WO2023041066A1 - Dérivé de dihydropyrazolone contenant de la pyrimidine, sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son application - Google Patents

Dérivé de dihydropyrazolone contenant de la pyrimidine, sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son application Download PDF

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WO2023041066A1
WO2023041066A1 PCT/CN2022/119440 CN2022119440W WO2023041066A1 WO 2023041066 A1 WO2023041066 A1 WO 2023041066A1 CN 2022119440 W CN2022119440 W CN 2022119440W WO 2023041066 A1 WO2023041066 A1 WO 2023041066A1
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membered
alkyl
heterocyclic group
cycloalkyl
aryl
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周国强
魏毅
袁宏斌
刘康志
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优领医药科技(香港)有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicine synthesis. It specifically relates to derivatives containing pyrimidodihydropyrazolones, their pharmaceutically acceptable salts and their preparation methods, and their application as biological inhibitors in the preparation of medicines for treating cancer.
  • Wee1-Like Protein Kinase 1 (Wee1-Like Protein Kinase 1, Wee1) is a member of the human Wee protein kinase family. It is highly conserved in evolution and exists in various eukaryotes in large quantities. Wee1 kinase is a key regulatory hub in DNA replication, histone transcription and chromosome condensation, and the abnormality of these biological processes will definitely affect the integrity of chromatin, the transmission of genetic material and the characteristics of epigenetics, the structure of histones Alteration, loss of chromosomes, structural changes of chromatin and the occurrence and development of malignant tumors are closely related.
  • the Wee protein kinase family includes Wee1-A, Wee1-B and Myt1 three protein kinases.
  • Wee1-A mainly exists in somatic cells
  • Wee1-B mainly exists in embryonic cells
  • Myt1 exists in both somatic cells and embryonic cells.
  • Wee1 kinase was originally studied from yeast, and Wee1 is a cell division cycle mutant with low expression in yeast.
  • Human Wee1 kinase is a key target in the regulation of cell cycle G2 phase to M phase. Before the cell cycle enters mitosis, Wee1 kinase promotes its completion of DNA replication and DNA damage repair. Wee1 is very active in the S phase and G2 phase of the cell cycle.
  • Cdc2 cell division control protein 2
  • Single-celled eukaryotes such as budding or fission yeast can survive after gene knockout of Wee1, and mouse embryos knocked out of Wee1 die at the blastocyst stage because the cells cannot continue to proliferate. Chromosome condensation is also regulated by Wee1 kinase. Fasulo et al.
  • Wee1 kinase is a key kinase involved in cell cycle G 2 /M checkpoint and DNA damage repair process. More than 50% of tumors have p53 gene deletion or mutation, which leads to the defect of cell cycle G 1 /S checkpoint, making the DNA replication and damage repair process of tumor cells more dependent on G 2 /M checkpoint. After inhibition of Wee1 kinase activity, the DNA damage of tumor cells cannot be repaired in time and enters the M phase, resulting in genome instability and chromosome loss, triggering mitotic catastrophe, and leading to tumor cell apoptosis. Weel kinase is highly expressed in many kinds of cancerous cells. By inhibiting Weel kinase, tumor cells can directly skip the DNA repair in G2 phase, enter mitosis in advance, cause tumor cell death, and achieve the purpose of treating cancer.
  • Polo-like Kinase 1 (Plk1) is mainly expressed in the G2 and M phases of the cell cycle - assisting the formation of the spindle, chromatid segregation and cytokinesis.
  • Plk1 plays a crucial role in various phases of the cell cycle, such as the cyclin B (Cyclin B)/cyclin-dependent kinase 1 (cyclin-dependent kinase 1, CDK1) complex that controls cells to enter mitosis.
  • Plk1 can also phosphorylate the anti-apoptotic protein Bcl-xl, and inhibiting Plk1 can reduce the expression of p-Bcl-xl gene, thereby promoting apoptosis.
  • Plk1 inhibitors can bring about side effects including myelosuppression. Recent studies have found that arterial wall cells in adult mammals are more sensitive to Plk1 inhibitors. Long-term use of Plk1 inhibitors can not only lead to high blood pressure, but also cause serious cardiovascular problems such as blood vessel rupture.
  • the technical problem to be solved by the present invention is that the existing Wee1 inhibitors have low selectivity to Plk1. Therefore, the present invention provides a kind of pyrimidodihydropyrazolone derivatives and pharmaceutically acceptable salts thereof And its preparation method and application.
  • the compound can inhibit Wee1, has better selectivity to Plk1, and can treat cancer.
  • the object of the present invention is to provide a kind of compound as shown in general formula (IA), its prodrug, its stereoisomer or its pharmaceutically acceptable salt:
  • X is CH or N
  • Y is C or N
  • Ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy , 3-12 membered heterocyclyloxy, C 6-14 ary
  • Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy , 3-12 membered heterocyclyloxy, C 6-14 ary
  • Ring C is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy , 3-12 membered heterocyclyloxy, C 6-14 ary
  • R is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -14aryl , 5-14 membered heteroaryl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -(CH 2 ) n SR a , -(CH 2 ) n NR b R a , -O(CH 2 ) n NR d R c , -(CH 2 ) n C(O)R a , -(CH 2 ) n C(O)NR b R a
  • R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 Heterocyclyl, C 6-14 aryl, 5-14 heteroaryl, C 3-12 cycloalkyloxy, 3-12 heterocyclyloxy, C 6-14 aryloxy or 5 -14-membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkane Thio, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl,
  • L is a linking group selected from L 1 , L 1 -L 2 , L 1 -L 2 -L 3 or L 1 -L 2 -L 3 -L 4 ;
  • R c , R d , Re , R f and R g are each independently selected from hydrogen, deuterium, halogen, hydroxyl , mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryloxy or 5-14 membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 Alkoxy , C 1-6 alkylthio, C 1-6 hydroxyal
  • any two of R c , R d , Re , R f and R g and the atoms where they are linked form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5 -14 membered heteroaryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further deuterium, halogen , hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -14 aryl,
  • any two R 1 and their atoms together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino , oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1 -6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl , C 3-12 cyclo
  • R 2-1 and R 2-2 are each independently C 1-6 alkyl
  • any two R 2 and their atoms are linked together to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, Amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl
  • One or more substituents
  • X, y and z are each independently an integer of 0 to 10;
  • n, n1 and n2 are each independently an integer of 0 to 10;
  • n and m1 are each independently 0, 1 or 2.
  • the object of the present invention is to provide a kind of compound shown in general formula (I), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, wherein the structure shown in general formula (I) is as follows:
  • X is CH or N
  • Ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy , 3-12 membered heterocyclyloxy, C 6-14 ary
  • Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy , 3-12 membered heterocyclyloxy, C 6-14 ary
  • R is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -14aryl , 5-14 membered heteroaryl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -(CH 2 ) n SR a , -(CH 2 ) n NR b R a , -O(CH 2 ) n NR d R c , -(CH 2 ) n C(O)R a , -(CH 2 ) n C(O)NR b R a
  • R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 Heterocyclyl, C 6-14 aryl, 5-14 heteroaryl, C 3-12 cycloalkyloxy, 3-12 heterocyclyloxy, C 6-14 aryloxy or 5 -14-membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkane Thio, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl,
  • L is a linking group selected from L 1 , L 1 -L 2 , L 1 -L 2 -L 3 or L 1 -L 2 -L 3 -L 4 ;
  • R c , R d , Re , R f and R g are each independently selected from hydrogen, deuterium, halogen, hydroxyl , mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryloxy or 5-14 membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 Alkoxy , C 1-6 alkylthio, C 1-6 hydroxyal
  • any two of R c , R d , Re , R f and R g and the atoms where they are linked form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5 -14 membered heteroaryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further deuterium, halogen , hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -14 aryl,
  • R 1-1 and R 1-2 are each independently selected from hydrogen, C 1-6 alkyl, 3-12 membered heterocyclic group or 3-12 membered heterocyclic ring substituted by one or more C 1-6 alkyl base;
  • any two R 1 and their atoms together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino , oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1 -6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl , C 3-12 cyclo
  • R 2-1 and R 2-2 are each independently C 1-6 alkyl
  • any two R 2 and their atoms are linked together to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, Amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl
  • One or more substituents
  • x and y are each independently an integer of 0 to 10;
  • n, n1 and n2 are each independently an integer of 0 to 10;
  • n and m1 are each independently 0, 1 or 2.
  • X is CH or N
  • R is C 1-6 alkyl or C 2-6 alkenyl, said C 1-6 alkyl and C 2-6 alkenyl, optionally, further replaced by deuterium, halogen and C 3-12 cycloalkyl Replaced by one or more substituents in;
  • Ring B is C 6-14 aryl or 5-14 membered heteroaryl
  • y 0, 1 or 2;
  • R 2-1 and R 2-2 are each independently C 1-6 alkyl
  • L is L 1 -L 2 -L 3 ;
  • L 1 is -(CR c R d ) n1 O- or -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is each independently 1 or 2;
  • L 2 is -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is 1 or 2;
  • L 3 is -O-, -(CR c R d ) n1 -or -NR e C(O)-;
  • R c and R d are each independently hydrogen or deuterium;
  • R e is hydrogen or deuterium;
  • n1 is 1;
  • Ring A is C 6-14 aryl or 5-14 membered heteroaryl
  • x is 1 or 2;
  • R 1-1 and R 1-2 are each independently hydrogen, C 1-6 alkyl, 3-12 membered heterocyclic group or 3-12 membered heterocyclic group substituted by one or more C 1-6 alkyl .
  • X is CH or N
  • R is C 1-6 alkyl or C 2-6 alkenyl, said C 1-6 alkyl and C 2-6 alkenyl, optionally, further replaced by deuterium, halogen and C 3-12 cycloalkyl Replaced by one or more substituents in;
  • Ring B is C 6-14 aryl or 5-14 membered heteroaryl
  • y 0, 1 or 2;
  • R 2-1 and R 2-2 are each independently C 1-6 alkyl
  • L is L 1 -L 2 -L 3 ; said L 1 is connected to said ring A;
  • L 1 is -(CR c R d ) n1 O- or -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is each independently 1 or 2; the ( CR c R d ) O in n1 O- is connected to said ring A or said L 2 ;
  • L 2 is -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is 1 or 2;
  • L 3 is -O-, -(CR c R d ) n1 -or -NR e C(O)-;
  • R c and R d are each independently hydrogen or deuterium;
  • R e is hydrogen or deuterium;
  • n1 is 1;
  • the C(O) in the -NR e C(O)- is connected to the ring B;
  • Ring A is C 6-14 aryl or 5-14 membered heteroaryl
  • x 2;
  • R is hydrogen, deuterium, halogen or cyano
  • R 1-1 and R 1-2 are each independently hydrogen, C 1-6 alkyl, 3-12 membered heterocyclic group or 3-12 membered heterocyclic group substituted by one or more C 1-6 alkyl .
  • X is CH or N.
  • R is C 1-6 alkyl or C 2-6 alkenyl, and said C 1-6 alkyl and C 2-6 alkenyl, optionally, are further replaced by deuterium , halogen and one or more substituents in C 3-12 cycloalkyl.
  • Ring B is C 6-14 aryl or 5-14 membered heteroaryl
  • y 0, 1 or 2;
  • R 2-1 and R 2-2 are each independently C 1-6 alkyl.
  • L is L 1 -L 2 -L 3 ;
  • L 1 is -(CR c R d ) n1 O- or -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is each independently 1 or 2;
  • L 2 is -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is 1 or 2;
  • L 3 is -O-, -(CR c R d ) n1 - or -NR e C(O)-;
  • R c and R d are each independently hydrogen or deuterium;
  • R e is hydrogen or deuterium;
  • n1 is 1.
  • L is L 1 -L 2 -L 3 ; said L 1 - is connected to said ring A;
  • L 1 is -(CR c R d ) n1 O- or -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is each independently 1 or 2; the ( CR c R d ) O in n1 O- is connected to said ring A or said L 2 ;
  • L 2 is -(CR c R d ) n1 -; R c and R d are each independently hydrogen or deuterium; n1 is 1 or 2;
  • L 3 is -O-, -(CR c R d ) n1 -or -NR e C(O)-;
  • R c and R d are each independently hydrogen or deuterium;
  • R e is hydrogen or deuterium;
  • n1 is 1;
  • C(O) in said -NR e C(O)- is connected to said ring B.
  • Ring A is C 6-14 aryl or 5-14 membered heteroaryl
  • x is 1 or 2;
  • R 1-1 and R 1-2 are each independently hydrogen, C 1-6 alkyl, 3-12 membered heterocyclic group or 3-12 membered heterocyclic group substituted by one or more C 1-6 alkyl .
  • Ring A is C 6-14 aryl or 5-14 membered heteroaryl
  • x 2;
  • R is hydrogen, deuterium, halogen or cyano
  • R 1-1 and R 1-2 are each independently hydrogen, C 1-6 alkyl, 3-12 membered heterocyclic group or 3-12 membered heterocyclic group substituted by one or more C 1-6 alkyl .
  • the C 1-6 alkyl in the R, can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso Butyl or tert-butyl can also be methyl, ethyl or isopropyl.
  • the C 2-6 alkenyl in the R, can be C 2-4 alkenyl, vinyl, propenyl or allyl.
  • said halogen can be fluorine, chlorine, bromine Or iodine, but also fluorine.
  • said C 3 -12 cycloalkyl in said R, when said C 1-6 alkyl and C 2-6 alkenyl are further substituted by C 3-12 cycloalkyl, said C 3 -12 cycloalkyl can be C 3-6 cycloalkyl, and can be cyclopropyl again.
  • said C 3-12 cycloalkyl group may be a saturated monocyclic ring.
  • the R can be any suitable material.
  • the R can be any suitable material.
  • the R can be any suitable material.
  • the R can be any suitable material.
  • the C 6-14 aryl group in the ring B, can be a phenyl group.
  • the 5-14 membered heteroaryl group in the ring B, can be a 5-6 membered heteroaryl group.
  • the number of heteroatoms in the 5-14 membered heteroaryl group can be 1 or 2.
  • the heteroatoms in the 5-14 membered heteroaryl group can be one or more of N, O and S, and can also be N .
  • the 5-14 membered heteroaryl group in the ring B, can be pyridyl, pyrimidyl or pyrazinyl.
  • the ring B is Wherein, X 4 is N or CH.
  • the C 1-6 alkyl group in the R 2 , can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl, can also be isopropyl.
  • said 3-12 membered heterocyclic group in said R 2 , can be a 3-6 membered heterocyclic group.
  • the number of heteroatoms in said 3-12 membered heterocyclic group can be 1 or 2.
  • the heteroatom in the 3-12 membered heterocyclic group can be one or more of N, O and S, and can also be O .
  • said 3-12 membered heterocyclic group may be oxetanyl.
  • said C 1-6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl Base, isobutyl or tert-butyl, can also be isopropyl.
  • said C 1-6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl Base, isobutyl or tert-butyl, can also be isopropyl.
  • said R 2 is
  • the C 6-14 aryl group in the ring A, can be a phenyl group.
  • the 5-14 membered heteroaryl group in the ring A, can be a 5-6 membered heteroaryl group.
  • the number of heteroatoms in the 5-14 membered heteroaryl group can be 1 or 2.
  • the heteroatoms in the 5-14 membered heteroaryl group can be one or more of N, O and S, or N .
  • the 5-14 membered heteroaryl in the ring A, can be pyridyl, pyrimidinyl or pyrazinyl.
  • the ring A is wherein, X 1 , X 2 and X 3 are each independently N or CR 1 ; each R 1 is independently -CN, F or H.
  • said halogen in said R 1 , can be fluorine, chlorine, bromine or iodine, or can be fluorine or bromine.
  • the 3-12 membered heterocyclic group in the R 1 , can be a monocyclic heterocyclic group, a spirocyclic heterocyclic group, a condensed ring heterocyclic group or a bridged ring heterocyclic group Ring base.
  • said 3-12 membered heterocyclic group may be a 6-membered monocyclic heterocyclic group.
  • said 3-12 membered heterocyclic group may be an 8-11 membered spirocyclic heterocyclic group.
  • said 3-12 membered heterocyclic group may be an 8-9 membered condensed ring heterocyclic group.
  • said 3-12 membered heterocyclic group may be an 8-9 membered bridged ring heterocyclic group.
  • the number of heteroatoms in said 3-12 membered heterocyclic group can be 1 or 2.
  • the heteroatom in said 3-12 membered heterocyclic group can be one or more of N, O and S, and can be N .
  • said C 1-6 alkyl can be Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl.
  • said C 1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and it can also be methyl.
  • said C 1-6 deuterated alkyl group may be trideuteromethyl.
  • said C 3-12 cycloalkyl when said 3-12 membered heterocyclic group is further substituted by C 3-12 cycloalkyl, said C 3-12 cycloalkyl It can be C 3-6 cycloalkyl, and it can also be cyclopropyl.
  • said C 3-12 cycloalkyl can be a saturated monocyclic ring.
  • said 3-12 membered heterocyclic group when said 3-12 membered heterocyclic group is further substituted by a 3-12 membered heterocyclic group, said 3-12 membered heterocyclic group It may be a 6-membered monocyclic heterocyclic group.
  • said 3-12 membered heterocyclic group when said 3-12 membered heterocyclic group is further substituted by a 3-12 membered heterocyclic group, said 3-12 membered heterocyclic group
  • the number of heteroatoms in can be 1 or 2.
  • said 3-12 membered heterocyclic group when said 3-12 membered heterocyclic group is further substituted by a 3-12 membered heterocyclic group, said 3-12 membered heterocyclic group
  • the heteroatom in can be one or more of N, O and S, and can also be N.
  • said 3-12 membered heterocyclic group is further substituted by one or more C 1-6 alkyl group 3-12 membered heterocyclic group
  • the C 1-6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and can also be methyl .
  • said 3-12 membered heterocyclic group is further substituted by one or more C 1-6 alkyl group 3-12 membered heterocyclic group
  • the 3-12 membered heterocyclic group can be a 6-membered monocyclic heterocyclic group.
  • said 3-12 membered heterocyclic group is further substituted by one or more C 1-6 alkyl group 3-12 membered heterocyclic group
  • the number of heteroatoms in the 3-12 membered heterocyclic group can be 1 or 2.
  • said 3-12 membered heterocyclic group is further substituted by one or more C 1-6 alkyl group 3-12 membered heterocyclic group
  • the heteroatom in the 3-12 membered heterocyclic group can be one or more of N, O and S, and can also be N.
  • the C 1-6 alkyl in the R 1-1 and R 1-2 , can be methyl, ethyl, n-propyl, isopropyl, n- Butyl, sec-butyl, isobutyl or tert-butyl, can also be methyl.
  • the 3-12 membered heterocyclic group may be a 6-membered monocyclic heterocyclic group.
  • the number of heteroatoms in said 3-12 membered heterocyclic group can be 1 or 2.
  • the heteroatom in the 3-12 membered heterocyclic group can be one of N, O and S or A variety of, but also N.
  • said 3-12 membered heterocyclic group substituted by one or more C 1-6 alkyl groups can be 6 membered monocyclic heterocyclyl.
  • said hetero in the 3-12 membered heterocyclic group substituted by one or more C 1-6 alkyl groups may be 1 or 2.
  • said hetero in the 3-12 membered heterocyclic group substituted by one or more C 1-6 alkyl groups Atoms can be one or more of N, O and S, and can also be N.
  • the R can be F, Cl, Br,
  • said R 1 can be
  • x is 2;
  • R is hydrogen, deuterium, halogen or cyano
  • the compound represented by the general formula (I) does not contain deuterium, and all hydrogens in it are hydrogens in natural abundance.
  • the heterocyclic group in the compound represented by the general formula (I) is a saturated heterocyclic ring.
  • the present invention also provides a preferred scheme, the compound shown, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, its specific structure is shown in general formula (V):
  • X 2 is N or CR 1 ;
  • L 1 is selected from -O-, -CH 2 -, -OCH 2 -, -CH 2 O-, -CH 2 CH 2 - or -OCH 2 CH 2 -;
  • R, R 1 and R 2 are as defined in general formula (I).
  • the present invention also provides a preferred scheme, the compound shown, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, its specific structure is shown in general formula (VI):
  • Ring A, ring B, L, X, R, R 1 , R 2 , x and y are as defined in general formula (I); z is an integer of 0-10.
  • the present invention also provides a preferred scheme, the compound shown, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, its specific structure is shown in general formula (VII):
  • Ring A, ring B, L, X, Y, R, R 1 , R 2 , x and y are as defined in general formula (I); z is an integer of 0-10.
  • the L 1 is selected from -O-, -CH 2 -, -OCH 2 -, -CH 2 O-, -CH 2 CH 2 - or -OCH 2 CH 2 -.
  • said L 2 is -O- or -CH 2 -.
  • said L 3 is -CH 2 -.
  • said L 1 is selected from -O-, -CH 2 -, -OCH 2 -, -CH 2 O-, -CH 2 CH 2 - or -OCH 2 CH 2 -;
  • the L 2 is -O- or -CH 2 -;
  • the L 3 is -CH 2 -.
  • said X 1 is N, CH or CF.
  • said X 2 is N, CH, CF or CCN.
  • said X 3 is N, CH or CF.
  • said X 4 is N or CH.
  • the X 1 is N, CH or CF; the X 2 is N, CH, CF or CCN; the X 3 is N, CH or CF; the X 4 is N or CH.
  • said R is selected from methyl, ethyl, isopropyl, cyclopropyl or allyl, said methyl, ethyl, isopropyl, cyclopropyl and Allyl, optionally, is further substituted with one or more substituents of fluoro, methyl, ethyl and cyclopropyl.
  • said R is selected from
  • R 1-1 and R 1-2 are each independently selected from hydrogen, C 1-6 alkyl, 3-12 membered heterocyclic group or 3-12 membered heterocyclic ring substituted by one or more C 1-6 alkyl base;
  • any two R 1 and their atoms together form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino , oxo, thio, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1 -3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, optionally substituted 3-8 membered heterocyclic group, C 6 -10 aryl, 5-10 member
  • the 6-10 membered heterocyclic group optionally, is further replaced by hydroxyl, oxo, C 1-3 alkyl, C 1-3 Haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted by cyano, C 2-3 alkenyl, C 2-3 One or more substituents in alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and C 1-3 alkyl substituted 3-8 membered heterocyclic group.
  • said R 1 is selected from F, Cl, Br,
  • any two R 2 and their atoms together form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 3 -8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, Oxo, thio, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1- 3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, One or more substituents in C 3-8 cycloalkyl
  • said R 2 is selected from H,
  • the object of the present invention is to provide a kind of compound shown in general formula (I), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, wherein the structure shown in general formula (I) is as follows:
  • X is CH or N
  • Ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy , 3-12 membered heterocyclyloxy, C 6-14 ary
  • Ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy , 3-12 membered heterocyclyloxy, C 6-14 ary
  • R is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -14aryl , 5-14 membered heteroaryl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -(CH 2 ) n SR a , -(CH 2 ) n NR b R a , -O(CH 2 ) n NR d R c , -(CH 2 ) n C(O)R a , -(CH 2 ) n C(O)NR b R a
  • R a and R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl , C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 Heterocyclyl, C 6-14 aryl, 5-14 heteroaryl, C 3-12 cycloalkyloxy, 3-12 heterocyclyloxy, C 6-14 aryloxy or 5 -14-membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkane Thio, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl,
  • L is a linking group selected from L 1 , L 1 -L 2 , L 1 -L 2 -L 3 or L 1 -L 2 -L 3 -L 4 ;
  • R c , R d , Re , R f and R g are each independently selected from hydrogen, deuterium, halogen, hydroxyl , mercapto, nitro, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryloxy or 5-14 membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 Alkoxy , C 1-6 alkylthio, C 1-6 hydroxyal
  • any two of R c , R d , Re , R f and R g and the atoms where they are linked form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5 -14 membered heteroaryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further deuterium, halogen , hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -14 aryl,
  • Each R is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkane Base, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryl Baseoxy or 5-14 membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl , C 2-6 alkenyl
  • any two R 1 and their atoms together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino , oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1 -6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl , C 3-12 cyclo
  • R is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated Alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3 -12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 3-12 cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryloxy Or 5-14 membered heteroaryloxy, the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1- 6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 al
  • any two R 2 and their atoms are linked together to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, Amino, oxo, thio, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl
  • One or more substituents
  • x and y are each independently an integer of 0 to 10;
  • n, n1 and n2 are each independently an integer of 0 to 10;
  • n and m1 are each independently 0, 1 or 2.
  • the ring A phenyl, 5-6 membered monocyclic heteroaryl, C 5-10 bicyclic fused cycloalkyl, 5-10 bicyclic fused heterocyclic group or 8-10 A two-membered fused ring heteroaryl.
  • the present invention also provides a preferred scheme, the compound shown, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, its specific structure is shown in general formula (II):
  • X 1 , X 2 and X 3 are each independently selected from N or CR 1 ;
  • X 4 is N or CR 2 ;
  • L, X, R, R 1 and R 2 are as defined in general formula (I).
  • the present invention also provides a preferred scheme, the compound shown, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, its specific structure is shown in general formula (III):
  • X 1 , X 2 and X 3 are each independently selected from N or CR 1 ;
  • X 4 is N or CR 2 ;
  • L 1 to L 3 , R, R 1 and R 2 are as defined in general formula (I).
  • the present invention also provides a preferred scheme, the compound shown, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, its specific structure is shown in general formula (IV):
  • X 1 , X 2 and X 3 are each independently selected from N or CR 1 ;
  • X 4 is N or CR 2 ;
  • R, R 1 and R 2 are as defined in general formula (I).
  • the L 1 is selected from -O-, -CH 2 -, -OCH 2 -, -CH 2 O-, -CH 2 CH 2 - or -OCH 2 CH 2 -.
  • said L 2 is -O- or -CH 2 -.
  • said L 3 is -CH 2 -.
  • said X 1 is N, CH or CF.
  • said X 2 is N, CH, CF or CCN.
  • said X 3 is N, CH or CF.
  • said X 4 is N or CH.
  • the R is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkane radical, 3-8 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group or -CH 2 R a , the amino group, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3- 8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10
  • R a is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkane Oxygen , C 1-3 alkylthio, C 1-3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl , C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, optionally, further replaced by de
  • said R 1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1 -3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterium Substituted alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the amino, C 1-3
  • any two R 1 and their atoms together form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino , oxo, thio, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1 -3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl , C 3-8 cycloalkyl,
  • said R 2 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1 -3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyloxy, 3-8 membered heterocyclyloxy, C 6-10 Aryloxy or 5-10 membered heteroaryloxy, said amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy , C 1-3 alkylthio, C 1-3 hydroxyalkyl , C 2-3 alkenyl, C 2-3 alkyn
  • any two R 2 and their atoms together form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally, further replaced by deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino , oxo, thio, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1 -3 hydroxyalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl , C 3-8 cycloalkyl,
  • each compound of the general formula shown above, its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, each of the compounds of the general formula shown above is specifically selected from from the following compounds:
  • the present invention also relates to a method for preparing a compound represented by general formula (III), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • R, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , L 1 , L 2 and L 3 are as defined in general formula (III).
  • the present invention also relates to a compound represented by formula (IIIa), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, and its specific structure is as follows:
  • R, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , L 1 , L 2 and L 3 are as defined in general formula (III).
  • the present invention also provides a preferred scheme, the compound shown above as shown in formula (IIIa), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, the above shown general formula
  • the compound is specifically selected from the following compounds:
  • the present invention also relates to an intermediate compound represented by formula (IIIa), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, and its specific structure is as follows:
  • R, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , L 1 , L 2 and L 3 are as defined in general formula (III).
  • the present invention also relates to a method for preparing a compound represented by general formula (IIIa), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, which is characterized in that it comprises the following steps,
  • the compound shown in formula (IIIa-1) and the compound shown in formula (IIIa-2) obtain the compound shown in formula (IIIa-3) through nucleophilic substitution reaction or carbon-nitrogen coupling reaction;
  • described carbon - Nitrogen coupling reaction is selected from Ullmann coupling reaction, Buchwald-Hartwig coupling reaction or Chan-Lam coupling reaction, etc.;
  • the compound shown in formula (IIIa-3) and the compound shown in formula (IIIa-4) directly or one of them is converted into a leaving group through further oxidation reaction, and then reacted by nucleophilic substitution to formula (IIIa-5) the compound shown in the formula; or, the compound shown in the formula (IIIa-3) and the compound shown in the formula (IIIa-4) obtain the compound shown in the formula (IIIa-5) through carbon-nitrogen coupling reaction; preferably, the carbon - Nitrogen coupling reaction is selected from Ullmann coupling reaction, Buchwald-Hartwig coupling reaction or Chan-Lam coupling reaction, etc.;
  • Z is selected from amino, halogen, C1-6 alkylthio, sulfonyl, sulfinyl, boronic acid or boronate; preferably amino, fluorine, chlorine, bromine, methylthio, methylsulfonyl, methylenesulfonyl Acyl, boronic acid or pinacol borate, etc.;
  • Z is selected from halogen, C 1-6 alkylthio, sulfonyl, sulfinyl, boronic acid or boric acid ester; preferably fluorine, chlorine, bromine, methylthio, methylsulfonyl, methylenesulfonyl, boronic acid or Pinacol borate, etc.;
  • Z is selected from amino, halogen, C1-6 alkylthio, sulfonyl, sulfinyl, boronic acid or boronate; preferably amino, fluorine, chlorine, bromine, methylthio, methylsulfonyl, methylenesulfonyl Acyl, boronic acid or pinacol borate, etc.;
  • Pg 1 and Pg 2 are hydroxyl protecting groups, each independently selected from methoxymethyl (MOM), tetrahydro-2H-pyran-2-yl (THP), p-methoxybenzyl (PMB) or tert-butyl Base diphenyl silyl (TBDPS), etc.;
  • MOM methoxymethyl
  • THP tetrahydro-2H-pyran-2-yl
  • PMB p-methoxybenzyl
  • TDPS tert-butyl Base diphenyl silyl
  • At least one of Z1 and Z3 is amino, and when one of them is amino, the other is halogen, C1-6 alkylthio, sulfonyl, sulfinyl, boric acid or boric acid ester;
  • R, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , L 1 , L 2 and L 3 are as defined in general formula (III).
  • the present invention also relates to a preparation method of an intermediate compound represented by general formula (IIIa), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, which is characterized in that it comprises the following steps,
  • the compound shown in formula (IIIa-1) and the compound shown in formula (IIIa-2) obtain the compound shown in formula (IIIa-3) through nucleophilic substitution reaction or carbon-nitrogen coupling reaction;
  • described carbon - Nitrogen coupling reaction is selected from Ullmann coupling reaction, Buchwald-Hartwig coupling reaction or Chan-Lam coupling reaction, etc.;
  • the compound shown in formula (IIIa-3) and the compound shown in formula (IIIa-4) directly or one of them is converted into a leaving group through further oxidation reaction, and then reacted by nucleophilic substitution to formula (IIIa-5) the compound shown in the formula; or, the compound shown in the formula (IIIa-3) and the compound shown in the formula (IIIa-4) obtain the compound shown in the formula (IIIa-5) through carbon-nitrogen coupling reaction; preferably, the carbon - Nitrogen coupling reaction is selected from Ullmann coupling reaction, Buchwald-Hartwig coupling reaction or Chan-Lam coupling reaction, etc.;
  • Z is selected from amino, halogen, C1-6 alkylthio, sulfonyl, sulfinyl, boronic acid or boronate; preferably amino, fluorine, chlorine, bromine, methylthio, methylsulfonyl, methylenesulfonyl Acyl, boronic acid or pinacol borate, etc.;
  • Z is selected from halogen, C 1-6 alkylthio, sulfonyl, sulfinyl, boronic acid or boric acid ester; preferably fluorine, chlorine, bromine, methylthio, methylsulfonyl, methylenesulfonyl, boronic acid or Pinacol borate, etc.;
  • Z is selected from amino, halogen, C1-6 alkylthio, sulfonyl, sulfinyl, boronic acid or boronate; preferably amino, fluorine, chlorine, bromine, methylthio, methylsulfonyl, methylenesulfonyl Acyl, boronic acid or pinacol borate, etc.;
  • Pg 1 and Pg 2 are hydroxyl protecting groups, each independently selected from methoxymethyl (MOM), tetrahydro-2H-pyran-2-yl (THP), p-methoxybenzyl (PMB) or tert-butyl Base diphenyl silyl (TBDPS), etc.;
  • MOM methoxymethyl
  • THP tetrahydro-2H-pyran-2-yl
  • PMB p-methoxybenzyl
  • TDPS tert-butyl Base diphenyl silyl
  • At least one of Z1 and Z3 is amino, and when one of them is amino, the other is halogen, C1-6 alkylthio, sulfonyl, sulfinyl, boric acid or boric acid ester;
  • R, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , L 1 , L 2 and L 3 are as defined in general formula (III).
  • the present invention also relates to a pharmaceutical composition, which comprises the above-mentioned compounds of the general formula, their prodrugs, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention also relates to a pharmaceutical composition, which contains the above-mentioned compounds of the general formulas, their prodrugs, their stereoisomers or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carrier or excipient.
  • the present invention further relates to the compound represented by the general formula (I), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation and treatment of diseases mediated by Weel use in medicines.
  • the present invention further relates to a compound represented by general formula (I), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a drug for treating abnormal cell growth the use of.
  • a compound represented by general formula (I) its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a drug for treating abnormal cell growth the use of.
  • the present invention further relates to the compound represented by the general formula (I), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, or, the above pharmaceutical composition in the preparation of a drug for treating tumor or cancer the use of.
  • the present invention further relates to the compound represented by the above-mentioned general formula (I), its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, or the use of the above-mentioned pharmaceutical composition in the preparation of a Weel inhibitor.
  • the Wee1 inhibitor is selective for Plk1.
  • the Wee1 inhibitor is used in vitro.
  • the present invention further relates to the compound represented by the general formula (I) above, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of Weel-mediated way of disease.
  • the present invention further relates to a method for treating abnormal growth of cells by the compound represented by the above general formula (I), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition .
  • the present invention further relates to the compound represented by the general formula (I), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for treating tumor or cancer .
  • the present invention further relates to the compound represented by the general formula (I) above, its prodrug, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of Weel-mediated disease use.
  • the present invention further relates to the compound represented by the general formula (I), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition to treat abnormal cell growth .
  • the present invention further relates to the compound represented by the general formula (I), its prodrug, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for treating tumor or cancer .
  • alkyl refers to a hydrocarbon group lacking one hydrogen in a saturated aliphatic chain hydrocarbon, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 An alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • alkylene refers to a group in which one hydrogen of an alkyl group is further substituted, that is, a hydrocarbon group lacking two hydrogens in a saturated aliphatic chain hydrocarbon, which is a straight-chain or branched chain group containing 1 to 20 carbon atoms , preferably an alkylene group having 1 to 8 carbon atoms, more preferably an alkylene group having 1 to 6 carbon atoms, and most preferably an alkylene group having 1 to 3 carbon atoms.
  • Non-limiting examples include “methylene” (-CH 2 -), “ethylene” (-(CH 2 ) 2 -), “n-propylene” (-(CH 2 ) 3 -), “ethylene Isopropyl” (-(CH)(CH 3 )(CH 2 )-), “n-butylene” (-(CH 2 ) 4 -), etc.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing at least two carbon atoms and at least one carbon-carbon double bond, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably containing An alkenyl group of 2 to 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms, most preferably an alkenyl group of 2 to 4 carbon atoms.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an unsaturated aliphatic alkynyl group containing at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight-chain or branched group containing 2 to 20 carbon atoms, preferably An alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms, most preferably an alkynyl group of 2 to 4 carbon atoms.
  • alkynyl containing at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight-chain or branched group containing 2 to 20 carbon atoms, preferably An alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms, most preferably an alkynyl group of 2 to 4 carbon atoms.
  • alkynyl ethynyl, 1-propynyl, 2-propynyl,
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic hydrocarbon substituent, the cycloalkyl ring atoms containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Cyclopropyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl, etc.
  • spirocycloalkyl refers to a polycyclic group containing 5 to 20 carbon atoms, sharing one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds, and which has no aromatic properties as a whole. (that is, the whole cannot form a conjugated ⁇ -electron system), but there can be one ring or multiple rings with a conjugated ⁇ -electron system.
  • the spirocycloalkyl ring atoms are preferably 6 to 14 carbon atoms, more preferably 7 to 10 carbon atoms.
  • the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl group.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group containing 5 to 20 carbon atoms, each ring in the system sharing adjacent pairs of carbon atoms with other rings in the system, wherein one or more rings can Containing one or more double bonds, the whole is not aromatic (that is, the whole cannot form a conjugated ⁇ -electron system), but there can be one ring or multiple rings with a conjugated ⁇ -electron system.
  • the fused cycloalkyl ring atoms are preferably 6 to 14 carbon atoms, more preferably 7 to 10 carbon atoms.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group containing 5 to 20 carbon atoms, any two rings sharing two carbon atoms that are not directly connected, which may contain one or more double bonds, and which as a whole are not It is aromatic (that is, the whole cannot form a conjugated ⁇ -electron system), but there can be one ring or multiple rings with a conjugated ⁇ -electron system.
  • the bridged cycloalkyl ring atoms are preferably 6 to 14 carbon atoms, more preferably 7 to 10 carbon atoms.
  • bridged cycloalkyl groups preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to a cycloalkyl or aryl ring, where the ring attached to the parent structure may be a cycloalkyl or aryl ring, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups 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, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, phosphorus, Heteroatoms of boron or S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Heterocyclyl preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetane, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl , dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, pyridonyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably Oxetane, tetrahydrofuranyl, tetrahydropyranyl, azepanyl, piperidinyl, pyridinonyl and piperazinyl.
  • Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups, etc.; wherein the spiro rings, condensed rings and bridged ring heterocyclic groups are optionally connected to other groups through single bonds, or through Any two or more atoms on the ring are further linked to other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group containing 5 to 20 ring atoms, one atom (called spiro atom) shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, phosphorus , boron or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, is not aromatic as a whole (ie cannot form a conjugated ⁇ -electron system as a whole), but may have a ring or rings with a conjugated ⁇ -electron system.
  • the spiroheterocyclyl ring atoms are preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group containing 5 to 20 ring atoms, each ring in the system sharing an adjacent pair of atoms with other rings in the system, wherein one or more ring atoms are selected from A heteroatom from nitrogen, oxygen, phosphorus, boron or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon.
  • One or more of its rings can contain one or more double bonds, and its whole is not aromatic (that is, it cannot form a conjugated ⁇ -electron system as a whole), but one or more rings can have a conjugated ⁇ -electron system .
  • the fused heterocyclyl ring atoms are preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic group containing 5 to 20 ring atoms, any two rings share two atoms that are not directly connected, wherein one or more ring atoms are selected from nitrogen, oxygen, A heteroatom of phosphorus, boron or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It may contain one or more double bonds, is not aromatic as a whole (ie cannot form a conjugated ⁇ -electron system as a whole), but may have a ring or rings with a conjugated ⁇ -electron system.
  • the bridging heterocyclyl ring atoms are preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to a cycloalkyl, heterocyclyl, aryl or heteroaryl ring, wherein the ring attached to the parent structure may be a cycloalkyl, heterocyclyl, aryl ring or Heteroaryl rings, non-limiting examples of which include:
  • aryl refers to a 6 to 20 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 14 aryl ring atoms Yuan, more preferably 6 to 10, such as phenyl and naphthyl. Phenyl is more preferred.
  • Aryl groups may be 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, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur or nitrogen and the like. Heteroaryl is divided into monocyclic heteroaryl and polycyclic heteroaryl; heteroaryl ring atoms are preferably 5 to 14 members, more preferably 5 to 10 members; monocyclic heteroaryl ring atoms are preferably 5 or 6 members Elements such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyr Zinc group, pyridazinyl group, oxadiazolyl group, etc., preferably pyridyl group, oxazolyl group, isoxazolyl
  • Polycyclic heteroaryl generally means that the heteroaryl ring is fused to aryl or heteroaryl to form a polycyclic fused heteroaryl, wherein the ring connected to the parent structure can be an aryl ring or a heteroaryl ring,
  • the polycyclic fused heteroaryl is preferably a bicyclic fused heteroaryl, non-limiting examples of bicyclic fused heteroaryl include:
  • Heteroaryl groups 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, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • haloalkyl refers to a group in which the hydrogens of an alkyl group are replaced by one or more halogens, wherein alkyl is as defined above.
  • Non-limiting examples of haloalkyl include: monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl , 1,1-difluoroethyl, 1,2-difluoroethyl, etc.
  • the haloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, It is independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycl
  • “Hydroxyalkyl” means an alkyl group in which a hydrogen is replaced by one or more hydroxy groups, wherein alkyl is as defined above.
  • Non-limiting examples of hydroxyalkyl groups include: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 1-hydroxybutyl, etc., hydroxyalkyl
  • the group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, carboxyl or carb
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy or butoxy, alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • alkylthio refers to -S-(alkyl), wherein alkyl is as defined above.
  • alkylthio include: methylthio, ethylthio, propylthio, butylthio, alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EA means ethyl acetate
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • DEAD means diethyl azodicarboxylate.
  • m-CPBA refers to m-chloroperoxybenzoic acid.
  • TFA trifluoroacetic acid
  • MeCN refers to acetonitrile
  • DMA refers to N,N-dimethylacetamide.
  • Et2O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone)dipalladium.
  • Pd/C means palladium on carbon
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi means methyllithium
  • n-BuLi refers to n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen described in the present invention can be replaced by its isotope deuterium, and any hydrogen in the example compounds involved in the present invention can also be replaced by deuterium.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogens in a group, preferably 5, more preferably 1 to 3 hydrogens are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • the compounds described herein can be synthesized by a variety of methods well known to those skilled in the art of organic synthesis, using starting materials that are commercially available or can be prepared by known experimental procedures.
  • the compounds of the present invention can be synthesized by using the following methods, or synthetic methods known in the field of synthetic organic chemistry, combined with method changes mastered by those skilled in the art.
  • Preferred synthetic methods include, but are not limited to, those described below. For a more detailed description of the individual reaction steps, see the "Examples" section below.
  • the starting materials in the synthesis steps can be synthesized using or according to methods known in the art, or can be purchased from Sigma-Aldrich Co.Ltd, Bide Pharmatech Ltd. ), Shaoyuan Chemical (Accela ChemBio Co.Ltd) and other companies.
  • LCMS data used for the characterization of the examples were obtained by an Agilent 1260-6120/6125 MSD system with DAD detector. Test methods include:
  • Pillar C18 4.6 ⁇ 50mm, 2.5 ⁇ m
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • silica gel chromatography is generally based on silica gel or prepacked silica gel column as the carrier, petroleum ether/ethyl acetate or dichloromethane/methanol and other systems as the eluent; reversed-phase silica gel chromatography is generally based on C18 silica gel column as the carrier, using UV Detectors (214nm and 254nm) and preparative LCMS were used for detection, and the mobile phases included systems such as acetonitrile/water (0.1% formic acid), acetonitrile/water (0.1% trifluoroacetic acid) and acetonitrile/water (0.1% ammonia).
  • Supercritical fluid chromatography generally adopts different types of columns as carriers, and uses a system such as CO 2 /methanol containing 0.2% NH 3 (7M ammonia
  • the resulting residue was dissolved in trifluoroacetic acid (150 mL) and stirred at 70°C for 1 hr. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethanol (300 mL) at 0°C, and 6M sodium hydroxide solution (550 mL) was added, and the resulting mixture was stirred at 25°C for 15 minutes. After the reaction was completed, the pH of the reaction solution was adjusted to 6 with 1M hydrochloric acid solution and extracted with dichloromethane (500 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained crude product was dispersed in a mixed solvent of dichloromethane (64mL) and petroleum ether (640mL) and stirred for 30 minutes, filtered, and the obtained filter cake was dried to obtain compound 1g (40.00g, yield: 66%).
  • Step 8 2-allyl-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6-methylthio-1,2 -Dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1h)
  • Step 9 2-allyl-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6-((4-(4- Methylpiperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)phenyl)amino)-1,2-dihydro-3H- Pyrazolo[3,4-d]pyrimidin-3-one (1i)
  • Step 10 2-allyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-(2-hydroxyethyl)-4 -(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1j)
  • Step 11 2 2 -allyl-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -dihydro-2 1 H-7-oxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine-4(1,3)-benzo Cycloheptan-2 3 -one (Example 1)
  • reaction solution is directly concentrated under reduced pressure, and the obtained crude product is passed through preparative HPLC (column: C18 spherical 40-60 ⁇ m, 100A, 80g; mobile phase: acetonitrile/water (containing 0.1% formic acid), 0-100%, 30min ; flow rate: 50mL/min) and lyophilized to obtain compound 2a (1.60g, yield: 78%).
  • Step 3 4-(4-Methylpiperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)aniline (2c)
  • Step 6 2-allyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro- 3H-pyrazolo[3,4-d]pyrimidin-3-one (2f)
  • Step 7 2-allyl-1-(4-(tert-butyldiphenylsilyloxy)-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-methylthio -1,2-Dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (2g)
  • Step 8 2-allyl-1-(4-(tert-butyldiphenylsilyloxy)-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-methylidene Sulfonyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (2h)
  • Step 9 2-allyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-(2-hydroxyethoxy)- 4-(4-Methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (2i)
  • Step 10 2 2 -allyl-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -dihydro-2 1 H-5,8-dioxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine-4(1,3) -Benzene heterocyclooctafan-2 3 -one (Example 2)
  • diethyl azodicarboxylate 13 mg, 0.075 mmol was added dropwise to a solution of compound 2i (22 mg, 0.038 mmol) and triphenylphosphine (201 mg, 0.77 mmol) in tetrahydrofuran (20 mL), and the resulting mixture Stir at 60°C for 16 hours.
  • reaction solution was diluted with water (100mL), extracted with ethyl acetate (200mL ⁇ 2), the combined organic phase was washed with saturated brine, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 4-(2-(tert-Butoxycarbonyl)-2-isopropylhydrazino)-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester (3c)
  • Step 7 2-Isopropyl-1-[6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl]-6-((4-(4- Methylpiperazin-1-yl)-3-(2-(tetrahydro-2H-pyran-2-yl)oxyethoxy)phenyl)amino)pyrazolo[3,4-d]pyrimidine -3-keto (3g)
  • Step 8 2-isopropyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-(2-hydroxyethoxy)- 4-(4-Methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (3h)
  • Step 9 2 2 -isopropyl-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -dihydro-2 1 H-5,8-dioxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine-4(1,3) -Benzene heterocyclooctafan-2 3 -one (Example 3)
  • reaction solution was diluted with water (50 mL), extracted with ethyl acetate (100 mL ⁇ 2), the combined organic phase was washed with saturated brine, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 5 2-(2,2-Difluoroethyl)-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6- Methylthio-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4e)
  • Step 6 2-(2,2-Difluoroethyl)-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6- Methylsulfinyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4f)
  • Step 7 2-(2,2-Difluoroethyl)-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6- ((4-(4-methylpiperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)amino)-1 ,2-Dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4g)
  • Step 8 2-(2,2-Difluoroethyl)-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-(2 -Hydroxyethoxy)-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3- Ketone (4h)
  • Step 9 2 2 -(2,2-difluoroethyl)-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-methylpiperazin-1-yl)-2 2 , 2 3 -Dihydro-2 1 H-5,8-dioxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine -4(1,3)-Benzene heterocyclooctafan-2 3 -one (Example 4)
  • Step 2 8-Methyl-3-(4-nitro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-3,8- Diazabicyclo(3.2.1)octane(6b)
  • Step 3 4-(8-Methyl-3,8-diazabicyclo(3.2.1)octane-3-yl)-3-(2-((tetrahydro-2H-pyran-2- base) oxy) ethoxy) aniline (6c)
  • step 3 of Example 1 For the synthetic steps of compound 6c (300 mg, yield: 68%), refer to step 3 of Example 1. Wherein compound 3b is used to replace compound 1b.
  • Step 4 2-allyl-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6-((4-(8- Methyl-3,8-diazabicyclo(3.2.1)octane-3-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy )phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (6d)
  • Step 5 2-allyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-(2-hydroxyethoxy)- 4-(8-Methyl-3,8-diazabicyclo(3.2.1)octane-3-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo(3, 4-d) Pyrimidin-3-one (6e)
  • Step 6 22 -allyl- 16- (2-hydroxypropan-2-yl) -44- (8-methyl-3,8-diazabicyclo(3.2.1)octane- 3-yl)-2 2 ,2 3 -dihydro-2 1 H-7-oxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2 ,4)-pyridine-4(1,3)-benzeneheterocyclic octafan-2 3 -one (Example 6)
  • Example 6 For the synthetic steps of Example 6 (12.9 mg, yield: 33%), refer to Step 11 of Example 1. Compound 1j is replaced by compound 6e.
  • Example 7 For the synthesis steps of Example 7 (2.0 mg), refer to Steps 1-6 of Example 6. Wherein, tert-butyl 3,8-diazabicyclo(3.2.1)octane-8-carboxylate was replaced by tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate.
  • Example 8 For the synthesis steps of Example 8 (13 mg), refer to Steps 2-6 of Example 6. Wherein (S)-1,3-dimethylpiperazine is used to replace compound 6a.
  • Example 9 For the synthesis steps of Example 9 (3.2 mg), refer to Steps 2-6 of Example 6. Wherein (R)-1,3-dimethylpiperazine is used to replace compound 6a.
  • Step 4 6-(4-methylpiperazin-1-yl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-amine ( 10d)
  • Step 5 2-allyl-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6-((6-(4- Methylpiperazin-1-yl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)amino)-1,2-di Hydrogen-3H-pyrazolo(3,4-d)pyrimidin-3-one (10e)
  • Step 6 2-allyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((5-(2-hydroxyethoxy)- 6-(4-Methylpiperazin-1-yl)pyridin-3-yl)amino)-1,2-dihydro-3H-pyrazolo(3,4-d)pyrimidin-3-one (10f)
  • step 10 of Example 1 For the synthetic steps of compound 10f (80 mg, yield: 36%), refer to step 10 of Example 1. Wherein compound 10e is used instead of compound 1i.
  • Step 7 2 2 -allyl-1 6 -(2-hydroxypropan-2-yl)-4 6 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -dihydro-2 1 H-5,8-dioxa-3-aza-2(1,6)-pyrazolo(3,4-d)pyrimidine-1(2,4),4(3,5)-di Pyridine heterocyclic octapan-2 3 -one (Example 10)
  • Example 10 For the synthetic steps of Example 10 (2.1 mg, yield: 9%), refer to Step 11 of Example 1. Compound 1j is replaced by compound 10f.
  • Step 3 4-((S)-2,4-Dimethylpiperazin-1-yl)-3-fluoro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy )ethoxy)aniline (17c)
  • Step 4 2-allyl-6-((4-((S)-2,4-dimethylpiperazin-1-yl)-3-fluoro-5-(2-((tetrahydro-2H -pyran-2-yl)oxy)ethoxy)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridine-2 -yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (17d)
  • Step 5 (S)-2-allyl-6-((4-(2,4-dimethylpiperazin-1-yl)-3-fluoro-5-(2-hydroxyethoxy)benzene Base)amino)-1-(4-hydroxyl-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d] Pyrimidin-3-one (17e)
  • Step 6 (S)-2 2 -allyl-4 4 -(2,4-dimethylpiperazin-1-yl)-4 5 -fluoro-1 6 -(2-hydroxypropan-2-yl )-2 2 ,2 3 -dihydro- 2 1 H-5,8-dioxa-3-aza-2(1,6)-pyrazolo(3,4-d)pyrimidine-1(2 ,4)-pyridine-4(1,3)-heterocyclic octafan-2 3 -one (embodiment 17)
  • Example 18 The synthesis of Example 18 refers to Example 17, the synthesis of Examples 26-31 refers to Example 6, and the characterization data are shown in the following table:
  • Step 2 ((1,3-Dioxyylidene-2,3-dihydro-1H-isoindol-2-yl)(2-fluoroprop-2-enyl)amino)methanoic acid-2-methanoic acid Propyl-2-yl ester (32b)
  • Step 4 4-(2-(2-Fluoroprop-1-en-3-yl)-2-(((2-methylprop-2-yl)oxy)carbonyl)ethylamino)-2- (Methylthio)pyrimidine-5-carboxylic acid ethyl ester (32d)
  • Step 6 2-(2-Fluoroprop-2-en-1-yl)-1-(6-(2-hydroxyprop-2-yl)-4-(methoxymethoxy)pyridine-2- base)-6-(methylmercapto)pyrazol[3,4-d]pyrimidin-3-one (32f)
  • Step 7 3-(5-Amino-2-((2S)-2,4-dimethylpiperazin-1-yl)phenyl)propan-1-ol (32 g)
  • Step 8 6-((4-((2S)-2,4-Dimethylpiperazin-1-yl)-3-(3-hydroxypropyl)phenyl)amino)-2-(2-fluoro Propyl-2-en-1-yl)-1-(6-(2-hydroxypropyl-2-yl)-4-(methoxymethoxy)pyridin-2-yl)pyrazol[3, 4-d]pyrimidin-3-one (32h)
  • Step 9 6-((4-((2S)-2,4-Dimethylpiperazin-1-yl)-3-(3-hydroxypropyl)phenyl)amino)-2-(2-fluoro Propyl-2-en-1-yl)-1-(6-(2-hydroxypropyl-2-yl)-4-(methoxymethoxy)pyridin-2-yl)pyrazol[3, 4-d]pyrimidin-3-one (32i)
  • Step 10 (S)-4 4 -(2,4-Dimethylpiperazin-1-yl)-2 2 -(2-fluoroallyl)-1 6- (2-hydroxypropan-2-yl )-2 2 ,2 3 -Dihydro- 2 1 H-8-oxa-3-aza-2(1,6)-pyrazolyl[3,4-d]pyrimidine-1(2,4) -Pyridine-4(1,3)-benzocyclohctane-2 3 -one (Example 32)
  • Step 1 4-(5-Amino-2-(4-methylpiperazin-1-yl)phenyl)butyl-1-ol (33a)
  • Step 2 2-allyl-6-((3-(4-hydroxybutyl)-4-(4-methylpiperazin-1-yl)amino)-1-(6-(2-hydroxypropyl) Base-2-yl)-4-(methoxymethoxy)-pyridin-2-yl)-1,2-dihydro-3H-pyrazol[3,4-d]pyrimidin-3-one (33b )
  • Step 3 2-allyl-1-(4-hydroxy-6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((3-(4-hydroxybutyl)- 4-(4-Methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazol[3,4-d]pyrimidin-3-one (33c)
  • Step 4 2 2 -allyl-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -dihydro-2 1 H-9-oxa-3-aza-2(1,6)-pyrazolyl[3,4-d]pyrimidine-1(2,4)-pyridine-4(1,3)-heterocycle Octano-2 3 -one (Example 33)
  • Step 4 4-(4-Methylpiperazin-1-yl)-3-((2-(pyran-2-yl)ethoxy)methyl)aniline (34d)
  • Step 5 2-(2-Fluoropropyl-2-en-1-yl)-1-(6-(-2-hydroxypropyl-2-yl)-4-(methoxymethoxy)pyridine -2-yl)-6-((4-(4-methylpyridin-1-yl)-3-((2-pyran-2-yloxy)ethoxy)methyl)phenyl)amino ) pyrazolyl[3,4-d]pyrimidin-3-one (34e)
  • Step 6 2-(2-Fluoropropyl-2-en-1-yl)-1-(4-hydroxy-6-(-2-hydroxypropyl-2-yl)pyridin-2-yl)-6 -((3-((2-hydroxyethoxy)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrazolyl[3,4-d]pyrimidine-3 - Ketone (34f)
  • Step 7 2 2 -(2-fluoroallyl)-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -Dihydro-2 1 H-6,9-Dioxa-3-aza-2(1,6)-pyrazolyl[3,4-d]pyrimidine-1(2,4)-pyridine-4 (1,3)-Heterocyclic octafan-2 3 -one (Example 34)
  • Step 1 1-(6-(2-Hydroxypropan-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6-((4-(4-methylpiperazine- 1-yl)-3-((2-(pyran-2-oxyl)ethoxy)methyl)phenyl)amino)-2-(prop-2-en-1-yl)pyrazolo[ 3,4-d]pyrimidin-3-one (35a)
  • Step 2 1-(4-Hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-((2-hydroxyethoxy)methyl)-4- (4-Methylpiperazin-1-yl)phenyl)amino)-2-(prop-2-en-1-yl)pyrazolo[3,4-d]pyrimidin-3-one (35b)
  • Step 3 2 2 -allyl-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -dihydro-2 1 H-6,9-dioxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine-4(1,3) -Heterocyclic octapan-2 3 -one (Example 35)
  • Step 1 tert-butyl (9-(2-formyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undec-3-yl)carboxylate (36a)
  • Step 2 tert-butyl (9-(2-(hydroxymethyl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undec-3-yl)carboxylate (36b)
  • Step 5 3-Methyl-9-(4-nitro-2-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)phenyl)- 3,9-diazaspiro[5.5]undecane (36e)
  • Step 6 4-(9-Methyl-3,9-diazaspiro[5.5]undec-3-yl)-3-((2-((tetrahydro-2H-pyran-2-yl )oxy)ethoxy)methyl)aniline (36f)
  • Step 7 2-allyl-1-(6-(2-hydroxyprop-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6-((4-(9 -Methyl-3,9-diazaspiro[5.5])undec-3-yl)-3-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy Base)methyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (36g)
  • Step 8 2-allyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-((2-hydroxyethoxy) Methyl)-4-(9-methyl)-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo [3,4-d]pyrimidin-3-one (36h)
  • Step 9 2 2 -allyl-1 6 -(2-hydroxypropyl-2-yl)-4 4 -(9-methyl-3,9-diazaspiro[5.5]undecyl- 3-yl)-2 2 ,2 3 -dihydro-2 1 H-6,9-dioxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine- 1(2,4)-pyridine-4(1,3)-heterocyclic octafan-2 3 -one (Example 36)
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained residue was purified by preparative HPLC (chromatographic column: Gemini-C18 150 ⁇ 21.2mm, 5 ⁇ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25%-30%; flow rate: 20mL/min) to obtain Example 36 (13 mg, yield: 17%).
  • Step 1 2-(2-Fluoro-allyl)-6-((5-(4-hydroxybutyl)-6-(4-methylpiperazin-1-yl)-pyridin-3-yl) Amino)-1-(6-(2-hydroxypropyl-2-yl)-4-(methoxymethoxy)pyridin-2-yl)pyrazolo[3,4-d]pyrimidine-3- Ketone (37a)
  • Step 2 2-(2-Fluoroallyl)-1-(4-hydroxy-6-(2-hydroxyprop-2-yl)pyridin-2-yl)-6-((5-(4-hydroxy Butyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3- Ketone (37b)
  • Step 3 2 2 -(2-fluoroallyl)-1 6 -(2-hydroxypropyl-2-yl)-4 6 -(4-methylpiperazin-1-yl)-2 2 ,2 3 -dihydro-2 1 H-9-oxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4),4(3,5 )-bipyridine-heterocyclic octafan-2 3 -one (Example 37)
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained residue was purified by preparative HPLC (chromatographic column: Gemini-C18 150 ⁇ 21.2mm, 5 ⁇ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20%-40%; flow rate: 20mL/min) to obtain Example 37 (30 mg, yield: 24%).
  • Step 5 4-(8-Methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((2-(pyran-2-oxyl)ethoxy ) methyl) aniline (38e)
  • Step 6 2-(2-Fluoro-prop-2-en-1-yl)-1-(6-2(-hydroxypropan-2-yl)-4-(methoxymethoxy)pyridine-2 -yl)-6-((4-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)-3-((2-(pyran-2-oxo base) ethoxy) methyl) amino) pyrazolo [3,4-d] pyrimidin-3-one (38f)
  • Step 7 2-(2-Fluoro-prop-2-en-1-yl)-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)-pyridin-2-yl)-6- ((3-((2-hydroxyethoxy)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino) Pyrazolo[3,4-d]pyrimidin-3-one (38g)
  • Step 8 2 2 -(2-fluoroallyl)-1 6 -(2-hydroxypropyl-2-yl)-4 4 -(8-methyl-3,8-diazabicyclo[3.2. 1] Octane-3-yl)-2 2 ,2 3 -dihydro-2 1 H-6,9-dioxa-3-aza-2(1,6)-pyrazolo[3,4 -d] pyrimidine-1(2,4)-pyridine-4(3,5)-heterocyclic octafan-2 3 -one (Example 38)
  • Step 4 4-(4-((2-(2-fluoroallyl)-1-(6-(2-hydroxypropyl-2-yl)-4-(methoxymethoxy)pyridine- 2-yl)-3-oxa-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-2-(4-hydroxybutyl)phenyl)piperazin-1-yl)carboxylic acid tert Butyl ester (39d)
  • Step 5 2-(2-Fluoroallyl)-1-(4-hydroxy-6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((3-(4- Hydroxybutyl)-4-(piperazin-1-yl)phenyl)amino)pyrazolo[3,4-d]pyrimidin-3-one (39e)
  • Step 6 2 2 -(2-Fluoroallyl)-1 6 -(2-hydroxypropan-2-yl)-4 4 -(piperazin-1-yl)-2 2 ,2 3 -dihydro- 2 1 H-9-oxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine-4(1,3)-hetero Cyclospan-2 3 -one (Example 39)
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained residue was purified by preparative HPLC (chromatographic column: Gemini-C18 150 ⁇ 21.2mm, 5 ⁇ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20%-40%; flow rate: 20mL/min) to obtain Example 39 (4.8 mg, yield: 12%).
  • Step 2 4-(2-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)but-3-yn-1-ol (40b)
  • Step 3 4-(5-Amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)butan-1-ol (40c)
  • Step 4 6-((3-(4-Hydroxybutyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-1-( 6-(2-Hydroxyprop-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-2-(propyl-2-en-1-yl)pyrazolo[3, 4-d]pyrimidin-3-one (40d)
  • Step 5 1-(4-Hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-(4-hydroxybutyl)-4-(4-(4 -Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-2-(propyl-2-en-1-yl)pyrazolo[3,4-d]pyrimidine-3 - Ketone (40e)
  • Step 6 2 2 -allyl-1 6 -(2-hydroxypropan-2-yl)-4 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)- 2 2 ,2 3 -Dihydro-2 1 H-9-oxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine -4(1,3)-heterocyclic octafan-2 3 -one (Example 40)
  • Step 1 tert-butyl 9-(2-bromo-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (41a)
  • Step 4 4-(2-(9-Methyl-3,9-diazaspiro[5.5]undec-3-yl)-5-nitrophenyl)3-butyn-1-ol ( 41d)
  • Step 5 4-(5-Amino-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)butan-1-ol (41e)
  • Step 6 2-allyl-6-((3-(4-hydroxybutyl)-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl) Phenyl)amino)-1-(6-(2-hydroxypropyl-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-1,2-dihydro-3H-pyridine Azolo[3,4-d]pyrimidin-3-one (41f)
  • Step 7 2-allyl-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-(4-hydroxybutyl)-4 -(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d ]pyrimidin-3-one (41g)
  • Step 8 2 2 -allyl-1 6 -(2-hydroxypropan-2-yl)-4 4 -(9-methyl-3,9-diazaspiro[5.5]undecane-3- base)-2 2 ,2 3 -dihydro-2 1 H-9-oxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4 )-pyridine-4(1,3)-heterocyclic octafan-2 3 -one (Example 41)
  • Step 1 2-(6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1 -yl)-4-(methoxymethoxy)pyridin-2-yl)-2-methylpropionitrile (42a)
  • Step 2 2-(6-(2-allyl-6-((4-(4-methylpiperazin-1-yl)-3-((2-((tetrahydro-2H-pyran- 2-yl)oxy)ethoxy)methyl)phenyl)amino)-3-oxa-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl) -4-(methoxymethoxy)pyridin-2-yl)-2-methylpropionitrile (42b)
  • Step 3 2-(6-(2-allyl-6-((3-((2-hydroxyethoxy)methyl)-4-(4-methylpiperazin-1-yl)phenyl )amino)-3-oxa-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-hydroxypyridin-2-yl)-2-methylpropane Nitrile (42c)
  • Step 4 2-(2 2 -allyl-4 4 -(4-methylpiperazin-1-yl)-2 3 -oxo-2 2 ,2 3 -dihydro-2 1 H-6, 9-dioxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4)-pyridine-4(1,3)-heterocyclic octapane -1 6 -yl)-2-methylpropionitrile (Example 42)
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained residue was purified by preparative HPLC (chromatographic column: Gemini-C18 150 ⁇ 21.2mm, 5 ⁇ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25%-30%; flow rate: 20mL/min) to obtain Example 42 (13.5 mg, yield: 16%).
  • Step 5 1-(4-Nitro-2-(((2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl)oxy)methyl) Phenyl)-4-(oxetan-3-yl)piperazine (43e)
  • Step 6 4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(((2-(3,4,5,6-tetrahydro-2H-pyran- 2-yloxy)ethyl)oxy)methyl)aniline (43f)
  • Step 7 1-(6-(2-Hydroxypropan-2-yl)-4-((methoxymethyl)oxy)pyridin-2-yl)-6-((4-(4-(oxy Heterobutan-3-yl)piperazin-1-yl)-3-(((2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl)oxy Base)methyl)phenyl)amino)-2-(prop-2-enyl)-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-one (43g)
  • Step 8 6-((3-(((2-Hydroxyethyl)oxy)methyl)-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl) Amino)-1-(4-hydroxy-6-(2-hydroxyprop-2-yl)pyridin-2-yl)-2-(prop-2-enyl)-2,3-dihydro-1H-pyridine Azolo[3,4-d]pyrimidin-3-one (43h)
  • Step 9 2 2 -Allyl-1 6 -(2-hydroxypropyl-2-yl)-4 4 -(4-(oxetan-3-yl)piperazin-1-yl)- 2 2 ,2 3 -Dihydro- 2 1 H-6,9-dioxa-3-aza-2(1,6)-pyrazolo[3,4-d]pyrimidine-1(2,4 )-pyridine-4(1,3)-heterocyclic octafan-2 3 -one (Example 43)
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained residue was purified by preparative HPLC (chromatographic column: Gemini-C18 150 ⁇ 21.2mm, 5 ⁇ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25%-30%; flow rate: 20mL/min) to obtain Example 43 (28 mg, yield: 16%).
  • Step 1 2-(2-fluoroallyl)-1-(6-(2-hydroxyprop-2-yl)-4-(methoxymethoxy)pyridin-2-yl)-6-( (4-(9-methyl-3,9-)diazaspiro[5.5]undecane-3-yl)-3-((2-((tetrahydro-2H-pyran-2-yl )oxy)ethoxy)methyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (44a)
  • Step 2 2-(2-fluoroallyl)-1-(4-hydroxy-6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((3-((2- Hydroxyethoxy)methyl)-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrazolo[3,4-d ]pyrimidin-3-one (44b)
  • Step 3 2 2 -(2-fluoroallyl)-1 6 -(2-hydroxypropan-2-yl)-4 4 -(9-methyl-3,9-diazaspiro[5.5 ]undec-3-yl)-2 2 ,2 3 -dihydro-2 1 H-6,9-dioxa-3-aza-2(1,6)-pyrazolo[3,4 -d] pyrimidine-1(2,4)-pyridine-4(1,3)-heterocyclic octafan-2 3 -one (Example 44)
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained residue was purified by preparative HPLC (chromatographic column: Gemini-C18 150 ⁇ 21.2mm, 5 ⁇ m; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25%-30%; flow rate: 20mL/min) to obtain Example 44 (16 mg, yield: 22%).
  • Step 2 4-(2-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)-5-nitropyridin-3-yl)-3-butyn-1-ol (45b)

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Abstract

L'invention concerne un dérivé de dihydropyrazolone contenant de la pyrimidine, un promédicament de celui-ci, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, ainsi que son procédé de préparation et une application de celui-ci. Le composé peut inhiber Wee1 et présente une meilleure sélectivité vis-à-vis de Plk1, et peut traiter le cancer.
PCT/CN2022/119440 2021-09-18 2022-09-16 Dérivé de dihydropyrazolone contenant de la pyrimidine, sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son application WO2023041066A1 (fr)

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WO2019074979A1 (fr) * 2017-10-09 2019-04-18 Girafpharma, Llc Composés hétérocycliques et leurs utilisations
WO2019085933A1 (fr) * 2017-11-01 2019-05-09 南京明德新药研发股份有限公司 Composé macrocyclique servant d'inhibiteur de wee1 et ses applications
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WO2020083404A1 (fr) * 2018-10-26 2020-04-30 南京明德新药研发有限公司 Dérivé de pyrimidopyrazolone en tant qu'inhibiteur de wee1 et son utilisation
WO2021168074A1 (fr) * 2020-02-18 2021-08-26 Theseus Pharmaceuticals, Inc. Composés macrocycliques et leurs utilisations
CN113387962A (zh) * 2020-03-12 2021-09-14 上海迪诺医药科技有限公司 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用

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AR060635A1 (es) * 2006-04-27 2008-07-02 Banyu Pharma Co Ltd Derivados de 1,2-dihidro-3h-pirazolo[3,4-d]pirimidin-3-ona, composiciones farmaceuticas que los comprenden y su uso en el tratamiento del cancer
CN109422754A (zh) * 2017-08-24 2019-03-05 上海迪诺医药科技有限公司 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用
CN115197221B (zh) * 2021-04-02 2024-05-24 轩竹(北京)医药科技有限公司 二氢吡唑并嘧啶酮类大环衍生物及其用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108623615A (zh) * 2017-03-23 2018-10-09 上海迪诺医药科技有限公司 吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用
WO2019074979A1 (fr) * 2017-10-09 2019-04-18 Girafpharma, Llc Composés hétérocycliques et leurs utilisations
WO2019085933A1 (fr) * 2017-11-01 2019-05-09 南京明德新药研发股份有限公司 Composé macrocyclique servant d'inhibiteur de wee1 et ses applications
WO2019134539A1 (fr) * 2018-01-05 2019-07-11 四川科伦博泰生物医药股份有限公司 Composé de dihydropyrazolone et de pyrimidine, son procédé de préparation et son utilisation
WO2020083404A1 (fr) * 2018-10-26 2020-04-30 南京明德新药研发有限公司 Dérivé de pyrimidopyrazolone en tant qu'inhibiteur de wee1 et son utilisation
WO2021168074A1 (fr) * 2020-02-18 2021-08-26 Theseus Pharmaceuticals, Inc. Composés macrocycliques et leurs utilisations
CN113387962A (zh) * 2020-03-12 2021-09-14 上海迪诺医药科技有限公司 吡唑并[3,4-d]嘧啶-3-酮衍生物、其药物组合物及应用

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