WO2023025136A1 - Isoindolinone compound and use thereof - Google Patents

Isoindolinone compound and use thereof Download PDF

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Publication number
WO2023025136A1
WO2023025136A1 PCT/CN2022/114183 CN2022114183W WO2023025136A1 WO 2023025136 A1 WO2023025136 A1 WO 2023025136A1 CN 2022114183 W CN2022114183 W CN 2022114183W WO 2023025136 A1 WO2023025136 A1 WO 2023025136A1
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alkyl
amino
cyano
mercapto
cooh
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PCT/CN2022/114183
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French (fr)
Chinese (zh)
Inventor
付利强
孔令龙
张雷
卢刚
夏怡丰
卢锦淳
舍卡·克莉丝汀
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杭州格博生物医药有限公司
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Publication of WO2023025136A1 publication Critical patent/WO2023025136A1/en

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present application belongs to the field of medicine.
  • the present application provides an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and its use in treating proliferative diseases.
  • the present application also provides a pharmaceutical composition comprising the compound or its salt described in the present application and a pharmaceutically acceptable carrier.
  • Cancer is a malignant disease that affects human health. There is a great medical need for the treatment of various types of cancer. Research has shown that cancer development is a complex event involving multiple factors and multiple steps.
  • CRBN Hydroxycerebroside
  • CRBN has multiple functions. CRBN can interact with the regulatory factor Cullins of ubiquitin ligase E3 to activate the activity of ubiquitin ligase E3, and promote the connection of substrate proteins and ubiquitin molecules to achieve ubiquitination. Ubiquitinated proteins are recognized by the proteasome and degraded. For example, CRBN can induce the ubiquitination and degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) containing zinc finger structure. Since these two transcription factors play a role in cancer cell proliferation, degrading them can have toxic effects on cancer cells.
  • IKZF1 transcription factors Ikaros
  • IKZF3 Aiolos
  • CRBN is the direct target of idomides, which can enhance the degradation of CRBN on tumor-related factors (Science, 2014, 343, 301-305). Methamides are also known as CRBN molecular glue. However, there are many toxic and side effects of thiaminides, which limits the application of thalidomides as anticancer drugs. For example, thalidomide can cause birth defects.
  • SALL4 Stetlike transcription factor 4
  • C2H2 Cys2-His2
  • the inventors of the present application have surprisingly found that the compound of the present application or a pharmaceutically acceptable salt thereof can effectively degrade IKZF, but has significantly reduced degradation of SALL4, so that the compound of the present application or a pharmaceutically acceptable salt thereof has excellent Anticancer activity and reduced toxic side effects.
  • the present application provides an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.
  • the first embodiment of the present application is a compound of structural formula (I) or a pharmaceutically acceptable salt thereof:
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 10 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 11 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • Q is CR 12 R 13 , n is 0, 1 or 2;
  • X 1 is independently selected from CR 14 or N at each occurrence thereof;
  • X is independently selected from CR 14' or N at each occurrence thereof;
  • X3 is independently selected from CR 14" or N at each occurrence thereof;
  • X4 is independently selected from CR 14"' or N at each occurrence thereof;
  • X 5 is selected from O, CR 15 R 16 , or NR 17 ,
  • R 12 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 13 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 14 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 14' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl),
  • R14 " at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1 - C6 alkyl, C2 - C6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl),
  • R 14"' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkene C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyl oxy, C 2 -C 6 alkanoyl, C 2 -C 6 Alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono - and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl),
  • R 15 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 16 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 17 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 18 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • T is N or CH
  • a 0, 1 or 2;
  • b 0, 1 or 2;
  • c 0, 1 or 2;
  • d 0, 1 or 2;
  • e 0, 1 or 2;
  • X 6 is N or C
  • X7 is N or C
  • X8 is N or C
  • X9 is N or C.
  • the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (III) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (IV) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (V) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (VI) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (VII) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (VIII) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (IX) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (X) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XI) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XII) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XIII) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XV) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XVI) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XVII) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XVIII) or a pharmaceutically acceptable salt thereof:
  • the compound of structural formula (I) is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 1 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R2 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • each occurrence of R is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R3 in each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R4 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • each occurrence of R is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R6 in each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • each occurrence of R is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R9 in each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 10 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 11 at each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 12 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 13 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro,
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 13 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 14' at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 Alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 Heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 Halogen, hydroxy,
  • R 14' at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methyl Oxy, Ethoxy, n-Propoxy, Isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy , ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14' at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 14" is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH at each occurrence thereof , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 Alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 Heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 Halogen, hydroxy,
  • R 14 " in each occurrence thereof is independently selected from nonexistent, hydrogen, fluoro, Chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R14 " at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy , ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14 " is independently selected at each occurrence of hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 14"' is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, - COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 Halogen, hydroxy, nitro, cyano,
  • R 14"' at each occurrence thereof is independently selected from nonexistent, hydrogen, Fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14"' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14"' at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 15 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 16 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 17 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyan
  • R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 18 at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, methyl, isopropyl.
  • a is 0. In any implementation of the application and any aspect thereof, a is 1. In any implementation of the application and any aspect thereof, a is 2.
  • b is 0. In any implementation of the application and any aspect thereof, b is 1. In any implementation of the application and any aspect thereof, b is 2.
  • c is 0. In any implementation of the application and any aspect thereof, c is 1. In any implementation of the application and any aspect thereof, c is 2.
  • d is 0. In any implementation of the application and any aspect thereof, d is 1. In any implementation of the application and any aspect thereof, d is 2.
  • e is 0. In any implementation of the application and any aspect thereof, e is 1. In any implementation of the application and any aspect thereof, e is 2.
  • n is zero. In any implementation of the application and any aspect thereof, n is 1. In any implementation of the application and any aspect thereof, n is 2.
  • Xi is N. In any implementation of the application and any aspect thereof, X 1 is CR 14 .
  • X 2 is N. In any implementation of the application and any aspect thereof, X 2 is CR 14′ .
  • X 3 is N. In any implementation of the present application and any aspect thereof, X 3 is CR 14 ′′ .
  • X 4 is N. In any implementation of the present application and any aspect thereof, X 4 is CR 14"' .
  • X is O. In any implementation of the application and any aspect thereof, X 5 is CR 15 R 16 . In any implementation of the application and any aspect thereof, X 5 is NR 17 .
  • X is N. In any implementation of the application and any aspect thereof, X is C.
  • X is N. In any implementation of the application and any aspect thereof, X is C.
  • X is N. In any implementation of the application and any aspect thereof, X is C.
  • X 9 is N. In any implementation of the application and any aspect thereof, X is C.
  • T is N. In any implementation of this application and any aspect thereof, T is CH.
  • salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate , lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisic acid salt, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate "mesylate", Esylate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule, such as acetate, succinate or other counterion.
  • the counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • pharmaceutically acceptable salts can have more than one charged atom in their structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
  • the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example by treating the free base with an inorganic or organic acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., such organic acids as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid , pyranosidic acids such as glucuronic acid or galacturonic acid, alpha-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc.
  • an inorganic or organic acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by oxidation with an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide such as It can be prepared by treating free acids with inorganic or organic bases such as compounds.
  • suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and those derived from sodium , calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium inorganic salts.
  • pharmaceutically acceptable indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith.
  • stereoisomer refers to compounds having the same chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds.
  • Stepoisomers may include “diastereomers” and “enantiomers”.
  • Diastereoisomers refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other.
  • Enantiomers refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • R” and “S” represent the configuration of substituents around one or more chiral atoms.
  • Compounds of the present application may be prepared as individual isomers by chiral synthesis or resolution from isomeric mixtures.
  • the disclosed compounds may possess one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. When the absolute stereochemistry of a stereocenter is not determined, the stereochemical configuration can be assigned as (*) at the indicated center.
  • the compounds described herein exist in optically active or racemic form. It is to be understood that the compounds described herein include racemic, optical, regioisomeric and stereoisomeric forms or combinations thereof which possess the therapeutically useful properties described herein.
  • the compounds described herein contain one or more chiral centers. These compounds may be prepared by any means including stereoselective synthesis, enantioselective synthesis or separation of mixtures of enantiomers or diastereomers. Resolution of a compound and its isomers can be achieved by any means including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation and chromatography.
  • substituted means that any one or more hydrogens on the designated atom or group are replaced by a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl group is C1-C2, C1-C3, or C1-C6. As used herein, a specified range refers to each member of the stated range as a separate species of alkyl group.
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms and is intended to mean each of these as independently type description.
  • C1-C4 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3 or 4 carbon atoms and is intended to mean that each of these is described as a separate species.
  • C0-Cn alkyl group is used herein in combination with another group, such as (C3-C7 cycloalkyl)C0-C4 alkyl or -C0-C4 alkyl (C3-C7 cycloalkyl), the indicated
  • the group in this case cycloalkyl, is either directly bonded by a single covalent bond (C0 alkyl) or linked by an alkyl chain (in this case 1, 2, 3 or 4 carbon atoms).
  • Alkyl groups may also be attached via other groups such as heteroatoms, as in -O-CO-C4alkyl (C3-C7cycloalkyl).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl , tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane.
  • alkyl groups are optionally substituted as described above.
  • Alkenyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may occur at stable points along the chain.
  • Non-limiting examples are C2-C8 alkenyl, C2-C6 alkenyl and C2-C4 alkenyl.
  • a specified range refers to each member of the stated range as a separate species of alkenyl group, as described above for the alkyl moiety.
  • alkenyl groups include, but are not limited to, ethenyl and propenyl.
  • an alkenyl group is optionally substituted as described above.
  • Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds which may occur at any stable point along the chain, for example C2-C8 alkynyl or C2- C6 alkynyl.
  • a specified range refers to each member of the stated range as a separate species of alkynyl group, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl , 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • an alkynyl group is optionally substituted as described above.
  • Alkoxy is an alkyl group as described above covalently bonded through an oxygen bridge (-O-).
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentyloxy Oxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methylpentyloxy .
  • an "alkylthio" or “thioalkyl” group is an alkyl group as described above with the indicated number of carbon atoms covalently bonded through a sulfur bridge (-S-).
  • alkoxy groups are optionally substituted as described above.
  • Alkenyloxy is such an alkenyl group that is covalently bonded to the group it replaces through an oxygen bridge (-O-).
  • an alkanoyl group is optionally substituted as described above.
  • Alkyl ester is an alkyl group as described herein covalently bonded through an ester bond.
  • a “carbocyclic group,” “carbocyclic ring” or “cycloalkyl” is a saturated or partially unsaturated (ie, non-aromatic) group that contains all carbon ring atoms.
  • Carbocyclic groups generally contain 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.
  • a cycloalkyl substituent may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom which may have two substituents may have a cycloalkyl group attached as a spiro group.
  • carbocycles include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings.
  • carbocycles are optionally substituted as described above.
  • a cycloalkyl group is a partially unsaturated (ie, non-aromatic) group containing all carbon ring atoms.
  • a "carbocycle-oxy group” is a monocyclic carbocycle or a mono- or bi-ring carbocycle group as described above attached to the group it replaces via an oxygen-O-linker.
  • Haloalkyl refers to branched and straight chain alkyl groups substituted with one or more halogen atoms, up to the maximum permissible number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.
  • Haloalkoxy refers to a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • Hydroalkyl is an alkyl group as previously described substituted with at least one hydroxy substituent.
  • Aminoalkyl is an alkyl group as previously described substituted with at least one amino substituent.
  • Halogen independently refers to any one of fluorine, chlorine, bromine and iodine.
  • Aryl refers to an aromatic group containing only carbon in an aromatic ring or ring.
  • the aryl group contains 1 to 3 separate or fused rings and has 6 to 18 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17 or 18) ring atoms, with no heteroatoms as ring members.
  • such aryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitutions may include fusion to a 5 to 7-membered saturated ring group optionally containing 1 or 2 heteroatoms independently selected from N, O and S to form, for example, 3, 4-methylenedioxyphenyl group.
  • Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is pendant. An example of a side ring is a phenyl group substituted by a phenyl group. In one embodiment, aryl groups are optionally substituted as described above.
  • Aryl includes bicyclic groups comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
  • Typical aryl groups include, but are not limited to, those formed from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydro Groups derived from naphthyl and the like.
  • aryl is a phenyl group.
  • heterocycle refers to rings having 3 to 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ) saturated or partially unsaturated (that is, having one or more double and/or triple bonds within the ring without aromaticity) carbon ring atom groups of ) ring atoms, wherein at least one ring atom is selected from nitrogen, oxygen, phosphorus and sulfur heteroatoms, and the remaining ring atoms are C, wherein one or more ring atoms are optionally substituted independently by one or more of the aforementioned substituents.
  • 3 to 18 e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18
  • saturated or partially unsaturated that is, having one or more double and/or triple bonds within the ring without aromaticity
  • the heterocycle can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), for example: bicyclic [4,5], [5,5], [5,6] or [6,6 ]Tie.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry” (W.A.Benjamin, New York, 1968) especially Chapters 1, 3, 4, 6, 7 and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950-present), especially Chapters 13, 14, 16, 19, and 28; and J.Am.Chem.Soc. (1960) 82:5566.
  • heterocycles include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperidonyl, morpholino Linyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidine base, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrole Linyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, di Thianyl, dithiolan
  • the heterocyclic groups herein are optionally substituted independently with one or more substituents described herein.
  • Heterocyclyl includes “heterocycloalkyl”.
  • Heterocycloalkyl is a saturated ring group. It may have, for example, 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, the remaining ring atoms being carbon. In a typical embodiment, nitrogen is a heteroatom.
  • Monocyclic heterocycloalkyl groups typically have 3 to about 8 ring atoms, or 4 to 6 ring atoms.
  • Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolinyl.
  • Heterocyclyl may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
  • heterocyclic epoxy group is a monocyclic or bicyclic heterocyclic group as previously described attached to the group it replaces via an oxy-O-linker.
  • Heteroaryl means a stable monocyclic aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, the remaining ring atoms being carbon, or at least one of the 5- to 10-membered (5, 6, 7, 8, 9, 10 stable bicyclic or tricyclic ring systems of aromatic rings.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Monocyclic heteroaryl groups typically have 5 to 8 ring atoms (5, 6, 7, 8).
  • bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, i.e., groups containing 9 or 10 ring atoms in which one 5- to 7-membered aromatic ring is fused to the second aromatic or nonaromatic ring.
  • the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in a heteroaryl group does not exceed two.
  • the total number of S and O atoms in the aromatic heterocycle does not exceed one.
  • heteroaryl groups include, but are not limited to, pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl , pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolyl, tetrahydro Isoquinolyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, indolyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridine Base, purinyl, oxy
  • Heteroaryl groups are optionally substituted independently with one or more substituents described herein.
  • Heteroaryloxy is said heteroaryl group bonded to the group it replaces via an oxygen-O-linker.
  • Heteroaryl may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
  • the present application also covers bicyclic, tricyclic, tetracyclic, pentacyclic and other polycyclic rings formed by one or more monocyclic rings selected from "cycloalkyl", “aryl” and “heteroaryl” in a manner permitted by valence. system.
  • cyano refers to -CN.
  • the compound of the present application is a compound of structural formula (X) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
  • -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X4 is N, CH, CF, C- CH3 ;
  • X 6 is N, CH, CF, C-CH 3 ;
  • X 7 is N, CH, CF, C-CH 3 ;
  • X9 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XI) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
  • -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X4 is N, CH, CF, C- CH3 ;
  • X 6 is N, CH, CF, C-CH 3 ;
  • X 7 is N, CH, CF, C-CH 3 ;
  • X9 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XII) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
  • -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X4 is N, CH, CF, C- CH3 ;
  • X 6 is N, CH, CF, C-CH 3 ;
  • X 7 is N, CH, CF, C-CH 3 ;
  • X9 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XIII) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
  • -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X4 is N, CH, CF, C- CH3 ;
  • X 6 is N, CH, CF, C-CH 3 ;
  • X 7 is N, CH, CF, C-CH 3 ;
  • X9 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • R 18 is hydrogen, fluoro, chloro, cyano, or methyl
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X6 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XV) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • R 18 is hydrogen, fluoro, chloro, cyano, or methyl
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X6 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XVI) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • R 18 is hydrogen, fluoro, chloro, cyano, or methyl
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X6 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XVII) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • R 18 is hydrogen, fluoro, chloro, cyano, or methyl
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X6 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XVIII) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • R 18 is hydrogen, fluoro, chloro, cyano, or methyl
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X6 is N, CH, CF, C- CH3 .
  • the compound of the present application is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
  • T N;
  • R is hydrogen, fluoro, cyano, or methyl
  • R 18 is hydrogen, fluoro, chloro, cyano, or methyl
  • X 5 is O
  • X 1 is N, CH, CF, C-CH 3 ;
  • X2 is N, CH, CF, C- CH3 ;
  • X 3 is N, CH, CF, C-CH 3 ;
  • X6 is N, CH, CF, C- CH3 .
  • the compound of the present application or a pharmaceutically acceptable salt thereof can effectively degrade IKZF. Accordingly, the compounds described herein, or salts thereof, are useful in the treatment of proliferative diseases. In addition, applicants have also discovered that compounds described herein or salts thereof do not simultaneously inhibit/degrade SALL4 when degrading IKZF. In other words, the compounds or salts thereof described herein can selectively degrade IKZF with reduced or no effects on other proteins/kinases, thereby exhibiting reduced or no toxic side effects compared to previous IKZF degraders/inhibitors toxic side effect.
  • the compounds described herein, or pharmaceutically acceptable salts thereof are useful in the treatment of proliferative diseases.
  • the present application also provides the use of the compound described in the present application or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating proliferative diseases.
  • the present invention further provides the compound or a pharmaceutically acceptable salt thereof for treating proliferative diseases.
  • the present application further provides a method for treating proliferative diseases, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject in need.
  • proliferative disease refers to a disease associated with some degree of abnormal cell proliferation, whether malignant or benign.
  • the proliferative disease is cancer.
  • the cancer is a solid tumor.
  • the cancer is a hematological malignancy.
  • proliferative disorder is not mutually exclusive when referred to in this application.
  • cancer includes cancer cells and/or benign or precancerous cells.
  • exemplary cancers include, but are not limited to, breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small Cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, cancer of lymphoid organs and myeloid malignancies including leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), giant myeloid leukemia , adult T-cell leukemia), lymphoma (small lymphocy
  • cancer also includes leukemias, carcinomas and sarcomas.
  • exemplary cancers include brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, and medulloblastoma.
  • Additional examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary malignant brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia , endometrial carcinoma, adrenocortical carcinoma, endocrine and exocrine pancreatic neoplasms, and prostate cancer.
  • cancer also includes leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, glioma, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, middle ear tumor, prostate cancer, etc.
  • the present application also provides a pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition described in the present application can be tablets, capsules, granules, syrups, suspensions, solutions, dispersions, sustained-release preparations for oral or non-oral administration, intravenous injection preparations, subcutaneous injection preparations, Inhalation preparations, transdermal preparations, rectal or vaginal suppositories.
  • the pharmaceutically acceptable carrier described in this application refers to the pharmaceutically acceptable carrier well known to those skilled in the art.
  • the pharmaceutically acceptable carrier in this application includes but is not limited to: fillers, wetting agents, binders, disintegrants, Lubricants, adhesives, glidants, taste masking agents, surfactants, preservatives, etc.
  • Fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, and the like.
  • Wetting agents and binders include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, sucrose, polyvinylpyrrolidone, and the like.
  • Disintegrants include, but are not limited to, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, and the like.
  • Lubricants include, but are not limited to, magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and the like.
  • Binders include, but are not limited to, gum arabic, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, dextrose, dextrin, dextrose, ethylcellulose, gelatin, liquid dextrose, guar Gum, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Magnesium Aluminum Silicate, Maltodextrin, Methylcellulose, Polymethacrylate, Polyvinylpyrrolidone, Pregelatinized Starch , Sodium Alginate, Sorbitol, Starch, Syrup and Tragacanth.
  • Glidants include, but are not limited to, colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc.
  • Taste-masking agents include, but are not limited to, aspartame, stevioside, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin.
  • Surfactants include, but are not limited to, Tween-80, poloxamers.
  • Preservatives include, but are not limited to, paraben, sodium benzoate, potassium sorbate, and the like.
  • compositions containing the active ingredients in various proportions are known, or will be apparent to those skilled in the art from the disclosure of this application. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995).
  • the method of preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents and the like.
  • the pharmaceutical compositions described herein are manufactured by known methods, including conventional mixing, dissolving or lyophilizing methods.
  • the proportion of active ingredient may vary from about 0.01% to about 99% by weight of a given unit dosage form.
  • the amount of active ingredient is such that an effective dosage level will be obtained.
  • Tablets, capsules, etc. described in the present application may contain: binders, such as tragacanth, acacia, cornstarch or gelatin; excipients, such as dicalcium phosphate; disintegrants, 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 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 or capsules may be coated with gelatin, wax, shellac or sugar or the like.
  • a syrup may contain the active ingredient, sucrose or fructose as a sweetening agent, methyl or propyl paraben 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 nontoxic in the amounts employed.
  • the active ingredient can be incorporated into sustained release formulations and sustained release devices.
  • the active ingredient can also be administered intravenously or intraperitoneally by infusion or injection.
  • Aqueous solutions of the active ingredient or its salts can be prepared, optionally mixed with nontoxic surfactants.
  • 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.
  • the dosage form of the pharmaceutical composition suitable for injection or infusion may comprise a sterile aqueous solution containing the active ingredient (optionally encapsulated in liposomes) suitable for extemporaneous preparation of sterile injectable or infusible solution or dispersion. or dispersion or sterile powder.
  • 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 ingredient 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 the freeze-drying technique which yield a powder of the active ingredient plus any additional required ingredient present in 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 pharmaceutical compositions of the present application can be dissolved or dispersed in effective amounts, optionally with the help of non-toxic 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 therapeutically effective amount of the active ingredient 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 at the discretion of the attending physician or clinician.
  • 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 a tablet.
  • the amount of a unit dose of active ingredient may be varied or adjusted from about 0.01 to about 1000 milligrams or more depending on the particular treatment involved.
  • 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.
  • a compound described herein, or a pharmaceutically acceptable salt thereof may also be administered in combination with one or more additional therapeutic agents useful in the treatment of cancer.
  • additional therapeutic agents include, but are not limited to, anthracyclines, cyclophosphamide, 5-fluorouracil, cisplatin, and the like.
  • the present application also includes a compound or a pharmaceutically acceptable salt thereof obtained by combining any group defined in any variable group of the present application.
  • This application also includes the following exemplary compounds.
  • the compounds of the present application can be synthesized by the following exemplary general synthesis methods or similar methods.
  • Various intermediate compounds may have various substituents as described herein, subject to valency permitting.
  • Compound 1A can be synthesized according to the following exemplary general synthesis method or a similar method.
  • Compound 1A and Compound 1B are obtained in the presence of a base to obtain Compound 1C, or Compound 1A and Compound 1D are subjected to reductive amination to obtain Compound 1E, and then undergo a chlorination reaction to obtain Compound 1C, and Compound 1C and Compound 1F are obtained in the presence of a base Compound 1G, then compound 1G in the presence of benzenesulfonic acid to give compound 1H.
  • Embodiment 1 compound 1
  • Embodiment 2 to 11 are synthesized with the similar method of embodiment 1
  • Embodiment 5 Compound 5
  • Embodiment 6 Compound 6
  • Embodiment 7 Compound 7
  • Embodiment 7-A compound 7-A
  • Embodiment 9 Compound 9
  • reaction solution was quenched with 50 mL of saturated ammonium chloride solution, extracted three times with 100 mL of ethyl acetate, the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product.
  • Intermediate 9-8 (80.0 mg, 0.256 mmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid/dioxane solution (4M, 1 mL) was added dropwise. The reaction solution was stirred at 25°C for 1 hour. Spin-dry under reduced pressure to obtain intermediate 9-9 (90 mg, crude product) as a white solid.
  • the obtained crude product was purified by preparative high-performance liquid chromatography (chromatographic column: Kromasil 100-5-C1830*150mm, mobile phase A: water (0.01% FA), mobile phase B: acetonitrile, 20 mL/min, gradient 25% B to 45% ) to obtain white solid compound 9 (2.76 mg, yield: 20.6%).
  • Example 10 Compounds 10-A and 10-B
  • Intermediate 10-2 (50.0mg, 158umol) was dissolved in dichloromethane (2mL), and hydrochloric acid/dioxane (4M, 790uL) was added dropwise to the solution. The mixture was stirred at 25°C for 1 hour. The reaction solution was spin-dried under reduced pressure to obtain intermediate 10-3 (40.0 mg, crude product) as a white solid. The crude product was used directly in the next step without further purification.
  • HT-1080 HT-1080 cells were purchased from the American Type Culture Collection (ATCC, catalog number CCL-121), and GSPT( ⁇ 1-138)/G575N and IKZF1 or SALL4 protein with HiBiT tag. The cells were cultured in DMEM medium supplemented with 10% fetal bovine serum. First use an acoustic dispenser (EDC ATS-100) to spot increasing concentrations of test compounds onto an empty 384-well plate in a 10-point dilution manner. The concentration range is generally 0.316 nanomolar to 10 micromolar.
  • the data was processed by the Collaborative Drug Discovery Vault software package, and the degradation value of each treatment sample (the percentage of the comparison DMSO sample) was calculated using the DMSO-treated sample as a reference value, and finally the degradation curve was made by a four-parameter logistic regression model, and the half Degradation concentration EC50 and DC50. Calculated as follows:
  • B Y max (highest value, i.e. IKZF1 or SALL4 readout in DMSO treated samples)
  • Dmax represents the maximum percentage of IKZF1 or SALL4 protein degradation achievable in the assay by compound treatment at the highest compound concentration.
  • Pomalidomide is a known compound with the following structural formula:
  • the following is a general method for detecting the ability of molecular glue compounds to inhibit cell proliferation in specific multiple myeloma cell lines (such as MM.1S).
  • MM.1S multiple myeloma cell lines
  • ATCC American Type Culture Collection
  • CRL-2974 the American Type Culture Collection
  • the cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum.
  • EDC ATS-100 acoustic dispenser
  • concentration range is generally 0.316 picomolar to 10 nanomolar. Values, and DMSO treatment was used as a control.
  • the above cell lines were inoculated on a 384-well plate, and the inoculation concentration was approximately 50 microliters of culture medium per well and contained 3000 cells. Place the inoculated 384-well plate in an incubator containing 5% carbon dioxide at 37°C for 120 hours. Finally, 20 microliters of CellTiter Glo lysis detection solution (Promega Company) was added to each well, and after incubation at room temperature for 30 minutes, the bioluminescence value was read on an EnVision multi-function plate reader (PerkinElmer Company).
  • the data is processed by the Collaborative Drug Discovery Vault software package, and the cell activity value (compared to the percentage of the DMSO sample) of each processed sample is calculated with the sample treated with DMSO as a reference value, and finally the degradation curve is made by a four-parameter logistic regression model, and calculated Half inhibitory concentration EC50 and IC50. Calculated as follows:
  • B Y max (highest value, i.e. cell viability readout in DMSO treated samples)
  • y cell viability readings after test sample treatment (normalized to cell viability readings in DMSO treated samples)
  • the present application also includes the technical solutions of any one of the items numbered below.
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0
  • R 10 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 11 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • Q is CR 12 R 13 , n is 0, 1 or 2;
  • X 1 is independently selected from CR 14 or N at each occurrence thereof;
  • X is independently selected from CR 14' or N at each occurrence thereof;
  • X3 is independently selected from CR 14" or N at each occurrence thereof;
  • X4 is independently selected from CR 14"' or N at each occurrence thereof;
  • X 5 is selected from O, CR 15 R 16 , or NR 17 ,
  • R 12 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 13 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 14 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 14' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl),
  • R14 " at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1 - C6 alkyl, C2 - C6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl),
  • R 14"' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkene C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyl oxy, C 2 -C 6 alkanoyl, C 2 -C 6 Alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono - and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl),
  • R 15 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 16 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 17 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • R 18 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC
  • T is N or CH
  • a 0, 1 or 2;
  • b 0, 1 or 2;
  • c 0, 1 or 2;
  • d 0, 1 or 2;
  • e 0, 1 or 2;
  • X 6 is N or C
  • X7 is N or C
  • X8 is N or C
  • X9 is N or C.
  • R 1 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 1 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 1 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 1 at each occurrence is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
  • R 2 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 2 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 2 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R2 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R3 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are
  • R3 at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 3 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R3 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
  • R 4 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 4 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 4 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R4 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 5 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 5 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 5 at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 5 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 6 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 6 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 6 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 6 at each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 7 at each occurrence is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally
  • R 7 at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R7 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 7 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 8 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 8 in each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 8 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R8 at each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 9 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R9 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R9 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 9 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 10 at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optional
  • R 10 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 10 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 10 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 11 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are
  • R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 11 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 11 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
  • R 12 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 12 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 12 at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 12 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
  • R 13 at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substid
  • R 13 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 13 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 13 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
  • R 14 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substitute
  • R 14 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
  • R 14' at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro , cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optional
  • R 14' at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino , mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14' at each occurrence is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl .
  • R 14 " in each occurrence thereof is independently selected from none, hydrogen, fluorine, chlorine, hydroxyl, nitro , cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substitute
  • R 14 in each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino , mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14 in each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14"' at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitric acid group, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 - C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, wherein the cycloalkyl, heterocyclyl,
  • R 14"' at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, Amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14"' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 14"' at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl base.
  • R 15 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substit
  • R 15 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 15 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 15 at each occurrence is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
  • R 16 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substit
  • R 16 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 16 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 16 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 17 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl
  • R 17 at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 17 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 17 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
  • R 18 at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optional
  • R 18 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 18 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
  • R 18 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, methyl, isopropyl base.

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Abstract

Provided are an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and a use thereof in the treatment of proliferative diseases. Further provided is a pharmaceutical composition comprising the compound or salt thereof according to the present application and a pharmaceutically acceptable carrier.

Description

异吲哚啉酮化合物及其用途Isoindolinone compounds and uses thereof 技术领域technical field
本申请属于医药领域。本申请提供了由结构式(I)表示的异吲哚啉酮化合物或其药学上可接受的盐，以及其在治疗增殖性疾病中的用途。本申请还提供了包含本申请所述化合物或其盐以及可药用载体的药物组合物。This application belongs to the field of medicine. The present application provides an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and its use in treating proliferative diseases. The present application also provides a pharmaceutical composition comprising the compound or its salt described in the present application and a pharmaceutically acceptable carrier.
背景技术Background technique
癌症是一种影响人类健康的恶性疾病。存在着巨大的医疗需求，以用于治疗各种类型的癌症。研究表明，癌症的发生是一个复杂的事件，涉及多个因素和多个步骤。Cancer is a malignant disease that affects human health. There is a great medical need for the treatment of various types of cancer. Research has shown that cancer development is a complex event involving multiple factors and multiple steps.
羟脑苷脂(Cereblon，CRBN)是一种大脑相关蛋白。CRBN具有多种功能。CRBN能与泛素连接酶E3的调节因子Cullins相互作用从而激活泛素连接酶E3的活性，并促进底物蛋白与泛素分子的连接而实现泛素化。泛素化之后的蛋白会被蛋白酶体识别并被降解。例如，CRBN能诱导含有锌指结构的转录因子Ikaros(IKZF1)和Aiolos(IKZF3)发生泛素化和降解。由于这两种转录因子在癌细胞增殖过程中发挥作用，所以降解此二者会对癌细胞产生毒性效应。CRBN是度胺类药物的直接靶点，度胺类药物能增强CRBN对肿瘤相关因子的降解作用(Science，2014，343，301-305)。度胺类药物也被称为CRBN分子胶。然而，度胺类药物存在很多毒副作用，这限制了度胺类药物作用抗癌药物的应用。例如，沙利度胺会造成胎儿畸形。Hydroxycerebroside (Cereblon, CRBN) is a brain-related protein. CRBN has multiple functions. CRBN can interact with the regulatory factor Cullins of ubiquitin ligase E3 to activate the activity of ubiquitin ligase E3, and promote the connection of substrate proteins and ubiquitin molecules to achieve ubiquitination. Ubiquitinated proteins are recognized by the proteasome and degraded. For example, CRBN can induce the ubiquitination and degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) containing zinc finger structure. Since these two transcription factors play a role in cancer cell proliferation, degrading them can have toxic effects on cancer cells. CRBN is the direct target of idomides, which can enhance the degradation of CRBN on tumor-related factors (Science, 2014, 343, 301-305). Methamides are also known as CRBN molecular glue. However, there are many toxic and side effects of thiaminides, which limits the application of thalidomides as anticancer drugs. For example, thalidomide can cause birth defects.
SALL4(Spaltlike transcription factor 4)是一种参与胎儿肢体发育的胚胎Cys2-His2(C2H2)型锌指转录因子。CRBN分子胶也会降解SALL4因子，这可能会在体内产生潜在毒性(Nature Chemical Biology，2018，14，981–987)。然而，CRBN分子胶降解等其他因子(SALL4因子)的能力不能通过其化学结构事先预测。因此，在IKZF降解物 的开发过程中需要仔细分析其对SALL4的活性。SALL4 (Spaltlike transcription factor 4) is an embryonic Cys2-His2 (C2H2) zinc finger transcription factor involved in fetal limb development. CRBN molecular glue also degrades SALL4 factor, which may cause potential toxicity in vivo (Nature Chemical Biology, 2018, 14, 981–987). However, the ability of CRBN molecular glue to degrade other factors (SALL4 factors) cannot be predicted in advance by their chemical structure. Therefore, careful analysis of its activity against SALL4 is required during the development of IKZF degradants.
总之，迫切需要开发更有效、更安全的癌症治疗方法。对SALL4低活性或无活性、IKZF降解物似乎具有吸引力。In conclusion, there is an urgent need to develop more effective and safer cancer treatments. With low or no activity on SALL4, IKZF degradants appear attractive.
发明简述Brief description of the invention
本申请发明人令人惊奇地发现，本申请化合物或其药学上可接受的盐能有效地降解IKZF、但具有显著降低的SALL4降解，使得本申请化合物或其药学上可接受的盐具有优异的抗癌活性和降低的毒副作用。The inventors of the present application have surprisingly found that the compound of the present application or a pharmaceutically acceptable salt thereof can effectively degrade IKZF, but has significantly reduced degradation of SALL4, so that the compound of the present application or a pharmaceutically acceptable salt thereof has excellent Anticancer activity and reduced toxic side effects.
发明详述Detailed description of the invention
本申请提供了由结构式(I)表示的异吲哚啉酮化合物或其药学上可接受的盐。The present application provides an isoindolinone compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.
本申请的第一个实施方案为具有结构式(I)的化合物或其可药用盐∶The first embodiment of the present application is a compound of structural formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000001
Figure PCTCN2022114183-appb-000001
其中：in:
R 1在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4 烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 2在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 3在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 4在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳 基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 5在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 6在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 7在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 8在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 9在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 10在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 10 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔 基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 11 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
Q为CR 12R 13，n是0、1或2； Q is CR 12 R 13 , n is 0, 1 or 2;
X 1在其每一次出现时独立地选自CR 14或N； X 1 is independently selected from CR 14 or N at each occurrence thereof;
X 2在其每一次出现时独立地选自CR 14’或N； X is independently selected from CR 14' or N at each occurrence thereof;
X 3在其每一次出现时独立地选自CR 14”或N； X3 is independently selected from CR 14" or N at each occurrence thereof;
X 4在其每一次出现时独立地选自CR 14”’或N； X4 is independently selected from CR 14"' or N at each occurrence thereof;
X 5选自O、CR 15R 16、或NR 17， X 5 is selected from O, CR 15 R 16 , or NR 17 ,
R 12在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 12 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 13在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳 基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 13 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14’在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl The group is optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14”在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R14 " at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1 - C6 alkyl, C2 - C6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl The group is optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14”’在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14"' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkene C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyl oxy, C 2 -C 6 alkanoyl, C 2 -C 6 Alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono - and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and hetero Aryl is optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 15在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 15 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 16在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 16 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 17在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔 基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 17 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 18在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 18 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
T为N或CH；T is N or CH;
a是0、1或2；a is 0, 1 or 2;
b是0、1或2；b is 0, 1 or 2;
c是0、1或2；c is 0, 1 or 2;
d是0、1或2；d is 0, 1 or 2;
e是0、1或2；e is 0, 1 or 2;
X 6是N或C； X 6 is N or C;
X 7是N或C； X7 is N or C;
X 8是N或C； X8 is N or C;
X 9是N或C。 X9 is N or C.
在本申请的第一个实施方案的第二个方面，结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：In a second aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000002
Figure PCTCN2022114183-appb-000002
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
在本申请的第一个实施方案的第三个方面，结构式(I)的化合物为结构式(III)的化合物或其药学上可接受的盐：In a third aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (III) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000003
Figure PCTCN2022114183-appb-000003
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
在本申请的第一个实施方案的第四个方面，结构式(I)的化合物为结构式(IV)的化合物或其药学上可接受的盐：In a fourth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (IV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000004
Figure PCTCN2022114183-appb-000004
其余变量如在第一个实施方案中描述和定义的。The remaining variables are as described and defined in the first embodiment.
在本申请的第一个实施方案的第五个方面，结构式(I)的化合物为结构式(V)的化合物或其药学上可接受的盐：In a fifth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (V) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000005
Figure PCTCN2022114183-appb-000005
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
在本申请的第一个实施方案的第六个方面，结构式(I)的化合物为结构式(VI)的化合物或其药学上可接受的盐：In a sixth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (VI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000006
Figure PCTCN2022114183-appb-000006
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
在本申请的第一个实施方案的第七个方面，结构式(I)的化合物为结构式(VII)的化合物或其药学上可接受的盐：In a seventh aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (VII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000007
Figure PCTCN2022114183-appb-000007
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
在本申请的第一个实施方案的第八个方面，结构式(I)的化合物为结构式(VIII)的化合物或其药学上可接受的盐：In an eighth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (VIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000008
Figure PCTCN2022114183-appb-000008
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
在本申请的第一个实施方案的第九个方面，结构式(I)的化合物为结构式(IX)的化合物或其药学上可接受的盐：In a ninth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (IX) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000009
Figure PCTCN2022114183-appb-000009
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十个方面，结构式(I)的化合物为结构式(X)的化合物或其药学上可接受的盐：In a tenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (X) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000010
Figure PCTCN2022114183-appb-000010
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十一个方面，结构式(I)的化合物为结构式(XI)的化合物或其药学上可接受的盐：In the eleventh aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000011
Figure PCTCN2022114183-appb-000011
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十二个方面，结构式(I)的化合物为结构式(XII)的化合物或其药学上可接受的盐：In a twelfth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000012
Figure PCTCN2022114183-appb-000012
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十三个方面，结构式(I)的化合物为结构式(XIII)的化合物或其药学上可接受的盐：In a thirteenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000013
Figure PCTCN2022114183-appb-000013
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十四个方面，结构式(I)的化合物为结构式(XIV)的化合物或其药学上可接受的盐：In a fourteenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000014
Figure PCTCN2022114183-appb-000014
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十五个方面，结构式(I)的化合物为结构式(XV)的化合物或其药学上可接受的盐：In a fifteenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000015
Figure PCTCN2022114183-appb-000015
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十六个方面，结构式(I)的化合物为结构式(XVI)的化合物或其药学上可接受的盐：In a sixteenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XVI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000016
Figure PCTCN2022114183-appb-000016
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十七个方面，结构式(I)的化合物为结构式(XVII)的化合物或其药学上可接受的盐：In the seventeenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XVII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000017
Figure PCTCN2022114183-appb-000017
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十八个方面，结构式(I)的化合物为结构式(XVIII)的化合物或其药学上可接受的盐：In an eighteenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XVIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000018
Figure PCTCN2022114183-appb-000018
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
本申请的第一个实施方案的第十九个方面，结构式(I)的化合物为结构式(XIV)的化合物或其药学上可接受的盐：In a nineteenth aspect of the first embodiment of the present application, the compound of structural formula (I) is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000019
Figure PCTCN2022114183-appb-000019
其余变量如在第一个实施方案及其任意方面中描述和定义的。The remaining variables are as described and defined in the first embodiment and any aspects thereof.
在本申请的任一实施及其任一方面中，R 1、R 1’、R 2、R 2’、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 14’、R 14”、R 14”’、R 15、R 16、R 17、R 18、R 19、R 20中的每一个独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，它们中的任一者在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000020
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，它们中的任一者在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000021
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，它们中的任一者在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation and any aspect of the present application, R 1 , R 1′ , R 2 , R 2′ , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R each independently _ _ _ _ _ _ _ _ _ _ _ _ selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl , C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl , -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl Substitution; preferably, any one of them is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, Isopropyl, Methoxy, Ethoxy, n-Propoxy, Isopropoxy,
Figure PCTCN2022114183-appb-000020
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, any one of them in each occurrence is independently selected from hydrogen, fluoro, Chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000021
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, any one of them is independently selected at each occurrence from hydrogen, fluoro, Cyano, Methyl, Isopropyl.
在本申请的任一实施及其任一方面中，R 1在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 1在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000022
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 1在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000023
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 1在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000022
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000023
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 1 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 2在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 2在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000024
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 2在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000025
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 2在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000024
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000025
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R2 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 3在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 3在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000026
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 3在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000027
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 3在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000026
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, each occurrence of R is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000027
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R3 in each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 4在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、 C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 4在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000028
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 4在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000029
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 4在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000028
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000029
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R4 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 5在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 5在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000030
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 5在其 每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000031
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 5在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000030
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, each occurrence of R is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000031
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 6在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 6在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000032
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 6在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000033
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 6在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000032
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000033
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R6 in each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 7在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂 芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 7在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000034
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 7在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000035
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 7在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000034
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000035
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 8在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 8在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000036
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 8在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧 基、
Figure PCTCN2022114183-appb-000037
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 8在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000036
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000037
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 9在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 9在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000038
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 9在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000039
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 9在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000038
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, each occurrence of R is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000039
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R9 in each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 10在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基 取代。优选地，R 10在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000040
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 10在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000041
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 10在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000040
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000041
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 10 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 11在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 11在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000042
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 11在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000043
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 11 在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000042
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000043
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 11 at each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 12在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 12在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000044
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 12在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000045
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 12在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000044
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000045
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 12 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 13在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 13在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000046
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 13在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000047
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 13在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R 13 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000046
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000047
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 13 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 14在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 14在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000048
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 14在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000049
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 14在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000048
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000049
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 14 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 14’在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、 C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 14’在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000050
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 14’在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000051
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 14’在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R 14' at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 Alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 Heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 Halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substituted. Preferably, R 14' at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methyl Oxy, Ethoxy, n-Propoxy, Isopropoxy,
Figure PCTCN2022114183-appb-000050
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R 14' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy , ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000051
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 14' at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 14”在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 14”在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000052
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 14”在 其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000053
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 14”在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R 14" is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH at each occurrence thereof , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 Alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 Heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 Halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substituted. Preferably, R 14 " in each occurrence thereof is independently selected from nonexistent, hydrogen, fluoro, Chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000052
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R14 " at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy , ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000053
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 14 " is independently selected at each occurrence of hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 14”’在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 14”’在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000054
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 14”’在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000055
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 14”’在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R 14"' is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, - COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 Halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substituted. Preferably, R 14"' at each occurrence thereof is independently selected from nonexistent, hydrogen, Fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000054
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R 14"' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000055
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 14"' at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 15在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂 芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 15在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000056
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 15在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000057
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 15在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000056
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000057
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 15 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 16在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 16在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000058
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 16在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧 基、
Figure PCTCN2022114183-appb-000059
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 16在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000058
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000059
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 16 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 17在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。优选地，R 17在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000060
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 17在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000061
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 17在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000060
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000061
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 17 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，R 18在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基 取代。优选地，R 18在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000062
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。更优选地，R 18在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000063
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。最优选地，R 18在其每一次出现时独立地选自氢、氟、氯、氰基、甲基、异丙基。 In any implementation of the present application and any aspect thereof, R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkane radical, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 hetero Cyclic group, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen , hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitution. Preferably, R at each occurrence thereof is independently selected from absent, hydrogen, fluoro, chloro, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy base, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000062
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. More preferably, R at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, Ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000063
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl. Most preferably, R 18 at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, methyl, isopropyl.
在本申请的任一实施及其任一方面中，a是0。在本申请的任一实施及其任一方面中，a是1。在本申请的任一实施及其任一方面中，a是2。In any implementation of the present application and any aspect thereof, a is 0. In any implementation of the application and any aspect thereof, a is 1. In any implementation of the application and any aspect thereof, a is 2.
在本申请的任一实施及其任一方面中，b是0。在本申请的任一实施及其任一方面中，b是1。在本申请的任一实施及其任一方面中，b是2。In any implementation of the application and any aspect thereof, b is 0. In any implementation of the application and any aspect thereof, b is 1. In any implementation of the application and any aspect thereof, b is 2.
在本申请的任一实施及其任一方面中，c是0。在本申请的任一实施及其任一方面中，c是1。在本申请的任一实施及其任一方面中，c是2。In any implementation of the application and any aspect thereof, c is 0. In any implementation of the application and any aspect thereof, c is 1. In any implementation of the application and any aspect thereof, c is 2.
在本申请的任一实施及其任一方面中，d是0。在本申请的任一实施及其任一方面中，d是1。在本申请的任一实施及其任一方面中，d是2。In any implementation of the application and any aspect thereof, d is 0. In any implementation of the application and any aspect thereof, d is 1. In any implementation of the application and any aspect thereof, d is 2.
在本申请的任一实施及其任一方面中，e是0。在本申请的任一实施及其任一方面中，e是1。在本申请的任一实施及其任一方面中，e是2。In any implementation of the application and any aspect thereof, e is 0. In any implementation of the application and any aspect thereof, e is 1. In any implementation of the application and any aspect thereof, e is 2.
在本申请的任一实施及其任一方面中，n是0。在本申请的任一实施及其任一方面中，n是1。在本申请的任一实施及其任一方面中，n是2。In any implementation of the application and any aspect thereof, n is zero. In any implementation of the application and any aspect thereof, n is 1. In any implementation of the application and any aspect thereof, n is 2.
在本申请的任一实施及其任一方面中，X 1是N。在本申请的任一实施及其任一方面中，X 1是CR 14。 In any implementation of the present application and any aspect thereof, Xi is N. In any implementation of the application and any aspect thereof, X 1 is CR 14 .
在本申请的任一实施及其任一方面中，X 2是N。在本申请的任一实施及其任一方面中，X 2是CR 14’。 In any implementation of the present application and any aspect thereof, X 2 is N. In any implementation of the application and any aspect thereof, X 2 is CR 14′ .
在本申请的任一实施及其任一方面中，X 3是N。在本申请的任一实施及其任一方面中，X 3是CR 14”。 In any implementation of the present application and any aspect thereof, X 3 is N. In any implementation of the present application and any aspect thereof, X 3 is CR 14 ″ .
在本申请的任一实施及其任一方面中，X 4是N。在本申请的任一实施及其任一方面中，X 4是CR 14”’。 In any implementation of the present application and any aspect thereof, X 4 is N. In any implementation of the present application and any aspect thereof, X 4 is CR 14"' .
在本申请的任一实施及其任一方面中，X 5是O。在本申请的任一实施及其任一方面中，X 5是CR 15R 16。在本申请的任一实施及其任一方面中，X 5是NR 17。 In any implementation of the application and any aspect thereof, X is O. In any implementation of the application and any aspect thereof, X 5 is CR 15 R 16 . In any implementation of the application and any aspect thereof, X 5 is NR 17 .
在本申请的任一实施及其任一方面中，X 6是N。在本申请的任一实施及其任一方面中，X 6是C。 In any implementation of the present application and any aspect thereof, X is N. In any implementation of the application and any aspect thereof, X is C.
在本申请的任一实施及其任一方面中，X 7是N。在本申请的任一实施及其任一方面中，X 7是C。 In any implementation of the present application and any aspect thereof, X is N. In any implementation of the application and any aspect thereof, X is C.
在本申请的任一实施及其任一方面中，X 8是N。在本申请的任一实施及其任一方面中，X 6是C。 In any implementation of the application and any aspect thereof, X is N. In any implementation of the application and any aspect thereof, X is C.
在本申请的任一实施及其任一方面中，X 9是N。在本申请的任一实施及其任一方面中，X 9是C。 In any implementation of the present application and any aspect thereof, X 9 is N. In any implementation of the application and any aspect thereof, X is C.
在本申请的任一实施及其任一方面中，T是N。在本申请的任一实施及其任一方面中，T是CH。In any implementation of the application and any aspect thereof, T is N. In any implementation of this application and any aspect thereof, T is CH.
术语“药学上可接受的盐”是指本发明化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐“甲磺酸盐(mesylate)”、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、双羟萘酸盐(即1,1'-亚甲基-双-(2- 羟基-3-萘甲酸)盐)、碱金属(例如，钠和钾)盐、碱土金属(例如，镁)盐和铵盐。药学上可接受的盐可涉及包含另一种分子，诸如乙酸根离子、琥珀酸根离子或其他抗衡离子。抗衡离子可以是使母体化合物上的电荷稳定化的任何有机或无机部分。此外，药学上可接受的盐在其结构中可以具有多于一个带电荷的原子。多个带电荷的原子是药学上可接受的盐的一部分的例子可以具有多个抗衡离子。因此，药学上可接受的盐可具有一个或多个带电荷的原子和/或一个或多个抗衡离子。The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate , lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisic acid salt, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate "mesylate", Esylate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salt), alkali metal ( For example, sodium and potassium), alkaline earth metal (eg, magnesium) and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as acetate, succinate or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, pharmaceutically acceptable salts can have more than one charged atom in their structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
如果本发明的化合物是碱，则期望的药学上可接受的盐可以通过本领域可用的任何合适的方法制备，例如用无机酸或有机酸处理游离碱来制备，该无机酸诸如为盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等，该有机酸诸如为乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷基酸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如柠檬酸或酒石酸、氨基酸如天冬氨酸或谷氨酸、芳族酸如苯甲酸或肉桂酸、磺酸如对甲苯磺酸或乙磺酸、等等。If the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example by treating the free base with an inorganic or organic acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., such organic acids as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid , pyranosidic acids such as glucuronic acid or galacturonic acid, alpha-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc.
如果本发明的化合物是酸，则期望的药学上可接受的盐可以通过任何合适的方法制备，例如用诸如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等无机或有机碱处理游离酸来制备。合适盐的示例性实例包括但不限于衍生自氨基酸如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺以及环胺如哌啶、吗啉和哌嗪的有机盐，以及衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by oxidation with an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide such as It can be prepared by treating free acids with inorganic or organic bases such as compounds. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and those derived from sodium , calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium inorganic salts.
术语“药学上可接受的”表明该物质或组合物必须在化学和/或毒理学上与包含制剂的其他成分和/或用其治疗的哺乳动物相容。The term "pharmaceutically acceptable" indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith.
本申请化合物可以各种立体异构形式存在。术语“立体异构体”是指具有相同化学构成和连接性的化合物，但是其原子在空间中的不同取向不能通过围绕单键旋转而相互转化。“立体异构体”可以包括“非对映异构体”和“对映异构体”。“非对映异构体”是指具有两个或更多个手性中心且其分子彼此不是镜像的立体异构体。“对映异构体”是指化合物的两个立体异构体，它们是彼此不可重叠的镜像。 “R”和“S”代表围绕一个或多个手性原子的取代基构型。本申请的化合物可以通过手性合成或从异构体混合物拆分来制备为单独的异构体。所公开的化合物可以具有一个或多个立体中心，并且每个立体中心可以独立地以R或S构型存在。当立体中心的绝对立体化学未确定时，立体化学构型可在指定中心指定为(*)。在一个实施方案中，本文所述的化合物以旋光或外消旋形式存在。应当理解，本文所述的化合物包括具有本文所述的治疗有用特性的外消旋、旋光、区域异构和立体异构形式或其组合。The compounds of the present application may exist in various stereoisomeric forms. The term "stereoisomer" refers to compounds having the same chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds. "Stereoisomers" may include "diastereomers" and "enantiomers". "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. "R" and "S" represent the configuration of substituents around one or more chiral atoms. Compounds of the present application may be prepared as individual isomers by chiral synthesis or resolution from isomeric mixtures. The disclosed compounds may possess one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. When the absolute stereochemistry of a stereocenter is not determined, the stereochemical configuration can be assigned as (*) at the indicated center. In one embodiment, the compounds described herein exist in optically active or racemic form. It is to be understood that the compounds described herein include racemic, optical, regioisomeric and stereoisomeric forms or combinations thereof which possess the therapeutically useful properties described herein.
在一个实施方案中，本申请所述的化合物含有一个或多个手性中心。这些化合物可通过任何方式制备，包括立体选择性合成、对映选择性合成或对映异构体或非对映异构体的混合物的分离。化合物及其异构体的拆分可通过任何方式实现，包括但不限于化学过程、酶促过程、分步结晶、蒸馏和色谱法。In one embodiment, the compounds described herein contain one or more chiral centers. These compounds may be prepared by any means including stereoselective synthesis, enantioselective synthesis or separation of mixtures of enantiomers or diastereomers. Resolution of a compound and its isomers can be achieved by any means including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation and chromatography.
定义definition
术语“取代的”指所指定的原子或基团上的任何一个或多个氢被选自所指示基团的部分所代替，前提条件是不超过所指定的原子的正常价。The term "substituted" means that any one or more hydrogens on the designated atom or group are replaced by a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded.
“烷基”为支链或直链饱和脂族烃基团。在一个实施方案中，烷基含1至约12个碳原子，更通常1至约6个碳原子或1至约4个碳原子。在一个实施方案中，烷基含1至约8个碳原子。在某些实施方案中，烷基为C1-C2、C1-C3或C1-C6。如本文所用，指定的范围指所述范围的每一个成员作为独立的种类的烷基基团。例如，如本文所用，术语C1-C6烷基指具有1、2、3、4、5或6个碳原子的直链或支链烷基基团并意在指这些中的每一者作为独立的种类描述。例如，如本文所用，术语C1-C4烷基指具有1、2、3或4个碳原子的直链或支链烷基基团并意在指这些中的每一者作为独立的种类描述。当C0-Cn烷基在本文中结合另一基团使用时，例如(C3-C7环烷基)C0-C4烷基 或-C0-C4烷基(C3-C7环烷基)，所指示的基团——在此情况下环烷基，或通过单一共价键(C0烷基)直接键合或通过烷基链(在此情况下1、2、3或4个碳原子)连接。烷基也可经由其它基团如杂原子连接，如在-O-C0-C4烷基(C3-C7环烷基)中。烷基的实例包括但不限于甲基、乙基、正-丙基、异丙基、正-丁基、异丁基、仲-丁基、叔-丁基、正-戊基、异戊基、叔-戊基、新戊基、正-己基、2-甲基戊烷、3-甲基戊烷、2,2-二甲基丁烷和2,3-二甲基丁烷。在一个实施方案中，烷基基团任选地被如上所述取代。"Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl group is C1-C2, C1-C3, or C1-C6. As used herein, a specified range refers to each member of the stated range as a separate species of alkyl group. For example, as used herein, the term C1-C6 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms and is intended to mean each of these as independently type description. For example, as used herein, the term C1-C4 alkyl refers to a straight or branched chain alkyl group having 1, 2, 3 or 4 carbon atoms and is intended to mean that each of these is described as a separate species. When a C0-Cn alkyl group is used herein in combination with another group, such as (C3-C7 cycloalkyl)C0-C4 alkyl or -C0-C4 alkyl (C3-C7 cycloalkyl), the indicated The group, in this case cycloalkyl, is either directly bonded by a single covalent bond (C0 alkyl) or linked by an alkyl chain (in this case 1, 2, 3 or 4 carbon atoms). Alkyl groups may also be attached via other groups such as heteroatoms, as in -O-CO-C4alkyl (C3-C7cycloalkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl , tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In one embodiment, alkyl groups are optionally substituted as described above.
“烯基”为具有一个或多个碳-碳双键的支链或直链脂族烃基团，所述双键可发生在沿链的稳定点处。非限制性实例有C2-C8烯基、C2-C6烯基和C2-C4烯基。如本文所用，指定的范围指所述范围的每一个成员作为独立的种类的烯基基团，如上面针对烷基部分所述。烯基的实例包括但不限于乙烯基和丙烯基。在一个实施方案中，烯基基团任选地被如上所述取代。"Alkenyl" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may occur at stable points along the chain. Non-limiting examples are C2-C8 alkenyl, C2-C6 alkenyl and C2-C4 alkenyl. As used herein, a specified range refers to each member of the stated range as a separate species of alkenyl group, as described above for the alkyl moiety. Examples of alkenyl groups include, but are not limited to, ethenyl and propenyl. In one embodiment, an alkenyl group is optionally substituted as described above.
“炔基”为具有一个或多个碳-碳三键的支链或直链脂族烃基团，所述三键可发生在沿链的任何稳定点处，例如C2-C8炔基或C2-C6炔基。如本文所用，指定的范围指所述范围的每一个成员作为独立的种类的炔基基团，如上面针对烷基部分所述。炔基的实例包括但不限于乙炔基、丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基和5-己炔基。在一个实施方案中，炔基基团任选地被如上所述取代。"Alkynyl" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds which may occur at any stable point along the chain, for example C2-C8 alkynyl or C2- C6 alkynyl. As used herein, a specified range refers to each member of the stated range as a separate species of alkynyl group, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl , 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, an alkynyl group is optionally substituted as described above.
“烷氧基”为通过氧桥(-O-)共价键合的如上所述烷基基团。烷氧基的实例包括但不限于甲氧基、乙氧基、正-丙氧基、异-丙氧基、正-丁氧基、2-丁氧基、叔-丁氧基、正-戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、正-己氧基、2-己氧基、3-己氧基和3-甲基戊氧基。类似地，“烷硫基”或“硫代烷基”基团为通过硫桥(-S-)共价键合的具有指定数量的碳原子的如上所述烷基基团。在一个实施方案中，烷氧基基团任选地被如上所述取代。"Alkoxy" is an alkyl group as described above covalently bonded through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentyloxy Oxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methylpentyloxy . Similarly, an "alkylthio" or "thioalkyl" group is an alkyl group as described above with the indicated number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, alkoxy groups are optionally substituted as described above.
“烯氧基”为通过氧桥(-O-)共价键合到其取代的基团的所述烯基基团。"Alkenyloxy" is such an alkenyl group that is covalently bonded to the group it replaces through an oxygen bridge (-O-).
“烷酰基”为通过羰基(C＝O)桥共价键合的如上所述烷基基团。羰基碳包括在碳数中，即C 2烷酰基为CH 3(C＝O)-基团。在一个实施方案中，烷酰基基团任选地被如上所述取代。 "Alkanoyl" is an alkyl group as described above covalently bonded through a carbonyl (C=O) bridge. The carbonyl carbon is included in the carbon number, ie a C 2 alkanoyl is a CH 3 (C=O)- group. In one embodiment, an alkanoyl group is optionally substituted as described above.
“烷基酯”为通过酯键共价键合的如本文所述烷基基团。酯键可在任一方向上，例如式-O(C＝O)烷基的基团或式-(C＝O)O烷基的基团。"Alkyl ester" is an alkyl group as described herein covalently bonded through an ester bond. The ester linkage can be in either direction, eg a group of formula -O(C=O)alkyl or a group of formula -(C=O)Oalkyl.
“碳环基团”“碳环环”或“环烷基”为包含所有碳环原子的饱和或部分不饱和(即，非芳族)基团。碳环基团通常含3至7个碳原子的1个环或各含3至7个碳原子的2个稠环。环烷基取代基可以是自取代的氮或碳原子的侧基，或者可具有两个取代基的取代碳原子可具有环烷基基团，其作为螺环基团连接。碳环的实例包括环己烯基、环己基、环戊烯基、环戊基、环丁烯基、环丁基和环丙基环。在一个实施方案中，碳环任选地被如上所述取代。在一个实施方案中，环烷基为含所有碳环原子的部分不饱和(即非芳族)基团。A "carbocyclic group," "carbocyclic ring" or "cycloalkyl" is a saturated or partially unsaturated (ie, non-aromatic) group that contains all carbon ring atoms. Carbocyclic groups generally contain 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms. A cycloalkyl substituent may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom which may have two substituents may have a cycloalkyl group attached as a spiro group. Examples of carbocycles include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings. In one embodiment, carbocycles are optionally substituted as described above. In one embodiment, a cycloalkyl group is a partially unsaturated (ie, non-aromatic) group containing all carbon ring atoms.
“碳环-氧基基团”为经由氧-O-连接基连接到其取代的基团的如上所述单环碳环或者单-或二-环碳环基团。A "carbocycle-oxy group" is a monocyclic carbocycle or a mono- or bi-ring carbocycle group as described above attached to the group it replaces via an oxygen-O-linker.
“卤代烷基”指被1个或多个卤素原子、至多最大许可数量的卤素原子所取代的支链和直链烷基基团。卤代烷基的实例包括但不限于三氟甲基、单氟甲基、二氟甲基、2-氟乙基和五氟乙基。"Haloalkyl" refers to branched and straight chain alkyl groups substituted with one or more halogen atoms, up to the maximum permissible number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.
“卤代烷氧基”指通过氧桥(醇原子团的氧)连接的如本文所述卤代烷基基团。"Haloalkoxy" refers to a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical).
“羟烷基”为被至少一个羟基取代基所取代的如前所述烷基基团。"Hydroxyalkyl" is an alkyl group as previously described substituted with at least one hydroxy substituent.
“氨基烷基”为被至少一个氨基取代基所取代的如前所述烷基基团。"Aminoalkyl" is an alkyl group as previously described substituted with at least one amino substituent.
“卤素”独立地指氟、氯、溴和碘中的任何一者。"Halogen" independently refers to any one of fluorine, chlorine, bromine and iodine.
“芳基”指在芳族环或环中仅含碳的芳族基团。在一个实施方案中，芳基基团含1至3个单独的或稠合的环并且具有6至18个(例如，6、7、8、9、10、11、12、13、14、15、16、17或18个)环原 子，无杂原子作为环成员。在指出时，这样的芳基基团可还被碳或非碳原子或基团所取代。此类取代可包括稠合到5至7-元饱和环基团，所述饱和环基团任选地含1或2个独立地选自N、O和S的杂原子，以形成例如3,4-亚甲基二氧苯基基团。芳基基团包括例如苯基和萘基，包括1-萘基和2-萘基。在一个实施方案中，芳基基团是侧基。侧环实例为被苯基基团所取代的苯基基团。在一个实施方案中，芳基基团任选地被如上所述取代。芳基包括双环基团，其包含与饱和、部分不饱和的环或芳族碳环或杂环稠合的芳族环。典型的芳基基团包括但不限于由苯(苯基)、取代的苯、萘、蒽、茚基、茚满基、1,2-二氢萘、1,2,3,4-四氢萘基等等衍生的基团。优选地，芳基为苯基基团。"Aryl" refers to an aromatic group containing only carbon in an aromatic ring or ring. In one embodiment, the aryl group contains 1 to 3 separate or fused rings and has 6 to 18 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17 or 18) ring atoms, with no heteroatoms as ring members. Where indicated, such aryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitutions may include fusion to a 5 to 7-membered saturated ring group optionally containing 1 or 2 heteroatoms independently selected from N, O and S to form, for example, 3, 4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is pendant. An example of a side ring is a phenyl group substituted by a phenyl group. In one embodiment, aryl groups are optionally substituted as described above. Aryl includes bicyclic groups comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, those formed from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydro Groups derived from naphthyl and the like. Preferably, aryl is a phenyl group.
如本文所用，术语“杂环”指具有3至18个(例如，3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个)个环原子的饱和或部分不饱和(即，在环内具有一个或多个双键和/或三键而无芳香性)碳环原子团，其中至少一个环原子为选自氮、氧、磷和硫的杂原子，其余的环原子为C，其中一个或多个环原子任选地被一个或多个上述取代基独立地取代。杂环可为具有3至7个环成员(2至6个碳原子和1至4个选自N、O、P和S的杂原子)的单环或具有6至10个环元(4至9个碳原子和1至6个选自N、O、P和S的杂原子)的双环，例如：双环[4,5]、[5,5]、[5,6]或[6,6]系。在一个实施方案中，唯一的杂原子为氮。在一个实施方案中，唯一的杂原子为氧。在一个实施方案中，唯一的杂原子为硫。杂环描述在Paquette,Leo A.；“Principles of Modern Heterocyclic Chemistry”(W.A.Benjamin,New York,1968)特别是第1、3、4、6、7和9章；“The Chemistry of Heterocyclic Compounds,A series of Monographs”(John Wiley&Sons,New York,1950至现在)特别是第13、14、16、19和28章；和J.Am.Chem.Soc.(1960)82:5566中。杂环的实例包括但不限于吡咯烷基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、哌啶酮基、吗啉基、硫代吗啉基、氧硫杂环己烷基(thioxanyl)、哌嗪基、高哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶 基、氧杂环庚基(oxepanyl)、硫杂环庚基(thiepanyl)、氧氮杂环基(oxazepinyl)、二氮杂环基(diazepinyl)、硫氮杂环基(thiazepinyl)、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧杂环戊基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、二氢异喹啉基、四氢异喹啉基、吡唑烷基咪唑啉基、咪唑烷基、2-氧杂-5-氮杂双环[2.2.2]辛烷、3-氧杂-8-氮杂双环[3.2.1]辛烷、8-氧杂-3-氮杂双环[3.2.1]辛烷、6-氧杂-3-氮杂双环[3.1.1]庚烷、2-氧杂5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、3-氮杂双环[4.1.0]庚烷基、氮杂双环[2.2.2]己烷基、3H-吲哚基、喹嗪基、N-吡啶基脲和吡咯并嘧啶。螺部分也包括在本定义的范围内。其中1或2个环碳原子被氧代基(＝O)部分所取代的杂环基团的实例有嘧啶酮基和1,1-二氧代基-硫代吗啉基。本文中的杂环基团任选地被一个或多个本文所述的取代基独立地取代。“杂环基”包括“杂环烷基”。“杂环烷基”为饱和环基团。其可具有例如1、2、3或4个独立地选自N、S和O的杂原子，其余环原子为碳。在一个典型的实施方案中，氮为杂原子。单环杂环烷基基团通常具有3至约8个环原子或4至6个环原子。杂环烷基基团的实例包括吗啉基、哌嗪基、哌啶基和吡咯啉基。“杂环基”可以含有1、2、3、4、或5个选自N、O和S的杂原子。As used herein, the term "heterocycle" refers to rings having 3 to 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ) saturated or partially unsaturated (that is, having one or more double and/or triple bonds within the ring without aromaticity) carbon ring atom groups of ) ring atoms, wherein at least one ring atom is selected from nitrogen, oxygen, phosphorus and sulfur heteroatoms, and the remaining ring atoms are C, wherein one or more ring atoms are optionally substituted independently by one or more of the aforementioned substituents. The heterocycle can be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), for example: bicyclic [4,5], [5,5], [5,6] or [6,6 ]Tie. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A.Benjamin, New York, 1968) especially Chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950-present), especially Chapters 13, 14, 16, 19, and 28; and J.Am.Chem.Soc. (1960) 82:5566. Examples of heterocycles include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperidonyl, morpholino Linyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidine base, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrole Linyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, di Thianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, dihydroisoquinolyl, tetrahydroisoquinolyl, pyrazolidinyl imidazolinyl, imidazolidine Base, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2 .1] octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0 ]hexyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexyl, 3H-indolyl, quinozinyl, N-pyridylurea and pyrrolopyrimidine . Spiro moieties are also included within the scope of this definition. Examples of heterocyclic groups in which 1 or 2 ring carbon atoms are replaced by an oxo (=O) moiety are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclic groups herein are optionally substituted independently with one or more substituents described herein. "Heterocyclyl" includes "heterocycloalkyl". "Heterocycloalkyl" is a saturated ring group. It may have, for example, 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, the remaining ring atoms being carbon. In a typical embodiment, nitrogen is a heteroatom. Monocyclic heterocycloalkyl groups typically have 3 to about 8 ring atoms, or 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolinyl. "Heterocyclyl" may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
“杂环氧基团”为经由氧-O-连接基连接到其取代的基团的如前所述单环杂环或双环杂环基团。A "heterocyclic epoxy group" is a monocyclic or bicyclic heterocyclic group as previously described attached to the group it replaces via an oxy-O-linker.
“杂芳基”指含1至3个或在一些实施方案中1至2个选自N、O和S的杂原子、其余环原子为碳的稳定单环芳族环，或者含至少一个其中含1至3个或在一些实施方案中1至2个选自N、O和S的杂原子、其余环原子为碳的5-至10-元(5、6、7、8、9、10元)芳族环的稳定双环或三环系。在一个实施方案中，唯一的杂原子为氮。在一个实施方案中，唯一的杂原子为氧。在一个实施方案中，唯一的杂原子为硫。单环杂芳基基团通常具有5至8个环原子(5、6、7、8个)。在一些实施方案中，双环杂芳基基团为9-至10-元杂芳基基团， 即含9或10个环原子的基团，其中一个5-至7-元芳族环稠合到第二个芳族或非芳族环。当杂芳基基团中S和O原子的总数超过1时，这些杂原子不彼此相邻。在一个实施方案中，杂芳基基团中S和O原子的总数不超过2。在另一个实施方案中，芳族杂环中S和O原子的总数不超过1。杂芳基基团的实例包括但不限于吡啶基(包括例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(包括例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、四氢呋喃基和呋喃并吡啶基。杂芳基基团任选地被一个或多个本文所述取代基独立地取代。“杂芳氧基”为经由氧-O-连接基键合到其取代的基团的所述杂芳基基团。“杂芳基”可以含有1、2、3、4、或5个选自N、O和S的杂原子。"Heteroaryl" means a stable monocyclic aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, the remaining ring atoms being carbon, or at least one of the 5- to 10-membered (5, 6, 7, 8, 9, 10 stable bicyclic or tricyclic ring systems of aromatic rings. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 to 8 ring atoms (5, 6, 7, 8). In some embodiments, bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, i.e., groups containing 9 or 10 ring atoms in which one 5- to 7-membered aromatic ring is fused to the second aromatic or nonaromatic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in a heteroaryl group does not exceed two. In another embodiment, the total number of S and O atoms in the aromatic heterocycle does not exceed one. Examples of heteroaryl groups include, but are not limited to, pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl , pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolyl, tetrahydro Isoquinolyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, indolyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridine Base, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, Quinazolinyl, quinoxalinyl, naphthyridyl, tetrahydrofuranyl and furopyridyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. "Heteroaryloxy" is said heteroaryl group bonded to the group it replaces via an oxygen-O-linker. "Heteroaryl" may contain 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S.
本申请还涵盖由一个或多个选自“环烷基”、“芳基”和“杂芳基”单环以化合价允许的方式形成的二环、三环、四环、五环等多环系统。The present application also covers bicyclic, tricyclic, tetracyclic, pentacyclic and other polycyclic rings formed by one or more monocyclic rings selected from "cycloalkyl", "aryl" and "heteroaryl" in a manner permitted by valence. system.
术语氰基是指-CN。The term cyano refers to -CN.
在一个方面，本申请化合物为结构式(X)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (X) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000064
Figure PCTCN2022114183-appb-000064
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
X 8是C，且R 18是氢、氟、氯、氰基、或甲基； X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
-(Q) n-是-(CH 2)-或-(CH 2) 2-； -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 4是N、CH、CF、C-CH 3； X4 is N, CH, CF, C- CH3 ;
X 6是N、CH、CF、C-CH 3； X 6 is N, CH, CF, C-CH 3 ;
X 7是N、CH、CF、C-CH 3； X 7 is N, CH, CF, C-CH 3 ;
X 9是N、CH、CF、C-CH 3。 X9 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XI)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000065
Figure PCTCN2022114183-appb-000065
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
X 8是C，且R 18是氢、氟、氯、氰基、或甲基； X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
-(Q) n-是-(CH 2)-或-(CH 2) 2-； -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 4是N、CH、CF、C-CH 3； X4 is N, CH, CF, C- CH3 ;
X 6是N、CH、CF、C-CH 3； X 6 is N, CH, CF, C-CH 3 ;
X 7是N、CH、CF、C-CH 3； X 7 is N, CH, CF, C-CH 3 ;
X 9是N、CH、CF、C-CH 3。 X9 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XII)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000066
Figure PCTCN2022114183-appb-000066
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
X 8是C，且R 18是氢、氟、氯、氰基、或甲基； X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
-(Q) n-是-(CH 2)-或-(CH 2) 2-； -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 4是N、CH、CF、C-CH 3； X4 is N, CH, CF, C- CH3 ;
X 6是N、CH、CF、C-CH 3； X 6 is N, CH, CF, C-CH 3 ;
X 7是N、CH、CF、C-CH 3； X 7 is N, CH, CF, C-CH 3 ;
X 9是N、CH、CF、C-CH 3。 X9 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XIII)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000067
Figure PCTCN2022114183-appb-000067
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
X 8是C，且R 18是氢、氟、氯、氰基、或甲基； X is C, and R is hydrogen, fluoro, chloro, cyano, or methyl;
-(Q) n-是-(CH 2)-或-(CH 2) 2-； -(Q) n - is -(CH 2 )- or -(CH 2 ) 2 -;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 4是N、CH、CF、C-CH 3； X4 is N, CH, CF, C- CH3 ;
X 6是N、CH、CF、C-CH 3； X 6 is N, CH, CF, C-CH 3 ;
X 7是N、CH、CF、C-CH 3； X 7 is N, CH, CF, C-CH 3 ;
X 9是N、CH、CF、C-CH 3。 X9 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XIV)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000068
Figure PCTCN2022114183-appb-000068
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
R 18是氢、氟、氯、氰基、或甲基； R 18 is hydrogen, fluoro, chloro, cyano, or methyl;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 6是N、CH、CF、C-CH 3。 X6 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XV)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000069
Figure PCTCN2022114183-appb-000069
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
R 18是氢、氟、氯、氰基、或甲基； R 18 is hydrogen, fluoro, chloro, cyano, or methyl;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 6是N、CH、CF、C-CH 3。 X6 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XVI)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XVI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000070
Figure PCTCN2022114183-appb-000070
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
R 18是氢、氟、氯、氰基、或甲基； R 18 is hydrogen, fluoro, chloro, cyano, or methyl;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 6是N、CH、CF、C-CH 3。 X6 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XVII)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XVII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000071
Figure PCTCN2022114183-appb-000071
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
R 18是氢、氟、氯、氰基、或甲基； R 18 is hydrogen, fluoro, chloro, cyano, or methyl;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 6是N、CH、CF、C-CH 3。 X6 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XVIII)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XVIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000072
Figure PCTCN2022114183-appb-000072
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
R 18是氢、氟、氯、氰基、或甲基； R 18 is hydrogen, fluoro, chloro, cyano, or methyl;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 6是N、CH、CF、C-CH 3。 X6 is N, CH, CF, C- CH3 .
在一个方面，本申请化合物为结构式(XIV)的化合物或其药学上可接受的盐：In one aspect, the compound of the present application is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000073
Figure PCTCN2022114183-appb-000073
其中：in:
T是N；T is N;
R 2是氢、氟、氰基、或甲基； R is hydrogen, fluoro, cyano, or methyl;
R 18是氢、氟、氯、氰基、或甲基； R 18 is hydrogen, fluoro, chloro, cyano, or methyl;
X 5是O； X 5 is O;
X 1是N、CH、CF、C-CH 3； X 1 is N, CH, CF, C-CH 3 ;
X 2是N、CH、CF、C-CH 3； X2 is N, CH, CF, C- CH3 ;
X 3是N、CH、CF、C-CH 3； X 3 is N, CH, CF, C-CH 3 ;
X 6是N、CH、CF、C-CH 3。 X6 is N, CH, CF, C- CH3 .
申请人发现，本申请化合物或其药学上可接受的盐能有效地降解IKZF。因此，本申请所述的化合物或其盐可用于治疗增殖性疾病。此外，申请人还发现本文所述的化合物或其盐在降解IKZF时不会同时抑制/降解SALL4。换言之，本申请所述的化合物或其盐可以选择性地降解IKZF，对其他蛋白质/激酶的影响降低或没有影响，从而与先前的IKZF降解剂/抑制剂相比表现出降低的毒副作用或没有毒副作用。Applicants found that the compound of the present application or a pharmaceutically acceptable salt thereof can effectively degrade IKZF. Accordingly, the compounds described herein, or salts thereof, are useful in the treatment of proliferative diseases. In addition, applicants have also discovered that compounds described herein or salts thereof do not simultaneously inhibit/degrade SALL4 when degrading IKZF. In other words, the compounds or salts thereof described herein can selectively degrade IKZF with reduced or no effects on other proteins/kinases, thereby exhibiting reduced or no toxic side effects compared to previous IKZF degraders/inhibitors toxic side effect.
本申请所述的化合物或其药学上可接受的盐可用于治疗增殖性疾病。本申请还提供了本申请所述的化合物或其药学上可接受的盐在制备用于治疗增殖性疾病的药物中的用途。本发明进一步提供了所述的化合物或其药学上可接受的盐，用于治疗增殖性疾病。本申请进一步提供了治疗增殖性疾病的方法，包括向有需要的受试者施用治疗有效量的所述的化合物或其药学上可接受的盐。The compounds described herein, or pharmaceutically acceptable salts thereof, are useful in the treatment of proliferative diseases. The present application also provides the use of the compound described in the present application or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating proliferative diseases. The present invention further provides the compound or a pharmaceutically acceptable salt thereof for treating proliferative diseases. The present application further provides a method for treating proliferative diseases, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject in need.
术语“增殖性疾病”或“细胞增殖性疾病”是指与某种程度的异常细胞增殖相关的疾病，无论是恶性的还是良性的。在一些实施方案 中，增殖性疾病是癌症。在一些方面，癌症是实体瘤。在一些方面，癌症是血液系统恶性肿瘤。术语“增殖性障碍”、“细胞增殖性障碍”、“癌症”、“癌性”和“肿瘤”在本申请中提及时并不相互排斥。The term "proliferative disease" or "cell proliferative disease" refers to a disease associated with some degree of abnormal cell proliferation, whether malignant or benign. In some embodiments, the proliferative disease is cancer. In some aspects, the cancer is a solid tumor. In some aspects, the cancer is a hematological malignancy. The terms "proliferative disorder", "cell proliferative disorder", "cancer", "cancerous" and "tumor" are not mutually exclusive when referred to in this application.
术语“癌症”包括癌细胞和/或良性或前癌细胞。示例性癌症包括但不限于乳腺癌、结肠癌、脑癌、前列腺癌、肾癌、胰腺癌、卵巢癌、头颈癌、黑素瘤、结直肠癌、胃癌、鳞癌、小细胞肺癌、非小细胞肺癌、睾丸癌、梅克尔细胞癌、胶质母细胞瘤、神经细胞瘤、淋巴器官的癌症和骨髓恶性肿瘤包括白血病(急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、急性单核细胞白血病(AMOL)、多毛细胞白血病(HCL)、T-细胞幼淋巴细胞白血病(T-PLL)、巨粒淋巴细胞白血病、成人T细胞白血病)、淋巴瘤(小淋巴细胞淋巴瘤(SLL)、霍奇金淋巴瘤(结节硬化型、混合细胞型、富于淋巴细胞型、淋巴细胞削减型或未削减型和结节性淋巴细胞主导的霍奇金淋巴瘤)、非霍奇金淋巴瘤(所有亚型)、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、B-细胞前淋巴细胞白血病、淋巴质浆细胞白血病(诸如瓦尔登斯特伦病巨球蛋白血症)、脾边缘带淋巴瘤、浆细胞肿瘤(浆细胞性骨髓瘤、浆细胞瘤、单克隆免疫球蛋白沉积物疾病、重链病)、结节外边缘区B细胞淋巴瘤(MALT淋巴瘤)、结节边缘区B细胞淋巴瘤(NMZL)、滤泡淋巴瘤、外套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、T细胞幼淋巴细胞白血病、T细胞巨粒淋巴细胞白血病、攻击性NK细胞白血病、成人T细胞白血病/淋巴瘤、结节外NK/T细胞淋巴瘤(鼻型)、肠病型T细胞淋巴瘤、肝脾T细胞淋巴瘤、亚顶级NK细胞淋巴瘤、蕈样真菌病/塞扎里综合征、原发性皮肤间CD30-阳性T细胞淋巴增生性病症、原发性皮肤间变性大细胞淋巴瘤、淋巴瘤样丘疹病、血管免疫母细胞性T细胞淋巴瘤、外周T细胞淋巴瘤(非特异性)、间变性大细胞淋巴瘤)、多发性骨髓瘤(浆细胞性骨髓瘤或卡勒病)。术语“癌症”还包括白血病、癌(carcinoma)和肉瘤。示例性的癌症包括脑癌，乳腺 癌，宫颈癌，结肠癌，头颈癌，肝癌，肾癌，肺癌，非小细胞肺癌，黑素瘤，间皮瘤，卵巢癌，肉瘤，胃癌，子宫癌和成神经管细胞瘤。另外的实例包括霍奇金病，非霍奇金淋巴瘤，多发性骨髓瘤，神经母细胞瘤，卵巢癌，横纹肌肉瘤，原发性血小板增多症，原发性巨球蛋白血症，原发性脑瘤，癌症，恶性胰腺胰岛瘤，恶性类癌，膀胱癌，恶化前皮肤病变，睾丸癌，淋巴瘤，甲状腺癌，神经母细胞瘤，食管癌，泌尿生殖道癌，恶性高钙血症，子宫内膜癌，肾上腺皮质癌，内分泌和外分泌胰腺的瘤，和前列腺癌。术语癌症还包括白血病、多发性骨髓瘤、淋巴瘤、肝癌、胃癌、乳腺癌、胆管细胞癌、胰腺癌、肺癌、大肠癌、骨肉瘤、黑色素瘤、人宫颈癌、神经胶质瘤、鼻咽癌、喉癌、食管癌、中耳肿瘤、前列腺癌等。The term "cancer" includes cancer cells and/or benign or precancerous cells. Exemplary cancers include, but are not limited to, breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small Cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, cancer of lymphoid organs and myeloid malignancies including leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), giant myeloid leukemia , adult T-cell leukemia), lymphoma (small lymphocytic lymphoma (SLL), Hodgkin lymphoma (nodular sclerosis, mixed cell, lymphocytic, lymphopenic or unreduced, and nodal nodular lymphocyte predominant Hodgkin lymphoma), non-Hodgkin lymphoma (all subtypes), chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic leukemia ( such as Waldenstrom's disease macroglobulinemia), splenic marginal zone lymphoma, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposit disease, heavy chain disease), nodules Outer marginal zone B-cell lymphoma (MALT lymphoma), nodal marginal zone B-cell lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma Lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, T-cell prolymphocytic leukemia, T-cell giant myeloid lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia/lymphoma, extranodal NK/T-cell lymphoma (nasal type), enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, subtopic NK-cell lymphoma, mycosis fungoides/Seza Li syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorder, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma tumor (nonspecific), anaplastic large cell lymphoma), multiple myeloma (plasma cell myeloma or Cuhler disease). The term "cancer" also includes leukemias, carcinomas and sarcomas. Exemplary cancers include brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, and medulloblastoma. Additional examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary malignant brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia , endometrial carcinoma, adrenocortical carcinoma, endocrine and exocrine pancreatic neoplasms, and prostate cancer. The term cancer also includes leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, glioma, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, middle ear tumor, prostate cancer, etc.
本申请还提供一种药物组合物，包含所述化合物或其药学上可接受的盐、以及任选地药学上可接受载体。本申请所述药物组合物可以是片剂、胶囊剂、颗粒剂、糖浆剂、悬浮液、溶液、分散剂、用于口服或非口服给药的缓释制剂、静脉注射制剂、皮下注射制剂、吸入制剂、透皮制剂、直肠或阴道栓剂。The present application also provides a pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition described in the present application can be tablets, capsules, granules, syrups, suspensions, solutions, dispersions, sustained-release preparations for oral or non-oral administration, intravenous injection preparations, subcutaneous injection preparations, Inhalation preparations, transdermal preparations, rectal or vaginal suppositories.
本申请所述药学上可接受载体是指本领域技术人员熟知的药学上可接受载体，本申请的药学上可接受载体包括但不限于：填充剂、润湿剂、黏合剂、崩解剂、润滑剂、粘合剂、助流剂、掩味剂、表面活性剂、防腐剂等。填充剂包括但不限于乳糖、微晶纤维素、淀粉、糖粉、糊精、甘露醇、硫酸钙等。润湿剂与黏合剂包括但不限于羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、明胶、蔗糖、聚乙烯吡咯烷酮等。崩解剂包括但不限于羧甲基淀粉钠、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、低取代羟丙基纤维素等。润滑剂包括但不限于硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇、月桂醇硫酸镁等。粘合剂包括但不限于阿拉伯胶、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、葡萄糖结合剂、糊精、右旋糖、乙基纤维素、明胶、液体葡萄糖、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、硅酸铝镁、麦芽糖糊精、甲基纤维素、聚甲基丙烯酸酯、聚乙 烯吡咯烷酮、预明胶化淀粉、藻酸钠、山梨醇、淀粉、糖浆和黄蓍胶。助流剂包括但不限于胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉。掩味剂包括但不限于阿斯巴坦、甜菊苷、果糖、葡萄糖、糖浆、蜂蜜、木糖醇、甘露醇、乳糖、山梨醇、麦芽糖醇、甘草甜素。表面活性剂包括但不限于吐温-80、泊洛沙姆。防腐剂包括但不限于尼泊金酯、苯甲酸钠、山梨酸钾等。The pharmaceutically acceptable carrier described in this application refers to the pharmaceutically acceptable carrier well known to those skilled in the art. The pharmaceutically acceptable carrier in this application includes but is not limited to: fillers, wetting agents, binders, disintegrants, Lubricants, adhesives, glidants, taste masking agents, surfactants, preservatives, etc. Fillers include, but are not limited to, lactose, microcrystalline cellulose, starch, powdered sugar, dextrin, mannitol, calcium sulfate, and the like. Wetting agents and binders include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, sucrose, polyvinylpyrrolidone, and the like. Disintegrants include, but are not limited to, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, and the like. Lubricants include, but are not limited to, magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and the like. Binders include, but are not limited to, gum arabic, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, dextrose, dextrin, dextrose, ethylcellulose, gelatin, liquid dextrose, guar Gum, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Magnesium Aluminum Silicate, Maltodextrin, Methylcellulose, Polymethacrylate, Polyvinylpyrrolidone, Pregelatinized Starch , Sodium Alginate, Sorbitol, Starch, Syrup and Tragacanth. Glidants include, but are not limited to, colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, and talc. Taste-masking agents include, but are not limited to, aspartame, stevioside, fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin. Surfactants include, but are not limited to, Tween-80, poloxamers. Preservatives include, but are not limited to, paraben, sodium benzoate, potassium sorbate, and the like.
制备各种含有各种比例活性成分的药物组合物的方法是已知的，或根据本申请的公开内容对于本领域技术人员是显而易见的。如REMINGTON’ S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述。制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。以已知的方法制造本申请所述药物组合物，包括常规的混合、溶解或冻干方法。Methods for preparing various pharmaceutical compositions containing the active ingredients in various proportions are known, or will be apparent to those skilled in the art from the disclosure of this application. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995). The method of preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents and the like. The pharmaceutical compositions described herein are manufactured by known methods, including conventional mixing, dissolving or lyophilizing methods.
在本申请所述药物组合物中，活性成分的比例可以变化，可占给定的单位剂型重量的大约0.01％至大约99％。在这种治疗有用的药物组合物制剂中，活性成分的量使得能够获得有效剂量水平。In the pharmaceutical compositions described herein, the proportion of active ingredient may vary from about 0.01% to about 99% by weight of a given unit dosage form. In the preparation of such therapeutically useful pharmaceutical compositions, the amount of active ingredient is such that an effective dosage level will be obtained.
本申请所述的片剂、胶囊剂等可以包含：粘合剂，如黄蓍胶、阿拉伯胶、玉米淀粉或明胶；赋形剂，如磷酸氢二钙；崩解剂，如玉米淀粉、马铃薯淀粉、藻酸等；润滑剂，如硬脂酸镁；和甜味剂，如蔗糖、果糖、乳糖或阿司帕坦；或调味剂，如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时，除了上面类型的材料，它还可以包含液体载体，如植物油或聚乙二醇。各种其他材料可以存在，作为包衣，或以其他方式改变固体单位剂型的物理形式。例如，片剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆可以包含活性成分，蔗糖或果糖作为甜味剂，对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂，染料和调味剂(如樱桃香料或桔子香料)。当然，用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量为无毒。此外，活性成分可以掺入缓释制剂和缓释装置中。Tablets, capsules, etc. described in the present application may contain: binders, such as tragacanth, acacia, cornstarch or gelatin; excipients, such as dicalcium phosphate; disintegrants, 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. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present, as coatings, or to otherwise modify the physical form of the solid unit dosage form. For example, tablets or capsules may be coated with gelatin, wax, shellac or sugar or the like. A syrup may contain the active ingredient, sucrose or fructose as a sweetening agent, methyl or propyl paraben as a preservative, a dye and flavoring such as cherry flavor or orange flavor. Of course, any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and nontoxic in the amounts employed. Additionally, the active ingredient can be incorporated into sustained release formulations and sustained release devices.
活性成分也可以通过输注或注射到静脉内或腹膜内施用。可以制备活性成分或其盐的水溶液，任选可混和无毒的表面活性剂。也可以 制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下，这些制剂包含防腐剂以防止微生物生长。The active ingredient can also be administered intravenously or intraperitoneally by infusion or injection. Aqueous solutions of the active ingredient or its salts can be prepared, optionally mixed with nontoxic surfactants. 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.
适于注射或输注的药物组合物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下，最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质，包括，例如水、乙醇、多元醇(例如，甘油、丙二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性，例如，通过脂质体的形成，通过在分散剂的情况下维持所需的粒子大小，或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下，优选包括等渗剂，如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如，单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。The dosage form of the pharmaceutical composition suitable for injection or infusion may comprise a sterile aqueous solution containing the active ingredient (optionally encapsulated in liposomes) suitable for extemporaneous preparation of sterile injectable or infusible solution or dispersion. or dispersion or sterile powder. 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. In many cases, it will be preferable 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 which delay absorption (eg, aluminum monostearate and gelatin).
通过将合适的溶剂中的需要量的活性成分与需要的上面列举的各种其他成分结合，然后进行过滤灭菌，制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下，优选的制备方法是真空干燥和冷冻干燥技术，这会产生活性成分加上任何另外需要的无菌过滤溶液中存在的成分的粉末。Sterile injectable solutions are prepared by incorporating the active ingredient in the required amount in an appropriate solvent with each of the other ingredients enumerated above as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional required ingredient present in sterile-filtered solution.
有用的固体载体包括粉碎的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物，本申请的药物组合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。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 pharmaceutical compositions of the present application can be dissolved or dispersed in effective amounts, optionally with the help of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use.
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等，直接用于使用者的皮肤上。Thickening agents (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials) can also be used with liquid carriers to form spreadable pastes, gels, and ointments , soap, etc., directly on the user's skin.
活性成分的治疗有效量，不仅取决于选择的特定的盐，而且取决 于施药方式、待治疗的疾病的性质和患者的年龄和状态，最终取决于在场医师或临床医生的决定。The therapeutically effective amount of the active ingredient 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 at the discretion of the attending physician or clinician.
上述制剂可以以单位剂型存在，该单位剂型是含有单位剂量的物理分散单元，适于向人体和其它哺乳动物体给药。单位剂型可以是胶囊或片剂。根据所涉及的具体治疗，活性成分的单位剂量的量可以在大约0.01到大约1000毫克或更多之间进行变化或调整。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 a tablet. The amount of a unit dose of active ingredient may be varied or adjusted from about 0.01 to about 1000 milligrams or more depending on the particular treatment involved.
本申请使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状，可以是预防性的；和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状；(b)抑制疾病的症状，即阻止其发展；或(c)缓解疾病的症状，即，导致疾病或症状退化。The term "treating" as used herein 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" as used herein 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.
本申请所述的化合物或其药学上可接受的盐也可以与一种或多种用于治疗癌症的另外的治疗剂组合施用。这种额外的治疗剂包括但不限于蒽环类、环磷酰胺、5-氟尿嘧啶、顺铂等。A compound described herein, or a pharmaceutically acceptable salt thereof, may also be administered in combination with one or more additional therapeutic agents useful in the treatment of cancer. Such additional therapeutic agents include, but are not limited to, anthracyclines, cyclophosphamide, 5-fluorouracil, cisplatin, and the like.
除非另有说明，本申请中使用的百分比、比例、比例或份数均以重量或体积计。本申请中使用的量是重量或体积量。本领域技术人员可以很容易地确定。All percentages, proportions, proportions or parts used in this application are by weight or volume unless otherwise indicated. Amounts used in this application are either gravimetric or volumetric amounts. Those skilled in the art can easily determine.
在本申请的还有一个方面，本申请还包括由本申请任一可变基团处所定义的任一基团组合的得到化合物或其药学上可接受的盐。In yet another aspect of the present application, the present application also includes a compound or a pharmaceutically acceptable salt thereof obtained by combining any group defined in any variable group of the present application.
本申请还包括以下示例性化合物。This application also includes the following exemplary compounds.
Figure PCTCN2022114183-appb-000074
Figure PCTCN2022114183-appb-000074
以下，本申请将通过实施例来说明本申请的有益效果。本领域技术人员将认识到这些示例是说明性的而非限制性的。这些示例不会以任何方式限制本申请的范围。以下实施例中所描述的实验方法，除另有说明外，均为常规方法；除非另有说明，试剂和材料均为市售品。Hereinafter, the present application will illustrate the beneficial effects of the present application through examples. Those skilled in the art will recognize that these examples are illustrative and not restrictive. These examples do not limit the scope of this application in any way. The experimental methods described in the following examples are conventional methods unless otherwise specified; all reagents and materials are commercially available unless otherwise specified.
实施例：Example:
本申请化合物可通过以下示例性通用合成方法或类似方法合成。在化合价允许的前提下，各种中间体化合物可以具有本申请所述的各种取代基。The compounds of the present application can be synthesized by the following exemplary general synthesis methods or similar methods. Various intermediate compounds may have various substituents as described herein, subject to valency permitting.
化合物1A可以按照以下示例性通用合成方法或类似方法合成。Compound 1A can be synthesized according to the following exemplary general synthesis method or a similar method.
Figure PCTCN2022114183-appb-000075
Figure PCTCN2022114183-appb-000075
化合物1A1和苯酚通过光延反应得到1A2，化合物1A2脱保护后经过偶联反应得到1A4，然后再脱保护后得到化合物1A。Compound 1A1 and phenol were reacted by Mitsunobu to obtain 1A2, and compound 1A2 was deprotected to obtain 1A4 through coupling reaction, and then deprotected to obtain compound 1A.
Figure PCTCN2022114183-appb-000076
Figure PCTCN2022114183-appb-000076
化合物1A和化合物1B在碱存在条件下得到化合物1C，或者化合物1A和化合物1D通过还原胺化反应得到化合物1E，然后再经过氯代反应得到化合物1C，化合物1C和化合物1F在碱存在条件下得到化合物1G，然后化合物1G在苯磺酸存在条件下得到化合物1H。Compound 1A and Compound 1B are obtained in the presence of a base to obtain Compound 1C, or Compound 1A and Compound 1D are subjected to reductive amination to obtain Compound 1E, and then undergo a chlorination reaction to obtain Compound 1C, and Compound 1C and Compound 1F are obtained in the presence of a base Compound 1G, then compound 1G in the presence of benzenesulfonic acid to give compound 1H.
实施例1:化合物1Embodiment 1: compound 1
Figure PCTCN2022114183-appb-000077
Figure PCTCN2022114183-appb-000077
步骤1：合成中间体1-2Step 1: Synthesis of Intermediate 1-2
Figure PCTCN2022114183-appb-000078
Figure PCTCN2022114183-appb-000078
将中间体1-1(3.94g,27.7mmol)以及三乙胺(1.87g,18.5mmol,2.6mL)溶于乙腈(15mL)，反应在90℃搅拌16个小时。将反应液旋干得到粗品。向粗品中加入乙酸乙酯(50mL)和水(20mL)，分液，将有机相用无水硫酸钠干燥，过滤旋干得到黄色油状的中间体1-2(2.70g,产率:93.5％)。Intermediate 1-1 (3.94g, 27.7mmol) and triethylamine (1.87g, 18.5mmol, 2.6mL) were dissolved in acetonitrile (15mL), and the reaction was stirred at 90°C for 16 hours. The reaction solution was spin-dried to obtain the crude product. Add ethyl acetate (50mL) and water (20mL) to the crude product, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter and spin dry to obtain yellow oily intermediate 1-2 (2.70g, yield: 93.5% ).
步骤2：合成中间体1-3Step 2: Synthesis of Intermediates 1-3
Figure PCTCN2022114183-appb-000079
Figure PCTCN2022114183-appb-000079
将2,5-二溴苯酚(4.5g,17.9mmol),中间体1-2(7g,22.4mmol),三苯基膦(7.03g,26.8mmol)溶于四氢呋喃(50mL)搅拌并换气三次，然后滴加偶氮二甲酸二异丙酯(5.42g,26.8mmol)，在20℃且在氮气保护下搅拌16小时。将反应液旋干得到粗品，通过柱层析分离(石油醚：乙酸乙酯＝1/0到1/1)得到无色油状的中间体1-3(8.4g,产率：67.2％)。LCMS(ESI +):m/z 490.8[M-56+H] +. Dissolve 2,5-dibromophenol (4.5g, 17.9mmol), intermediate 1-2 (7g, 22.4mmol), triphenylphosphine (7.03g, 26.8mmol) in tetrahydrofuran (50mL), stir and ventilate three times , and then diisopropyl azodicarboxylate (5.42 g, 26.8 mmol) was added dropwise, and stirred at 20° C. for 16 hours under nitrogen protection. The reaction solution was spin-dried to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 1/0 to 1/1) to obtain intermediate 1-3 (8.4 g, yield: 67.2%) as a colorless oil. LCMS(ESI + ):m/z 490.8[M-56+H] + .
步骤3：合成中间体1-4Step 3: Synthesis of Intermediates 1-4
Figure PCTCN2022114183-appb-000080
Figure PCTCN2022114183-appb-000080
将中间体1-3(8.4g,15.4mmol)溶于甲醇(40mL)和水(10mL)中，加入碳酸钾(6.38g,46.1mmol)。反应液在20℃下搅拌16小时。向反应液中加入二氯甲烷(150mL)和水(60mL)，有机相分离，用无水硫酸钠干燥，在减压下过滤和浓缩得到粗品。采用柱层析(二氯甲烷/甲醇＝1/0到20/1)纯化。获得了无色油状的中间体1-4(6.65g，产率：95.1％)。LCMS(ESI +):m/z 450.91[M+H] +。 Intermediate 1-3 (8.4 g, 15.4 mmol) was dissolved in methanol (40 mL) and water (10 mL), and potassium carbonate (6.38 g, 46.1 mmol) was added. The reaction solution was stirred at 20°C for 16 hours. Dichloromethane (150 mL) and water (60 mL) were added to the reaction solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. Purification was performed by column chromatography (dichloromethane/methanol = 1/0 to 20/1). Intermediate 1-4 was obtained as a colorless oil (6.65 g, yield: 95.1%). LCMS (ESI + ): m/z 450.91 [M+H] + .
步骤4：合成中间体1-5Step 4: Synthesis of Intermediates 1-5
Figure PCTCN2022114183-appb-000081
Figure PCTCN2022114183-appb-000081
将中间体1-4(5.65g,12.6mmol),(R)-(+)-2,2-双(二苯膦基)-1,1-联萘 (1.09g,1.76mmol),碳酸铯(12.3g,37.7mmol)和醋酸钯(140.9mg,628umol)置于甲苯(80mL)中，用氮气换气三次，在85℃氮气气氛下搅拌16小时。将反应液过滤并用二氯甲烷(80mL)洗涤滤饼。然后进行浓缩，得到粗品。采用柱层析(石油醚/乙酸乙酯＝1/0到5/1)进行纯化。得到黄色油状的中间体1-5(1.07g,产率：23.1％)。LCMS(ESI+):m/z315[M-56+H] +. Intermediate 1-4 (5.65g, 12.6mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthalene (1.09g, 1.76mmol), cesium carbonate (12.3g, 37.7mmol) and palladium acetate (140.9mg, 628umol) were placed in toluene (80mL), purged with nitrogen three times, and stirred at 85°C under a nitrogen atmosphere for 16 hours. The reaction was filtered and the filter cake was washed with dichloromethane (80 mL). It was then concentrated to give the crude product. Purification was performed by column chromatography (petroleum ether/ethyl acetate=1/0 to 5/1). Intermediate 1-5 was obtained as yellow oil (1.07 g, yield: 23.1%). LCMS(ESI+):m/z315[M-56+H] + .
步骤5：合成中间体1-6Step 5: Synthesis of Intermediates 1-6
Figure PCTCN2022114183-appb-000082
Figure PCTCN2022114183-appb-000082
将中间体1-5(189mg,512umol)，氰化锌(300mg,2.55mmol)和1,1-双(二苯基磷)二茂铁氯化钯(37.4mg,51.2umol)置于N,N-二甲基甲酰胺(3mL)中，用氮气换气三次，用微波在130℃下搅拌2小时。反应液用乙酸乙酯(30mL)稀释，加水(40mL)，用30mL乙酸乙酯萃取两次。合并的有机层用饱和食盐水(10mL)洗涤两次，用无水硫酸钠干燥，过滤，减压浓缩，得到粗品。采用柱层析(石油醚/乙酸乙酯＝1/0到5/1)进行纯化，得到无色油状的中间体1-6(100mg,产率：61.3％)。LCMS(ESI+):m/z316.3[M+H] +. Intermediate 1-5 (189mg, 512umol), zinc cyanide (300mg, 2.55mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (37.4mg, 51.2umol) were placed under N, In N-dimethylformamide (3 mL), purged with nitrogen three times, stirred at 130° C. for 2 hours by microwave. The reaction solution was diluted with ethyl acetate (30 mL), added with water (40 mL), and extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification was performed by column chromatography (petroleum ether/ethyl acetate=1/0 to 5/1) to obtain intermediate 1-6 (100 mg, yield: 61.3%) as a colorless oil. LCMS(ESI+):m/z316.3[M+H] + .
步骤：合成中间体1-7Step: Synthesis of Intermediates 1-7
Figure PCTCN2022114183-appb-000083
Figure PCTCN2022114183-appb-000083
将中间体1-6(100mg,317.09umol)溶于二氯甲烷(1mL)，加入盐酸/二氧六环(4M,80uL)，在15℃搅拌2小时。将反应液旋干得到中间体1-7(76mg,粗品,HCl)，性状为黄色固体。LCMS(ESI +):m/z 216.2[M+H] +. Intermediate 1-6 (100mg, 317.09umol) was dissolved in dichloromethane (1mL), hydrochloric acid/dioxane (4M, 80uL) was added, and stirred at 15°C for 2 hours. The reaction solution was spin-dried to obtain Intermediate 1-7 (76 mg, crude product, HCl) as a yellow solid. LCMS(ESI + ):m/z 216.2[M+H] + .
步骤7：合成中间体1-8Step 7: Synthesis of Intermediates 1-8
Figure PCTCN2022114183-appb-000084
Figure PCTCN2022114183-appb-000084
将α,α′-二氯对二甲苯(159mg,906umol)溶于N,N-二甲基甲酰胺(1mL)和乙腈(1mL)，加入N,N-二异丙基乙胺(117mg,906umol,)和中间体1-7(76mg,302umol)。反应液在60℃搅拌1.5小时。将反应液中的乙腈旋掉，然后加入水(10mL)稀释，并用10mL乙酸乙酯萃取三次。将有机相合并，用10mL饱和食盐水洗两次，用无水硫酸钠干燥，过滤，旋干得到粗品。采用柱层析(石油醚/乙酸乙酯＝1/0到1/1)进行纯化，得到黄色油状的中间体1-8(65mg,产率：53.5％)。Dissolve α,α'-dichloro-p-xylene (159mg, 906umol) in N,N-dimethylformamide (1mL) and acetonitrile (1mL), add N,N-diisopropylethylamine (117mg, 906umol,) and intermediate 1-7 (76mg, 302umol). The reaction solution was stirred at 60°C for 1.5 hours. The acetonitrile in the reaction solution was spun off, then diluted with water (10 mL), and extracted three times with 10 mL of ethyl acetate. The organic phases were combined, washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. Purification was performed by column chromatography (petroleum ether/ethyl acetate=1/0 to 1/1) to obtain Intermediate 1-8 (65 mg, yield: 53.5%) as a yellow oil.
LCMS(ESI +):m/z 354.01[M+H] +. LCMS(ESI + ):m/z 354.01[M+H] + .
步骤8：合成中间体1-9Step 8: Synthesis of Intermediates 1-9
Figure PCTCN2022114183-appb-000085
Figure PCTCN2022114183-appb-000085
将中间体1-8(65mg,184umol)和中间体1-10(61.4mg,184umol)溶于N,N-二甲基甲酰胺(1.5mL)，加入碳酸钾(50.8mg,367umol)。反应液在45℃搅拌16小时。向反应液中加入水(10mL)和乙酸乙酯(30mL)，将有机相分离出来，用10mL水洗两次，用无水硫酸钠干燥，过滤，旋干得到粗品。采用柱层析(二氯甲烷/甲醇＝1/0到10/1)进行纯化，得到无色油状的中间体1-9(127mg,粗品)，粗品直接用于下一步。Intermediate 1-8 (65mg, 184umol) and Intermediate 1-10 (61.4mg, 184umol) were dissolved in N,N-dimethylformamide (1.5mL), and potassium carbonate (50.8mg, 367umol) was added. The reaction was stirred at 45°C for 16 hours. Water (10 mL) and ethyl acetate (30 mL) were added to the reaction solution, the organic phase was separated, washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. Purification was carried out by column chromatography (dichloromethane/methanol=1/0 to 10/1) to obtain intermediate 1-9 (127 mg, crude product) as a colorless oil, which was directly used in the next step.
LCMS(ESI +):m/z 652.7[M+H] +. LCMS(ESI + ):m/z 652.7[M+H] + .
步骤9：合成化合物1Step 9: Synthesis of compound 1
Figure PCTCN2022114183-appb-000086
Figure PCTCN2022114183-appb-000086
将中间体1-9(127mg,195umol)和苯磺酸(40.1mg,253umol)溶于乙腈(5mL)，用氮气置换三次。反应液在85℃搅拌16小时。将反应液旋干，通过高效液相色谱柱分离(甲酸条件)得到粗品，采用柱层析(二氯甲烷/甲醇＝1/0～10/1)进行纯化，再用乙腈(3mL)打浆，得到白色固体的化合物1(18mg,产率：16.0％)。Intermediate 1-9 (127mg, 195umol) and benzenesulfonic acid (40.1mg, 253umol) were dissolved in acetonitrile (5mL) and replaced with nitrogen three times. The reaction was stirred at 85°C for 16 hours. The reaction solution was spin-dried, separated by high-performance liquid chromatography (formic acid condition) to obtain the crude product, purified by column chromatography (dichloromethane/methanol=1/0-10/1), and then slurried with acetonitrile (3mL). Compound 1 (18 mg, yield: 16.0%) was obtained as a white solid.
LCMS(ESI +):m/z 578.1[M+H] +. LCMS(ESI + ):m/z 578.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.99(br s,1H),7.52-7.44(m,3H),7.38-7.31(m,4H),7.26-7.19(m,1H),7.08(d,J＝2.0Hz,1H),6.96(d,J＝8.8Hz,1H),5.24(s,2H),5.16-5.04(m,1H),4.47-4.35(m,1H),4.31-4.19(m,2H),3.94-3.80(m,2H),3.63-3.46(m,2H),3.28-3.17(m,1H),2.97-2.73(m,4H),2.63-2.53(m,1H),2.47-2.36(m,1H)2.19-2.08(m,1H),2.03-1.92(m,1H),1.77(t,J＝10.8Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.99(br s,1H),7.52-7.44(m,3H),7.38-7.31(m,4H),7.26-7.19(m,1H),7.08( d,J=2.0Hz,1H),6.96(d,J=8.8Hz,1H),5.24(s,2H),5.16-5.04(m,1H),4.47-4.35(m,1H),4.31-4.19 (m,2H),3.94-3.80(m,2H),3.63-3.46(m,2H),3.28-3.17(m,1H),2.97-2.73(m,4H),2.63-2.53(m,1H) ,2.47-2.36(m,1H),2.19-2.08(m,1H),2.03-1.92(m,1H),1.77(t,J=10.8Hz,1H).
实施例1-A：化合物1-AExample 1-A: Compound 1-A
Figure PCTCN2022114183-appb-000087
Figure PCTCN2022114183-appb-000087
LCMS(ESI+):m/z 578.1[M+H] +. LCMS(ESI+):m/z 578.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),7.52-7.44(m,3H),7.39-7.31(m,4H),7.25-7.20(m,1H),7.08(d,J＝2.0Hz,1H),6.96(d,J＝8.8Hz,1H),5.24(s,2H),5.17-5.07(m,1H),4.47-4.35(m,1H),4.32-4.21(m,2H),3.91-3.81(m,2H),3.67-3.43(m,2H),3.26(s,1H),2.99-2.85 (m,3H),2.84-2.76(m,1H),2.59(br s,1H),2.45-2.38(m,1H),2.20-2.09(m,1H),2.04-1.92(m,1H),1.83-1.73(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H),7.52-7.44(m,3H),7.39-7.31(m,4H),7.25-7.20(m,1H),7.08(d ,J=2.0Hz,1H),6.96(d,J=8.8Hz,1H),5.24(s,2H),5.17-5.07(m,1H),4.47-4.35(m,1H),4.32-4.21( m,2H),3.91-3.81(m,2H),3.67-3.43(m,2H),3.26(s,1H),2.99-2.85(m,3H),2.84-2.76(m,1H),2.59( br s,1H),2.45-2.38(m,1H),2.20-2.09(m,1H),2.04-1.92(m,1H),1.83-1.73(m,1H).
实施例1-B：化合物1-BExample 1-B: Compound 1-B
Figure PCTCN2022114183-appb-000088
Figure PCTCN2022114183-appb-000088
LCMS(ESI+):m/z 578.1[M+H] +. LCMS(ESI+):m/z 578.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),8.18(s,0.889H),7.59-7.41(m,3H),7.40-7.28(m,4H),7.22(dd,J＝1.6,8.4Hz,1H),7.08(d,J＝1.6Hz,1H),6.96(d,J＝8.4Hz,1H),5.24(s,2H),5.11(dd,J＝5.2,13.2Hz,1H),4.49-4.33(m,1H),4.32-4.18(m,2H),3.92-3.80(m,2H),3.55-3.52(m,2H),3.31-3.31(m,1H),2.92-2.78(m,4H),2.61-2.55(m,1H),2.44-2.38(m,1H),2.17-2.07(m,1H),2.03-1.92(m,1H),1.77(t,J＝10.8Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H),8.18(s,0.889H),7.59-7.41(m,3H),7.40-7.28(m,4H),7.22(dd, J=1.6,8.4Hz,1H),7.08(d,J=1.6Hz,1H),6.96(d,J=8.4Hz,1H),5.24(s,2H),5.11(dd,J=5.2,13.2 Hz,1H),4.49-4.33(m,1H),4.32-4.18(m,2H),3.92-3.80(m,2H),3.55-3.52(m,2H),3.31-3.31(m,1H), 2.92-2.78(m,4H),2.61-2.55(m,1H),2.44-2.38(m,1H),2.17-2.07(m,1H),2.03-1.92(m,1H),1.77(t,J =10.8Hz,1H).
实施例2到11用实施例1的类似方法合成Embodiment 2 to 11 are synthesized with the similar method of embodiment 1
实施例2：化合物2Example 2: Compound 2
Figure PCTCN2022114183-appb-000089
Figure PCTCN2022114183-appb-000089
LCMS(ESI+):m/z 585.1[M+H] +. LCMS(ESI+):m/z 585.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),7.54-7.43(m,3H),7.39-7.30(m,4H),6.98-6.90(m,1H),6.76-6.68(m,1H),6.63-6.56(m,1H), 5.23(s,2H),5.17-5.06(m,1H),4.54-4.36(m,2H),4.32-4.20(m,1H),4.15-4.04(m,1H),3.53(s,2H),3.14-2.82(m,4H),2.73-2.64(m,1H),2.55(s,1H),2.46-2.41(m,1H),2.36-2.25(m,2H),2.23-2.15(m,1H),2.07-1.94(m,2H),1.92-1.82(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H),7.54-7.43(m,3H),7.39-7.30(m,4H),6.98-6.90(m,1H),6.76-6.68 (m,1H),6.63-6.56(m,1H),5.23(s,2H),5.17-5.06(m,1H),4.54-4.36(m,2H),4.32-4.20(m,1H),4.15 -4.04(m,1H),3.53(s,2H),3.14-2.82(m,4H),2.73-2.64(m,1H),2.55(s,1H),2.46-2.41(m,1H),2.36 -2.25(m,2H),2.23-2.15(m,1H),2.07-1.94(m,2H),1.92-1.82(m,1H).
实施例3：化合物3Example 3: Compound 3
Figure PCTCN2022114183-appb-000090
Figure PCTCN2022114183-appb-000090
LCMS(ESI+):m/z 596.1[M+H] +. LCMS(ESI+):m/z 596.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.99(s,1H),7.46(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),7.33-7.28(m,1H),7.25-7.20(m,1H),7.15-7.05(m,2H),6.96(d,J＝8.8Hz,1H),5.24(s,2H),5.17-5.05(m,1H),4.45-4.34(m,1H),4.33-4.16(m,2H),3.93-3.80(m,2H),3.62-3.47(m,2H),3.27-3.22(m,1H),2.96-2.84(m,3H),2.83-2.76(m,1H),2.58(br s,1H),2.44(br s,1H),2.19-2.09(m,1H),2.03-1.93(m,1H),1.86-1.71(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ10.99(s, 1H), 7.46(d, J=8.0Hz, 2H), 7.36(d, J=8.0Hz, 2H), 7.33-7.28(m, 1H),7.25-7.20(m,1H),7.15-7.05(m,2H),6.96(d,J＝8.8Hz,1H),5.24(s,2H),5.17-5.05(m,1H),4.45 -4.34(m,1H),4.33-4.16(m,2H),3.93-3.80(m,2H),3.62-3.47(m,2H),3.27-3.22(m,1H),2.96-2.84(m, 3H),2.83-2.76(m,1H),2.58(br s,1H),2.44(br s,1H),2.19-2.09(m,1H),2.03-1.93(m,1H),1.86-1.71( m,1H).
实施例4：化合物4Example 4: Compound 4
Figure PCTCN2022114183-appb-000091
Figure PCTCN2022114183-appb-000091
步骤1：合成中间体4-4Step 1: Synthesis of Intermediate 4-4
Figure PCTCN2022114183-appb-000092
Figure PCTCN2022114183-appb-000092
将中间体1-7(109mg,387umol)和2-甲基-4-羟甲基苯甲醛溶解在二氯甲 烷(8mL)中，并向该溶液中加入无水三乙胺(191mg,1.89mmol),然后再加入无水乙酸(114mg,1.89mmol)调节pH值至5～6,混合液在室温搅拌0.5小时。然后再向该混合液中加入醋酸硼氢化钠(240mg,1.13mmol)并室温反应16小时。反应液加入水(10mL)淬灭，并使用乙酸乙酯萃取(30mL*3)，合并有机相，使用无水硫酸钠干燥，过滤，旋干，得到粗品。所得粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到3：1)得到黄色油状中间体4-4(200mg,66％yield)。LCMS(ESI+):m/z 350.06[M+H]Intermediate 1-7 (109mg, 387umol) and 2-methyl-4-hydroxymethylbenzaldehyde were dissolved in dichloromethane (8mL), and anhydrous triethylamine (191mg, 1.89mmol ), and then added anhydrous acetic acid (114mg, 1.89mmol) to adjust the pH value to 5-6, and the mixture was stirred at room temperature for 0.5 hours. Then sodium acetate borohydride (240 mg, 1.13 mmol) was added to the mixture and reacted at room temperature for 16 hours. The reaction solution was quenched by adding water (10 mL), and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The obtained crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to obtain yellow oily intermediate 4-4 (200 mg, 66% yield). LCMS(ESI+):m/z 350.06[M+H]
步骤2：合成中间体4-5Step 2: Synthesis of Intermediates 4-5
Figure PCTCN2022114183-appb-000093
Figure PCTCN2022114183-appb-000093
将中间体4-4(200mg,572umol)溶解在二氯甲烷(5mL)中，并向溶液中加入氯化亚砜(340mg,2.86mmol)。反应液室温下搅拌1小时。在减压下旋干浓缩得到白色固体中间体4-5(185mg,粗品)。Intermediate 4-4 (200 mg, 572 umol) was dissolved in dichloromethane (5 mL), and thionyl chloride (340 mg, 2.86 mmol) was added to the solution. The reaction solution was stirred at room temperature for 1 hour. Spinning to dryness and concentrating under reduced pressure gave white solid intermediate 4-5 (185 mg, crude product).
Figure PCTCN2022114183-appb-000094
Figure PCTCN2022114183-appb-000094
LCMS(ESI +):m/z 592.1[M+H] +. LCMS(ESI + ):m/z 592.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),7.48(d,J＝8.00Hz,1H),7.31-7.35(m,2H),7.26 7.30(m,3H),7.22(d,J＝1.2Hz,1H),7.08(d,J＝2.0Hz,1H),6.96(d,J＝8.8Hz,1H),5.19(s,2H),5.11(d,J＝13.2Hz, 1H),4.38-4.53(m,1H),4.21-4.32(m,2H),3.79-3.95(m,2H),3.43-3.55(m,2H),3.21(br s,1H),2.89(br s,2H),2.72-2.83(m,2H),2.61-2.54(m,1H),2.41-2.47(m,1H),2.35(s,3H),2.12-2.22(m,1H),1.98(d,J＝8.00Hz,1H),1.81(t,J＝10.8Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H),7.48(d,J=8.00Hz,1H),7.31-7.35(m,2H),7.26 7.30(m,3H),7.22 (d, J=1.2Hz, 1H), 7.08(d, J=2.0Hz, 1H), 6.96(d, J=8.8Hz, 1H), 5.19(s, 2H), 5.11(d, J=13.2Hz , 1H),4.38-4.53(m,1H),4.21-4.32(m,2H),3.79-3.95(m,2H),3.43-3.55(m,2H),3.21(br s,1H),2.89( br s,2H),2.72-2.83(m,2H),2.61-2.54(m,1H),2.41-2.47(m,1H),2.35(s,3H),2.12-2.22(m,1H),1.98 (d,J=8.00Hz,1H),1.81(t,J=10.8Hz,1H).
实施例4-A：化合物4-AExample 4-A: Compound 4-A
Figure PCTCN2022114183-appb-000095
Figure PCTCN2022114183-appb-000095
LCMS(ESI +):m/z 592.1[M+H] +. LCMS(ESI + ):m/z 592.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H)7.42-7.57(m,1H),7.13-7.35(m,6H),7.08(d,J＝2.0Hz,1H),6.96(d,J＝8.4Hz,1H),5.19(s,2H),5.11(d,J＝13.2Hz,1H),4.41(d,J＝18.4Hz,1H),4.15-4.29(m,2H),3.80-3.96(m,2H),3.44-3.54(m,2H),3.18-3.21(m,1H),2.83-2.97(m,2H),2.75(d,J＝16.0Hz,2H),2.52-2.53(m,1H),2.44-2.42(m,2H),2.35(s,3H),2.23-2.11(m,1H),1.92-2.03(m,1H),1.77-1.87(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H)7.42-7.57(m,1H),7.13-7.35(m,6H),7.08(d,J＝2.0Hz,1H),6.96 (d, J=8.4Hz, 1H), 5.19(s, 2H), 5.11(d, J=13.2Hz, 1H), 4.41(d, J=18.4Hz, 1H), 4.15-4.29(m, 2H) ,3.80-3.96(m,2H),3.44-3.54(m,2H),3.18-3.21(m,1H),2.83-2.97(m,2H),2.75(d,J＝16.0Hz,2H),2.52 -2.53(m,1H),2.44-2.42(m,2H),2.35(s,3H),2.23-2.11(m,1H),1.92-2.03(m,1H),1.77-1.87(m,1H) .
实施例5：化合物5Embodiment 5: Compound 5
Figure PCTCN2022114183-appb-000096
Figure PCTCN2022114183-appb-000096
LCMS(ESI +):m/z 579.2[M+H] +. LCMS(ESI + ):m/z 579.2[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),8.65(s,1H),7.91(dd,J＝ 2.0,8.0Hz,1H),7.57-7.45(m,2H),7.36(dd,J＝8.0,10.2Hz,2H),7.23(dd,J＝2.0,8.4Hz,1H),7.09(d,J＝2.0Hz,1H),6.97(d,J＝8.8Hz,1H),5.29(s,2H),5.11(dd,J＝5.2,13.6Hz,1H),4.55-4.37(m,1H),4.33-4.20(m,2H),3.97-3.82(m,2H),3.73-3.58(m,2H),3.26-3.22(m,1H),3.00-2.86(m,3H),2.86-2.76(m,1H),2.53-2.52(m,1H),2.43-2.43(m,1H),2.25-2.19(m,1H),2.03-1.93(m,1H),1.91-1.80(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H),8.65(s,1H),7.91(dd,J＝2.0,8.0Hz,1H),7.57-7.45(m,2H), 7.36(dd, J=8.0,10.2Hz,2H),7.23(dd,J=2.0,8.4Hz,1H),7.09(d,J=2.0Hz,1H),6.97(d,J=8.8Hz,1H ),5.29(s,2H),5.11(dd,J＝5.2,13.6Hz,1H),4.55-4.37(m,1H),4.33-4.20(m,2H),3.97-3.82(m,2H), 3.73-3.58(m,2H),3.26-3.22(m,1H),3.00-2.86(m,3H),2.86-2.76(m,1H),2.53-2.52(m,1H),2.43-2.43(m ,1H),2.25-2.19(m,1H),2.03-1.93(m,1H),1.91-1.80(m,1H).
实施例6:化合物6Embodiment 6: Compound 6
Figure PCTCN2022114183-appb-000097
Figure PCTCN2022114183-appb-000097
LCMS(ESI +):m/z 614.1[M+H] +. LCMS(ESI + ):m/z 614.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),7.62-7.54(m,1H),7.44-7.37(m,1H),7.27-7.20(m,3H),7.17-7.13(m,1H),7.11-7.07(m,1H),7.00-6.95(m,1H),5.32-5.24(m,2H),5.14-5.05(m,1H),4.40-4.14(m,3H),3.95-3.81(m,2H),3.60-3.53(m,2H),3.29-3.27(m,1H),2.93-2.79(m,4H),2.60-2.53(m,1H),2.43-2.37(m,1H),2.23-2.13(m,1H),2.01-1.91(m,1H),1.85-1.73(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H),7.62-7.54(m,1H),7.44-7.37(m,1H),7.27-7.20(m,3H),7.17-7.13 (m,1H),7.11-7.07(m,1H),7.00-6.95(m,1H),5.32-5.24(m,2H),5.14-5.05(m,1H),4.40-4.14(m,3H) ,3.95-3.81(m,2H),3.60-3.53(m,2H),3.29-3.27(m,1H),2.93-2.79(m,4H),2.60-2.53(m,1H),2.43-2.37( m,1H),2.23-2.13(m,1H),2.01-1.91(m,1H),1.85-1.73(m,1H).
实施例7:化合物7Embodiment 7: Compound 7
Figure PCTCN2022114183-appb-000098
Figure PCTCN2022114183-appb-000098
LCMS(ESI+):m/z 596.1[M+H] +. LCMS(ESI+):m/z 596.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),7.60-7.48(m,2H),7.40(d,J＝8.4Hz,1H),7.35(d,J＝7.6Hz,1H),7.25-7.18(m,3H),7.10-7.05(m,1H),6.97(d,J＝8.8Hz,1H),5.27(s,2H),5.14-5.07(m,1H),4.42-4.34(m,1H),4.32-4.15(m,2H),3.92-3.82(m,2H),3.69-3.50(m,2H),3.30-3.28(m,1H),2.97-2.76(m,4H),2.58-2.54(m,1H),2.44-2.39(m,1H),2.21-2.11(m,1H),2.01-1.91(m,1H),1.84-1.74(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ10.98(s, 1H), 7.60-7.48(m, 2H), 7.40(d, J=8.4Hz, 1H), 7.35(d, J=7.6Hz, 1H), 7.25-7.18(m, 3H), 7.10-7.05(m, 1H), 6.97(d, J＝8.8Hz, 1H), 5.27(s, 2H), 5.14-5.07(m, 1H), 4.42 -4.34(m,1H),4.32-4.15(m,2H),3.92-3.82(m,2H),3.69-3.50(m,2H),3.30-3.28(m,1H),2.97-2.76(m, 4H),2.58-2.54(m,1H),2.44-2.39(m,1H),2.21-2.11(m,1H),2.01-1.91(m,1H),1.84-1.74(m,1H).
实施例7-A:化合物7-AEmbodiment 7-A: compound 7-A
Figure PCTCN2022114183-appb-000099
Figure PCTCN2022114183-appb-000099
LCMS(ESI +):m/z 596.2[M+H] +. LCMS(ESI + ):m/z 596.2[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),7.60-7.48(m,2H),7.43-7.32(m,2H),7.27-7.17(m,3H),7.08(m,1H),6.96(m,1H),5.27(s,2H),5.15-5.04(m,1H),4.40-4.19(m,3H),3.91-3.81(m,2H),3.58-3.54(m,2H),3.28-3.22(m,1H),2.95-2.78(m,4H),2.61-2.53(m,1H),2.47-2.39(m,1H),2.20-2.12(m,1H),2.00-1.94(m,1H),1.83-1.76(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(s,1H),7.60-7.48(m,2H),7.43-7.32(m,2H),7.27-7.17(m,3H),7.08(m ,1H),6.96(m,1H),5.27(s,2H),5.15-5.04(m,1H),4.40-4.19(m,3H),3.91-3.81(m,2H),3.58-3.54(m ,2H),3.28-3.22(m,1H),2.95-2.78(m,4H),2.61-2.53(m,1H),2.47-2.39(m,1H),2.20-2.12(m,1H),2.00 -1.94(m,1H),1.83-1.76(m,1H).
实施例8：化合物8Example 8: Compound 8
Figure PCTCN2022114183-appb-000100
Figure PCTCN2022114183-appb-000100
LCMS(ESI+):m/z 597.4[M+H]+.LCMS(ESI+):m/z 597.4[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ10.99(s,1H),8.65(d,J＝1.6Hz,1H),7.92(dd,J＝2.0,8.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.36(dd,J＝2.0,11.6Hz,1H),7.23(dd,J＝2.0,8.4Hz,1H),7.15(dd,J＝2.0,7.2Hz,1H),7.09(d,J＝2.0Hz,1H),6.98(d,J＝8.8Hz,1H),5.30(s,2H),5.11(dd,J＝5.2,13.2Hz,1H),4.44-4.37(m,1H),4.32-4.19(m,2H),3.94-3.81(m,2H),3.75-3.62(m,2H),3.47(s,2H),2.96-2.93(m,1H),2.93-2.89(m,1H),2.87-2.81(m,1H),2.59-2.55(m,1H),2.44-2.42(m,1H),2.29-2.20(m,1H),2.03-1.94(m,1H),1.88(t,J＝10.8Hz,1H). 1 H NMR (400MHz, DMSO-d 6 )δ10.99(s, 1H), 8.65(d, J=1.6Hz, 1H), 7.92(dd, J=2.0, 8.0Hz, 1H), 7.53(d, J＝8.0Hz, 1H), 7.36(dd, J＝2.0, 11.6Hz, 1H), 7.23(dd, J＝2.0, 8.4Hz, 1H), 7.15(dd, J＝2.0, 7.2Hz, 1H), 7.09(d, J=2.0Hz, 1H), 6.98(d, J=8.8Hz, 1H), 5.30(s, 2H), 5.11(dd, J=5.2, 13.2Hz, 1H), 4.44-4.37(m ,1H),4.32-4.19(m,2H),3.94-3.81(m,2H),3.75-3.62(m,2H),3.47(s,2H),2.96-2.93(m,1H),2.93-2.89 (m,1H),2.87-2.81(m,1H),2.59-2.55(m,1H),2.44-2.42(m,1H),2.29-2.20(m,1H),2.03-1.94(m,1H) ,1.88(t,J=10.8Hz,1H).
实施例9:化合物9Embodiment 9: Compound 9
Figure PCTCN2022114183-appb-000101
Figure PCTCN2022114183-appb-000101
步骤1:合成中间体9-2Step 1: Synthesis of intermediate 9-2
Figure PCTCN2022114183-appb-000102
Figure PCTCN2022114183-appb-000102
将中间体9-1(5.00g,24.6mmol)溶解在四氢呋喃(28mL)中，置换氮 气，并降温至-78℃，然后将二异丙基氨基锂(2M,13.55mL)缓慢加入至混合液中，保持温度在-70℃以下，反应30分钟。然后将丙炔酸乙酯(2.28g,27.1mmol)缓慢加入混合液中，反应30分钟，移除干冰浴，室温下继续反应1小时。反应液用50mL饱和氯化铵溶液淬灭，使用100mL乙酸乙酯萃取三次，合并有机相，使用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干，得到粗品。所得粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到4：1)得到无色油状中间体9-2(4.00g,产率：53.9％)。Intermediate 9-1 (5.00g, 24.6mmol) was dissolved in tetrahydrofuran (28mL), nitrogen was replaced, and the temperature was lowered to -78°C, then lithium diisopropylamide (2M, 13.55mL) was slowly added to the mixture , keep the temperature below -70°C, and react for 30 minutes. Then ethyl propiolate (2.28 g, 27.1 mmol) was slowly added to the mixture, reacted for 30 minutes, removed the dry ice bath, and continued to react for 1 hour at room temperature. The reaction solution was quenched with 50 mL of saturated ammonium chloride solution, extracted three times with 100 mL of ethyl acetate, the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The obtained crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 4:1) to obtain intermediate 9-2 (4.00 g, yield: 53.9%) as a colorless oil.
1H NMR(400MHz,DMSO-d 6)δ7.74-7.68(m,1H),7.67-7.60(m,1H),7.31-7.23(m,1H),6.81-6.74(m,1H),5.79(d,J＝6.0Hz,1H),4.18(q,J＝7.2Hz,2H),1.25-1.20(m,3H). 1 H NMR (400MHz,DMSO-d 6 )δ7.74-7.68(m,1H),7.67-7.60(m,1H),7.31-7.23(m,1H),6.81-6.74(m,1H),5.79 (d,J=6.0Hz,1H),4.18(q,J=7.2Hz,2H),1.25-1.20(m,3H).
步骤2:合成中间体9-3Step 2: Synthesis of intermediate 9-3
Figure PCTCN2022114183-appb-000103
Figure PCTCN2022114183-appb-000103
将中间体9-2(2.82g,9.37mmol)溶解在二氧六环(6mL)中，并向溶液中加入三乙胺(2.37g，23.41mL)，混合液加热至60℃搅拌12个小时。反应液冷却至室温，倾倒入30mL水中，使用20mL乙酸乙酯萃取三次，收集有机相，使用饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干，得到粗品。所得粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到10：1)得到黄色油状中间体9-3(2.08g,产率：73.8％)。Intermediate 9-2 (2.82g, 9.37mmol) was dissolved in dioxane (6mL), and triethylamine (2.37g, 23.41mL) was added to the solution, and the mixture was heated to 60°C and stirred for 12 hours . The reaction solution was cooled to room temperature, poured into 30 mL of water, extracted three times with 20 mL of ethyl acetate, collected the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The obtained crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain yellow oily intermediate 9-3 (2.08g, yield: 73.8%).
1H NMR(400MHz,CDCl 3)δ7.93(m,1H),7.75-7.62(m,2H),7.09(m,1H),6.85(m,1H),4.30(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ7.93(m,1H),7.75-7.62(m,2H),7.09(m,1H),6.85(m,1H),4.30(q,J=7.2Hz, 2H), 1.35(t, J=7.2Hz, 3H).
步骤3:合成中间体9-4Step 3: Synthesis of intermediate 9-4
Figure PCTCN2022114183-appb-000104
Figure PCTCN2022114183-appb-000104
将中间体9-3(2.00g,6.64mmol)溶解在N,N-二甲基甲酰胺(8mL)中，并向溶液中加入无水乙二胺(520mg,8.63mmol),混合液加热至60℃搅拌18小时。反应液冷却至室温，溶解在10mL乙酸乙酯中，过滤得到滤饼，干燥得到黄色固体中间体9-4(1.6g,产率：69.4％)。Intermediate 9-3 (2.00g, 6.64mmol) was dissolved in N,N-dimethylformamide (8mL), and anhydrous ethylenediamine (520mg, 8.63mmol) was added to the solution, and the mixture was heated to Stir at 60°C for 18 hours. The reaction solution was cooled to room temperature, dissolved in 10 mL of ethyl acetate, filtered to obtain a filter cake, and dried to obtain a yellow solid intermediate 9-4 (1.6 g, yield: 69.4%).
1H NMR(400MHz,DMSO-d 6)δ8.25-8.16(m,1H),7.78(d,J＝2.8Hz,1H),7.63(dd,J＝2.8,9.2Hz,1H),7.16(d,J＝9.2Hz,1H),4.17-4.05(m,2H),3.45-3.40(m,1H),3.32-3.27(m,1H),3.19-3.08(m,1H),2.92-2.76(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.25-8.16 (m, 1H), 7.78 (d, J = 2.8Hz, 1H), 7.63 (dd, J = 2.8, 9.2Hz, 1H), 7.16 ( d,J＝9.2Hz,1H),4.17-4.05(m,2H),3.45-3.40(m,1H),3.32-3.27(m,1H),3.19-3.08(m,1H),2.92-2.76( m,2H).
步骤4:合成中间体9-5Step 4: Synthesis of intermediate 9-5
Figure PCTCN2022114183-appb-000105
Figure PCTCN2022114183-appb-000105
中间体9-4(1.50g,5.08mmol)溶解在三氟乙酸(18mL)，并向溶液中加入三乙基硅氢(3.28g,28.2mmol)。反应液在25℃下搅拌8小时。减压旋干得到白色固体中间体9-5(400mg,产率：26.6％)。粗品没有进一步纯化，直接用于下一步反应。Intermediate 9-4 (1.50 g, 5.08 mmol) was dissolved in trifluoroacetic acid (18 mL), and triethylsilylhydrogen (3.28 g, 28.2 mmol) was added to the solution. The reaction solution was stirred at 25°C for 8 hours. Spin-dry under reduced pressure to obtain white solid intermediate 9-5 (400 mg, yield: 26.6%). The crude product was directly used in the next reaction without further purification.
1H NMR(400M Hz,DMSO-d 6)δ7.92(s,1H),7.24-7.06(m,2H),6.80(d,J＝8.8Hz,1H),3.92-3.81(m,1H),3.77-3.69(m,1H),3.30-3.07(m,3H),2.80-2.69(m,1H),2.68-2.59(m,1H),2.23-2.09(m,1H),1.96-1.86(m,1H). 1 H NMR (400M Hz,DMSO-d 6 )δ7.92(s,1H),7.24-7.06(m,2H),6.80(d,J＝8.8Hz,1H),3.92-3.81(m,1H) ,3.77-3.69(m,1H),3.30-3.07(m,3H),2.80-2.69(m,1H),2.68-2.59(m,1H),2.23-2.09(m,1H),1.96-1.86( m,1H).
步骤5:合成中间体9-6Step 5: Synthesis of Intermediate 9-6
Figure PCTCN2022114183-appb-000106
Figure PCTCN2022114183-appb-000106
中间体9-5(400mg,1.42mmol)溶解在四氢呋喃(10mL)中，置换氮气，25℃下向溶液中缓慢滴加硼烷四氢呋喃溶液(1M,4.27mL)，混合液升温至60℃，搅拌2小时。反应液冷却至25℃，并置于冰水浴中降温至0℃，逐滴滴加20mL甲醇淬灭反应。室温下搅拌超过30分钟，旋干，得到粗品。所得粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到1：4)得到白色固体中间体9-6(200mg,产率：45.8％)。Intermediate 9-5 (400mg, 1.42mmol) was dissolved in tetrahydrofuran (10mL), nitrogen was replaced, borane tetrahydrofuran solution (1M, 4.27mL) was slowly added dropwise to the solution at 25°C, the mixture was heated to 60°C, stirred 2 hours. The reaction solution was cooled to 25 °C, and placed in an ice-water bath to cool down to 0 °C, and 20 mL of methanol was added dropwise to quench the reaction. Stir at room temperature for more than 30 minutes and spin dry to obtain the crude product. The obtained crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 1:4) to obtain white solid intermediate 9-6 (200 mg, yield: 45.8%).
1H NMR(400MHz,DMSO-d 6)δ7.22-7.09(m,2H),6.78(d,J＝8.8Hz,1H),3.88-3.75(m,1H),3.10-2.92(m,3H),2.84-2.53(m,4H),2.30-2.17(m,1H),1.95-1.81(m,1H),1.65-1.48(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ7.22-7.09(m,2H),6.78(d,J＝8.8Hz,1H),3.88-3.75(m,1H),3.10-2.92(m,3H ),2.84-2.53(m,4H),2.30-2.17(m,1H),1.95-1.81(m,1H),1.65-1.48(m,1H).
步骤6:合成中间体9-7Step 6: Synthesis of intermediate 9-7
Figure PCTCN2022114183-appb-000107
Figure PCTCN2022114183-appb-000107
中间体9-6(200mg,0.750mmol)溶解在二氯甲烷(5mL)中，向溶液中加入二碳酸二叔丁酯(245mg,1.12mmol)和4-二甲氨基吡啶(19mg,0.15mmol)。反应液在25℃下反应8小时。旋干，得粗品，所得粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到4：1)得到白色固体中间体9-7(240mg,产率：82.1％)。Intermediate 9-6 (200mg, 0.750mmol) was dissolved in dichloromethane (5mL), and di-tert-butyl dicarbonate (245mg, 1.12mmol) and 4-dimethylaminopyridine (19mg, 0.15mmol) were added to the solution . The reaction solution was reacted at 25° C. for 8 hours. The crude product was spin-dried to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 4:1) to obtain white solid intermediate 9-7 (240 mg, yield: 82.1%).
LCMS(ESI +):m/z 366.92[M+H] +. LCMS(ESI + ):m/z 366.92[M+H] + .
步骤7:合成中间体9-8Step 7: Synthesis of Intermediate 9-8
Figure PCTCN2022114183-appb-000108
Figure PCTCN2022114183-appb-000108
中间体9-7(150mg,0.410mmol)，氰化锌(72.0mg,0.620mmol)溶解在N,N-二甲基甲酰胺(3mL)中，置换氮气，向溶液中加入三(二亚苄基丙酮)二钯(187mg,0.210mmol)和2-二环己基亚膦基-2,6-二甲氧基联苯(201mg,0.490mmol)，反应液氮气氛围下加热至100℃搅拌4小时。反应液倒入10mL水中，用20mL乙酸乙酯萃取三次，收集有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干，得粗品，所得粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到1：1)得到黄色油状中间体9-8(80mg,产率：53.1％)。Intermediate 9-7 (150mg, 0.410mmol), zinc cyanide (72.0mg, 0.620mmol) was dissolved in N,N-dimethylformamide (3mL), nitrogen was replaced, and tris(dibenzyl Dipalladium (187mg, 0.210mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (201mg, 0.490mmol), heated to 100°C under a liquid nitrogen atmosphere and stirred for 4 hours . The reaction solution was poured into 10 mL of water, extracted three times with 20 mL of ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether : ethyl acetate=1:0 to 1:1) to obtain yellow oily intermediate 9-8 (80 mg, yield: 53.1%).
步骤8:合成中间体9-9Step 8: Synthesis of Intermediate 9-9
Figure PCTCN2022114183-appb-000109
Figure PCTCN2022114183-appb-000109
中间体9-8(80.0mg,0.256mmol)溶解在二氯甲烷(2mL)中，逐滴加入盐酸/二氧六环溶液(4M,1mL)。反应液在25℃下搅拌1小时。减压旋干得到白色固体中间体9-9(90mg，粗品)。Intermediate 9-8 (80.0 mg, 0.256 mmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid/dioxane solution (4M, 1 mL) was added dropwise. The reaction solution was stirred at 25°C for 1 hour. Spin-dry under reduced pressure to obtain intermediate 9-9 (90 mg, crude product) as a white solid.
LCMS(ESI +):m/z 214.2[M+H] +. LCMS(ESI + ):m/z 214.2[M+H] + .
步骤9:合成中间体9-10Step 9: Synthesis of intermediates 9-10
Figure PCTCN2022114183-appb-000110
Figure PCTCN2022114183-appb-000110
中间体9-9(60.0mg,0.240mmol)，α,α′-二氯对二甲苯(65.0mg,0.36.0 mmol)，三乙胺(125mg,1.20mmol)溶解在醋酸异丙酯(2mL)中，反应液25℃下搅拌12小时。倾倒入5mL水中，用10mL乙酸乙酯萃取三次，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干，得粗品，所得粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到2：1)得到黄色粉末中间体9-10(30mg,产率：19.9％)。Intermediate 9-9 (60.0mg, 0.240mmol), α,α′-dichloro-p-xylene (65.0mg, 0.36.0 mmol), triethylamine (125mg, 1.20mmol) were dissolved in isopropyl acetate (2mL ), the reaction solution was stirred at 25°C for 12 hours. Poured into 5 mL of water, extracted three times with 10 mL of ethyl acetate, collected the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether: ethyl acetate Esters = 1:0 to 2:1) gave yellow powder intermediate 9-10 (30 mg, yield: 19.9%).
LCMS(ESI +):m/z 352.05[M+H] +. LCMS(ESI + ):m/z 352.05[M+H] + .
步骤10:合成中间体9-11Step 10: Synthesis of intermediates 9-11
Figure PCTCN2022114183-appb-000111
Figure PCTCN2022114183-appb-000111
中间体9-10(30.0mg,85.3μmol)，中间体1-10(57.0mg,170μmol)，碳酸钾(18.0mg,127μmol)溶解在N,N-二甲基甲酰胺(2mL)中，反应液加热至50℃搅拌8小时。反应液倾倒入5mL水中，用10mL乙酸乙酯萃取三次，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干，得到粗品，所得粗品经硅胶柱层析分离(二氯甲烷：甲醇＝1：0到10：1)得到黄色粉末中间体9-11(15mg,产率：19.9％)。Intermediate 9-10 (30.0 mg, 85.3 μmol), Intermediate 1-10 (57.0 mg, 170 μmol), potassium carbonate (18.0 mg, 127 μmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction The solution was heated to 50°C and stirred for 8 hours. The reaction solution was poured into 5 mL of water, extracted three times with 10 mL of ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product, which was separated by silica gel column chromatography (dichloromethane :methanol=1:0 to 10:1) to obtain yellow powder intermediate 9-11 (15 mg, yield: 19.9%).
LCMS(ESI +):m/z 650.6[M+H] +. LCMS(ESI + ):m/z 650.6[M+H] + .
步骤11:合成化合物9Step 11: Synthesis of compound 9
Figure PCTCN2022114183-appb-000112
Figure PCTCN2022114183-appb-000112
中间体9-11(15.0mg,23.0μmol)，苯磺酸(6mg,34μmol)溶解在乙腈(2mL)中，反应液加热至90℃搅拌8小时。反应液用20mL二氯甲烷 和乙酸乙酯(4：1)稀释，10mL饱和碳酸氢钠洗涤三次，旋干，得到粗品。所得粗品经高效液相制备色谱纯化(色谱柱:Kromasil 100-5-C1830*150mm,流动相A:水(0.01％FA),流动相B:乙腈,20mL/min,梯度25％B到45％)得到白色固体化合物9(2.76mg,产率：20.6％)。Intermediate 9-11 (15.0 mg, 23.0 μmol), benzenesulfonic acid (6 mg, 34 μmol) were dissolved in acetonitrile (2 mL), and the reaction solution was heated to 90° C. and stirred for 8 hours. The reaction solution was diluted with 20 mL of dichloromethane and ethyl acetate (4:1), washed three times with 10 mL of saturated sodium bicarbonate, and spin-dried to obtain a crude product. The obtained crude product was purified by preparative high-performance liquid chromatography (chromatographic column: Kromasil 100-5-C1830*150mm, mobile phase A: water (0.01% FA), mobile phase B: acetonitrile, 20 mL/min, gradient 25% B to 45% ) to obtain white solid compound 9 (2.76 mg, yield: 20.6%).
LCMS(ESI +):m/z 576.1[M+H] +. LCMS(ESI + ):m/z 576.1[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(br s,1H),7.55-7.43(m,3H),7.42-7.25(m,6H),6.95-6.84(m,1H),5.23(s,2H),5.11(dd,J＝5.2,13.2Hz,1H),4.46-4.19(m,2H),3.99-3.86(m,1H),3.52-3.48(m,2H),3.26-3.10(m,1H),2.96-2.78(m,4H),2.74-2.56(m,3H),2.48-2.37(m,1H),2.14-2.04(m,1H),2.02-1.94(m,1H),1.93-1.76(m,2H),1.62-1.48(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(br s,1H),7.55-7.43(m,3H),7.42-7.25(m,6H),6.95-6.84(m,1H),5.23( s,2H),5.11(dd,J＝5.2,13.2Hz,1H),4.46-4.19(m,2H),3.99-3.86(m,1H),3.52-3.48(m,2H),3.26-3.10( m,1H),2.96-2.78(m,4H),2.74-2.56(m,3H),2.48-2.37(m,1H),2.14-2.04(m,1H),2.02-1.94(m,1H), 1.93-1.76(m,2H),1.62-1.48(m,1H).
实施例10:化合物10-A和10-BExample 10: Compounds 10-A and 10-B
Figure PCTCN2022114183-appb-000113
Figure PCTCN2022114183-appb-000113
中间体10-1的合成参考专利WO2020094084Synthesis of intermediate 10-1 reference patent WO2020094084
步骤1:合成中间体10-2Step 1: Synthesis of intermediate 10-2
Figure PCTCN2022114183-appb-000114
Figure PCTCN2022114183-appb-000114
将中间体10-1(1.00g,3.26mmol)溶于乙腈(10mL)中，接着加入氰化亚铜(351mg,3.92mmol)和亚硝酸叔丁酯(1.35g,13.1mmol),在25℃下搅拌30分钟.然后升温至80℃反应3小时。然后将反应冷却到室温倒入100mL水中，接着使用150mL乙酸乙酯萃取两次，合并有机相，使用100mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤浓缩，得到粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到3：1)得到白色固体中间体10-2(70.0mg,产率：6.8％)。Intermediate 10-1 (1.00g, 3.26mmol) was dissolved in acetonitrile (10mL), followed by adding cuprous cyanide (351mg, 3.92mmol) and tert-butyl nitrite (1.35g, 13.1mmol), at 25°C Under stirring for 30 minutes. Then the temperature was raised to 80°C for 3 hours. Then the reaction was cooled to room temperature and poured into 100mL of water, followed by extraction twice with 150mL of ethyl acetate, the organic phases were combined, washed with 100mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration, and the crude product was subjected to silica gel column chromatography Isolation (petroleum ether: ethyl acetate = 1:0 to 3:1) gave white solid intermediate 10-2 (70.0 mg, yield: 6.8%).
1H NMR(400MHz,DMSO-d 6)δ8.17(d,J＝2.0Hz,1H),7.41(d,J＝2.0Hz,1H),4.55-4.47(m,1H),4.45-4.39(m,1H),4.03-3.98(m,2H),3.97-3.91(m,1H),3.59-3.49(m,1H),2.97-2.81(m,2H),2.70-2.59(m,1H),1.43(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.17(d, J=2.0Hz, 1H), 7.41(d, J=2.0Hz, 1H), 4.55-4.47(m, 1H), 4.45-4.39( m,1H),4.03-3.98(m,2H),3.97-3.91(m,1H),3.59-3.49(m,1H),2.97-2.81(m,2H),2.70-2.59(m,1H), 1.43(s,9H).
步骤2:合成中间体10-3Step 2: Synthesis of intermediate 10-3
Figure PCTCN2022114183-appb-000115
Figure PCTCN2022114183-appb-000115
中间体10-2(50.0mg,158umol)溶解在二氯甲烷(2mL)中，向溶液中滴加盐酸/二氧六环(4M,790uL)。混合液在25℃下搅拌1小时。反应液通过减压旋干得到白色固体中间体10-3(40.0mg,粗品)。粗品直接用于下一步，没有进一步纯化。Intermediate 10-2 (50.0mg, 158umol) was dissolved in dichloromethane (2mL), and hydrochloric acid/dioxane (4M, 790uL) was added dropwise to the solution. The mixture was stirred at 25°C for 1 hour. The reaction solution was spin-dried under reduced pressure to obtain intermediate 10-3 (40.0 mg, crude product) as a white solid. The crude product was used directly in the next step without further purification.
步骤3:合成中间体10-5Step 3: Synthesis of intermediate 10-5
Figure PCTCN2022114183-appb-000116
Figure PCTCN2022114183-appb-000116
中间体10-3(40.0mg,158umol,HCl盐),三乙胺(80.1mg,791umol)溶解在N,N-二甲基甲酰胺(3mL)中，然后加入α,α′-二氯对二甲苯(41.6mg,237umol)混合液在50℃搅拌5小时。将反应液倒入100mL水中，接着使用15mL乙酸乙酯萃取两次，合并有机相，使用10mL饱和氯化钠水溶液洗涤三次，无水硫酸钠干燥，过滤浓缩，得到粗品经硅胶柱层析分离(石油醚：乙酸乙酯＝1：0到1：1)得到黄色固体中间体10-5(40.0mg,产率：71.2％)Intermediate 10-3 (40.0mg, 158umol, HCl salt), triethylamine (80.1mg, 791umol) was dissolved in N,N-dimethylformamide (3mL), and then α,α′-dichloro The xylene (41.6mg, 237umol) mixture was stirred at 50°C for 5 hours. The reaction solution was poured into 100 mL of water, then extracted twice with 15 mL of ethyl acetate, the organic phases were combined, washed three times with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration, and the crude product was separated by silica gel column chromatography ( Petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain yellow solid intermediate 10-5 (40.0 mg, yield: 71.2%)
步骤4:合成中间体10-6Step 4: Synthesis of intermediate 10-6
Figure PCTCN2022114183-appb-000117
Figure PCTCN2022114183-appb-000117
中间体10-5(32.0mg,90.18umol)，中间体1-10(39.2mg,117umol)，碳酸钾(18.7mg,135umol)溶解在N,N-二甲基甲酰胺(2mL)中，混合液加热至50℃搅拌8小时。将反应液使用20mL乙酸乙酯稀释,用10mL5％氯化锂水溶液洗涤三次，无水硫酸钠干燥，过滤浓缩，得到粗品经薄层析板分离(二氯甲烷：甲醇＝10：1)得到无色油状中间体10-6(35.0mg,产率：58.9％)。Intermediate 10-5 (32.0mg, 90.18umol), Intermediate 1-10 (39.2mg, 117umol), potassium carbonate (18.7mg, 135umol) were dissolved in N,N-dimethylformamide (2mL), mixed The solution was heated to 50°C and stirred for 8 hours. The reaction solution was diluted with 20 mL of ethyl acetate, washed three times with 10 mL of 5% lithium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated by thin chromatography (dichloromethane: methanol = 10: 1) to obtain Oily intermediate 10-6 (35.0 mg, yield: 58.9%).
LCMS(ESI+):m/z 653.3[M+H] +. LCMS(ESI+):m/z 653.3[M+H] + .
步骤5:合成化合物10Step 5: Synthesis of Compound 10
Figure PCTCN2022114183-appb-000118
Figure PCTCN2022114183-appb-000118
中间体10-6(35.0mg,53.6umol)溶解在乙腈(5mL)中，然后加入苯磺酸(17.0mg,107umol)。混合液加热至90℃搅拌20小时。监测发现有关键中间体形成。再加入苯磺酸(17.0mg,107umol)。混合液继续在90℃加热搅拌12h。将反应液冷却到室温后，倒入15mL饱和碳酸氢钠水溶液中，接着使用20mL二氯甲烷萃取两次，合并有机相，使用20mL饱和氯化钠水溶液洗涤两次，无水硫酸钠干燥，过滤浓缩，得到粗品，粗品通过高效液相制备色谱纯化(色谱柱:Kromasil 100-5-C18 30*150mm,流动相A:水(0.01％FA),流动相B:乙腈,20mL/min,梯度10％B到50％)得到白色固体化合物10(10.0mg,产率：32.2％)。Intermediate 10-6 (35.0 mg, 53.6 umol) was dissolved in acetonitrile (5 mL), then benzenesulfonic acid (17.0 mg, 107 umol) was added. The mixture was heated to 90°C and stirred for 20 hours. Monitoring revealed the formation of key intermediates. Additional benzenesulfonic acid (17.0 mg, 107 umol) was added. The mixture was heated and stirred at 90°C for 12h. After cooling the reaction solution to room temperature, pour it into 15 mL of saturated aqueous sodium bicarbonate solution, then extract twice with 20 mL of dichloromethane, combine the organic phases, wash twice with 20 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and filter Concentrate to obtain the crude product, the crude product is purified by preparative high performance liquid chromatography (chromatographic column: Kromasil 100-5-C18 30*150mm, mobile phase A: water (0.01% FA), mobile phase B: acetonitrile, 20mL/min, gradient 10 %B to 50%) to obtain white solid compound 10 (10.0 mg, yield: 32.2%).
LCMS(ESI+):m/z 579.3[M+H] +. LCMS(ESI+):m/z 579.3[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.99(br s,1H),8.14(d,J＝1.6Hz,1H),7.54-7.42(m,3H),7.41-7.29(m,5H),5.24(s,2H),5.12(dd,J＝5.2,13.2Hz,1H),4.51-4.22(m,4H),3.97-3.85(m,1H),3.60-3.52(m,2H),2.95-2.85(m,5H),2.60-2.56(m,1H),2.49-2.44(m,1H),2.15-1.94(m,2H),1.80(t,J＝10.8Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.99(br s,1H),8.14(d,J=1.6Hz,1H),7.54-7.42(m,3H),7.41-7.29(m,5H) ,5.24(s,2H),5.12(dd,J=5.2,13.2Hz,1H),4.51-4.22(m,4H),3.97-3.85(m,1H),3.60-3.52(m,2H),2.95 -2.85(m,5H),2.60-2.56(m,1H),2.49-2.44(m,1H),2.15-1.94(m,2H),1.80(t,J＝10.8Hz,1H).
步骤6:合成化合物10-A和10-BStep 6: Synthesis of compounds 10-A and 10-B
Figure PCTCN2022114183-appb-000119
Figure PCTCN2022114183-appb-000119
化合物10(10.0mg,17.3umol)经过手性分离色谱柱(DAICEL  CHIRALPAK OJ(250mm*30mm,10um)，流动相:[Neu-ETOH]；二氧化碳％：60％-60％,min)分离得到白色固体化合物10-A(1.32mg,产率：13.2％)和10-B(5mg,产率：50.0％)Compound 10 (10.0mg, 17.3umol) was separated by a chiral separation column (DAICEL CHIRALPAK OJ (250mm*30mm, 10um), mobile phase: [Neu-ETOH]; carbon dioxide %: 60%-60%, min) to obtain a white Solid compound 10-A (1.32 mg, yield: 13.2%) and 10-B (5 mg, yield: 50.0%)
化合物10-A：Compound 10-A:
LCMS(ESI +):m/z 579.3[M+H] +. LCMS(ESI + ):m/z 579.3[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.99(br s,1H),8.14(d,J＝2.0Hz,1H),7.53-7.43(m,3H),7.43-7.30(m,5H),5.24(s,2H),5.17-5.07(m,1H),4.51-4.20(m,4H),3.94-3.85(m,1H),3.56-3.53(m,2H),3.17-2.76(m,5H),2.61-2.58(m,1H),2.45-2.42(m,1H),2.11-1.95(m,2H),1.80(t,J＝10.8Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.99(br s,1H),8.14(d,J=2.0Hz,1H),7.53-7.43(m,3H),7.43-7.30(m,5H) ,5.24(s,2H),5.17-5.07(m,1H),4.51-4.20(m,4H),3.94-3.85(m,1H),3.56-3.53(m,2H),3.17-2.76(m, 5H),2.61-2.58(m,1H),2.45-2.42(m,1H),2.11-1.95(m,2H),1.80(t,J＝10.8Hz,1H).
化合物10-B：Compound 10-B:
LCMS(ESI +):m/z 579.4[M+H] +. LCMS(ESI + ):m/z 579.4[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(br s,1H),8.13(s,1H),7.54-7.42(m,3H),7.41-7.26(m,5H),5.24(s,2H),5.17-5.02(m,1H),4.52-4.20(m,4H),3.89(t,J＝9.6Hz,1H),3.59-3.51(m,2H),3.08-2.75(m,5H),2.64-2.56(m,1H),2.45-2.38(m,1H),2.13-1.92(m,2H),1.80(t,J＝10.8Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(br s,1H),8.13(s,1H),7.54-7.42(m,3H),7.41-7.26(m,5H),5.24(s, 2H),5.17-5.02(m,1H),4.52-4.20(m,4H),3.89(t,J＝9.6Hz,1H),3.59-3.51(m,2H),3.08-2.75(m,5H) ,2.64-2.56(m,1H),2.45-2.38(m,1H),2.13-1.92(m,2H),1.80(t,J=10.8Hz,1H).
实施例11-A：化合物11-AExample 11-A: Compound 11-A
Figure PCTCN2022114183-appb-000120
Figure PCTCN2022114183-appb-000120
LCMS(ESI +):m/z 597.3[M+H] +. LCMS(ESI + ):m/z 597.3[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(br s,1H),8.14(d,J＝2.4Hz,1H),7.60-7.48(m,2H),7.43-7.38(m,1H),7.38-7.30(m,2H),7.27-7.19(m, 2H),5.27(s,2H),5.11(dd,J＝5.2,13.2Hz,1H),4.53-4.44(m,1H),4.42-4.16(m,3H),3.96-3.84(m,1H),3.62-3.54(m,3H),2.96-2.86(m,4H),2.63-2.62(m,1H),2.47-2.44(m,1H),2.17-2.04(m,1H),2.02-1.92(m,1H),1.82(t,J＝10.8Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.98(br s,1H),8.14(d,J=2.4Hz,1H),7.60-7.48(m,2H),7.43-7.38(m,1H) ,7.38-7.30(m,2H),7.27-7.19(m,2H),5.27(s,2H),5.11(dd,J＝5.2,13.2Hz,1H),4.53-4.44(m,1H),4.42 -4.16(m,3H),3.96-3.84(m,1H),3.62-3.54(m,3H),2.96-2.86(m,4H),2.63-2.62(m,1H),2.47-2.44(m, 1H), 2.17-2.04(m, 1H), 2.02-1.92(m, 1H), 1.82(t, J=10.8Hz, 1H).
实施例11-B：化合物11-BExample 11-B: Compound 11-B
Figure PCTCN2022114183-appb-000121
Figure PCTCN2022114183-appb-000121
LCMS(ESI +):m/z 597.3[M+H] +. LCMS(ESI + ):m/z 597.3[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.97(br.s.,1H),8.14(d,J＝2.4Hz,1H),7.63-7.47(m,2H),7.45-7.31(m,3H),7.28-7.16(m,2H),5.27(s,2H),5.10(dd,J＝5.2,13.2Hz,1H),4.55-4.43(m,1H),4.42-4.16(m,3H),3.95-3.84(m,1H),3.66-3.52(m,3H),2.99-2.82(m,4H),2.61-2.57(m,1H),2.46-2.40(m,1H),2.15-2.04(m,1H),2.01-1.92(m,1H),1.82(t,J＝10.8Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.97(br.s., 1H), 8.14(d, J=2.4Hz, 1H), 7.63-7.47(m, 2H), 7.45-7.31(m, 3H), 7.28-7.16(m, 2H), 5.27(s, 2H), 5.10(dd, J=5.2, 13.2Hz, 1H), 4.55-4.43(m, 1H), 4.42-4.16(m, 3H) ,3.95-3.84(m,1H),3.66-3.52(m,3H),2.99-2.82(m,4H),2.61-2.57(m,1H),2.46-2.40(m,1H),2.15-2.04( m,1H),2.01-1.92(m,1H),1.82(t,J＝10.8Hz,1H).
实施例12：化合物12Example 12: Compound 12
Figure PCTCN2022114183-appb-000122
Figure PCTCN2022114183-appb-000122
LCMS(ESI +):m/z 597.4[M+H] +. LCMS(ESI + ):m/z 597.4[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.98(br s,1H),8.13(s,1H),7.65-7.24(m,6H),7.12(d,J＝5.6Hz,1H),5.24(s,2H),5.17-5.04(m,1H),4.57- 4.12(m,5H),3.95-3.83(m,1H),3.62-3.52(m,2H),3.01-2.74(m,4H),2.63-2.61(m,1H),2.41-2.37(m,1H),2.13-1.94(m,2H),1.80(t,J＝10.6Hz,1H) 1 H NMR (400MHz,DMSO-d 6 )δ10.98(br s,1H),8.13(s,1H),7.65-7.24(m,6H),7.12(d,J=5.6Hz,1H),5.24 (s,2H),5.17-5.04(m,1H),4.57-4.12(m,5H),3.95-3.83(m,1H),3.62-3.52(m,2H),3.01-2.74(m,4H) ,2.63-2.61(m,1H),2.41-2.37(m,1H),2.13-1.94(m,2H),1.80(t,J＝10.6Hz,1H)
IKZF1和SALL4蛋白质降解实验(HiBiT标签生物发光检测)IKZF1 and SALL4 protein degradation experiment (HiBiT label bioluminescent detection)
以下是在特定细胞株(比如HT-1080)中检测分子胶化合物诱导IKZF1和SALL4蛋白质降解的通用方法。以HT-1080为例，HT-1080细胞购自美国模式培养收集中心(ATCC，目录号CCL-121)，在此细胞中通过慢病毒转导的方式稳定表达GSPT(Δ1-138)/G575N和带有HiBiT标签的IKZF1或者SALL4蛋白。该细胞使用DMEM培养液添加10％的胎牛血清进行培养。先使用声学分配器(EDC ATS-100)以10点稀释方式将递增浓度的测试化合物点样到空的384孔板上，浓度范围一般为0.316纳摩尔到10微摩尔，每档为半个对数值，并以DMSO处理作为对照。实验时将上述稳定细胞株接种到384孔板上，接种浓度大约为每孔35微升培养液并含有1万个细胞。将接种好的384孔板放入37摄氏度并含有5％二氧化碳的培养箱中培养20小时。最后在每个孔中加入35微升的Nano-Glo HiBiT裂解检测溶液(Promega公司)，室温孵育30分钟后在EnVision多功能读板仪(PerkinElmer公司)上读取生物发光数值。通过Collaborative Drug Discovery Vault软件包处理数据，并以DMSO处理的样品作为参照值计算每个处理样品的降解值(对比DMSO样品的百分比)，最后通过四参数逻辑回归模型制作降解曲线，并计算出半降解浓度EC50和DC50。计算公式如下：The following is a general method for detecting the degradation of IKZF1 and SALL4 proteins induced by molecular glue compounds in specific cell lines (such as HT-1080). Taking HT-1080 as an example, HT-1080 cells were purchased from the American Type Culture Collection (ATCC, catalog number CCL-121), and GSPT(Δ1-138)/G575N and IKZF1 or SALL4 protein with HiBiT tag. The cells were cultured in DMEM medium supplemented with 10% fetal bovine serum. First use an acoustic dispenser (EDC ATS-100) to spot increasing concentrations of test compounds onto an empty 384-well plate in a 10-point dilution manner. The concentration range is generally 0.316 nanomolar to 10 micromolar. Values, and DMSO treatment was used as a control. During the experiment, the above-mentioned stable cell lines were inoculated on a 384-well plate, and the inoculation concentration was approximately 35 microliters of culture medium per well and contained 10,000 cells. Place the inoculated 384-well plate in an incubator containing 5% carbon dioxide at 37°C for 20 hours. Finally, 35 microliters of Nano-Glo HiBiT lysis detection solution (Promega Company) was added to each well, and after incubation at room temperature for 30 minutes, the bioluminescence value was read on an EnVision multi-function plate reader (PerkinElmer Company). The data was processed by the Collaborative Drug Discovery Vault software package, and the degradation value of each treatment sample (the percentage of the comparison DMSO sample) was calculated using the DMSO-treated sample as a reference value, and finally the degradation curve was made by a four-parameter logistic regression model, and the half Degradation concentration EC50 and DC50. Calculated as follows:
y＝(A+((B-A)/(1+((C/x) AD)))) y=(A+((BA)/(1+((C/x) A D))))
其中：in:
A＝Y min(测试样品处理后IKZF1或者SALL4读数的最低值，通过适配曲线计算得到) A=Y min (the lowest value of IKZF1 or SALL4 reading after the test sample is processed, calculated by fitting curve)
B＝Y max(最高值，即DMSO处理的样品中IKZF1或者SALL4读数) B=Y max (highest value, i.e. IKZF1 or SALL4 readout in DMSO treated samples)
C＝EC 50半降解浓度 C=EC 50 half-degradation concentration
D＝希尔(Hill)斜率D = Hill slope
x＝化合物的浓度x = concentration of compound
EC 50＝当y＝(Y max-Y min)/2时的测试样品浓度 EC 50 = test sample concentration when y=(Y max -Y min )/2
DC 50＝当y＝50％的DMSO处理的样品中IKZF1或者SALL4读数时的测试样品浓度 DC50 = test sample concentration when y = 50% of IKZF1 or SALL4 readings in DMSO-treated samples
y＝测试样品处理后的IKZF1或者SALL4读数(标准化于DMSO处理的样品中IKZF1或者SALL4读数)y = IKZF1 or SALL4 readings after test sample treatment (normalized to IKZF1 or SALL4 readings in DMSO-treated samples)
D max＝(1-Y min/Y max)*100％ D max ＝(1-Y min /Y max )*100％
D max表示在最高化合物浓度下通过化合物处理在测定中可以实现的最大IKZF1或SALL4蛋白质降解百分比。 Dmax represents the maximum percentage of IKZF1 or SALL4 protein degradation achievable in the assay by compound treatment at the highest compound concentration.
IKZF1与SALL4降解活性列表IKZF1 and SALL4 degradation activity list
表1Table 1
Figure PCTCN2022114183-appb-000123
Figure PCTCN2022114183-appb-000123
Figure PCTCN2022114183-appb-000124
Figure PCTCN2022114183-appb-000124
泊马度胺是结构式如下的已知化合物：Pomalidomide is a known compound with the following structural formula:
Figure PCTCN2022114183-appb-000125
Figure PCTCN2022114183-appb-000125
MM.1S细胞株增殖测试MM.1S cell line proliferation test
以下是在特定的多发性骨髓瘤细胞株(比如MM.1S)中检测分子胶 化合物抑制细胞增殖能力的通用方法。以MM.1S为例，MM.1S细胞株购自美国模式培养收集中心(ATCC，目录号CRL-2974)。该细胞使用RPMI-1640培养液添加10％的胎牛血清进行培养。先使用声学分配器(EDC ATS-100)以10点稀释方式将递增浓度的测试化合物点样到空的384孔板上，浓度范围一般为0.316皮摩尔到10纳摩尔，每档为半个对数值，并以DMSO处理作为对照。实验时将上述细胞株接种到384孔板上，接种浓度大约为每孔50微升培养液并含有3000个细胞。将接种好的384孔板放入37摄氏度并含有5％二氧化碳的培养箱中培养120小时。最后在每个孔中加入20微升的CellTiter Glo裂解检测溶液(Promega公司)，室温孵育30分钟后在EnVision多功能读板仪(PerkinElmer公司)上读取生物发光数值。通过Collaborative Drug Discovery Vault软件包处理数据，并以DMSO处理的样品作为参照值计算每个处理样品的细胞活性值(对比DMSO样品的百分比)，最后通过四参数逻辑回归模型制作降解曲线，并计算出半抑制浓度EC50和IC50。计算公式如下：The following is a general method for detecting the ability of molecular glue compounds to inhibit cell proliferation in specific multiple myeloma cell lines (such as MM.1S). Taking MM.1S as an example, the MM.1S cell line was purchased from the American Type Culture Collection (ATCC, catalog number CRL-2974). The cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum. First, use an acoustic dispenser (EDC ATS-100) to spot increasing concentrations of test compounds onto an empty 384-well plate in a 10-point dilution manner. The concentration range is generally 0.316 picomolar to 10 nanomolar. Values, and DMSO treatment was used as a control. During the experiment, the above cell lines were inoculated on a 384-well plate, and the inoculation concentration was approximately 50 microliters of culture medium per well and contained 3000 cells. Place the inoculated 384-well plate in an incubator containing 5% carbon dioxide at 37°C for 120 hours. Finally, 20 microliters of CellTiter Glo lysis detection solution (Promega Company) was added to each well, and after incubation at room temperature for 30 minutes, the bioluminescence value was read on an EnVision multi-function plate reader (PerkinElmer Company). The data is processed by the Collaborative Drug Discovery Vault software package, and the cell activity value (compared to the percentage of the DMSO sample) of each processed sample is calculated with the sample treated with DMSO as a reference value, and finally the degradation curve is made by a four-parameter logistic regression model, and calculated Half inhibitory concentration EC50 and IC50. Calculated as follows:
y＝(A+((B-A)/(1+((C/x) AD)))) y=(A+((BA)/(1+((C/x) A D))))
其中：in:
A＝Y min(测试样品处理后细胞活性读数的最低值，通过适配曲线计算得到) A=Y min (minimum value of cell viability reading after test sample treatment, calculated by fitting curve)
B＝Y max(最高值，即DMSO处理的样品中细胞活性读数) B=Y max (highest value, i.e. cell viability readout in DMSO treated samples)
C＝EC 50半抑制浓度 C = EC50 half-inhibitory concentration
D＝希尔(Hill)斜率D = Hill slope
x＝化合物的浓度x = concentration of compound
EC 50＝当y＝(Y max-Y min)/2时的测试样品浓度 EC 50 = test sample concentration when y=(Y max -Y min )/2
IC 50＝当y＝50％的DMSO处理的样品中细胞活性读数时的测试样品浓度 IC50 = test sample concentration at which y = 50% of the cell viability reading in DMSO-treated samples
y＝测试样品处理后的细胞活性读数(标准化于DMSO处理的样品中细胞活性读数)y = cell viability readings after test sample treatment (normalized to cell viability readings in DMSO treated samples)
MM.1S细胞株增殖抑制活性列表MM.1S cell line proliferation inhibitory activity list
表2Table 2
Figure PCTCN2022114183-appb-000126
Figure PCTCN2022114183-appb-000126
本申请还包括如下编号的项目中的任一者的技术方案。The present application also includes the technical solutions of any one of the items numbered below.
1、由结构式(I)表示的化合物或其药学上可接受的盐：1. A compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000127
Figure PCTCN2022114183-appb-000127
其中：in:
R 1在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 2在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 3在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、 C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 4在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 5在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 6在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6 烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 7在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 8在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 9在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、 C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 10在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 10 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 11 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
Q为CR 12R 13，n是0、1或2； Q is CR 12 R 13 , n is 0, 1 or 2;
X 1在其每一次出现时独立地选自CR 14或N； X 1 is independently selected from CR 14 or N at each occurrence thereof;
X 2在其每一次出现时独立地选自CR 14’或N； X is independently selected from CR 14' or N at each occurrence thereof;
X 3在其每一次出现时独立地选自CR 14”或N； X3 is independently selected from CR 14" or N at each occurrence thereof;
X 4在其每一次出现时独立地选自CR 14”’或N； X4 is independently selected from CR 14"' or N at each occurrence thereof;
X 5选自O、CR 15R 16、或NR 17， X 5 is selected from O, CR 15 R 16 , or NR 17 ,
R 12在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔 基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 12 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 13在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 13 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14’在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6 烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl The group is optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14”在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R14 " at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1 - C6 alkyl, C2 - C6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl The group is optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 14”’在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14"' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkene C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyl oxy, C 2 -C 6 alkanoyl, C 2 -C 6 Alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono - and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and hetero Aryl is optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 15在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、 C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 15 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 16在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 16 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 17在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 17 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
R 18在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、 -COOH、或C 1-C 6烷基取代； R 18 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
T为N或CH；T is N or CH;
a是0、1或2；a is 0, 1 or 2;
b是0、1或2；b is 0, 1 or 2;
c是0、1或2；c is 0, 1 or 2;
d是0、1或2；d is 0, 1 or 2;
e是0、1或2；e is 0, 1 or 2;
X 6是N或C； X 6 is N or C;
X 7是N或C； X7 is N or C;
X 8是N或C； X8 is N or C;
X 9是N或C。 X9 is N or C.
2、根据项目1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：2. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000128
Figure PCTCN2022114183-appb-000128
3、根据项目1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：3. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000129
Figure PCTCN2022114183-appb-000129
4、根据项目1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：4. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000130
Figure PCTCN2022114183-appb-000130
5、根据项目1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：5. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000131
Figure PCTCN2022114183-appb-000131
6、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(VI)的化合物或其药学上可接受的盐：6. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (VI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000132
Figure PCTCN2022114183-appb-000132
7、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(VII)的化合物或其药学上可接受的盐：7. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (VII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000133
Figure PCTCN2022114183-appb-000133
8、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(VIII)的化合物或其药学上可接受的盐：8. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (VIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000134
Figure PCTCN2022114183-appb-000134
9、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(IX)的化合物或其药学上可接受的盐：9. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (IX) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000135
Figure PCTCN2022114183-appb-000135
10、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(X)的化合物或其药学上可接受的盐：10. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (X) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000136
Figure PCTCN2022114183-appb-000136
11、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XI)的化合物或其药学上可接受的盐：11. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000137
Figure PCTCN2022114183-appb-000137
12、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XII)的化合物或其药学上可接受的盐：12. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000138
Figure PCTCN2022114183-appb-000138
13、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XIII)的化合物或其药学上可接受的盐：13. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000139
Figure PCTCN2022114183-appb-000139
14、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XIV)的化合物或其药学上可接受的盐：14. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000140
Figure PCTCN2022114183-appb-000140
15、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XV)的化合物或其药学上可接受的盐：15. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000141
Figure PCTCN2022114183-appb-000141
16、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XVI)的化合物或其药学上可接受的盐：16. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XVI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000142
Figure PCTCN2022114183-appb-000142
17、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XVII)的化合物或其药学上可接受的盐：17. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XVII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000143
Figure PCTCN2022114183-appb-000143
18、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XVIII)的化合物或其药学上可接受的盐：18. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XVIII) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000144
Figure PCTCN2022114183-appb-000144
19、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XIV)的化合物或其药学上可接受的盐：19. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the compound is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022114183-appb-000145
Figure PCTCN2022114183-appb-000145
20、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 1在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 20. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 1 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
21、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 1在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧 基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000146
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 21. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 1 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000146
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
20、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 1在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000147
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 20. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 1 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000147
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
23、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 1在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 23. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 1 at each occurrence is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
24、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 2在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 24. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 2 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
25、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 2在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000148
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 25. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 2 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000148
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
26、根据前述项目中任一项所述的化合物或其药学上可接受的盐， 其中：R 2在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000149
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 26. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 2 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000149
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
27、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 2在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 27. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R2 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
28、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 3在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 28. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R3 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
29、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 3在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000150
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 29. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R3 at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000150
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
30、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 3在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000151
三氟甲 基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 30. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 3 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000151
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
31、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 3在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 31. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R3 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
32、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 4在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 32. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 4 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
33、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 4在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000152
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 33. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 4 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000152
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
34、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 4在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000153
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 34. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 4 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000153
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
35、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 4在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 35. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R4 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
36、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 5在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6 卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 36. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 5 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
37、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 5在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000154
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 37. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 5 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000154
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
38、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 5在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000155
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 38. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 5 at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000155
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
39、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 5在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 39. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 5 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
40、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 6在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 40. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 6 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
41、根据前述项目中任一项所述的化合物或其药学上可接受的盐， 其中：R 6在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000156
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 41. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 6 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000156
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
42、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 6在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000157
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 42. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 6 is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000157
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
43、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 6在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 43. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 6 at each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
44、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 7在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 44. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 7 at each occurrence is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
45、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 7在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000158
三氟甲 基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 45. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 7 at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000158
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
46、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 7在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000159
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 46. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R7 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000159
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
47、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 7在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 47. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 7 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
48、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 8在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 48. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 8 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
49、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 8在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000160
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 49. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 8 in each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000160
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
50、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 8在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000161
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 50. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 8 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000161
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
51、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 8在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 51. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R8 at each occurrence thereof is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
52、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 9在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 52. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 9 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
53、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 9在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000162
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 53. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R9 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000162
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
54、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 9在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000163
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 54. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R9 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000163
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
55、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 9在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 55. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 9 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
56、根据前述项目中任一项所述的化合物或其药学上可接受的盐， 其中：R 10在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 56. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 10 at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
57、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 10在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000164
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 57. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 10 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000164
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
58、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 10在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000165
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 58. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 10 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000165
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
59、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 10在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 59. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 10 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
60、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 11在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳 基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 60. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 11 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
61、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 11在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000166
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 61. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 11 at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000166
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
62、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 11在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000167
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 62. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 11 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000167
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
63、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 11在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 63. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 11 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
64、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 12在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 64. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 12 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
65、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 12在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧 基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000168
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 65. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 12 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000168
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
66、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 12在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000169
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 66. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 12 at each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000169
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
67、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 12在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 67. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 12 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
68、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 13在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 68. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 13 at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
69、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 13在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000170
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 69. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 13 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000170
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
70、根据前述项目中任一项所述的化合物或其药学上可接受的盐， 其中：R 13在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000171
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 70. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 13 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000171
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
71、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 13在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 71. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 13 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
72、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 72. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
73、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000172
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 73. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000172
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
74、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000173
三氟甲 基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 74. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000173
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
75、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 75. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 at each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
76、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14’在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 76. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14' at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro , cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
77、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14’在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000174
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 77. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14' at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino , mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000174
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
78、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14’在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000175
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 78. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000175
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
79、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14’在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 79. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14' at each occurrence is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl .
80、根据前述项目中任一项所述的化合物或其药学上可接受的盐， 其中：R 14”在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 80. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 " in each occurrence thereof is independently selected from none, hydrogen, fluorine, chlorine, hydroxyl, nitro , cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
81、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14”在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000176
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 81. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 " in each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino , mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000176
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
82、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14”在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000177
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 82. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 " in each occurrence thereof is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000177
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
83、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14”在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 83. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14 " in each occurrence thereof is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl .
84、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14”’在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳 基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 84. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14"' at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitric acid group, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 - C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are any Optionally substituted with 1, 2, 3 or 4 halo, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
85、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14”’在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000178
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 85. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14"' at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, Amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000178
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
86、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14”’在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000179
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 86. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14"' at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000179
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
87、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 14”’在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 87. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 14"' at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl base.
88、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 15在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 88. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 15 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
89、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 15在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧 基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000180
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 89. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 15 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000180
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
90、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 15在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000181
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 90. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 15 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000181
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
91、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 15在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 91. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 15 at each occurrence is independently selected from hydrogen, fluorine, cyano, methyl, isopropyl.
92、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 16在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 92. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 16 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
93、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 16在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000182
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 93. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 16 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000182
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
94、根据前述项目中任一项所述的化合物或其药学上可接受的盐， 其中：R 16在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000183
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 94. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 16 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000183
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
95、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 16在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 95. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 16 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
96、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 17在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 96. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 17 at each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
97、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 17在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000184
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 97. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 17 at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000184
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
98、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 17在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000185
三氟甲 基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 98. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 17 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000185
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
99、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 17在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。 99. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 17 at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl, isopropyl.
100、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 18在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代。 100. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 18 at each occurrence thereof is independently selected from the group consisting of absent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl.
101、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 18在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000186
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 101. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 18 at each occurrence thereof is independently selected from absent, hydrogen, fluorine, chlorine, cyano, amino, Mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000186
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
102、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 18在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
Figure PCTCN2022114183-appb-000187
三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基。 102. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 18 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, amino, mercapto, - COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure PCTCN2022114183-appb-000187
Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl.
103、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中：R 18在其每一次出现时独立地选自氢、氟、氯、氰基、甲基、异丙基。 103. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein: R 18 at each occurrence is independently selected from hydrogen, fluorine, chlorine, cyano, methyl, isopropyl base.
104、根据前述项目中任一项所述的化合物或其药学上可接受的 盐，其中a是0。104. The compound according to any one of the preceding items, wherein a is 0, or a pharmaceutically acceptable salt thereof.
105、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中a是1。105. The compound according to any one of the preceding items, wherein a is 1, or a pharmaceutically acceptable salt thereof.
106、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中a是2。106. The compound according to any one of the preceding items, wherein a is 2, or a pharmaceutically acceptable salt thereof.
107、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中b是0。107. The compound according to any one of the preceding items, wherein b is 0, or a pharmaceutically acceptable salt thereof.
108、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中b是1。108. The compound according to any one of the preceding items, wherein b is 1, or a pharmaceutically acceptable salt thereof.
109、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中b是2。109. The compound according to any one of the preceding items, wherein b is 2, or a pharmaceutically acceptable salt thereof.
110、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中c是0。110. The compound according to any one of the preceding items, wherein c is zero, or a pharmaceutically acceptable salt thereof.
111、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中c是1。111. The compound according to any one of the preceding items, wherein c is 1, or a pharmaceutically acceptable salt thereof.
112、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中c是2。112. The compound according to any one of the preceding items, wherein c is 2, or a pharmaceutically acceptable salt thereof.
113、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中d是0。113. The compound according to any one of the preceding items, wherein d is 0, or a pharmaceutically acceptable salt thereof.
114、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中d是1。114. The compound according to any one of the preceding items, wherein d is 1, or a pharmaceutically acceptable salt thereof.
115、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中d是2。115. The compound according to any one of the preceding items, wherein d is 2, or a pharmaceutically acceptable salt thereof.
116、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中e是0。116. The compound according to any one of the preceding items, wherein e is 0, or a pharmaceutically acceptable salt thereof.
117、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中e是1。117. The compound according to any one of the preceding items, wherein e is 1, or a pharmaceutically acceptable salt thereof.
118、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中e是2。118. The compound according to any one of the preceding items, wherein e is 2, or a pharmaceutically acceptable salt thereof.
119、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中n是0。119. The compound according to any one of the preceding items, wherein n is 0, or a pharmaceutically acceptable salt thereof.
120、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中n是1。120. The compound according to any one of the preceding items, wherein n is 1, or a pharmaceutically acceptable salt thereof.
121、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中n是2。121. The compound according to any one of the preceding items, wherein n is 2, or a pharmaceutically acceptable salt thereof.
122、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 1是N。 122. The compound according to any one of the preceding items, wherein X 1 is N, or a pharmaceutically acceptable salt thereof.
123、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 1是CR 14。 123. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 14 .
124、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 2是N。 124. The compound according to any one of the preceding items, wherein X2 is N, or a pharmaceutically acceptable salt thereof.
125、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 2是CR 14’。 125. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X 2 is CR 14′ .
126、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 3是N。 126. The compound according to any one of the preceding items, wherein X3 is N, or a pharmaceutically acceptable salt thereof.
127、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 3是CR 14”。 127. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X3 is CR14 " .
128、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 4是N。 128. The compound according to any one of the preceding items, wherein X 4 is N, or a pharmaceutically acceptable salt thereof.
129、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 4是CR 14”’。 129. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X4 is CR14"' .
130、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 5是O。 130. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X5 is O.
131、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 5是CR 15R 16。 131. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X5 is CR15R16 .
132、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 5是NR 17。 132. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X5 is NR17 .
133、根据前述项目中任一项所述的化合物或其药学上可接受的 盐，其中X 6是N。 133. The compound according to any one of the preceding items, wherein X6 is N, or a pharmaceutically acceptable salt thereof.
134、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 6是C。 134. The compound according to any one of the preceding items, wherein X6 is C, or a pharmaceutically acceptable salt thereof.
135、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 7是N。 135. The compound according to any one of the preceding items, wherein X7 is N, or a pharmaceutically acceptable salt thereof.
136、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 7是C。 136. The compound according to any one of the preceding items, wherein X7 is C, or a pharmaceutically acceptable salt thereof.
137、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 8是N。 137. The compound according to any one of the preceding items, wherein X8 is N, or a pharmaceutically acceptable salt thereof.
138、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 6是C。 138. The compound according to any one of the preceding items, wherein X6 is C, or a pharmaceutically acceptable salt thereof.
139、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 9是N。 139. The compound according to any one of the preceding items, wherein X 9 is N, or a pharmaceutically acceptable salt thereof.
140、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中X 9是C。 140. The compound according to any one of the preceding items, wherein X9 is C, or a pharmaceutically acceptable salt thereof.
141、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中T是N。141. The compound according to any one of the preceding items, wherein T is N, or a pharmaceutically acceptable salt thereof.
142、根据前述项目中任一项所述的化合物或其药学上可接受的盐，其中T是CH。142. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein T is CH.

Claims (59)

  1. 由结构式(I)表示的化合物或其药学上可接受的盐：A compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100001
    Figure PCTCN2022114183-appb-100001
    其中：in:
    R 1在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 2在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、 -COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 3在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 4在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 5在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 6在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、 氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 7在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 8在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 9在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷 基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 10在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 10 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 11在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 11 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    Q为CR 12R 13，n是0、1或2； Q is CR 12 R 13 , n is 0, 1 or 2;
    X 1在其每一次出现时独立地选自CR 14或N； X 1 is independently selected from CR 14 or N at each occurrence thereof;
    X 2在其每一次出现时独立地选自CR 14’或N； X is independently selected from CR 14' or N at each occurrence thereof;
    X 3在其每一次出现时独立地选自CR 14”或N； X3 is independently selected from CR 14" or N at each occurrence thereof;
    X 4在其每一次出现时独立地选自CR 14”’或N； X4 is independently selected from CR 14"' or N at each occurrence thereof;
    X 5选自O、CR 15R 16、或NR 17， X 5 is selected from O, CR 15 R 16 , or NR 17 ,
    R 12在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 12 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 13在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 13 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 14在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 14’在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝 基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl The group is optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 14”在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R14 " at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C1 - C6 alkyl, C2 - C6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkane base ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl The group is optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 14”’在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 14"' at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkene C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyl oxy, C 2 -C 6 alkanoyl, C 2 -C 6 Alkyl ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono - and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and hetero Aryl is optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 15在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6 烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 15 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 16在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 16 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 17在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 17 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxyl, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    R 18在其每一次出现时独立地选自不存在、氢、卤素、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 2-C 6烯氧基、C 2-C 6炔氧基、C 2-C 6烷酰基、C 2-C 6烷基酯、C 1-C 6烷硫基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4 烷基(C 3-C 7环烷基)、-O-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代； R 18 at each occurrence thereof is independently selected from absent, hydrogen, halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkyl Ester, C 1 -C 6 alkylthio, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl , (mono- and Di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), -OC 0 -C 4 alkyl (C 3 - C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl;
    T为N或CH；T is N or CH;
    a是0、1或2；a is 0, 1 or 2;
    b是0、1或2；b is 0, 1 or 2;
    c是0、1或2；c is 0, 1 or 2;
    d是0、1或2；d is 0, 1 or 2;
    e是0、1或2；e is 0, 1 or 2;
    X 6是N或C； X 6 is N or C;
    X 7是N或C； X7 is N or C;
    X 8是N或C； X8 is N or C;
    X 9是N或C。 X9 is N or C.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100002
    Figure PCTCN2022114183-appb-100002
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100003
    Figure PCTCN2022114183-appb-100003
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100004
    Figure PCTCN2022114183-appb-100004
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述结构式(I)的化合物为结构式(II)的化合物或其药学上可接受的盐：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of structural formula (I) is a compound of structural formula (II) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100005
    Figure PCTCN2022114183-appb-100005
  6. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(VI)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (VI) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100006
    Figure PCTCN2022114183-appb-100006
  7. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(VII)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (VII) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100007
    Figure PCTCN2022114183-appb-100007
  8. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(VIII)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (VIII) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100008
    Figure PCTCN2022114183-appb-100008
    Figure PCTCN2022114183-appb-100009
    Figure PCTCN2022114183-appb-100009
  9. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(IX)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IX) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100010
    Figure PCTCN2022114183-appb-100010
  10. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(X)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (X) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100011
    Figure PCTCN2022114183-appb-100011
  11. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XI)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (XI) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100012
    Figure PCTCN2022114183-appb-100012
  12. 根据前述权利要求中任一项所述的化合物或其药学上可接受 的盐，其中所述化合物为结构式(XII)的化合物或其药学上可接受的盐：The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XII) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100013
    Figure PCTCN2022114183-appb-100013
  13. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XIII)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XIII) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100014
    Figure PCTCN2022114183-appb-100014
  14. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XIV)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100015
    Figure PCTCN2022114183-appb-100015
  15. 根据前述权利要求中任一项所述的化合物或其药学上可接受 的盐，其中所述化合物为结构式(XV)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XV) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100016
    Figure PCTCN2022114183-appb-100016
  16. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XVI)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XVI) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100017
    Figure PCTCN2022114183-appb-100017
  17. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XVII)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XVII) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100018
    Figure PCTCN2022114183-appb-100018
  18. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XVIII)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XVIII) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100019
    Figure PCTCN2022114183-appb-100019
  19. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物为结构式(XIV)的化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (XIV) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100020
    Figure PCTCN2022114183-appb-100020
  20. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 1在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、 氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 1在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100021
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 1在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100022
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 1在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100021
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100022
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  21. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 2在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 2在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100023
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 2在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100024
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 2 在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100023
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R in each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100024
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R in each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  22. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 3在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 3在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100025
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 3在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100026
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 3在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 3 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R is independently selected at each occurrence of Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100025
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R in each occurrence thereof is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100026
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R in each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  23. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 4在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 4在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧 基、
    Figure PCTCN2022114183-appb-100027
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 4在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100028
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 4在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 4 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R is independently selected at each occurrence of Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100027
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100028
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  24. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 5在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 5在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100029
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 5在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100030
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 5在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100029
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100030
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  25. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 6在其每一次出现时独立地选自不存在、氢、氟、氯、 羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 6在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100031
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 6在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100032
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 6在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100031
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R in each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100032
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R in each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  26. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 7在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 7在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100033
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 7 在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100034
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 7在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 7 at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100033
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100034
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  27. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 8在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 8在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100035
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 8在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100036
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 8在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 8 is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100035
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100036
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  28. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 9在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷 基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 9在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100037
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 9在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100038
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 9在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 9 is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100037
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100038
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  29. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 10在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 10在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100039
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 10在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧 基、
    Figure PCTCN2022114183-appb-100040
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 10在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 10 at each occurrence thereof is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100039
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R in each occurrence thereof is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100040
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  30. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 11在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 11在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100041
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 11在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100042
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 11在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 11 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R 11 at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100041
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R in each occurrence thereof is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100042
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  31. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 12在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、 杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 12在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100043
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 12在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100044
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 12在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 12 is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100043
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100044
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  32. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 13在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 13在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100045
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 13在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧 基、
    Figure PCTCN2022114183-appb-100046
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 13在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 13 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100045
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100046
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  33. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 14在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 14在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100047
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 14在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100048
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 14在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 14 is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R 14 at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100047
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100048
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  34. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 14’在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、 杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 14’在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100049
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 14’在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100050
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 14’在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 14' at each occurrence is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3, or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl; preferably, R 14' is independently at each occurrence selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropyl Oxygen,
    Figure PCTCN2022114183-appb-100049
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano radical, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100050
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, Methyl, isopropyl.
  35. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 14”在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 14”在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100051
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 14”在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧 基、
    Figure PCTCN2022114183-appb-100052
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 14”在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 14 " in each occurrence thereof is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, Cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 Alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 ring alkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl; preferably, R 14" is independently at each occurrence thereof selected from nonexistent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropyl Oxygen,
    Figure PCTCN2022114183-appb-100051
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R 14 " in each occurrence thereof is independently selected from hydrogen, fluoro, chloro, cyano radical, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100052
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R 14 " in each occurrence thereof is independently selected from hydrogen, fluoro, cyano, Methyl, isopropyl.
  36. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 14”’在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 14”’在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100053
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 14”’在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100054
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 14”’在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 14"' is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro at each occurrence thereof , cyano, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl C 1 -C 6 alkyl, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally is optionally substituted by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl; preferably, R 14"' at each occurrence thereof independently selected from absence, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100053
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R 14"' at each occurrence is independently selected from hydrogen, fluoro, chloro, Cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100054
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R 14"' in each occurrence is independently selected from hydrogen, fluoro, cyano , methyl, isopropyl.
  37. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 15在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、 杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 15在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100055
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 15在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100056
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 15在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 15 is independently selected from the group consisting of nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R 15 at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100055
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100056
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  38. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 16在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 16在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100057
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 16在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧 基、
    Figure PCTCN2022114183-appb-100058
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 16在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 16 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R 16 at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100057
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100058
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  39. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 17在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 17在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100059
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 17在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100060
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 17在其每一次出现时独立地选自氢、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R 17 at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100059
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100060
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, fluoro, cyano, methyl base, isopropyl.
  40. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 18在其每一次出现时独立地选自不存在、氢、氟、氯、羟基、硝基、氰基、氨基、巯基、-COOH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、羟基C 1-C 6烷基、氨基C 1-C 6烷基、(单-和二-C 1-C 6烷基氨基)C 0-C 4烷基、-C 0-C 4烷基(C 3-C 7环烷基)、C 3-C 12杂环基、C 6-C 12芳基和C 5-C 10杂芳基，其中所述环烷基、 杂环基、芳基和杂芳基任选地被1、2、3或4个卤素、羟基、硝基、氰基、氨基、巯基、-COOH、或C 1-C 6烷基取代；优选地，R 18在其每一次出现时独立地选自不存在、氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100061
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；更优选地，R 18在其每一次出现时独立地选自氢、氟、氯、氰基、氨基、巯基、-COOH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、
    Figure PCTCN2022114183-appb-100062
    三氟甲基、单氟甲基、二氟甲基、2-氟乙基、五氟乙基；最优选地，R 18在其每一次出现时独立地选自氢、氯、氟、氰基、甲基、异丙基。     A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 18 is independently selected from nonexistent, hydrogen, fluorine, chlorine, hydroxyl, nitro, cyano at each occurrence thereof radical, amino, mercapto, -COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkane group, amino C 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkane radical), C 3 -C 12 heterocyclyl, C 6 -C 12 aryl and C 5 -C 10 heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by 1, 2, 3 or 4 halogen, hydroxy, nitro, cyano, amino, mercapto, -COOH, or C 1 -C 6 alkyl substitutions; preferably, R 18 at each occurrence thereof is independently selected from Absent, hydrogen, fluorine, chlorine, cyano, amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy ,
    Figure PCTCN2022114183-appb-100061
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; more preferably, R at each occurrence is independently selected from hydrogen, fluoro, chloro, cyano , amino, mercapto, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
    Figure PCTCN2022114183-appb-100062
    Trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, pentafluoroethyl; most preferably, R at each occurrence is independently selected from hydrogen, chlorine, fluorine, cyano , methyl, isopropyl.
  41. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：T是N。A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: T is N.
  42. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：R 2是氢、氟、氰基、或甲基。 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 2 is hydrogen, fluoro, cyano, or methyl.
  43. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 8是C，且R 18是氢、氟、氯、氰基、或甲基。 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X 8 is C, and R 18 is hydrogen, fluoro, chloro, cyano, or methyl.
  44. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：-(Q) n-是-(CH 2)-或-(CH 2) 2-。 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: -(Q) n- is -( CH2 )- or -( CH2 ) 2- .
  45. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 5是O。 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X is O.
  46. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 1是N、CH、CF、C-CH 3。 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X1 is N, CH, CF, C- CH3 .
  47. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 2是N、CH、CF、C-CH 3。 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X2 is N, CH, CF, C- CH3 .
  48. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 3是N、CH、CF、C-CH 3。 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X3 is N, CH, CF, C- CH3 .
  49. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 4是N、CH、CF、C-CH 3。 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X4 is N, CH, CF, C- CH3 .
  50. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 6是N、CH、CF、C-CH 3。 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X6 is N, CH, CF, C- CH3 .
  51. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 7是N、CH、CF、C-CH 3。 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X7 is N, CH, CF, C- CH3 .
  52. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中：X 9是N、CH、CF、C-CH 3。 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: X9 is N, CH, CF, C- CH3 .
  53. 根据前述权利要求中任一项所述的化合物或其药学上可接受的盐，其中所述化合物是如下化合物或其药学上可接受的盐：A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein said compound is the following compound, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022114183-appb-100063
    Figure PCTCN2022114183-appb-100063
  54. 一种药物组合物，其包含权利要求1-53中任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。A pharmaceutical composition comprising the compound according to any one of claims 1-53 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  55. 根据权利要54的药物组合物，其中所述药物组合物是片剂、胶囊剂、颗粒剂、糖浆剂、悬浮液、溶液、分散剂、用于口服或非口服给药的缓释制剂、静脉注射制剂、皮下注射制剂、吸入制剂、透皮制剂、直肠或阴道栓剂。The pharmaceutical composition according to claim 54, wherein said pharmaceutical composition is tablet, capsule, granule, syrup, suspension, solution, dispersion, sustained-release preparation for oral or parenteral administration, intravenous Injectable preparations, subcutaneous injection preparations, inhalation preparations, transdermal preparations, rectal or vaginal suppositories.
  56. 根据权利要求1-53中任一项所述的化合物或其药学上可接受的盐在制备用于治疗增殖性疾病的药物中的用途。Use of the compound according to any one of claims 1-53 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating proliferative diseases.
  57. 根据权利要求1-53中任一项所述的化合物或其药学上可接受的盐，用于治疗增殖性疾病。The compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, for use in the treatment of proliferative diseases.
  58. 一种在有需要的受试者中治疗增殖性疾病的方法，包括向有需要的受试者施用治疗有效量的根据权利要求1-53中任一项所述的化合物或其药学上可接受的盐。A method of treating a proliferative disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to any one of claims 1-53, or a pharmaceutically acceptable compound thereof, to a subject in need thereof of salt.
  59. 根据权利要求56-58所述的用途、化合物或其药学上可接受的盐或方法，其中所述增殖性疾病包括：乳腺癌、结肠癌、脑癌、前列腺癌、肾癌、胰腺癌、卵巢癌、头颈癌、黑素瘤、结直肠癌、胃癌、鳞癌、小细胞肺癌、非小细胞肺癌、睾丸癌、梅克尔细胞癌、胶质母细胞瘤、神经细胞瘤、淋巴器官的癌症和骨髓恶性肿瘤包括白血病(急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、急性单核细胞白血病(AMOL)、多毛细胞白血病(HCL)、T-细胞幼淋巴细胞白血病(T-PLL)、巨粒淋巴细胞白血病、成人T细胞白血病)、淋巴瘤(小淋巴细胞淋巴瘤(SLL)、霍奇金淋巴瘤(结节硬化型、混合细胞型、富于淋巴细胞型、淋巴细胞削减型或未削减型和结节性淋巴细胞主导的霍奇金淋巴瘤)、非霍奇金淋巴瘤(所有亚型)、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、B-细胞前淋巴细胞白血病、淋巴质浆细胞白血病(诸如瓦尔登斯特伦病巨球蛋白血症)、脾边缘带淋巴瘤、浆细胞肿瘤(浆细胞性骨髓瘤、浆细胞瘤、单克隆免疫球蛋白沉积物疾病、重链病)、结节外边缘区B细胞淋巴瘤(MALT淋巴瘤)、结节边缘区B细胞淋巴瘤(NMZL)、滤 泡淋巴瘤、外套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、T细胞幼淋巴细胞白血病、T细胞巨粒淋巴细胞白血病、攻击性NK细胞白血病、成人T细胞白血病/淋巴瘤、结节外NK/T细胞淋巴瘤(鼻型)、肠病型T细胞淋巴瘤、肝脾T细胞淋巴瘤、亚顶级NK细胞淋巴瘤、蕈样真菌病/塞扎里综合征、原发性皮肤间CD30-阳性T细胞淋巴增生性病症、原发性皮肤间变性大细胞淋巴瘤、淋巴瘤样丘疹病、血管免疫母细胞性T细胞淋巴瘤、外周T细胞淋巴瘤(非特异性)、间变性大细胞淋巴瘤)、多发性骨髓瘤(浆细胞性骨髓瘤或卡勒病)。The use, compound or pharmaceutically acceptable salt or method according to claims 56-58, wherein the proliferative disease comprises: breast cancer, colon cancer, brain cancer, prostate cancer, kidney cancer, pancreatic cancer, ovarian cancer Carcinoma, head and neck cancer, melanoma, colorectal cancer, gastric cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, testicular cancer, Merkel cell carcinoma, glioblastoma, neuroblastoma, cancer of lymphoid organs and myeloid malignancies including leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), hirsutism leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), giant myeloid lymphocytic leukemia, adult T-cell leukemia), lymphoma (small lymphocytic lymphoma (SLL), Hodgkin lymphoma (node nodular sclerosis, mixed cellularity, lymphocytic, lymphopenic or unreduced and nodular lymphocyte-predominant Hodgkin lymphoma), non-Hodgkin lymphoma (all subtypes), chronic Lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic leukemia (such as Waldenstrom's disease macroglobulinemia), marginal zone lymphoma of the spleen, plasma cell neoplasms (plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposit disease, heavy chain disease), extranodal marginal zone B-cell lymphoma (MALT lymphoma), nodular marginal zone B-cell lymphoma (NMZL), filter Follicular lymphoma, Mantle cell lymphoma, Diffuse large B-cell lymphoma, Mediastinal (thymic) large B-cell lymphoma, Intravascular large B-cell lymphoma, Primary effusion lymphoma, Burkitt lymphoma/ Leukemia, T-cell prolymphocytic leukemia, T-cell giant myeloid lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia/lymphoma, extranodal NK/T-cell lymphoma (nasal type), enteropathic T-cell Lymphoma, hepatosplenic T-cell lymphoma, subtopic NK-cell lymphoma, mycosis fungoides/Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorder, primary cutaneous anaplastic lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (nonspecific), anaplastic large cell lymphoma), multiple myeloma (plasma cell myeloma or card strangle disease).
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CN102822165A (en) * 2010-02-11 2012-12-12 细胞基因公司 Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
CN111247138A (en) * 2017-08-25 2020-06-05 拜欧赛里克斯公司 Ether compound and use thereof
CN111989322A (en) * 2018-04-23 2020-11-24 细胞基因公司 Substituted 4-aminoisoindoline-1, 3-dione compounds and their use for treating lymphomas
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