WO2022100688A1 - Modulateur de kinase hpk1, son procédé de préparation et son utilisation - Google Patents

Modulateur de kinase hpk1, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022100688A1
WO2022100688A1 PCT/CN2021/130283 CN2021130283W WO2022100688A1 WO 2022100688 A1 WO2022100688 A1 WO 2022100688A1 CN 2021130283 W CN2021130283 W CN 2021130283W WO 2022100688 A1 WO2022100688 A1 WO 2022100688A1
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hydrogen
alkyl
independently selected
methyl
cycloalkyl
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PCT/CN2021/130283
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Chinese (zh)
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邓贤明
黄伟
张建明
云彩红
黄鑫
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南京红云生物科技有限公司
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Priority to CN202180075195.4A priority Critical patent/CN116438172A/zh
Publication of WO2022100688A1 publication Critical patent/WO2022100688A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to an HPK1 kinase regulator, a preparation method and application thereof.
  • HPK1 hematopoietic progenitor kinase 1
  • HPK1 belongs to the MAP4K family and is mainly distributed in blood cells, such as T cells, B cells, macrophages, dendritic cells, and neutrophils.
  • HPK1 is involved in the regulation of various immune cell signaling pathways, and is a negative regulator of T cell receptor (TCR)-mediated signaling pathways.
  • TCR T cell receptor
  • TCR T cell receptor
  • HPK1 in the cytoplasm is recruited to the plasma membrane, and the activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as a docking site for the negative regulatory protein 14-3-3p, and finally disrupting the TCR signaling complex stability (Hernandez et al Cell Rep. 2018 25:80).
  • Prostaglandin E2 can cause T cells to not efficiently produce cytokines such as IL-2, and to not proliferate normally and then undergo apoptosis. These phenomena can be reversed by knocking down HPK1. Moreover, in a mouse model, HPK1 knockout T cells can significantly inhibit the formation of Lewis lung cancer (Alzabin S. et al. Cancer Immunol. Immunother. 2010, 59:419). In addition, both in vitro and in vivo models, HPK1-deficient dendritic cells can more efficiently present antigens (Alzabin S. et al., J Immunol. 2009, 182:6187).
  • the present invention provides compounds shown below:
  • One object of the present invention is to provide a class of compounds or stereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, which have the activity of modulating HPK1.
  • Another object of the present invention is to provide a preparation method of the above compound.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned compound.
  • Another object of the present invention is to provide the use of the above-mentioned compounds or pharmaceutical compositions comprising the above-mentioned compounds in cancer immunotherapy.
  • Another object of the present invention is to provide the use of the above-mentioned compound or a pharmaceutical composition comprising the above-mentioned compound in the preparation of a medicament for the prevention and/or treatment of cancer or other diseases.
  • Another object of the present invention is to provide a method of treating cancer comprising administering to a subject an effective amount of a compound of the present invention or a composition comprising the same.
  • the present invention is achieved through the following technical solutions.
  • the present invention provides compounds of the following general formula:
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R 2 is selected from:
  • Z 1 and Z 2 are each independently selected from C1-C6 alkyl, C3-C8 cycloalkyl;
  • Z 3 and Z 4 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, and Z 4 is not hydrogen ;
  • Z 5 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing alkyl, C3-C8 heteroatom-containing cycloalkyl;
  • Z 6 and Z 7 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, or Z 6 , Z 7 together with the N atoms to which they are commonly attached to form a substituted or unsubstituted 4-8 membered heterocycle containing 1 to 2 heteroatoms, the substituents being selected from halogen, C1-C6 alkyl, C3-C8 cycloalkyl ;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy group (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl);
  • R 4 and R 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, and R 4 and R 5 are not hydrogen at the same time.
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N, O, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N.
  • Z 1 , Z 2 are each independently selected from C1-C6 alkyl.
  • Z 1 , Z 2 are methyl groups.
  • Z 3 , Z 4 are each independently selected from hydrogen, C1-C6 alkyl, haloC1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 is not hydrogen.
  • Z3, Z4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -CF3 , and Z4 is not hydrogen.
  • Z 3 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z 4 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z3 is selected from hydrogen, methyl, ethyl, cyclopropyl.
  • Z4 is selected from methyl, ethyl, isopropyl, -CF3 , cyclopropyl.
  • Z 5 is selected from C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z5 is selected from methyl, ethyl, isopropyl, cyclopropyl.
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are formed together with the N atom to which they are commonly attached (preferably ).
  • Z6 is hydrogen, methyl; Z7 is selected from methyl, ethyl, isopropyl, cyclopropyl; or, Z6 , Z7 are formed together with the N atom to which they are commonly attached
  • R3 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, cyano, nitro, methyl, ethyl, methoxy, cyclopropyl, vinyl.
  • R 4 , R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, and R 4 , R 5 are not both hydrogen.
  • R4 is selected from hydrogen, fluorine, chlorine, methyl
  • R5 is selected from hydrogen, methyl
  • R4 , R5 are not both hydrogen.
  • the present invention provides a compound of the general formula represented by formula (I), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable compound thereof solvates,
  • Z 1 and Z 2 are each independently selected from C1-C6 alkyl, C3-C8 cycloalkyl;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy group (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl);
  • R 4 and R 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, and R 4 and R 5 are not hydrogen at the same time.
  • Z 1 , Z 2 are each independently selected from C1-C6 alkyl.
  • Z 1 , Z 2 are methyl groups.
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably selected from direct bond, methylene; Y is selected from hydrogen, C1-C6 alkyl, preferably selected from C1-C6 alkyl, or preferably selected from hydrogen , methyl, or more preferably methyl.
  • R 1 is , L is selected from direct bond, C1-C6 alkylene, preferably direct bond, methylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen, methyl.
  • R 1 is , L is a direct bond; Y is selected from hydrogen and C1-C6 alkyl, preferably from hydrogen and methyl.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N, O, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N.
  • R3 is selected from hydrogen, halogen, C1-C6 alkyl (eg, methyl, ethyl), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, , vinyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, cyclopropyl, vinyl.
  • R 4 , R 5 are each independently selected from hydrogen, fluorine, chlorine, and R 4 , R 5 are not both hydrogen.
  • R 4 is chloro and R 5 is hydrogen.
  • the present invention provides a compound of the general formula represented by formula (II), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable compound thereof solvates,
  • Z 3 and Z 4 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, and Z 4 is not hydrogen;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy group (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl);
  • R 4 and R 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, and R 4 and R 5 are not hydrogen at the same time.
  • Z 3 , Z 4 are each independently selected from hydrogen, C1-C6 alkyl, haloC1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 is not hydrogen.
  • Z3, Z4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -CF3 , and Z4 is not hydrogen.
  • Z 3 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z 4 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z3 is selected from hydrogen, methyl, ethyl, cyclopropyl.
  • Z4 is selected from methyl, ethyl, isopropyl, -CF3 , cyclopropyl.
  • R 1 is selected from and R 1 is not hydrogen.
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is selected from , each L is independently selected from a direct bond, a C1-C6 alkylene group, preferably a direct bond, a methylene group; each Y is independently selected from hydrogen, a C1-C6 alkyl group, preferably a C1-C6 alkyl group , or preferably selected from hydrogen, methyl, or more preferably methyl.
  • R 1 is , L is a direct bond; Y is selected from hydrogen and C1-C6 alkyl, preferably from hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene; each Z is independently selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N - Dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from CH, N.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N, O, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N.
  • R 3 is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl), C1- C6 alkoxy (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, methyl, methoxy, cyclopropyl.
  • R 4 , R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, and R 4 , R 5 are not both hydrogen.
  • R4 is selected from hydrogen, fluorine, chlorine, methyl
  • R5 is selected from H, methyl
  • R4 , R5 are not both hydrogen.
  • the present invention provides a compound of the general formula represented by formula (III), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable compound thereof solvates,
  • Z 5 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing alkyl, C3-C8 heteroatom-containing cycloalkyl;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy group (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl);
  • R 4 and R 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, and R 4 and R 5 are not hydrogen at the same time.
  • Z 5 is selected from C1-C6 alkyl, C3-C8 cycloalkyl.
  • Z 5 is selected from C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z5 is selected from methyl, ethyl, isopropyl, cyclopropyl.
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is selected from , each L is independently selected from a direct bond, a C1-C6 alkylene group, preferably a direct bond, a methylene group; each Y is independently selected from hydrogen, a C1-C6 alkyl group, preferably a C1-C6 alkyl group , or preferably selected from hydrogen, methyl, or more preferably methyl.
  • R 1 is , L is a direct bond;
  • Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably methyl.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene; each Z is independently selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N - Dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N, O, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N.
  • R3 is selected from hydrogen, halogen, haloC1-C6 alkyl (eg, trifluoromethyl), C1-C6 alkyl (eg, methyl), C1-C6 alkoxy (eg, , methoxy), C3-C6 cycloalkyl (eg, cyclopropyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, cyclopropyl.
  • R 4 , R 5 are each independently selected from hydrogen, fluorine, chlorine, and R 4 , R 5 are not both hydrogen.
  • R 4 is selected from fluoro, chloro, and R 5 is hydrogen.
  • the present invention provides a compound of the general formula represented by formula (IV), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable compound thereof solvates,
  • Z 6 and Z 7 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, or, Z 6 , Z 7 and Their commonly connected N atoms together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-2 heteroatoms, and the substituents are selected from halogen, C1-C6 alkyl, C3-C8 cycloalkyl;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy group (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl);
  • R 4 and R 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, and R 4 and R 5 are not hydrogen at the same time.
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are formed together with the N atom to which they are commonly attached (preferably ).
  • Z 6 is hydrogen, methyl;
  • Z 7 is selected from methyl, ethyl, isopropyl, cyclopropyl; or, Z 6 , Z 7 are formed together with the N atom to which they are commonly attached
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is selected from , each L is independently selected from a direct bond, a C1-C6 alkylene group, preferably a direct bond, a methylene group; each Y is independently selected from hydrogen, a C1-C6 alkyl group, preferably a C1-C6 alkyl group , or preferably selected from hydrogen, methyl, or more preferably methyl.
  • R 1 is , L is a direct bond;
  • Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably methyl.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene; each Z is independently selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N - Dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N, O, S.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from C, CH, N.
  • R3 is selected from hydrogen, halogen, haloC1-C6 alkyl (eg, trifluoromethyl), C1-C6 alkyl (eg, methyl), C1-C6 alkoxy (eg, , methoxy), C3-C6 cycloalkyl (eg, cyclopropyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, cyclopropyl.
  • R 4 , R 5 are each independently selected from hydrogen, fluorine, chlorine, and R 4 , R 5 are not both hydrogen.
  • R 4 is selected from fluoro, chloro, and R 5 is hydrogen.
  • the present invention provides compounds of the following general formula:
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R 2 is selected from:
  • Z 1 and Z 2 are each independently selected from C1-C6 alkyl, C3-C8 cycloalkyl;
  • Z 3 and Z 4 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, and Z 4 is not hydrogen ;
  • Z 5 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing alkyl, C3-C8 heteroatom-containing cycloalkyl;
  • Z 6 and Z 7 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, or Z 6 , Z 7 together with the N atoms to which they are commonly attached to form a substituted or unsubstituted 4-8 membered heterocycle containing 1 to 2 heteroatoms, the substituents being selected from halogen, C1-C6 alkyl, C3-C8 cycloalkyl ;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl).
  • C1-C6 alkyl eg, methyl, ethyl
  • C1-C6 alkoxy eg, methoxy
  • C3-C6 cycloalkyl eg, cyclopropyl
  • C2-C6 alkenyl eg, vinyl
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • Z 1 , Z 2 are each independently selected from C1-C6 alkyl.
  • Z 1 , Z 2 are methyl groups.
  • Z 3 , Z 4 are each independently selected from hydrogen, C1-C6 alkyl, haloC1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 is not hydrogen.
  • Z3, Z4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -CF3 , and Z4 is not hydrogen.
  • Z 3 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z 4 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z3 is selected from hydrogen, methyl, ethyl, cyclopropyl.
  • Z4 is selected from methyl, ethyl, isopropyl, -CF3 , cyclopropyl.
  • Z 5 is selected from C1-C6 alkyl.
  • Z5 is selected from methyl, ethyl, isopropyl.
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl.
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are each independently selected from hydrogen, methyl, ethyl, isopropyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are formed together with the N atom to which they are commonly attached (preferably ).
  • Z6 is hydrogen, methyl; Z7 is selected from methyl, ethyl, isopropyl; or, Z6 , Z7 are formed together with the N atom to which they are commonly attached
  • R3 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, cyano, nitro, methyl, ethyl, methoxy, cyclopropyl, vinyl.
  • the present invention provides a compound of the general formula represented by formula (I'), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. accepted solvates,
  • Z 1 and Z 2 are each independently selected from C1-C6 alkyl, C3-C8 cycloalkyl;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl).
  • C1-C6 alkyl eg, methyl, ethyl
  • C1-C6 alkoxy eg, methoxy
  • C3-C6 cycloalkyl eg, cyclopropyl
  • C2-C6 alkenyl eg, vinyl
  • Z 1 , Z 2 are each independently selected from C1-C6 alkyl.
  • Z 1 , Z 2 are methyl groups.
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably selected from direct bond, methylene; Y is selected from hydrogen, C1-C6 alkyl, preferably selected from C1-C6 alkyl, or preferably selected from hydrogen , methyl, or more preferably methyl.
  • R 1 is , L is selected from direct bond, C1-C6 alkylene, preferably direct bond, methylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen, methyl.
  • R 1 is , L is a direct bond; Y is selected from hydrogen and C1-C6 alkyl, preferably from hydrogen and methyl.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • R3 is selected from hydrogen, halogen, C1-C6 alkyl (eg, methyl, ethyl), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, , vinyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, cyclopropyl, vinyl.
  • the present invention provides a compound of general formula (II'), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. accepted solvates,
  • Z 3 and Z 4 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, and Z 4 is not hydrogen;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl).
  • C1-C6 alkyl eg, methyl, ethyl
  • C1-C6 alkoxy eg, methoxy
  • C3-C6 cycloalkyl eg, cyclopropyl
  • C2-C6 alkenyl eg, vinyl
  • Z 3 , Z 4 are each independently selected from hydrogen, C1-C6 alkyl, haloC1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 is not hydrogen.
  • Z3, Z4 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -CF3 , and Z4 is not hydrogen.
  • Z 3 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z 4 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z3 is selected from hydrogen, methyl, ethyl, cyclopropyl.
  • Z4 is selected from methyl, ethyl, isopropyl, -CF3 , cyclopropyl.
  • R 1 is selected from and R 1 is not hydrogen.
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is selected from , each L is independently selected from a direct bond, a C1-C6 alkylene group, preferably a direct bond, a methylene group; each Y is independently selected from hydrogen, a C1-C6 alkyl group, preferably a C1-C6 alkyl group , or preferably selected from hydrogen, methyl, or more preferably methyl.
  • R 1 is , L is a direct bond; Y is selected from hydrogen and C1-C6 alkyl, preferably from hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene; each Z is independently selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N - Dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • R 3 is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl), C1- C6 alkoxy (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, methyl, methoxy, cyclopropyl.
  • the present invention provides a compound of the general formula represented by formula (III'), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. accepted solvates,
  • Z 5 is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing alkyl, C3-C8 heteroatom-containing cycloalkyl;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl).
  • C1-C6 alkyl eg, methyl, ethyl
  • C1-C6 alkoxy eg, methoxy
  • C3-C6 cycloalkyl eg, cyclopropyl
  • C2-C6 alkenyl eg, vinyl
  • Z 5 is selected from C1-C6 alkyl.
  • Z5 is selected from methyl, ethyl, isopropyl.
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is selected from , each L is independently selected from a direct bond, a C1-C6 alkylene group, preferably a direct bond, a methylene group; each Y is independently selected from hydrogen, a C1-C6 alkyl group, preferably a C1-C6 alkyl group , or preferably selected from hydrogen, methyl, or more preferably methyl.
  • R 1 is , L is a direct bond;
  • Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably methyl.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene; each Z is independently selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N - Dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • R3 is selected from hydrogen, halogen, haloC1-C6 alkyl (eg, trifluoromethyl), C1-C6 alkyl (eg, methyl), C1-C6 alkoxy (eg, , methoxy), C3-C6 cycloalkyl (eg, cyclopropyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, cyclopropyl.
  • the present invention provides a compound of the general formula represented by formula (IV'), or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. accepted solvates,
  • Z 6 and Z 7 are each independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, or, Z 6 , Z 7 and Their commonly connected N atoms together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-2 heteroatoms, and the substituents are selected from halogen, C1-C6 alkyl, C3-C8 cycloalkyl;
  • R 1 is selected from and R 1 is not hydrogen
  • Each L is independently selected from direct bond, C1-C6 alkylene
  • Each Y is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, R a R b N-C1-C6 alkyl, HO-C1-C6 alkyl;
  • Each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, HO-C1-C6 alkyl, R a R b N-, R a R b N-C1-C6 alkyl;
  • R a , R b are each independently selected from hydrogen, C1-C6 alkyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C, CH, CH 2 , N, NH, O, S;
  • R is selected from hydrogen, halogen, halogenated C1-C6 alkyl (eg, trifluoromethyl), cyano, nitro, C1-C6 alkyl (eg, methyl, ethyl), C1-C6 alkoxy (eg, methoxy), C3-C6 cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl (eg, vinyl).
  • C1-C6 alkyl eg, methyl, ethyl
  • C1-C6 alkoxy eg, methoxy
  • C3-C6 cycloalkyl eg, cyclopropyl
  • C2-C6 alkenyl eg, vinyl
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl.
  • Z 6 , Z 7 are each independently selected from hydrogen, C1-C6 alkyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are each independently selected from hydrogen, methyl, ethyl, isopropyl, and Z 6 , Z 7 are not both hydrogen.
  • Z 6 , Z 7 are formed together with the N atom to which they are commonly attached (preferably ).
  • Z6 is hydrogen, methyl; Z7 is selected from methyl, ethyl, isopropyl; or, Z6 , Z7 are formed together with the N atom to which they are commonly attached
  • each L is independently selected from a direct bond, methylene, ethylene.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, R a R b N-.
  • each Z is independently selected from hydrogen, hydroxy, C1-C6 alkoxy, R a R b N-.
  • each Y is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl.
  • each Z is independently selected from hydrogen, hydroxy, amino, N,N-dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene; Y is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, HO-C1 -C6 alkyl, R a R b N-C1-C6 alkyl, preferably selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-(N,N-di methylamino)ethyl.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, C1-C6 alkoxy, R a R b N-, preferably hydrogen, hydroxyl, N,N- Dimethylamino, methoxy.
  • R 1 is When L is selected from direct bond, C1-C6 alkylene, preferably from direct bond, methylene, ethylene.
  • R 1 is selected from , L is a direct key.
  • R 1 is selected from , each L is independently selected from a direct bond, a C1-C6 alkylene group, preferably a direct bond, a methylene group; each Y is independently selected from hydrogen, a C1-C6 alkyl group, preferably a C1-C6 alkyl group , or preferably selected from hydrogen, methyl, or more preferably methyl.
  • R 1 is , L is a direct bond;
  • Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably methyl.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene.
  • R 1 is , L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably hydrogen and methyl.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Y is selected from hydrogen, C1-C6 alkyl, preferably from C1-C6 alkyl, or preferably from hydrogen, methyl, or more preferably is methyl.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, N,N-dimethylamino.
  • R 1 is When , L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N-dimethylamino.
  • R 1 is selected from , each L is independently selected from C1-C6 alkylene, preferably ethylene; each Z is independently selected from hydrogen, hydroxyl, R a R b N-, preferably hydrogen, hydroxyl, amino, N,N - Dimethylamino.
  • R 1 is When L is selected from C1-C6 alkylene, preferably ethylene; Z is selected from hydroxyl, C1-C6 alkoxy, R a R b N-, preferably selected from hydroxyl, methoxy, N,N- Dimethylamino.
  • R a , R b are each independently selected from H, methyl.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, O, S.
  • X 1 , X 2 , X 3 , X 4 are each independently selected from C, CH, N, S.
  • R3 is selected from hydrogen, halogen, haloC1-C6 alkyl (eg, trifluoromethyl), C1-C6 alkyl (eg, methyl), C1-C6 alkoxy (eg, , methoxy), C3-C6 cycloalkyl (eg, cyclopropyl).
  • R3 is selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, cyclopropyl.
  • the present invention provides compounds of the following general formula:
  • R1 is selected from :
  • L is selected from a direct bond, methylene or
  • Y is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl base, 2-(N,N-dipropylamino)ethyl, 2-(N,N-diisopropylamino)ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethyl oxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-cyclopropoxyethyl;
  • Z is selected from hydrogen, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, amino, N,N-dimethylamino, N,N-diethylamino, N,N- Dipropylamino, N,N-diisopropylamino;
  • X 1 , X 2 , X 3 , X 4 each independently selected from C, N, O, S;
  • R 2 is selected from:
  • Z 1 and Z 2 are each independently selected from C1-C6 alkyl, C3-C8 cycloalkyl;
  • Z 3 and Z 4 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl, and Z 4 is not hydrogen ;
  • Z 5 is selected from C1-C6 alkyl, C1-C6 fluorine-containing alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing alkyl, C3-C8 heteroatom-containing cycloalkyl;
  • Z 6 and Z 7 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl, or Z 6 , Z 7 together with N forms a substituted or unsubstituted 4-8 membered ring containing 1-2 heteroatoms, and the substituent is selected from halogen, C1-C6 alkyl, C3-C8 cycloalkyl;
  • R3 is selected from:
  • C1-C6 fluoroalkyl eg, trifluoromethyl
  • the present invention also provides a method for preparing the compound described in any of the above-mentioned technical solutions, comprising the following steps:
  • the metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine) palladium, bistriphenylphosphonium palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium , tris(dibenzylideneacetone)dipalladium;
  • the alkaline conditions refer to the conditions in which any of the following substances exist: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, hydroxide Potassium, sodium hydride, potassium hydride;
  • Described acidic condition refers to the condition that any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid;
  • the present invention also provides a method for preparing the compound described in any of the above-mentioned technical solutions, comprising the following steps:
  • the metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine) palladium, bistriphenylphosphonium palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium , tris(dibenzylideneacetone)dipalladium;
  • the alkaline conditions refer to the conditions in which any of the following substances exist: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, hydroxide Potassium, sodium hydride, potassium hydride;
  • Described acidic condition refers to the condition that any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate substance, and optional pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition further comprises other tumor immunotherapy drugs.
  • the other tumor immunotherapy drugs are selected from PD-1 mAb, PD-L1 mAb, CTLA-4 mAb, TIM-3 mAb, TGF ⁇ mAb, LAG3 antagonist, TLR4 agonist , TLR7 agonists, TLR8 agonists, TLR9 agonists, STING agonists, CAR-T cells, or any combination thereof.
  • Methods of preparing various pharmaceutical compositions containing amounts of active ingredients are known, or will be apparent to those skilled in the art in light of the present disclosure. Methods of preparing such pharmaceutical compositions include incorporating suitable pharmaceutical excipients, carriers, diluents, and the like, as described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995).
  • the pharmaceutical formulations of the present invention are manufactured by known methods, including conventional mixing, dissolving or lyophilization methods.
  • the compounds of the present invention can be formulated into pharmaceutical compositions and administered to a patient by various routes suitable for the chosen mode of administration, eg, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
  • the compounds of the present invention can be administered systemically, eg, orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
  • a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier.
  • the active compound may be incorporated with one or more excipients and presented in the form of swallowable tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like use.
  • Such compositions and preparations should contain at least 0.1% active compound.
  • the proportions of such compositions and formulations may, of course, vary and may range from about 1% to about 99% by weight of a given unit dosage form.
  • the active compound is in an amount such that an effective dosage level can be obtained.
  • Tablets, troches, pills, capsules, etc. may also contain: a binder, such as tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium hydrogen phosphate; a disintegrant, such as cornstarch, Potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavoring agents, such as peppermint, oil of wintergreen, or cherry flavor.
  • a binder such as tragacanth, acacia, cornstarch, or gelatin
  • an excipient such as dicalcium hydrogen phosphate
  • a disintegrant such as cornstarch, Potato starch, alginic acid, etc.
  • lubricants such as magnesium stearate
  • sweeteners such as sucrose, fructose, lactose, or aspartame
  • flavoring agents such as pepper
  • any materials may be present, as coatings, or to otherwise alter the physical form of the solid unit dosage form.
  • tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl or propylparaben as a preservative, a dye and a flavoring (such as cherry or orange flavor).
  • any materials used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts to be used.
  • the active compounds can be incorporated into sustained release formulations and sustained release devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Aqueous solutions of the active compounds or salts thereof can be prepared, optionally mixed with nontoxic surfactants.
  • Dispersions in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injection or infusion can include sterile aqueous solutions or dispersions of the active ingredient (optionally encapsulated in liposomes) containing the active ingredient suitable for extemporaneous preparation in sterile injectable or infusible solutions or dispersions. or sterile powder.
  • the liquid carrier can be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, nontoxic glycerides, and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the desired particle size in the case of dispersions, or by the use of surfactants.
  • Prevention of microorganisms can be brought about by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases it is preferred to include isotonic agents such as sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use of compositions delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent with various of the other ingredients enumerated above as required, followed by filtered sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional required ingredients previously present in sterile-filtered solutions .
  • Useful solid carriers include pulverized solids (eg, talc, clays, microcrystalline cellulose, silica, alumina, and the like).
  • Useful liquid carriers include water, ethanol or ethylene glycol, or water-ethanol/ethylene glycol mixtures, in which the compounds of the present invention may be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants eg, fragrances
  • additional antimicrobial agents can be added to optimize properties for a given use.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified inorganic materials can also be used with liquid carriers to form coatable pastes, gels, ointments , soap, etc., directly on the user's skin.
  • unit dosage form which are physically discrete units containing unitary dosages, suitable for administration to the human and other mammalian bodies.
  • the unit dosage form can be a capsule or tablet, or a number of capsules or tablets.
  • the amount of active ingredient in a unit dose may vary or be adjusted from about 0.1 to about 1000 mg or more.
  • milk liposomes such as milk liposomes, microspheres and nanospheres
  • microparticle dispersion systems including polymeric micelles, nanoemulsion, submicroemuls
  • Pharmaceutical preparations such as microcapsules, microspheres, liposomes and niosomes (also known as nonionic surfactant vesicles).
  • the present invention also provides the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or the above pharmaceutical composition Use in the preparation of a medicament for preventing and/or treating cancer or other diseases, or for modulating an immune response, or for modulating HPK1 kinase activity and/or function.
  • the present invention also provides a method for preventing and/or treating cancer or other diseases, comprising administering to a subject in need thereof a preventive and/or therapeutically effective amount of the compound described in any of the above technical solutions, its stereoisomer body, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or the above-mentioned pharmaceutical composition.
  • the present invention also provides a method for regulating HPK1 kinase activity and/or function, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of the compound described in any of the above technical solutions, its stereoisomer body, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or the above-mentioned pharmaceutical composition.
  • the present invention also provides a method for modulating an immune response, comprising administering to a subject in need thereof an effective amount of the compound, its stereoisomer, its prodrug, or its pharmacy An acceptable salt or a pharmaceutically acceptable solvate or a pharmaceutical composition of the above.
  • the present invention also provides the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or the above pharmaceutical composition , which is used to prevent and/or treat cancer or other diseases, or to modulate immune responses, or to modulate HPK1 kinase activity and/or function.
  • the present invention also provides the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate in combination with PD-1, Application of PD-L1, CTLA-4, TIM-3, TGF ⁇ and its receptors, LAG3 antagonists or TLR4, TLR7, TLR8, TLR9, STING agonists in cancer immunotherapy.
  • the present invention also provides the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate for immunization with CAR-T
  • the use of combination therapy in cancer immunotherapy The use of combination therapy in cancer immunotherapy.
  • the CAR-T immunotherapy refers to: chimeric antigen receptor T cell immunotherapy, the basic principle of which is to use the patient's own immune cells to remove cancer cells, which belongs to a type of cell therapy.
  • the present invention also provides the compound described in any of the above technical solutions, its stereoisomers, its prodrugs, or its pharmaceutically acceptable salts or pharmaceutically acceptable solvates or the compounds comprising the compounds Use of a pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of cancer or other diseases.
  • the present invention also provides a method for preventing and/or treating cancer or other diseases, comprising administering to a subject in need thereof a preventive and/or therapeutically effective amount of the above-mentioned compound or its stereoisomer, its prodrug, Its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the above-mentioned pharmaceutical composition.
  • the present invention also provides the above-mentioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the above-mentioned pharmaceutical composition, which are used for prevention and treatment /or to treat cancer or other diseases.
  • modulating HPK1 kinase activity and/or function of the present invention is “inhibiting HPK1 kinase activity and/or function”.
  • HPK1 kinase modulators of the invention are “HPK1 kinase inhibitors”.
  • the "cancer or other disease” of the present invention is a “cancer or other disease associated with HPK1 kinase.”
  • Cancers described in the present invention include lymphoma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, intestinal cancer, colon cancer, rectal cancer, lung adenocarcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, and skin cancer , epithelial cell carcinoma, glioblastoma, gastrointestinal stromal tumor, leukemia, nasopharyngeal carcinoma, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, kidney cancer, thyroid cancer, vulvar cancer, anal cancer, Cancer of the penis, esophagus, biliary tract, head and neck, and hematological malignancies.
  • CAR-T cells are cells used in CAR-T therapy (Chimeric Antigen Receptor T-Cell Immunotherapy).
  • CAR-T therapy technicians activate T cells through genetic engineering technology, and install the positioning and navigation device CAR (Tumor Chimeric Antigen Receptor) to transform the ordinary "fighter” of T cells into a "super soldier”.
  • CAR-T cells using their "positioning navigation device” CAR, specifically identify tumor cells in the body, and release a large number of various effectors through immune action. They can efficiently kill tumor cells, so as to achieve the purpose of treating malignant tumors.
  • tumor immunotherapy drug should be understood in a broad sense, which not only includes traditional drugs, such as PD-1 monoclonal antibody, PD-L1 monoclonal antibody, CTLA-4 monoclonal antibody, TIM-3 monoclonal antibody, TGF ⁇ Monoclonal antibodies, LAG3 antagonists, TLR4 agonists, TLR7 agonists, TLR8 agonists, TLR9 agonists, STING agonists, also include "live drugs” that are different from traditional drugs, such as CAR-T cells.
  • modulating an immune response refers to the improvement of any immunogenic response to an antigen.
  • improvement of an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, improved activation of T cells (e.g., CD4 T cells, CD8 T cells), regulatory T cells (e.g., CD4 T cells, CD8 T cells) proliferation of T cells), regulation of B cell proliferation, improved survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (eg, dendritic cells), improved antigen clearance, modulation of cytokine production by T cells (eg , interleukin-2), improved resistance to prostaglandin E2-induced immunosuppression, and improved CD8 T cell priming and/or cytolytic activity.
  • treating generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) prevention of disease or symptoms in a patient susceptible to a disease or condition but not yet diagnosed; (b) suppression of symptoms of disease, That is, preventing its development; or (c) alleviating the symptoms of the disease, ie, causing the disease or symptoms to regress.
  • vertebrate refers to a mammal.
  • Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats.
  • the mammal refers to a human.
  • an “effective amount” refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the necessary dose and time, or an amount effective to achieve the desired effect of modulating the immune response, or an amount effective to achieve the desired modulating HPK1 kinase activity and /or the amount of functional effect.
  • a “therapeutically effective amount” of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit a desired response in the individual.
  • a therapeutically effective amount also encompasses an amount in which any toxic or detrimental consequences of the substance/molecule are outweighed by the therapeutically beneficial effects.
  • a prophylactically effective amount refers to an amount effective at the dose and time necessary to achieve the desired prophylactic effect. Usually, but not necessarily, a prophylactically effective amount will be less than a therapeutically effective amount because the prophylactic dose is administered to the subject prior to the onset of the disease or at an early stage of the disease.
  • a therapeutically effective amount of the drug reduces the number of cancer cells; shrinks the tumor size; inhibits (ie, slows to some extent, preferably stops) infiltration of cancer cells into surrounding organs; inhibits (ie, slows to some extent, preferably stops) ) tumor metastasis; some degree of inhibition of tumor growth; and/or some degree of alleviation of one or more symptoms associated with cancer.
  • C1-C6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl, or the independently disclosed "C1-C4 alkyl", or Independently disclosed "C1-C3 alkyl”.
  • C1-C6 alkyl refers to any straight or branched chain group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc., or eg "C1-C4 alkyl", or eg "C1-C3 alkyl”.
  • C1-C4 alkyl refers to any straight or branched chain group containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base, tert-butyl, etc.
  • C1-C3 alkyl refers to any straight or branched chain group containing 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and the like.
  • alkylene refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a linear or branched saturated hydrocarbon radical.
  • it can be "C1-C6 alkylene", “C1-C4 alkylene” or "C1-C3 alkylene”.
  • Specific examples include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2 -CH2-), isopropylidene ( -CH2 - CH ( CH3 )-), Ethane-1,1-diyl, 2-methoxypropane-1,1-diyl, 2-hydroxypropane-1,1-diyl, 2-methyl-2-hydroxypropane-1,1- Two bases and so on.
  • C1-C6 alkylene refers to any linear or branched saturated hydrocarbon group containing 1 to 6 carbon atoms, a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms, such as methylene , ethylene, n-propylene, isopropylidene, etc.
  • C1-C4 alkylene refers to any linear or branched saturated hydrocarbon group containing 1 to 4 carbon atoms, a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms, such as methylene , ethylene, n-propylene, isopropylidene, etc.
  • C1-C3 alkylene refers to any linear or branched saturated hydrocarbon group containing 1 to 3 carbon atoms, a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms, such as methylene , ethylene, n-propylene, isopropylidene, etc.
  • C3-C8 cycloalkyl refers to a hydrocarbon with a 3-8 membered monocyclic ring system having a saturated ring, and the C3-C8 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C3-C6 cycloalkyl refers to a hydrocarbon having a 3-6 membered monocyclic ring system with a saturated ring, and the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cyano refers to a -CN residue.
  • nitro refers to the -NO 2 group.
  • Heteroatoms are N, O or S.
  • Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • alkoxy refers to any of the above-mentioned alkyl groups (eg C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.), cycloalkane group (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl), which is attached to the rest of the molecule through an oxygen atom (-O-).
  • alkyl groups eg C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.
  • cycloalkane group eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl
  • heteroaryl refers to an aromatic heterocycle, typically a 5-, 6-, 7-, 8-membered heterocycle having 1 to 3 heteroatoms selected from N, O or S; heteroaryl
  • the base ring can optionally be further fused or attached to aromatic and non-aromatic carbocyclic and heterocyclic rings.
  • Non-limiting examples of such heteroaryl groups are eg pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thioxazolyl, pyrrolyl, benzene yl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuranyl, benzothienyl, benzol,3-dioxolane (benzodioxin), isoindoline, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1, 2,3-triazolyl, 2,3-indoline, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenz
  • heteroaryl may be, for example, thiazolyl, isothiazolyl, thioxazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, furyl, thienyl, and the like.
  • halo-C1-C6 alkyl refers to one or more hydrogen atoms in the alkyl or cycloalkyl group Substituted by halogen atoms, such as fluorine, chlorine, bromine.
  • the alkyl or cycloalkyl is as defined above.
  • the term "halo C1 - C6 alkyl” is preferably fluoro, eg -CF3 , -CHF2 , -CH2F , -CH2CH2F , -CH2CHF2 , -CH2CHF2 , -CH2 CF 3 etc.
  • Fluorine-containing alkyl refers to a group in which the alkyl backbone is substituted with one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl, and the like.
  • the alkyl group is as defined above.
  • C1-C6 fluorine-containing alkyl refers to a group in which the C1-C6 alkyl backbone is substituted with one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl and the like.
  • C1-C3 fluoroalkyl refers to a group in which the C1-C3 alkyl backbone is substituted with one or more fluoro groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl Base et al.
  • Fluorine-containing cycloalkyl refers to a group in which the cycloalkyl backbone is substituted with one or more fluorine groups, for example, 2-fluoro-cyclopropyl, 3-fluoro-cyclopropyl, 2,3-difluoro Cyclopropyl etc.
  • the cycloalkyl group is as defined above.
  • C3-C8 fluorine-containing cycloalkyl refers to a group in which the C3-C8 cycloalkyl backbone is substituted with one or more fluorine groups, for example, 2-fluoro-cyclopropyl, 3-fluoro-cyclopropyl base, 2,3-difluorocyclopropyl, etc.
  • C3-C6 fluorine-containing cycloalkyl refers to a group in which the C3-C6 cycloalkyl backbone is substituted with one or more fluorine groups, for example, 2-fluoro-cyclopropyl, 3-fluoro -Cyclopropyl, 2,3-difluorocyclopropyl, etc.
  • C1-C6 heteroatom-containing alkyl refers to a group formed by replacing one or more carbon atoms in the C1-C6 alkyl skeleton with one or more heteroatoms, such as "C1-C6 oxygen-containing "alkyl” or "C1-C6 sulfur-containing alkyl", etc., for example, Wait.
  • Oxygen-containing alkyl refers to a group in which the alkyl backbone is substituted with one or more alkoxy groups, eg, methoxyethyl, methoxyethoxymethyl, and the like.
  • C1-C6 oxyalkyl refers to a group in which the C1-C6 alkyl backbone is substituted with one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxy methyl, etc.
  • a C1-C3 oxyalkyl group refers to a group in which the C1-C3 alkyl backbone is substituted with one or more C1-C6 alkoxy groups.
  • C3-C8 heteroatom-containing cycloalkyl or "C3-C6 heteroatom-containing cycloalkyl” means that one or more carbon atoms in the C3-C8 cycloalkyl skeleton or C3-C6 cycloalkyl skeleton are The group formed by the substitution of one or more heteroatoms, for example, can be "C3-C8 oxygen-containing cycloalkyl", “C3-C6 oxygen-containing cycloalkyl”, “C3-C8 sulfur-containing cycloalkyl” or " C3-C6 sulfur-containing cycloalkyl”, specific examples are pyrrolidine, imidazolidine, pyrazolidine, thiazolidine, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl and the like.
  • C3-C8 oxygen-containing cycloalkyl refers to a group in which the C3-C8 cycloalkyl backbone is substituted with one or more C1-C6 alkoxy groups.
  • C3-C8 cycloalkyl or C1-C6 alkoxy is as described above.
  • C3-C6 oxygen-containing cycloalkyl refers to a group in which the C3-C6 cycloalkyl backbone is substituted with one or more C1-C6 alkoxy groups. Among them, the definition of C3-C6 cycloalkyl or C1-C6 alkoxy is as described above.
  • heterocycle refers to a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur alternative.
  • heterocycles are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dihydrofuran Oxolane, piperidine, piperazine, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl and the like.
  • 6-membered heterocycle refers to a 6-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur.
  • Non-limiting examples of 6-membered heterocyclyl groups are, for example, pyran, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl, and the like.
  • 5-membered heterocycle refers to a 5-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur.
  • Non-limiting examples of 5-membered heterocyclyl groups are, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane, and the like.
  • any group whose name is a compound name such as "HO-C1-C6 alkyl” or "R a R b N-C1-C6 alkyl"
  • any group whose name is a compound name should refers to moieties conventionally derived therefrom such as constructed from hydroxy-substituted C1-C6 alkyl or from R a R b N-substituted C1-C6 alkyl, wherein C1-C6 alkyl is as defined above .
  • Other similar compound names can be understood with reference to the foregoing.
  • R 1 is selected from , if L is a direct bond, the structural formula of R 1 is Other similar definitions can be understood with reference to the foregoing.
  • prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs only undergo this reaction under biological conditions to become the active compound, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Edited by Manfred E. Wolff, 5th ed.).
  • examples of the term "pharmaceutically acceptable salts of compounds” are organic acid addition salts formed from organic acids that form pharmaceutically acceptable anions, including but not limited to formate, acetate, Propionate, Benzoate, Maleate, Fumarate, Succinate, Tartrate, Citrate, Ascorbate, Alpha-Ketoglutarate, Alpha-Glycerophosphate, Alkyl Sulfonate acid salt or aryl sulfonate; preferably, the alkyl sulfonate is methyl sulfonate or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate .
  • Suitable inorganic salts may also be formed including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate, and the like.
  • compositions can be obtained using standard procedures well known in the art, eg, by reacting a sufficient amount of a basic compound with a suitable acid to provide a pharmaceutically acceptable anion.
  • Thin-layer chromatography was performed on silica gel GF254 precoated plates (Qingdao Ocean Chemical Factory). Column chromatography on silica gel (300-400 mesh, Yantai Zhifu District Huangwu Silica Silica Development Reagent Factory) at medium pressure or by using an ISCO Combiflash Rf200 rapid purification system with prepacked silica cartridges (ISCO or Welch) Chromatographic separation. The components were developed by UV light (wavelength 254 nm) and by iodine vapor.
  • Electrospray (ESI) mass spectra were acquired on a Finnigan LCQ ion trap.
  • HPLC-UV-MS analysis for evaluating compound purity was performed by combining ion trap MS equipment with HPLC system SSP4000 (Thermo Separation Products) equipped with autosampler LC Pal (CTC Analytics) and UV6000LP diode array Detector (UV detection 215-400 nm). Device control, data acquisition and processing were performed with Xcalibur 1.2 software (Finnigan). HPLC chromatography was performed at room temperature and a flow rate of 1 mL/min using a Waters X Terra RP 18 column (4.6 x 50 mm; 3.5 ⁇ m).
  • Mobile phase A was ammonium acetate 5mM buffer (using acetic acid to give pH 5.5):acetonitrile 90:10, mobile phase B ammonium acetate 5mM buffer (using acetic acid to give pH 5.5):acetonitrile 10:90; gradient 0 to 100% B This was done for 7 minutes, then 100% B was held for 2 minutes before re-equilibration.
  • W, R 3 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 are as described above.
  • 5-Amino-6-nitro group was obtained by the reaction of 6-nitroquinoxaline (cas: 6639-87-8, Bide, Shanghai) and hydroxylamine hydrochloride (cas: 5470-11-1, Annagy, Shanghai) Quinoxaline, converted into 5-chloro-6-nitroquinoxaline, and further reacted with mesylmethylamide (cas: 1184-85-6, Bi De, Shanghai) to obtain The final reduction of nitro derived.
  • the following intermediates were obtained in a similar manner:
  • the raw materials involved are: methylamine (cas: 74-89-5, Annagy, Shanghai), ethylamine (cas: 75-04-7, Aladdin, Shanghai), cyclopropylamine (cas: 765- 30-0, Annagi, Shanghai), trifluoromethanesulfonyl chloride (cas: 421-83-0, Aladdin, Shanghai), ethylsulfonyl chloride (cas: 594-44-5, Annagi, Shanghai) , isopropylsulfonyl chloride (cas: 10147-37-2, TCI, Shanghai), cyclopropylsulfonyl chloride (cas: 139631-62-2, Annagy, Shanghai), methylsulfonyl chloride (cas: 124- 63-0, West Asia Reagents, Shandong).
  • the raw materials involved are:
  • Acetaldehyde (cas: 75-07-0, Sinopharm Reagent, Shanghai), bromoisopropane (cas: 75-26-3, McLean, Shanghai), bromocyclopropane (cas: 4333-56-6, Bi obtained, Shanghai), 2-dimethylaminochloroethane hydrochloride (cas: 4584-46-7, Aikang, Jiangsu), N-Boc-3-hydroxyazetidine (cas: 141699-55- 0, Bide, Shanghai), N-Boc-3-hydroxypyrrolidine (cas: 103057-44-9, Bide, Shanghai), tert-butyl 4-hydroxyazepane-1-carboxylate (cas : 478832-21-2, Bide, Shanghai), Tetrahydropyran-4-ol (cas: 2081-44-9, Bide, Shanghai), Tetrahydrothiopyran-4-ol (cas: 29683-23 -6, Bide, Shanghai), tetrahydro-2H-thiopyran-4-ol-1
  • the raw materials involved are: 4-dimethylaminopiperidine (cas: 50533-97-6, Shaoyuan, Shanghai), 4-methoxypiperidine (cas: 4045-24-3, Bide, Shanghai), N-methylhomopiperazine (cas: 4318-37-0, Bide, Shanghai), tetrahydropyrrole (cas: 123-75-1, Aladdin, Shanghai), 3-hydroxypyrrolidine (cas: 40499- 83-0, Bide, Shanghai), 3-N,N-dimethylaminopyrrolidine (cas: 64021-83-6, TCI, Shanghai), azetidine (cas: 503-29-7, Bide, Shanghai), azetidine-3-ol (cas: 45347-82-8, Bide, Shanghai), N,N-dimethylazeridin-3-amine (cas: 138022-85 -2, Bide, Shanghai), 3-Boc-aminoazetidine (cas: 91188-13-5, Bide, Shanghai), 2-bromoethanol (cas: 540-5
  • the first step Compound 1 (500 mg, 2.26 mmol) was dissolved in DMF (5 mL), NaH (60% content, dispersed in liquid paraffin, 180 mg, 4.52 mmol) was added in batches at 0 °C, and 2 , 4-Dichloro-5-bromopyrimidine (618 mg, 2.71 mmol), the reaction was carried out by heating for 1 hour, and the completion of the reaction was detected by TLC and LCMS. 100 mL of water was added, a solid was precipitated, filtered, and dried to obtain compound 2 (371 mg), which was directly used in the next step.
  • the second step Compound 2 (41.3 mg, 0.1 mmol), compound 3 (18.0 mg, 0.1 mmol) and methanesulfonic acid (19 ⁇ L, 0.3 mmol) were heated in t-BuOH (2 mL) at 80°C for 4 h, and detected by TLC and LCMS The reaction is complete. After cooling, the reaction mixture was concentrated, purified by silica gel column (eluted with dichloromethane/methanol), and then purified by preparative HPLC (with 0.35% trifluoroacetic acid in water and methanol as mobile phase) to obtain compound I-1 ( 25.8 mg).
  • the first step Compound 2 (82.5 mg, 0.2 mmol), compound 4 (53.2 mg, 0.2 mmol) and diisopropylethylamine (66 ⁇ L, 0.4 mmol) were heated in DMSO (2 mL) at 100 ° C for 12 h, TLC and The reaction was completed by LCMS detection. After cooling, add water (50 mL) to dilute, extract with DCM (30 mL ⁇ 3), combine the organic phases, wash with saturated brine (50 mL ⁇ 2), dry over anhydrous Na 2 SO 4 , filter and concentrate, and the residue is purified by silica gel column (with Dichloromethane/methanol elution) to give compound 5 (91 mg).
  • the first step compound 5 (0.062 mmol, 40 mg), vinylboronic acid pinacol ester (0.186 mmol, 31 ⁇ L), PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.0062 mmol, 5.0 mg), Na 2 CO 3 ( 0.186 mmol, 19.8 mg) was dispersed in 1,4-dioxane (1 mL) and water (0.5 mL), and the reaction system was heated at 100 degrees Celsius for 4 h after replacing nitrogen.
  • HPK1 The enzymatic activity of HPK1 was tested by ADP-Glo kit (Cat#V9102) of Promega Company, and the experimental buffer conditions were: 40mM HEPES, 150mM NaCl, 20mM MgCl 2 , pH 7.5.
  • the experimental conditions were 500 nM HPK1 (MAP4K1) kinase incubated with 10 ⁇ M ATP, 1 ⁇ M MBP Protein kinase substrate (SignalChem, Lot #E3237-5) and small molecule compounds for 90 minutes. The initial concentration of small molecule compounds was 10 ⁇ M, and there were 8 concentration points in 3-fold dilution.
  • Luminescence intensity data were read by Perkin Elmer's Envision microplate reader. The experimental results are shown in the table below.
  • ++++ represents IC 50 ⁇ 100 nM; +++ represents 100 nM ⁇ IC 50 ⁇ 500 nM; ++ represents 500 nM ⁇ IC 50 ⁇ 2000 nM.
  • the compounds of the present invention have very good HPK1 kinase inhibitory activity.

Abstract

La présente invention concerne un modulateur de kinase HPK1, son procédé de préparation et son utilisation. L'invention concerne en particulier un composé représenté par la formule (A) ou un stéréoisomère, un promédicament, un sel pharmaceutiquement acceptable ou un solvate pharmaceutiquement acceptable de celui-ci, un procédé de préparation du composé, une composition pharmaceutique comprenant le composé, une utilisation de ces composés pour prévenir et/ou traiter le cancer ou d'autres maladies, ou pour moduler des réponses immunitaires, ou pour moduler l'activité et/ou la fonctionnalité d'une kinase HPK1.
PCT/CN2021/130283 2020-11-13 2021-11-12 Modulateur de kinase hpk1, son procédé de préparation et son utilisation WO2022100688A1 (fr)

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US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds

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Publication number Priority date Publication date Assignee Title
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds

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