WO2023025136A1 - Composé d'isoindolinone et son utilisation - Google Patents

Composé d'isoindolinone et son utilisation 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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English (en)
Chinese (zh)
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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/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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

L'invention concerne un composé d'isoindolinone représenté par la formule structurale (I) ou un sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci dans le traitement de maladies prolifératives. L'invention concerne en outre une composition pharmaceutique comprenant le composé ou son sel selon la présente invention et un support pharmaceutiquement acceptable.
PCT/CN2022/114183 2021-08-27 2022-08-23 Composé d'isoindolinone et son utilisation WO2023025136A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102822165A (zh) * 2010-02-11 2012-12-12 细胞基因公司 芳基甲氧基异吲哚啉衍生物和包括其的组合物及它们的使用方法
CN111247138A (zh) * 2017-08-25 2020-06-05 拜欧赛里克斯公司 醚化合物和其用途
CN111606883A (zh) * 2019-02-25 2020-09-01 上海科技大学 基于戊二酰亚胺骨架的含硫化合物及其应用
CN111989322A (zh) * 2018-04-23 2020-11-24 细胞基因公司 取代的4-氨基异吲哚啉-1,3-二酮化合物以及它们用于治疗淋巴瘤的用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102822165A (zh) * 2010-02-11 2012-12-12 细胞基因公司 芳基甲氧基异吲哚啉衍生物和包括其的组合物及它们的使用方法
CN111247138A (zh) * 2017-08-25 2020-06-05 拜欧赛里克斯公司 醚化合物和其用途
CN111989322A (zh) * 2018-04-23 2020-11-24 细胞基因公司 取代的4-氨基异吲哚啉-1,3-二酮化合物以及它们用于治疗淋巴瘤的用途
CN111606883A (zh) * 2019-02-25 2020-09-01 上海科技大学 基于戊二酰亚胺骨架的含硫化合物及其应用

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