non-aromatic cyclic group, one of the rings in the condensed ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom.
  • ring atoms such as carbon atoms, nitrogen atoms or sulfur atoms
  • in the ring structure may optionally be substituted by oxo.
  • the "8-11 membered fused ring aryl group” in the present invention refers to an unsaturated, unsaturated ring structure containing 8-11 ring carbon atoms formed by sharing two adjacent atoms with each other.
  • Aromatic cyclic groups include "9-10 membered fused ring aryl groups", and specific examples include but are not limited to naphthyl.
  • the "8-11 membered condensed ring heteroaryl" in the present invention refers to a group formed by two or more ring structures sharing two adjacent atoms with each other, containing 8-11 ring atoms ( An unsaturated aromatic ring structure in which at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Wherein, ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure may optionally be substituted by oxo.
  • the fusion method can be 5-membered nitrogen-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 6-membered Nitrogen-containing heteroaryl and 5-6-membered nitrogen-containing heteroaryl, 5-6-membered aryl and 5-6-heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolopyrrole, pyrrolopyrimidine, Pyrrolopyridine, pyrazolopyrrole, pyrazolopyrimidine, pyrazolothiophene, pyrazoloxazole, benzofuryl, benzoisofuryl, benzothienyl, indolyl, isoindolyl, Benzoxazolyl, benzimidazolyl, etc.
  • the "5-7 membered heteroaryl" in the present invention refers to an aromatic monocyclic ring containing 5-7 ring atoms (wherein at least one ring atom is a heteroatom, such as nitrogen atom, oxygen atom or sulfur atom) cyclic group.
  • ring atoms such as carbon atoms, nitrogen atoms or sulfur atoms
  • oxo may optionally be substituted by oxo.
  • the heteroatoms in the "nitrogen-containing heteroaryl” are at least Contains a nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or, contains a nitrogen atom and 1 or 2 other heteroatoms (such as oxygen atoms and/or sulfur atoms), or, contains 2 nitrogen atoms atom and 1 or 2 other heteroatoms (such as oxygen and/or sulfur atoms).
  • 5-7 membered heteroaryl include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl , imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1, 2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepanyl, 1,3-diazepanyl Wait.
  • N described in the present invention refers to the following structure:
  • Each R 4 in the present invention means that when m is 2, 3 or 4, each R 4 among multiple R 4 is independently selected from the groups described in the above technical scheme.
  • each R 4 ' in the present invention means that when m is 2, 3 or 4, each R 4 ' in multiple R 4 's is independently selected from the groups described in the above technical scheme.
  • Each R 5 in the present invention means that when n is 2, 3 or 4, each R 5 among multiple R 5 is independently selected from the groups described in the above technical scheme.
  • each R 5 ' in the present invention means that when n is 2, 3 or 4, each R 5 ' in multiple R 5 's is independently selected from the groups described in the above technical scheme.
  • each R 6 in the present invention means that when X, X 1 and X 2 are "-CH(R 6 )-" at the same time, each R 6 in multiple R 6 is independently selected from the above technical solutions group described.
  • each R 7 in the present invention means that when X, X 1 and X 2 are "-N(R 7 )-" at the same time, each R 7 in multiple R 7 is independently selected from the above technical solutions group described.
  • the link between ring A and the adjacent ring can be a single bond or The double bond, mainly depends on the structure of ring A.
  • the “pharmaceutically acceptable salt” in the present invention refers to the salt formed by the acidic functional group (such as -COOH, -OH, -SO 3 H, etc.) present in the compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, salts formed with nitrogen-containing organic bases; and salts formed with appropriate inorganic or organic anions (acids) of basic functional groups (such as -NH2, etc.) present in compounds , including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.).
  • the acidic functional group such as -COOH, -OH, -SO 3 H, etc.
  • base an appropriate inorganic or organic cation
  • salts formed with appropriate inorganic or organic anions (acids) of basic functional groups such
  • the “isomer” in the present invention means that the compound of the present invention contains one or more asymmetric centers, so it can be used as racemate and racemic mixture, single enantiomer, diastereoisomer Mixtures and individual diastereomers.
  • the compounds of the present invention may have asymmetric centers, each of which independently produces two optical isomers.
  • the scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers.
  • the compounds described in the present invention may exist in the form of tautomers (one of functional group isomers), which have different points of attachment of hydrogen by displacement of one or more double bonds, for example, ketones and its alkenes
  • the alcohol form is a keto-enol tautomer.
  • the compound of the present invention contains a spiro ring structure. Affected by the three-dimensional structure of the ring, substituents on the ring may exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers. Each tautomer and mixtures thereof are included within the scope of the present invention. Enantiomers, diastereoisomers, racemates, mesoisomers, cis-trans isomers, tautomers, geometric isomers, epimers and their Mixtures and the like are included in the scope of the present invention.
  • the compounds of the present invention may be prepared in the form of individual enantiomers by enantiospecific synthesis or resolution from enantiomeric mixtures.
  • Conventional resolution techniques include resolution of enantiomeric mixtures of starting materials or final products using various well known chromatographic methods.
  • stereochemistry of a disclosed compound is named or depicted by a structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% by weight relative to the other stereoisomers Or 99.9% pure by weight.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight.
  • Optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.
  • the compound of the present invention has excellent PARP7 inhibitory effect, and it has good pharmacokinetic properties in vivo, long-lasting effect and high bioavailability.
  • the compound of the present invention has good therapeutic effect on cancer, and has high stability of liver microsome.
  • the preparation process of the compound of the present invention is simple, the drug has high purity and stable quality, and is easy to carry out large-scale industrial production.
  • DIPEA N,N-Diisopropylethylamine
  • DMSO Dimethylsulfoxide
  • KOtBu Potassium tert-butoxide
  • TFA Trifluoroacetic acid
  • DCM Dichloromethane
  • HATU N,N,N′,N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate
  • TfOH trifluoromethanesulfonic acid
  • DABCO triethylenediamine
  • DMF N,N-dimethyl
  • DMA N,N-dimethylacetamide
  • Pd(tBu 3 P) 2 bis(tri-tert-butylphosphine) palladium
  • TMSCF 3 (trifluoromethyl)trimethylsilane
  • PhI( OAc) 2 iodobenzene diacetate
  • NBS N-bromosuccinimide
  • NMP N-methylpyr
  • reaction solution was poured into a saturated sodium bicarbonate solution, extracted 3 times with dichloromethane, the dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by reverse phase column (70% methanol/water system) and silica gel preparation plate (Ethyl acetate was used as developing solvent) to obtain the target compound (25 mg, two-step yield: 32.4%).
  • the reaction solution was poured into a saturated sodium bicarbonate solution, extracted 3 times with dichloromethane, the dichloromethane layers were combined, the solvent was distilled off under reduced pressure, and the residue was purified by a reverse-phase column (70% methanol/water system) and a silica gel preparation plate Purification (ethyl acetate as developing solvent) gave the target compound (12 mg, yield: 52.2%).
  • the reaction solution was poured into a saturated sodium bicarbonate solution, extracted 3 times with dichloromethane, the dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified on a silica gel plate (ethyl acetate was a developing solvent) and high-pressure HPLC ( 90% methanol/water system) to obtain the target compound (8 mg, yield: 21.8%).
  • the organic phase was spin-dried under reduced pressure
  • reaction solution was poured into saturated sodium bicarbonate solution, extracted 3 times with dichloromethane, the dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by reverse phase column (50% acetonitrile/water system) to obtain the target compound ( 7mg, yield 6.8%).
  • Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(trifluoromethyl)-1H-indole-2-carboxylate 780 mg, 1.9 mmol was dissolved in EA ( 6 mL), added hydrochloric acid ethyl acetate solution (30 mL), and reacted at 25°C for 1 h. After the reaction was completed, it was spin-dried and used directly for the next reaction.
  • the reaction solution was poured into saturated sodium bicarbonate solution, extracted 3 times with dichloromethane, the dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by reverse phase column (50% acetonitrile/water system) to obtain the target compound ( 22 mg, yield 89.9%).
  • ethyl acetate hydrochloride solution (4 mL) was added to the solution containing 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-ethyl-5-(trifluoromethyl)-1H- Ethyl pyrrolo[2,3-b]pyridine-2-carboxylate (150mg, 0.35mmol) in ethyl acetate (4mL) was reacted at 30°C for 3h. After the reaction was completed, the reaction solution was directly evaporated to dryness under reduced pressure to obtain a crude product, which was directly used in the next reaction.
  • reaction solution was poured into a saturated sodium bicarbonate solution, extracted 3 times with dichloromethane, the dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified by reverse phase column (70% methanol/water system) and silica gel preparation plate (Ethyl acetate is the developer) to obtain the target compound (40mg, two-step combined yield: 32.0%)
  • TfOH (0.5mL) was added dropwise to the )-8,9-dihydropyridin[3',2':4,5]pyrrole[1,2-a]pyrazin-7(6H)-yl)-3-oxopropoxy)propane-2 -yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (70mg, 0.10mmol) in trifluoroacetic acid (5mL) was reacted at 25°C for 0.5h.
  • Trifluoroacetic acid (4mL) was added dropwise to a solution of pyrazine-7(6H)-carboxylate (740mg, 1.9mmol) in dichloromethane (8mL), stirred at 25°C for 2h, the reaction was completed, and the reaction was spin-dried solution, the crude product (1.3 g) was obtained, which was directly used in the next reaction.
  • the reaction solution Concentrate, adjust the pH to alkaline with saturated sodium bicarbonate solution, extract the aqueous phase once with DCM, combine the organic phases and concentrate to obtain the target compound (2.6 g, yield 90.3%).
  • the reaction liquid was extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (40mg, yield: 98.3% ).
  • the reaction solution was spin-dried under reduced pressure, and the residue was purified on a large silica gel plate (ethyl acetate was used as a developing solvent) to obtain the target compound (65 mg, yield: 60.4%).
  • the reaction solution was poured into a saturated sodium bicarbonate solution, extracted 3 times with dichloromethane, the dichloromethane layers were combined, the solvent was removed under reduced pressure, and the residue was purified on a silica gel preparation plate (ethyl acetate as a developing solvent) to obtain the target compound (25 mg, Yield: 47.1%).
  • Test substance the compound in Table 1 of the present invention, its structural formula and preparation method are shown in the preparation example of the present invention
  • Compound A is prepared according to the prior art method, and the structure of compound A is as follows;
  • DMSO dimethyl sulfoxide
  • PBS phosphate buffer saline
  • PBST Phosphate buffered saline containing Tween 20;
  • PARP7 enzyme use 1 ⁇ PARP buffer to prepare PARP7 enzyme working solution
  • Streptavidin-HRP solution use blocking buffer to dilute 50 ⁇ streptavidin-HRP into 1 ⁇ working solution;
  • Detection solution Substrate A solution and substrate B solution are mixed 1:1, prepared immediately for use, and mixed on ice.
  • Blocking 200 ⁇ l blocking buffer solution 3/well, incubate at room temperature for 60 minutes;
  • test compound 5 ⁇ l/well; add 5 ⁇ l 0.1% DMSO to positive control wells and blank wells;
  • Add enzyme add 20 ⁇ l/well PARP7 enzyme to positive control wells and test compound wells, add 20 ⁇ l 1 ⁇ PARP buffer to blank wells, and incubate at room temperature for 1 hour;
  • Curves were obtained by fitting the data using non-linear S-curve regression, from which relative IC50 values were calculated.
  • the compounds in Table 1 of the present invention have good inhibitory activity on PARP7, and their IC 50 values are all less than 1 ⁇ M. Among them, the IC 50 values of the test representative compounds are all less than 100 nM, showing good inhibitory activity.
  • Test substance the compound in Table 1 of the present invention, its structural formula and preparation method are shown in the preparation example of the present invention
  • Compound A is prepared according to the prior art method, and the structure of compound A is as follows;
  • DMSO dimethyl sulfoxide
  • GI 50 The concentration of the compound corresponding to 50% inhibition of cell growth
  • test compound gradient dilution solution take 10 mM test compound stock solution and perform 3-fold serial gradient dilution with DMSO. Take 2 ⁇ L of the compound diluted in DMSO and add it to 198 ⁇ L of culture solution containing 10% FBS to prepare 10 times the test substance. The highest concentration of the test substance is 100 ⁇ M, and the concentration of DMSO is 1%. There are 8 concentration gradients in total.
  • day 0 (D0) plates were used for CTG detection.
  • the data were fitted using non-linear S-curve regression to generate dose-response curves, from which absolute GI 50 values were calculated.
  • the compounds in Table 1 of the present invention have a good inhibitory effect on NCI-H1373 cell proliferation, and the GI 50 value of some compounds on NCI-H1373 cell proliferation inhibition is less than 100nM.

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Abstract

La présente invention concerne le domaine technique des médicaments et, en particulier, un composé inhibiteur de la kinase PARP7 représenté par la formule générale (I), un sel ou isomère pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique contenant le composé et le sel ou isomère pharmaceutiquement acceptable de celui-ci, un procédé de préparation du composé et du sel ou isomère pharmaceutiquement acceptable de celui-ci, et une utilisation du composé et du sel ou isomère pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/094808 2021-05-25 2022-05-25 Inhibiteur de parp7 WO2022247839A1 (fr)

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WO2020223229A1 (fr) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Formes solides d'un inhibiteur de parp7
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2021087018A1 (fr) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones utilisées en tant qu'inhibiteurs de parp7
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CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2020223229A1 (fr) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Formes solides d'un inhibiteur de parp7
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