WO2023011610A1 - Composé de benzodioxane, son procédé de préparation et son application - Google Patents

Composé de benzodioxane, son procédé de préparation et son application Download PDF

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Publication number
WO2023011610A1
WO2023011610A1 PCT/CN2022/110398 CN2022110398W WO2023011610A1 WO 2023011610 A1 WO2023011610 A1 WO 2023011610A1 CN 2022110398 W CN2022110398 W CN 2022110398W WO 2023011610 A1 WO2023011610 A1 WO 2023011610A1
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Prior art keywords
piperidinyl
piperazinyl
methyl
hydrogen
formyl
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PCT/CN2022/110398
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English (en)
Chinese (zh)
Inventor
邓贤明
黄伟
吴振华
云彩红
张建明
黄鑫
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南京红云生物科技有限公司
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Priority to CN202280054455.4A priority Critical patent/CN117794923A/zh
Publication of WO2023011610A1 publication Critical patent/WO2023011610A1/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
    • A61K31/505—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to benzodioxane compounds, their preparation method and application.
  • Small-molecule inhibitors targeting EGFR block the combination of EGFR and adenosine triphosphate (ATP), thereby inhibiting EGFR activation and downstream signaling pathways, causing tumor cell growth, proliferation, and metastasis stagnation, leading to cell death, and achieving Effective control of EGFR-mediated tumors.
  • ATP adenosine triphosphate
  • the pathogenic EGFR further undergoes point mutations, resulting in the inability of small molecules to effectively bind to it, and the inhibitory effect decreases or even disappears, such as the most common The T790M mutation.
  • researchers have found a new generation of inhibitors that can effectively combine with drug-resistant EGFR through structural optimization, so as to overcome the problem of drug resistance.
  • the second-generation inhibitor afatinib can effectively overcome the T790M mutation by forming a covalent bond with the 797-position cysteine residue of EGFR.
  • the third-generation inhibitor osimertinib is also a covalent inhibitor, and because of its weak activity against wild-type EGFR, it reduces the toxic and side effects of the second-generation drugs.
  • drug resistance will still appear after osimertinib treatment (Nature Medicine, 2015, 21, 560-562), the main mechanism is that the 797 cysteine residue of EGFR is mutated to a serine residue (C797S), resulting in cysteine
  • C797S serine residue
  • the covalent bond between the sulfhydryl group of the amino acid residue and the inhibitor disappears, and the interaction between the two is greatly weakened, resulting in drug resistance.
  • C797S serine residue
  • the present invention provides compounds as shown below:
  • One object of the present invention is to provide a class of compounds with the activity of inhibiting EGFR kinase, their stereoisomers, their prodrugs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates.
  • Another object of the present invention is to provide the preparation method of the above compound.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.
  • Another object of the present invention is to provide the use of the above compound and the pharmaceutical composition comprising the above compound in the preparation of medicaments for the prevention and/or treatment of EGFR kinase-mediated 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 or composition of the present invention.
  • the present invention is achieved through the following technical solutions.
  • the present invention provides compounds of the following general formula (A):
  • R 1 is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • 1-imidazolyl 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- formyl,
  • Morpholinyl-4-formyl Thiophanolinyl-4-formyl, 2,6-Dimethylmorpholinyl-4-formyl,
  • Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,
  • Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
  • Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl Pyridyl-1-sulfonyl,
  • Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;
  • R2 is selected from:
  • Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl group, and Z2 is not hydrogen;
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing Alkyl, C3-C8 heteroatom-containing cycloalkyl;
  • Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl, or, Z 4 , Z 5 together with N form a substituted or unsubstituted 4-8 membered ring containing 1 to 2 heteroatoms, the substituents are selected from halogen, C1-C6 Alkyl, C3-C8 cycloalkyl;
  • R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl (for example, trifluoromethyl), C1-C6 alkyl (for example, methyl, ethyl or isopropyl), C1-C6 alkoxy (for example, methoxy or ethoxy), C3-C6 cycloalkyl (for example, cyclopropyl) , C2-C6 alkenyl;
  • R 3 , R 4 and the carbon atoms attached to them together form a 5-membered ring containing one N, O or S atom.
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • 1-imidazolyl 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- formyl,
  • Morpholinyl-4-formyl Thiophanolinyl-4-formyl, 2,6-Dimethylmorpholinyl-4-formyl,
  • Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,
  • Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
  • Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl Pyridyl-1-sulfonyl,
  • Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;
  • R2 is selected from:
  • Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl group, and Z2 is not hydrogen;
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C8 cycloalkyl, C1-C6 heteroatom-containing Alkyl, C3-C8 heteroatom-containing cycloalkyl;
  • Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl, C3-C6 fluorine-containing cycloalkyl, or, Z 4 , Z 5 together with N form a substituted or unsubstituted 4-8 membered ring containing 1 to 2 heteroatoms, the substituents are selected from halogen, C1-C6 Alkyl, C3-C8 cycloalkyl;
  • R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl (for example, trifluoromethyl), C1-C6 alkyl (for example, methyl, ethyl or isopropyl), C1-C6 alkoxy (for example, methoxy or ethoxy), C3-C6 cycloalkyl (for example, cyclopropyl) , C2-C6 alkenyl;
  • R 3 , R 4 and the carbon atoms attached to them together form a 5-membered ring containing one N, O or S atom.
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,
  • Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,
  • Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- )piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl.
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 2 is not for hydrogen.
  • Z 1 , Z 2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 2 is not hydrogen.
  • Z 1 , Z 2 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z 2 is not hydrogen.
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl.
  • Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z is selected from methyl, ethyl, isopropyl, cyclopropyl.
  • Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 4 , Z5 is not simultaneously hydrogen.
  • Z 4 and Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time.
  • Z 4 and Z 5 are each independently selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl, and Z 4 and Z 5 are not hydrogen at the same time.
  • R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen Alkyl, C1-C6 fluorinated alkyl, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl.
  • R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing Alkyl, C2-C6 alkenyl.
  • R 3 , R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoro Methyl, vinyl, 1-methyl-vinyl.
  • R 3 , R 4 together with the carbon atoms to which they are attached, form
  • R 3 , R 4 together with the carbon atoms to which they are attached, form
  • the present invention provides compounds represented by the following formula I:
  • R 1 is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • 1-imidazolyl 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- formyl,
  • Morpholinyl-4-formyl Thiophanolinyl-4-formyl, 2,6-Dimethylmorpholinyl-4-formyl,
  • Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,
  • Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
  • Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl Pyridyl-1-sulfonyl,
  • Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;
  • Z2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;
  • R3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1 -C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl;
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl
  • R 3 , R 4 and the carbon atoms attached to them together form a 5-membered ring containing one N, O or S atom.
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • 1-imidazolyl 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyridine Azol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-iso Propylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropyl Pyrazol-4-yl, 1-cyclopropylpyrazol-5-yl,
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- formyl,
  • Morpholinyl-4-formyl Thiophanolinyl-4-formyl, 2,6-Dimethylmorpholinyl-4-formyl,
  • Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl,
  • Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
  • Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl Pyridyl-1-sulfonyl,
  • Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;
  • Z2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;
  • R3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1 -C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl;
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl
  • R 3 , R 4 and the carbon atoms attached to them together form a 5-membered ring containing one N, O or S atom.
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-( 2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-( 2-
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,
  • Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- ) piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl,
  • Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1- )piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl.
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • R is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • R is selected from
  • Y is selected from hydrogen, fluorine, methoxy, trifluoromethoxy,
  • Y is selected from hydrogen, fluorine,
  • Y3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2-hydroxyl) ethylamino, 2-hydroxyethylamino, 2-N,N-dimethylaminoethylamino, N -Methyl-N-(2-N,N-dimethylamino)ethylamino, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(piperazin-1-)piperidinyl, N-methyl-4-piperidinyl , piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methyl- Azetidin-3-yl)piperazinyl, 4-(aze
  • Y is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, benzyl , cyclopropylmethylene, vinyl, N-methyl-4-piperidinyl, N-methyl Piperazinyl, 4-hydroxypiperidinyl,
  • Y 5 is hydrogen
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time;
  • Y is selected from hydrogen, methoxy,
  • Y3 is selected from 4-(N-methylpiperazin-1-)piperidinyl, 4-N,N-dimethylaminopiperidinyl, N-methyl-N-(2-N,N-di Methylamino) ethylamino;
  • Y is selected from hydrogen, methyl, ethyl
  • Y is selected from hydrogen
  • R is selected from
  • Y is selected from hydrogen, fluorine, methoxy, trifluoromethoxy,
  • Y is selected from hydrogen, fluorine,
  • Y3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2-hydroxyl) ethylamino, 2-hydroxyethylamino, 2-N,N-dimethylaminoethylamino, N -Methyl-N-(2-N,N-dimethylamino)ethylamino, 3-(N,N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(piperazin-1-)piperidinyl, N-methylpiperazinyl, N- (N-methyl-4-piperidinyl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(azetidin-3-yl ) piperazinyl, 4-(azetidin-3-yl ) piperazin
  • Y is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, benzyl , cyclopropylmethylene, vinyl, N-methyl-4-piperidinyl, N-methyl Piperazinyl, 4-hydroxypiperidinyl,
  • Y 5 is hydrogen
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time;
  • Y is selected from hydrogen, methoxy
  • Y3 is selected from 4-(N-methylpiperazin-1-)piperidinyl, 4-N,N-dimethylaminopiperidinyl;
  • Y is selected from hydrogen, methyl, ethyl
  • Y is selected from hydrogen
  • Z is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z is selected from hydrogen, methyl, ethyl, cyclopropyl.
  • Z 2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z is selected from methyl, ethyl, isopropyl, cyclopropyl.
  • R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C2-C6 Alkenyl.
  • R is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoromethyl, vinyl, 1-Methyl-vinyl.
  • R 4 is selected from hydrogen, C1-C6 alkyl.
  • R4 is hydrogen
  • R 3 , R 4 together with the carbon atoms to which they are attached, form
  • R 3 , R 4 together with the carbon atoms to which they are attached, form
  • the present invention provides compounds represented by the following formula II:
  • R 1 is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;
  • R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2-C6 alkenyl;
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl.
  • R is wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • R is wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • R is in:
  • Y is selected from hydrogen, methoxy,
  • Y2 is hydrogen
  • Y is selected from N-methylpiperazinyl, 4-(N-methylpiperazin-1-)piperidinyl, N-(N-methyl-4-piperidinyl)piperazinyl,
  • Y 4 is ethyl
  • Y5 is hydrogen.
  • R is selected from
  • Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z is selected from methyl, ethyl, isopropyl, cyclopropyl.
  • R is selected from fluoro, chloro, bromo, iodo, C2-C6 alkenyl.
  • R is selected from bromo, vinyl.
  • R 4 is selected from hydrogen, C1-C6 alkyl.
  • R4 is hydrogen
  • the present invention provides the compound shown in the following formula III:
  • R 1 is selected from
  • Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen:
  • Y 1 , Y 2 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time;
  • Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time ;
  • R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2-C6 alkenyl;
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl.
  • R is wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • R is wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time:
  • R is in:
  • Y is selected from hydrogen, methoxy,
  • Y2 is hydrogen
  • Y is selected from N-methylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl,
  • Y 4 is ethyl
  • Y5 is hydrogen.
  • R is selected from
  • Z 4 and Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time.
  • Z is selected from hydrogen, C1-C6 alkyl, preferably hydrogen; Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl.
  • Z is selected from hydrogen and Z is selected from methyl, ethyl, isopropyl, cyclopropyl.
  • R is selected from fluoro, chloro, bromo, iodo, C2-C6 alkenyl.
  • R is selected from bromo, vinyl.
  • R 4 is selected from hydrogen, C1-C6 alkyl.
  • R4 is hydrogen
  • C1-C6 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
  • C1-C6 alkyl refers to any straight-chain or branched group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.
  • C1-C3 alkyl refers to any linear or branched chain group containing 1-3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.
  • deuterated alkyl refers to a group formed after one or more hydrogen atoms in any of the above-mentioned alkyl groups (such as C1-C6 alkyl, C1-C3 alkyl, etc.) are replaced by deuterium atoms, for example, deuterated
  • the alkyl group may be deuterated methyl, deuterated ethyl, deuterated n-propyl or deuterated isopropyl and the like.
  • the deuteromethyl group may be monodeuteromethyl group, dideuteromethyl group or trideuteromethyl group.
  • oxyalkyl group refers to a group in which the alkyl skeleton is substituted by one or more alkoxy groups, for example, methoxyethyl, methoxyethoxymethyl and the like.
  • a C1-C6 oxyalkyl group refers to a group in which the C1-C6 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxy base methyl etc.
  • a C1-C3 oxyalkyl group refers to a group in which a C1-C3 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups.
  • C2-C6 alkenyl refers to any straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl Base etc.
  • C3-C8 cycloalkyl refers to a 3-8-membered monocyclic hydrocarbon having a saturated ring, and the C3-C8 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C3-C6 cycloalkyl refers to a 3-6-membered monocyclic hydrocarbon having a saturated ring, and the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • cyano refers to a -CN residue.
  • nitro refers to a -NO2 group.
  • heteroatom refers to N, O or S.
  • alkoxy refers to any of the above-mentioned alkyl (such as C1-C6 alkyl, C1-C3 alkyl, etc.), cycloalkyl (such as C3-C6 cycloalkane group), which is attached to the rest of the molecule through an oxygen atom (-O-).
  • heteroaryl refers to an aromatic heterocycle, usually 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 said heteroaryl groups are e.g.
  • pyridyl pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiaxazolyl, pyrrolyl, benzene Base-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuryl, benzothienyl, benzo1,3-dioxolane (benzodioxol), isoindolinyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1, 2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, benzopyranyl, 2,
  • heterocyclyl refers to 3-, 4-, 5-, 6- and 7-membered saturated or partially unsaturated carbocyclic rings in which one or more carbon atoms Replaced by heteroatoms such as nitrogen, oxygen and sulfur.
  • heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3- Dioxolane, piperidine, piperazine, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, etc.
  • 6-membered heterocyclyl 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.
  • 6-membered heterocyclic groups are, for example, pyran, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl, and the like.
  • 5-membered heterocyclyl 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 heterocyclic groups are, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane, and the like.
  • heterocyclic group refers to the above-mentioned “heterocyclic group” replaced by one or more "C1-C6 alkyl", “C1-C3 alkyl”, “C3-C6 cycloalkyl", etc. replace.
  • Fluorine-containing alkyl group refers to a group in which the above-mentioned alkyl skeleton (such as C1-C6 alkyl group) is replaced by one or more fluorine groups, such as monofluoromethyl, difluoroethyl, trifluoromethyl wait.
  • C1-C6 fluorine-containing alkyl group refers to a group in which the above-mentioned C1-C6 alkyl skeleton is substituted by one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl wait.
  • C1-C3 fluorine-containing alkyl group refers to a group in which the C1-C3 alkyl skeleton is substituted by one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl Base etc.
  • fluorine-containing alkoxy refers to any of the above-mentioned fluorine-containing alkyl groups (such as C1-C6 fluorine-containing alkyl groups, C1-C3 fluorine-containing alkyl groups, etc.) which are connected to the rest of the molecule through an oxygen atom (-O-) Moieties, such as trifluoromethoxy, etc.
  • C1-C6 heteroatom-containing alkyl group refers to a group in which one or more carbon atoms in the C1-C6 alkyl skeleton are replaced by one or more heteroatoms such as nitrogen, oxygen and sulfur, for example, wait.
  • C3-C8 heteroatom-containing cycloalkyl refers to a group in which one or more carbon atoms in the C3-C8 cycloalkyl skeleton are replaced by one or more heteroatoms such as nitrogen, oxygen and sulfur,
  • heteroatoms such as nitrogen, oxygen and sulfur
  • any group whose name is a compound name such as "fluorine-containing oxyalkyl” shall refer to the moiety from which it is conventionally derived, such as from a fluorinated group Substituted oxyalkyl groups wherein alkyl is as defined above. Similarly, there is also “fluorinated alkoxy”.
  • arylamino shall mean a moiety conventionally derived therefrom, for example constructed from an amino group substituted with an aryl group, wherein aryl is as defined above. Similarly, the meaning of “heteroarylamino” can be understood. Similarly, “hydroxysulfonyl”, “aminosulfonyl” and the like are to be understood.
  • alkylamino dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, alkoxyformyl, etc. compound group, wherein the alkyl, alkoxy, etc. moieties are as defined above.
  • R 3 and R 4 are each independently selected from” means that the groups represented by R 3 and R 4 may be the same or different, and there is no restriction on each other.
  • R 3 and R 4 are each independently selected from hydrogen or methyl, which means that R 3 is selected from hydrogen or methyl, and R 4 is selected from hydrogen or methyl.
  • Other similar definitions can be understood with reference to the foregoing.
  • each of the above-mentioned substituents may be further substituted by one or more of the above-mentioned groups, if appropriate.
  • oxygen-containing substituted or unsubstituted five-seven-membered ring or "nitrogen-containing substituted or unsubstituted five-seven-membered ring” refers to 5-, 6- or 7-membered saturated or partially unsaturated carbon A ring in which one or more carbon atoms are replaced by oxygen or nitrogen.
  • Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.
  • substituted or unsubstituted five-seven-membered ring refers to a 5-, 6- or 7-membered saturated or partially unsaturated carbocyclic ring.
  • Non-limiting examples are, for example, cyclopentane, cyclohexane, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene (cyclohexa-1,3-diene, cyclohexa-1,4 -diene), etc.
  • substituted or unsubstituted 4-8 membered ring containing 1 to 2 heteroatoms refers to a 4-, 5-, 6-, 7- or 8-membered saturated or partially unsaturated carbocyclic ring, one or 2 carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur.
  • Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.
  • 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 invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they are inactive 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 (Manfred E. Wolff ed., 5th ed.).
  • examples of the term "pharmaceutically acceptable salts of compounds of formula (A), (I), (II) or (III)" are organic salts formed from organic acids that form pharmaceutically acceptable anions.
  • Acid addition salts including but not limited to formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerophosphate, alkylsulfonate or arylsulfonate; preferably, the alkylsulfonate is methanesulfonate or ethylsulfonate; The arylsulfonate is benzenesulfonate or p-toluenesulfonate.
  • Suitable inorganic salts may also be formed including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate, and carbonate, sulfate or
  • compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid to furnish a pharmaceutically acceptable anion.
  • 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) prophylaxis of a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed; (b) suppressing the symptoms of the disease, ie arresting its development; or (c) alleviating the symptoms of the disease, ie causing regression of the disease or symptoms.
  • the present invention provides a pharmaceutical composition, which comprises the compound described in any of the above technical schemes, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate material, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition further comprises EGFR mAb.
  • the EGFR mAb is cetuximab or a biosimilar thereof.
  • biological analogue refers to an antibody product whose sequence is identical to that of cetuximab, and whose physical and chemical properties, biological activity, clinical safety and efficacy are also consistent with those of cetuximab.
  • the pharmaceutical formulations of the present invention are manufactured in known ways, including conventional mixing, dissolving or lyophilization methods.
  • the compounds of the invention can be formulated into pharmaceutical compositions and administered to a patient by various routes suitable for the chosen mode of administration, for example, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
  • the compounds of the present invention may 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, which can be compressed into tablets.
  • a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and presented in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, discs, etc. use.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the proportion of such compositions and preparations may of course vary and may comprise from about 1% to about 99% by weight of a given unit dosage form.
  • the amount of active compound is such that an effective dosage level will be obtained.
  • Tablets, troches, pills, capsules, etc. may also contain: binders, such as tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, 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 liquid carrier such as vegetable oil or polyethylene glycol.
  • any material may be present, as coatings, or to otherwise modify the physical form of the solid unit dosage form.
  • tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar or 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 flavoring such as cherry flavor or orange flavor.
  • any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed.
  • the active compounds can be incorporated into sustained release formulations and devices.
  • the active compounds can also be administered intravenously or intraperitoneally by infusion or injection.
  • Aqueous solutions of the active compound, or a salt thereof can be prepared, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injection or infusion may comprise sterile aqueous solutions or dispersions containing the active ingredient (optionally encapsulated in liposomes) suitable for extemporaneous preparation of sterile injectable or infusible solutions or dispersions. elixirs or sterile powders. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil, nontoxic glycerides, and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersants, or by the use of surfactants.
  • Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents such as sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay absorption (eg, aluminum monostearate and gelatin).
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in an appropriate solvent with each of the other ingredients enumerated above as required, followed by filtered sterilization.
  • the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional required ingredient present in a previously sterile-filtered solution. .
  • Useful solid carriers include comminuted solids (eg, talc, clays, microcrystalline cellulose, silica, alumina, and the like).
  • Useful liquid carriers include water, ethanol or glycol or water-ethanol/glycol mixtures, in which the compounds of this invention can be dissolved or dispersed in effective amounts, optionally with the aid of nontoxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use.
  • Thickening agents can also be used with liquid carriers to form spreadable pastes, gels, and ointments , soap, etc., directly on the user's skin.
  • the therapeutic requirement of the compound or its active salt or derivative depends not only on the particular salt chosen, but also on the mode of administration, the nature of the disease to be treated and the age and condition of the patient, and ultimately on the attending physician or clinician decision.
  • the formulations described above can be presented in unit dosage form, which are physically discrete units containing unit dosages, suitable for administration to the human and other mammalian bodies.
  • the unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets.
  • the amount of a unit dose of active ingredient may be varied or adjusted from about 0.1 to about 1000 milligrams or more depending on the particular treatment involved.
  • emulsion liposomes such as emulsion liposomes, microspheres and nanospheres, such as the use of particle dispersion systems including polymeric micelles, nanoemulsions, submicroemulsions and microemulsions.
  • Drugs prepared from microcapsules, microspheres, liposomes and niosomes also known as nonionic surfactant vesicles.
  • the present invention also provides the preparation method of the compound described in any of the above technical schemes, comprising the following steps:
  • the metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride , Three (dibenzylideneacetone) dipalladium;
  • the basic conditions refer to the conditions under 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;
  • the acidic conditions refer to the conditions under which any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid;
  • R 3 -Y represents the boronic acid corresponding to R 3 (ie ), borate (ie ), tin reagent (such as n-tributyltin reagent that is ) or alkyne reagents (such as trimethylsilylacetylene ie );
  • R 1 , R 2 , R 3 and R 4 are detailed in the previous description.
  • the present invention also provides stereoisomers, prodrugs, or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the compounds described in any of the above technical schemes, and medicaments containing the compounds
  • the present invention also provides a method for preventing and/or treating EGFR kinase-mediated cancer and other diseases, which comprises administering a preventive and/or therapeutically effective amount of the above-mentioned compound or its stereoisomer to a subject in need , its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the above pharmaceutical composition.
  • the method is for the prevention and/or treatment of lung cancer (preferably non-small cell lung cancer).
  • lung cancer preferably non-small cell lung cancer.
  • the method is used to prevent and/or treat EGFR kinase 19Del, L858R, T790M, C797S or combinations thereof mutant lung cancer (preferably non-small cell lung cancer).
  • the method is used to prevent and/or treat EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/ C797S triple mutation lung cancer (preferably non-small cell lung cancer).
  • 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 is used for preventing and / or treatment of EGFR kinase-mediated cancer and other diseases, preferably for the prevention and / or treatment of lung cancer (preferably non-small cell lung cancer), more preferably for the prevention and / or treatment of EGFR kinase 19Del, L858R, T790M, C797S or its Combined mutation lung cancer (preferably non-small cell lung cancer), most preferably for the prevention and/or treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation Or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer).
  • lung cancer
  • a vertebrate refers to a vertebrate.
  • a vertebrate is a mammal.
  • Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats.
  • a mammal is a human.
  • an effective amount refers to the amount effective to achieve the desired therapeutic or preventive effect at the necessary dosage and time.
  • 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 are outweighed by the therapeutically beneficial effects of the substance/molecule.
  • a “prophylactically effective amount” refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic effect.
  • the prophylactically effective amount will be lower than the therapeutically effective amount because the prophylactic dose is administered to the subject before the onset of the disease or at an early stage of the disease.
  • the therapeutically effective amount of the drug reduces the number of cancer cells; reduces tumor volume; inhibits (i.e. slows down to some extent, preferably stops) the infiltration of cancer cells into surrounding organs; inhibits (i.e. slows down to some extent, preferably stops) ) tumor metastasis; inhibition of tumor growth to a certain extent; and/or alleviation of one or more symptoms associated with cancer to a certain extent.
  • Thin-layer chromatography was performed on silica gel GF254 pre-coated plates (Qingdao Ocean Chemical Factory). Column chromatographic separation over silica gel (300-400 mesh, Huangwu Silica Gel Development Reagent Factory, Zhifu District, Yantai City) under medium pressure or by using ISCO Combiflash Rf200 rapid purification system with prepacked silica gel cartridges (ISCO or Welch) for column chromatography Chromatographic separation. The composition was visualized by UV light (wavelength 254nm) and by iodine vapor.
  • Electrospray (ESI) mass spectra were obtained with 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 215-400nm). Equipment 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 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 90:10
  • mobile phase B ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 10:90; gradient from 0 to 100% B was run for 7 minutes, then held at 100% B for 2 minutes before rebalancing.
  • the raw materials involved are:
  • the raw materials involved are:
  • the raw materials involved are:
  • the raw materials involved are:
  • 2-methoxy-3-nitro-6-chloropyridine was obtained by reacting 2,6-dichloro-3-nitropyridine with sodium methoxide (cas: 124-41-4, Anaiji, Shanghai), and then React with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to get Reduction of amino derived.
  • the raw materials involved are:
  • the raw materials involved are:
  • Cyclopropylamine (cas: 765-30-0, Anaiji, Shanghai), Methanesulfonylmethylamine (cas: 1184-85-6, Bi De, Shanghai), Methylsulfonamide (cas: 3144- 09-0, Bide, Shanghai), methylamine (cas: 74-89-5, Anaiji, Shanghai), ethylsulfonyl chloride (cas: 594-44-5, Anaiji, Shanghai), isopropyl Sulfonyl chloride (cas: 10147-37-2, TCI, Shanghai), cyclopropylsulfonyl chloride (cas: 139631-62-2, Anaiji, Shanghai).
  • the raw materials involved are:
  • the raw materials involved are:
  • Ethylamine (cas: 75-04-7, Aladdin, Shanghai), Isopropylamine (cas: 75-31-0, Anaiji, Shanghai), Cyclopropylamine (cas: 765-30-0, Anaji, Shanghai)
  • the first step Dissolve compound 1 (200mg, 0.77mmol) in DMF (2mL), add NaH (60% content, dispersed in liquid paraffin, 62mg, 1.54mmol) in batches at 0°C, and add 2 , 4-dichloro-5-bromopyrimidine (194mg, 0.85mmol), reacted for 1 hour from heating, and TLC and LCMS detected that the reaction was complete. After adding 100 mL of water, solids were precipitated, filtered, and drained to obtain compound 2 (281 mg), which was directly used in the next step.
  • Step 2 Compound 2 (45mg, 0.1mmol), Compound 3 (22mg, 0.1mmol) and methanesulfonic acid (19 ⁇ L, 0.3mmol) were heated in t-BuOH (2mL) at 100°C for 4h, TLC and LCMS detected that the reaction was complete . After cooling, the reaction mixture was concentrated, purified by silica gel column (eluted with dichloromethane/methanol), and then purified by preparative HPLC (with water and methanol containing 0.35% trifluoroacetic acid as mobile phase) to obtain compound I-1 ( 51 mg).
  • the third step Compound I-1 (0.051mmol, 32mg), vinylboronic acid pinacol ester (0.102mmol, 17 ⁇ L), PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.0051mmol, 4.1mg), Na 2 CO 3 (0.20mmol, 22mg) was dispersed in 1,4-dioxane (1mL) and water (0.5mL), and the reaction system was heated at 100°C for 4h after nitrogen replacement. TLC and LC-MS detect that the reaction is complete, and the reaction system is diluted with 50 mL of water and extracted with DCM.
  • the silica gel column is purified (eluted with dichloromethane/methanol), and then subjected to preparative HPLC (with 0.35% trifluoro Acetic acid (water and methanol as mobile phase) was purified to obtain compound I-79 (15.7 mg).
  • compound 4 is the same as compound 2 prepared from compound 1 and 2,4-dichloro-7-(2-trimethylsilethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine obtained by the method.
  • the second step compound 4 (54.1mg, 0.1mmol), compound 5 (23.5mg, 0.1mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (7.2mg, 0.015mmol) , Tris(dibenzylideneacetone) dipalladium (9.2mg, 0.01mmol) and potassium carbonate (41.4mg, 0.3mmol) were dispersed in t-BuOH (2mL), and the reaction system was preheated to 100 It was heated and stirred in an oil bath at °C, and after 6 hours, it was detected by TLC and LCMS that the reaction was complete. After cooling, it was diluted with water (50 mL), extracted with DCM (50 mL), the organic phase was concentrated, and purified by silica gel column (eluted with dichloromethane/methanol) to obtain compound 6 (55.7 mg).
  • Step 3 Compound 6 (35mg, 0.047mmol) was stirred in TFA/DCM (1/2mL) at room temperature for 2 hours, TLC and LCMS detected that the reaction was complete, concentrated, the residue was dissolved in methanol (2mL), and 25% ammonia water was added (1 mL), after 4 hours at room temperature, LCMS detected that the reaction was complete.
  • Step 1 Compound 8 (334 mg) can be obtained from compound 7 (250 mg, 1.09 mmol) and 2,4-dichloro-5-bromopyrimidine (274 mg, 1.2 mmol) by the same method as compound 2.
  • Step 1 Dissolve compound 9 (300mg, 1.23mmol), cesium fluoride (19mg, 0.12mmol), cesium carbonate (802mg, 2.46mmol) in DMF (3mL), add 2,4-dichloro - 5-bromopyrimidine (308 mg, 1.35 mmol), reacted for 5 hours by heating up, and the reaction was completed by TLC and LCMS. After adding 100 mL of water, solids were precipitated, filtered, and dried to obtain compound 10 (418 mg), which was directly used in the next step.
  • DMEM Dulbecco's modified eagle medium
  • RPMI1640 containing 10% fetal bovine serum, 100 ⁇ g/mL ampicillin, 100 ⁇ g/mL streptomycin
  • MTS reaction solution containing 2 mg/mL of MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt); 100 ⁇ g/mL of PES (phenazine methosulfate).
  • Compound test the cells were inserted into a 96-well culture plate, the volume of the cell solution was 90 ⁇ L, and then 10 ⁇ L of compounds of various gradient concentrations were added, with the highest concentration being 10 ⁇ M, which were successively diluted by 1/3, and a total of 8 concentration points were set.
  • the system contains 0.1% DMSO (dimethyl sulfoxide).
  • the mixed compound cell plate was placed in a cell culture incubator (37°C; 5% CO 2 ) for 48 hours, and then 20 ⁇ L of MTS reaction solution was added, mixed and placed in a cell culture incubator (37°C; 5% CO 2 ) Incubate for 1-4 h; use a microplate reader (VARIOSKAN FLASH, Thermo) to measure the OD value at a wavelength of 490 nm.
  • a microplate reader VARIOSKAN FLASH, Thermo
  • Inhibition rate% 1-(OD experimental group-OD blank group)/(OD negative group-OD blank group)*100%
  • the rest of the compounds also have excellent inhibitory activity on the growth of the above-mentioned kinase stably transfected cell lines.

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Abstract

L'invention concerne un composé de benzodioxane, son procédé de préparation et son application. En particulier, la présente invention concerne un composé ayant une activité inhibitrice de l'EGFR, un sel pharmaceutiquement acceptable ou un solvate pharmaceutiquement acceptable de celui-ci, un procédé de préparation associé, une composition pharmaceutique contenant le composé et une utilisation de ces composés dans la préparation d'un médicament pour la prévention et/ou le traitement du cancer à médiation par la kinase EGFR et d'autres maladies.
PCT/CN2022/110398 2021-08-06 2022-08-05 Composé de benzodioxane, son procédé de préparation et son application WO2023011610A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1882578A (zh) * 2003-09-16 2006-12-20 诺瓦提斯公司 作为zap－70和/或syk抑制剂的2,4－二(杂)芳基氨基嘧啶衍生物
WO2009112490A1 (fr) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides en tant qu'inhibiteurs de zap-70
WO2019015655A1 (fr) * 2017-07-19 2019-01-24 正大天晴药业集团股份有限公司 Composé aryl-phosphore-oxygène utilisé en tant qu'inhibiteur de kinase egfr
WO2020253860A1 (fr) * 2019-06-21 2020-12-24 江苏豪森药业集团有限公司 Inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation
WO2021018003A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
WO2021104305A1 (fr) * 2019-11-26 2021-06-03 上海翰森生物医药科技有限公司 Inhibiteur d'un dérivé polycyclique contenant de l'azote, son procédé de préparation et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1882578A (zh) * 2003-09-16 2006-12-20 诺瓦提斯公司 作为zap－70和/或syk抑制剂的2,4－二(杂)芳基氨基嘧啶衍生物
WO2009112490A1 (fr) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides en tant qu'inhibiteurs de zap-70
WO2019015655A1 (fr) * 2017-07-19 2019-01-24 正大天晴药业集团股份有限公司 Composé aryl-phosphore-oxygène utilisé en tant qu'inhibiteur de kinase egfr
WO2020253860A1 (fr) * 2019-06-21 2020-12-24 江苏豪森药业集团有限公司 Inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation
WO2021018003A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
WO2021104305A1 (fr) * 2019-11-26 2021-06-03 上海翰森生物医药科技有限公司 Inhibiteur d'un dérivé polycyclique contenant de l'azote, son procédé de préparation et son utilisation

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