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WO2025140369A1 - Compounds with two azaheterocycles substituted isoindolinone skeleton and uses thereof - Google Patents

Compounds with two azaheterocycles substituted isoindolinone skeleton and uses thereof Download PDF

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Publication number
WO2025140369A1
WO2025140369A1 PCT/CN2024/142598 CN2024142598W WO2025140369A1 WO 2025140369 A1 WO2025140369 A1 WO 2025140369A1 CN 2024142598 W CN2024142598 W CN 2024142598W WO 2025140369 A1 WO2025140369 A1 WO 2025140369A1
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Prior art keywords
dione
piperidine
methyl
oxoisoindolin
piperazin
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French (fr)
Chinese (zh)
Inventor
杨小宝
任超伟
孙仁红
赵宝寅
傅旭宏
李岩
周跃东
杨森
邓梅桂
蒋素萍
任印波
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Gluetacs Therapeutics Shanghai Co Ltd
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Gluetacs Therapeutics Shanghai Co Ltd
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Priority to CN202480003740.2A priority Critical patent/CN120548310A/en
Publication of WO2025140369A1 publication Critical patent/WO2025140369A1/en
Pending legal-status Critical Current
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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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present disclosure relates to a compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof and uses thereof, in particular, uses thereof for preventing or treating diseases or disorders including tumors or cancer.
  • Thalidomide, lenalidomide and other phthalimide immunomodulatory drugs have significant efficacy in the treatment of multiple myeloma and autoimmune diseases.
  • IMDs phthalimide immunomodulatory drugs
  • CRBN E3 ubiquitin ligase cereblon
  • substrate proteins such as transcription factors IKZF1/3, etc.
  • the polyubiquitinated substrate proteins are recognized and degraded by the proteasome, thereby producing pharmacological effects including anti-tumor and immunomodulation.
  • Molecular glue protein degraders directly target and degrade target proteins, and have potential advantages such as targeting "undruggable” targets. Moreover, molecular glue degraders usually have small molecular weights and good drugability, so the research and development of this type of drug is highly valued. Based on the CRBN E3 ubiquitin ligase and molecular glue degradation mechanism, a series of compounds have been developed, such as the marketed pomalidomide, and CC-122, CC-220, CC-90009, CC-99282 and CC-92480, BMS-986470, DKY709 of Novartis, CFT7455 of C4 Therapeutics, MRT-6160 of Monte Rosa, etc.
  • the degradation substrates of these molecular glues have also expanded from the initially discovered transcription factors IKZF1/3 to casein kinase 1 ⁇ (CK1 ⁇ ), zinc finger protein 91 (ZFP91), WIZ, transcription factor IKZF2, translation factor GSPT1 and immune disease target Vav1, etc.
  • the degradation of these protein substrates will enable the molecular glue to exert immunomodulatory, anti-inflammatory and anti-tumor pharmacological activities.
  • the structural novelty of the molecular glue candidate compounds discovered so far is very limited, and diversified skeleton design and development of more molecular glues have become research hotspots in this field.
  • Ring B is optionally substituted with n2 R d2 groups, each R d2 being independently deuterium, C 1-6 alkyl (e.g., C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (e.g., perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.), halogenated C 1-6 alkyl (e.g., halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF
  • C 1-6 alkoxy e.g. C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
  • halogenated C 1-6 alkoxy e.g.
  • R c represents a bond.
  • ring B is directly connected to ring C.
  • examples of straight or branched C 1-10 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, and octyl.
  • examples of C3-30 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl (e.g., C5 - C20 spirocyclyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decyl, spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl
  • the C3-30 cycloalkyl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, oxo, C1-6 alkyl, halo-substituted C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halo-substituted C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.
  • substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, oxo, C1-6 alkyl, halo-substituted C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halo-substitute
  • examples of 4- to 30-membered heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxypiperidinyl, difluoropiperidinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanyl, dioxanyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepanyl, 4,5-diazepanyl, 1,3-dia
  • the C5-30 aryl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl , deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.
  • substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl , deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl.
  • examples of 5- to 30-membered heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl , benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,
  • the 5- to 30-membered heteroaryl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl.
  • substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substit
  • Ring C is optionally substituted by n3 Rd3 groups, each Rd3 independently representing deuterium, C1-6 alkyl (e.g. C1-5 alkyl, C1-4 alkyl or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C1-6 alkyl, halogenated C1-6 alkyl (e.g.
  • halogenated C1-4 alkyl such as F3C- , FCH2- , F2CH- , ClCH2- , Cl2CH- , CF3CF2- , CF3CHF- , CHF2CF2- , CHF2CHF- , CF3CH2- or CH2ClCH2- ) , C1-6 alkoxy (e.g.
  • ring C represents a C3-30 cycloalkylene group, examples of which include, but are not limited to, C3-20 cycloalkylene, C3-15 cycloalkylene , and C3-11 cycloalkylene, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decahydronaphthylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, spirocyclylene (e.g., C5 - C20 spirocycloalkylene and C3-11 cycloalkylene) 5-15 spirocyclylene (e.g., spiro[3.3]heptanylene, spiro[2.5]
  • the cycloalkylene group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, hydroxy, amino, thiol, nitro, halogen, cyano, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl.
  • substituents selected from deuterium, hydroxy, amino, thiol, nitro, halogen, cyano, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl,
  • the arylene group is optionally substituted with one or more (e.g., 1-6, 1-4, 1-3, 2-6 or 1) substituents selected from deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl.
  • substituents selected from deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alky
  • ring D represents C3-30 cycloalkyl (e.g., C3-20 cycloalkyl, or C3-15 cycloalkyl), 4 to 30 membered heterocyclyl (e.g., 4 to 20 membered heterocyclyl, or 4 to 15 membered heterocyclyl), C5-30 aryl (e.g., C5-20 aryl, or C5-15 aryl), or 5 to 30 membered heteroaryl (e.g., 5 to 20 membered heteroaryl, or 5 to 15 membered heteroaryl).
  • C3-30 cycloalkyl e.g., C3-20 cycloalkyl, or C3-15 cycloalkyl
  • 4 to 30 membered heterocyclyl e.g., 4 to 20 membered heterocyclyl, or 4 to 15 membered heterocyclyl
  • C5-30 aryl e.g., C5-20 aryl, or C5-15 aryl
  • Ring D is optionally substituted by n4 R d4 groups
  • each R d4 is each independently deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl
  • n4 represents an integer of 0 , 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • ring D represents a C3-30 cycloalkyl group, examples of which include, but are not limited to, a C3-20 cycloalkyl group, a C3-15 cycloalkyl group, and a C3-11 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl (e.g., C5 - C20 spirocyclyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl,
  • ring D represents a 4- to 30-membered heterocyclic group, examples of which include, but are not limited to, 4- to 20-membered, 4- to 15-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 5- to 15-membered, and 5- to 9-membered heterocyclic groups, such as azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl
  • ring D represents a 5- to 30-membered heteroaryl, examples of which are not limited to 5- to 20-membered heteroaryl, 5- to 15-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, and 5- to 6-membered heteroaryl, such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindole, indolyl, benzofuranyl, benzophenone ...
  • oxazolo[4,5-d]pyrimidinyl pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl.
  • X represents:
  • ring A represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group, a wherein n1 is an alkylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, a 5- to 20-membered nitrogen-containing heterocyclylene group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alken
  • Ring C represents a cycloalkylene group (e.g., a C 3-30 cycloalkylene group, a C 3-20 cycloalkylene group, or a C 3-15 cycloalkylene group), a heterocyclylene group wherein the ring C is optionally substituted with n3 R d3 groups, and each R d3 independently represents deuterium, C 1-6 alkyl , deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy , halogenated ...
  • n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g.
  • n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • X represents:
  • ring A represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group, a wherein n1 is an alkylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, a 5- to 20-membered nitrogen-containing heterocyclylene group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alken
  • R c2 represents H, deuterium, halogen, an optionally substituted straight chain or branched chain alkyl group (e.g.
  • n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g.
  • X represents:
  • ring A represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group, a wherein n1 is an alkylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, a 5- to 20-membered nitrogen-containing heterocyclylene group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alken
  • n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and ring D represents a heterocyclic group (e.g., a 4- to 30-membered heterocyclic group, a 4- to 20-membered heterocyclic group or a 4- to 15-membered heterocyclic group), a cycloalkyl group (Rd4)n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g.
  • the compound of formula (I) is also a compound of formula (I-5): wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , (R a5 ) m , R and X are as defined above for the compound of formula (I) and its embodiments.
  • the compound of formula (I-5) is also a compound of formula (I-5-2): wherein Z 1 , (R a5 ) m , R, L and X are as defined above for the compound of formula (I) and its embodiments.
  • the compound of formula (I-5) is also a compound of formula (I-5-3): wherein Z 1 , (R a5 ) m , R and X are as defined above for the compound of formula (I) and its embodiments.
  • the compounds of the present disclosure may have a stereo configuration and therefore may exist in more than one stereoisomer form.
  • the present disclosure also relates to optically enriched compounds having a stereo configuration, such as about greater than 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures.
  • polymorphic forms of compounds of the present disclosure or salts of compounds of the present disclosure are also provided.
  • the salts of compounds of the present disclosure may be pharmaceutically acceptable salts, including but not limited to hydrohalides (including hydrochlorides, hydrobromides), sulfates, citrates, maleates, benzenesulfonates, glycolates, ⁇ -D-glucoheptonates, D-gluconates, L-lactates, L-malates, malonates, mandelates, phosphates, propionates, succinates, tartrates, p-toluenesulfonates, valerates, palmitates, sebacates, stearates, laurates, acetates, adipates, carbonates, p-chlorobenzenesulfonates, edisylate, fumarates
  • the compounds of the present invention can be present in pharmaceutically acceptable solvents such as water, ethanol, etc.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials.
  • the carrier must be "acceptable” if it is compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and is not harmful to the patient.
  • the pharmaceutical composition of the present disclosure further comprises at least one second therapeutic agent, such as an anticancer agent.
  • the second therapeutic agent can be combined with the compound of formula (I) described in the present disclosure to treat the disease or condition described in the present disclosure.
  • the second therapeutic agent includes but is not limited to a chemotherapeutic agent, an immunotherapeutic agent, a gene therapy agent, etc.
  • the pharmaceutical composition described in the present disclosure comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared into a suitable formulation form according to a suitable administration route (including but not limited to nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural cavity administration, intrathecal administration and intravenous administration), such as spray preparations, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (such as soft capsules, hard capsules, enteric-coated capsules), dragees, lozenges, powders, granules, powder injections, suppositories, or liquid preparations (such as suspensions (such as aqueous or oily suspensions), solutions, emulsions or syrups), or conventional injection forms such as injectable solutions (such as sterile injection solutions prepared according to methods
  • the compound of formula (I) described in the present disclosure is used as a medicament.
  • the medicament of the present disclosure or the pharmaceutical composition of the present disclosure may be present in a medicine box/packaged product.
  • the medicine box/packaged product may include a package or container.
  • the package or container includes, but is not limited to, an ampoule, a blister package, a medicinal plastic bottle, a vial, a medicinal glass bottle, a container, a syringe, a laminated flexible package, a co-extruded film infusion container, a test tube, and a dispensing device, etc.
  • the medicine box/packaged product may include a product instruction manual.
  • the diseases or conditions include: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes.
  • infectious diseases inflammatory diseases
  • autoimmune diseases anemia
  • hemorrhagic shock transplant rejection
  • multiple organ dysfunction syndrome MODS
  • sarcoidosis adult respiratory distress syndrome
  • cardiovascular disease cardiovascular disease
  • Richter syndrome (RS) Richter syndrome
  • the disease or condition includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia (CML), chronic myeloid leukemia, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute B-cell leukemia, T-cell leukemia, acute T-cell leukemia, lymphoma cell leukemia, monocytic leukemia, myelomonocytic leukemia; lymphomas, including diffuse large B-cell lympho
  • a therapeutically effective amount of a compound of formula (I) described in the present disclosure, or a pharmaceutical composition comprising a compound of formula (I) as an active ingredient described in the present disclosure is administered to the subject by at least one administration method selected from nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural space administration, intrathecal administration and intravenous administration.
  • treatment refers to administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, to slow down (mitigate) the development of an undesirable disease or condition (e.g., a tumor).
  • an undesirable disease or condition e.g., a tumor.
  • the beneficial or desired clinical results of the present disclosure include, but are not limited to, alleviating symptoms, reducing the severity of the disease, stabilizing the state of the disease, delaying or slowing the progression of the disease, improving or alleviating the condition, and alleviating the disease.
  • the "therapeutically effective amount" of the disclosed compounds depends on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the age, sex and weight of the patient, the patient's overall medical condition, the mode and time of administration, the rate of excretion, co-administration, and the progression of the disease or condition of the patient being treated. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.
  • the patient or subject for treatment mentioned above refers to an animal, such as a mammal, including but not limited to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice, etc.
  • the compound of formula (I) disclosed herein can be prepared by reacting a compound of formula (M1) with a compound of formula (M2): wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 , ( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc , Ring C, m1, (R d3 ) n3 , Ring D, and (R d4 ) n4 are as defined in the compounds of formula (I) and various sub-embodiments thereof disclosed herein;
  • the nitrogen-containing heterocycle A represents a 4- to 30-membered nitrogen-containing heterocycle (preferably, a 4- to 20-membered nitrogen-containing heterocycle; more preferably, a 4- to 15-membered nitrogen-containing heterocycle);
  • R represents an optionally substituted straight or branched C 1-5 alkylene group;
  • R represents -CH2- , -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4- or -( CH2 ) 5- ; wherein the above groups are optionally substituted with substituents selected from deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl and C2-6 alkenyl.
  • the nitrogen-containing heterocyclic ring A after the hydrogen atom on N is removed by reaction, obtains the nitrogen-containing heterocyclic group A.
  • the nitrogen-containing heterocyclic ring A represents a 4- to 30-membered nitrogen-containing heterocyclic ring (preferably, a 4- to 20-membered nitrogen-containing heterocyclic ring; more preferably, a 4- to 15-membered nitrogen-containing heterocyclic ring).
  • the nitrogen-containing heterocyclic group A represents a 4- to 30-membered nitrogen-containing heterocyclic group (preferably, a 4- to 20-membered nitrogen-containing heterocyclic group; more preferably, a 4- to 15-membered nitrogen-containing heterocyclic group).
  • the compound of formula (M1) reacts with the compound of formula (M2) to undergo an amine alkylation reaction.
  • the amine alkylation reaction can be carried out, for example, in the presence of an organic base and sodium iodide at room temperature to 80°C (e.g., 40°C to 60°C, 40°C to 50°C, or 50°C to 60°C).
  • the compound of formula (M1) is prepared by reacting a compound of formula (M3) with methanesulfonic anhydride or methanesulfonyl chloride: wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 and R are as defined in the compounds of formula (I) and its various sub-embodiments disclosed herein.
  • R may represent CH2 .
  • the compound of formula (M1) can be prepared by a halogenation reaction of a compound of formula (M3) with a hydrohalic acid: wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 and R are as defined in the compounds of formula (I) and its various sub-embodiments disclosed herein.
  • R may represent CH2 .
  • the compound of formula (M3) (wherein R represents CH 2 ) can be prepared by coupling reaction of the compound of formula (M4) with (tributyltin)methanol under a palladium catalyst: wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 and Z5 are as defined in the compounds of formula (I) and various subembodiments thereof disclosed herein.
  • the coupling reaction can be carried out, for example, in the presence of tetrakis(triphenylphosphine)palladium and 1,4-dioxane (or DMF) at 40°C to 120°C.
  • the compound of formula (M4) is prepared by subjecting the compound of formula (M5) to an amine transesterification reaction with the compound of formula (M6): wherein the groups Ra1 , Ra2 , Ra3 , Ra4 and ( Ra5 ) m are as defined in the compounds of formula (I) and various sub-embodiments thereof disclosed herein.
  • C1 -C10alkyl examples include C1-9alkyl , C1-8alkyl , C2-8alkyl , C1-7alkyl, C1-6alkyl , C1-5alkyl , C1-4alkyl , C1 - C3alkyl , and C1 - C2alkyl .
  • Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl.
  • heterocyclyl or “heterocycloalkyl”, used alone or in combination, refers to a 4- to 30-membered (alternatively 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 13-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered or 5- to 15-membered) monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1
  • the heterocyclyl group may be unsubstituted or substituted as explicitly defined (e.g. mono-, di-, tri- or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, haloC 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, haloC 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)—, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.
  • the substituents are optionally selected from deuterium, hydroxyl, amino, mercapto, nitro,
  • nitrogen-containing heterocyclic group examples include, but are not limited to, nitrogen-containing monocyclic heterocyclic groups (e.g., 4- to 30-membered nitrogen-containing monocyclic heterocyclic groups and 4- to 20-membered nitrogen-containing monocyclic heterocyclic groups), nitrogen-containing bridged heterocyclic groups (e.g., 5- to 30-membered nitrogen-containing bridged heterocyclic groups, 5- to 20-membered nitrogen-containing bridged heterocyclic groups, 5- to 15-membered nitrogen-containing bridged heterocyclic groups, 7- to 20-membered nitrogen-containing bridged heterocyclic groups, or 7- to 15-membered nitrogen-containing bridged heterocyclic groups), nitrogen-containing fused heterocyclic groups (e.g., 5- to 30-membered nitrogen-containing fused heterocyclic groups and 5- to 20-membered nitrogen-containing fused heterocyclic groups), and nitrogen-containing spiro heterocyclic groups (e.g., 5- to 30-membered nitrogen-containing spiro heterocyclic groups (e
  • nitrogen-bridged heterocyclic groups examples include, but are not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, octahydro-1H-indolyl, and azaspirocyclic groups (e.g., 5- to 20-membered azaspirocyclic groups, such as 3-azaspiro[5.5]undec-3-yl).
  • azaspirocyclic groups e.g., 5- to 20-membered azaspirocycl
  • the nitrogen-containing heterocyclic group may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy , halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)—, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.
  • the substituents are optionally selected from deuterium, hydroxyl, amino, mer
  • heterocyclylene examples include, but are not limited to, monocyclic heterocyclylene (e.g., 4 to 30-membered monocyclic heterocyclylene, and 4 to 20-membered monocyclic heterocyclylene), bridging heterocyclylene (e.g., 5 to 30-membered bridging heterocyclylene, 5 to 20-membered bridging heterocyclylene, 7 to 20-membered bridging heterocyclylene, or 7 to 15-membered bridging heterocyclylene), fused heterocyclylene (e.g., 5 to 30-membered fused heterocyclylene, and 5 to 20-membered fused heterocyclylene), and spiro heterocyclylene (e.g., 5 to 30-membered spiro heterocyclylene, and 5 to 20-membered spiro heterocyclylene).
  • monocyclic heterocyclylene e.g., 4 to 30-membered monocyclic heterocyclylene, and 4 to 20-membered mono
  • bridged, fused, and spiro heterocyclyl groups include, but are not limited to, 6-azabicyclo[3.1.1]heptanylene, 2,5-diazabicyclo[2.2.1]heptanylene, 3,6-diazabicyclo[3.1.1]heptanylene, 3-azabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 2,5-diazabicyclo[2.2.2]octanylene, octahydro-1H-indolylene, and azaspirocyclylene (e.g., a 5- to 20-membered azaspirocyclylene, such as 3-azaspiro[5.5]undecylene).
  • azaspirocyclylene e.g., a 5- to 20-membered azaspirocyclylene, such as 3-azaspiro[5.5
  • the heterocyclylene group may be unsubstituted or substituted as explicitly defined (e.g. mono-, di-, tri- or polysubstituted), wherein the substituents may be optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.
  • the substituents may be optionally selected from deuterium, hydroxyl, amino, mercapto,
  • nitrogen-containing heterocyclylene or “nitrogen-containing heterocycloalkylene”, used alone or in combination, refers to a 4- to 30-membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one nitrogen atom and optionally containing one or more (e.g., containing 1
  • nitrogen-containing heterocyclylene examples include, but are not limited to, nitrogen-containing monocyclic heterocyclylene (e.g., 4- to 30-membered nitrogen-containing monocyclic heterocyclylene, and 4- to 20-membered nitrogen-containing monocyclic heterocyclylene), nitrogen-containing bridged heterocyclyl (e.g., 5- to 30-membered nitrogen-containing bridged heterocyclyl, 5- to 20-membered nitrogen-containing bridged heterocyclyl, 7- to 20-membered nitrogen-containing bridged heterocyclyl, or 7- to 15-membered nitrogen-containing bridged heterocyclyl), nitrogen-containing fused heterocyclyl (e.g., 5- to 30-membered nitrogen-containing fused heterocyclyl and 5- to 20-membered nitrogen-containing fused heterocyclyl), and nitrogen-containing spiro heterocyclyl (e.g., 5- to 30-membered nitrogen-containing spiro heterocyclyl and 5- to 20-membered nitrogen-containing s), and nitrogen-containing
  • nitrogen-containing monocyclic heterocyclylene groups include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanylidene, diazepanylidene (e.g., 1,4-diazepanylidene, 4,5-diazepanylidene, 1,3-diazepanylidene) and diazepanylidene.
  • azetidinyl pyrrolidinyl
  • imidazolidinyl imidazolidinyl
  • pyrazolidinyl imidazolidinyl
  • pyrazolidinyl imidazolidinyl
  • pyrazolidinyl imidazolidinyl
  • nitrogen-containing bridged heterocyclic groups examples include, but are not limited to, 6-azabicyclo[3.1.1]heptanylidene, 2,5-diazabicyclo[2.2.1]heptanylidene, 3,6-diazabicyclo[3.1.1]heptanylidene, 3-azabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 2,5-diazabicyclo[2.2.2]octanylidene, octahydro-1H-indolylidene, and azaspirocyclic groups (e.g., 5 to 20 membered azaspirocyclic groups, such as 3-azaspiro[5.5]undecylidene).
  • azaspirocyclic groups e.g., 5 to 20 membered azaspirocyclic groups, such as 3-
  • 2-butenyl 2-butenyl
  • bicyclo[2.2.1]heptane also known as bicyclo[2.2.1]heptane
  • norbornane has a definition known to those skilled in the art.
  • bicyclo[2.2.1]heptane or “norbornane” refers to a monovalent radical of bicyclo[2.2.1]heptane, i.e., the radical remaining after any one of the hydrogen atoms in bicyclo[2.2.1]heptane is removed.
  • adamantyl include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, 9-adamantyl, and 10-adamantyl.
  • noradamantane also known as noradamantane, or octahydro-2,5-methanopentalene
  • noradamantane also known as noradamantane, or octahydro-2,5-methanopentalene
  • noradamantane has the definition known to those skilled in the art, and its structural formula is shown below, for example:
  • “noradamantyl” refers to a monovalent group of noradamantane, i.e., the group remaining after any one hydrogen in noradamantane is removed.
  • noradamantyl include, but are not limited to, 1-noradamantyl, 2-noradamantyl, 3-noradamantyl, 4-noradamantyl, 5-noradamantyl, 6-noradamantyl, 7-noradamantyl, 8-noradamantyl, and 9-noradamantyl.
  • adamantanamine has a definition known to those skilled in the art, i.e., refers to adamantane having an amino substituent, wherein the amino group can replace the hydrogen on any carbon position of the adamantane.
  • An example of "adamantanamine” can be adamantane-1-amine (its corresponding English chemical name is adamantan-1-amine or Tricyclo[3.3.1.1 3,7 ]decan-1-amine; CAS: 768-94-5), having the following structural formula
  • salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, and polymorphs of the compounds of formula (I) described in the present disclosure are also encompassed within the scope of the present disclosure.
  • the salt or pharmaceutically acceptable salt of the compound of formula (I) refers to a non-toxic inorganic or organic acid and/or base addition salt.
  • examples include: sulfate, hydrohalide (including hydrochloride, hydrobromide), maleate, sulfonate, citrate/citrate, lactate, lactobionate, L-tartrate, fumarate, L-malate, L-lactate, ⁇ -ketoglutarate, hippurate, D-glucuronate, D-gluconate, ⁇ -D-glucoheptonate, glycolate, mucate, L-ascorbate, orotate, picrate, glycinate, alanine, arginine, cinnamate, laurate, pamoate, sebacate, benzenesulfonate, methanesulfonate, ethanesulfonate, edisylate, formate, acetate, 2,2-dich
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, that carries or transports a compound useful in the present disclosure to a patient or administers it to a patient so that it can perform its intended function. Typically, such a construct is carried or transported from one organ or part of the body to another organ or part of the body.
  • the carrier must be “acceptable” if it is compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and is not harmful to the patient.
  • materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; phosphate buffered solutions as surfactants; and other nontoxic compatible substances used in pharmaceutical formulations.
  • room temperature refers to ambient temperature, for example, a temperature of 20-30°C.
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to a complex in which the solvent molecule is water.
  • chiral refers to a molecule that has the property of being non-superimposable on its mirror image; whereas “achiral” refers to a molecule that is superimposable on its mirror image.
  • enantiomers refers to two non-superimposable isomers of a compound that are mirror images of each other.
  • diastereomer refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.
  • p-menthane also known as p-methane
  • p-menthanyl refers to a monovalent group of p-menthane, that is, the group remaining after any hydrogen on any carbon position of p-menthane is removed. Representative examples include but are not limited to
  • m-menthane (also known as m-methane) has a definition known to those skilled in the art, and its structural formula is shown below:
  • m-menthanyl refers to a monovalent group of m-menthane, that is, the group remaining after any hydrogen on any carbon position of m-menthane is removed. Representative examples include but are not limited to
  • quinuclidine also known as Quihuclidine
  • whose chemical name is 1-azabicyclo[2.2.2]octane has a definition known to those skilled in the art, and its structural formula is shown below:
  • quinuclidine group refers to a monovalent group of quinuclidine, that is, the group remaining after any hydrogen on any carbon at any position of quinuclidine is removed. Representative examples include but are not limited to
  • Figure 1 shows the Western Blot experimental results of the degradation of target substrate protein by the compounds of the present invention in hPBMC cells.
  • LC-MS spectrum was measured on Sciex API 2000 mass spectrometer with Agilent 1100 binary pump, DAD and ELSD or Agilent 1260-6125B single quadrupole liquid-mass spectrometer with Agilent 1260 quaternary pump, DAD and ELSD, HPLC preparation was measured on SHIMADZU LC-20AP instrument, HPLC purity was measured on SHIMADZU LC-30AP or Waters The reaction was measured on a 1525 instrument. All reactions were carried out under air atmosphere unless otherwise specified; the reaction was followed by TLC or LC-MS
  • Solvents and reagents were processed as follows: DCM, DMF, anhydrous EtOH and anhydrous MeOH were purchased from Sinopharm Group; preparative-grade CH 3 CN and deionized water were used for HPLC preparation; other reaction substrates, reagents and drugs were directly purchased from commercial channels unless otherwise specified, or were synthesized using or according to methods known in the art.
  • the compounds and/or pharmaceutically acceptable salts thereof disclosed herein can be synthesized using commercially available raw materials by synthetic techniques known in the art.
  • the synthetic schemes described below illustrate the preparation methods of most compounds.
  • the starting materials or reagents used in each scheme can be purchased from commercial sources or prepared by methods known to those skilled in the art.
  • Salts, racemates, enantiomers, phosphates, sulfates, hydrochlorides and prodrug forms of the compounds of formula (I) disclosed herein can be prepared by those skilled in the art according to conventional techniques in the art.
  • groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4, Z5 , nitrogen-containing heterocyclic ring A, ( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc , ring C, m1, ( Rd3 ) n3 , ring D and ( Rd4 ) n4 are as defined in the compounds of formula (I) and their respective sub-embodiments disclosed herein.
  • the group LE of substrate 1 represents Cl, Br, I, OMs, OTs, or ONs.
  • Substrate 2 is a compound corresponding to the X moiety containing a nitrogen-containing heterocyclic ring in the compound of formula (I).
  • the amine alkylation reaction in Scheme 1 can be carried out, for example, in the presence of DIEA and sodium iodide, or triethylamine and sodium iodide, at room temperature to 80° C. (e.g., 40° C. to 60° C., 40° C. to 50° C., or 50° C. to 60° C.).
  • the molar ratio of substrate 1 to substrate 2 can be, for example, 1:1.1 to 2, 1:1.1 to 1.5, 1:1.1 to 1.2, or 1:1.2 to 1.3, etc.
  • scheme 1 For example, the specific operations of scheme 1 can be as follows:
  • the bromide substrate 1 (1.3 eq.) and substrate 2 (1.0 eq.) were dissolved in anhydrous DMF (2 mL), and then triethylamine (3.0 eq.) and sodium iodide (1.0 eq.) were added to the solution.
  • the reaction solution was stirred at 50°C for 2 hours. LCMS detected that the reaction was complete.
  • the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to obtain the target compound.
  • the target compound (GT-04379) was prepared by referring to the method of synthesis scheme 1 (white solid, 35 mg, yield 50%).
  • 1 H NMR 400 MHz, MeOD
  • LCMS (ESI) C 36 H 39 F 3 N 5 O 3 + [M+H] + : calculated value 646.
  • the target compound (GT-04380) (white solid, 19 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-5037) (white solid, 49 mg, yield 52%) was prepared by referring to the method of synthesis scheme 1.
  • Example 13 Preparation of 3-(5-((4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04595)
  • Example 14 Preparation of 3-(5-((4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04596)
  • the target compound (GT-05160) (white solid, 50 mg, yield 48%) was prepared by referring to the method of synthesis scheme 1.
  • the target compound (GT-04604) (white solid, 29 mg, yield 33%) was prepared by referring to the method of synthesis scheme 1.
  • 1 H NMR 400 MHz, MeOD
  • 7.84 s, 1H
  • 7.34-7.30 m, 2H
  • 7.17-7.15 m, 1H
  • the target compound (GT-04605) (white solid, 30 mg, yield 34%) was prepared by referring to the method of synthesis scheme 1 .
  • NMR 400MHz, MeOD
  • ⁇ 7.82-7.77(m, 2H), 7.35-7.27(m, 2H), 7.18-7.16(m, 1H), 5.19(dd, J 13.4, 5.2Hz, 1H), 4.72-4.50(m, 4H), 3.78-3.73(m, 3H), 3.68-3.54(m, 4H), 3.49-3.47(m, 2H), 3.28-3.11(m, 4H), 3.02-2.85(m, 2 H), 2.84-2.74(m, 1H), 2.59-2.44(m, 3H), 2.22-2.13(m, 3H).
  • the target compound (GT-04606) was prepared by referring to the method of synthesis scheme 1 (white solid, 23 mg, yield 26%).
  • 1 H NMR 400 MHz, MeOD
  • LCMS (ESI) C 29 H 33 Cl 2 FN 5 O 3 + [M+H] +
  • the target compound (GT-04607) (white solid, 25 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, MeOD
  • LCMS (ESI) C 29 H 33 Cl 2 FN 5 O 3 + [M+H] + : calculated value 588.19, found value 588.2.
  • the target compound (GT-05212) (white solid, 23 mg, 25%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-04989) (white solid, 14 mg, 17%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-04931) (white solid, 23 mg, 26%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-04932) (white solid, 32 mg, 36%) was prepared by referring to the method of synthesis scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-05105) (white solid, 12 mg, 10%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-05208) (white solid, 20 mg, 17%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C
  • the target compound (GT-05042) (white solid, 11 mg, 9%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C 35 H 39 F 2 N 6 O 2 S + [M+H] + : calculated value 645.28,
  • the target compound (GT-04941) (white solid, 15 mg, 18%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C 35 H 41 N 6 O 3 + [M+H] + : calculated value 59
  • the target compound (GT-05255) (white solid, 34 mg, 37%) was prepared by referring to the method of Synthesis Scheme 1 .
  • LCMS (ESI) C 35 H 39 N 6 O 4 + [M+H] + : calculated value 607.30, found value 607.3.
  • Example 51 Preparation of 3-(6-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09863)
  • the target compound GT-09863 (16 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound GT-09939 (14 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound GT-09935 (8 mg, white solid, yield 12%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C 29 H 34 Cl 2 N 5 O 2 S + [M
  • the target compound GT-09687 (13 mg, white solid, yield 19%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS
  • the target compound GT-09575 (31 mg, white solid, yield 43%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C 29 H 32 Cl 2 F 2 N 5 O 2 S + [
  • the target compound GT-09693 (11 mg, white solid, yield 16%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C 29 H 32 Cl 2 F 2 N 5 O 2 S + [M+H] + : Calculated value 622.16, measured value 622.2.
  • the target compound GT-09688 (12 mg, white solid, yield 17%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • LCMS ES
  • the target compound GT-09694 (10 mg, white solid, yield 15%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound GT-09861 (13 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • ⁇ 11.15 s, 1H
  • 7.89 s, 1H
  • the target compound GT-09940 (10 mg, white solid, yield 15%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound GT-09864 (11 mg, white solid, yield 16%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS
  • the target compound GT-09615 (15 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound GT-09355 (11 mg, white solid, yield 20%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound GT-09206 (31 mg, white solid, yield 41%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound GT-09359 (17 mg, white solid, yield 33%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C 29 H 31 FN 7 O 5 + [M+H] + : calculated value 576.24, found value 576.3.
  • the target compound GT-09360 (38 mg, white solid, yield 69%) was prepared by referring to the method of Synthesis Scheme 1.
  • Example 80 Preparation of 1-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-09208)
  • the target compound GT-09208 (34 mg, white solid, yield 46%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09188) (white solid, 27 mg, yield 46%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09189) (white solid, 20 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09190) (white solid, 10 mg, yield 17%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09337) (white solid, 16 mg, yield 27%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09339) (yellow solid, 19 mg, yield 32%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09340) (white solid, 12 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09342) (yellow solid, 18 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 1.
  • Example 104 Preparation of 3-(5-((4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09347)
  • the target compound (GT-09347) (white solid, 22 mg, yield 42%) was prepared by referring to the method of Synthesis Scheme 1.
  • Example 106 Preparation of 3-(6-((4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09349)
  • Example 107 Preparation of 3-(7-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09350)
  • Example 108 Preparation of 3-(5-(2-(4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09351)
  • the target compound (GT-09351) (white solid, 23 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09389) (white solid, 23 mg, yield 38%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09390) (white solid, 9 mg, yield 11%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09393) (yellow solid, 20 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09417) (white solid, 35 mg, yield 59%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • LCMS ESI
  • the target compound (GT-09418) (white solid, 31 mg, yield 52%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09420) (white solid, 31 mg, yield 54%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09421) (white solid, 39 mg, yield 67%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09422) (white solid, 27 mg, yield 47%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • ⁇ 11.03 (s, 1H), 7.77-7.62 (m, 3H), 7.40-7.25 (m, 2H), 7.20-7.09 (m, 1H), 5.17-5.08 (m, 1H), 4.85-4.38 (m, 4H), 3.71-3.66 (m, 2H), 3.41-3 .37 (m, 2H), 3.18 (s, 8H), 2.98-2.86 (m, 2H), 2.62 (d, J 17.6 Hz, 1H), 2.47-2.37 (m, 1H), 2.35-2.26 (m, 1H), 2.23-2.11 (m, 1H), 2.08-1.99 (m, 1H).
  • LCMS (ESI) C 29 H 32 Cl 2 F 2 N 5 O 3 + [M+H] + : calculated value 606.18, found value 606.2.
  • the target compound (GT-09430) (white solid, 23 mg, yield 39%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09431) (white solid, 18 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1.
  • Example 135 Preparation of 5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09432)
  • the target compound (GT-09432) (white solid, 27 mg, yield 46%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ESI) C 29 H 30 Cl 2 F 2 N 5 O 4 + [M+H] + : calculated value 620.16, found
  • the target compound (GT-09433) (white solid, 30 mg, yield 51%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • ⁇ 11.14 (s, 1H), 7.99-7.92 (m, 1H), 7.92-7.85 (m, 2H), 7.38-7.33 (m, 2H), 7.20-7.14 (m, 1H), 5.16 (dd, J 12.7, 5.4 Hz, 1H), 4.23 (s, 2H), 3.
  • Example 137 Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09599)
  • Example 138 Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09600)
  • the target compound (GT-09600) (white solid, 20 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS ESI
  • the target compound (GT-09601) (white solid, 16 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • LCMS (ESI) C 30 H 30 Cl 2 F 3 N 4
  • Example 140 Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09602)
  • the target compound (GT-09602) (white solid, 6 mg, yield 11%) was prepared by referring to the method of Synthesis Scheme 1.
  • Example 141 Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09635)
  • the target compound (GT-09635) (white solid, 18 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09636) (white solid, 23 mg, yield 41%) was prepared by referring to the method of Synthesis Scheme 1.
  • LCMS (ES1) C 30 H 31 Cl 2 F 2 N 4 O 3 + [M+H] + : calculated value 603.17,
  • the target compound (GT-09638) (white solid, 17 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09641) (white solid, 16 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09644) (white solid, 14 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09645) (white solid, 12 mg, yield 20%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09647) (white solid, 15 mg, yield 24%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09648) (white solid, 18 mg, yield 15%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09649) (white solid, 10 mg, yield 16%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • LCMS ESI
  • the target compound (GT-09650) (yellow solid, 10 mg, yield 16%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09655) (white solid, 35 mg, yield 59%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09656) (white solid, 26 mg, yield 44%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09658) (white solid, 36 mg, yield 62%) was prepared by referring to the method of Synthesis Scheme 1.
  • the target compound (GT-09659) (white solid, 28 mg, yield 499%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09660) (white solid, 24 mg, yield 42%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09661) (white solid, 24 mg, yield 41%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • Example 164 Preparation of 3-(5-(3-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09662)
  • the target compound (GT-09668) (white solid, 23 mg, yield 40%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • Example 171 Preparation of 3-(6-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09669)
  • Example 172 Preparation of 3-(7-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09670)
  • Example 173 Preparation of 3-(5-(2-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09671)
  • the target compound (GT-09672) (white solid, 35 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 1.
  • Example 175 Preparation of 5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09673)
  • the target compound (GT-09673) (white solid, 13 mg, yield 22%) was prepared by referring to the method of Synthesis Scheme 1.
  • 1 H NMR 400 MHz, DMSO
  • LCMS
  • Example 176 Preparation of 4-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09674)
  • the target compound (GT-09676) (white solid, 10 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 4.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09677) (white solid, 6 mg, yield 17%) was prepared by referring to the method of Synthesis Scheme 4.
  • 1 H NMR 400 MHz, DMSO
  • the target compound (GT-09678) (white solid, 13 mg, yield 35%) was prepared by referring to the method of Synthesis Scheme 4.
  • the target compound (GT-09710) (white solid, 7 mg, yield 19%) was prepared by referring to the method of Synthesis Scheme 4.
  • the target compound (GT-09711) (white solid, 11 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4.
  • the target compound (GT-09712) (white solid, 8 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 4.
  • 1 H NMR 400 MHz, DMSO
  • LCMS
  • Table I-8 Inhibitory activity of the disclosed compounds on tumor cell proliferation (IC 50 , nM)
  • the symbols A+++, A++, A+, A, B, C, D, E, F, and G indicate the following: 0nM ⁇ A++++ ⁇ 2nM; 2nM ⁇ A+++ ⁇ 5nM; 5nM ⁇ A++ ⁇ 10nM; 10nM ⁇ A+ ⁇ 20nM; 20nM ⁇ A ⁇ 50nM; 50nM ⁇ B ⁇ 100nM; 100nM ⁇ C ⁇ 200nM; 200nM ⁇ D ⁇ 500nM; 500nM ⁇ E ⁇ 1000nM; 1000nM ⁇ F ⁇ 5000nM; 5000nM ⁇ G ⁇ 10000nM; 10000nM ⁇ H.
  • the symbol “-” means not detected.
  • hPBMC cells with a cell density of 1 ⁇ 10 6 cells/mL were revived according to the PBMC cell resuscitation operating instructions (Miaoshun (Shanghai) Biotechnology Co., Ltd.), and then treated with the compounds of the present disclosure (including the compounds in Table 1 and the compounds of each example) at concentrations of 500nM and 50nM.
  • a negative control group (DMSO) and a positive control group were also set up: the corresponding commercial immunomodulatory drugs (lenalidomide), which were treated with the same treatment method as the compounds of the present disclosure.
  • Method for reading half degradation concentration (drug concentration corresponding to 50% protein degradation, i.e. DC 50 ): Compare the gray value of the Western blotting band after drug treatment with the gray value of the Western blotting band after blank DMSO treatment, and read the drug concentration range when the gray value is half of the gray value of the Western blotting band after blank DMSO treatment.
  • the DC 50 value can be calculated by using ImageJ software to read the gray value of the corresponding Western blotting band after drug treatment, and the relationship curve between drug concentration and gray value can be fitted to estimate the drug concentration corresponding to half of the gray value.
  • the % remaining protein content refers to the amount of target protein remaining in the cells after the cells are treated with a protein degrading compound.
  • Calculation method of protein residual content % Use Image J software to read the gray value of the corresponding Western blotting band after drug (protein degrader) treatment. Divide the gray value of the corresponding Western blotting band after drug treatment by the gray value of the corresponding Western blotting band of the internal reference protein, and normalize the obtained quotient to obtain the relative residual content % of the target protein after protein degrader treatment.
  • Target protein degradation rate % 1-target protein remaining content %
  • Table II-1 The results of the effects of the compounds disclosed herein (including the compounds in Table 1 and the compounds in the examples) on the expression of substrate proteins in cells are listed in the following Table II-1.
  • Table II-1 Degradation results of the disclosed compounds on substrate proteins WEE1, IKZF1, IKZF2, IKZF3, CK1 ⁇ and GSPT1 Note: In Table II-1, A means 0% ⁇ substrate protein remaining content ⁇ 80%, B means 80% ⁇ substrate protein remaining content ⁇ 100%.
  • the degradation effect of the compounds of the present invention on the target substrate protein is shown in Table II-1 and Figure 1. From the experimental results in Table II-1 and Figure 1, it can be seen that the compounds of the present invention can significantly degrade substrate proteins (such as WEE1 protein, IKZF1/2/3 protein, CK1 ⁇ protein, GSPT1 protein, etc.). Compared with lenalidomide, the compounds of the present invention have a significant improvement in the efficiency of inducing the degradation of substrate proteins, and can also selectively induce the degradation of substrate proteins, so that they can be used to treat indications related to substrate proteins.
  • substrate proteins such as WEE1 protein, IKZF1/2/3 protein, CK1 ⁇ protein, GSPT1 protein, etc.
  • the CEREBLON BINDING KITS kit (specification 10,000 tests; reagent number: 64BDCRBNPEH; supplier CISBIO) was used to detect the CRBN binding ability of the test compound by HTRF (homogeneous time-resolved fluorescence) method.
  • the specific method is as follows: 1. According to the instructions of the CEREBLON BINDING KITS kit, the compounds to be tested in the present disclosure (including the compounds in Table 1 and the example compounds) and lenalidomide were serially diluted, specifically using diluent #9 (1X) solution as the diluent, and setting multiple concentration gradients.
  • the dilution operation can be performed in one of the following two ways: (1) The first dilution method: The test compounds of the present disclosure (including the compounds in Table 1 and the example compounds) were diluted 5-fold from the highest concentration of 40 ⁇ M, and a total of 7 concentrations were set from high to low (40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256 ⁇ M). Subsequently, the diluted test compounds of the present disclosure and the corresponding detection reagents were added to each well of the 96-well plate, and the final test concentrations of the test compounds in each well reached 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064 ⁇ M, respectively.
  • a second dilution method can be used: the test compound of the present disclosure (including the compounds in Table 1 and the example compounds) is diluted 4 times from the highest concentration of 8 ⁇ M, and a total of 2 concentrations (8 ⁇ M, 2 ⁇ M) are set.
  • the diluted test compound of the present disclosure and the corresponding detection reagent are added to each well, and the final test concentration of the test compound in each well reaches 2 ⁇ M and 0.5 ⁇ M, respectively.
  • the experimental operation is described as follows using the diluted 8 ⁇ M test compound and lenalidomide solution as an example. 2.
  • Table III-1 HTRF inhibitory activity of the compounds of the present invention (including but not limited to the compounds in Table 1 and the compounds of the examples) (IC 50 , ⁇ M)
  • the symbols a1, a, b, c, d and e have the following meanings: 0 ⁇ a0 ⁇ 0.1 ⁇ M, 0.1 ⁇ M ⁇ a ⁇ 0.5 ⁇ M, 0.5 ⁇ M ⁇ b ⁇ 1 ⁇ M, 1 ⁇ M ⁇ c ⁇ 1.5 ⁇ M, 1.5 ⁇ M ⁇ d ⁇ 1.9 ⁇ M, 1.9 ⁇ M ⁇ e ⁇ 10 ⁇ M, 10 ⁇ M ⁇ f.
  • Table III-2 Compounds of the present invention (including but not limited to compounds in Table 1 and Example compounds) at 2 ⁇ M and 0.5 ⁇ M concentrations CRBN binding affinity screening
  • the symbols a1, a2, a3, a4, a5, a6 and a7 have the following meanings: 0% ⁇ a ⁇ 10%, 10% ⁇ a1 ⁇ 20%, 20% ⁇ a2 ⁇ 30%, 30% ⁇ a3 ⁇ 40%, 40% ⁇ a4 ⁇ 53%, 53% ⁇ a5 ⁇ 60%, 60% ⁇ a6 ⁇ 70%, 70% ⁇ a7 ⁇ 80%, 80% ⁇ a8 ⁇ 100%.
  • Tables III-1 and III-2 show that the compounds of the present invention (including but not limited to the compounds in Table 1 and the compounds of the examples) have lower or equivalent IC 50 values than lenalidomide, or have higher inhibition rates, and exhibit stronger binding affinity to CRBN.
  • PBMCs were cultured at 37°C, 5% CO2 , and then seeded in 96-well plates at 1 ⁇ 107 cells/well.
  • Test compounds (including compounds in Table 1 and Example compounds) were dissolved in DMSO and diluted to the corresponding concentrations, so that the final concentration of DMSO added to the cell culture did not exceed 0.5%.
  • the cells were stimulated with lipopolysaccharide (LPS; 1 ng/ml) and continued to be cultured for 18-20 hours, and then the supernatant was collected, diluted with serum-free medium, and the TNF- ⁇ level was tested using an ELISA kit, and then Graphpad Prism 7.0 was used to calculate the IC50 .
  • LPS lipopolysaccharide
  • TNF- ⁇ expression Down-regulation of TNF- ⁇ expression is an important factor in the anti-tumor effect of immunomodulators. After treatment with the compounds of the present invention, TNF- ⁇ levels are inhibited in a dose-dependent manner.
  • the pharmacokinetic properties of the disclosed compounds are tested using conventional pharmacokinetic experimental methods.
  • test compounds of the present disclosure are orally administered to experimental animals to evaluate the pharmacokinetic properties of the compounds of the present disclosure.
  • the experimental animals used can be adult healthy rodents (e.g., mice, rats (e.g., Sprague-Dawley (SD) rats), guinea pigs) or non-rodents (rabbits, dogs, and monkeys) commonly used in pharmacokinetic experiments.
  • the experimental animals used in the present disclosure are mice.
  • the experimental animals were divided into two groups, a control group (blank plasma was collected) and an oral administration group (dosage was 10 mg/kg or 30 mg/kg). Blood samples were collected at predetermined sampling time points after administration, for example, the blood collection time points were: 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration. Blank plasma was collected from the control group.
  • the plasma samples were pre-treated before analysis: 10 ⁇ L 50% acetonitrile and 200 ⁇ L internal standard solution (the internal standard solution was an acetonitrile solution containing 50 ng/ml dexamethasone) were added to 10 ⁇ L plasma sample.
  • the plasma samples of the blank control group were not added with internal standard, but with the same volume of acetonitrile.
  • the treated samples were vortexed and centrifuged, and the supernatant was taken for LC-MS/MS injection analysis.
  • the concentration of the compound in the plasma sample to be tested was determined by LC-MS/MS analysis. According to the blood drug concentration data determined by LC-MS/MS analysis, the pharmacokinetic parameters of the test compound were calculated using the pharmacokinetic calculation software WinNonlinv8.1 non-compartmental model.
  • DMPK pharmacokinetic
  • the inventors have detected the effects of the compounds of the present invention on the release of a series of inflammatory factors from peripheral blood mononuclear cells (PBMCs) triggered by phytohemagglutinin or eBioscience TM cell stimulation complex (comprising PMA and Ionomycin), including TNF- ⁇ , IL-2, IL-5, IL-10, IL-1 ⁇ , IL-6, IL-1 ⁇ , granulocyte-macrophage colony stimulating factor (GM-CSF), etc.
  • PBMCs peripheral blood mononuclear cells
  • eBioscience TM cell stimulation complex comprising PMA and Ionomycin
  • TNF- ⁇ TNF- ⁇
  • IL-2 phytohemagglutinin or eBioscience TM cell stimulation complex
  • IL-1 ⁇ IL-1 ⁇
  • IL-6 granulocyte-macrophage colony stimulating factor
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • autoimmune diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS)
  • IL-1 ⁇ is associated with cancer, autoimmune diseases, infectious diseases, and other inflammatory diseases, and is involved in the inflammatory process of autoimmune diseases.
  • diseases such as rheumatoid arthritis and systemic lupus erythematosus
  • the increase of IL-1 ⁇ can reflect the degree and activity of inflammatory response.
  • IL-2, IL-5, IL-10, and GM-CSF may also be associated with a variety of inflammatory diseases and autoimmune diseases.
  • Test compounds including compounds in Table 1 and compounds in Examples were prepared into 10 mM stock solutions using DMSO. 2) The test compound was diluted 10 times with DMSO with 1 mM as the highest concentration to obtain compounds with 2 concentration gradients. 3) Dilute the test compound with culture medium to 5 times the final concentration of the corresponding effect. 4) Add the diluted compound to the corresponding cell wells according to the following layout at 25 ⁇ L/well. The final concentration of the compound is Start with 1 ⁇ M and dilute 10 times, with a total of 2 concentration points.
  • PHA or PMA + Ionomycin was added to the cell wells at 25 ⁇ L/well to a final concentration of PHA of 1 ⁇ g/mL (TNF- ⁇ , IL-10, IL-6, IL-1 ⁇ , IFN- ⁇ , IL-2, IL-12p40, IL-1 ⁇ , IL-8), or a final concentration of PMA of 81 nM/mL (IL-4, IL-5, IL-13, GM-CSF and IL-17A), or a final concentration of Ionomycin of 1.34 ⁇ M/mL (IL-4, IL-5, IL-13, GM-CSF and IL-17A). 6) The cell plate was placed in a high humidity, 37°C, 5% CO2 incubator and incubated for 24 hours. Cell Plate Layout:
  • Flow cytometer detection Use a flow cytometer to detect the mixture. The flow cytometer excites the fluorescent markers on the microspheres with lasers, collects and analyzes the fluorescent signals, and thus quantitatively determines the cytokine concentration in the sample. (3) Further analysis is required based on the data collected by flow cytometry.
  • FACP is usually used for data processing to generate detailed cytokine concentration (TNF- ⁇ , IL-10, IL-6, IL-1 ⁇ , IFN- ⁇ , IL-2, IL-12p40, IL-1 ⁇ , IL-8, IL-4, IL-5, IL-13, GM-CSF and IL-17A) reports.
  • cytokine concentration TNF- ⁇ , IL-10, IL-6, IL-1 ⁇ , IFN- ⁇ , IL-2, IL-12p40, IL-1 ⁇ , IL-8, IL-4, IL-5, IL-13, GM-CSF and IL-17A
  • Inhibition rate % [(Ac-As)/(Ac-Ab)] ⁇ 100%
  • OA of sample (cells + PHA/PMA + Ionomycin + test compound)
  • Ac OA of positive cell control (cells + PHA/PMA + Ionomycin + DMSO)
  • Ab OA of blank control (cells + culture medium + DMSO)
  • XY-analysis/Nonlinear regression curve IC50 curve fitting was performed using the data from the R-squared fitting method (fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters) and the IC50 value was calculated.
  • Table IV Inhibition rate of the compounds of the present invention (including but not limited to the compounds in Table 1 and the compounds in the examples) on inflammatory factors at concentrations of 1 ⁇ M and 0.1 ⁇ M (%)
  • symbols IV1, IV2, IV3, IV4, IV5, IV6, IV7, IV8, IV9, IV10, IV11, IV12, IV13 The meanings of IV1 and IV14 are as follows: -320% ⁇ IV1 ⁇ -200%, -200% ⁇ IV2 ⁇ -100%, -100% ⁇ IV3 ⁇ -50%, -50% ⁇ IV4 ⁇ 0%, 0% ⁇ IV5 ⁇ 10%, 10% ⁇ IV6 ⁇ 20%, 20% ⁇ IV7 ⁇ 30%, 30% ⁇ IV8 ⁇ 40%, 40% ⁇ IV9 ⁇ 50%, 50% ⁇ IV10 ⁇ 60%, 60% ⁇ IV11 ⁇ 70%, 70% ⁇ IV12 ⁇ 80%, 80% ⁇ IV13 ⁇ 90%, 90% ⁇ IV14 ⁇ 100%.
  • the symbol "-" means not detected.
  • the experimental results show that the disclosed compounds (including compounds in Table 1 and Example compounds) show excellent regulatory ability in regulating the level of cytokine production associated with inflammatory diseases and autoimmune diseases, and their inhibitory effect is more significant than that of the positive control drug lenalidomide.
  • the positive control drug lenalidomide has an increasing effect on IL-2 or IL-10, which will produce an inflammatory reaction.
  • patients have the risk of toxic effects such as rashes.
  • the disclosed compounds have an inhibitory or no obvious stimulating effect on IL-2 and IL-10, which has a greater advantage in treating immune system diseases.
  • the disclosed compounds have a broad prospect of becoming a potential therapy for treating a variety of inflammatory diseases, autoimmune diseases (such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and its arthritis, systemic lupus erythematosus, atopic dermatitis, and suppurative hidradenitis, etc.).
  • autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and its arthritis, systemic lupus erythematosus, atopic dermatitis, and suppurative hidradenitis, etc.
  • mice After the experimental animals were grouped, the backs of all mice were shaved, and except for the Control group, the animals in the other groups were topically applied with imiquimod cream once a day for 7 consecutive days. At the same time, according to the above table, each group was given solvent control, positive control drug or test substance once a day for 7 consecutive days.
  • Scoring of gross lesion score (PASI method): During the last 3 days of modeling and drug administration, the changes in skin lesions of mice in each group were observed once a day. PASI method: The erythema, scaling and infiltration thickening of the skin lesions were scored separately, and the three scores were added together to form the total score. PASI scoring standard: 0 points, none; 1 point, mild; 2 points, moderate; 3 points, severe; 4 points, extremely severe.
  • mice were euthanized by inhalation of excessive CO 2.
  • the skin from three different parts of the back lesions was taken with a 6 mm punch and weighed and recorded, and the average weight was calculated.
  • Skin tissue homogenates from lesions were used to detect the levels of IL-23p19, IL-12p40, IL-17, and TNF- ⁇ .
  • the experimental data were expressed as Mean ⁇ SD.
  • the data between the two groups were analyzed using SPSS statistics, and p ⁇ 0.05 was considered to be a significant difference.
  • the experimental results show that the disclosed compound has an improving effect on imiquimod-induced psoriasis-like lesions on the back skin of mice, and can be used to treat psoriasis.
  • test substances including compounds in Table 1 and example compounds
  • Wistar rats induced with bovine type II collagen (Chondrex) once a day for 21 consecutive days to study the pharmacodynamic effects of the compounds of the present invention on the rat arthritis model (CIA).
  • CIA rat arthritis model
  • each group of animals is given solvent control, positive control drug or test substance by oral gavage (or subcutaneous injection) according to the above table, once a day for 21 consecutive days.
  • the start of drug administration was recorded as day 0. Five days after drug administration, i.e., 2 hours after drug administration on the fifth day, blood was collected from the jugular vein of the experimental animals, allowed to stand for more than 30 minutes, centrifuged to separate serum, and stored at -80°C. Serum TNF- ⁇ , IL-1 ⁇ , and IL-6 were detected by ELISA.
  • the animals were euthanized by inhalation of excessive CO 2.
  • the spleen and thymus of the animals were collected, weighed, and the organ coefficient was calculated.
  • Pathological examination The foot joint tissue of one side was fixed in 10% neutral formalin solution, decalcified and embedded in paraffin for preparation of pathological sections and HE staining for pathological observation. Observation indicators: 1. Infiltration of synovial inflammatory cells (lymphocytes, plasma cells); 2. Synovial tissue hyperplasia; 3. Synovial pannus; 4. Fibrinoid necrosis on the synovial surface. Scoring method: 0, 1, 2, 3, 4 five levels: "0" not seen; "1"mild;"2"moderate;"3"severe; “4”: Extremely severe.
  • the experimental data were expressed as Mean ⁇ SEM.
  • the data between the two groups were analyzed using Excel-T test, and p ⁇ 0.05 was considered to be significantly different.
  • the scoring data were analyzed using SPSS non-parametric test Mann-Whitney U test, and p ⁇ 0.05 was considered to be significantly different.
  • the experimental results show that the disclosed compounds can regulate the levels of serum inflammatory factors in CIA model rats induced by bovine type II collagen, have a significant improvement effect on swelling of the rat limbs, and can be used to treat arthritis.

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Abstract

The present disclosure relates to a compound represented by formula (I) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof and a use thereof. The present disclosure also relates to pharmaceutical compositions comprising, as an active ingredient, the compound represented by formula (I) or the salt, enantiomer, stereoisomer, solvate, polymorph thereof, and a use thereof. In the present disclosure, the compounds designed and synthesized can effectively prevent or treat diseases or conditions related to celeblon protein, including tumors or cancers.

Description

具有双氮杂环取代的异吲哚啉酮骨架的化合物及其应用Compounds having dinitrogen heterocyclic substituted isoindolinone skeletons and their applications 技术领域Technical Field

本公开涉及式(I)的化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物及其应用，尤其是其用于预防或治疗包括肿瘤或癌症的疾病或病症的应用。
The present disclosure relates to a compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof and uses thereof, in particular, uses thereof for preventing or treating diseases or disorders including tumors or cancer.

背景技术Background Art

沙利度胺、来那度胺等邻苯二甲酰亚胺类免疫调节药物(IMiDs)在治疗多发性骨髓瘤及自身免疫疾病方面疗效显著，但直至2010年，其直接结合蛋白才被鉴定出为E3泛素连接酶cereblon(CRBN)，随后证实该类药物与CRBN结合后，可作为分子胶水招募底物蛋白(如转录因子IKZF1/3等)，使CRBN和底物蛋白之间发生蛋白蛋白相互作用进而将这些底物蛋白泛素化，多聚泛素化后的底物蛋白被蛋白酶体识别并降解，从而产生抗肿瘤、免疫调节等在内的药理学作用。分子胶蛋白降解剂直接靶向降解清除靶蛋白，具有靶向“不可成药”靶点等潜在优势。而且分子胶降解剂通常分子量小、成药性好，因此该类药物的研发受到高度重视。基于CRBN E3泛素连接酶和分子胶降解机制，又有一系列的化合物被开发出来，如已上市的泊马度胺以及正在进行临床试验的百时美施贵宝(BMS)公司的CC-122、CC-220、CC-90009、CC-99282和CC-92480、BMS-986470、诺华(Novartis)公司的DKY709、以及C4 Therapeutics的CFT7455，Monte Rosa的MRT-6160等。这些分子胶的降解底物也从最初发现的转录因子IKZF1/3扩展到酪蛋白激酶1α(CK1α)、锌指蛋白91(ZFP91)、WIZ、转录因子IKZF2、翻译因子GSPT1和免疫疾病靶点Vav1等，这些蛋白底物的降解会使分子胶发挥免疫调节、抗炎和抗肿瘤等药效活性。目前已发现的分子胶候选化合物的结构新颖性十分有限，多样化骨架设计、开发更多的分子胶成为该领域的研究热点。Thalidomide, lenalidomide and other phthalimide immunomodulatory drugs (IMiDs) have significant efficacy in the treatment of multiple myeloma and autoimmune diseases. However, it was not until 2010 that their direct binding protein was identified as E3 ubiquitin ligase cereblon (CRBN). It was subsequently confirmed that after binding to CRBN, this type of drug can act as a molecular glue to recruit substrate proteins (such as transcription factors IKZF1/3, etc.), causing protein-protein interactions between CRBN and substrate proteins, and then ubiquitination of these substrate proteins. The polyubiquitinated substrate proteins are recognized and degraded by the proteasome, thereby producing pharmacological effects including anti-tumor and immunomodulation. Molecular glue protein degraders directly target and degrade target proteins, and have potential advantages such as targeting "undruggable" targets. Moreover, molecular glue degraders usually have small molecular weights and good drugability, so the research and development of this type of drug is highly valued. Based on the CRBN E3 ubiquitin ligase and molecular glue degradation mechanism, a series of compounds have been developed, such as the marketed pomalidomide, and CC-122, CC-220, CC-90009, CC-99282 and CC-92480, BMS-986470, DKY709 of Novartis, CFT7455 of C4 Therapeutics, MRT-6160 of Monte Rosa, etc. The degradation substrates of these molecular glues have also expanded from the initially discovered transcription factors IKZF1/3 to casein kinase 1α (CK1α), zinc finger protein 91 (ZFP91), WIZ, transcription factor IKZF2, translation factor GSPT1 and immune disease target Vav1, etc. The degradation of these protein substrates will enable the molecular glue to exert immunomodulatory, anti-inflammatory and anti-tumor pharmacological activities. The structural novelty of the molecular glue candidate compounds discovered so far is very limited, and diversified skeleton design and development of more molecular glues have become research hotspots in this field.

因此，本专利申请基于CRBN E3泛素连接酶设计开发一系列新颖的分子胶降解剂，可以用于治疗和/或预防降解蛋白介导的或与其相关的疾病或病症。Therefore, this patent application designs and develops a series of novel molecular glue degraders based on CRBN E3 ubiquitin ligase, which can be used to treat and/or prevent diseases or conditions mediated by or related to degraded proteins.

发明内容Summary of the invention

鉴于以上，本公开的目的在于提供新颖的具有双氮杂环取代的异吲哚啉酮骨架的蛋白降解化合物，它们的制备方法，用途，以及它们的使用方法。In view of the above, the object of the present disclosure is to provide novel protein degradation compounds having a dinitrogen heterocycle-substituted isoindolinone skeleton, their preparation methods, uses, and methods of using them.

为实现上述目的及其他相关目的，在一方面，本公开提供一种式(I)化合物或其盐、立体异构体(包括对映异构体、非对映异构体)、溶剂化物或多晶型物：

其中
Z1表示C(O)、C(S)、CH2或CD2，Z2、Z3和Z4各自独立地表示C(O)或C(S)；
Z5表示CH或N；
Ra1、Ra2、Ra3和Ra4各自独立地表示氢、氘、卤素、C1-6烷基、卤代C1-6烷基、氘代C1-6烷
基、C1-6烷氧基、氘代C1-6烷氧基或卤代C1-6烷氧基；
(Ra5)m表示与其连接的异吲哚啉环可选地被m个Ra5取代，各Ra5相同或不同且各自独立地
表示氘、卤素、羟基、巯基、硝基、氨基、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基或C2-6炔基；
m表示整数0、1、2或3；
R表示C(O)或可选取代的直链或支链的C1-5亚烷基；
X表示：

其中环A表示含氮亚杂环基，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各
自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0-20的整数；
环B表示含氮亚杂环基，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独
立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0-20的整数；
Rc表示C(O)、CRc1Rc2或键，其中Rc1和Rc2各自独立地表示H、氘、卤素、可选经取
代的直链或支链烷基、可选经取代的环烷基、可选经取代的杂环基、可选经取代的芳基或可选经取代的杂芳基；
环C表示亚环烷基、亚杂环基、亚芳基或亚杂芳基，m1表示0或1的整数，(Rd3)n3表
示环C可选地被n3个Rd3基团取代，各Rd3各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0-20的整数；和
环D表示杂环基、环烷基、芳基或杂芳基，(Rd4)n4表示环D可选地被n4个Rd4基团取
代，各Rd4各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0-20的整数。To achieve the above-mentioned object and other related objects, in one aspect, the present disclosure provides a compound of formula (I) or a salt, stereoisomer (including enantiomer, diastereomer), solvate or polymorph thereof:

in
Z 1 represents C(O), C(S), CH 2 or CD 2 , and Z 2 , Z 3 and Z 4 each independently represent C(O) or C(S);
Z 5 represents CH or N;
Ra1 , Ra2 , Ra3 and Ra4 each independently represent hydrogen, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy or halogenated C1-6 alkoxy;
(R a5 ) m represents that the isoindoline ring connected thereto is optionally substituted by m R a5 , each R a5 being the same or different and independently representing deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
m represents an integer 0, 1, 2 or 3;
R represents C(O) or an optionally substituted linear or branched C 1-5 alkylene group;
X means:

wherein ring A represents a nitrogen-containing heterocyclic group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0-20;
Ring B represents a nitrogen-containing heterocyclic group, (R d2 ) n2 represents that Ring B is optionally substituted by n2 R d2 groups, each R d2 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n2 represents an integer of 0-20;
R c represents C(O), CR c1 R c2 or a bond, wherein R c1 and R c2 each independently represent H, deuterium, halogen, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
Ring C represents a cycloalkylene group, a heterocyclylene group, an arylene group or a heteroarylene group, m1 represents an integer of 0 or 1, (R d3 ) n3 represents that ring C is optionally substituted by n3 R d3 groups, each R d3 each independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n3 represents an integer of 0 to 20; and ring D represents a heterocyclyl group, a cycloalkyl group, an aryl group or a heteroaryl group, (R d4 ) n4 represents that ring D is optionally substituted by n4 R d4 groups, each R d4 each independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 wherein n4 represents an integer of 0-20; n5 represents a C 1-6 alkoxy group, a halogenated ... amino group, a hydroxyl group, a mercapto group, a cyano group, an oxo group, a C 2-6 alkynyl group or a C 2-6 alkenyl group; and n6 represents an integer of 0-20.

在另一方面，本公开提供一种药物组合物，其包含所述的式(I)化合物或其医药学上可接受的盐、立体异构体(包括对映异构体、非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物，及至少一种医药学上可接受的载体。In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug or polymorph, and at least one pharmaceutically acceptable carrier.

在另一方面，本公开还提供一种药盒或试剂盒，其包含：式(I)化合物或其药学上可接受的盐或包含其的药物组合物。In another aspect, the present disclosure also provides a medicine box or a test kit, which comprises: a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

在另一方面，本公开提供所述的式(I)化合物，或其医药学上可接受的盐、对映异构体、非对映异构体、溶剂化物、前药或多晶型物，其用作药物。In another aspect, the present disclosure provides the compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, prodrug or polymorph thereof, for use as a medicament.

在另一方面，本公开提供所述的式(I)化合物，或其医药学上可接受的盐、立体异构体(包括对映异构体、非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物或本公开所述的药物组合物，其用于治疗或预防与cereblon蛋白相关的疾病或病症。In another aspect, the present disclosure provides the compound of formula (I), or its pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug or polymorph or the pharmaceutical composition of the present disclosure, which is used for treating or preventing diseases or disorders associated with cereblon protein.

在另一方面，本公开提供所述的式(I)化合物，或其医药学上可接受的盐、立体异构体(包括对映异构体、非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物或本公开所述的药物组合物，其用于治疗或预防选自以下的疾病或病症：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome，RS)、急性肝功能衰竭和糖尿病。On the other hand, the present disclosure provides the compound of formula (I), or its pharmaceutically acceptable salt, stereoisomer (including enantiomers, diastereomers), solvate, isotopically enriched analog, prodrug or polymorph or the pharmaceutical composition described in the present disclosure, which is used to treat or prevent the following diseases or conditions: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes.

在另一方面，本公开还提供所述的式(I)化合物或其医药学上可接受的盐、立体异构体(包括对映异构体、非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物或本公开所述的药物组合物的用途，其是用于制备用以治疗或预防与cereblon蛋白相关的疾病或病症的药物。On the other hand, the present disclosure also provides the use of the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug or polymorph or the pharmaceutical composition of the present disclosure, which is used to prepare a drug for treating or preventing a disease or condition associated with cereblon protein.

在另一方面，本公开还提供所述的式(I)化合物或其医药学上可接受的盐、立体异构体(包括对映异构体、非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物或本公开所述的药物组合物的用途，其是用于制备用以预防或治疗选自以下的的疾病或病症的药物：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome，RS)、急性肝功能衰竭和糖尿病。On the other hand, the present disclosure also provides the use of the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotope-enriched analog, prodrug or polymorph or the pharmaceutical composition described in the present disclosure, which is used to prepare a drug for preventing or treating a disease or condition selected from the following: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes.

在另一方面，本公开还提供一种治疗或预防与cereblon蛋白相关的疾病或病症的方法，其包括向受试者施用治疗有效量的所述的式(I)化合物，或其医药学上可接受的盐、立体异构体(包括对映异构体、非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物，或本公开所述的药物组合物。On the other hand, the present disclosure also provides a method for treating or preventing a disease or condition associated with cereblon protein, comprising administering to a subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug or polymorph thereof, or a pharmaceutical composition described in the present disclosure.

在另一方面，本公开还提供一种治疗或预防受试者中的疾病或病症的方法，其包括向所述受试者施用治疗有效量的所述的式(I)化合物或其药学上可接受的盐，或所述的药物组合物，其中所述疾病或病症是选自：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome，RS)、急性肝功能衰竭和糖尿病。On the other hand, the present disclosure also provides a method for treating or preventing a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, wherein the disease or condition is selected from: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes.

在另一方面，本公开还提供制备式(I)化合物的方法，其包括使式(M1)化合物与式(M2)化合物反应制备得到式(I)化合物：

其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5、含氮亚杂环A、(Rd1)n1、环B、
(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D、和(Rd4)n4如本公开式(I)化合物及其各子实施方案中所定义；和
R表示可选取代的直链或支链的C1-5亚烷基；
LE表示Cl、Br、I、甲磺酰氧基、对甲苯磺酰氧基、邻硝基苯磺酰基、C(O)Cl或COOH；
和
式(I)化合物的Xa相应地表示由以下通式表示的结构：

其中含氮亚杂环基A是含氮杂环A去除N上的氢原子获得的二价基团，所述含氮亚杂环
基A表示4至30元含氮亚杂环基(优选地，4至20元含氮亚杂环基；更优选地，4至15元含氮亚杂环基)，所述含氮杂环A表示4至30元含氮杂环(优选地，4至20元含氮杂环；更优选地，4至15元含氮杂环)，以及
(Rd1)n1、环B、(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D、和(Rd4)n4如本公开式(I)化合物及
其各子实施方案中所定义。
发明详述In another aspect, the present disclosure also provides a method for preparing a compound of formula (I), comprising reacting a compound of formula (M1) with a compound of formula (M2) to obtain a compound of formula (I):

wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 , nitrogen-containing heterocyclic ring A, ( Rd1 ) n1 , ring B,
( Rd2 ) n2 , Rc , ring C, m1, ( Rd3 ) n3 , ring D, and ( Rd4 ) n4 are as defined in the compounds of formula (I) and various sub-embodiments thereof disclosed herein; and
R represents an optionally substituted straight or branched C 1-5 alkylene group;
LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, o-nitrobenzenesulfonyl, C(O)Cl or COOH;
Xa of the compound of formula (I) corresponds to a structure represented by the following general formula:

wherein the nitrogen-containing heterocyclic group A is a divalent group obtained by removing a hydrogen atom from N of a nitrogen-containing heterocyclic group A, the nitrogen-containing heterocyclic group A represents a 4- to 30-membered nitrogen-containing heterocyclic group (preferably, a 4- to 20-membered nitrogen-containing heterocyclic group; more preferably, a 4- to 15-membered nitrogen-containing heterocyclic group), the nitrogen-containing heterocyclic group A represents a 4- to 30-membered nitrogen-containing heterocycle (preferably, a 4- to 20-membered nitrogen-containing heterocycle; more preferably, a 4- to 15-membered nitrogen-containing heterocycle), and
( Rd1 ) n1 , Ring B, ( Rd2 ) n2 , Rc , Ring C, m1, ( Rd3 ) n3 , Ring D, and ( Rd4 ) n4 are as defined in the compounds of formula (I) and various subembodiments thereof disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION

提供以下详细描述作为示例性具体实施方案，以帮助本领域普通技术人员理解和实施本公开内容。然而，应当认识到，这样的描述并不旨在限制本公开的范围，在不脱离本公开精神和范围的前提下，本公开描述的具体实施方案还可进行各种修饰和变化，这些变化和改进都落入要求保护的本公开范围内。
I.化合物
式(I)化合物 The following detailed description is provided as an exemplary specific embodiment to help those of ordinary skill in the art understand and implement the present disclosure. However, it should be appreciated that such description is not intended to limit the scope of the present disclosure, and the specific embodiments described in the present disclosure may also be subjected to various modifications and changes without departing from the spirit and scope of the present disclosure, and these changes and improvements all fall within the scope of the present disclosure claimed.
I. Compounds
Compound of formula (I)

本公开提供一种式(I)化合物或其盐(包括药学上可接受的盐)、立体异构体(包括对映异构体、非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物：


其中Z1、Z2、Z3、Z4、Z5、Ra1、Ra2、Ra3、Ra4、(Ra5)m、R和X如上文的式(I)化合物及其各实
施方案中所定义。The present disclosure provides a compound of formula (I) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer, diastereomer), solvate, isotopically enriched analog, prodrug or polymorph:


wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Ra 1 , Ra 2 , Ra 3 , Ra 4 , (Ra 5 ) m , R and X are as defined above for the compound of formula (I) and its embodiments.

本公开提供的式(I)化合物或其盐(包括药学上可接受的盐)、立体异构体(包括对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物对CRBN具有结合力，有助于招募底物蛋白，可以作为分子胶结合CRBN E3泛素连接酶。本公开的式(I)化合物或其盐(包括药学上可接受的盐)、立体异构体(包括对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物亦可以降解底物蛋白(例如IKZF1/2/3/4蛋白、WEE1蛋白、CK1α蛋白、GSPT1蛋白、ZFP91蛋白等)。本公开的式(I)化合物或其盐(包括药学上可接受的盐)、立体异构体(包括对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物具有抗肿瘤活性，或具有优异的药代动力学特性，可以用作为肿瘤病人的治疗药物。The compound of formula (I) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotope-enriched analog, prodrug or polymorph provided by the present disclosure has binding force to CRBN, helps to recruit substrate proteins, and can be used as a molecular glue to bind CRBN E3 ubiquitin ligase. The compound of formula (I) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotope-enriched analog, prodrug or polymorph disclosed by the present disclosure can also degrade substrate proteins (such as IKZF1/2/3/4 protein, WEE1 protein, CK1α protein, GSPT1 protein, ZFP91 protein, etc.). The compound of formula (I) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotope-enriched analog, prodrug or polymorph disclosed by the present disclosure has anti-tumor activity, or has excellent pharmacokinetic properties, and can be used as a therapeutic drug for tumor patients.

在本公开的一些实施方案中，Ra1、Ra2、Ra3和Ra4相同或不同且各自独立地表示H、氘(即，D)、C1-6烷基(例如C1-3烷基，例如甲基、乙基、或丙基)、卤代C1-6烷基(例如卤代C1-4烷基，例如三氟甲基)、氘代C1-6烷基、C1-6烷氧基(例如C1-4烷氧基，例如甲氧基)、氘代C1-6烷氧基或卤代C1-6烷氧基(例如卤代C1-4烷氧基，例如三氟甲氧基)。在本公开的一些子实施方案中，Ra1、Ra2、Ra3和Ra4各自独立地表示H。In some embodiments of the present disclosure, Ra1 , Ra2 , Ra3 and Ra4 are the same or different and each independently represents H, deuterium (i.e., D), C1-6 alkyl (e.g., C1-3 alkyl, such as methyl, ethyl, or propyl), halogenated C1-6 alkyl (e.g., halogenated C1-4 alkyl, such as trifluoromethyl), deuterated C1-6 alkyl, C1-6 alkoxy (e.g., C1-4 alkoxy, such as methoxy), deuterated C1-6 alkoxy or halogenated C1-6 alkoxy (e.g., halogenated C1-4 alkoxy, such as trifluoromethoxy). In some sub-embodiments of the present disclosure, Ra1 , Ra2 , Ra3 and Ra4 each independently represent H.

在本公开的一些实施方案中，Z1表示C(O)、C(S)、CH2或CD2。In some embodiments of the present disclosure, Z 1 represents C(O), C(S), CH 2 or CD 2 .

在本公开的一些实施方案中，Z2、Z3和Z4表示C(O)或C(S)。In some embodiments of the present disclosure, Z 2 , Z 3 and Z 4 represent C(O) or C(S).

在本公开的一些实施方案中，Z1、Z2、Z3和Z4表示C(O)。In some embodiments of the present disclosure, Z 1 , Z 2 , Z 3 and Z 4 represent C(O).

在本公开的一些实施方案中，Z1表示CH2，Z2、Z3和Z4表示C(O)。In some embodiments of the present disclosure, Z 1 represents CH 2 , and Z 2 , Z 3 and Z 4 represent C(O).

在本公开的一些实施方案中，Z1表示CH2，Z2表示C(S)，Z3和Z4表示C(O)。In some embodiments of the present disclosure, Z 1 represents CH 2 , Z 2 represents C(S), and Z 3 and Z 4 represent C(O).

在本公开的一些实施方案中，Z1表示CH2，Z3表示C(S)，Z2和Z4表示C(O)。In some embodiments of the present disclosure, Z 1 represents CH 2 , Z 3 represents C(S), and Z 2 and Z 4 represent C(O).

在本公开的一些实施方案中，Z1表示CH2，Z4表示C(S)，Z2和Z3表示C(O)。In some embodiments of the present disclosure, Z 1 represents CH 2 , Z 4 represents C(S), and Z 2 and Z 3 represent C(O).

在本公开的一些实施方案中，Z1表示CH2，Z2和Z4表示C(S)，和Z3表示C(O)。In some embodiments of the present disclosure, Z 1 represents CH 2 , Z 2 and Z 4 represent C(S), and Z 3 represents C(O).

在本公开的一些实施方案中，Z1表示CH2，Z2和Z3表示C(S)，和Z4表示C(O)。In some embodiments of the present disclosure, Z 1 represents CH 2 , Z 2 and Z 3 represent C(S), and Z 4 represents C(O).

在本公开的一些实施方案中，Z1表示CH2，Z2、Z3、Z4表示C(S)。In some embodiments of the present disclosure, Z 1 represents CH 2 , and Z 2 , Z 3 , and Z 4 represent C(S).

在本公开的一些实施方案中，Z1表示C(S)，Z2、Z3和Z4表示C(O)。In some embodiments of the present disclosure, Z 1 represents C(S), and Z 2 , Z 3 and Z 4 represent C(O).

在本公开的一些实施方案中，Z2表示C(S)，Z1、Z3和Z4表示C(O)。In some embodiments of the present disclosure, Z 2 represents C(S), and Z 1 , Z 3 and Z 4 represent C(O).

在本公开的一些实施方案中，Z3表示C(S)，Z1、Z2和Z4表示C(O)。In some embodiments of the present disclosure, Z 3 represents C(S), and Z 1 , Z 2 and Z 4 represent C(O).

在本公开的一些实施方案中，Z4表示C(S)，Z1、Z2和Z3表示C(O)。In some embodiments of the present disclosure, Z 4 represents C(S), and Z 1 , Z 2 and Z 3 represent C(O).

在本公开的一些实施方案中，Z1、Z2表示C(S)，Z3、Z4表示C(O)。In some embodiments of the present disclosure, Z 1 and Z 2 represent C(S), and Z 3 and Z 4 represent C(O).

在本公开的一些实施方案中，Z1、Z3表示C(S)，Z2、Z4表示C(O)。In some embodiments of the present disclosure, Z 1 and Z 3 represent C(S), and Z 2 and Z 4 represent C(O).

在本公开的一些实施方案中，Z1、Z4表示C(S)，Z2、Z3表示C(O)。In some embodiments of the present disclosure, Z 1 and Z 4 represent C(S), and Z 2 and Z 3 represent C(O).

在本公开的一些实施方案中，Z1、Z2、Z3表示C(S)，Z4表示C(O)。In some embodiments of the present disclosure, Z 1 , Z 2 , and Z 3 represent C(S), and Z 4 represents C(O).

在本公开的一些实施方案中，Z1、Z2、Z4表示C(S)，Z3表示C(O)。In some embodiments of the present disclosure, Z 1 , Z 2 , and Z 4 represent C(S), and Z 3 represents C(O).

在本公开的一些实施方案中，Z1、Z3、Z4表示C(S)，Z2表示C(O)。In some embodiments of the present disclosure, Z 1 , Z 3 , and Z 4 represent C(S), and Z 2 represents C(O).

在本公开的一些实施方案中，Z1、Z2、Z3、Z4表示C(S)。In some embodiments of the present disclosure, Z 1 , Z 2 , Z 3 , Z 4 represent C(S).

在本公开的一些实施方案中，Z5表示CH或N。In some embodiments of the present disclosure, Z 5 represents CH or N.

在本公开的一些实施方案中，(Ra5)m表示与其连接的式(I)的异吲哚啉环可选地被m个Ra5取代，各Ra5相同或不同且各自独立地表示氘、卤素(例如氟、氯、溴或碘)、羟基、巯基、硝基、氨基、氰基、C1-6烷基(例如C1-5烷基、C1-4烷基或C1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基或己基)、卤代C1-6烷基(例如卤代C1-4烷基，例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-或CH2ClCH2-)、氘代C1-6烷基(例如全氘代C1-6烷基、全氘代C1-5烷基或全氘代C1- 4烷基，例如CD3、CD3CD2-、CD3CD2CD2-等)、C1-6烷氧基(例如C1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氘代C1-6烷氧基、卤代C1-6烷氧基(例如卤代C1-4烷氧基，例如F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-)、C2-6烯基(例如乙烯基)或C2-6炔基(例如乙炔基)，和m表示整数0、1、2或3。本公开的一些子实施方案中，m表示整数0、1或2。在本公开的一些子实施方案中，各Ra5相同或不同且各自独立地表示氘、卤素(例如氟、氯、溴或碘)、羟基、巯基、硝基、氨基、氰基、C1-4烷基(例如C1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C1-4烷基(例如卤代C1-3烷基，例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-或CH2ClCH2-)、C1-4烷氧基(例如C1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)或卤代C1-4烷氧基(例如卤代C1-3烷氧基，例如F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-)。In some embodiments of the present disclosure, (R a5 ) m represents that the isoindoline ring of formula (I) attached thereto is optionally substituted by m R a5 , each R a5 being the same or different and independently representing deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, thiol, nitro, amino, cyano, C 1-6 alkyl (e.g. C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (e.g. halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C C 1-6 alkyl (e.g., perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.), C 1-6 alkoxy (e.g., C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy (e.g., halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-), C 2-6 alkenyl (e.g., vinyl) or C 2-6 alkynyl (e.g., ethynyl), and m represents an integer of 0, 1, 2 or 3. In some subembodiments of the present disclosure, m represents an integer of 0, 1 or 2. In some sub-embodiments of the present disclosure, each Ra5 is the same or different and each independently represents deuterium, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxyl, thiol, nitro, amino, cyano, C1-4 alkyl (e.g., C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C1-4 alkyl (e.g., halogenated C1-3 alkyl, such as F3C- , FCH2- , F2CH- , ClCH2- , Cl2CH- , CF3CF2- , CF3CHF- , CHF2CF2- , CHF2CHF- , CF3CH2- or CH2ClCH2- ), C1-4 alkoxy (e.g., C1-3 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec- butyloxy or tert - butyloxy ) , or halogenated C1-4 alkoxy (e.g., halogenated C1-3 alkyl, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy). 1-3 alkoxy groups, for example F3CO- , FCH2 - O-, F2CH-O-, ClCH2 -O-, Cl2CH - O- , CF3CF2 -O-, CF3CHF -O-, CHF2CF2 - O- , CHF2CHF -O-, CF3CH2 -O- or CH2ClCH2 - O- ).

在本公开的实施方案中，取代基的数量原则上不受任何限制或自动受构建单元的大小限制。In the embodiments of the present disclosure, the number of substituents is in principle not subject to any restrictions or automatically limited by the size of the building block.

在本公开的一些实施方案中，R表示C(O)或可选取代的直链或支链的C1-5亚烷基(例如C1-4亚烷基、C1-3亚烷基、C1-2亚烷基或亚甲基)。所述C1-5亚烷基可选地被选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代。In some embodiments of the present disclosure, R represents C (O) or an optionally substituted straight or branched C 1-5 alkylene (e.g., C 1-4 alkylene, C 1-3 alkylene, C 1-2 alkylene, or methylene). The C 1-5 alkylene is optionally substituted with a substituent selected from deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, amino, hydroxyl, sulfhydryl, cyano, oxo, C 2-6 alkynyl, and C 2-6 alkenyl.

在本公开的一些实施方案中，R表示C(O)。In some embodiments of the present disclosure, R represents C(O).

在本公开的一些实施方案中，R表示-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-或-(CH2)5-；其中上述基团可选地被选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代。In some embodiments of the present disclosure, R represents -CH2- , -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4- or -( CH2 ) 5- ; wherein the above groups are optionally substituted with substituents selected from deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl and C2-6 alkenyl.

在本公开的一些实施方案中，X表示：

其中
环A表示含氮亚杂环基，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地
表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0-20的整数；
环B表示含氮亚杂环基，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地
表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0-20的整数；
Rc表示C(O)、CRc1Rc2或键，其中Rc1和Rc2各自独立地表示H、氘、卤素、可选经取代的
直链或支链烷基、可选经取代的环烷基、可选经取代的杂环基、可选经取代的芳基或可选经取代的杂芳基；
环C表示亚环烷基、亚杂环基、亚芳基或亚杂芳基，m1表示0或1的整数，(Rd3)n3表示
环C可选地被n3个Rd3基团取代，各Rd3各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0-20的整数；和
环D表示杂环基、环烷基、芳基或杂芳基，(Rd4)n4表示环D可选地被n4个Rd4基团取代，
各Rd4各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0-20的整数。In some embodiments of the present disclosure, X represents:

wherein ring A represents a nitrogen-containing heterocyclic group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0-20;
Ring B represents a nitrogen-containing heterocyclic group, (R d2 ) n2 represents that Ring B is optionally substituted by n2 R d2 groups, each R d2 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n2 represents an integer of 0-20;
R c represents C(O), CR c1 R c2 or a bond, wherein R c1 and R c2 each independently represent H, deuterium, halogen, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;
Ring C represents a cycloalkylene group, a heterocyclylene group, an arylene group or a heteroarylene group, m1 represents an integer of 0 or 1, (R d3 ) n3 represents that ring C is optionally substituted by n3 R d3 groups, each R d3 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n3 represents an integer of 0-20; and ring D represents a heterocyclyl group, a cycloalkyl group, an aryl group or a heteroaryl group, (R d4 ) n4 represents that ring D is optionally substituted by n4 R d4 groups,
Each R d4 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n4 represents an integer of 0-20.

在本公开的一些实施方案中，环A表示4至30元含氮亚杂环基(包括4至25元含氮亚杂环基、4至20元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)。环A可选地被n1个Rd1基团取代，各Rd1各自独立地为氘、C1-6烷基(例如C1-5烷基、C1-4烷基或C1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基或己基)、氘代C1-6烷基(例如全氘代C1-6烷基、全氘代C1-5烷基或全氘代C1-4烷基，例如CD3、CD3CD2-、CD3CD2CD2-等)、卤代C1-6烷基(例如卤代C1-4烷基，例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-或CH2ClCH2-)、C1-6烷氧基(例如C1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、卤代C1-6烷氧基(例如卤代C1-4烷氧基，例如F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-)、卤素(例如氟、氯、溴或碘)、氨基、羟基、巯基、氰基、氧代基、C2-6炔基(例如乙炔基)或C2-6烯基(例如乙烯基)，和n1表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, ring A represents a 4- to 30-membered nitrogen-containing heterocyclylene group (including a 4- to 25-membered nitrogen-containing heterocyclylene group, a 4- to 20-membered nitrogen-containing heterocyclylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, and a 5- to 20-membered nitrogen-containing heterocyclylene group). Ring A is optionally substituted with n1 Rd1 groups, each Rd1 being independently deuterium, C1-6 alkyl (e.g., C1-5 alkyl, C1-4 alkyl or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C1-6 alkyl (e.g., perdeuterated C1-6 alkyl, perdeuterated C1-5 alkyl or perdeuterated C1-4 alkyl, such as CD3 , CD3CD2- , CD3CD2CD2- , etc.), halogenated C1-6 alkyl (e.g. , halogenated C1-4 alkyl, such as F3C- , FCH2- , F2CH- , ClCH2- , Cl2CH- , CF3CF2- , CF3CHF- , CHF2CF2- , CHF2CHF- , CF C 3 CH 2 -or CH 2 ClCH 2 -), C 1-6 alkoxy (e.g. C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkoxy (e.g. halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-), halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxy, mercapto, cyano, oxo, C 2-6 alkynyl (e.g. ethynyl) or C 3 CH 2 -or CH 2 ClCH 2 -), C 1-6 alkoxy (e.g. C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkoxy (e.g. halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-), 2-6 alkenyl (e.g., vinyl), and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

在本公开的一些实施方案中，环A表示亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚哌啶基、亚哌嗪基、氮杂环庚亚基、二氮杂环庚亚基、氮杂环辛亚基、二氮杂环辛亚基、氮杂双环[3.1.1]庚烷亚基、氮杂双环[2.2.1]庚烷亚基、氮杂双环[3.2.1]辛烷亚基、氮杂双环[2.2.2]辛烷亚基、二氮杂双环[3.1.1]庚烷亚基、二氮杂双环[2.2.1]庚烷亚基、二氮杂双环[3.2.1]辛烷亚基、二氮杂双环[2.2.2]辛烷亚基、亚奎宁环基、2，6-二氮杂螺[3.3]庚烷亚基、2，7-二氮杂螺[3.5]壬烷亚基、2，8-二氮杂螺[4.5]癸烷亚基、3，9-二氮杂螺[5.5]十一烷亚基、3-氮杂螺[5.5]十一烷亚基、7-氮杂螺[3.5]壬烷亚基、8-氮杂螺[4.5]癸烷亚基或八氢吡咯并[3，4-c]吡咯亚基，其可选地被一或多个(例如1-20、1-15、1-10、1-5、1-4或1-3个)选自氘、C1-6烷基(例如C1-5烷基、C1-4烷基或C1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基或己基)、氘代C1-6烷基、卤代C1-6烷基(例如卤代C1-4烷基，例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-或CH2ClCH2-)、C1-6烷氧基(例如C1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、卤代C1-6烷氧基(例如卤代C1-4烷氧基，例如F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-)、卤素(例如氟、氯、溴或碘)、氨基、羟基、巯基、氰基、氧代基、C2-6炔基(例如乙炔基)和C2-6烯基(例如乙烯基)的取代基取代。In some embodiments of the present disclosure, ring A represents an azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanylidene, diazepanylidene, azaocinylidene, diazaocinylidene, azabicyclo[3.1.1]heptanylidene, azabicyclo[2.2.1]heptanylidene, azabicyclo[3.2.1]octanylidene, azabicyclo[2.2.2]octanylidene, diazabicyclo[3.1.1]heptanylidene, diazabicyclo[2.2.1]heptanylidene, diazabicyclo[3.2.1]octanylidene, diazabicyclo[3.1.1]heptanylidene, diazabicyclo[2.2.1]heptanylidene, diazabicyclo[3.2.1]octanylidene, diazabicyclo[3.1.1]heptanylidene, diazabicyclo[2.2.1]heptanylidene, diazabicyclo[3.2.1]octanylidene, diazabicyclo[3.1.1]heptanylidene bicyclo[2.2.2]octanylidene, quinuclidinyl, 2,6-diazaspiro[3.3]heptanylidene, 2,7-diazaspiro[3.5]nonaneylidene, 2,8-diazaspiro[4.5]decaneylidene, 3,9-diazaspiro[5.5]undecaneylidene, 3-azaspiro[5.5]undecaneylidene, 7-azaspiro[3.5]nonaneylidene, 8-azaspiro[4.5]decaneylidene or octahydropyrrolo[3,4-c]pyrroleylidene, which may be optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1-5, 1-4 or 1-3) selected from deuterium, C C 1-6 alkyl (e.g. C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl, halogenated C 1-6 alkyl (e.g. halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (e.g. C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkoxy (e.g. halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 The alkylene group may be substituted with a substituent selected from the group consisting of aryl (e.g., aryl -O-, F2CH- O- , ClCH2 - O- , Cl2CH - O- , CF3CF2 -O-, CF3CHF -O-, CHF2CF2-O-, CHF2CHF -O-, CF3CH2- O- or CH2ClCH2 - O- ), halogen (e.g., fluorine, chlorine, bromine or iodine), amino, hydroxyl, mercapto, cyano, oxo, C2-6 alkynyl (e.g., ethynyl) and C2-6 alkenyl (e.g., vinyl).

在本公开的一些实施方案中，环B表示4至30元含氮亚杂环基(包括4至25元含氮亚杂环基、4至20元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)。环B可选地被n2个Rd2基团取代，各Rd2各自独立地为氘、C1-6烷基(例如C1-5烷基、C1-4烷基或C1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基或己基)、氘代C1-6烷基(例如全氘代C1-6烷基、全氘代C1-5烷基或全氘代C1-4烷基，例如CD3、CD3CD2-、CD3CD2CD2-等)、卤代C1-6烷基(例如卤代C1-4烷基，例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-或CH2ClCH2-)、C1-6烷氧基(例如C1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、卤代C1-6烷氧基(例如卤代C1-4烷氧基，例如F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-)、卤素(例如氟、氯、溴或碘)、氨基、羟基、巯基、氰基、氧代基、C2-6炔基(例如乙炔基)或C2-6烯基(例如乙烯基)，和n2表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, Ring B represents a 4- to 30-membered nitrogen-containing heterocyclylene group (including a 4- to 25-membered nitrogen-containing heterocyclylene group, a 4- to 20-membered nitrogen-containing heterocyclylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, and a 5- to 20-membered nitrogen-containing heterocyclylene group). Ring B is optionally substituted with n2 R d2 groups, each R d2 being independently deuterium, C 1-6 alkyl (e.g., C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (e.g., perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.), halogenated C 1-6 alkyl (e.g., halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF C 3 CH 2 -or CH 2 ClCH 2 -), C 1-6 alkoxy (e.g. C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkoxy (e.g. halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-), halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxy, mercapto, cyano, oxo, C 2-6 alkynyl (e.g. ethynyl) or C 3 CH 2 -or CH 2 ClCH 2 -), C 1-6 alkoxy (e.g. C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkoxy (e.g. halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-), 2-6 alkenyl (e.g., vinyl), and n2 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

在本公开的一些实施方案中，环B表示亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚哌啶基、亚哌嗪基、氮杂环庚亚基、二氮杂环庚亚基、氮杂环辛亚基、二氮杂环辛亚基、氮杂双环[3.1.1]庚烷亚基、氮杂双环[2.2.1]庚烷亚基、氮杂双环[3.2.1]辛烷亚基、氮杂双环[2.2.2]辛烷亚基、二氮杂双环[3.1.1]庚烷亚基、二氮杂双环[2.2.1]庚烷亚基、二氮杂双环[3.2.1]辛烷亚基、二氮杂双环[2.2.2]辛烷亚基、亚奎宁环基、2，6-二氮杂螺[3.3]庚烷亚基、2，7-二氮杂螺[3.5]壬烷亚基、2，8-二氮杂螺[4.5]癸烷亚基、3，9-二氮杂螺[5.5]十一烷亚基、3-氮杂螺[5.5]十一烷亚基、7-氮杂螺[3.5]壬烷亚基、8-氮杂螺[4.5]癸烷亚基或八氢吡咯并[3，4-c]吡咯亚基，其可选地被一或多个(例如1-20、1-15、1-10、1-5、1-4或1-3个)选自氘、C1-6烷基(例如C1-5烷基、C1-4烷基或C1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基或己基)、氘代C1-6烷基、卤代C1-6烷基(例如卤代C1-4烷基，例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-或CH2ClCH2-)、C1-6烷氧基(例如C1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、卤代C1-6烷氧基(例如卤代C1-4烷氧基，例如F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-)、卤素(例如氟、氯、溴或碘)、氨基、羟基、巯基、氰基、氧代基、C2-6炔基(例如乙炔基)和C2-6烯基(例如乙烯基)的取代基取代。In some embodiments of the present disclosure, Ring B represents an azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanylidene, diazepanylidene, azaocinylidene, diazaocinylidene, azabicyclo[3.1.1]heptanylidene, azabicyclo[2.2.1]heptanylidene, azabicyclo[3.2.1]octanylidene, azabicyclo[2.2.2]octanylidene, diazabicyclo[3.1.1]heptanylidene, diazabicyclo[2.2.1]heptanylidene, diazabicyclo[3.2.1]octanylidene, diazabicyclo[3.1.1]heptanylidene, diazabicyclo[2.2.1]heptanylidene, diazabicyclo[3.2.1]octanylidene, diazabicyclo[3.1.1]heptanylidene, diazabicyclo[2.2.1]heptanylidene, diazabicyclo[3.2.1]octanylidene, diazabicyclo[3.1.1]heptanylidene bicyclo[2.2.2]octanylidene, quinuclidinyl, 2,6-diazaspiro[3.3]heptanylidene, 2,7-diazaspiro[3.5]nonaneylidene, 2,8-diazaspiro[4.5]decaneylidene, 3,9-diazaspiro[5.5]undecaneylidene, 3-azaspiro[5.5]undecaneylidene, 7-azaspiro[3.5]nonaneylidene, 8-azaspiro[4.5]decaneylidene or octahydropyrrolo[3,4-c]pyrroleylidene, which may be optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1-5, 1-4 or 1-3) selected from deuterium, C C 1-6 alkyl (e.g. C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl, halogenated C 1-6 alkyl (e.g. halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (e.g. C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkoxy (e.g. halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 The alkylene group may be substituted with a substituent selected from the group consisting of aryl (e.g., aryl -O-, F2CH- O- , ClCH2 - O- , Cl2CH - O- , CF3CF2 -O-, CF3CHF -O-, CHF2CF2-O-, CHF2CHF -O-, CF3CH2- O- or CH2ClCH2 - O- ), halogen (e.g., fluorine, chlorine, bromine or iodine), amino, hydroxyl, mercapto, cyano, oxo, C2-6 alkynyl (e.g., ethynyl) and C2-6 alkenyl (e.g., vinyl).

在本公开的一些实施方案中，Rc表示C(O)。In some embodiments of the present disclosure, R c represents C(O).

在本公开的一些实施方案中，Rc表示键。当Rc表示键时，环B直接连接环C。In some embodiments of the present disclosure, R c represents a bond. When R c represents a bond, ring B is directly connected to ring C.

在本公开的一些实施方案中，Rc表示CRc1Rc2，其中Rc1和Rc2各自独立地表示H、氘、卤素、可选经取代的直链或支链C1-10烷基(例如可选经取代的直链或支链C1-6烷基或可选经取代的直链或支链C1-3烷基)、可选经取代的C3-30环烷基(例如可选经取代的C3-20环烷基，或可选经取代的C3-15环烷基)、可选经取代的C5-30芳基(例如可选经取代的C5-20芳基，或可选经取代的C5-15芳基)、可选经取代的4至30元杂环基(例如可选经取代的4至20元杂环基，或可选经取代的4至15元杂环基)或可选经取代的5至30元杂芳基(例如可选经取代的5至20元杂芳基，或可选经取代的5至15元杂芳基)。在一些实施方案中，直链或支链C1-10烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、特戊基、己基、庚基和辛基。在一些实施方案中，直链或支链C1-10烷基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、卤素、氨基、羟基、巯基、氰基、硝基、氧代基、C1-6烷基、氘代C1-6烷基、卤代C1- 6烷基、C1-6烷氧基、卤代C1-6烷氧基、C2-6炔基和C2-6烯基的取代基取代。在一些实施方案中，C3-30环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、螺环烷基(例如C5-C20螺环基，例如螺[3.3]庚烷基、螺[2.5]辛烷基、螺[3.5]壬烷基、螺[4.4]壬烷基、螺[4.5]癸烷基、螺[5.5]十一烷基)、对薄荷烷基、间薄荷烷基、或桥环烷基(例如C6-C20桥环基，例如金刚烷基、降金刚烷基、冰片基、降冰片基、二环[2.2.1]庚烷基、2-氧代二环[2.2.1]庚烷基或二环[2.2.1]庚烯基)。在一些实施方案中，C3-30环烷基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。在一些实施方案中，4至30元杂环基的实例包括但不限于氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、四氢吡啶基、二羟基哌啶基、二氟哌啶基、吗啉基、硫代吗啉基、氮杂环庚烷基、氮杂环辛烷基、二氧杂环己基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1，4-二氮杂环庚烷基，4，5-二氮杂环庚烷基，1，3-二氮杂环庚烷基)、二氮杂环辛烷基、桥杂环基(例如6至20元桥杂环基，例如6-氮杂双环[3.1.1]庚烷基、2，5-二氮杂双环[2.2.1]庚烷基、3，6-二氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、2，5-二氮杂双环[2.2.2]辛烷基和奎宁环基)、和氮杂螺环基(例如5至20元氮杂螺环基，例如2，6-二氮杂螺[3.3]庚烷基、2，7-二氮杂螺[3.5]壬烷基、2，8-二氮杂螺[4.5]癸烷基、3，9-二氮杂螺[5.5]十一烷基、3-氮杂螺[5.5]十一烷基和7-氮杂螺[3.5]壬烷基)、或八氢吡咯并[3，4-c]吡咯基。在一些实施方案中，4至30元杂环基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、卤素、羟基、巯基、氨基、氰基、氧代基、C1-6烷基、卤代C1- 6烷基、氘代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。在一些实施方案中，C5-30芳基的实例包括但不限于苯基或萘基。在一些实施方案中，C5-30芳基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1- 6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。在一些实施方案中，5至30元杂芳基的实例包括但不限于呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲哚啉基、苯并呋喃基、苯并二氢吡喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2，1，3]噁二唑基、苯并[2，1，3]噻二唑基、苯并[1，2，3]噻二唑基、2-氧代-2，3-二氢-1H-苯并[d]咪唑基、苯并[b][1，4]噁嗪基、3，4-二氢-2H-苯并[b][1，4]噁嗪基、喹啉基、异喹啉基、1，2，3，4-四氢喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、1，2，3，4-四氢喹喔啉基、酞嗪基、5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪基、4，5，6，7-四氢噻吩并[3，2-c]吡啶基、5-氧代-6，7-二氢噻吩并[3，2-d]嘧啶基、噻吩并[2，3-d]嘧啶基、噻吩并[3，2-d]嘧啶基、异噁唑并[4，5-c]吡啶基、异噁唑并[4，5-c]嘧啶基、异噁唑并[4，5-d]嘧啶基、吡唑并[1，5-a]吡啶基、吡唑并[1，5-a]嘧啶基、咪唑并[1，2-a]吡啶基、1H-吡咯并[3，2-b]吡啶基、1H-吡咯并[2，3-b]吡啶基、吡咯并[2，1-b]噻唑基、咪唑并[2，1-b]噻唑基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶基、或6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶基。在一些实施方案中，5至30元杂芳基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。In some embodiments of the present disclosure, R c represents CR c1 R c2 , wherein R c1 and R c2 each independently represent H, deuterium, halogen, optionally substituted straight or branched C 1-10 alkyl (e.g., optionally substituted straight or branched C 1-6 alkyl or optionally substituted straight or branched C 1-3 alkyl), optionally substituted C 3-30 cycloalkyl (e.g., optionally substituted C 3-20 cycloalkyl, or optionally substituted C 3-15 cycloalkyl), optionally substituted C 5-30 aryl (e.g., optionally substituted C 5-20 aryl, or optionally substituted C The invention also includes an optionally substituted 4- to 30-membered heterocyclyl (e.g., an optionally substituted 4- to 20-membered heterocyclyl, or an optionally substituted 4- to 15-membered heterocyclyl), or an optionally substituted 5- to 30-membered heteroaryl (e.g., an optionally substituted 5- to 20-membered heteroaryl, or an optionally substituted 5- to 15-membered heteroaryl). In some embodiments, examples of straight or branched C 1-10 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, and octyl. In some embodiments, a straight chain or branched C1-10 alkyl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, C1-6 alkyl, deuterated C1-6 alkyl , halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkynyl, and C2-6 alkenyl. In some embodiments, examples of C3-30 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl (e.g., C5 - C20 spirocyclyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decyl, spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl (e.g., C6 - C20 bridged cycloalkyl, such as adamantyl, noradamantyl, bornyl, norbornyl, bicyclo[2.2.1]heptanyl, 2-oxobicyclo[2.2.1]heptanyl, or bicyclo[2.2.1]heptenyl). In some embodiments, the C3-30 cycloalkyl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, oxo, C1-6 alkyl, halo-substituted C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy, halo-substituted C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, examples of 4- to 30-membered heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxypiperidinyl, difluoropiperidinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanyl, dioxanyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepanyl, 4,5-diazepanyl, 1,3-diazepanyl), diazepanyl, bridged heterocyclyl (e.g., 6- to 20-membered bridged heterocyclyl, e.g., 6-azabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[3.1.1]heptyl, 1 ,4-diazabicyclo[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 3,9-diazaspiro[5.5]undecyl, 3-azaspiro[5.5]undecyl and 7-azaspiro[3.5]nonyl), or octahydropyrrolo[3,4-c]pyrrolyl. In some embodiments, the 4-30 membered heterocyclyl is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxyl, thiol, amino, cyano, oxo, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl. In some embodiments, examples of C 5-30 aryl include, but are not limited to , phenyl or naphthyl. In some embodiments, the C5-30 aryl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C1-6 alkyl, halogenated C1-6 alkyl , deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, examples of 5- to 30-membered heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl , benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4- tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimidinyl, isoxazolo[4,5-d]pyrimidinyl, pyrazole pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl. In some embodiments, the 5- to 30-membered heteroaryl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl.

在本公开的一些实施方案中，m1表示1的整数，环C表示4至30元亚杂环基(例如4至20元亚杂环基，或4至15元亚杂环基)、C3-30亚环烷基(例如C3-20亚环烷基，或C3-15亚环烷基)、C5-30亚芳基(例如C5-20亚芳基，或C5-15亚芳基)或5至30元亚杂芳基(例如5至20元亚杂芳基，或5至15元亚杂芳基)。环C可选地被n3个Rd3基团取代，各Rd3各自独立地表示氘、C1-6烷基(例如C1-5烷基、C1-4烷基或C1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基或己基)、氘代C1-6烷基、卤代C1-6烷基(例如卤代C1-4烷基，例如F3C-、FCH2-、F2CH-、ClCH2-、Cl2CH-、CF3CF2-、CF3CHF-、CHF2CF2-、CHF2CHF-、CF3CH2-或CH2ClCH2-)、C1-6烷氧基(例如C1-4烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、卤代C1-6烷氧基(例如卤代C1-4烷氧基，例如F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-)、卤素(例如氟、氯、溴或碘)、氨基、羟基、巯基、氰基、氧代基、C2-6炔基(例如乙炔基)或C2-6烯基(例如乙烯基)，n3表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, m1 represents an integer of 1, and ring C represents a 4- to 30-membered heterocyclylene (e.g., a 4- to 20-membered heterocyclylene, or a 4- to 15-membered heterocyclylene), a C3-30 cycloalkylene (e.g., a C3-20 cycloalkylene, or a C3-15 cycloalkylene), a C5-30 arylene (e.g., a C5-20 arylene, or a C5-15 arylene), or a 5- to 30-membered heteroarylene (e.g., a 5- to 20-membered heteroarylene, or a 5- to 15-membered heteroarylene). Ring C is optionally substituted by n3 Rd3 groups, each Rd3 independently representing deuterium, C1-6 alkyl (e.g. C1-5 alkyl, C1-4 alkyl or C1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C1-6 alkyl, halogenated C1-6 alkyl (e.g. halogenated C1-4 alkyl, such as F3C- , FCH2- , F2CH- , ClCH2- , Cl2CH- , CF3CF2- , CF3CHF- , CHF2CF2- , CHF2CHF- , CF3CH2- or CH2ClCH2- ) , C1-6 alkoxy (e.g. C1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert- butyloxy ), halogenated C1-6 alkyl or CH2ClCH2- O- ); n3 represents an integer of 0, 1 , 2 , 3 , 4 , 5 , 6, 7 , 8, 9 , 10, 11 , 12, 13, 14 , 15, 16 , 17 , 18 , 19 or 20 .

在一些实施方案中，环C表示4至30元亚杂环基，其实例包括但不限于4-至20-元、4-至15-元、4-至12-元、4-至11-元、4-至10-元、4-至9-元、4-至8-元、4-至7-元、4-至6-元、5-至15-元、和5-元至9-元亚杂环基，例如亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚氮杂环庚烷基、亚氮杂环辛烷基、亚二氧杂环己基、亚氮杂环庚烷基、亚氮杂环辛烷基、二氮杂环庚烷亚基(例如1，4-二氮杂环庚烷亚基，4，5-二氮杂环庚烷亚基，1，3-二氮杂环庚烷亚基)、二氮杂环辛烷亚基、亚桥杂环基(例如6至20元亚桥杂环基，例如6-氮杂双环[3.1.1]庚烷亚基、2，5-二氮杂双环[2.2.1]庚烷亚基、3，6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、2，5-二氮杂双环[2.2.2]辛烷亚基和亚奎宁环基)、亚氮杂螺环基(例如5至20元亚氮杂螺环基，例如2，6-二氮杂螺[3.3]庚烷亚基、2，7-二氮杂螺[3.5]壬烷亚基、2，8-二氮杂螺[4.5]癸烷亚基、3，9-二氮杂螺[5.5]十一烷亚基、3-氮杂螺[5.5]十一烷亚基和7-氮杂螺[3.5]壬烷亚基)、或八氢吡咯并[3，4-c]吡咯亚基。亚杂环基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1- 6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。In some embodiments, ring C represents a 4- to 30-membered heterocyclylene, examples of which include, but are not limited to, 4- to 20-membered, 4- to 15-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 5- to 15-membered, and 5- to 9-membered heterocyclylene, such as azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, furanyl, tetrahydropyranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, azepanylene, azocanylidene, dioxanylene, azepanylene, azocanylidene, diazepanylene, diazepanylene, diazepanylene, diazepanylene (e.g., 1,4-diazepanylene, 4,5-diazepanylene, 1,3-diazepanylene), diazepanylene , a sub-bridged heterocyclic group (e.g., a 6- to 20-membered sub-bridged heterocyclic group, such as a 6-azabicyclo[3.1.1]heptanyl group, a 2,5-diazabicyclo[2.2.1]heptanyl group, a 3,6-diazabicyclo[3.1.1]heptanyl group, a 3-azabicyclo[3.2.1]octanyl group, a 3,8-diazabicyclo[3.2.1]octanyl group, a 3,8-diazabicyclo[3.2.1]octanyl group, a 2,5-diazabicyclo[2.2.2] octanyl and quinuclidinyl), azaspirocyclyl (e.g., a 5- to 20-membered azaspirocyclyl, such as 2,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl and 7-azaspiro[3.5]nonanyl), or octahydropyrrolo[3,4-c]pyrrolyl. The heterocyclylene group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, hydroxy, amino, thiol, nitro, halogen, cyano, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, C 2-6 alkenyl , and C 2-6 alkynyl.

在一些实施方案中，环C表示亚C3-30环烷基，其实例包括但不限于C3-20亚环烷基、C3- 15亚环烷基和C3-11亚环烷基，例如亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、2，3-二氢-1H-茚亚基、亚螺环基(例如C5-C20亚螺环烷基和C5-15亚螺环基，例如螺[3.3]庚烷亚基、螺[2.5]辛烷亚基、螺[3.5]壬烷亚基、螺[4.4]壬烷亚基、螺[4.5]癸烷亚基、螺[5.5]十一烷亚基)、亚对薄荷烷基、亚间薄荷烷基、或亚桥环烷基(例如C6-C20亚桥环烷基，例如亚金刚烷基、亚降金刚烷基、亚冰片基、亚降冰片烷基、二环[2.2.1]庚烷亚基、2-氧代二环[2.2.1]庚烷亚基和二环[2.2.1]庚烯亚基)。亚环烷基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。In some embodiments, ring C represents a C3-30 cycloalkylene group, examples of which include, but are not limited to, C3-20 cycloalkylene, C3-15 cycloalkylene , and C3-11 cycloalkylene, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decahydronaphthylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, spirocyclylene (e.g., C5 - C20 spirocycloalkylene and C3-11 cycloalkylene) 5-15 spirocyclylene (e.g., spiro[3.3]heptanylene, spiro[2.5]octanylene, spiro[3.5]nonanylene, spiro[4.4]nonanylene, spiro[4.5]decanylene, spiro[5.5]undecanylene), p-menthanylene, m-menthanylene, or bridged cycloalkylene (e.g., C6 - C20 bridged cycloalkylene, such as adamantylene, noradamantylene, bornylene, norbornylene, bicyclo[2.2.1]heptanylene, 2-oxobicyclo[2.2.1]heptanylene and bicyclo[2.2.1]heptenylene). The cycloalkylene group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, hydroxy, amino, thiol, nitro, halogen, cyano, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl.

在一些实施方案中，环C表示C5-30亚芳基，其实例包括但不限于C5-20亚芳基、C6-20亚芳基、C5-15亚芳基和C6-15亚芳基，例如亚苯基或亚萘基。亚芳基可选地被一或多个(例如1-6个、1-4个、1-3个、2-6个或1个)选自氘、羟基、氨基、巯基、硝基、卤素、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。In some embodiments, ring C represents C 5-30 arylene, examples of which include but are not limited to C 5-20 arylene, C 6-20 arylene, C 5-15 arylene and C 6-15 arylene, such as phenylene or naphthylene. The arylene group is optionally substituted with one or more (e.g., 1-6, 1-4, 1-3, 2-6 or 1) substituents selected from deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl.

在一些实施方案中，环C表示5至30元亚杂芳基，其实例包括但不限于5-至20-元亚杂芳基，5-至15-元、5-至10-元、5-至9-元、5-至8-元、5-至7-元和5-至6元亚杂芳基，例如亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚三嗪基、亚吲哚基、亚异吲哚基、亚吲哚啉基、亚苯并呋喃基、亚苯并二氢吡喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2，1，3]噁二唑基、亚苯并[2，1，3]噻二唑基、亚苯并[1，2，3]噻二唑基、2-氧代-2，3-二氢-1H-苯并[d]咪唑亚基、亚苯并[b][1，4]噁嗪基、3，4-二氢-2H-苯并[b][1，4]噁嗪亚基、亚喹啉基、亚异喹啉基、1，2，3，4-四氢喹啉亚基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、1，2，3，4-四氢喹喔啉亚基、亚酞嗪基、5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪亚基、4，5，6，7-四氢噻吩并[3，2-c]吡啶亚基、5-氧代-6，7-二氢噻吩并[3，2-d]嘧啶亚基、噻吩并[2，3-d]嘧啶亚基、噻吩并[3，2-d]嘧啶亚基、异噁唑并[4，5-c]吡啶亚基、异噁唑并[4，5-c]嘧啶亚基、异噁唑并[4，5-d]嘧啶亚基、吡唑并[1，5-a]吡啶亚基、吡唑并[1，5-a]嘧啶亚基、咪唑并[1，2-a]吡啶亚基、1H-吡咯并[3，2-b]吡啶亚基、1H-吡咯并[2，3-b]]吡啶亚基、吡咯并[2，1-b]噻唑亚基、咪唑并[2，1-b]噻唑亚基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶亚基、或6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶亚基。亚杂芳基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代。In some embodiments, ring C represents a 5- to 30-membered heteroarylene group, examples of which are not limited to 5- to 20-membered heteroarylene groups, 5- to 15-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, and 5- to 6-membered heteroarylene groups, such as furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, triazinylene, indolylene, isoindolylene, indolinylene, Benzofuranylene, benzodihydropyranylene, isobenzofuranylene, benzothiophenylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolylene, benzo[b][1,4]oxazinylene, 3,4-dihydro-2H-benzo[b][1,4]oxazinylene, quinolylene, isoquinolylene , 1,2,3,4-tetrahydroquinolinylidene, naphthyridinylidene, cinnolinylidene, quinazolinylidene, quinoxalinylidene, 1,2,3,4-tetrahydroquinoxalinylidene, phthalazinylidene, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinylidene, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylidene, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinylidene, thieno[2,3-d]pyrimidinylidene, thieno[3,2-d]pyrimidinylidene, isoxazolo[4,5-c]pyridinylidene, isoxazolo[4,5-c] pyrimidine subunit, isoxazolo[4,5-d]pyrimidine subunit, pyrazolo[1,5-a]pyrimidine subunit, pyrazolo[1,5-a]pyrimidine subunit, imidazo[1,2-a]pyrimidine subunit, 1H-pyrrolo[3,2-b]pyrimidine subunit, 1H-pyrrolo[2,3-b]pyrimidine subunit, pyrrolo[2,1-b]thiazolyl subunit, imidazo[2,1-b]thiazolyl subunit, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine subunit, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine subunit. The heteroarylene group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, halogen, hydroxy, thiol, nitro, amino, cyano, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl.

在本公开的一些实施方案中，当m1表示0，即环C不存在时，Rc直接连接环D。In some embodiments of the present disclosure, when m1 represents 0, ie, ring C does not exist, R c is directly connected to ring D.

在本公开的一些实施方案中，环D表示C3-30环烷基(例如C3-20环烷基，或C3-15环烷基)、4至30元杂环基(例如4至20元杂环基，或4至15元杂环基)、C5-30芳基(例如C5-20芳基，或C5-15芳基)或5至30元杂芳基(例如5至20元杂芳基，或5至15元杂芳基)。环D可选地被n4个Rd4基团取代，各Rd4各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2- 6烯基，和n4表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, ring D represents C3-30 cycloalkyl (e.g., C3-20 cycloalkyl, or C3-15 cycloalkyl), 4 to 30 membered heterocyclyl (e.g., 4 to 20 membered heterocyclyl, or 4 to 15 membered heterocyclyl), C5-30 aryl (e.g., C5-20 aryl, or C5-15 aryl), or 5 to 30 membered heteroaryl (e.g., 5 to 20 membered heteroaryl, or 5 to 15 membered heteroaryl). Ring D is optionally substituted by n4 R d4 groups, each R d4 is each independently deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n4 represents an integer of 0 , 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

在一些实施方案中，环D表示C3-30环烷基，其实例包括但不限于C3-20环烷基、C3-15环烷基和C3-11环烷基，例如环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、螺环烷基(例如C5-C20螺环基，例如螺[3.3]庚烷基、螺[2.5]辛烷基、螺[3.5]壬烷基、螺[4.4]壬烷基、螺[4.5]癸烷基、螺[5.5]十一烷基)、对薄荷烷基、间薄荷烷基、或桥环烷基(例如C6-C20桥环基，例如金刚烷基、降金刚烷基、冰片基、降冰片基、二环[2.2.1]庚烷基、2-氧代二环[2.2.1]庚烷基或二环[2.2.1]庚烯基)。环烷基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代。In some embodiments, ring D represents a C3-30 cycloalkyl group, examples of which include, but are not limited to, a C3-20 cycloalkyl group, a C3-15 cycloalkyl group, and a C3-11 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl (e.g., C5 - C20 spirocyclyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decyl, spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or a bridged cycloalkyl group (e.g., C6 -C The cycloalkyl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6, or 1) substituents selected from deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen , amino, hydroxy, thiol, cyano, oxo, C 2-6 alkynyl , and C 2-6 alkenyl .

在一些实施方案中，环D表示4至30元杂环基，其实例包括但不限于4-至20-元、4-至15-元、4-至12-元、4-至11-元、4-至10-元、4-至9-元、4-至8-元、4-至7-元、4-至6-元、5-至15-元、和5-元至9-元杂环基，例如氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、四氢吡啶基、二羟基哌啶基、二氟哌啶基、吗啉基、硫代吗啉基、氮杂环庚烷基、氮杂环辛烷基、二氧杂环己基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1，4-二氮杂环庚烷基，4，5-二氮杂环庚烷基，1，3-二氮杂环庚烷基)、二氮杂环辛烷基、桥杂环基(例如6至20元桥杂环基，例如6-氮杂双环[3.1.1]庚烷基、2，5-二氮杂双环[2.2.1]庚烷基、3，6-二氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、2，5-二氮杂双环[2.2.2]辛烷基和奎宁环基)、和氮杂螺环基(例如5至20元氮杂螺环基，例如2，6-二氮杂螺[3.3]庚烷基、2，7-二氮杂螺[3.5]壬烷基、2，8-二氮杂螺[4.5]癸烷基、3，9-二氮杂螺[5.5]十一烷基、3-氮杂螺[5.5]十一烷基和7-氮杂螺[3.5]壬烷基)、和八氢吡咯并[3，4-c]吡咯基。杂环基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代。In some embodiments, ring D represents a 4- to 30-membered heterocyclic group, examples of which include, but are not limited to, 4- to 20-membered, 4- to 15-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 5- to 15-membered, and 5- to 9-membered heterocyclic groups, such as azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxypiperidinyl, difluoropiperidinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanyl, dioxanyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepanyl, 4,5-diazepanyl, 1,3-diazepanyl), diazepanyl, heterocyclooctanyl, bridged heterocyclic groups (e.g., 6- to 20-membered bridged heterocyclic groups, such as 6-azabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2. 2.2]octanyl and quinuclidine), and azaspirocyclyl (e.g., a 5- to 20-membered azaspirocyclyl, such as 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 3,9-diazaspiro[5.5]undecyl, 3-azaspiro[5.5]undecyl and 7-azaspiro[3.5]nonyl), and octahydropyrrolo[3,4-c]pyrrolyl. The heterocyclyl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6 or 1) substituents selected from deuterium, C1-6 alkyl, deuterated C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, halogen, amino, hydroxy, thiol, cyano, oxo, C2-6 alkynyl and C2-6 alkenyl.

在一些实施方案中，环D表示C5-30芳基，其实例包括但不限于C5-20芳基、C6-20芳基、C5-15芳基和C6-15芳基，例如苯基或萘基，其可选地被一或多个(例如1-7个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、C2-6炔基和C2-6烯基的取代基取代。In some embodiments, ring D represents C5-30 aryl, examples of which include, but are not limited to, C5-20 aryl, C6-20 aryl, C5-15 aryl and C6-15 aryl, such as phenyl or naphthyl, which is optionally substituted with one or more (e.g., 1-7, 1-6, 1-4, 1-3, 2-6 or 1) substituents selected from deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halo-substituted C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, C2-6 alkynyl and C2-6 alkenyl.

在一些实施方案中，环D表示5至30元杂芳基，其实例包括但不限于5-至20-元杂芳基，5-至15-元、5-至10-元、5-至9-元、5-至8-元、5-至7-元和5-至6元杂芳基，例如呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲哚啉基、苯并呋喃基、苯并二氢吡喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2，1，3]噁二唑基、苯并[2，1，3]噻二唑基、苯并[1，2，3]噻二唑基、2-氧代-2，3-二氢-1H-苯并[d]咪唑基、苯并[b][1，4]噁嗪基、3，4-二氢-2H-苯并[b][1，4]噁嗪基、喹啉基、异喹啉基、1，2，3，4-四氢喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、1，2，3，4-四氢喹喔啉基、酞嗪基、5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪基、4，5，6，7-四氢噻吩并[3，2-c]吡啶基、5-氧代-6，7-二氢噻吩并[3，2-d]嘧啶基、噻吩并[2，3-d]嘧啶基、噻吩并[3，2-d]嘧啶基、异噁唑并[4，5-c]吡啶基、异噁唑并[4，5-c]嘧啶基、异噁唑并[4，5-d]嘧啶基、吡唑并[1，5-a]吡啶基、吡唑并[1，5-a]嘧啶基、咪唑并[1，2-a]吡啶基、1H-吡咯并[3，2-b]吡啶基、1H-吡咯并[2，3-b]吡啶基、吡咯并[2，1-b]噻唑基、咪唑并[2，1-b]噻唑基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶基、或6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶基。杂芳基可选地被一或多个(例如1-20个、1-15个、1-10个、1-6个、1-4个、1-3个、2-6个或1个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、C2-6炔基和C2-6烯基的取代基取代。In some embodiments, ring D represents a 5- to 30-membered heteroaryl, examples of which are not limited to 5- to 20-membered heteroaryl, 5- to 15-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, and 5- to 6-membered heteroaryl, such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindole, indolyl, benzofuranyl, benzophenone ... dihydropyranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, quinolyl, isoquinolyl, 1,2,3,4- tetrahydroquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimid ... oxazolo[4,5-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl. The heteroaryl group is optionally substituted with one or more (e.g., 1-20, 1-15, 1-10, 1-6, 1-4, 1-3, 2-6 or 1) substituents selected from deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, amino, hydroxy, thiol, cyano, C 2-6 alkynyl and C 2-6 alkenyl.

在本公开的一些实施方案中，X表示：

其中
环A表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
环B表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
Rc表示C(O)、CRc1Rc2或键，其中Rc1和Rc2各自独立地表示H、氘、卤素、可选经取代的
直链或支链烷基(例如可选经取代的直链或支链C1-10烷基、可选经取代的直链或支链C1-6烷基或可选经取代的直链或支链C1-3烷基)、可选经取代的环烷基(例如可选经取代的C3-30环烷基、可选经取代的C3-20环烷基或可选经取代的C3-15环烷基)、可选经取代的杂环基(例如可选经取代的4至30元杂环基、可选经取代的4至20元杂环基或可选经取代的4至15元杂环基)、可选经取代的芳基(例如可选经取代的C5- 30芳基、可选经取代的C5-20芳基或可选经取代的C5-15芳基)或可选经取代的杂芳基(例如可选经取代的5至30元杂芳基、可选经取代的5至20元杂芳基或可选经取代的5至15元杂芳基)；
环C表示亚环烷基(例如C3-30亚环烷基、C3-20亚环烷基或C3-15亚环烷基)、亚杂环基
(例如4至30元亚杂环基、4至20元亚杂环基或4至15元亚杂环基)、亚芳基(例如C5-30亚芳基、C5-20亚芳基或C5-15亚芳基)或亚杂芳基(例如5至30元亚杂芳基、5至20元亚杂芳基或5至15元亚杂芳基)，m1表示0或1的整数，(Rd3)n3表示环C可选地被n3个Rd3基团取代，各Rd3各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；和
环D表示杂环基(例如4至30元杂环基、4至20元杂环基或4至15元杂环基)、环烷基
(例如C3-30环烷基、C3-20环烷基或C3-15环烷基)、芳基(例如C5-30芳基、C5-20芳基或C5-15芳基)或杂芳基(例如5至30元杂芳基、5至20元杂芳基或5至15元杂芳基)，(Rd4)n4表示环D可选地被n4个Rd4基团取代，各Rd4各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, X represents:

Wherein ring A represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group, a
wherein n1 is an alkylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, a 5- to 20-membered nitrogen-containing heterocyclylene group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
Ring B represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group,
wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 , 18 , 19 or 20 ; wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3 , 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19 or 20;
R c represents C(O), CR c1 R c2 or a bond, wherein R c1 and R c2 each independently represent H, deuterium, halogen, optionally substituted straight or branched chain alkyl (e.g. optionally substituted straight or branched chain C 1-10 alkyl, optionally substituted straight or branched chain C 1-6 alkyl, or optionally substituted straight or branched chain C 1-3 alkyl), optionally substituted cycloalkyl (e.g. optionally substituted C 3-30 cycloalkyl, optionally substituted C 3-20 cycloalkyl, or optionally substituted C 3-15 cycloalkyl), optionally substituted heterocyclyl (e.g. optionally substituted 4 to 30 membered heterocyclyl, optionally substituted 4 to 20 membered heterocyclyl, or optionally substituted 4 to 15 membered heterocyclyl), optionally substituted aryl (e.g. optionally substituted C 5-30 aryl , optionally substituted C 5-20 aryl, or optionally substituted C 5-15 membered aryl) or an optionally substituted heteroaryl (eg, an optionally substituted 5-30 membered heteroaryl, an optionally substituted 5-20 membered heteroaryl, or an optionally substituted 5-15 membered heteroaryl);
Ring C represents a cycloalkylene group (e.g., a C 3-30 cycloalkylene group, a C 3-20 cycloalkylene group, or a C 3-15 cycloalkylene group), a heterocyclylene group
wherein the ring C is optionally substituted with n3 R d3 groups, and each R d3 independently represents deuterium, C 1-6 alkyl , deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy , halogenated ... 2-6 alkenyl, and n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and ring D represents a heterocyclic group (e.g., a 4- to 30-membered heterocyclic group, a 4- to 20-membered heterocyclic group or a 4- to 15-membered heterocyclic group), a cycloalkyl group
(Rd4)n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), ( Rd4 ) n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), 2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

在本公开的一些实施方案中，X表示：

其中
环A表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
环B表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
Rc1和Rc2各自独立地表示H、氘、卤素、可选经取代的直链或支链烷基(例如可选经取代
的直链或支链C1-10烷基、可选经取代的直链或支链C1-6烷基或可选经取代的直链或支链C1-3烷基)、可选经取代的环烷基(例如可选经取代的C3-30环烷基、可选经取代的C3-20环烷基或可选经取代的C3-15环烷基)、可选经取代的杂环基(例如可选经取代的4至30元杂环基、可选经取代的4至20元杂环基或可选经取代的4至15元杂环基)、可选经取代的芳基(例如可选经取代的C5-30芳基、可选经取代的C5-20芳基或可选经取代的C5-15芳基)或可选经取代的杂芳基(例如可选经取代的5至30元杂芳基、可选经取代的5至20元杂芳基或可选经取代的5至15元杂芳基)；
环C表示亚环烷基(例如C3-30亚环烷基、C3-20亚环烷基或C3-15亚环烷基)、亚杂环基
(例如4至30元亚杂环基、4至20元亚杂环基或4至15元亚杂环基)、亚芳基(例如C5-30亚芳基、C5-20亚芳基或C5-15亚芳基)或亚杂芳基(例如5至30元亚杂芳基、5至20元亚杂芳基或5至15元亚杂芳基)，m1表示0或1的整数，(Rd3)n3表示环C可选地被n3个Rd3基团取代，各Rd3各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；和
环D表示杂环基(例如4至30元杂环基、4至20元杂环基或4至15元杂环基)、环烷基
(例如C3-30环烷基、C3-20环烷基或C3-15环烷基)、芳基(例如C5-30芳基、C5-20芳基或C5-15芳基)或杂芳基(例如5至30元杂芳基、5至20元杂芳基或5至15元杂芳基)，(Rd4)n4表示环D可选地被n4个Rd4基团取代，各Rd4各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, X represents:

Wherein ring A represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group, a
wherein n1 is an alkylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, a 5- to 20-membered nitrogen-containing heterocyclylene group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
Ring B represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group,
wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 , 18 , 19 or 20 ; wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3 , 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19 or 20;
Rc1 and Rc2 each independently represent H, deuterium, halogen, optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C1-10 alkyl, optionally substituted straight or branched chain C1-6 alkyl, or optionally substituted straight or branched chain C1-3 alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C3-30 cycloalkyl, optionally substituted C3-20 cycloalkyl, or optionally substituted C3-15 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted 4 to 30 membered heterocyclyl, optionally substituted 4 to 20 membered heterocyclyl, or optionally substituted 4 to 15 membered heterocyclyl), optionally substituted aryl (e.g., optionally substituted C5-30 aryl, optionally substituted C5-20 aryl, or optionally substituted C3-15 cycloalkyl); 5-15 membered aryl) or an optionally substituted heteroaryl (eg, an optionally substituted 5-30 membered heteroaryl, an optionally substituted 5-20 membered heteroaryl, or an optionally substituted 5-15 membered heteroaryl);
Ring C represents a cycloalkylene group (e.g., a C 3-30 cycloalkylene group, a C 3-20 cycloalkylene group, or a C 3-15 cycloalkylene group), a heterocyclylene group
wherein the ring C is optionally substituted with n3 R d3 groups, and each R d3 independently represents deuterium, C 1-6 alkyl , deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy , halogenated ... 2-6 alkenyl, and n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and ring D represents a heterocyclic group (e.g., a 4- to 30-membered heterocyclic group, a 4- to 20-membered heterocyclic group or a 4- to 15-membered heterocyclic group), a cycloalkyl group
(Rd4)n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), ( Rd4 ) n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), 2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

在本公开的一些实施方案中，X表示：

其中
环A表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
环B表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
Rc1表示H、氘、卤素或可选经取代的直链或支链烷基(例如可选经取代的直链或支链C1-
10烷基、可选经取代的直链或支链C1-6烷基或可选经取代的直链或支链C1-3烷基)；
Rc2表示H、氘、卤素、可选经取代的直链或支链烷基(例如可选经取代的直链或支链C1-
10烷基、可选经取代的直链或支链C1-6烷基或可选经取代的直链或支链C1-3烷基)、可选经取代的环烷基(例如可选经取代的C3-30环烷基、可选经取代的C3-20环烷基或可选经取代的C3-15环烷基)、可选经取代的杂环基(例如可选经取代的4至30元杂环基、可选经取代的4至20元杂环基或可选经取代的4至15元杂环基)、可选经取代的芳基(例如可选经取代的C5-30芳基、可选经取代的C5-20芳基或可选经取代的C5- 15芳基)或可选经取代的杂芳基(例如可选经取代的5至30元杂芳基、可选经取代的5至20元杂芳基或可选经取代的5至15元杂芳基)；和
环D表示杂环基(例如4至30元杂环基、4至20元杂环基或4至15元杂环基)、环烷基
(例如C3-30环烷基、C3-20环烷基或C3-15环烷基)、芳基(例如C5-30芳基、C5-20芳基或C5-15芳基)或杂芳基(例如5至30元杂芳基、5至20元杂芳基或5至15元杂芳基)，(Rd4)n4表示环D可选地被n4个Rd4基团取代，各Rd4各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, X represents:

Wherein ring A represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group, a
wherein n1 is an alkylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, a 5- to 20-membered nitrogen-containing heterocyclylene group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
Ring B represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group,
wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 , 18 , 19 or 20 ; wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3 , 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19 or 20;
R c1 represents H, deuterium, halogen or an optionally substituted straight chain or branched chain alkyl group (e.g. an optionally substituted straight chain or branched chain C 1-
10 alkyl, optionally substituted linear or branched C 1-6 alkyl, or optionally substituted linear or branched C 1-3 alkyl);
R c2 represents H, deuterium, halogen, an optionally substituted straight chain or branched chain alkyl group (e.g. an optionally substituted straight chain or branched chain C 1-
The present invention may be selected from the group consisting of an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted linear or branched C1-3 alkyl group, an optionally substituted cycloalkyl group (e.g., an optionally substituted C3-30 cycloalkyl group, an optionally substituted C3-20 cycloalkyl group, or an optionally substituted C3-15 cycloalkyl group), an optionally substituted heterocyclyl group (e.g., an optionally substituted 4 to 30 membered heterocyclyl group, an optionally substituted 4 to 20 membered heterocyclyl group, or an optionally substituted 4 to 15 membered heterocyclyl group), an optionally substituted aryl group (e.g., an optionally substituted C5-30 aryl group, an optionally substituted C5-20 aryl group, or an optionally substituted C5- wherein the ring D represents an optionally substituted 5- to 30-membered heteroaryl, an optionally substituted 5- to 20-membered heteroaryl, or an optionally substituted 5- to 15-membered heteroaryl; and the ring D represents a heterocyclyl (e.g., a 4- to 30-membered heterocyclyl, a 4- to 20-membered heterocyclyl, or a 4- to 15-membered heterocyclyl), a cycloalkyl
(Rd4)n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), ( Rd4 ) n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), 2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

在本公开的一些实施方案中，X表示：

其中
环A表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
环B表示含氮亚杂环基(包括4至30元含氮亚杂环基、4至25元含氮亚杂环基、4至20
元含氮亚杂环基、4至15元含氮亚杂环基和5至20元含氮亚杂环基)，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
环C表示亚环烷基(例如C3-30亚环烷基、C3-20亚环烷基或C3-15亚环烷基)、亚杂环基
(例如4至30元亚杂环基、4至20元亚杂环基或4至15元亚杂环基)、亚芳基(例如C5-30亚芳基、C5-20亚芳基或C5-15亚芳基)或亚杂芳基(例如5至30元亚杂芳基、5至20元亚杂芳基或5至15元亚杂芳基)，m1表示0或1的整数，(Rd3)n3表示环C可选地被n3个Rd3基团取代，各Rd3各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；和
环D表示杂环基(例如4至30元杂环基、4至20元杂环基或4至15元杂环基)、环烷基
(例如C3-30环烷基、C3-20环烷基或C3-15环烷基)、芳基(例如C5-30芳基、C5-20芳基或C5-15芳基)或杂芳基(例如5至30元杂芳基、5至20元杂芳基或5至15元杂芳基)，(Rd4)n4表示环D可选地被n4个Rd4基团取代，各Rd4各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。In some embodiments of the present disclosure, X represents:

Wherein ring A represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group, a
wherein n1 is an alkylene group, a 4- to 15-membered nitrogen-containing heterocyclylene group, a 5- to 20-membered nitrogen-containing heterocyclylene group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
Ring B represents a nitrogen-containing heterocyclic group (including a 4- to 30-membered nitrogen-containing heterocyclic group, a 4- to 25-membered nitrogen-containing heterocyclic group, a 4- to 20-membered nitrogen-containing heterocyclic group,
wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 , 18 , 19 or 20 ; wherein n2 is an integer selected from the group consisting of 0, 1, 2, 3 , 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19 or 20;
Ring C represents a cycloalkylene group (e.g., a C 3-30 cycloalkylene group, a C 3-20 cycloalkylene group, or a C 3-15 cycloalkylene group), a heterocyclylene group
wherein the ring C is optionally substituted with n3 R d3 groups, and each R d3 independently represents deuterium, C 1-6 alkyl , deuterated C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy , halogenated ... 2-6 alkenyl, and n3 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and ring D represents a heterocyclic group (e.g., a 4- to 30-membered heterocyclic group, a 4- to 20-membered heterocyclic group or a 4- to 15-membered heterocyclic group), a cycloalkyl group
(Rd4)n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), ( Rd4 ) n4 represents that ring D is optionally substituted by n4 Rd4 groups, and each Rd4 independently represents deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C2-6 alkynyl or C3-15 cycloalkyl, aryl (e.g. C5-30 aryl, C5-20 aryl or C5-15 aryl) or heteroaryl (e.g. 5-30 membered heteroaryl, 5-20 membered heteroaryl or 5-15 membered heteroaryl), 2-6 alkenyl, and n4 represents an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

在本公开的一些实施方案中，X的实例包括但不限于：
In some embodiments of the present disclosure, examples of X include, but are not limited to:

在本公开的一些实施方案中，式(I)化合物也是式(I-1)化合物、式(I-2)化合物、式(I-3)化合物或式(I-4)化合物：

其中基团Ra1、Ra2、Ra3、Ra4、Z1、Z2、Z3、Z4、Z5、(Ra5)m、R和X如上文式(I)化合物及
其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I) is also a compound of formula (I-1), a compound of formula (I-2), a compound of formula (I-3), or a compound of formula (I-4):

wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , Z1 , Z2 , Z3 , Z4 , Z5 , ( Ra5 ) m , R and X are as defined above for the compounds of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I)化合物也是式(I-5)化合物：

其中Z1、Z2、Z3、Z4、Z5、(Ra5)m、R和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I) is also a compound of formula (I-5):

wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , (R a5 ) m , R and X are as defined above for the compound of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I-5)化合物也是式(I-5-1)化合物：

其中Z1、(Ra5)m、R和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I-5) is also a compound of formula (I-5-1):

wherein Z 1 , (R a5 ) m , R and X are as defined above for the compound of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I-5)化合物也是式(I-5-1A)化合物：

其中(Ra5)m、R和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I-5) is also a compound of formula (I-5-1A):

wherein (R a5 ) m , R and X are as defined above for the compound of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I-5)化合物也是式(I-5-1B)化合物：

其中(Ra5)m、R、L和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I-5) is also a compound of formula (I-5-1B):

wherein (R a5 ) m , R, L and X are as defined above for the compound of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I-5)化合物也是式(I-5-2)化合物：

其中Z1、(Ra5)m、R、L和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I-5) is also a compound of formula (I-5-2):

wherein Z 1 , (R a5 ) m , R, L and X are as defined above for the compound of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I-5)化合物也是式(I-5-2A)化合物：

其中(Ra5)m、R、L和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I-5) is also a compound of formula (I-5-2A):

wherein (R a5 ) m , R, L and X are as defined above for the compound of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I-5)化合物也是式(I-5-2B)化合物：

其中(Ra5)m、R、L和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I-5) is also a compound of formula (I-5-2B):

wherein (R a5 ) m , R, L and X are as defined above for the compound of formula (I) and its embodiments.

在本公开的一些实施方案中，式(I-5)化合物也是式(I-5-3)化合物：

其中Z1、(Ra5)m、R和X如上文式(I)化合物及其各实施方案中所定义。In some embodiments of the present disclosure, the compound of formula (I-5) is also a compound of formula (I-5-3):

wherein Z 1 , (R a5 ) m , R and X are as defined above for the compound of formula (I) and its embodiments.

特别优选的是本发明表1中的化合物及其盐(尤其医药学上可接受的盐，例如它们的盐酸盐)、对映异构体、非对映异构体、溶剂化物或多晶型物：
表1本发明的化合物



























II.化合物的其它形式(包括化合物的盐、对映异构体、立体异构体、溶剂化物、同位素富集
类似物、前药或多晶型物)Particularly preferred are the compounds in Table 1 of the present invention and their salts (especially pharmaceutically acceptable salts, such as their hydrochlorides), enantiomers, diastereomers, solvates or polymorphs:
Table 1 Compounds of the present invention



























II. Other forms of the compound (including salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs or polymorphs of the compound)

本公开的化合物具有式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)、式(I-5-1)、式(I-5-1A)、式(I-5-1B)、式(I-5-2)、式(I-5-2A)、式(I-5-2B)或式(I-5-3)中任一个的结构。除非另有说明，否则当提及本公开的化合物时，是指包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)、式(I-5-1)、式(I-5-1A)、式(I-5-1B)、式(I-5-2)、式(I-5-2A)、式(I-5-2B)或式(I-5-3)中任一个的化合物以及落入这些通式范围内的具体化合物。The compounds of the present disclosure have the structure of any one of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-5-1), formula (I-5-1A), formula (I-5-1B), formula (I-5-2), formula (I-5-2A), formula (I-5-2B) or formula (I-5-3). Unless otherwise indicated, when referring to the compounds of the present disclosure, it refers to compounds including any one of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-5-1), formula (I-5-1A), formula (I-5-1B), formula (I-5-2), formula (I-5-2A), formula (I-5-2B) or formula (I-5-3) and specific compounds falling within the scope of these general formulas.

应认识到本公开的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)、式(I-5-1)、式(I-5-1A)、式(I-5-1B)、式(I-5-2)、式(I-5-2A)、式(I-5-2B)或式(I-5-3)的化合物)可具有立体构型，因此能以一种以上的立体异构体形式存在。本公开还涉及光学富集的具有立体构型的化合物，如约大于90％ee，如约95％ee或97％ee，或大于99％ee，以及其混合物，包括外消旋混合物。本文使用的“光学富集的”意指对映异构体的混合物由显著更大比例的一种对映体组成，并且可通过对映体过量(ee％)描述。异构体的纯化和异构体混合物的分离可以通过本领域已知的标准技术(例如，柱色谱、制备型TLC、制备型HPLC、不对称合成(例如，通过使用手性中间体)和/或手性拆分等)来实现。It should be recognized that the compounds of the present disclosure (including compounds of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-5-1), (I-5-1A), (I-5-1B), (I-5-2), (I-5-2A), (I-5-2B) or (I-5-3)) may have a stereo configuration and therefore may exist in more than one stereoisomer form. The present disclosure also relates to optically enriched compounds having a stereo configuration, such as about greater than 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures. "Optically enriched" as used herein means that the mixture of enantiomers is composed of a significantly greater proportion of one enantiomer and can be described by enantiomeric excess (ee%). Purification of isomers and separation of isomeric mixtures can be achieved by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates) and/or chiral resolution, etc.).

在一些实施方案中，还提供本公开化合物的多晶型形式或本公开化合物的盐。本公开的化合物的盐可以是药学上可接受的盐，包括但不限于氢卤酸盐(包括盐酸盐、氢溴酸盐)、硫酸盐、柠檬酸盐、马来酸盐、苯磺酸盐、乙醇酸盐、α-D-葡庚糖酸盐、D-葡萄糖酸盐、L-乳酸盐、L-苹果酸盐、丙二酸盐、扁桃酸盐、磷酸盐、丙酸盐、琥珀酸盐、酒石酸盐、对甲苯磺酸盐、戊酸盐、棕榈酸盐、癸二酸盐、硬脂酸盐、月桂酸盐、乙酸盐、己二酸盐、碳酸盐、对氯苯磺酸盐、乙二磺酸盐、富马酸盐、D-葡萄糖醛酸盐、α-酮戊二酸盐、马尿酸盐、2-羟基乙磺酸盐、乳糖酸盐、2-萘磺酸盐、油酸盐、胆酸盐、对苯二甲酸盐、L-抗坏血酸盐、樟脑酸盐、乙磺酸盐、甲酸盐、氢溴酸盐、甲磺酸盐、草酸盐、苯甲酸盐、水杨酸盐、丙酮酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、对氯苯磺酸盐、1，5-萘二磺酸盐、3-羟基-2-萘甲酸盐、1-羟基-2-萘甲酸盐、2-萘磺酸盐、三氟乙酸盐和羟乙酸盐等。本公开的化合物能以非溶剂化物或溶剂化物的形式存在于药学上可接受的溶剂如水、乙醇等中。在一些实施方案中，本公开化合物可以制备成前体药物或前药。前体药物在机体内能转化成母体药物而发挥作用。在一些实施方案中，还提供经同位素标记的本公开化合物，同位素的实例包括氘(D或2H)。
III.药物组合物/制剂In some embodiments, polymorphic forms of compounds of the present disclosure or salts of compounds of the present disclosure are also provided. The salts of compounds of the present disclosure may be pharmaceutically acceptable salts, including but not limited to hydrohalides (including hydrochlorides, hydrobromides), sulfates, citrates, maleates, benzenesulfonates, glycolates, α-D-glucoheptonates, D-gluconates, L-lactates, L-malates, malonates, mandelates, phosphates, propionates, succinates, tartrates, p-toluenesulfonates, valerates, palmitates, sebacates, stearates, laurates, acetates, adipates, carbonates, p-chlorobenzenesulfonates, edisylate, fumarates The compounds of the present invention can be present in pharmaceutically acceptable solvents such as water, ethanol, etc. in the form of non-solvates or solvates. In some embodiments, the compounds of the present invention can be prepared into prodrugs or prodrugs. Prodrugs can be converted into parent drugs in the body and play a role. In some embodiments, isotope-labeled compounds of the present invention are also provided, and examples of isotopes include deuterium (D or 2 H).
III. Pharmaceutical Compositions/Formulations

在一些实施方案中，本公开提供一种药物组合物，其包含作为活性成分的本公开的化合物或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物，及至少一种药学上可接受的载体。In some embodiments, the present disclosure provides a pharmaceutical composition comprising as an active ingredient a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.

在一些实施方案中，药学上可接受的载体包括但不限于填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、着色剂、溶剂或包封材料。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害，载体必须是“可接受的”。药学上可接受的载体的材料的一些实例包括：糖，如乳糖，葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；粉状黄蓍胶；麦芽；明胶；滑石；赋形剂，如可可脂和栓剂蜡；油，如花生油，棉籽油，红花油，芝麻油，橄榄油，玉米油和大豆油；二醇，如丙二醇；多元醇，如甘油，山梨糖醇，甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；表面活性剂磷酸盐缓冲溶液；聚氧乙烯，聚乙烯吡咯烷酮，聚丙烯酰胺，泊洛沙姆；和药物制剂中使用的其他无毒相容物质。In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials. The carrier must be "acceptable" if it is compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and is not harmful to the patient. Some examples of materials for pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; phosphate buffered solutions of surfactants; polyoxyethylene, polyvinyl pyrrolidone, polyacrylamide, poloxamer; and other nontoxic compatible substances used in pharmaceutical formulations.

本公开所述的药物组合物，进一步包括至少一种第二治疗剂，例如抗癌剂。第二治疗剂可与本公开所述式(I)化合物联合治疗本公开所述的疾病或病症。第二治疗剂包括但不限于化疗剂、免疫治疗剂、基因治疗剂等。The pharmaceutical composition of the present disclosure further comprises at least one second therapeutic agent, such as an anticancer agent. The second therapeutic agent can be combined with the compound of formula (I) described in the present disclosure to treat the disease or condition described in the present disclosure. The second therapeutic agent includes but is not limited to a chemotherapeutic agent, an immunotherapeutic agent, a gene therapy agent, etc.

本公开所述的包含作为活性成分的如本公开所述的式(I)化合物或其药学上可接受的盐的药物组合物可根据合适的给药途径(包括但不限于鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药)被制备成合适的制剂形式，例如喷雾制剂、贴剂、片剂(例如常规片剂、分散片、口腔崩解片)、胶囊(例如软胶囊、硬胶囊、肠溶胶囊)、糖衣丸、含片、散剂、颗粒剂、粉针剂、栓剂，或液体制剂(例如混悬剂(例如水性或油性混悬剂)、溶液、乳剂或糖浆剂)，或常规注射剂型例如可注射的溶液剂(例如根据本领域已知方法采用水、林格氏溶液或等渗氯化钠溶液等作为载体或溶剂来配制的无菌注射溶液)或冻干组合物。本领域技术人员还可根据需要将所述的式(I)化合物制备成常规的、可分散的、可咀嚼的、口腔速崩解的或快速溶解的制剂，或缓释胶囊或控释胶囊。The pharmaceutical composition described in the present disclosure comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared into a suitable formulation form according to a suitable administration route (including but not limited to nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural cavity administration, intrathecal administration and intravenous administration), such as spray preparations, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (such as soft capsules, hard capsules, enteric-coated capsules), dragees, lozenges, powders, granules, powder injections, suppositories, or liquid preparations (such as suspensions (such as aqueous or oily suspensions), solutions, emulsions or syrups), or conventional injection forms such as injectable solutions (such as sterile injection solutions prepared according to methods known in the art using water, Ringer's solution or isotonic sodium chloride solution as a carrier or solvent) or lyophilized compositions. Those skilled in the art can also prepare the compound of formula (I) into conventional, dispersible, chewable, oral fast-disintegrating or fast-dissolving preparations, or sustained-release capsules or controlled-release capsules as needed.

作为活性成分的如本公开所述的式(I)化合物被包含在药学上可接受的载体或稀释剂中，其量足以向受试者递送用于需治疗的适应症的治疗有效量，而不会在所治疗的受试者中引起严重的毒性作用。用于本文提及的所有疾病或病症的活性化合物的给药剂量为，例如约5ng/kg受试者体重/天至500mg/kg受试者体重/天，约10ng/kg受试者体重/天至300mg/kg受试者体重/天，例如0.1至100mg/kg受试者体重/天，或0.5至约25mg/kg受试者体重/天。The compound of formula (I) as described in the present disclosure as an active ingredient is contained in a pharmaceutically acceptable carrier or diluent, and its amount is sufficient to deliver to the subject a therapeutically effective amount for the indication to be treated, without causing serious toxic effects in the treated subject. The dosage of the active compound for all diseases or conditions mentioned herein is, for example, about 5 ng/kg subject weight/day to 500 mg/kg subject weight/day, about 10 ng/kg subject weight/day to 300 mg/kg subject weight/day, for example 0.1 to 100 mg/kg subject weight/day, or 0.5 to about 25 mg/kg subject weight/day.

本公开所述的式(I)化合物或其药学上可接受的盐可以任何合适的制剂形式方便地给药，合适的制剂形式的规格包括但不限于每单位剂型含有少于1mg，1mg至3000mg，5mg至1000mg，例如5至500mg，25至250mg活性成分。
IV.药盒(kit)/包装制品The compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present disclosure can be conveniently administered in any suitable dosage form, and the specifications of suitable dosage forms include but are not limited to less than 1 mg, 1 mg to 3000 mg, 5 mg to 1000 mg, for example 5 to 500 mg, 25 to 250 mg of active ingredient per unit dosage form.
IV.Kit/Packaging Products

本公开所述的式(I)化合物，或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物，其是用作药剂。本公开的药剂或本公开的药物组合物可以存在于药盒/包装制品中。药盒/包装制品可以包括包装或容器。包装或容器包括但不限于安瓶(ampoule)、泡罩包装、药用塑料瓶、小瓶、药用玻璃瓶、容器、注射器、层压软包装、共挤膜输液容器、试管和分配装置等。药盒/包装制品可以包含产品使用说明书。
V.治疗方法和用途The compound of formula (I) described in the present disclosure, or its pharmaceutically acceptable salt, solvate, isotope-enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers, is used as a medicament. The medicament of the present disclosure or the pharmaceutical composition of the present disclosure may be present in a medicine box/packaged product. The medicine box/packaged product may include a package or container. The package or container includes, but is not limited to, an ampoule, a blister package, a medicinal plastic bottle, a vial, a medicinal glass bottle, a container, a syringe, a laminated flexible package, a co-extruded film infusion container, a test tube, and a dispensing device, etc. The medicine box/packaged product may include a product instruction manual.
V. Treatment Methods and Uses

本公开所述的式(I)化合物，或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物，还可以用作药剂。尤其是，本公开所述的式(I)化合物，或其药学上可接受的盐、溶剂化物、同位素富集类似物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物可以用于制备用于预防及/或治疗疾病或病症的药物。所述疾病或病症包括与cereblon蛋白相关的疾病或病症的药物。The compounds of formula (I) described in the present disclosure, or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, can also be used as medicaments. In particular, the compounds of formula (I) described in the present disclosure, or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof can be used to prepare drugs for preventing and/or treating diseases or conditions. The diseases or conditions include drugs for diseases or conditions associated with cereblon proteins.

在一些实施方案中，所述疾病或病症包括：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome，RS)、急性肝功能衰竭和糖尿病。In some embodiments, the diseases or conditions include: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes.

在一些实施方案中，所述疾病或病症包括但不限于：骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性髓性白血病(CML)、慢性粒细胞白血病、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性B淋巴细胞白血病、T淋巴细胞白血病、急性T淋巴细胞白血病、淋巴瘤细胞白血病、单核细胞白血病、髓性单核细胞白血病；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、免疫母细胞T细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤(FL)、Burkitt′s淋巴瘤、边缘区淋巴瘤(MZL)、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤；伯基特淋巴瘤(Burkitt′s淋巴瘤)；甲状腺癌；黑色素瘤；肺癌，包括肺腺癌、肺鳞癌、非小细胞肺癌、小细胞肺癌；炎症性肌纤维母细胞瘤；结直肠癌；肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括三阴性乳腺癌、偶发性乳腺癌、乳腺管癌和考登病患者；胰腺癌；中枢神经系统癌症；神经母细胞瘤；神经胶质瘤；外周神经上皮瘤；髓外浆细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；子宫癌；头颈癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；皮肤癌；里希特氏综合征(Richter syndrome，RS)；脓毒综合征；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、银屑病关节炎、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎、化脓性汗腺炎、痛风、I型糖尿病、荨麻疹、炎症性肠病(包括克罗恩病和溃疡性结肠炎)；角结膜干燥症；炎症性疾病，包括肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎；脑型疟疾；感染性疾病，包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等；感染性休克；结核病；细菌性脑膜炎；慢性阻塞性肺疾病；哮喘；出血性休克；器官(包括肾、心脏、肺)或组织移植排斥反应；糖尿病；类肉瘤病；成人呼吸窘迫综合征；贫血；小儿再生障碍性贫血；心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症)；恶病质和败血症休克所致的多器官功能衰竭；和急性肝功能衰竭。In some embodiments, the disease or condition includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia (CML), chronic myeloid leukemia, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute B-cell leukemia, T-cell leukemia, acute T-cell leukemia, lymphoma cell leukemia, monocytic leukemia, myelomonocytic leukemia; lymphomas, including diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, immunoblastic T-cell lymphoma , CD20-positive lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Burkitt's lymphoma, marginal zone lymphoma (MZL), primary lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin lymphoma; Burkitt's lymphoma; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; brain glioma; glioblastoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer, including triple-negative breast cancer, sporadic Patients with breast cancer, ductal carcinoma, and Cowden disease; pancreatic cancer; central nervous system cancer; neuroblastoma; glioma; peripheral neuroepithelial tumor; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; head and neck cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various lipogenic tumors, Ewing sarcoma/primitive neuroectodermal tumor (Ewing/P NETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; skin cancer; Richter syndrome (RS); sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis/ Dermatomyositis, Sjögren's syndrome, atopic dermatitis, hidradenitis suppurativa, gout, type 1 diabetes, urticaria, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); keratoconjunctivitis sicca; inflammatory diseases, including pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, AIDS, COVID-19 novel coronavirus infection, Gram-negative bacteria infection, Gram-positive bacteria infection, tuberculosis, etc.; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplant rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia in children; cardiovascular disease (such as coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure caused by cachexia and septic shock; and acute liver failure.

本公开提供用于预防及/或治疗受试者中的疾病或病症的方法，包括向所述受试者施用治疗有效量的本公开所述的式(I)化合物，或其药学上可接受的盐，或本公开所述的包含作为活性成分的式(I)化合物或其药学上可接受的盐的药物组合物。在一些实施方案中，所述疾病或病症包括所述与cereblon蛋白相关的疾病或病症。所述疾病或病症如本文中所定义。The present disclosure provides a method for preventing and/or treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described in the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient as described in the present disclosure. In some embodiments, the disease or condition includes the disease or condition associated with the cereblon protein. The disease or condition is as defined herein.

在用于预防及/或治疗受试者中的(与cereblon蛋白相关的疾病或病症的)方法中，通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式将治疗有效量的本公开所述的式(I)化合物、或本公开所述的包含作为活性成分的式(I)化合物的药物组合物施用至所述受试者。In the method for preventing and/or treating (a disease or condition associated with cereblon protein) in a subject, a therapeutically effective amount of a compound of formula (I) described in the present disclosure, or a pharmaceutical composition comprising a compound of formula (I) as an active ingredient described in the present disclosure, is administered to the subject by at least one administration method selected from nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural space administration, intrathecal administration and intravenous administration.

术语“治疗”或“处理”是指向受试者施用本公开所述的式(I)化合物或其药学上可接受的盐，或包含作为活性成分的式(I)化合物或其药学上可接受的盐的药物组合物，以减缓(减轻)不希望发生的疾病或病症(例如肿瘤)的发展。本公开的有益的或期望的临床结果包括但不限于：减轻症状，减轻疾病的严重程度，稳定疾病的状态，延迟或延缓疾病进展，改善或缓和病情，以及缓解疾病。The term "treatment" or "treatment" refers to administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, to slow down (mitigate) the development of an undesirable disease or condition (e.g., a tumor). The beneficial or desired clinical results of the present disclosure include, but are not limited to, alleviating symptoms, reducing the severity of the disease, stabilizing the state of the disease, delaying or slowing the progression of the disease, improving or alleviating the condition, and alleviating the disease.

本公开化合物的“治疗有效量”取决于多种因素，包括所用特定化合物的活性、该化合物的代谢稳定性和作用时间长度、患者的年龄、性别和体重，患者的总体医学状况，给药方式和时间，排泄率，联合用药，以及所治疗患者的疾病或病症进展情况。本领域技术人员能够根据这些和其它因素来确定合适的剂量。The "therapeutically effective amount" of the disclosed compounds depends on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the age, sex and weight of the patient, the patient's overall medical condition, the mode and time of administration, the rate of excretion, co-administration, and the progression of the disease or condition of the patient being treated. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.

应当理解的是，使用一种或多种活性化合物和/或组合物及其剂量的选择取决于个体的基本情况(通常应该使个人情况达到最佳的效果)。给药和给药方案应该在本领域技术人员的能力范围内，并且合适的剂量取决于许多因素包括普通技术医生，兽医或研究者知识能力水平(见例如李俊主编，“临床药理学”，第4版，人民卫生出版社(2008))。It should be understood that the choice of using one or more active compounds and/or compositions and their dosages depends on the individual's basic conditions (generally, the individual's conditions should be optimized). Administration and dosing regimens should be within the capabilities of those skilled in the art, and appropriate dosages depend on many factors including the knowledge and ability level of the ordinary skilled physician, veterinarian or researcher (see, e.g., Li Jun, ed., "Clinical Pharmacology," 4th edition, People's Medical Publishing House (2008)).

上述治疗的患者或受试者是指动物，例如哺乳动物，包括但不限于灵长类动物(如人类)、牛、绵羊、山羊、马、狗、猫、兔、豚鼠、大鼠、小鼠等。
VI.制备方法The patient or subject for treatment mentioned above refers to an animal, such as a mammal, including but not limited to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice, etc.
VI. Preparation Method

本公开式(I)化合物可以通过式(M1)化合物与式(M2)化合物反应制备得到：

其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5、(Rd1)n1、环B、(Rd2)n2、Rc、
环C、m1、(Rd3)n3、环D、和(Rd4)n4如本公开式(I)化合物及其各子实施方案中所定义；
含氮杂环A表示4至30元含氮杂环(优选地，4至20元含氮杂环；更优选地，4至15元
含氮杂环)；
R表示可选取代的直链或支链的C1-5亚烷基；
LE表示Cl、Br、I、甲磺酰氧基、对甲苯磺酰氧基、邻硝基苯磺酰基、C(O)Cl或COOH；
和
式(I)化合物的Xa相应地表示由以下通式表示的结构：

其中含氮亚杂环基A表示4至30元含氮亚杂环基(优选地，4至20元含氮亚杂环基；更
优选地，4至15元含氮亚杂环基)，
(Rd1)n1、环B、(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D、和(Rd4)n4如本公开式(I)化合物及
其各子实施方案中所定义。The compound of formula (I) disclosed herein can be prepared by reacting a compound of formula (M1) with a compound of formula (M2):

wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 , ( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc ,
Ring C, m1, (R d3 ) n3 , Ring D, and (R d4 ) n4 are as defined in the compounds of formula (I) and various sub-embodiments thereof disclosed herein;
The nitrogen-containing heterocycle A represents a 4- to 30-membered nitrogen-containing heterocycle (preferably, a 4- to 20-membered nitrogen-containing heterocycle; more preferably, a 4- to 15-membered nitrogen-containing heterocycle);
R represents an optionally substituted straight or branched C 1-5 alkylene group;
LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, o-nitrobenzenesulfonyl, C(O)Cl or COOH;
Xa of the compound of formula (I) corresponds to a structure represented by the following general formula:

wherein the nitrogen-containing heterocyclic group A represents a 4- to 30-membered nitrogen-containing heterocyclic group (preferably, a 4- to 20-membered nitrogen-containing heterocyclic group; more preferably, a 4- to 15-membered nitrogen-containing heterocyclic group),
( Rd1 ) n1 , Ring B, ( Rd2 ) n2 , Rc , Ring C, m1, ( Rd3 ) n3 , Ring D, and ( Rd4 ) n4 are as defined in the compounds of formula (I) and various subembodiments thereof disclosed herein.

在本公开的制备式(I)化合物的方法的一些实施方案中，R表示-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-或-(CH2)5-；其中上述基团可选地被选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代。In some embodiments of the method for preparing the compound of formula (I) disclosed herein, R represents -CH2- , -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4- or -( CH2 ) 5- ; wherein the above groups are optionally substituted with substituents selected from deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl and C2-6 alkenyl.

在本公开的制备式(I)化合物的方法的一些实施方案中，含氮杂环A在经过反应去除N上的氢原子后，得到含氮亚杂环基A。在一些实施方案中，含氮杂环A表示4至30元含氮杂环(优选地，4至20元含氮杂环；更优选地，4至15元含氮杂环)。含氮亚杂环基A表示4至30元含氮亚杂环基(优选地，4至20元含氮亚杂环基；更优选地，4至15元含氮亚杂环基)。In some embodiments of the method for preparing the compound of formula (I) disclosed herein, the nitrogen-containing heterocyclic ring A, after the hydrogen atom on N is removed by reaction, obtains the nitrogen-containing heterocyclic group A. In some embodiments, the nitrogen-containing heterocyclic ring A represents a 4- to 30-membered nitrogen-containing heterocyclic ring (preferably, a 4- to 20-membered nitrogen-containing heterocyclic ring; more preferably, a 4- to 15-membered nitrogen-containing heterocyclic ring). The nitrogen-containing heterocyclic group A represents a 4- to 30-membered nitrogen-containing heterocyclic group (preferably, a 4- to 20-membered nitrogen-containing heterocyclic group; more preferably, a 4- to 15-membered nitrogen-containing heterocyclic group).

在本公开的制备式(I)化合物的方法的一些实施方案中，当LE表示Cl、Br、I、甲磺酰氧基、对甲苯磺酰氧基、或邻硝基苯磺酰基时，式(M1)化合物与式(M2)化合物发生胺烷基化反应。在一些实施方案中，胺烷基化反应可以例如在有机碱和碘化钠的存在下在室温至80℃(例如40℃～60℃、40℃～50℃、或50℃～60℃)条件下进行。有机碱的实例包括但不限于DIEA或三乙胺。在一些实施方案中，式(M1)化合物与式(M2)化合物的摩尔比可以为例如1：1.0～2，1：1.1～2，1：1.1～1.5，1：1.1～1.2，或1：1.2～1.3等。In some embodiments of the method for preparing a compound of formula (I) disclosed herein, when LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, or o-nitrobenzenesulfonyl, the compound of formula (M1) reacts with the compound of formula (M2) to undergo an amine alkylation reaction. In some embodiments, the amine alkylation reaction can be carried out, for example, in the presence of an organic base and sodium iodide at room temperature to 80°C (e.g., 40°C to 60°C, 40°C to 50°C, or 50°C to 60°C). Examples of organic bases include, but are not limited to, DIEA or triethylamine. In some embodiments, the molar ratio of the compound of formula (M1) to the compound of formula (M2) can be, for example, 1:1.0 to 2, 1:1.1 to 2, 1:1.1 to 1.5, 1:1.1 to 1.2, or 1:1.2 to 1.3, etc.

在本公开的制备式(I)化合物的方法的一些实施方案中，当LE表示COOH时，式(M1)化合物与式(M2)化合物发生酰胺缩合反应。在一些实施方案中，酰胺缩合反应可以例如在有机碱和HATU的存在下在室温条件下进行。有机碱的实例包括但不限于DIEA或三乙胺。在一些实施方案中，式(M1)化合物与式(M2)化合物的摩尔比可以为例如1：1.0～2，1：1.1～2，1：1.1～1.5，1：1.1～1.2，或1：1.2～1.3等。In some embodiments of the method for preparing a compound of formula (I) disclosed herein, when LE represents COOH, an amide condensation reaction occurs between a compound of formula (M1) and a compound of formula (M2). In some embodiments, the amide condensation reaction can be carried out, for example, in the presence of an organic base and HATU at room temperature. Examples of organic bases include, but are not limited to, DIEA or triethylamine. In some embodiments, the molar ratio of the compound of formula (M1) to the compound of formula (M2) can be, for example, 1:1.0-2, 1:1.1-2, 1:1.1-1.5, 1:1.1-1.2, or 1:1.2-1.3, etc.

在本公开的制备式(I)化合物的方法的一些实施方案中，当基团LE表示甲磺酰氧基时，通过使式(M3)化合物与甲烷磺酸酐或甲烷磺酰氯发生反应制备得到式(M1)化合物：

其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5和R如本公开式(I)化合物及其
各子实施方案中所定义。在一些实施方案中，R可以表示CH2。In some embodiments of the method for preparing a compound of formula (I) disclosed herein, when the group LE represents a methanesulfonyloxy group, the compound of formula (M1) is prepared by reacting a compound of formula (M3) with methanesulfonic anhydride or methanesulfonyl chloride:

wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 and R are as defined in the compounds of formula (I) and its various sub-embodiments disclosed herein. In some embodiments, R may represent CH2 .

在本公开的制备式(I)化合物的方法的一些实施方案中，当基团LE表示Cl、Br或I时，式(M1)化合物可以通过式(M3)化合物与氢卤酸发生卤代反应制备得到：

其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5和R如本公开式(I)化合物及其
各子实施方案中所定义。在一些实施方案中，R可以表示CH2。In some embodiments of the method for preparing the compound of formula (I) disclosed herein, when the group LE represents Cl, Br or I, the compound of formula (M1) can be prepared by a halogenation reaction of a compound of formula (M3) with a hydrohalic acid:

wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 and R are as defined in the compounds of formula (I) and its various sub-embodiments disclosed herein. In some embodiments, R may represent CH2 .

在本公开的制备式(I)化合物的方法的一些实施方案中，式(M3)化合物(其中R表示CH2)可以通过使式(M4)化合物与(三丁基锡)甲醇在钯催化剂催化下发生偶联反应制备得到：

其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4和Z5如本公开式(I)化合物及其各子
实施方案中所定义。In some embodiments of the method for preparing the compound of formula (I) disclosed herein, the compound of formula (M3) (wherein R represents CH 2 ) can be prepared by coupling reaction of the compound of formula (M4) with (tributyltin)methanol under a palladium catalyst:

wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 and Z5 are as defined in the compounds of formula (I) and various subembodiments thereof disclosed herein.

在一些实施方案中，偶联反应可以例如在四(三苯基磷)钯和1，4-二氧六环(或DMF)的存在下在40℃至120℃条件下进行。In some embodiments, the coupling reaction can be carried out, for example, in the presence of tetrakis(triphenylphosphine)palladium and 1,4-dioxane (or DMF) at 40°C to 120°C.

在一些实施方案中，当式(M4)化合物中的Z5表示N，且Z1表示C(O)、CH2或CD2，Z2、Z3和Z4各自独立地表示C(O)时，通过使式(M5)化合物与式(M6)化合物发生胺酯交换反应制备得到式(M4)化合物：

其中基团Ra1、Ra2、Ra3、Ra4和(Ra5)m如本公开式(I)化合物及其各子实施方案中所定义。In some embodiments, when Z 5 in the compound of formula (M4) represents N, and Z 1 represents C(O), CH 2 or CD 2 , and Z 2 , Z 3 and Z 4 each independently represent C(O), the compound of formula (M4) is prepared by subjecting the compound of formula (M5) to an amine transesterification reaction with the compound of formula (M6):

wherein the groups Ra1 , Ra2 , Ra3 , Ra4 and ( Ra5 ) m are as defined in the compounds of formula (I) and various sub-embodiments thereof disclosed herein.

在一些实施方案中，胺酯交换反应可以在CH3ONa和甲醇的存在下在室温条件下进行。替代地，胺酯交换反应还可以在CH3OLi或Cs2CO3和甲醇的存在下在40℃至90℃条件下进行，或者在DBU和THF的存在下在40℃至90℃条件下进行。In some embodiments, the amine transesterification reaction can be carried out in the presence of CH 3 ONa and methanol at room temperature. Alternatively, the amine transesterification reaction can be carried out in the presence of CH 3 OLi or Cs 2 CO 3 and methanol at 40° C. to 90° C., or in the presence of DBU and THF at 40° C. to 90° C.

在一些实施方案中，当式(M4)化合物中的Z1表示C(O)、C(S)、CH2或CD2，Z2、Z3和Z4各自独立地表示C(O)或C(S)，且Z1、Z2、Z3和Z4中至少一个表示C(S)时，通过使式(M7)的化合物与硫化试剂(thionating agent)发生硫化作用(thionation)来制备得到式(M4)的化合物：

其中式(M7)的化合物的Z6表示C(O)、CH2或CD2；以及基团Ra1、Ra2、Ra3、Ra4和(Ra5)m如
本公开式(I)化合物及其各子实施方案中所定义。当起始原料式(M7)的化合物的Z6表示CH2或CD2时，在产物式(M4)的硫羰基化合物中对应的Z1表示CH2或CD2。当起始原料式(M7)的化合物的Z6表示C(O)时，在产物式(M4)的硫羰基化合物中对应的Z1表示C(O)或C(S)。In some embodiments, when Z 1 in the compound of formula (M4) represents C(O), C(S), CH 2 or CD 2 , Z 2 , Z 3 and Z 4 each independently represent C(O) or C(S), and at least one of Z 1 , Z 2 , Z 3 and Z 4 represents C(S), the compound of formula (M4) is prepared by thionating the compound of formula (M7) with a thionating agent:

wherein Z 6 of the compound of formula (M7) represents C(O), CH 2 or CD 2 ; and groups Ra1 , Ra2 , Ra3 , Ra4 and ( Ra5 ) m are as defined in the compounds of formula (I) and their respective sub-embodiments disclosed herein. When Z 6 of the compound of the starting material formula (M7) represents CH 2 or CD 2 , the corresponding Z 1 in the thiocarbonyl compound of the product formula (M4) represents CH 2 or CD 2 . When Z 6 of the compound of the starting material formula (M7) represents C(O), the corresponding Z 1 in the thiocarbonyl compound of the product formula (M4) represents C(O) or C(S).

在一些实施方案中，硫化试剂的实例包括但不限于二硫化碳，六甲基二硅硫烷，硫，硫脲，硫化氢，五硫化二磷，劳森试剂(Lawesson′s Reagent；CAS号：19172-47-5)，Belleau’s试剂(CAS号：88816-02-8)，和Davy’s试剂(CAS号：82737-61-9)等。In some embodiments, examples of sulfurizing agents include, but are not limited to, carbon disulfide, hexamethyldisilathane, sulfur, thiourea, hydrogen sulfide, phosphorus pentasulfide, Lawesson’s Reagent (CAS No.: 19172-47-5), Belleau’s Reagent (CAS No.: 88816-02-8), and Davy’s Reagent (CAS No.: 82737-61-9), etc.

在一些实施方案中，式(M7)的化合物与硫化试剂(例如劳森试剂)在溶剂(例如1，4-二氧六环)中在40℃至150℃条件下反应，制备得到式(M4)的硫羰基化合物。In some embodiments, the compound of formula (M7) is reacted with a sulfiding agent (eg, Lawesson's reagent) in a solvent (eg, 1,4-dioxane) at 40° C. to 150° C. to prepare a thiocarbonyl compound of formula (M4).

在一些实施方案中，式(M4)硫羰基化合物的Z1、Z2、Z3和Z4中至少一个表示C(S)。在一些实施方案中，式(M4)硫羰基化合物的Z1、Z2、Z3和Z4中至少两个表示C(S)。在一些实施方案中，Z1、Z2、Z3和Z4中至少三个表示C(S)。在一些实施方案中，Z1、Z2、Z3和Z4均表示C(S)。
VII.定义In some embodiments, at least one of Z 1 , Z 2 , Z 3 and Z 4 of the thiocarbonyl compound of formula (M4) represents C(S). In some embodiments, at least two of Z 1 , Z 2 , Z 3 and Z 4 of the thiocarbonyl compound of formula (M4) represent C(S). In some embodiments, at least three of Z 1 , Z 2 , Z 3 and Z 4 represent C(S). In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 all represent C(S).
VII. Definitions

除非另有说明，否则本说明书中所使用的下列词语、短语和符号通用地具有如下所述的含义。Unless otherwise specified, the following words, phrases and symbols used in this specification generally have the meanings described below.

通常，本文所用的命名法(包括IUPAC命名法)和下文描述的实验室程序(包括用于细胞培养、有机化学、分析化学和药理学等)是本领域众所周知的并且通常使用的那些。除非另有定义，否则结合本文描述的本公开内容的本文使用的所有科学和技术术语具有本领域技术人员通常理解的相同含义。另外，在权利要求书和/或说明书中，用语“一”或“一个”与术语“包含”或名词结合使用时，其含义可能是“一个”，但也与“一个或多个”，“至少一个”和“一个或多于一个”的含义一致。类似地，用语“另一个”或“其它”可以表示至少第二个或更多。In general, the nomenclature used herein (including IUPAC nomenclature) and the laboratory procedures described below (including for cell culture, organic chemistry, analytical chemistry and pharmacology, etc.) are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the present disclosure described herein have the same meanings as commonly understood by those skilled in the art. In addition, in the claims and/or the specification, when the term "one" or "an" is used in conjunction with the term "comprising" or a noun, its meaning may be "one", but it is also consistent with the meaning of "one or more", "at least one" and "one or more than one". Similarly, the term "another" or "other" can mean at least a second or more.

应该理解的是，每当本文用术语“包括”或“包含”描述各个方面时，还提供了其他由“由...组成”和/或“基本上由...组成”描述的类似方面。It should be understood that whenever various aspects are described herein with the terms "including" or "comprising," other similar aspects described by "consisting of" and/or "consisting essentially of" are also provided.

单独或组合使用的术语“约”在本文中用于意指近似、大致、大约或在...左右。当术语“约”与数值范围联合使用时，它通过使边界延伸高于和低于阐述的数值来修饰那个范围。一般来说，术语“约”可通过向上或向下(增高或降低)变化例如10％、5％、2％或1％来修饰数值高于和低于所述的值。The term "about", used alone or in combination, is used herein to mean approximately, roughly, approximately, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" can modify a numerical value above and below the stated value by a variation upward or downward (increase or decrease), for example, 10%, 5%, 2%, or 1%.

在本文中，单独或组合使用的用语“......表示键”意指其是键连接体(即表示其不存在)。例如用语“Rc表示键”意指Rc是键连接体。换言之，当Rc为键时，式(I)结构的环B基团直接连接至式(I)结构中的环C。As used herein, the phrase "...... represents a bond", used alone or in combination, means that it is a bond linker (i.e., it means that it is absent). For example, the phrase "R c represents a bond" means that R c is a bond linker. In other words, when R c is a bond, the ring B group of the structure of formula (I) is directly connected to the ring C in the structure of formula (I).

在本文中，单独或组合使用的用语“可选取代”意指指示的基团可以未被取代或被一个或多个如本文定义的取代基取代。在本文中，用语“可选地被......取代”与“未取代或取代的”可以互换使用。术语“取代的”通常表示所提及结构中的一或多个氢被相同或不同的具体取代基取代。取代基的数量原则上不受任何限制，或自动受构建单元的大小(即，构建单元的可被替换的氢原子的总数量)限制，或如本文中所明确定义。In this article, the term "optionally substituted" used alone or in combination means that the indicated group can be unsubstituted or substituted by one or more substituents as defined herein. In this article, the term "optionally substituted by..." and "unsubstituted or substituted" can be used interchangeably. The term "substituted" generally means that one or more hydrogens in the structure mentioned are replaced by the same or different specific substituents. The number of substituents is in principle not subject to any restrictions, or is automatically limited by the size of the building block (that is, the total number of hydrogen atoms that can be replaced by the building block), or as clearly defined herein.

在本文中，由波形线断裂的键显示所绘示基团与分子的其他部分的连接点。例如，下文所绘示的一价基团X

表示所述基团X的环A与式(I)结构的基团R连接。In this document, a bond broken by a wavy line shows the point of attachment of the depicted group to the rest of the molecule. For example, the monovalent group X

The ring A representing the group X is connected to the group R of the structure of formula (I).

在本文中，单独或组合使用的术语“被一或多个选自......的取代基取代”中的用语“一或多个”可以是指所提及的基团的部分或全部的氢被取代基替换，取代基的数量包括但不限于1-40个，例如1-30个，例如1-25个，1-20个，1-15个，1-10个，1-5个，1-4个，1-3个，1-2个或1个。该数量原则上不受任何限制或自动受构建单元的大小限制，例如当所提及的基团是甲基时，取代基的数量可以是1-3个。In this document, the term "one or more" in the term "substituted by one or more substituents selected from..." used alone or in combination may mean that part or all of the hydrogens of the mentioned group are replaced by substituents, and the number of substituents includes but is not limited to 1-40, such as 1-30, such as 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2 or 1. This number is in principle not subject to any restrictions or automatically limited by the size of the building block, for example, when the mentioned group is methyl, the number of substituents can be 1-3.

在本文中，单独或组合使用的术语“氘代”是指所提及的基团的一或多个氢被氘原子替代。As used herein, the term "deuterated," alone or in combination, means that one or more hydrogens of the referenced group are replaced by a deuterium atom.

在本文中，单独或组合使用的术语“氧代”或“氧代基”指＝O。As used herein, the term "oxo" or "oxo," alone or in combination, refers to =0.

在本文中，单独或组合使用的术语“羰基”指C(O)或C(＝O)。As used herein, the term "carbonyl," alone or in combination, refers to C(O) or C(=O).

在本文中，单独或组合使用的术语“硫代羰基”或“硫羰基”指C(S)或C(＝S)。[0046] As used herein, the term "thiocarbonyl" or "thiocarbonyl," as used alone or in combination, refers to C(S) or C(=S).

在本文中，单独或组合使用的术语“卤素原子”或“卤素”是指氟、氯、溴或碘。As used herein, the term "halogen atom" or "halogen", alone or in combination, refers to fluorine, chlorine, bromine or iodine.

在本文中，单独或组合使用的术语“烷基”是指直链或支链的烷基。术语“Cx-Cy烷基”或“Cx-y烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链烷基。本发明中单独或组合使用的术语“C1-C10烷基”是指含有1至10个碳原子的直链或支链烷基。术语“C1-C10烷基”的实例包括C1-9烷基，C1-8烷基，C2-8烷基，C1-7烷基，C1-6烷基，C1-5烷基，C1-4烷基，C1-C3烷基，和C1-C2烷基。代表性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、特戊基、及己基。本公开的术语“C1-3烷基”或“C1-C3烷基”是指含有1至3个碳原子的烷基，其代表性实例包括甲基、乙基、正丙基及异丙基。在本公开中，所述“烷基”是可选地经取代的，取代基可选是一或多个(例如1-10个、1-6、1-5、1-4、或1-3个)选自例如卤素、羟基、氰基、C1-3烷基、C1-3烷氧基、卤代C1-6烷氧基、卤代C1-6烷基(例如三氟甲基)、C3-6环烷基和4元至7元杂环基的取代基。As used herein, the term "alkyl" used alone or in combination refers to a straight or branched alkyl group. The term " Cx - Cyalkyl " or " Cxyalkyl " (x and y are each an integer) refers to a straight or branched alkyl group containing x to y carbon atoms. The term " C1 - C10alkyl " used alone or in combination in the present invention refers to a straight or branched alkyl group containing 1 to 10 carbon atoms. Examples of the term " C1 -C10alkyl" include C1-9alkyl , C1-8alkyl , C2-8alkyl , C1-7alkyl, C1-6alkyl , C1-5alkyl , C1-4alkyl , C1 - C3alkyl , and C1 - C2alkyl . Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl. The term "C 1-3 alkyl" or "C 1 -C 3 alkyl" of the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms, and representative examples thereof include methyl, ethyl, n-propyl and isopropyl. In the present disclosure, the "alkyl" is optionally substituted, and the substituents may be one or more (e.g., 1-10, 1-6, 1-5, 1-4, or 1-3) selected from, for example, halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-6 alkoxy, halogenated C 1-6 alkyl (e.g., trifluoromethyl), C 3-6 cycloalkyl, and 4- to 7-membered heterocyclyl.

在本文中，单独或组合使用的术语“卤代烷基”是指被一或多个卤素取代的直链或支链的烷基，其中所述烷基中的一或多个氢被卤素替代。术语“卤代Cx-Cy烷基”或“卤代Cx-y烷基”(x及y各自为整数)是指被一或多个卤素取代的含有x至y个碳原子的直链或支链烷基。本公开中单独或组合使用的术语“卤代C1-10烷基”是指被一或多个卤素取代的含有1至10个碳原子的直链或支链烷基。本公开的卤代C1-10烷基的实例包括卤代C1-9烷基，例如卤代C1-8烷基，卤代C2-8烷基，卤代C1-7烷基，卤代C1-6烷基，卤代C1-5烷基，或卤代C1-4烷基。代表性实例包括卤代甲基、卤代乙基、卤代正丙基、卤代异丙基、卤代正丁基、卤代异丁基、卤代仲丁基、卤代叔丁基、卤代戊基、卤代异戊基、卤代新戊基、卤代特戊基、卤代己基、卤代庚基、卤代辛基、卤代壬基及卤代癸基。本公开的术语“卤代C1-3烷基”或“卤代C1-C3烷基”是指被一或多个卤素取代的含有1至3个碳原子的烷基，其代表性实例包括卤代甲基(例如三氟甲基)、卤代乙基、卤代正丙基及卤代异丙基。As used herein, the term "haloalkyl" used alone or in combination refers to a straight or branched alkyl group substituted with one or more halogens, wherein one or more hydrogens in the alkyl group are replaced with halogens. The term "halogenated Cx - Cyalkyl " or "halogenated Cxyalkyl " (x and y are each integers) refers to a straight or branched alkyl group containing x to y carbon atoms substituted with one or more halogens. The term "halogenated C1-10alkyl " used alone or in combination in the present disclosure refers to a straight or branched alkyl group containing 1 to 10 carbon atoms substituted with one or more halogens. Examples of the halogenated C1-10alkyl group of the present disclosure include halogenated C1-9alkyl groups, such as halogenated C1-8alkyl groups, halogenated C2-8alkyl groups, halogenated C1-7alkyl groups, halogenated C1-6alkyl groups, halogenated C1-5alkyl groups, or halogenated C1-4alkyl groups. Representative examples include halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, haloisobutyl, halosec-butyl, halotert-butyl, halopentyl, haloisopentyl, haloneopentyl, halotert-pentyl, halohexyl, haloheptyl, halooctyl, halononyl and halodecyl. The term "halogenated C 1-3 alkyl" or "halogenated C 1 -C 3 alkyl" of the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms substituted by one or more halogens, and representative examples thereof include halomethyl (e.g., trifluoromethyl), haloethyl, halo-n-propyl and haloisopropyl.

在本文中，单独或组合使用的术语“氘代烷基”是指被一或多个氘原子取代的直链或支链的烷基，其中所述烷基中的一或多个氢被氘原子替代。术语“氘代Cx-Cy烷基”或“氘代Cx-y烷基”(x及y各自为整数)是指被一或多个氘原子取代的含有x至y个碳原子的直链或支链烷基。本公开中单独或组合使用的术语“氘代C1-10烷基”是指被一或多个氘原子取代的含有1至10个碳原子的直链或支链烷基。本公开的氘代C1-10烷基的实例包括氘代C1-9烷基，例如氘代C1-8烷基，氘代C2-8烷基，氘代C1-7烷基，氘代C1-6烷基，氘代C1-5烷基，或氘代C1-4烷基。代表性实例包括全氘代甲基(CD3)、全氘代乙基(CD3CD2)、全氘代正丙基、全氘代异丙基、全氘代正丁基、全氘代异丁基、全氘代仲丁基、全氘代叔丁基、全氘代戊基、全氘代异戊基、全氘代新戊基、全氘代特戊基和全氘代己基。本公开的术语“氘代C1-3烷基”或“氘代C1-C3烷基”是指被一或多个氘原子取代的含有1至3个碳原子的烷基，其代表性实例包括全氘代甲基(CD3-)和全氘代乙基(CD3CD2)。As used herein, the term "deuterated alkyl" used alone or in combination refers to a straight or branched alkyl group substituted with one or more deuterium atoms, wherein one or more hydrogens in the alkyl group are replaced with deuterium atoms. The term "deuterated Cx - Cy alkyl" or "deuterated Cxy alkyl" (x and y are each an integer) refers to a straight or branched alkyl group containing x to y carbon atoms substituted with one or more deuterium atoms. The term "deuterated C1-10 alkyl" used in the present disclosure alone or in combination refers to a straight or branched alkyl group containing 1 to 10 carbon atoms substituted with one or more deuterium atoms. Examples of deuterated C 1-10 alkyl groups disclosed herein include deuterated C 1-9 alkyl groups, such as deuterated C 1-8 alkyl groups, deuterated C 2-8 alkyl groups, deuterated C 1-7 alkyl groups, deuterated C 1-6 alkyl groups, deuterated C 1-5 alkyl groups, or deuterated C 1-4 alkyl groups. Representative examples include perdeuterated methyl (CD 3 ), perdeuterated ethyl (CD 3 CD 2 ), perdeuterated n-propyl groups, perdeuterated isopropyl groups, perdeuterated n-butyl groups, perdeuterated isobutyl groups, perdeuterated sec-butyl groups, perdeuterated tert-butyl groups, perdeuterated pentyl groups, perdeuterated isopentyl groups, perdeuterated neopentyl groups, perdeuterated tert-pentyl groups, and perdeuterated hexyl groups. The term "deuterated C 1-3 alkyl" or "deuterated C 1 -C 3 alkyl" of the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms substituted by one or more deuterium atoms, and representative examples thereof include perdeuterated methyl (CD 3 -) and perdeuterated ethyl (CD 3 CD 2 ).

在本文中，单独或组合使用的术语“亚烷基”(其与“亚烷基链”可互换使用)是指由碳和氢组成的直链或支链的二价饱和烃基团，是直链或支链烷基的二价基团形式。术语“Cx-Cy亚烷基”或“Cx-y亚烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链的亚烷基。本发明中单独或组合使用的术语“C1-C5亚烷基”是指含有1至5个碳原子的直链或支链亚烷基，其实例包括但不限于C1-C4亚烷基，C1-C3亚烷基，和C1-C2亚烷基。代表性实例包括但不限于亚甲基(即-CH2-)、亚乙基(例如-CH2CH2-)、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚叔丁基、亚戊基、亚异戊基、亚新戊基和亚特戊基。在本公开中，所述“亚烷基”是可选地经取代的，取代基可选是一或多个(例如1-10个、1-6、1-5、1-4、或1-3个)选自例如氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基的取代基。As used herein, the term "alkylene" (which is used interchangeably with "alkylene chain"), used alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen, which is a divalent radical form of a straight or branched alkyl group. The term " Cx - Cy alkylene" or " Cxy alkylene" (x and y are each integers) refers to a straight or branched alkylene containing x to y carbon atoms. The term " C1 - C5 alkylene" used alone or in combination in the present invention refers to a straight or branched alkylene containing 1 to 5 carbon atoms, examples of which include, but are not limited to, C1 - C4 alkylene, C1 - C3 alkylene, and C1 - C2 alkylene. Representative examples include, but are not limited to, methylene (i.e., -CH2- ), ethylene (e.g. , -CH2CH2- ), propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, and tert-pentylene. In the present disclosure, the "alkylene" is optionally substituted, and the substituents may be optionally one or more (e.g., 1-10, 1-6, 1-5, 1-4, or 1-3) substituents selected from, for example, deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH-, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“烷氧基”是指直链或支链烷氧基，其结构式为烷基-O-。可选地，烷氧基的烷基部分可包含1-10个(例如1-6、1-4、或1-3个)碳原子。“烷氧基”的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基等。术语“C1-C6烷氧基”或“C1-6烷氧基”是指含有1至6个碳原子的直链或支链烷氧基。C1- 6烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、戊氧基及己氧基。As used herein, the term "alkoxy", used alone or in combination, refers to a straight or branched chain alkoxy group having the structural formula alkyl-O-. Optionally, the alkyl portion of the alkoxy group may contain 1-10 (e.g., 1-6, 1-4, or 1-3) carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. The term "C 1 -C 6 alkoxy" or "C 1-6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms. Representative examples of C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentoxy, and hexyloxy.

在本文中，单独或组合使用的术语“卤代烷氧基”是指被一或多个卤素取代的烷氧基。可选地，烷氧基的烷基部分可包含1-10个(例如1-6、1-4、或1-3个)碳原子。“卤代烷氧基”的实例包括卤代C1-6烷氧基和卤代C1-4烷氧基。代表性实例包括但不限于F3C-O-、FCH2-O-、F2CH-O-、ClCH2-O-、Cl2CH-O-、CF3CF2-O-、CF3CHF-O-、CHF2CF2-O-、CHF2CHF-O-、CF3CH2-O-或CH2ClCH2-O-。As used herein, the term "haloalkoxy", used alone or in combination, refers to an alkoxy group substituted with one or more halogens. Optionally, the alkyl portion of the alkoxy group may contain 1-10 (e.g., 1-6, 1-4, or 1-3) carbon atoms. Examples of "haloalkoxy" include halogenated C 1-6 alkoxy and halogenated C 1-4 alkoxy. Representative examples include, but are not limited to, F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O-, or CH 2 ClCH 2 -O-.

在本发明中，单独或组合使用的术语“杂芳基”是指含有至少一个具有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的芳香族环的5-至30-元(可选地为5-至20-元、5至15元、5至12元、5至11元、5至10元、5至9元、5至8元、5至7元、5至6元、6至15元、6至9元或6-至20-元)单环或二环或多环烃基团。二环或多环杂芳基包括双环、三环、四环或多环杂芳基，其含有的一个环是具有一或多个(例如1-4、1-3、1-2或1个)独立地选自O、S和N的杂原子的芳香族环，并且含有的其它环可为饱和、部分不饱和环或芳香族环并且可为碳环或含有一或多个(例如1-4、1-3、1-2或1个)独立地选自O、S和N的杂原子。单环杂芳基的实例包括(但不限于)呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、四唑基、和三嗪基。双环杂芳基的实例包括(但不限于)吲哚基、异吲哚基、异吲哚啉基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2，1，3]噁二唑基、苯并[2，1，3]噻二唑基、苯并[1，2，3]噻二唑基、喹啉基、异喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、噁唑并吡啶基、呋喃并吡啶基、喋啶基、嘌呤基、吡啶并吡啶基、吡唑并[1，5-a]吡啶基、吡唑并[1，5-a]嘧啶基、咪唑并[1，2-a]吡啶基、1H-吡咯并[3，2-b]吡啶基、1H-吡咯并[2，3-b]吡啶基、吡咯并[2，1-b]噻唑基、咪唑并[2，1-b]噻唑基、色烷基和6，7-二氢噻吩并[3，2-d]嘧啶基。三环或多环杂芳基的实例包括(但不限于)吖啶基、苯并吲哚基、咔唑基、二苯并呋喃基、呫吨基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶基和6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶基。所述杂芳基基团可未被取代或被取代。经取代的杂芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的杂芳基，其中取代基可选地选自例如氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。In the present invention, the term "heteroaryl", used alone or in combination, refers to a 5- to 30-membered (optionally 5- to 20-membered, 5- to 15-membered, 5- to 12-membered, 5- to 11-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 6- to 15-membered, 6- to 9-membered or 6- to 20-membered) monocyclic or bicyclic or polycyclic hydrocarbon group containing at least one aromatic ring having 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic, tetracyclic or polycyclic heteroaryl groups, one of which contains an aromatic ring having one or more (e.g., 1-4, 1-3, 1-2 or 1) heteroatoms independently selected from O, S and N, and the other rings contained may be saturated, partially unsaturated or aromatic and may be carbocyclic or contain one or more (e.g., 1-4, 1-3, 1-2 or 1) heteroatoms independently selected from O, S and N. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridinyl, furanopyridinyl, pteridinyl, purinyl, pyridopyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, chromanyl and 6,7-dihydrothieno[3,2-d]pyrimidinyl. Examples of tricyclic or polycyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, xanthenyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, and 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl. The heteroaryl groups may be unsubstituted or substituted. Substituted heteroaryl refers to a heteroaryl group substituted one or more times (e.g., 1-4, 1-3 times, or 1-2 times) with substituents, wherein the substituents are optionally selected from, for example, deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl, and C 2-6 alkenyl.

在本发明中，单独或组合使用的术语“亚杂芳基”是指含有至少一个具有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的芳香族环的5-至30-元(可选地为5-至20-元、5至15元、5至12元、5至11元、5至10元、5至9元、5至8元、5至7元、5至6元、6至15元、6至9元或6-至20-元)单环或二环或多环烃的二价基团。二环或多环亚杂芳基包括双环、三环、四环或多环亚杂芳基，其含有的一个环是具有一或多个(例如1-4、1-3、1-2或1个)独立地选自O、S和N的杂原子的芳香族环，并且含有的其它环可为饱和、部分不饱和环或芳香族环并且可为碳环或含有一或多个(例如1-4、1-3、1-2或1个)独立地选自O、S和N的杂原子。单环亚杂芳基的实例包括(但不限于)亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚四唑基、和亚三嗪基。双环亚杂芳基的实例包括(但不限于)亚吲哚基、亚异吲哚基、亚异吲哚啉基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2，1，3]噁二唑基、亚苯并[2，1，3]噻二唑基、亚苯并[1，2，3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、亚噁唑并吡啶基、亚呋喃并吡啶基、亚喋啶基、亚嘌呤基、亚吡啶并吡啶基、吡唑并[1，5-a]吡啶亚基、吡唑并[1，5-a]嘧啶亚基、咪唑并[1，2-a]吡啶亚基、1H-吡咯并[3，2-b]吡啶亚基、1H-吡咯并[2，3-b]吡啶亚基、吡咯并[2，1-b]噻唑亚基、咪唑并[2，1-b]噻唑亚基、亚色烷基和6，7-二氢噻吩并[3，2-d]嘧啶亚基。三环或多环亚杂芳基的实例包括(但不限于)亚吖啶基、亚苯并吲哚基、亚咔唑基、亚二苯并呋喃基、亚呫吨基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶亚基和6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶亚基。所述亚杂芳基基团可未被取代或被取代。经取代的亚杂芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的亚杂芳基，其中取代基可选地选自例如氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。In the present invention, the term "heteroarylene", used alone or in combination, refers to a divalent group of a 5- to 30-membered (optionally 5- to 20-membered, 5- to 15-membered, 5- to 12-membered, 5- to 11-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 6- to 15-membered, 6- to 9-membered or 6- to 20-membered) monocyclic or bicyclic or polycyclic hydrocarbon containing at least one aromatic ring having 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen and sulfur. Bicyclic or polycyclic heteroarylene groups include bicyclic, tricyclic, tetracyclic or polycyclic heteroarylene groups, one of which contains an aromatic ring having one or more (e.g., 1-4, 1-3, 1-2 or 1) heteroatoms independently selected from O, S and N, and the other rings contained may be saturated, partially unsaturated or aromatic and may be carbocyclic or contain one or more (e.g., 1-4, 1-3, 1-2 or 1) heteroatoms independently selected from O, S and N. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene. Examples of bicyclic heteroarylene groups include, but are not limited to, indolylene, isoindolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolinylene, isoquinolinylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoline oxalinyl, phthalazinyl, oxazolopyridinyl, furanopyridinyl, pteridinyl, purinyl, pyridopyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolylene, imidazo[2,1-b]thiazolylene, chromanyl and 6,7-dihydrothieno[3,2-d]pyrimidinyl. Examples of tricyclic or polycyclic heteroarylene groups include, but are not limited to, acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, xanthenylene, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinylene and 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinylene. The heteroarylene groups may be unsubstituted or substituted. Substituted heteroarylene refers to a heteroarylene group substituted one or more times (e.g., 1-4, 1-3 times, or 1-2 times) with substituents, wherein the substituents are optionally selected from, for example, deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl, and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“芳基”是指包含5至30个(例如5-20、5-15、5-12、5-10、5-9、5-8、5-7、5-6、6-15、6-9或6-20个)碳原子并且可选地包含一个或多个稠合环的一价芳香烃基团，例如苯基或萘基或芴基。在本公开中，所述“芳基”是可选地经取代的芳基。经取代的芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的芳基，例如芳基被取代基单取代、双取代、三取代或多取代，其中取代基可选地选自例如氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。In this article, the term "aryl", used alone or in combination, refers to a monovalent aromatic hydrocarbon group containing 5 to 30 (e.g., 5-20, 5-15, 5-12, 5-10, 5-9, 5-8, 5-7, 5-6, 6-15, 6-9 or 6-20) carbon atoms and optionally containing one or more fused rings, such as phenyl or naphthyl or fluorenyl. In the present disclosure, the "aryl" is an optionally substituted aryl. Substituted aryl refers to aryl substituted one or more times (e.g., 1-4, 1-3 or 1-2 times) with substituents, for example, aryl is mono-substituted, di-substituted, tri-substituted or poly-substituted with substituents, wherein the substituents are optionally selected from, for example, deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本公开中，单独或组合使用的术语“亚芳基”是指包含5至30个(例如5-20、5-15、5-12、5-10、5-9、5-8、5-7、5-6、6-15、6-9或6-20个)碳原子并且可选地包含一个或多个稠合环的二价芳香烃基团，例如亚苯基(例如

Figure PCTCN2024142598-ftappb-I100058
)或亚萘基或亚芴基。在本公开中，所述“亚芳基”是可选地经取代的亚芳基。经取代的亚芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的亚芳基，例如亚芳基被取代基单取代、双取代、三取代或多取代，其中取代基可选地选自例如氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1- 6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。In the present disclosure, the term "arylene", used alone or in combination, refers to a divalent aromatic hydrocarbon group containing 5 to 30 (e.g., 5-20, 5-15, 5-12, 5-10, 5-9, 5-8, 5-7, 5-6, 6-15, 6-9 or 6-20) carbon atoms and optionally containing one or more fused rings, such as phenylene (e.g.
Figure PCTCN2024142598-ftappb-I100058
) or naphthylene or fluorenylene. In the present disclosure, the "arylene group" is an optionally substituted arylene group. Substituted arylene refers to an arylene group substituted one or more times (e.g., 1-4, 1-3 or 1-2 times) with substituents, for example, the arylene group is mono-substituted, di-substituted, tri-substituted or poly-substituted with substituents, wherein the substituents are optionally selected from, for example, deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“环烷基”是指饱和或部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环或三环或多环环烃基，其含有的碳原子数量包括但不限于3至30个碳原子(即C3-30环烷基)，3至25个碳原子(即C3-25环烷基)，3至20个碳原子(即C3-20环烷基)，3至15个碳原子(即C3-15环烷基)，3至12个碳原子(即C3-12环烷基)，3至11个碳原子(即C3-11环烷基)，3至10个碳原子(即C3-10环烷基)，3至8个碳原子(即C3-8环烷基)，3至7个碳原子(即C3-7环烷基)，3至6个碳原子(即C3-6环烷基)，4至20个碳原子(即C4-20环烷基)，4至15个碳原子(即C4-15环烷基)，4至12个碳原子(即C4-12环烷基)，和4至10个碳原子(即C4-10环烷基)。术语“环烷基”包括单环、双环、三环和多环环烷基，其具有3至30个碳原子。术语“环烷基”的实例包括但不限于单环环烷基、桥环烷基(例如C5-30桥环烷基、C5-20桥环烷基、C5-15桥环烷基和C7-15桥环烷基)、稠环烷基(例如C5-30稠环烷基、C5-20稠环烷基、C5-15稠环烷基、C6-30稠环烷基、C6-20稠环烷基、C6-15稠环烷基、C7-30稠环烷基、C7-20稠环烷基、C7-15稠环烷基和C8-15稠环烷基)和螺环烷基(例如C5-30螺环烷基、C5-20螺环烷基、C5-15螺环烷基、C6-30螺环烷基、C6-20螺环烷基、C6-15螺环烷基、C7-30螺环烷基、C7-20螺环烷基、C7-15螺环烷基和C8-15螺环烷基)。单环环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。稠环烷基、螺环烷基和桥环烷基的实例包括但不限于十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、C5-20螺环烷基、C5-15螺环烷基、金刚烷基、降金刚烷基、冰片基和降冰片烷基(IUPAC系统命名为二环[2.2.1]庚烷基)。在本文中，所述“环烷基”是可选地经单取代的或多取代的，例如但不限于，2，2-，2，3-，2，4-，2，5-，或2，6-二取代的环己基。所述经取代的“环烷基”的取代基可选地是一或多个(例如1-5、1-4、1-3、1-2、或1个)选自例如氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基的取代基。术语“C3-6环烷基”的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基和环己基。As used herein, the term "cycloalkyl" used alone or in combination refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic or bicyclic or tricyclic or polycyclic hydrocarbon radical containing, but not limited to, 3 to 30 carbon atoms (i.e., C3-30 cycloalkyl), 3 to 25 carbon atoms (i.e., C3-25 cycloalkyl), 3 to 20 carbon atoms (i.e., C3-20 cycloalkyl), 3 to 15 carbon atoms (i.e., C3-15 cycloalkyl), 3 to 12 carbon atoms (i.e., C3-12 cycloalkyl), 3 to 11 carbon atoms (i.e., C3-11 cycloalkyl), 3 to 10 carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 carbon atoms (i.e., C3-8 cycloalkyl), 3 to 7 carbon atoms (i.e., C3-7 cycloalkyl), 3 to 6 carbon atoms (i.e., C3-8 cycloalkyl). The term "cycloalkyl" includes monocyclic , bicyclic, tricyclic and polycyclic cycloalkyl groups having 3 to 30 carbon atoms. Examples of the term “cycloalkyl” include, but are not limited to, monocyclic cycloalkyl, bridged cycloalkyl (e.g., C5-30 bridged cycloalkyl, C5-20 bridged cycloalkyl, C5-15 bridged cycloalkyl, and C7-15 bridged cycloalkyl), fused cycloalkyl (e.g., C5-30 fused cycloalkyl, C5-20 fused cycloalkyl, C5-15 fused cycloalkyl, C6-30 fused cycloalkyl, C6-20 fused cycloalkyl, C6-15 fused cycloalkyl, C7-30 fused cycloalkyl, C7-20 fused cycloalkyl, C7-15 fused cycloalkyl, and C8-15 fused cycloalkyl ) and spirocycloalkyl (e.g., C5-30 spirocycloalkyl, C5-20 spirocycloalkyl, C5-15 spirocycloalkyl, C6-30 spirocycloalkyl, C6-20 spirocycloalkyl, C6-15 spirocycloalkyl, C7-30 spirocycloalkyl, C8-20 spirocycloalkyl, C8-15 spirocycloalkyl, and C8-15 fused cycloalkyl). The term "cycloalkyl" refers to a group consisting of C 7-20 spirocycloalkyl, C 7-15 spirocycloalkyl and C 8-15 spirocycloalkyl. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyls, spirocycloalkyls and bridged cycloalkyls include, but are not limited to, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, C 5-20 spirocycloalkyl, C 5-15 spirocycloalkyl, adamantyl, noradamantyl, bornyl and norbornyl (IUPAC systematic name: bicyclo[2.2.1]heptyl). In this article, the "cycloalkyl" is optionally monosubstituted or polysubstituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkyl" may optionally be one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) selected from, for example, deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH-, C 2-6 alkynyl and C 2-6 alkenyl. Examples of the term "C 3-6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl.

在本文中，单独或组合使用的术语“Cx-y螺环烷基”(x及y各自为整数)是指含有x至y个碳原子的螺环烷基。本发明中单独或组合使用的术语“C5-30螺环烷基”是指含有5至30个(例如但不限于5-20，5-15，7-20，7-15，5-11，5-10，和7-9个)碳原子的螺环烷基。术语“C5-30螺环基”包括“C5-20螺环基”、“C5-15螺环基”、“C7-15螺环烷基”和“C7-20螺环烷基”，其代表性实例包括但不限于螺[3.3]庚烷基、螺[2.5]辛烷基、螺[3.5]壬烷基、螺[4.4]壬烷基、螺[4.5]癸烷基和螺[5.5]十一烷基。所述“C5-30螺环烷基”可选地进一步经选自例如氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基的取代基中的一个或多个(例如1-10个、1-6、1-5、1-4、或1-3个)取代。In this article, the term "C xy spirocycloalkyl" (x and y are each an integer) used alone or in combination refers to a spirocycloalkyl containing x to y carbon atoms. The term "C 5-30 spirocycloalkyl" used alone or in combination in the present invention refers to a spirocycloalkyl containing 5 to 30 (for example, but not limited to 5-20, 5-15, 7-20, 7-15, 5-11, 5-10, and 7-9) carbon atoms. The term "C 5-30 spirocyclyl" includes "C 5-20 spirocyclyl", "C 5-15 spirocyclyl", "C 7-15 spirocycloalkyl" and "C 7-20 spirocycloalkyl", and its representative examples include but are not limited to spiro [3.3] heptyl, spiro [2.5] octyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decyl and spiro [5.5] undecyl. The "C 5-30 spirocycloalkyl" may optionally be further substituted with one or more (e.g., 1-10 , 1-6, 1-5, 1-4, or 1-3) substituents selected from, for example, deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy , optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH-, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“Cx-y桥环烷基”(x及y各自为整数)是指含有x至y个碳原子的桥环烷基。本发明中单独或组合使用的术语“C5-30桥环烷基”是指含有5至30个(例如但不限于5-20，6-20，7-20，5-15，7-15，5-11，5-10，和7-9个)碳原子的桥环烷基。术语“C5-30桥环烷基”包括“C5-C20桥环基”、“C6-C20桥环基”、“C7-C20桥环基”、“C5-15桥环烷基”和“C7-C15桥环基”，其代表性实例包括但不限于金刚烷基(amadantanyl)、降金刚烷基、冰片基、降冰片烷基(系统命名为二环[2.2.1]庚烷基)、2-氧代二环[2.2.1]庚烷基、二环[2.2.1]庚烯基和立方烷基(cubanyl)。所述“C5-30桥环烷基”可选地经1至10个(例如1-6、1-5、1-4、或1-3个)选自以下的取代基取代：氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。As used herein, the term "C xy bridged cycloalkyl" (x and y are each an integer) used alone or in combination refers to a bridged cycloalkyl group containing x to y carbon atoms. The term "C 5-30 bridged cycloalkyl" used alone or in combination in the present invention refers to a bridged cycloalkyl group containing 5 to 30 (for example, but not limited to, 5-20, 6-20, 7-20, 5-15, 7-15, 5-11, 5-10, and 7-9) carbon atoms. The term “C 5-30 bridged cycloalkyl” includes “C 5 -C 20 bridged cycloalkyl”, “C 6 -C 20 bridged cycloalkyl”, “C 7 -C 20 bridged cycloalkyl”, “C 5-15 bridged cycloalkyl” and “C 7 -C 15 bridged cycloalkyl”, representative examples of which include, but are not limited to, adamantanyl, noradamantanyl, bornyl, norbornyl (systematically named bicyclo[2.2.1]heptyl), 2-oxobicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl and cubanyl. The “C 5-30 bridged cycloalkyl” is optionally substituted with 1 to 10 (e.g. 1-6, 1-5, 1-4, or 1-3) substituents selected from the group consisting of deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本发明中，单独或组合使用的术语“亚环烷基”是指饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环或三环或多环环烃二价基团，其含有的碳原子数量包括但不限于3至30个碳原子(即C3-30环烷基)，3至25个碳原子(即C3-25环烷基)，3至20个碳原子(即C3-20亚环烷基)，3至15个碳原子(即C3-15亚环烷基)，3至12个碳原子(即C3-12亚环烷基)，3至11个碳原子(即C3-11亚环烷基)，3至10个碳原子(即C3-10亚环烷基)，3至8个碳原子(即C3-8亚环烷基)，3至7个碳原子(即C3-7亚环烷基)，3至6个碳原子(即C3-6亚环烷基)，4至20个碳原子(即C4-20亚环烷基)，4至15个碳原子(即C4-15亚环烷基)，4至12个碳原子(即C4-12亚环烷基)，和4至10个碳原子(即C4-10亚环烷基)。术语“亚环烷基”包括单环、双环、三环和多环烃二价基团，其具有3至30个碳原子。术语“亚环烷基”的实例包括但不限于单环亚环烷基、亚桥环烷基(例如C5-30亚桥环烷基、C5-20亚桥环烷基、C5-15亚桥环烷基和C7-15亚桥环烷基)、亚稠环烷基(例如C5-30亚稠环烷基、C5- 20亚稠环烷基、C5-15亚稠环烷基、C6-30亚稠环烷基、C6-20亚稠环烷基、C6-15亚稠环烷基、C7-30亚稠环烷基、C7-20亚稠环烷基、C7-15亚稠环烷基和C8-15亚稠环烷基)和亚螺环烷基(例如C5- 30亚螺环烷基、C5-20亚螺环烷基、C5-15亚螺环烷基、C6-30亚螺环烷基、C6-20亚螺环烷基、C6-15亚螺环烷基、C7-30亚螺环烷基、C7-20亚螺环烷基、C7-15亚螺环烷基和C8-15亚螺环烷基)。单环亚环烷基的代表性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、和亚环辛基。亚稠环烷基、亚螺环烷基和亚桥环烷基的实例包括但不限于亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、2，3-二氢-1H-茚亚基、C5- 20亚螺环基(例如C5-15亚螺环基)、亚金刚烷基、亚降金刚烷基和亚降冰片烷基(IUPAC系统命名为双环[2.2.1]庚烷亚基)。在本公开中，所述“亚环烷基”是可选地经单取代的或多取代的，例如但不限于，2，2-，2，3-，2，4-，2，5-，或2，6-二取代的环己基。所述经取代的“亚环烷基”的取代基可选地是一或多个(例如1-5、1-4、1-3、1-2、或1个)选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基的取代基。In the present invention, the term "cycloalkylene" used alone or in combination refers to a saturated and partially unsaturated (i.e., having one or more double bonds, but not completely conjugated) monocyclic or bicyclic or tricyclic or polycyclic hydrocarbon divalent group, the number of carbon atoms contained in it includes but is not limited to 3 to 30 carbon atoms (i.e., C3-30 cycloalkyl), 3 to 25 carbon atoms (i.e., C3-25 cycloalkyl), 3 to 20 carbon atoms (i.e., C3-20 cycloalkylene), 3 to 15 carbon atoms (i.e., C3-15 cycloalkylene), 3 to 12 carbon atoms (i.e., C3-12 cycloalkylene), 3 to 11 carbon atoms (i.e., C3-11 cycloalkylene), 3 to 10 carbon atoms (i.e., C3-10 cycloalkylene), 3 to 8 carbon atoms (i.e., C3-8 cycloalkylene), 3 to 7 carbon atoms (i.e., C3-7 cycloalkylene), 3 to 6 carbon atoms (i.e., C3-6 The term "cycloalkylene" includes monocyclic , bicyclic , tricyclic and polycyclic hydrocarbon divalent groups having 3 to 30 carbon atoms. Examples of the term “cycloalkylene” include, but are not limited to, monocyclic cycloalkylene, bridged cycloalkylene (e.g., C5-30 bridged cycloalkylene, C5-20 bridged cycloalkylene, C5-15 bridged cycloalkylene , and C7-15 bridged cycloalkylene), fused cycloalkylene (e.g., C5-30 fused cycloalkylene, C5-20 fused cycloalkylene, C5-15 fused cycloalkylene, C6-30 fused cycloalkylene, C6-20 fused cycloalkylene, C6-15 fused cycloalkylene, C7-30 fused cycloalkylene, C7-20 fused cycloalkylene , C7-15 fused cycloalkylene, and C8-15 fused cycloalkylene) and spirocycloalkylene (e.g., C5-30 spirocycloalkylene, C5-20 spirocycloalkylene, C5-15 spirocycloalkylene, C6-30 spirocycloalkylene, C The representative examples of monocyclic cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene , cyclopentylene , cyclopentenylene, cyclohexylene , cyclohexenylene , cycloheptylene, and cyclooctylene . Examples of fused cycloalkylene, spirocycloalkylene, and bridged cycloalkylene groups include, but are not limited to, decahydronaphthylene, octahydropentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, C 5-20 spirocycloalkylene (e.g., C 5-15 spirocycloalkylene ), adamantylene, noradamantylene, and norbornylene (IUPAC system name is bicyclo[2.2.1]heptanylene). In the present disclosure, the "cycloalkylene" is optionally mono-substituted or poly-substituted, for example, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkylene" may optionally be one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH-, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“Cx-y亚螺环烷基”或“Cx-y亚螺环基”(x及y各自为整数)是指含有x至y个碳原子的亚螺环烷基。本发明中单独或组合使用的术语“C5-30亚螺环烷基”是指含有5至30个(例如5-20，5-15，7-20，7-15，5-11，5-10，7-9个)碳原子的亚螺环烷基。术语“C5-30亚螺环烷基”包括“C5-20亚螺环烷基”、“C5-15亚螺环烷基”、“C7-15亚螺环烷基”和“C7-20亚螺环烷基”，其代表性实例包括但不限于螺[3.3]庚烷亚基、螺[2.5]辛烷亚基、螺[3.5]壬烷亚基、螺[4.4]壬烷亚基、螺[4.5]癸烷亚基和螺[5.5]十一烷亚基。所述“C5-30亚螺环烷基”可选地进一步经一个或多个(例如1-10个、1-6、1-5、1-4、或1-3个)选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基的取代基取代。As used herein, the term "C xy spirocycloalkylene" or "C xy spirocyclylene" (x and y are each an integer) used alone or in combination refers to a spirocycloalkylene group containing x to y carbon atoms. The term "C 5-30 spirocycloalkylene" used alone or in combination in the present invention refers to a spirocycloalkylene group containing 5 to 30 (e.g., 5-20, 5-15, 7-20, 7-15, 5-11, 5-10, 7-9) carbon atoms. The term " C5-30 spirocycloalkylene" includes " C5-20 spirocycloalkylene", " C5-15 spirocycloalkylene", " C7-15 spirocycloalkylene" and " C7-20 spirocycloalkylene", representative examples of which include but are not limited to spiro[3.3]heptanediyl, spiro[2.5]octanedeyl, spiro[3.5]nonanediyl, spiro[4.4]nonanediyl, spiro[4.5]decanediyl and spiro[5.5]undecanediyl. The "C 5-30 spirocycloalkylene" is optionally further substituted with one or more (e.g. 1-10, 1-6, 1-5, 1-4, or 1-3) substituents selected from deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH-, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“Cx-y亚桥环烷基”或“Cx-y亚桥环基”(x及y各自为整数)是指含有x至y个碳原子的亚桥环烷基。本发明中单独或组合使用的术语“C5-30亚桥环烷基”是指含有5至30个(例如但不限于5-20，6-20，7-20，5-15，7-15，5-11，5-10，和7-9个)碳原子的亚桥环烷基。术语“C5-30亚桥环烷基”包括“C5-20亚桥环烷基”、“C6-20亚桥环烷基”、“C7-20亚桥环烷基”、“C5-15亚桥环烷基”和“C7-15亚桥环烷基”，其代表性实例包括但不限于亚金刚烷基、亚降金刚烷基、亚冰片基、二环[2.2.1]庚烷亚基、2-氧代二环[2.2.1]庚烷亚基、二环[2.2.1]庚烯亚基和亚立方烷基。所述“C5-30亚桥环烷基”可选地进一步经一个或多个(例如1-10个、1-6、1-5、1-4、或1-3个)选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1- 6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基的取代基取代。As used herein, the term "C xy cycloalkylene" or "C xy cycloalkylene" (x and y are each an integer) used alone or in combination refers to a cycloalkylene containing x to y carbon atoms. The term "C 5-30 cycloalkylene" used alone or in combination in the present invention refers to a cycloalkylene containing 5 to 30 (for example, but not limited to, 5-20, 6-20, 7-20, 5-15, 7-15, 5-11, 5-10, and 7-9) carbon atoms. The term “C 5-30 bridged cycloalkylene” includes “C 5-20 bridged cycloalkylene”, “C 6-20 bridged cycloalkylene”, “C 7-20 bridged cycloalkylene”, “C 5-15 bridged cycloalkylene” and “C 7-15 bridged cycloalkylene”, representative examples of which include, but are not limited to, adamantylene, noradamantylene, bornylene, bicyclo[2.2.1]heptanylene, 2-oxobicyclo[2.2.1]heptanylene, bicyclo[2.2.1]heptenylene and cubanylene. The “C 5-30 bridged cycloalkylene” may optionally be further substituted with one or more (e.g. 1-10, 1-6, 1-5, 1-4, or 1-3) substituents selected from deuterium, hydroxyl, amino, thiol, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy , optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“杂环基”或“杂环烷基”是指含有一个或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的4至30元(可选地为4至30元、4至25元、4至20元、4至15元、4至14元、4至13元、4至12元、4至11元、4至10元、4至9元、4至8元、4至7元、4至6元、4至5元、5元至9元、5至30元、5至20元或5至15元)单环、双环、三环或多环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)环烃基。术语“杂环基”的实例包括但不限于单环杂环基(例如4至30元单环杂环基和4至20元单环杂环基)、桥杂环基(例如5至30元桥杂环基、5至20元桥杂环基、7至20元桥杂环基和7至15元桥杂环基)、稠杂环基(例如5至30元稠杂环基和5至20元稠杂环基)和螺杂环基(例如5至30元螺杂环基和5至20元螺杂环基)。单环杂环基的代表性实例包括但不限于氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧杂环己基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1，4-二氮杂环庚烷-1-基)和二氮杂环辛烷基。桥杂环基、稠杂环基和螺杂环基的实例包括但不限于6-氮杂双环[3.1.1]庚烷-3-基、2，5-二氮杂双环[2.2.1]庚烷-2-基、3，6-二氮杂双环[3.1.1]庚烷-3-基、3-氮杂双环[3.2.1]辛烷-8-基、3，8-二氮杂双环[3.2.1]辛烷-8-基、3，8-二氮杂双环[3.2.1]辛烷-3-基、2，5-二氮杂双环[2.2.2]辛烷-2-基、八氢-1H-吲哚基、和氮杂螺环基(例如5至20元氮杂螺环基，例如3-氮杂螺[5.5]十一烷-3-基)。所述杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选地选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。As used herein, the term "heterocyclyl" or "heterocycloalkyl", used alone or in combination, refers to a 4- to 30-membered (alternatively 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 13-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered or 5- to 15-membered) monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Examples of the term “heterocyclyl” include, but are not limited to, monocyclic heterocyclyl (e.g., 4- to 30-membered monocyclic heterocyclyl and 4- to 20-membered monocyclic heterocyclyl), bridged heterocyclyl (e.g., 5- to 30-membered bridged heterocyclyl, 5- to 20-membered bridged heterocyclyl, 7- to 20-membered bridged heterocyclyl and 7- to 15-membered bridged heterocyclyl), fused heterocyclyl (e.g., 5- to 30-membered fused heterocyclyl and 5- to 20-membered fused heterocyclyl) and spiro heterocyclyl (e.g., 5- to 30-membered spiro heterocyclyl and 5- to 20-membered spiro heterocyclyl). Representative examples of monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepan-1-yl), and diazacyclooctanyl. Examples of bridged heterocyclic groups, fused heterocyclic groups, and spiro heterocyclic groups include, but are not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, octahydro-1H-indolyl, and azaspirocyclic groups (e.g., 5- to 20-membered azaspirocyclic groups, such as 3-azaspiro[5.5]undec-3-yl). The heterocyclyl group may be unsubstituted or substituted as explicitly defined (e.g. mono-, di-, tri- or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, haloC 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, haloC 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)—, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“含氮杂环基”或“含氮杂环烷基”是指含有一个氮原子和可选地含有一个或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的4至30元(例如4至30元、4至25元、4至20元、4至15元、4至14元、4至13元、4至12元、4至11元、4至10元、4至9元、4至8元、4至7元、4至6元、4至5元、5元至9元、5至30元、5至20元或5至15元)单环、双环、三环或多环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)环烃基。术语“含氮杂环基”的实例包括但不限于含氮单环杂环基(例如4至30元含氮单环杂环基和4至20元含氮单环杂环基)、含氮桥杂环基(例如5至30元含氮桥杂环基、5至20元含氮桥杂环基、5至15元含氮桥杂环基、7至20元含氮桥杂环基或7至15元含氮桥杂环基)、含氮稠杂环基(例如5至30元含氮稠杂环基和5至20元含氮稠杂环基)和含氮螺杂环基(例如5至30元含氮螺杂环基和5至20元含氮螺杂环基)。含氮单环杂环基的代表性实例包括但不限于氮杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1，4-二氮杂环庚烷-1-基)和二氮杂环辛烷基。含氮桥杂环基、含氮稠杂环基和含氮螺杂环基的实例包括但不限于6-氮杂双环[3.1.1]庚烷-3-基、2，5-二氮杂双环[2.2.1]庚烷-2-基、3，6-二氮杂双环[3.1.1]庚烷-3-基、3-氮杂双环[3.2.1]辛烷-8-基、3，8-二氮杂双环[3.2.1]辛烷-8-基、3，8-二氮杂双环[3.2.1]辛烷-3-基、2，5-二氮杂双环[2.2.2]辛烷-2-基、八氢-1H-吲哚基、和氮杂螺环基(例如5至20元氮杂螺环基，例如3-氮杂螺[5.5]十一烷-3-基)。所述含氮杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选地选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。As used herein, the term "nitrogen-containing heterocyclyl" or "nitrogen-containing heterocycloalkyl", used alone or in combination, refers to a 4- to 30-membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 13-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cyclic hydrocarbon group containing one nitrogen atom and optionally containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Examples of the term “nitrogen-containing heterocyclic group” include, but are not limited to, nitrogen-containing monocyclic heterocyclic groups (e.g., 4- to 30-membered nitrogen-containing monocyclic heterocyclic groups and 4- to 20-membered nitrogen-containing monocyclic heterocyclic groups), nitrogen-containing bridged heterocyclic groups (e.g., 5- to 30-membered nitrogen-containing bridged heterocyclic groups, 5- to 20-membered nitrogen-containing bridged heterocyclic groups, 5- to 15-membered nitrogen-containing bridged heterocyclic groups, 7- to 20-membered nitrogen-containing bridged heterocyclic groups, or 7- to 15-membered nitrogen-containing bridged heterocyclic groups), nitrogen-containing fused heterocyclic groups (e.g., 5- to 30-membered nitrogen-containing fused heterocyclic groups and 5- to 20-membered nitrogen-containing fused heterocyclic groups), and nitrogen-containing spiro heterocyclic groups (e.g., 5- to 30-membered nitrogen-containing spiro heterocyclic groups and 5- to 20-membered nitrogen-containing spiro heterocyclic groups). Representative examples of nitrogen-containing monocyclic heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepan-1-yl), and diazacyclooctanyl. Examples of nitrogen-bridged heterocyclic groups, nitrogen-fused heterocyclic groups, and nitrogen-containing spiro heterocyclic groups include, but are not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, octahydro-1H-indolyl, and azaspirocyclic groups (e.g., 5- to 20-membered azaspirocyclic groups, such as 3-azaspiro[5.5]undec-3-yl). The nitrogen-containing heterocyclic group may be unsubstituted or substituted as explicitly defined (e.g., mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy , halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)—, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“亚杂环基”或“亚杂环烷基”是指含有一个或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的4至30元(例如4至30元、4至25元、4至20元、4至15元、4至14元、4至13元、4至12元、4至11元、4至10元、4至9元、4至8元、4至7元、4至6元、4至5元、5元至9元、5至30元、5至20元或5至15元)单环、双环、三环或多环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)二价环烃基。术语“亚杂环基”的实例包括但不限于单环亚杂环基(例如4至30元单环亚杂环基、和4至20元单环亚杂环基)、亚桥杂环基(例如5至30元亚桥杂环基、5至20元亚桥杂环基、7至20元亚桥杂环基或7至15元亚桥杂环基)、亚稠杂环基(例如5至30元亚稠杂环基、和5至20元亚稠杂环基)和亚螺杂环基(例如5至30元亚螺杂环基、和5至20元亚螺杂环基)。单环亚杂环基的代表性实例包括但不限于亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚氮杂环庚烷基、亚氮杂环辛烷基、亚二氧杂环己基、二氮杂环庚烷亚基(例如1，4-二氮杂环庚烷亚基，4，5-二氮杂环庚烷亚基，1，3-二氮杂环庚烷亚基)和二氮杂环辛烷亚基。亚桥杂环基、亚稠杂环基和亚螺杂环基的实例包括但不限于6-氮杂双环[3.1.1]庚烷亚基、2，5-二氮杂双环[2.2.1]庚烷亚基、3，6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、2，5-二氮杂双环[2.2.2]辛烷亚基、八氢-1H-吲哚亚基、和亚氮杂螺环基(例如5至20元亚氮杂螺环基，例如3-氮杂螺[5.5]十一烷亚基)。所述亚杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1- 6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。As used herein, the term "heterocyclylene" or "heterocycloalkylene", used alone or in combination, refers to a 4- to 30-membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 13-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon radical containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Examples of the term “heterocyclylene” include, but are not limited to, monocyclic heterocyclylene (e.g., 4 to 30-membered monocyclic heterocyclylene, and 4 to 20-membered monocyclic heterocyclylene), bridging heterocyclylene (e.g., 5 to 30-membered bridging heterocyclylene, 5 to 20-membered bridging heterocyclylene, 7 to 20-membered bridging heterocyclylene, or 7 to 15-membered bridging heterocyclylene), fused heterocyclylene (e.g., 5 to 30-membered fused heterocyclylene, and 5 to 20-membered fused heterocyclylene), and spiro heterocyclylene (e.g., 5 to 30-membered spiro heterocyclylene, and 5 to 20-membered spiro heterocyclylene). Representative examples of monocyclic heterocyclylene groups include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, azepanylene, azocanylidene, dioxanylene, diazepanylidene (e.g., 1,4-diazepanylidene, 4,5-diazepanylidene, 1,3-diazepanylidene) and diazepanylidene. Examples of bridged, fused, and spiro heterocyclyl groups include, but are not limited to, 6-azabicyclo[3.1.1]heptanylene, 2,5-diazabicyclo[2.2.1]heptanylene, 3,6-diazabicyclo[3.1.1]heptanylene, 3-azabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 2,5-diazabicyclo[2.2.2]octanylene, octahydro-1H-indolylene, and azaspirocyclylene (e.g., a 5- to 20-membered azaspirocyclylene, such as 3-azaspiro[5.5]undecylene). The heterocyclylene group may be unsubstituted or substituted as explicitly defined (e.g. mono-, di-, tri- or polysubstituted), wherein the substituents may be optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“含氮亚杂环基”或“含氮亚杂环烷基”是指含有一个氮原子和可选地含有一个或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的4至30元(例如4至30元、4至25元、4至20元、4至15元、4至14元、4至12元、4至11元、4至10元、4至9元、4至8元、4至7元、4至6元、4至5元、5元至9元、5至30元、5至20元或5至15元)单环、双环、三环或多环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)二价环烃基。术语“含氮亚杂环基”的实例包括但不限于含氮单环亚杂环基(例如4至30元含氮单环亚杂环基、和4至20元含氮单环亚杂环基)、含氮亚桥杂环基(例如5至30元含氮亚桥杂环基、5至20元含氮亚桥杂环基、7至20元含氮亚桥杂环基或7至15元含氮亚桥杂环基)、含氮亚稠杂环基(例如5至30元含氮亚稠杂环基和5至20元含氮亚稠杂环基)和含氮亚螺杂环基(例如5至30元含氮亚螺杂环基和5至20元含氮亚螺杂环基)。含氮单环亚杂环基的代表性实例包括但不限于亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚氮杂环庚烷基、亚氮杂环辛烷基、二氮杂环庚烷亚基(例如1，4-二氮杂环庚烷亚基，4，5-二氮杂环庚烷亚基，1，3-二氮杂环庚烷亚基)和二氮杂环辛烷亚基。含氮亚桥杂环基、含氮亚稠杂环基和含氮亚螺杂环基的实例包括但不限于6-氮杂双环[3.1.1]庚烷亚基、2，5-二氮杂双环[2.2.1]庚烷亚基、3，6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、2，5-二氮杂双环[2.2.2]辛烷亚基、八氢-1H-吲哚亚基、和亚氮杂螺环基(例如5至20元亚氮杂螺环基，例如3-氮杂螺[5.5]十一烷亚基)。所述含氮亚杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选选自氘、羟基、氨基、巯基、硝基、卤素、氰基、氧代基、可选氘代的C1-6烷基、卤代C1-6烷基、可选氘代的C3-6环烷基、可选氘代的C1-6烷氧基、卤代C1-6烷氧基、可选氘代的C1-6烷基-NH-、NH2-C1-6亚烷基、可选氘代的C1-6烷基-NHC(O)-、可选氘代的C1-6烷基-C(O)NH-、C2-6炔基和C2-6烯基。As used herein, the term "nitrogen-containing heterocyclylene" or "nitrogen-containing heterocycloalkylene", used alone or in combination, refers to a 4- to 30-membered (e.g., 4- to 30-membered, 4- to 25-membered, 4- to 20-membered, 4- to 15-membered, 4- to 14-membered, 4- to 12-membered, 4- to 11-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 4- to 7-membered, 4- to 6-membered, 4- to 5-membered, 5- to 9-membered, 5- to 30-membered, 5- to 20-membered, or 5- to 15-membered) monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one nitrogen atom and optionally containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Examples of the term “nitrogen-containing heterocyclylene” include, but are not limited to, nitrogen-containing monocyclic heterocyclylene (e.g., 4- to 30-membered nitrogen-containing monocyclic heterocyclylene, and 4- to 20-membered nitrogen-containing monocyclic heterocyclylene), nitrogen-containing bridged heterocyclyl (e.g., 5- to 30-membered nitrogen-containing bridged heterocyclyl, 5- to 20-membered nitrogen-containing bridged heterocyclyl, 7- to 20-membered nitrogen-containing bridged heterocyclyl, or 7- to 15-membered nitrogen-containing bridged heterocyclyl), nitrogen-containing fused heterocyclyl (e.g., 5- to 30-membered nitrogen-containing fused heterocyclyl and 5- to 20-membered nitrogen-containing fused heterocyclyl), and nitrogen-containing spiro heterocyclyl (e.g., 5- to 30-membered nitrogen-containing spiro heterocyclyl and 5- to 20-membered nitrogen-containing spiro heterocyclyl). Representative examples of nitrogen-containing monocyclic heterocyclylene groups include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanylidene, diazepanylidene (e.g., 1,4-diazepanylidene, 4,5-diazepanylidene, 1,3-diazepanylidene) and diazepanylidene. Examples of nitrogen-containing bridged heterocyclic groups, nitrogen-containing fused heterocyclic groups, and nitrogen-containing spiro heterocyclic groups include, but are not limited to, 6-azabicyclo[3.1.1]heptanylidene, 2,5-diazabicyclo[2.2.1]heptanylidene, 3,6-diazabicyclo[3.1.1]heptanylidene, 3-azabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 2,5-diazabicyclo[2.2.2]octanylidene, octahydro-1H-indolylidene, and azaspirocyclic groups (e.g., 5 to 20 membered azaspirocyclic groups, such as 3-azaspiro[5.5]undecylidene). The nitrogen-containing heterocyclylene group may be unsubstituted or substituted as clearly defined (e.g., mono-, di-, tri-, or polysubstituted), wherein the substituents may be optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, oxo, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH—, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)—, optionally deuterated C 1-6 alkyl-C(O)NH—, C 2-6 alkynyl and C 2-6 alkenyl.

在本文中，单独或组合使用的术语“炔基”是指具有一个或多个(例如1至3个、1至2个或1个)碳碳叁键的包含2至8个(例如2至6个、2至5个、2至4个、较优选2个)碳原子的直链或支链一价烃基。“炔基”的实例包括C2-8炔基、C2-6炔基或C2-4炔基，其代表性实例包括但不限于乙炔基、1-丙炔基、1-丁炔基和1，3-二炔基。As used herein, the term "alkynyl", used alone or in combination, refers to a straight or branched monovalent hydrocarbon group containing 2 to 8 (e.g., 2 to 6, 2 to 5, 2 to 4, more preferably 2) carbon atoms having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds. Examples of "alkynyl" include C2-8 alkynyl, C2-6 alkynyl, or C2-4 alkynyl, and representative examples thereof include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-diynyl.

在本文中，单独或组合使用的术语“烯基”是指具有一个或多个(例如1至3个、1至2个或1个)碳碳双键的包含2至8个碳原子(例如2至6个、2至5个碳原子，或2至4个、2至3个或2个碳原子)的直链或支链一价烃基。“烯基”的实例包括C2-8烯基、C2-6烯基或C2- 4烯基，其代表性实例包括但不限于乙烯基(例如CH2＝CH-)、1-丙烯基、烯丙基、1-丁烯基、2-丁烯基、3-丁烯基、异丁烯基、戊烯基、正-戊-2，4-二烯基、1-甲基-丁-1-烯基、2-甲基-丁-1-烯基、3-甲基-丁-1-烯基、1-甲基-丁-2-亚基、2-甲基-丁-2-亚基、3-甲基-丁-2-亚基、1-甲基-丁-3-烯基、2-甲基-丁-3-烯基、3-甲基-丁-3-烯基和己烯基。As used herein, the term "alkenyl," alone or in combination, refers to a straight or branched monovalent hydrocarbon group containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3 or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds. Examples of “alkenyl” include C 2-8 alkenyl, C 2-6 alkenyl or C 2-4 alkenyl, representative examples of which include, but are not limited to, vinyl (e.g., CH 2 =CH—), 1-propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, pentenyl, n-penta-2,4-dienyl, 1-methyl-but-1-enyl, 2-methyl-but-1-enyl, 3-methyl-but-1-enyl, 1-methyl-but-2-ylidene, 2-methyl-but-2-ylidene, 3-methyl-but-2-ylidene, 1-methyl-but-3-enyl, 2-methyl-but-3-enyl, 3-methyl-but-3-enyl and hexenyl.

在本文中，术语“冰片”或“冰片烷”(又称1，7，7-trimethylbicyclo[2.2.1]heptane；camphane；bornylane)具有本领域技术人员已知的定义。在本文中，术语“冰片烷基”或“冰片基”是指冰片烷的一价基团，即冰片烷中的任意一个氢去掉后剩余的基团。“冰片基”的代表性实例包括但不限于1，7，7-三甲基二环[2.2.1]庚烷-2-基、1，7，7-三甲基二环[2.2.1]庚烷-3-基、1，7，7-三甲基二环[2.2.1]庚烷-4-基、1，7，7-三甲基二环[2.2.1]庚烷-5-基、或1，7，7-三甲基二环[2.2.1]庚烷-6-基、

Figure PCTCN2024142598-ftappb-I100059
As used herein, the term "bornyl" or "bornane" (also known as 1,7,7-trimethylbicyclo[2.2.1]heptane; camphane; bornylane) has a definition known to those skilled in the art. As used herein, the term "bornyl" or "bornyl" refers to a monovalent radical of bornane, i.e., the radical remaining after any one of the hydrogen atoms in bornane is removed. Representative examples of "bornyl" include, but are not limited to, 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl, 1,7,7-trimethylbicyclo[2.2.1]heptane-3-yl, 1,7,7-trimethylbicyclo[2.2.1]heptane-4-yl, 1,7,7-trimethylbicyclo[2.2.1]heptane-5-yl, or 1,7,7-trimethylbicyclo[2.2.1]heptane-6-yl,
Figure PCTCN2024142598-ftappb-I100059

在本文中，术语“二环[2.2.1]庚烷”(又称bicyclo[2.2.1]heptane)或“降冰片烷”，具有本领域技术人员已知的定义。在本文中，“二环[2.2.1]庚烷基”或“降冰片(烷)基”是指二环[2.2.1]庚烷的一价基团，即二环[2.2.1]庚烷中的任意一个氢去掉后剩余的基团。“二环[2.2.1]庚烷基”的代表性实例包括但不限于二环[2.2.1]庚烷-2-基、二环[2.2.1]庚烷-3-基、二环[2.2.1]庚烷-4-基、二环[2.2.1]庚烷-5-基和二环[2.2.1]庚烷-6-基。As used herein, the term "bicyclo[2.2.1]heptane" (also known as bicyclo[2.2.1]heptane) or "norbornane" has a definition known to those skilled in the art. As used herein, "bicyclo[2.2.1]heptane" or "norbornane" refers to a monovalent radical of bicyclo[2.2.1]heptane, i.e., the radical remaining after any one of the hydrogen atoms in bicyclo[2.2.1]heptane is removed. Representative examples of "bicyclo[2.2.1]heptane" include, but are not limited to, bicyclo[2.2.1]heptane-2-yl, bicyclo[2.2.1]heptane-3-yl, bicyclo[2.2.1]heptane-4-yl, bicyclo[2.2.1]heptane-5-yl, and bicyclo[2.2.1]heptane-6-yl.

在本文中，术语“二环[2.2.1]庚烯”又称bicyclo[2.2.1]heptene)，具有本领域技术人员已知的定义。在本文中，“二环[2.2.1]庚烯基”是指二环[2.2.1]庚烯的一价基团，即二环[2.2.1]庚烯中的任意一个氢去掉后剩余的基团。“二环[2.2.1]庚烯基”的代表性实例包括但不限于二环[2.2.1]庚-5-烯-2-基、二环[2.2.1]庚-5-烯-3-基和二环[2.2.1]庚-5-烯-7-基。As used herein, the term "bicyclo[2.2.1]heptene" is also known as bicyclo[2.2.1]heptene and has a definition known to those skilled in the art. As used herein, "bicyclo[2.2.1]heptenyl" refers to a monovalent group of bicyclo[2.2.1]heptene, i.e., the group remaining after any one of the hydrogen atoms in bicyclo[2.2.1]heptene is removed. Representative examples of "bicyclo[2.2.1]heptenyl" include, but are not limited to, bicyclo[2.2.1]hept-5-ene-2-yl, bicyclo[2.2.1]hept-5-ene-3-yl, and bicyclo[2.2.1]hept-5-ene-7-yl.

在本文中，术语“金刚烷”(又称Tricyclo[3.3.1.13，7]decane)具有本领域技术人员已知的定义，其结构式例如如下所示：

Figure PCTCN2024142598-ftappb-I100060
在本文中，“金刚烷基”是指金刚烷的一价基团，即金刚烷中的任意一个氢去掉后剩余的基团。“金刚烷基”的代表性实例包括但不限于1-金刚烷基、2-金刚烷基、3-金刚烷基、4-金刚烷基、5-金刚烷基、6-金刚烷基、7-金刚烷基、8-金刚烷基、9-金刚烷基和10-金刚烷基。In this document, the term "adamantane" (also known as Tricyclo[3.3.1.1 3,7 ]decane) has the definition known to those skilled in the art, and its structural formula is shown below, for example:
Figure PCTCN2024142598-ftappb-I100060
Herein, "adamantyl" refers to a monovalent group of adamantane, i.e., the group remaining after any hydrogen in adamantane is removed. Representative examples of "adamantyl" include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, 9-adamantyl, and 10-adamantyl.

在本文中，术语“降金刚烷”(又称为noradamantane，或octahydro-2，5-methanopentalene(译文：八氢-2，5-甲桥并环戊二烯))具有本领域技术人员已知的定义，其结构式例如如下所示：

Figure PCTCN2024142598-ftappb-I100061
在本文中，“降金刚烷基”是指降金刚烷的一价基团，即降金刚烷中的任意一个氢去掉后剩余的基团。“降金刚烷基”的代表性实例包括但不限于1-降金刚烷基、2-降金刚烷基、3-降金刚烷基、4-降金刚烷基、5-降金刚烷基、6-降金刚烷基、7-降金刚烷基、8-降金刚烷基和9-降金刚烷基。In this document, the term "noradamantane" (also known as noradamantane, or octahydro-2,5-methanopentalene) has the definition known to those skilled in the art, and its structural formula is shown below, for example:
Figure PCTCN2024142598-ftappb-I100061
Herein, "noradamantyl" refers to a monovalent group of noradamantane, i.e., the group remaining after any one hydrogen in noradamantane is removed. Representative examples of "noradamantyl" include, but are not limited to, 1-noradamantyl, 2-noradamantyl, 3-noradamantyl, 4-noradamantyl, 5-noradamantyl, 6-noradamantyl, 7-noradamantyl, 8-noradamantyl, and 9-noradamantyl.

在本文中，术语“金刚烷胺”具有本领域技术人员已知的定义，即是指具有氨基取代基的金刚烷，其中氨基可以取代在金刚烷任意位置的碳上的氢。“金刚烷胺”的一实施例可以是金刚烷-1-胺(其对应英文化学名称为adamantan-1-amine或Tricyclo[3.3.1.13，7]decan-1-amine；CAS：768-94-5)，具有以下结构式

Figure PCTCN2024142598-ftappb-I100062
As used herein, the term "adamantanamine" has a definition known to those skilled in the art, i.e., refers to adamantane having an amino substituent, wherein the amino group can replace the hydrogen on any carbon position of the adamantane. An example of "adamantanamine" can be adamantane-1-amine (its corresponding English chemical name is adamantan-1-amine or Tricyclo[3.3.1.1 3,7 ]decan-1-amine; CAS: 768-94-5), having the following structural formula
Figure PCTCN2024142598-ftappb-I100062

本公开所述式(I)化合物的盐或药学上可接受的盐、对映异构体、立体异构体、溶剂化物、多晶型物亦涵盖于本公开范围内。The salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, and polymorphs of the compounds of formula (I) described in the present disclosure are also encompassed within the scope of the present disclosure.

在本公开的所有实施方式中，所述式(I)化合物的盐或药学上可接受的盐是指无毒无机的或有机的酸和/或碱加成盐。示例包括：硫酸盐、氢卤酸盐(包括盐酸盐、氢溴酸盐)、马来酸盐、磺酸盐、柠檬酸盐/枸橼酸盐、乳酸盐、乳糖酸盐、L-酒石酸盐、富马酸盐、L-苹果酸盐、L-乳酸盐、α-酮戊二酸盐、马尿酸盐、D-葡萄糖醛酸盐、D-葡萄糖酸盐、α-D-葡庚糖酸盐、乙醇酸盐、粘酸盐、L-抗坏血酸盐、乳清酸盐、苦味酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、月桂酸盐、帕莫酸盐、癸二酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、乙二磺酸盐、甲酸盐、乙酸盐、2，2-二氯乙酸盐、三甲基乙酸盐、丙酸盐、戊酸盐、棕榈酸盐、三苯基乙酸盐、2-乙基-丁二酸盐、碘酸盐、烟酸盐、L-焦谷氨酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、硝酸盐、龙胆酸盐、胆酸盐、水杨酸盐、对苯二酸盐、戊二酸盐、己二酸盐、硬脂酸盐、油酸盐、十一烯酸盐、樟脑酸盐、樟脑磺酸盐、十二基磺酸盐、磷酸盐、硫氰酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、碳酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、丙酮酸盐、对氯苯磺酸盐、1，5-萘二磺酸盐、3-羟基-2-萘甲酸盐、1-羟基-2-萘甲酸盐、2-萘磺酸盐、羟乙酸盐、三氟乙酸盐、对苯二甲酸盐和对甲苯磺酸盐等。In all embodiments of the present disclosure, the salt or pharmaceutically acceptable salt of the compound of formula (I) refers to a non-toxic inorganic or organic acid and/or base addition salt. Examples include: sulfate, hydrohalide (including hydrochloride, hydrobromide), maleate, sulfonate, citrate/citrate, lactate, lactobionate, L-tartrate, fumarate, L-malate, L-lactate, α-ketoglutarate, hippurate, D-glucuronate, D-gluconate, α-D-glucoheptonate, glycolate, mucate, L-ascorbate, orotate, picrate, glycinate, alanine, arginine, cinnamate, laurate, pamoate, sebacate, benzenesulfonate, methanesulfonate, ethanesulfonate, edisylate, formate, acetate, 2,2-dichloroacetate, trimethylacetate, propionate, valerate, palmitate, triphenylacetate , 2-ethyl-succinate, iodate, nicotinate, L-pyroglutamate, L-proline salt, ferulate, 2-hydroxyethanesulfonate, nitrate, gentisate, cholate, salicylate, terephthalate, glutarate, adipate, stearate, oleate, undecylenate, camphorate, camphorsulfonate, dodecylsulfonate, phosphate, thiocyanate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, carbonate, malonate, benzoate, mandelate, succinate, pyruvate, p-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, 3-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoate, 2-naphthalenesulfonate, glycolate, trifluoroacetate, terephthalate and p-toluenesulfonate, etc.

“药学上可接受的载体”是指药学上可接受的材料，例如填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或包封材料，将本公开中有用的化合物携带或运输到患者体内或给予患者，使得其可以执行其预期功能。通常，这样的构建体从一个器官或身体的一部分携带或运输到另一个器官或身体的一部分。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害，载体必须是“可接受的”。可用作药学上可接受的载体的材料的一些实例包括：糖，如乳糖，葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；粉状黄蓍胶；麦芽；明胶；滑石；赋形剂，如可可脂和栓剂蜡；油，如花生油，棉籽油，红花油，芝麻油，橄榄油，玉米油和大豆油；二醇，如丙二醇；多元醇，如甘油，山梨糖醇，甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；表面活性剂磷酸盐缓冲溶液；和药物制剂中使用的其他无毒相容物质。"Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, that carries or transports a compound useful in the present disclosure to a patient or administers it to a patient so that it can perform its intended function. Typically, such a construct is carried or transported from one organ or part of the body to another organ or part of the body. The carrier must be "acceptable" if it is compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and is not harmful to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; phosphate buffered solutions as surfactants; and other nontoxic compatible substances used in pharmaceutical formulations.

本公开的术语“室温”是指周围环境温度，例如20-30℃的温度。The term "room temperature" of the present disclosure refers to ambient temperature, for example, a temperature of 20-30°C.

在本文中，“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。As used herein, "stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.

在本文中，术语“溶剂化物”是指一种或多种溶剂分子和本发明化合物的缔合物或络合物。溶剂的实例包括水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指溶剂分子是水的络合物。As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

在本文中，术语“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。As used herein, the term "chiral" refers to a molecule that has the property of being non-superimposable on its mirror image; whereas "achiral" refers to a molecule that is superimposable on its mirror image.

在本文中，术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。As used herein, the term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

在本文中，术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。As used herein, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

在本文中，“对薄荷烷”(又称p-methane)具有本领域技术人员已知的定义，其结构式例如如下所示：

Figure PCTCN2024142598-ftappb-I100063
在本文中，“对薄荷烷基”是指对薄荷烷的一价基团，即对薄荷烷任意位置的碳上的任意一个氢去掉后剩余的基团。代表性实例包括但不限于
Figure PCTCN2024142598-ftappb-I100064
Figure PCTCN2024142598-ftappb-I100065
In this document, "p-menthane" (also known as p-methane) has a definition known to those skilled in the art, and its structural formula is shown below, for example:
Figure PCTCN2024142598-ftappb-I100063
In this article, "p-menthanyl" refers to a monovalent group of p-menthane, that is, the group remaining after any hydrogen on any carbon position of p-menthane is removed. Representative examples include but are not limited to
Figure PCTCN2024142598-ftappb-I100064
Figure PCTCN2024142598-ftappb-I100065

在本文中，“间薄荷烷”(又称m-methane)具有本领域技术人员已知的定义，其结构式例如如下所示：

Figure PCTCN2024142598-ftappb-I100066
在本文中，“间薄荷烷基”是指间薄荷烷的一价基团，即间薄荷烷任意位置的碳上的任意一个氢去掉后剩余的基团。代表性实例包括但不限于
Figure PCTCN2024142598-ftappb-I100067
Figure PCTCN2024142598-ftappb-I100068
In this article, "m-menthane" (also known as m-methane) has a definition known to those skilled in the art, and its structural formula is shown below:
Figure PCTCN2024142598-ftappb-I100066
In this article, "m-menthanyl" refers to a monovalent group of m-menthane, that is, the group remaining after any hydrogen on any carbon position of m-menthane is removed. Representative examples include but are not limited to
Figure PCTCN2024142598-ftappb-I100067
Figure PCTCN2024142598-ftappb-I100068

在本文中，“奎宁环”(又称Quihuclidine)，其化学名称为1-氮杂二环[2.2.2]辛烷，具有本领域技术人员已知的定义，其结构式例如如下所示：

Figure PCTCN2024142598-ftappb-I100069
在本文中，“奎宁环基”是指奎宁环的一价基团，即奎宁环任意位置的碳上的任意一个氢去掉后剩余的基团。代表性实例包括但不限于
Figure PCTCN2024142598-ftappb-I100070
In this document, "quinuclidine" (also known as Quihuclidine), whose chemical name is 1-azabicyclo[2.2.2]octane, has a definition known to those skilled in the art, and its structural formula is shown below:
Figure PCTCN2024142598-ftappb-I100069
In this article, "quinuclidine group" refers to a monovalent group of quinuclidine, that is, the group remaining after any hydrogen on any carbon at any position of quinuclidine is removed. Representative examples include but are not limited to
Figure PCTCN2024142598-ftappb-I100070

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1显示本发明化合物在hPBMC细胞中对目标底物蛋白降解的Western Blot实验结果。Figure 1 shows the Western Blot experimental results of the degradation of target substrate protein by the compounds of the present invention in hPBMC cells.

实施例Example

在下列说明中，为了提供对本发明的彻底了解而提出许多具体细节。本发明可在不具有部分或所有这些具体细节的情况下实施。在其他情况下，为了不对本发明造成不必要的混淆，不详述众所周知的过程操作。虽然本发明将结合具体实施例来进行说明，但应当理解的是，这并非旨在将本发明限制于这些实施例。In the following description, many specific details are set forth in order to provide a thorough understanding of the present invention. The present invention may be implemented without some or all of these specific details. In other cases, well-known process operations are not described in detail in order not to cause unnecessary confusion to the present invention. Although the present invention will be described in conjunction with specific embodiments, it should be understood that this is not intended to limit the present invention to these embodiments.

整个说明书及实施例中使用下列缩写：
AcOH            醋酸
Boc             叔丁氧基羰基
DCM            二氯甲烷
DIEA或DIPEA     N，N-二异丙基乙胺
DMF             N，N-二甲基甲酰胺
DMSO           二甲基亚砜
EA              乙酸乙酯
ESI              电喷雾离子化
equiv            当量
EtOH            乙醇
EtOAc            乙酸乙酯
HPLC            高效液相层析
HRMS           高分辨率质谱
LC-MS           液相色谱-质谱联用
LRMS           低分辨率质谱
LC              液相层析
Me              甲基
MeCN            乙腈
MeOH           甲醇
MS              质谱
MsCl             甲烷磺酰氯
MsO-            甲磺酰氧基
Ms2O            甲烷磺酸酐
1H NMR          核磁共振氢谱
MeO-            甲氧基
ONs             邻硝基苯磺酰基
rt                室温
tBu              叔丁基
TEA             三乙胺
TFA             三氟乙酸
TfO-             三氟甲磺酰氧基
TLC             薄层层析
TMS             三甲基硅烷基
TsO-             对甲苯磺酰氧基
Xantphos          4，5-双(二苯基膦)-9，9-二甲基氧杂蒽
X-Phos            2-二环己基膦-2′，4′，6′-三异丙基联苯The following abbreviations are used throughout the specification and examples:
AcOH Acetic acid
Boc tert-Butyloxycarbonyl
DCM Dichloromethane
DIEA or DIPEA N,N-diisopropylethylamine
DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
EA Ethyl acetate
ESI Electrospray ionization
equiv equivalent
EtOH
EtOAc Ethyl acetate
HPLC High Performance Liquid Chromatography
HRMS High Resolution Mass Spectrometry
LC-MS Liquid chromatography-mass spectrometry
LRMS Low Resolution Mass Spectrometry
LC Liquid Chromatography
Me Methyl
MeCN Acetonitrile
MeOH Methanol
MS
MsCl Methanesulfonyl chloride
MsO - Methanesulfonyloxy
Ms 2 O Methanesulfonic anhydride
1 H NMR Nuclear Magnetic Resonance Proton Spectroscopy
MeO-Methoxy
ONs o-nitrobenzenesulfonyl
rt room temperature
tBu tert-butyl
TEA Triethylamine
TFA Trifluoroacetic acid
TfO -trifluoromethanesulfonyloxy
TLC Thin Layer Chromatography
TMS Trimethylsilyl
TsO- p-Toluenesulfonyloxy
Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

在本发明中，1H NMR谱采用Bruker-500MHz型核磁共振仪测定，用含0.1％TMS(作为内标)的CD3OD(δ＝3.31ppm)做溶剂；或用含0.1％TMS(作为内标)的CDCl3(δ＝7.26ppm)做溶剂；或使用含0.03％TMS(作为内标)的DMSO-d6(δ＝2.50ppm)做溶剂；LC-MS谱在具有Agilent 1100二元泵以及DAD及ELSD的Sciex API 2000型质谱仪或在具有Agilent 1260四元泵、DAD及ELSD的Agilent 1260-6125B型单四极杆液-质联用仪上测定，HPLC制备在SHIMADZU LC-20AP型仪器上测定，HPLC纯度在SHIMADZU LC-30AP或Waters 1525型仪器上测定。所有反应未作特别说明均在空气氛围下进行；反应用TLC或LC-MS跟踪。In the present invention, 1 H NMR spectrum was measured by Bruker-500MHz nuclear magnetic resonance instrument, using CD 3 OD (δ=3.31ppm) containing 0.1% TMS (as internal standard) as solvent; or CDCl 3 (δ=7.26ppm) containing 0.1% TMS (as internal standard) as solvent; or DMSO-d 6 (δ=2.50ppm) containing 0.03% TMS (as internal standard) as solvent; LC-MS spectrum was measured on Sciex API 2000 mass spectrometer with Agilent 1100 binary pump, DAD and ELSD or Agilent 1260-6125B single quadrupole liquid-mass spectrometer with Agilent 1260 quaternary pump, DAD and ELSD, HPLC preparation was measured on SHIMADZU LC-20AP instrument, HPLC purity was measured on SHIMADZU LC-30AP or Waters The reaction was measured on a 1525 instrument. All reactions were carried out under air atmosphere unless otherwise specified; the reaction was followed by TLC or LC-MS.

溶剂及试剂处理如下：反应所用溶剂DCM、DMF、无水EtOH、无水MeOH均购自国药集团；HPLC制备所用的是制备级CH3CN及去离子水；其它反应底物、试剂和药品未经特别说明均可通过市售渠道直接购买获得，或者可以采用或按照本领域已知的方法合成得到。Solvents and reagents were processed as follows: DCM, DMF, anhydrous EtOH and anhydrous MeOH were purchased from Sinopharm Group; preparative-grade CH 3 CN and deionized water were used for HPLC preparation; other reaction substrates, reagents and drugs were directly purchased from commercial channels unless otherwise specified, or were synthesized using or according to methods known in the art.

下述实施例中所用的材料、试剂，如无特别说明，均可从商业途径购买来直接使用，或者可以采用或按照本领域已知的方法合成得到。Unless otherwise specified, the materials and reagents used in the following examples can be purchased from commercial sources and used directly, or can be synthesized by or according to methods known in the art.

通用合成方法General synthetic method

本公开所述的化合物和/或其药学上可接受的盐，可以使用市售原料通过本领域已知的合成技术合成得到。下文描述的合成方案举例说明了大部分化合物的制备方法。各方案中使用的起始原料或试剂均可从商购途径购买得到或者通过本领域技术人员已知的方法制备得到。本领域技术人员可根据本领域常规技术制备本公开式(I)化合物的盐、外消旋体、对映异构体、磷酸盐、硫酸盐、盐酸盐和前药形式。The compounds and/or pharmaceutically acceptable salts thereof disclosed herein can be synthesized using commercially available raw materials by synthetic techniques known in the art. The synthetic schemes described below illustrate the preparation methods of most compounds. The starting materials or reagents used in each scheme can be purchased from commercial sources or prepared by methods known to those skilled in the art. Salts, racemates, enantiomers, phosphates, sulfates, hydrochlorides and prodrug forms of the compounds of formula (I) disclosed herein can be prepared by those skilled in the art according to conventional techniques in the art.

合成方案1：

Figure PCTCN2024142598-ftappb-I100071

方案1Synthesis Scheme 1:
Figure PCTCN2024142598-ftappb-I100071

Solution 1

在方案1中，基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5、含氮杂环A、(Rd1)n1、环B、(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D和(Rd4)n4如本公开的式(I)化合物及其各子实施方案中所定义。底物1的基团LE表示Cl、Br、I、OMs、OTs、或ONs。底物2是与式(I)化合物中含有含氮杂环的X部分对应的化合物。In Scheme 1, groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4, Z5 , nitrogen-containing heterocyclic ring A, ( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc , ring C, m1, ( Rd3 ) n3 , ring D and ( Rd4 ) n4 are as defined in the compounds of formula (I) and their respective sub-embodiments disclosed herein. The group LE of substrate 1 represents Cl, Br, I, OMs, OTs, or ONs. Substrate 2 is a compound corresponding to the X moiety containing a nitrogen-containing heterocyclic ring in the compound of formula (I).

方案1中的胺烷基化反应可以例如在DIEA和碘化钠，或三乙胺和碘化钠的存在下在室温至80℃(例如40℃～60℃、40℃～50℃、或50℃～60℃)条件下进行。底物1与底物2的摩尔比可以为例如1：1.1～2，1：1.1～1.5，1：1.1～1.2，或1：1.2～1.3等。The amine alkylation reaction in Scheme 1 can be carried out, for example, in the presence of DIEA and sodium iodide, or triethylamine and sodium iodide, at room temperature to 80° C. (e.g., 40° C. to 60° C., 40° C. to 50° C., or 50° C. to 60° C.). The molar ratio of substrate 1 to substrate 2 can be, for example, 1:1.1 to 2, 1:1.1 to 1.5, 1:1.1 to 1.2, or 1:1.2 to 1.3, etc.

例如，方案1的具体操作可以如下：For example, the specific operations of scheme 1 can be as follows:

将溴代物底物1(1.3eq.)和底物2(1.0eq.)溶于无水DMF(2mL)中，随后向溶液中加入三乙胺(3.0eq.)和碘化钠(1.0eq.)。反应液在50℃下搅拌2小时。LCMS检测反应完成。反应液过滤，滤液用高效液相色谱纯化得目标化合物。The bromide substrate 1 (1.3 eq.) and substrate 2 (1.0 eq.) were dissolved in anhydrous DMF (2 mL), and then triethylamine (3.0 eq.) and sodium iodide (1.0 eq.) were added to the solution. The reaction solution was stirred at 50°C for 2 hours. LCMS detected that the reaction was complete. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to obtain the target compound.

合成方案2：(磺酸酯化；Sulfonate ester formation)

Figure PCTCN2024142598-ftappb-I100072

方案2Synthesis Scheme 2: (Sulfonate ester formation)
Figure PCTCN2024142598-ftappb-I100072

Solution 2

方案2中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4和Z5如本公开的式(I)化合物及其各子实施方案中所定义。In Scheme 2, the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 and Z5 are as defined in the compounds of formula (I) and various subembodiments thereof of the present disclosure.

在方案2中，反应底物的取代基-CH2-OH可以在异吲哚啉基的苯环上的4-、5-、6-、或7-位，所制得的产物2-2、2-3的取代基-CH2-OMs也相应地位于异吲哚啉基的苯环上的4-、5-、6-、或7-位。In Scheme 2, the substituent -CH2-OH of the reaction substrate can be located at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolyl group, and the substituent -CH2-OMs of the obtained products 2-2 and 2-3 are also correspondingly located at the 4-, 5-, 6-, or 7-position on the benzene ring of the isoindolyl group.

合成方案3：

Figure PCTCN2024142598-ftappb-I100073

方案3Synthesis Scheme 3:
Figure PCTCN2024142598-ftappb-I100073

Solution 3

在方案3中，基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5、含氮杂环A、(Rd1)n1、环B、(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D和(Rd4)n4如本公开的式(I)化合物及其各子实施方案中所定义。步骤(2)底物2是与合成方案1中的底物2相同的化合物。In Scheme 3, groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3, Z4 , Z5 , nitrogen-containing heterocyclic ring A, ( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc , ring C, m1, ( Rd3 ) n3 , ring D and ( Rd4 ) n4 are as defined in the compounds of formula (I) and their respective sub-embodiments disclosed herein. Step (2) Substrate 2 is the same compound as Substrate 2 in Synthesis Scheme 1.

例如，方案3的具体操作可以如下：For example, the specific operations of scheme 3 can be as follows:

将羟基底物(1.0eq.)溶于无水DMF(0.5mL)和DCM(5mL)中，随后向溶液中加入二异丙基乙基胺(3.0eq.)和甲烷磺酸酐(0.9eq.)。反应液在室温下搅拌5分钟。TLC检测反应完成后，向溶液中加入相应底物胺(1.0eq.)的DMF(0.5mL)溶液，反应在室温下继续搅拌3小时。LCMS检测反应完成。反应液过滤，浓缩，残余物用高效液相色谱纯化得目标化合物。The hydroxyl substrate (1.0 eq.) was dissolved in anhydrous DMF (0.5 mL) and DCM (5 mL), and then diisopropylethylamine (3.0 eq.) and methanesulfonic anhydride (0.9 eq.) were added to the solution. The reaction solution was stirred at room temperature for 5 minutes. After the TLC reaction was completed, a DMF (0.5 mL) solution of the corresponding substrate amine (1.0 eq.) was added to the solution, and the reaction was continued to stir at room temperature for 3 hours. LCMS detected that the reaction was complete. The reaction solution was filtered and concentrated, and the residue was purified by high performance liquid chromatography to obtain the target compound.

合成方案4：

Figure PCTCN2024142598-ftappb-I100074

方案4Synthesis Scheme 4:
Figure PCTCN2024142598-ftappb-I100074

Solution 4

在方案4中，基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5、含氮杂环A、(Rd1)n1、环B、(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D和(Rd4)n4如本公开的式(I)化合物及其各子实施方案中所定义。In Scheme 4, groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3, Z4 , Z5 , nitrogen-containing heterocyclic ring A, ( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc , ring C, m1, ( Rd3 ) n3 , ring D and ( Rd4 ) n4 are as defined in the compounds of formula (I) and various subembodiments thereof disclosed herein.

方案4的具体操作可以如下：The specific operations of scheme 4 can be as follows:

将羧酸底物1(1.1eq.)和底物2(1.0eq.)溶于无水DMF(2mL)中，随后向溶液中加入三乙胺(3.0eq.)和HATU(1.3eq.)。反应液在室温下搅拌2小时。LCMS检测反应完成。反应液过滤，滤液用高效液相色谱纯化得目标化合物。Carboxylic acid substrate 1 (1.1 eq.) and substrate 2 (1.0 eq.) were dissolved in anhydrous DMF (2 mL), and then triethylamine (3.0 eq.) and HATU (1.3 eq.) were added to the solution. The reaction solution was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to obtain the target compound.

合成方案5：

Figure PCTCN2024142598-ftappb-I100075

方案5Synthesis Scheme 5:
Figure PCTCN2024142598-ftappb-I100075

Solution 5

方案5中Z6表示C(O)、CH2或CD2。Z1表示C(O)、C(S)、CH2或CD2，Z2、Z3和Z4各自独立地表示C(O)或C(S)，其中Z1、Z2、Z3和Z4中至少一个表示C(S)。当Z6表示C(O)时，Z1表示C(O)或C(S)。当Z6表示CH2或CD2时，Z1对应地表示CH2或CD2。In Scheme 5, Z 6 represents C(O), CH 2 or CD 2. Z 1 represents C(O), C(S), CH 2 or CD 2 , and Z 2 , Z 3 and Z 4 each independently represent C(O) or C(S), wherein at least one of Z 1 , Z 2 , Z 3 and Z 4 represents C(S). When Z 6 represents C(O), Z 1 represents C(O) or C(S). When Z 6 represents CH 2 or CD 2 , Z 1 represents CH 2 or CD 2 correspondingly.

方案5中的硫化试剂劳森试剂还可以替换成其它合适的硫化试剂，例如但不限于二硫化碳，六甲基二硅硫烷，硫，硫脲，硫化氢，五硫化二磷，Belleau’s试剂，和Davy’s试剂等。The sulfurizing agent Lawesson's reagent in Scheme 5 can also be replaced by other suitable sulfurizing agents, such as but not limited to carbon disulfide, hexamethyldisilathane, sulfur, thiourea, hydrogen sulfide, phosphorus pentasulfide, Belleau’s reagent, and Davy’s reagent.

在方案5中，步骤1的反应底物5-1的取代基Br可以在异吲哚啉基的苯环上的4-、5-、6-、或7-位，所制得的中间产物的取代基Br以及步骤2产物的取代基-CH2-OH也相应地位于异吲哚啉基的苯环上的4-、5-、6-、或7-位。Ra1、Ra2、Ra3、Ra4和(Ra5)m如本公开的式(I)化合物及其各子实施方案中所定义。In Scheme 5, the substituent Br of the reaction substrate 5-1 of step 1 can be located at the 4-, 5-, 6-, or 7-position on the phenyl ring of the isoindolyl group, and the substituent Br of the intermediate product obtained and the substituent -CH2-OH of the product of step 2 are also located at the 4-, 5-, 6-, or 7-position on the phenyl ring of the isoindolyl group, respectively. Ra1 , Ra2 , Ra3 , Ra4 , and ( Ra5 ) are as defined in the compounds of formula (I) and their respective sub-embodiments disclosed herein.

在方案5的一些实施方案中，式(I)化合物的Z1、Z2、Z3和Z4中至少一个表示C(S)。在一些实施方案中，式(I)化合物的Z1、Z2、Z3和Z4中至少两个表示C(S)。在一些实施方案中，Z1、Z2、Z3和Z4中至少三个表示C(S)。在一些实施方案中，Z1、Z2、Z3和Z4均表示C(S)。In some embodiments of Scheme 5, at least one of Z 1 , Z 2 , Z 3 and Z 4 of the compound of formula (I) represents C(S). In some embodiments, at least two of Z 1 , Z 2 , Z 3 and Z 4 of the compound of formula (I) represent C(S). In some embodiments, at least three of Z 1 , Z 2 , Z 3 and Z 4 represent C(S). In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 all represent C(S).

根据目标化合物，上述各方案以及其反应底物、反应条件(包括反应用量、温度、时间等)、后处理等可通过本领域技术人员熟知的技术和方法进行适当修改和调整以获得所需的目标化合物，并且所得的目标化合物可根据本领域技术人员熟知的方法，进一步通过取代基等进行修饰而获得其他目标化合物。
实施例Depending on the target compound, the above-mentioned schemes and their reaction substrates, reaction conditions (including reaction amount, temperature, time, etc.), post-treatment, etc. can be appropriately modified and adjusted by techniques and methods well known to those skilled in the art to obtain the desired target compound, and the obtained target compound can be further modified by substituents, etc. according to methods well known to those skilled in the art to obtain other target compounds.
Example

中间体实施例1：3-(5-(羟甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GTC00170)的制备

Figure PCTCN2024142598-ftappb-I100076
Intermediate Example 1: Preparation of 3-(5-(hydroxymethyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GTC00170)
Figure PCTCN2024142598-ftappb-I100076

参照合成方案5的方法制备目标化合物(GTC00170)。The target compound (GTC00170) was prepared according to the method of Synthesis Scheme 5.

步骤1：向3-(5-溴-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(20g，61.891mmol)的1，4-二氧六环(200mL)溶液中加入劳森试剂(11.26g，27.851mmol)。反应混合物在110℃下搅拌反应12小时。TLC薄层层析检测反应完成。浓缩反应混合物，残余物经柱层析纯化，得灰白色固体状的3-(5-溴-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(10g，29.480mmol，收率47.64％)。Step 1: To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20 g, 61.891 mmol) in 1,4-dioxane (200 mL) was added Lawesson's reagent (11.26 g, 27.851 mmol). The reaction mixture was stirred at 110°C for 12 hours. The reaction was complete by TLC thin layer chromatography. The reaction mixture was concentrated and the residue was purified by column chromatography to give 3-(5-bromo-1-thioisoindolin-2-yl)piperidine-2,6-dione (10 g, 29.480 mmol, yield 47.64%) as an off-white solid.

步骤2：向3-(5-溴-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(6g，17.688mmol)和(三丁基-λ4-锡基)甲醇(8.52g，26.532mmol)在1，4-二氧六环(60mL)中的溶液中加入XPhos Pd G3(0.1g，0.147mmol)。反应混合物在100℃下在氩气气氛中搅拌反应3小时。浓缩反应混合物，残余物经柱层析纯化，得灰色固体状的3-(5-(羟甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(1g，收率19.46％)。1H NMR(400MHz，DMSO)δ11.17(s，1H)，7.91(d，J＝7.9Hz，1H)，7.66(s，1H)，7.55(d，J＝8.0Hz，1H)，6.09-5.91(m，1H)，5.49(t，J＝5.7Hz，1H)，4.91-4.67(m，4H)，3.13-2.93(m，1H)，2.79-2.58(m，2H)，2.16(dd，J＝8.9，3.6Hz，1H).LCMS(ESI)C14H15N2O3S+[M+H]+：计算值，291.08实测值，291.0。Step 2: XPhos Pd G3 (0.1 g, 0.147 mmol) was added to a solution of 3-(5-bromo-1-thioisoindolin-2-yl)piperidine-2,6-dione (6 g, 17.688 mmol) and (tributyl-λ4-tinyl)methanol (8.52 g, 26.532 mmol) in 1,4-dioxane (60 mL). The reaction mixture was stirred at 100°C under argon atmosphere for 3 hours. The reaction mixture was concentrated and the residue was purified by column chromatography to give 3-(5-(hydroxymethyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (1 g, yield 19.46%) as a gray solid. 1 H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 6.09-5.91 (m, 1H), 5.49 (t, J=5.7 Hz, 1H), 4.91-4.67 (m, 4H), 3.13-2.93 (m, 1H), 2.79-2.58 (m, 2H), 2.16 (dd, J=8.9, 3.6 Hz, 1H). LCMS (ESI) C 14 H 15 N 2 O 3 S + [M+H] +: calculated, 291.08 found, 291.0.

中间体实施例2：3-(4-(羟甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GTC00504)的制备

Figure PCTCN2024142598-ftappb-I100077
Intermediate Example 2: Preparation of 3-(4-(hydroxymethyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GTC00504)
Figure PCTCN2024142598-ftappb-I100077

参照合成方案5的方法或中间体实施例1的方法制备目标化合物(GTC00504)(灰色固体，0.8g，收率33.32％)。1HNMR(400MHz，DMSO)δ11.12(s，1H)，7.80(d，J＝7.4Hz，1H)，7.61(d，J＝7.4Hz，1H)，7.53(t，J＝7.6Hz，1H)，5.98(d，J＝8.3Hz，1H)，5.37(d，J＝5.4Hz，1H)，4.79(dd，J＝49.7，20.2Hz，2H)，4.65(d，J＝4.1Hz，2H)，2.96(s，1H)，2.64(d，J＝18.4Hz，2H)，2.09(dd，J＝8.9，3.5Hz，1H).LCMS(ESI)C14H15N2O3S+[M+H]+：计算值，291.08实测值，291.0。The target compound (GTC00504) (gray solid, 0.8 g, yield 33.32%) was prepared by referring to the method of Synthesis Scheme 5 or the method of Intermediate Example 1. 1 HNMR (400MHz, DMSO) δ11.12 (s, 1H), 7.80 (d, J=7.4Hz, 1H), 7.61 (d, J=7.4Hz, 1H), 7.53 (t, J=7.6Hz, 1H), 5.98 (d, J=8.3Hz, 1H), 5.37 (d, J=5. 4Hz, 1H), 4.79 (dd, J=49.7, 20.2Hz, 2H), 4.65 (d, J=4.1Hz, 2H), 2.96 (s, 1H), 2.64 (d, J=18.4Hz, 2H), 2.09 (dd, J=8.9, 3.5Hz, 1H). LCMS (ESI) C 14 H 15 N 2 O 3 S + [M+H]+: calcd., 291.08 found, 291.0.

中间体实施例3：3-(6-(羟甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GTC00505)的制备

Figure PCTCN2024142598-ftappb-I100078
Intermediate Example 3: Preparation of 3-(6-(hydroxymethyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GTC00505)
Figure PCTCN2024142598-ftappb-I100078

参照合成方案5的方法或中间体实施例1的方法制备目标化合物(GTC00505)(灰色固体，1g，收率38.91％)。1HNMR(400MHz，DMSO)δ11.06(d，J＝31.4Hz，1H)，7.86(d，J＝19.3Hz，1H)，7.60(d，J＝7.8Hz，2H)，5.95(d，J＝8.9Hz，1H)，5.41(t，J＝5.7Hz，1H)，4.82-4.60(m，4H)，3.00-2.90(m，1H)，2.64(d，J＝17.9Hz，1H)，2.54(s，1H)，2.16-2.05(m，1H).LCMS(ESI)C14H15N2O3S+[M+H]+：计算值，291.08实测值，291.0。The target compound (GTC00505) (grey solid, 1 g, yield 38.91%) was prepared by referring to the method of Synthesis Scheme 5 or the method of Intermediate Example 1. 1 H NMR (400 MHz, DMSO) δ 11.06 (d, J = 31.4 Hz, 1H), 7.86 (d, J = 19.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 5.95 (d, J = 8.9 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.82-4.60 (m, 4H), 3.00-2.90 (m, 1H), 2.64 (d, J = 17.9 Hz, 1H), 2.54 (s, 1H), 2.16-2.05 (m, 1H). LCMS (ESI) C 14 H 15 N 2 O 3 S + [M+H] +: calculated, 291.08 found, 291.0.

中间体实施例4：(2-(2，6-二氧代哌啶-3-基)-1-硫代异吲哚啉-5-基)甲基甲磺酸酯(GTC00505)的制备

Figure PCTCN2024142598-ftappb-I100079
Intermediate Example 4: Preparation of (2-(2,6-dioxopiperidin-3-yl)-1-thioisoindolin-5-yl)methyl methanesulfonate (GTC00505)
Figure PCTCN2024142598-ftappb-I100079

参照合成方案5的方法或中间体实施例1的方法制备目标化合物(GTC00505)(灰色固体，1g，收率38.91％)。1HNMR(400MHz，DMSO)δ11.06(d，J＝31.4Hz，1H)，7.86(d，J＝19.3Hz，1H)，7.60(d，J＝7.8Hz，2H)，5.95(d，J＝8.9Hz，1H)，5.41(t，J＝5.7Hz，1H)，4.82-4.60(m，4H)，3.00-2.90(m，1H)，2.64(d，J＝17.9Hz，1H)，2.54(s，1H)，2.16-2.05(m，1H).LCMS(ESI)C14H15N2O3S+[M+H]+：计算值，291.08实测值，291.0。The target compound (GTC00505) (grey solid, 1 g, yield 38.91%) was prepared by referring to the method of Synthesis Scheme 5 or the method of Intermediate Example 1. 1 H NMR (400 MHz, DMSO) δ 11.06 (d, J = 31.4 Hz, 1H), 7.86 (d, J = 19.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 5.95 (d, J = 8.9 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.82-4.60 (m, 4H), 3.00-2.90 (m, 1H), 2.64 (d, J = 17.9 Hz, 1H), 2.54 (s, 1H), 2.16-2.05 (m, 1H). LCMS (ESI) C 14 H 15 N 2 O 3 S + [M+H] +: calculated, 291.08 found, 291.0.

实施例1：3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04329)的制备Example 1: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04329)

参照合成方案1的方法制备目标化合物(GT-04329)(白色固体，28mg，收率37％).1H NMR(400MHz，MeOD)δ7.82(d，J＝7.8Hz，1H)，7.74(s，1H)，7.62(d，J＝7.7Hz，1H)，7.61-7.50(m，4H)，7.32-7.29(m，4H)，7.25-7.22(m，2H)，5.08(dd，J＝13.3，5.2Hz，1H)，5.04-4.88(m，1H)，4.48-4.40(m，4H)，3.60-3.56(m，2H)，3.51-3.42(m，5H)，3.18-3.01(m，5H)，2.88-2.67(m，2H)，2.48-2.23(m，4H)，2.17-1.97(m，3H).LCMS(ESI)C36H42N5O3 +[M+H]+：计算值592.23，实测值592.3.The target compound (GT-04329) (white solid, 28 mg, yield 37%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ 7.82 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.61-7.50 (m, 4H), 7.32-7.29 (m, 4H), 7.25-7.22 (m, 2H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H) , 5.04-4.88 (m, 1H), 4.48-4.40 (m, 4H), 3.60-3.56 (m, 2H), 3.51-3.42 (m, 5H), 3.18-3.01 (m, 5H), 2.88-2.67 (m, 2H), 2.48-2.23 (m, 4H), 2.17-1.97 (m, 3H). LCMS (ESI) C 36 H 42 N 5 O 3 + [M+H] + : calculated value 592.23, found value 592.3.

实施例2：3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04330)的制备Example 2: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04330)

参照合成方案1的方法制备目标化合物(GT-04330)(白色固体，34mg，收率43％).1H NMR(400MHz，MeOD)δ7.76-7.70(m，1H)，7.66(d，J＝7.8Hz，1H)，7.58-7.55(m，4H)，7.33-7.29(m，4H)，7.25-7.22(m，2H)，5.08(dd，J＝13.3，5.2Hz，1H)，5.04-4.89(m，1H)，4.60-4.48(m，4H)，3.70-3.61(m，2H)，3.59-3.40(m，5H)，3.20-2.98(m，6H)，2.91-2.75(m，1H)，2.73-2.66(m，1H)，2.51-2.39(m，1H)，2.38-2.31(m，2H)，2.17-1.95(m，3H).LCMS(ESI)C36H41FN5O3 +[M+H]+：计算值610.32，实测值610.3.The target compound (GT-04330) (white solid, 34 mg, yield 43%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.76-7.70 (m, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.58-7.55 (m, 4H), 7.33-7.29 (m, 4H), 7.25-7.22 (m, 2H), 5.08 (dd, J=13.3, 5.2 Hz, 1H), 5.04-4.89 (m, 1H), 4.60-4 .48 (m, 4H), 3.70-3.61 (m, 2H), 3.59-3.40 (m, 5H), 3.20-2.98 (m, 6H), 2.91-2.75 (m, 1H), 2.73-2.66 (m, 1H), 2.51-2.39 (m, 1H), 2.38-2.31 (m, 2H), 2.17-1.95 (m, 3H). LCMS (ESI) C 36 H 41 FN 5 O 3 + [M+H] + : calculated value 610.32, found value 610.3.

实施例3：3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04331)的制备Example 3: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04331)

参照合成方案1的方法制备目标化合物(GT-04331)(白色固体，34mg，收率43％).1H NMR(400MHz，MeOD)δ7.82(d，J＝6.0Hz，1H)，7.65-7.50(m，5H)，7.35-7.29(m，4H)，7.25-7.22(m，2H)，5.08(dd，J＝13.3，5.2Hz，1H)，5.04-4.89(m，1H)，4.55-4.36(m，4H)，3.68-3.62(m，2H)，3.57-3.38(m，5H)，3.20-2.94(m，6H)，2.88-2.75(m，1H)，2.72-2.66(m，1H)，2.49-2.26(m，3H)，2.12-2.03(m，3H).LCMS(ESI)C36H41FN5O3 +[M+H]+：计算值610.32，实测值610.3.The target compound (GT-04331) (white solid, 34 mg, yield 43%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.82 (d, J=6.0 Hz, 1H), 7.65-7.50 (m, 5H), 7.35-7.29 (m, 4H), 7.25-7.22 (m, 2H), 5.08 (dd, J=13.3, 5.2 Hz, 1H), 5.04-4.89 (m, 1H), 4.55-4 .36 (m, 4H), 3.68-3.62 (m, 2H), 3.57-3.38 (m, 5H), 3.20-2.94 (m, 6H), 2.88-2.75 (m, 1H), 2.72-2.66 (m, 1H), 2.49-2.26 (m, 3H), 2.12-2.03 (m, 3H). LCMS (ESI) C 36 H 41 FN 5 O 3 + [M+H] + : calculated value 610.32, found value 610.3.

实施例4：3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04597)的制备Example 4: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04597)

参照合成方案1的方法制备目标化合物(GT-04597)(白色固体，39mg，收率45％).1H NMR(400MHz，MeOD)δ7.54(s，1H)，7.52-7.40(m，4H)，7.37(d，J＝9.6Hz，1H)，7.27(t，J＝6.9Hz，4H)，7.23-7.16(m，2H)，5.05(dd，J＝13.3，5.1Hz，1H)，4.71(s，2H)，4.48(q，J＝17.9Hz，2H)，4.39(s，2H)，3.60-3.54(m，2H)，3.41-3.23(m，5H)，3.14-3.06(m，3H)，3.01-2.92(m，1H)，2.89-2.76(m，2H)，2.69(d，J＝15.5Hz，1H)，2.48-2.36(m，1H)，2.36-2.22(m，2H)，2.16-1.88(m，3H).LCMS(ESI)C36H41FN5O3 +[M+H]+：计算值610.32，实测值610.3.The target compound (GT-04597) (white solid, 39 mg, yield 45%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, MeOD) δ7.54 (s, 1H), 7.52-7.40 (m, 4H), 7.37 (d, J = 9.6 Hz, 1H), 7.27 (t, J = 6.9 Hz, 4H), 7.23-7.16 (m, 2H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.71 (s, 2H), 4.48 (q, J = 17.9 Hz, 2H), 4.39 (s, 5H), 3.20-3.54 (m, 2H), 3.60-3.54 (m, 2H), 3.41-3.23 (m, 5H), 3.14-3.06 (m, 3H), 3.01-2.92 (m, 1H), 2.89-2.76 (m, 2H), 2.69 (d, J=15.5 Hz, 1H), 2.48-2.36 (m, 1H), 2.36-2.22 (m, 2H), 2.16-1.88 (m, 3H). LCMS (ESI) C 3 6 H 4 1 FN 5 O 3 + [M+H] + : calculated value 610.32, found value 610.3.

实施例5：3-(4-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04598)的制备Example 5: Preparation of 3-(4-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04598)

参照合成方案1的方法制备目标化合物(GT-04598)(白色固体，46mg，收率54％).1H NMR(400MHz，MeOD)δ7.97(d，J＝7.6Hz，1H)，7.90(d，J＝7.6Hz，1H)，7.72(t，J＝7.6Hz，1H)，7.63-7.52(m，4H)，7.41-7.37(m，4H)，7.34-7.21(m，2H)，5.24(dd，J＝13.4，5.1Hz，1H)，4.80(d，J＝17.4Hz，1H)，4.67(d，J＝17.4Hz，1H)，4.58-4.42(m，2H)，3.82-3.65(m，2H)，3.56-3.49(m，1H)，3.46-3.37(m，4H)，3.32-3.27(m，5H)，3.26-3.20(m，1H)，3.03-2.90(m，2H)，2.83(d，J＝15.8Hz，1H)，2.61-2.53(m，1H)，2.46-2.38(m，2H)，2.31-2.20(m，1H)，2.18-2.09(m，2H).LCMS(ESI)C36H42N5O3 +[M+H]+：计算值592.33，实测值592.3.The target compound (GT-04598) (white solid, 46 mg, yield 54%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.97 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.63-7.52 (m, 4H), 7.41-7.37 (m, 4H), 7.34-7.21 (m, 2H), 5.24 (dd, J = 13.4, 5.1 Hz, 1H), 4.80 (d, J = 17.4 Hz, 1H), 4.67 (d, J = 17.4 Hz, 1H), 4.58-4.42 (m, 2H), 3.82-3.65 (m, 2H), 3.56-3.49 (m, 1H), 3.46-3.37 (m, 4H), 3.32-3.27 (m, 5H), 3.26-3.20 (m, 1H), 3.03-2.90 (m, 2H), 2.83 (d, J=15.8 Hz, 1H), 2.61-2.53 (m, 1H), 2.46-2.38 (m, 2H), 2.31-2.20 (m, 1H), 2.18-2.09 (m, 2H). LCMS (ESI) C 36 H 42 N 5 O 3 + [M+H] + : calculated value 592.33, found value 592.3.

实施例6：3-(6-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04599)的制备Example 6: Preparation of 3-(6-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04599)

参照合成方案1的方法制备目标化合物(GT-04599)(白色固体，8mg，收率9％).1H NMR(400MHz，MeOD)δ7.98(s，1H)，7.87(d，J＝7.9Hz，1H)，7.77(d，J＝7.9Hz，1H)，7.63(d，J＝6.3Hz，4H)，7.40(t，J＝7.2Hz，4H)，7.34-7.32(m，2H)，5.19(dd，J＝13.3，5.1Hz，1H)，4.64-4.52(m，4H)，3.70-3.67(m，2H)，3.61-3.40(m，6H)，3.24-3.05(m，5H)，3.03-2.86(m，2H)，2.87-2.75(m，1H)，2.59-2.51(m，1H)，2.48-2.41(m，2H)，2.28-2.16(m，1H)，2.14-2.03(m，2H).LCMS(ESI)C36H42N5O3 +[M+H]+：计算值592.33，实测值592.3.The target compound (GT-04599) (white solid, 8 mg, yield 9%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, MeOD) δ7.98 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 6.3 Hz, 4H), 7.40 (t, J = 7.2 Hz, 4H), 7.34-7.32 (m, 2H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.64-4.52 (m, 4H), 3.70-3.67 (m, 2H), 3.61-3.40 (m, 6H), 3.24-3.05 (m, 5H), 3.03-2.86 (m, 2H), 2.87-2.75 (m, 1H), 2.59-2.51 (m, 1H), 2.48-2.41 (m, 2H), 2.28-2.16 (m, 1H), 2.14-2.03 (m, 2H). LCMS (ESI) C 36 H 42 N 5 O 3 + [M+H] + : calculated value 592.33, found value 592.3.

实施例7：3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04376)的制备Example 7: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04376)

参照合成方案1的方法制备目标化合物(GT-04376)(白色固体，31mg，收45％).1H NMR(400MHz，MeOD)δ7.82(d，J＝7.8Hz，1H)，7.69(s，1H)，7.60-7.58(m，5H)，7.40-7.37(m，4H)，7.34-7.30(m，2H)，5.36(s，1H)，5.08(dd，J＝13.3，5.2Hz，1H)，4.56-4.36(m，4H)，3.68-3.61(m，1H)，3.53-3.50(m，1H)，3.43-3.31(m，2H)，3.14-3.09(m，9H)，2.88-2.78(m，1H)，2.73-2.65(m，1H)，2.44-2.31(m，1H)，2.17-2.01(m，3H).LCMS(ESI)C36H40F2N5O3 +[M+H]+：计算值628.31，实测值628.3.The target compound (GT-04376) (white solid, 31 mg, yield 45%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.82 (d, J=7.8 Hz, 1H), 7.69 (s, 1H), 7.60-7.58 (m, 5H), 7.40-7.37 (m, 4H), 7.34-7.30 (m, 2H), 5.36 (s, 1H), 5.08 (dd, J=13.3, 5.2 Hz, 1H), 4.56-4.36 (m , 4H), 3.68-3.61 (m, 1H), 3.53-3.50 (m, 1H), 3.43-3.31 (m, 2H), 3.14-3.09 (m, 9H), 2.88-2.78 (m, 1H), 2.73-2.65 (m, 1H), 2.44-2.31 (m, 1H), 2.17-2.01 (m, 3H). LCMS (ESI) C 36 H 40 F 2 N 5 O 3 + [M+H] + : calculated value 628.31, found value 628.3.

实施例8：3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04377)的制备Example 8: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04377)

参照合成方案1的方法制备目标化合物(GT-04377)(白色固体，41mg，收58％).1H NMR(400MHz，MeOD)δ7.68-7.62(m，2H)，7.59-7.55(m，4H)，7.40-7.36(m，4H)，7.34-7.30(m，2H)，5.35(s，1H)，5.08(dd，J＝13.4，5.1Hz，1H)，4.62-4.44(m，3H)，4.36(brs，2H)，3.70-3.62(m，1H)，3.53-3.40(m，1H)，3.35-3.28(m，1H)，3.16-3.01(m，9H)，2.87-2.78(m，1H)，2.74-2.64(m，1H)，2.48-2.38(m，1H)，2.16-1.99(m，3H).LCMS(ESI)C36H39F3N5O3 +[M+H]+：计算值646.30，实测值646.3.The target compound (GT-04377) (white solid, 41 mg, yield 58%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.68-7.62 (m, 2H), 7.59-7.55 (m, 4H), 7.40-7.36 (m, 4H), 7.34-7.30 (m, 2H), 5.35 (s, 1H), 5.08 (dd, J=13.4, 5.1 Hz, 1H), 4.62-4.44 (m, 3H), 4.36 (brs, 3H), 3.70-3.62 (m, 1H), 3.53-3.40 (m, 1H), 3.35-3.28 (m, 1H), 3.16-3.01 (m, 9H), 2.87-2.78 (m, 1H), 2.74-2.64 (m, 1H), 2.48-2.38 (m, 1H), 2.16-1.99 (m, 3H). LCMS (ESI) C 36 H 39 F 3 N 5 O 3 + [M+H] + : calculated value 646.30, found value 646.3.

实施例9：3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04378)的制备Example 9: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04378)

参照合成方案1的方法制备目标化合物(GT-04378)(白色固体，40mg，收57％).1H NMR(400MHz，MeOD)δ7.74(d，J＝5.9Hz，1H)，7.60-7.58(m，4H)，7.54(d，J＝8.6Hz，1H)，7.40-7.36(m，4H)，7.35-7.29(m，2H)，5.35(s，1H)，5.12-5.03(m，1H)，4.53-4.39(m，2H)，4.36(brs，2H)，3.68-3.59(m，1H)，3.53-3.39(m，1H)，3.36-3.23(m，2H)，3.20-2.93(m，9H)，2.88-2.76(m，1H)，2.74-2.64(m，1H)，2.43-2.36(m，1H)，2.15-1.97(m，3H).LCMS(ESI)C36H39F3N5O3 +[M+H]+：计算值646.30，实测值646.3.The target compound (GT-04378) (white solid, 40 mg, yield 57%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.74 (d, J = 5.9 Hz, 1H), 7.60-7.58 (m, 4H), 7.54 (d, J = 8.6 Hz, 1H), 7.40-7.36 (m, 4H), 7.35-7.29 (m, 2H), 5.35 (s, 1H), 5.12-5.03 (m, 1H), 4.53-4.39 (m, 2H), 4. 36 (brs, 2H), 3.68-3.59 (m, 1H), 3.53-3.39 (m, 1H), 3.36-3.23 (m, 2H), 3.20-2.93 (m, 9H), 2.88-2.76 (m, 1H), 2.74-2.64 (m, 1H), 2.43-2.36 (m, 1H), 2.15-1.97 (m, 3H). LCMS (ESI) C 36 H 39 F 3 N 5 O 3 + [M+H] + : calculated value 646.30, found value 646.3.

实施例10：3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04379)的制备Example 10: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04379)

参照合成方案1的方法制备目标化合物(GT-04379)(白色固体，35mg，收50％).1H NMR(400MHz，MeOD)δ7.57(d，J＝7.4Hz，4H)，7.42-7.36(m，5H)，7.34-7.32(m，2H)，7.29-7.23(m，1H)，5.35(s，1H)，5.03(dd，J＝13.2，6.6Hz，1H)，4.53-4.34(m，2H)，4.16(brs，2H)，3.48-3.39(m，1H)，3.33-3.22(m，2H)，3.20-2.95(m，9H)，2.82-2.77(m，2H)，2.74-2.63(m，1H)，2.44-2.33(m，1H)，2.10-1.94(m，3H).LCMS(ESI)C36H39F3N5O3 +[M+H]+：计算值646.30，实测值646.3.The target compound (GT-04379) was prepared by referring to the method of synthesis scheme 1 (white solid, 35 mg, yield 50%). 1 H NMR (400 MHz, MeOD) δ7.57 (d, J = 7.4 Hz, 4H), 7.42-7.36 (m, 5H), 7.34-7.32 (m, 2H), 7.29-7.23 (m, 1H), 5.35 (s, 1H), 5.03 (dd, J = 13.2, 6.6 Hz, 1H), 4.53-4.34 (m, 2H) , 4.16 (brs, 2H), 3.48-3.39 (m, 1H), 3.33-3.22 (m, 2H), 3.20-2.95 (m, 9H), 2.82-2.77 (m, 2H), 2.74-2.63 (m, 1H), 2.44-2.33 (m, 1H), 2.10-1.94 (m, 3H). LCMS (ESI) C 36 H 39 F 3 N 5 O 3 + [M+H] + : calculated value 646.30, found value 646.3.

实施例11：3-(4-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04380)的制备Example 11: Preparation of 3-(4-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04380)

参照合成方案1的方法制备目标化合物(GT-04380)(白色固体，19mg，收28％).1H NMR(400MHz，MeOD)δ7.79-7.77(m，1H)，7.65(t，J＝7.0Hz，1H)，7.60-7.55(m，4H)，7.54-7.50(m，1H)，7.40-7.36(m，4H)，7.35-7.28(m，2H)，5.35(brs，1H)，5.18-5.04(m，1H)，4.68-4.47(m，2H)，4.31-4.03(m，2H)，3.52-3.43(m，1H)，3.41-3.25(m，2H)，3.20-2.94(m，9H)，2.94-2.75(m，2H)，2.72-2.68(m，1H)，2.51-2.29(m，1H)，2.19-2.06(m，1H)，2.06-1.90(m，2H).LCMS(ESI)C36H40F2N5O3 +[M+H]+：计算值628.31，实测值628.3.The target compound (GT-04380) (white solid, 19 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, MeOD) δ7.79-7.77 (m, 1H), 7.65 (t, J=7.0 Hz, 1H), 7.60-7.55 (m, 4H), 7.54-7.50 (m, 1H), 7.40-7.36 (m, 4H), 7.35-7.28 (m, 2H), 5.35 (brs, 1H), 5.18-5.04 (m, 1H), 4.68-4.47 (m, 3H), 4.31-4.03 (m, 2H), 3.52-3.43 (m, 1H), 3.41-3.25 (m, 2H), 3.20-2.94 (m, 9H), 2.94-2.75 (m, 2H), 2.72-2.68 (m, 1H), 2.51-2.29 (m, 1H), 2.19-2.06 (m, 1H), 2.06-1.90 (m, 2H). LCMS (ESI) C 36 H 40 F 2 N 5 O 3 + [M+H] + : calculated value 628.31, found value 628.3.

实施例12：3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-5037)的制备Example 12: Preparation of 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-5037)

参照合成方案1的方法制备目标化合物(GT-5037)(白色固体，49mg，收52％).1H NMR(400MHz，DMSO-d6)δ11.00(s，1H)，8.73(d，J＝4.8Hz，1H)，7.93-7.89(m，1H)，7.87-7.78(m，2H)，7.74-7.70(m，4H)，7.50-7.36(m，4H)，5.89(s，1H)，5.14(dd，J＝13.2，5.1Hz，1H)，4.52-4.36(m，4H)，3.63-3.52(m，4H)，3.47-3.23(m，4H)，3.21-3.12(m，4H)，2.98-2.82(m，2H)，2.61(d，J＝16.8Hz，1H)，2.43(dd，J＝13.2，4.5Hz，1H)，2.26-2.09(m，1H)，2.03-1.99(m，2H).LCMS(ESI)C35H39F2N6O3 +[M+H]+：计算值629.30，实测值629.3.The target compound (GT-5037) (white solid, 49 mg, yield 52%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ11.00 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 7.93-7.89 (m, 1H), 7.87-7.78 (m, 2H), 7.74-7.70 (m, 4H), 7.50-7.36 (m, 4H), 5.89 (s, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.52-4.36 (m, 4H), 3.63-3.52 (m, 4H), 3.47-3.23 (m, 4H), 3.21-3.12 (m, 4H), 2.98-2.82 (m, 2H), 2.61 (d, J=16.8 Hz, 1H), 2.43 (dd, J=13.2, 4.5 Hz, 1H), 2.26-2.09 (m, 1H), 2.03-1.99 (m, 2H) . LCMS (ESI ) C35H39F2N6O3 + [M+H] + : calculated value 629.30, found value 629.3.

实施例13：3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04595)的制备Example 13: Preparation of 3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04595)

参照合成方案1的方法制备目标化合物(GT-04595)(白色固体，16mg，收35％).1H NMR(400MHz，MeOD)δ7.91(d，J＝8.0Hz，1H)，7.71(s，1H)，7.64(d，J＝7.8Hz，1H)，7.36(d，J＝8.2Hz，2H)，7.28(d，J＝8.2Hz，2H)，5.20(dd，J＝13.4，5.0Hz，1H)，4.64-4.50(m，2H)，4.43-4.25(m，2H)，3.65-3.56(m，2H)，3.31-3.09(m，6H)，3.01-2.86(m，3H)，2.84-2.78(m，2H)，2.72-2.66(m，1H)，2.59-2.44(m，4H)，2.28-2.11(m，2H)，2.09-1.93(m，3H)，1.62-1.48(m，2H)，1.08(s，3H)，1.05(s，3H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound (GT-04595) (white solid, 16 mg, yield 35%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.91 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 5.20 (dd, J = 13.4, 5.0 Hz, 1H), 4.64-4.50 (m, 2H), 4.43-4.25 (m, 2H), 3.65-3. 56 (m, 2H), 3.31-3.09 (m, 6H), 3.01-2.86 (m, 3H), 2.84-2.78 (m, 2H), 2.72-2.66 (m, 1H), 2.59-2.44 (m, 4H), 2.28-2.11 (m, 2H), 2.09-1.93 (m, 3H), 1.62-1.48 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例14：3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04596)的制备Example 14: Preparation of 3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04596)

参照合成方案1的方法制备目标化合物(GT-04596)(白色固体，17mg，收37％).1H NMR(400MHz，MeOD)δ7.77-7.68(m，2H)，7.37(d，J＝8.4Hz，2H)，7.29(d，J＝8.5Hz，2H)，5.20(dd，J＝13.3，5.0Hz，1H)，4.63(q.J＝17.3Hz，2H)，4.33-4.21(m，2H)，3.66-3.56(m，2H)，3.47-3.39(m，3H)，3.29-3.18(m，2H)，3.07-2.88(m，3H)，2.85-2.78(m，3H)，2.70-2.42(m，4H)，2.29-2.14(m，2H)，2.04-1.95(m，4H)，1.57-1.52(m，2H)，1.08(s，3H)，1.05(s，3H).LCMS(ESI)C38H44ClF3N5O4 +[M+H]+：计算值726.30，实测值726.3.The target compound (GT-04596) (white solid, 17 mg, yield 37%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.77-7.68 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 5.20 (dd, J = 13.3, 5.0 Hz, 1H), 4.63 (qJ = 17.3 Hz, 2H), 4.33-4.21 (m, 2H), 3.66-3.56 (m, 2H), 3.47-3 .39 (m, 3H), 3.29-3.18 (m, 2H), 3.07-2.88 (m, 3H), 2.85-2.78 (m, 3H), 2.70-2.42 (m, 4H), 2.29-2.14 (m, 2H), 2.04-1.95 (m, 4H), 1.57-1.52 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H). LCMS (ESI) C 38 H 44 ClF 3 N 5 O 4 + [M+H] + : calculated value 726.30, found value 726.3.

实施例15：3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-05160)的制备Example 15: Preparation of 3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-05160)

参照合成方案1的方法制备目标化合物(GT-05160)(白色固体，50mg，收48％).1H NMR(400MHz，DMSO-d6)δ11.01(s，1H)，7.77(d，J＝7.8Hz，1H)，7.69-7.64(m，1H)，7.60-7.54(m，1H)，7.44(d，J＝8.3Hz，2H)，7.14(d，J＝8.3Hz，2H)，5.13(dd，J＝13.2，5.1Hz，1H)，4.48(d，J＝16.8Hz，1H)，4.35(d，J＝16.8Hz，1H)，4.15-3.87(m，1H)，3.55(brs，3H)，3.28-3.20(m，3H)，3.05-2.97(m，4H)，2.91-2.82(m，4H)，2.66-2.59(m，4H)，2.47-2.36(m，1H)，2.34-2.21(m，3H)，2.02(brs，3H)，1.96-1.84(m，1H)，1.83-1.73(m，1H)，1.44(m，2H)，0.96(s，6H).LCMS(ESI)C38H47ClF2N5O3 +[M+H]+：计算值694.33，实测值694.4.The target compound (GT-05160) (white solid, 50 mg, yield 48%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ11.01 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.48 (d, J = 16.8 Hz, 1H), 4.35 (d, J = 16.8 Hz, 1H), 4.15-3.8 7 (m, 1H), 3.55 (brs, 3H), 3.28-3.20 (m, 3H), 3.05-2.97 (m, 4H), 2.91-2.82 (m, 4H), 2.66-2.59 (m, 4H), 2.47-2.36 (m, 1H), 2.34-2.21 (m, 3H), 2.02 (brs, 3H), 1.96-1.84 (m, 1H), 1.83-1.73 (m, 1H), 1.44 (m, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 7 ClF 2 N 5 O 3 + [M+H] + : calculated value 694.33, found value 694.4.

实施例16：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04604)的制备Example 16: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04604)

参照合成方案1的方法制备目标化合物(GT-04604)(白色固体，29mg，收33％).1H NMR(400MHz，MeOD)δ7.94(d，J＝7.8Hz，1H)，7.84(s，1H)，7.73(d，J＝7.6Hz，1H)，7.34-7.30(m，2H)，7.17-7.15(m，1H)，5.19(dd，J＝13.7，4.9Hz，1H)，4.64-4.46(m，4H)，3.79-3.58(m，7H)，3.50-3.43(m，2H)，3.20-3.13(m，4H)，3.01-2.86(m，1H)，2.84-2.78(m，1H)，2.60-2.45(m，3H)，2.25-2.12(m，3H).LCMS(ESI)C29H34Cl2N5O3 +[M+H]+：计算值570.20，实测值570.2.The target compound (GT-04604) (white solid, 29 mg, yield 33%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.94 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.34-7.30 (m, 2H), 7.17-7.15 (m, 1H), 5.19 (dd, J = 13.7, 4.9 Hz, 1H), 4.64-4. 46 (m, 4H), 3.79-3.58 (m, 7H), 3.50-3.43 (m, 2H), 3.20-3.13 (m, 4H), 3.01-2.86 (m, 1H), 2.84-2.78 (m, 1H), 2.60-2.45 (m, 3H), 2.25-2.12 (m, 3H). LCMS (ESI) C 29 H 34 Cl 2 N 5 O 3 + [M+H] + : calculated value 570.20, found value 570.2.

实施例17：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04605)的制备Example 17: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04605)

参照合成方案1的方法制备目标化合物(GT-04605)(白色固体，30mg，收34％).1H NMR(400MHz，MeOD)δ7.82-7.77(m，2H)，7.35-7.27(m，2H)，7.18-7.16(m，1H)，5.19(dd，J＝13.4，5.2Hz，1H)，4.72-4.50(m，4H)，3.78-3.73(m，3H)，3.68-3.54(m，4H)，3.49-3.47(m，2H)，3.28-3.11(m，4H)，3.02-2.85(m，2H)，2.84-2.74(m，1H)，2.59-2.44(m，3H)，2.22-2.13(m，3H).LCMS(ESI)C29H33Cl2FN5O3 +[M+H]+：计算值588.19，实测值588.2.The target compound (GT-04605) (white solid, 30 mg, yield 34%) was prepared by referring to the method of synthesis scheme 1 . NMR (400MHz, MeOD) δ7.82-7.77(m, 2H), 7.35-7.27(m, 2H), 7.18-7.16(m, 1H), 5.19(dd, J=13.4, 5.2Hz, 1H), 4.72-4.50(m, 4H), 3.78-3.73(m, 3H), 3.68-3.54(m, 4H), 3.49-3.47(m, 2H), 3.28-3.11(m, 4H), 3.02-2.85(m, 2 H), 2.84-2.74(m, 1H), 2.59-2.44(m, 3H), 2.22-2.13(m, 3H).LCMS(ESI)C 29 H 33 Cl 2 FN 5 O 3 + [M+H] + : Calculated value 588.19, found value 588.2.

实施例18：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04606)的制备Example 18: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04606)

参照合成方案1的方法制备目标化合物(GT-04606)(白色固体，23mg，收26％).1H NMR(400MHz，MeOD)δ7.93(d，J＝6.1Hz，1H)，7.71(d，J＝8.6Hz，1H)，7.39-7.28(m，2H)，7.19(dd，J＝7.1，2.5Hz，1H)，5.20(dd，J＝13.3，5.1Hz，1H)，4.65-4.46(m，4H)，3.83-3.72(m，3H)，3.68-3.59(m，4H)，3.52-3.41(m，2H)，3.30-3.12(m，4H)，2.97-2.88(m，1H)，2.85-2.78(m，1H)，2.57-2.50(m，3H)，2.30-2.13(m，3H).LCMS(ESI)C29H33Cl2FN5O3 +[M+H]+：计算值588.19，实测值588.2.The target compound (GT-04606) was prepared by referring to the method of synthesis scheme 1 (white solid, 23 mg, yield 26%). 1 H NMR (400 MHz, MeOD) δ7.93 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.39-7.28 (m, 2H), 7.19 (dd, J = 7.1, 2.5 Hz, 1H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.65-4.46 (m, 4H), 3 .83-3.72 (m, 3H), 3.68-3.59 (m, 4H), 3.52-3.41 (m, 2H), 3.30-3.12 (m, 4H), 2.97-2.88 (m, 1H), 2.85-2.78 (m, 1H), 2.57-2.50 (m, 3H), 2.30-2.13 (m, 3H). LCMS (ESI) C 29 H 33 Cl 2 FN 5 O 3 + [M+H] + : calculated value 588.19, found value 588.2.

实施例19：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04607)的制备Example 19: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04607)

参照合成方案1的方法制备目标化合物(GT-04607)(白色固体，25mg，收28％).1H NMR(400MHz，MeOD)δ7.64(s，1H)，7.46(d，J＝9.6Hz，1H)，7.33-7.32(m，2H)，7.20-7.16(m，2H)，5.21-5.14(m，1H)，4.58(d，J＝8.2Hz，2H)，4.50-4.48(m，3H)，3.74-3.62(m，6H)，3.22-3.18(m，4H)，3.04-2.71(m，4H)，2.52-2.49(m，4H)，2.23-2.16(m，4H).LCMS(ESI)C29H33Cl2FN5O3 +[M+H]+：计算值588.19，实测值588.2.The target compound (GT-04607) (white solid, 25 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, MeOD) δ 7.64 (s, 1H), 7.46 (d, J = 9.6 Hz, 1H), 7.33-7.32 (m, 2H), 7.20-7.16 (m, 2H), 5.21-5.14 (m, 1H), 4.58 (d, J = 8.2 Hz, 2H), 4.50-4.48 (m, 3H), 3.74-3.62 (m, 6H), 3.22-3.18 (m, 4H), 3.04-2.71 (m, 4H), 2.52-2.49 (m, 4H), 2.23-2.16 (m, 4H). LCMS (ESI) C 29 H 33 Cl 2 FN 5 O 3 + [M+H] + : calculated value 588.19, found value 588.2.

实施例20：3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04609)的制备Example 20: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04609)

参照合成方案1的方法制备目标化合物(GT-04609)(白色固体，8mg，收10％).1H NMR(400MHz，MeOD)δ7.96(d，J＝7.7Hz，1H)，7.92(d，J＝7.7Hz，1H)，7.71(t，J＝7.7Hz，1H)，7.35-7.26(m，2H)，7.18-7.16(m，1H)，5.23(dd，J＝13.2，5.2Hz，1H)，4.68(d，J＝17.4Hz，1H)，4.52-4.49(m，2H)，3.84-3.66(m，5H)，3.59-3.57(m，2H)，3.46-3.32(m，5H)，3.24-3.18(m，2H)，3.03-2.89(m，1H)，2.84-2.81(m，1H)，2.60-2.47(m，3H)，2.38-2.16(m，3H).LCMS(ESI)C29H34Cl2N5O3 +[M+H]+：计算值570.20，实测值570.2.The target compound (GT-04609) (white solid, 8 mg, yield 10%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.96 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.35-7.26 (m, 2H), 7.18-7.16 (m, 1H), 5.23 (dd, J = 13.2, 5.2 Hz, 1H), 4.68 (d, J = 17.4 Hz, 1H), 4.70 (d, J = 20.9 Hz, 1H), 4.97 (d, J = 16.3 Hz, 1H), 4.10 (d, J = 21.9 Hz, 1H), 4.61 (d, J = 23.7 Hz, 1H), 4.59 (d, J = 24.8 Hz, 1H), 4.84 (d, J = 25.9 Hz, 1H), 4.60 (d, J = 26.8 Hz, 1H), 4.5 .52-4.49 (m, 2H), 3.84-3.66 (m, 5H), 3.59-3.57 (m, 2H), 3.46-3.32 (m, 5H), 3.24-3.18 (m, 2H), 3.03-2.89 (m, 1H), 2.84-2.81 (m, 1H), 2.60-2.47 (m, 3H), 2.38-2.16 (m, 3H). LCMS (ESI) C 29 H 34 Cl 2 N 5 O 3 + [M+H] + : calculated value 570.20, found value 570.2.

实施例21：3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04608)的制备Example 21: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04608)

参照合成方案1的方法制备目标化合物(GT-04608)(白色固体，5mg，收6％).1H NMR(400MHz，MeOD)δ7.89(s，1H)，7.73(d，J＝7.3Hz，1H)，7.66(d，J＝8.1Hz，1H)，7.24-7.20(m，2H)，7.08(dd，J＝6.4，2.9Hz，1H)，5.08(dd，J＝13.3，5.2Hz，1H)，4.47(dd，J＝31.5，17.7Hz，2H)，4.38-4.32(m，2H)，3.61-3.50(m，2H)，3.48-3.25(m，8H)，3.06-2.91(m，3H)，2.83-2.78(m，1H)，2.74-2.65(m，1H)，2.46-2.39(m，1H)，2.38-2.33(m，2H)，2.11-2.07(m，1H)，2.04-1.90(m，2H).LCMS(ESI)C29H34Cl2N5O3 +[M+H]+：计算值570.20，实测值570.2.The target compound (GT-04608) (white solid, 5 mg, yield 6%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, MeOD) δ7.89 (s, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.24-7.20 (m, 2H), 7.08 (dd, J = 6.4, 2.9 Hz, 1H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 4.47 (dd, J = 31.5, 17.7 Hz, 2H), 4.38-4 .32 (m, 2H), 3.61-3.50 (m, 2H), 3.48-3.25 (m, 8H), 3.06-2.91 (m, 3H), 2.83-2.78 (m, 1H), 2.74-2.65 (m, 1H), 2.46-2.39 (m, 1H), 2.38-2.33 (m, 2H), 2.11-2.07 (m, 1H), 2.04-1.90 (m, 2H). LCMS (ESI) C 29 H 34 Cl 2 N 5 O 3 + [M+H] + : calculated value 570.20, found value 570.2.

实施例22：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-05212)的制备Example 22: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-05212)

参照合成方案1的方法制备目标化合物(GT-05212)(白色固体，23mg，25％).1H NMR(400MHz，DMSO-d6)δ11.02(s，1H)，7.79(d，J＝7.7Hz，1H)，7.75-7.69(m，2H)，7.66-7.58(m，1H)，7.39-7.33(m，2H)，7.18-7.16(m，1H)，5.14(dd，J＝13.1，5.2Hz，1H)，4.90(s，1H)，4.51(d，J＝17.2Hz，1H)，4.38(d，J＝17.2Hz，1H)，4.27-4.06(m，2H)，3.35-3.08(m，10H)，3.00-2.84(m，2H)，2.82-2.65(m，1H)，2.61(d，J＝16.9Hz，1H)，2.47-2.38(m，1H)，2.33-2.30(m，1H)，2.25-2.09(m，1H)，2.08-1.95(m，1H).LCMS(ESI)C29H32Cl2F2N5O3 +[M+H]+：计算值606.18，实测值606.2.The target compound (GT-05212) (white solid, 23 mg, 25%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ11.02 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.75-7.69 (m, 2H), 7.66-7.58 (m, 1H), 7.39-7.33 (m, 2H), 7.18-7.16 (m, 1H), 5.14 (dd, J=13.1, 5.2 Hz, 1H), 4.90 (s, 1H), 4.51 (d, J=17.2 Hz, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.27-4.06 (m, 2H), 3.35-3.08 (m, 10H), 3.00-2.84 (m, 2H), 2.82-2.65 (m, 1H), 2.61 (d, J = 16.9 Hz, 1H), 2.47-2.38 (m, 1H), 2.33-2.30 (m, 1H), 2.25-2.09 (m, 1H), 2.08-1.95 (m, 1H ) . LCMS (ESI) C29H32Cl2F2N5O3 + [ M+H] + : calculated value 606.18, found value 606.2 .

实施例23：3-(5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04989)的制备Example 23: Preparation of 3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04989)

参照合成方案1的方法制备目标化合物(GT-04989)(白色固体，14mg，17％).1H NMR(400MHz，DMSO-d6)δ11.52(s，1H)，11.02(s，1H)，8.10(dd，J＝8.9，5.2Hz，1H)，7.87-7.81(m，2H)，7.74-7.71(m，1H)，7.61(dd，J＝9.1，2.1Hz，1H)，7.28-7.23(m，1H)，5.15(dd，J＝13.4，5.1Hz，1H)，4.63-4.33(m，5H)，4.24-4.01(m，2H)，3.69-3.39(m，8H)，3.08-3.04(m，1H)，3.04-2.85(m，3H)，2.61(d，J＝15.4Hz，1H)，2.47-2.41(m，1H)，2.39-2.32(m，2H)，2.28-2.09(m，2H)，2.03-1.98(m，1H).LCMS(ESI)C30H34FN6O4 +[M+H]+：计算值561.26，实测值561.3.The target compound (GT-04989) (white solid, 14 mg, 17%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 11.02 (s, 1H), 8.10 (dd, J = 8.9, 5.2 Hz, 1H), 7.87-7.81 (m, 2H), 7.74-7.71 (m, 1H), 7.61 (dd, J = 9.1, 2.1 Hz, 1H), 7.28-7.23 (m, 1H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.63 -4.33 (m, 5H), 4.24-4.01 (m, 2H), 3.69-3.39 (m, 8H), 3.08-3.04 (m, 1H), 3.04-2.85 (m, 3H), 2.61 (d, J=15.4 Hz, 1H), 2.47-2.41 (m, 1H), 2.39-2.32 (m, 2H), 2.28-2.09 (m, 2H), 2.03-1.98 (m, 1H). LCMS (ESI) C 30 H 34 FN 6 O 4 + [M+H] + : calculated value 561.26, found value 561.3.

实施例24：3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04931)的制备Example 24: Preparation of 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04931)

参照合成方案1的方法制备目标化合物(GT-04931)(白色固体，23mg，26％).1H NMR(400MHz，DMSO)δ11.01(s，1H)，8.05(dd，J＝8.9，5.2Hz，1H)，7.79(d，J＝7.5Hz，1H)，7.70(dd，J＝16.6，7.1Hz，1H)，7.62-7.56(m，2H)，7.21(td，J＝9.1，2.1Hz，1H)，5.14(dd，J＝13.2，5.1Hz，1H)，4.50(d，J＝17.0Hz，1H)，4.37(d，J＝17.2Hz，1H)，4.14(dd，J＝48.4，14.3Hz，1H)，3.83-3.57(m，6H)，3.36-2.99(m，6H)，2.99-2.84(m，2H)，2.61(d，J＝16.6Hz，1H)，2.42(dd，J＝13.3，4.5Hz，2H)，2.25-1.93(m，3H).LCMS(ESI)C30H32F3N6O4 +[M+H]+：计算值597.24，实测值597.3.The target compound (GT-04931) (white solid, 23 mg, 26%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ11.01 (s, 1H), 8.05 (dd, J=8.9, 5.2 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.70 (dd, J=16.6, 7.1 Hz, 1H), 7.62-7.56 (m, 2H), 7.21 (td, J=9.1, 2.1 Hz, 1H), 5.14 (dd, J=13.2, 5.1 Hz, 1H), 4.50 (d, J=17 .0 Hz, 1H), 4.37 (d, J = 17.2 Hz, 1H), 4.14 (dd, J = 48.4, 14.3 Hz, 1H), 3.83-3.57 (m, 6H), 3.36-2.99 (m, 6H), 2.99-2.84 (m, 2H), 2.61 (d, J = 16.6 Hz, 1H), 2.42 (dd, J = 13.3, 4.5 Hz, 2H), 2.25-1.93 (m, 3H). LCMS (ESI) C 30 H 32 F 3 N 6 O 4 + [M+H] + : calculated value 597.24, found value 597.3.

实施例25：3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-04932)的制备Example 25: Preparation of 3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-04932)

参照合成方案1的方法制备目标化合物(GT-04932)(白色固体，32mg，36％).1H NMR(400MHz，DMSO)δ11.00(s，1H)，8.25(s，1H)，7.80-7.69(m，2H)，7.63(s，1H)，7.54(d，J＝7.6Hz，1H)，7.34(td，J＝9.1，2.1Hz，1H)，5.13(dd，J＝13.2，5.0Hz，1H)，4.49(d，J＝17.4Hz，1H)，4.36(d，J＝17.5Hz，1H)，4.21-4.04(m，1H)，3.99-3.90(m，4H)，3.64-3.50(m，3H)，3.48-3.35(m，3H)，3.22-3.10(m，1H)，3.00-2.85(m，1H)，2.85-2.67(m，1H)，2.61(d，J＝16.8Hz，2H)，2.47-2.31(m，3H)，2.26-2.14(m，3H)，2.07-1.92(m，1H).LCMS(ESI)C31H33F3N5O4 +[M+H]+：计算值596.25，实测值596.3.The target compound (GT-04932) (white solid, 32 mg, 36%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.25 (s, 1H), 7.80-7.69 (m, 2H), 7.63 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.34 (td, J = 9.1, 2.1 Hz, 1H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4.36 (d, J = 17.5 Hz, 1H), 4.21-4. 04 (m, 1H), 3.99-3.90 (m, 4H), 3.64-3.50 (m, 3H), 3.48-3.35 (m, 3H), 3.22-3.10 (m, 1H), 3.00-2.85 (m, 1H), 2.85-2.67 (m, 1H), 2.61 (d, J=16.8 Hz, 2H), 2.47-2.31 (m, 3H), 2.26-2.14 (m, 3H), 2.07-1.92 (m, 1H). LCMS (ESI) C 31 H 33 F 3 N 5 O 4 + [M+H] + : calculated value 596.25, found value 596.3.

实施例26：3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-05105)的制备Example 26: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-05105)

参照合成方案1的方法制备目标化合物(GT-05105)(白色固体，12mg，10％).1H NMR(400MHz，DMSO-d6)δ11.14(s，1H)，7.91(d，J＝7.7Hz，1H)，7.88-7.79(m，4H)，7.60(s，1H)，7.49(d，J＝8.3Hz，1H)，7.47-7.43(m，4H)，7.41-7.34(m，2H)，6.05-5.86(m，2H)，5.62-5.59(m，1H)，4.80(d，J＝9.3Hz，1H)，4.70(t，J＝10.3Hz，1H)，3.21-3.08(m，6H)，3.08-2.89(m，8H)，2.65(d，J＝17.9Hz，2H)，2.12-2.06(m，2H)，1.97-1.74(m，2H).LCMS(ESI)C36H40F2N5O2S+[M+H]+：计算值644.29，实测值644.3.The target compound (GT-05105) (white solid, 12 mg, 10%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.88-7.79 (m, 4H), 7.60 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.47-7.43 (m, 4H), 7.41-7.34 (m, 2H), 6.05-5.86 (m, 2H), 5. 62-5.59 (m, 1H), 4.80 (d, J = 9.3 Hz, 1H), 4.70 (t, J = 10.3 Hz, 1H), 3.21-3.08 (m, 6H), 3.08-2.89 (m, 8H), 2.65 (d, J = 17.9 Hz, 2H), 2.12-2.06 (m, 2H), 1.97-1.74 (m, 2H). LCMS (ESI) C 36 H 40 F 2 N 5 O 2 S + [M+H] + : calculated value 644.29, found value 644.3.

实施例27：3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-05208)的制备Example 27: Preparation of 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-05208)

参照合成方案1的方法制备目标化合物(GT-05208)(白色固体，20mg，17％).1H NMR(400MHz，DMSO-d6)δ11.15(s，1H)，8.74(d，J＝4.7Hz，1H)，7.95-7.91(m，2H)，7.84-7.81(m，1H)，7.72-7.67(m，3H)，7.63(d，J＝7.9Hz，1H)，7.53-7.36(m，4H)，6.04-5.85(m，1H)，4.94-4.81(m，1H)，4.75-4.70(m，1H)，4.48-4.15(m，2H)，3.36-3.19(m，5H)，3.11-3.03(m，8H)，2.98-2.80(m，2H)，2.68-2.63(m，1H)，2.18-1.88(m，3H)，1.32(t，J＝6.5Hz，1H).LCMS(ESI)C35H39F2N6O2S+[M+H]+：计算值645.28，实测值645.3.The target compound (GT-05208) (white solid, 20 mg, 17%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ11.15 (s, 1H), 8.74 (d, J=4.7 Hz, 1H), 7.95-7.91 (m, 2H), 7.84-7.81 (m, 1H), 7.72-7.67 (m, 3H), 7.63 (d, J=7.9 Hz, 1H), 7.53-7.36 (m, 4H), 6.04-5.85 (m, 1H), 4.9 4-4.81 (m, 1H), 4.75-4.70 (m, 1H), 4.48-4.15 (m, 2H), 3.36-3.19 (m, 5H), 3.11-3.03 (m, 8H), 2.98-2.80 (m, 2H), 2.68-2.63 (m, 1H), 2.18-1.88 (m, 3H), 1.32 (t, J=6.5 Hz, 1H). LCMS (ESI) C 35 H 39 F 2 N 6 O 2 S + [M+H] + : calculated value 645.28, found value 645.3.

实施例28：3-(6-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-05042)的制备Example 28: Preparation of 3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-05042)

参照合成方案1的方法制备目标化合物(GT-05042)(白色固体，11mg，9％).1H NMR(400MHz，DMSO-d6)δ11.15(s，1H)，8.74(d，J＝4.6Hz，1H)，7.87-7.82(m，2H)，7.71-7.67(m，4H)，7.67-7.62(m，1H)，7.49-7.43(m，4H)，5.95-5.86(m，1H)，4.90-4.85(m，1H)，4.73-4.62(m，1H)，4.48-4.34(m，2H)，3.16-3.05(m，6H)，2.98-2.82(m，4H)，2.66(d，J＝16.7Hz，2H)，2.15-1.96(m，5H)，1.34-1.31(m，4H).LCMS(ESI)C35H39F2N6O2S+[M+H]+：计算值645.28，实测值645.3.The target compound (GT-05042) (white solid, 11 mg, 9%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.74 (d, J = 4.6 Hz, 1H), 7.87-7.82 (m, 2H), 7.71-7.67 (m, 4H), 7.67-7.62 (m, 1H), 7.49-7.43 (m, 4H), 5.95-5.86 (m, 1H), 4.90- 4.85 (m, 1H), 4.73-4.62 (m, 1H), 4.48-4.34 (m, 2H), 3.16-3.05 (m, 6H), 2.98-2.82 (m, 4H), 2.66 (d, J=16.7 Hz, 2H), 2.15-1.96 (m, 5H), 1.34-1.31 (m, 4H). LCMS (ESI) C 35 H 39 F 2 N 6 O 2 S + [M+H] + : calculated value 645.28, found value 645.3.

实施例29：1-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-04941)的制备Example 29: Preparation of 1-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-04941)

参照合成方案1的方法制备目标化合物(GT-04941)(白色固体，15mg，18％).1H NMR(400MHz，DMSO)δ10.69(s，1H)，7.91-7.82(m，2H)，7.75(d，J＝7.4Hz，1H)，7.53-7.43(m，4H)，7.38-7.31(m，4H)，7.27-7.21(m，2H)，4.80(d，J＝17.0Hz，1H)，4.57(d，J＝15.6Hz，1H)，4.42(brs，2H)，3.79(t，J＝7.0Hz，2H)，3.67-3.47(m，7H)，3.14-3.06(m，2H)，3.03-2.73(m，7H)，2.33-2.22(m，2H)，2.17-2.06(m，2H).LCMS(ESI)C35H41N6O3 +[M+H]+：计算值593.32，实测值593.3.The target compound (GT-04941) (white solid, 15 mg, 18%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 7.91-7.82 (m, 2H), 7.75 (d, J = 7.4 Hz, 1H), 7.53-7.43 (m, 4H), 7.38-7.31 (m, 4H), 7.27-7.21 (m, 2H), 4.80 (d, J = 17.0 Hz, 1H), 4.57 ( d, J = 15.6 Hz, 1H), 4.42 (brs, 2H), 3.79 (t, J = 7.0 Hz, 2H), 3.67-3.47 (m, 7H), 3.14-3.06 (m, 2H), 3.03-2.73 (m, 7H), 2.33-2.22 (m, 2H), 2.17-2.06 (m, 2H). LCMS (ESI) C 35 H 41 N 6 O 3 + [M+H] + : calculated value 593.32, found value 593.3.

实施例30：5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-05255)的制备Example 30: Preparation of 5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-05255)

参照合成方案1的方法制备目标化合物(GT-05255)(白色固体，34mg，37％).1H NMR(400MHz，DMSO-d6)δ10.93(s，1H)，8.15-8.10(m，1H)，7.65-7.44(m，4H)，7.40-7.31(m，5H)，7.31-7.14(m，3H)，4.52-4.41(m，2H)，3.82(t，J＝6.7Hz，1H)，3.63-3.48(m，4H)，3.27-3.13(m，4H)，3.06-2.94(m，3H)，2.90-2.83(m，4H)，2.35-2.22(m，3H)，2.14-2.04(m，2H)，1.96-1.85(m，1H).LCMS(ESI)C35H39N6O4 +[M+H]+：计算值607.30，实测值607.3.The target compound (GT-05255) (white solid, 34 mg, 37%) was prepared by referring to the method of Synthesis Scheme 1 . NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 8.15-8.10 (m, 1H), 7.65-7.44 (m, 4H) ,7.40-7.31(m,5H),7.31-7.14(m,3H),4.52-4.41(m,2H),3.82(t,J＝6.7Hz , 1H), 3.63-3.48(m, 4H), 3.27-3.13(m, 4H), 3.06-2.94(m, 3H), 2.90-2.83( m, 4H), 2.35-2.22 (m, 3H), 2.14-2.04 (m, 2H), 1.96-1.85 (m, 1H). LCMS (ESI) C 35 H 39 N 6 O 4 + [M+H] + : calculated value 607.30, found value 607.3.

实施例31：1-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-04942)的制备Example 31: Preparation of 1-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-04942)

参照合成方案1的方法制备目标化合物(GT-04942)(白色固体，22mg，24％).1H NMR(400MHz，DMSO)δ10.67(s，1H)，7.92-7.76(m，5H)，7.74-7.63(m，1H)，7.63-7.52(m，1H)，7.45-7.42(m，4H)，7.40-7.31(m，2H)，5.59(d，J＝9.0Hz，1H)，4.77(d，J＝16.4Hz，1H)，4.55(d，J＝16.1Hz，1H)，3.80-3.76(m，3H)，3.28-3.19(m，4H)，3.14-3.10(m，3H)，3.05-2.96(m，5H)，2.93-2.81(m，2H)，2.78-2.72(m，2H)，1.99-1.81(m，2H).LCMS(ESI)C35H39F2N6O3 +[M+H]+：计算值629.30，实测值629.3.The target compound (GT-04942) (white solid, 22 mg, 24%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ10.67 (s, 1H), 7.92-7.76 (m, 5H), 7.74-7.63 (m, 1H), 7.63-7.52 (m, 1H), 7.45-7.42 (m, 4H), 7.40-7.31 (m, 2H), 5.59 (d, J=9.0 Hz, 1H), 4.77 (d, J=16.4 Hz, 1 3H), 4.55 (d, J=16.1 Hz, 1H), 3.80-3.76 (m, 3H), 3.28-3.19 (m, 4H), 3.14-3.10 (m, 3H), 3.05-2.96 (m, 5H), 2.93-2.81 (m, 2H), 2.78-2.72 (m, 2H), 1.99-1.81 (m, 2H). LCMS (ESI) C 35 H 39 F 2 N 6 O 3 + [M+H] + : calculated value 629.30, found value 629.3.

实施例32：5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-05256)的制备Example 32: Preparation of 5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-05256)

参照合成方案1的方法制备目标化合物(GT-05256)(白色固体，22mg，23％).1H NMR(400MHz，DMSO-d6)δ10.91(s，1H)，8.08-8.00(m，2H)，7.98-7.95(m，1H)，7.90-7.79(m，4H)，7.44(t，J＝7.4Hz，4H)，7.38-7.35(m，2H)，5.59(brs，1H)，4.20-4.04(m，2H)，3.65-3.61(m，4H)，3.27-3.17(m，4H)，3.18-3.08(m，4H)，3.06-2.98(m，5H)，2.02-1.78(m，2H).LCMS(ESI)C35H37F2N6O4 +[M+H]+：计算值643.28，实测值643.3.The target compound (GT-05256) (white solid, 22 mg, 23%) was prepared by referring to the method of Synthesis Scheme 1 . NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 8.08-8.00 (m, 2H), 7.98-7.95 (m, 1H), 7.90-7.79 (m, 4H), 7.44 (t, J=7.4Hz, 4H), 7.38-7.35 (m, 2H), 5. 59(brs, 1H), 4.20-4.04(m, 2H), 3.65-3.61(m, 4H), 3.27-3.17(m, 4H), 3.18-3.08(m, 4H), 3.06-2.98(m, 5H), 2.02-1.78(m, 2H).LCMS(ESI)C 35 H 37 F 2 N 6 O 4 + [M+H] + : Calculated value 643.28, measured value 643.3.

实施例33：1-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-05082)的制备Example 33: Preparation of 1-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-05082)

参照合成方案1的方法制备目标化合物(GT-05082)(白色固体，80mg，71％).1H NMR(400MHz，DMSO-d6)δ10.69(s，1H)，8.74(d，J＝4.8Hz，1H)，7.94-7.89(m，1H)，7.85-7.80(m，2H)，7.76-7.61(m，4H)，7.44-7.40(m，4H)，5.87(s，1H)，4.80(d，J＝16.7Hz，1H)，4.57(d，J＝16.5Hz，1H)，4.31(brs，2H)，3.80-3.77(m，4H)，3.23-3.10(m，4H)，3.10-2.97(m，6H)，2.88-2.81(m，2H)，2.79-2.73(m，1H)，2.19-1.90(m，2H).LCMS(ESI)C34H38F2N7O3 +[M+H]+：计算值630.30，实测值630.3.The target compound (GT-05082) (white solid, 80 mg, 71%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.94-7.89 (m, 1H), 7.85-7.80 (m, 2H), 7.76-7.61 (m, 4H), 7.44-7.40 (m, 4H), 5.87 (s, 1H), 4.80 (d, J = 16.7 Hz, 1H), 4.57 (d, J=16.5 Hz, 1H), 4.31 (brs, 2H), 3.80-3.77 (m, 4H), 3.23-3.10 (m, 4H), 3.10-2.97 (m, 6H), 2.88-2.81 (m, 2H), 2.79-2.73 (m, 1H), 2.19-1.90 (m, 2H). LCMS (ESI) C 34 H 38 F 2 N 7 O 3 + [M+H] + : calculated value 630.30, found value 630.3.

实施例34：5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-05257)的制备Example 34: Preparation of 5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-05257)

参照合成方案1的方法制备目标化合物(GT-05257)(白色固体，13mg，13％).1H NMR(400MHz，DMSO-d6)δ10.92(s，1H)，8.74(d，J＝4.7Hz，1H)，8.06(s，1H)，7.92(t，J＝7.5Hz，1H)，7.76-7.61(m，4H)，7.49-7.40(m，5H)，5.86(s，1H)，4.30(s，2H)，3.80-3.75(m，4H)，3.19-3.00(m，13H)，2.09-1.93(m，2H).LCMS(ESI)C34H36F2N7O4 +[M+H]+：计算值644.28，实测值644.3.The target compound (GT-05257) (white solid, 13 mg, 13%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.74 (d, J = 4.7 Hz, 1H), 8.06 (s, 1H), 7.92 (t, J = 7.5 Hz, 1H), 7.76-7.61 (m, 4H), 7.49-7.40 (m, 5H), 5.86 (s, 1H), 4.30 (s, 2H), 3.80-3.75 (m, 4H), 3.19-3.00 (m, 13H), 2.09-1.93 (m, 2H). LCMS (ESI) C 34 H 36 F 2 N 7 O 4 + [M+H] + : Calculated value 644.28, measured value 644.3.

实施例35：1-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-05335)的制备Example 35: Preparation of 1-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-05335)

参照合成方案1的方法制备目标化合物(GT-05335)(白色固体，25mg，23％).1H NMR(400MHz，DMSO-d6)δ10.68(s，1H)，7.82(d，J＝7.7Hz，1H)，7.69(s，1H)，7.60(s，1H)，7.38(d，J＝8.5Hz，2H)，7.25(d，J＝8.4Hz，2H)，4.78(d，J＝17.1Hz，1H)，4.56(d，J＝16.9Hz，1H)，4.36-3.92(m，2H)，3.78(t，J＝6.1Hz，3H)，3.25-3.17(m，7H)，3.07-2.95(m，2H)，2.94-2.82(m，2H)，2.79-2.73(m，2H)，2.44-2.33(m，3H)，2.18-2.00(m，1H)，1.96-1.89(m，2H)，1.83-1.72(m，2H)，1.50-1.34(m，2H)，1.00(s，3H)，0.97(s，3H).LCMS(ESI)C37H44F2N6O4 +[M+H]+：计算值709.31，实测值709.3.The target compound (GT-05335) (white solid, 25 mg, 23%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.78 (d, J = 17.1 Hz, 1H), 4.56 (d, J = 16.9 Hz, 1H), 4.36-3.92 (m, 2H), 3.78 (t, J = 6.1 Hz , 3H), 3.25-3.17 (m, 7H), 3.07-2.95 (m, 2H), 2.94-2.82 (m, 2H), 2.79-2.73 (m, 2H), 2.44-2.33 (m, 3H), 2.18-2.00 (m, 1H), 1.96-1.89 (m, 2H), 1.83-1.72 (m, 2H), 1.50-1.34 (m, 2H), 1.00 (s, 3H), 0.97 (s, 3H). LCMS (ESI) C 37 H 44 F 2 N 6 O 4 + [M+H] + : calculated value 709.31, found value 709.3.

实施例36：5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-05271)的制备Example 36: Preparation of 5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-05271)

参照合成方案1的方法制备目标化合物(GT-05271)(白色固体，20mg，19％).1H NMR(400MHz，DMSO-d6)δ10.92(s，1H)，8.08-8.01(m，2H)，7.93-7.90(m，1H)，7.39(d，J＝8.4Hz，2H)，7.25(d，J＝8.4Hz，2H)，4.12-3.96(m，3H)，3.33-3.13(m，9H)，3.12-2.96(m，4H)，2.69-2.57(m，2H)，2.42-2.37(m，3H)，2.19-2.04(m，1H)，1.90(d，J＝16.6Hz，1H)，1.82-1.70(m，3H)，1.50-1.35(m，2H)，1.00(s，3H)，0.97(s，3H).LCMS(ESI)C37H42ClF2N6O5 +[M+H]+：计算值723.29，实测值723.3.The target compound (GT-05271) (white solid, 20 mg, 19%) was prepared by referring to the method of synthesis scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.08-8.01 (m, 2H), 7.93-7.90 (m, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.12-3.96 (m, 3H), 3.33-3.13 (m, 9H), 3.12-2. 96 (m, 4H), 2.69-2.57 (m, 2H), 2.42-2.37 (m, 3H), 2.19-2.04 (m, 1H), 1.90 (d, J=16.6 Hz, 1H), 1.82-1.70 (m, 3H), 1.50-1.35 (m, 2H), 1.00 (s, 3H), 0.97 (s, 3H). LCMS (ESI) C 3 7 H 4 2 ClF 2 N 6 O 5 + [M+H] + : calculated value 723.29, found value 723.3.

实施例37：5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-05270)的制备Example 37: Preparation of 5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-05270)

参照合成方案1的方法制备目标化合物(GT-05270)(白色固体，26mg，25％).1H NMR(400MHz，DMSO-d6)δ10.92(s，1H)，8.04-8.00(m，2H)，7.98-7.90(m，1H)，7.45(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，4.99(s，1H)，3.82(t，J＝6.7Hz，4H)，3.27-3.19(m，6H)，3.12-2.96(m，6H)，2.86(t，J＝6.7Hz，4H)，2.70-2.57(m，3H)，2.29(brs，2H)，2.04(brs，2H)，1.47(t，J＝6.8Hz，2H)，0.96(s，6H).LCMS(ESI)C37H44ClF2N6O4 +[M+H]+：计算值709.31，实测值709.3.The target compound (GT-05270) (white solid, 26 mg, 25%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.04-8.00 (m, 2H), 7.98-7.90 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.99 (s, 1H), 3.82 (t, J = 6.7 Hz, 4H), 3.27-3.19 (m, 6H), 3.12-2.96 (m, 6H), 2.86 (t, J = 6.7 Hz, 4H), 2.70-2.57 (m, 3H), 2.29 (brs, 2H), 2.04 (brs, 2H), 1.47 (t, J = 6.8 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 7 H 4 4 ClF 2 N 6 O 4 + [M+H] + : calculated value 709.31, found value 709.3.

实施例38：5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-05258)的制备Example 38: Preparation of 5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-05258)

参照合成方案1的方法制备目标化合物(GT-05258)(白色固体，16mg，17％).1H NMR(400MHz，DMSO-d6)δ10.92(s，1H)，8.02(s，2H)，7.94-7.92(m，1H)，7.36-7.32(m，2H)，7.20-7.17(m，1H)，4.99(s，1H)，4.11-3.91(m，2H)，3.36-3.17(m，13H)，3.13-3.01(m，3H)，2.28-2.18(m，1H)，2.09-1.89(m，1H).LCMS(ESI)C28H29Cl2F2N6O4 +[M+H]+：计算值621.16，实测值621.2.The target compound (GT-05258) (white solid, 16 mg, 17%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.02 (s, 2H), 7.94-7.92 (m, 1H), 7.36-7.32 (m, 2H), 7.20-7.17 (m, 1H), 4.99 (s, 1H), 4.11-3.91 (m, 2H), 3.36-3.17 (m, 13H), 3.13-3.01 (m, 3H), 2.28-2.18 (m, 1H), 2.09-1.89 (m, 1H). LCMS (ESI) C 28 H 29 Cl 2 F 2 N 6 O 4 + [M+H] + : Calculated value 621.16, measured value 621.2.

实施例39：3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-05333)的制备Example 39: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-05333)

参照合成方案1的方法制备目标化合物GT-05333(26mg，白色固体，收率24％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，7.77(dd，J＝7.9，1.7Hz，1H)，7.68(d，J＝8.9Hz，1H)，7.63-7.58(m，2H)，7.38(t，J＝7.9Hz，1H)，7.26(dd，J＝7.6，1.3Hz，1H)，5.75(s，1H)，5.13(dd，J＝13.3，5.1Hz，2H)，4.49(d，J＝17.9Hz，2H)，4.37(d，J＝17.9Hz，2H)，4.10-3.82(m，5H)，3.43-3.39(m，4H)，3.23-3.14(m，1H)，2.96-2.89(m，2H)，2.67-2.63(m，2H)，2.47-2.39(m，2H)，2.07-1.98(m，2H).LCMS(ESI)C30H31Cl2F2N4O3 +[M+H]+：计算值603.17，实测值603.2.The target compound GT-05333 (26 mg, white solid, yield 24%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.63-7.58 (m, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.6, 1.3 Hz, 1H), 5.75 (s, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 2 3H), 4.49 (d, J = 17.9 Hz, 2H), 4.37 (d, J = 17.9 Hz, 2H), 4.10-3.82 (m, 5H), 3.43-3.39 (m, 4H), 3.23-3.14 (m, 1H), 2.96-2.89 (m, 2H), 2.67-2.63 (m, 2H), 2.47-2.39 (m, 2H), 2.07-1.98 (m, 2H). LCMS (ESI) C 30 H 31 Cl 2 F 2 N 4 O 3 + [M+H] + : calculated value 603.17, found value 603.2.

实施例40：3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09941)的制备Example 40: Preparation of 3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09941)

参照合成方案1的方法制备目标化合物GT-09941(7mg，白色固体，收率11％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，7.96(d，J＝7.9Hz，1H)，7.89(s，1H)，7.85(d，J＝8.0Hz，1H)，7.75(d，J＝8.2Hz，1H)，7.60(s，1H)，7.49(d，J＝8.1Hz，2H)，7.40-7.30(m，4H)，7.24(brs，2H)，5.95(d，J＝8.9Hz，1H)，4.87(d，J＝20.5Hz，1H)，4.77(d，J＝20.4Hz，1H)，4.63(s，1H)，4.43(s，2H)，3.59-3.48(m，4H)，3.32-3.18(m，4H)，3.05-2.83(m，6H)，2.67-2.63(m，2H)，2.31-2.21(m，2H)，2.17-2.06(m，3H).LCMS(ESI)C36H42N5O2S+[M+H]+：计算值608.31，实测值608.3.The target compound GT-09941 (7 mg, white solid, yield 11%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.40-7.30 (m, 4H), 7.24 (brs, 2H), 5.95 (d, J = 8.9 Hz, 1H), 4.87 (d, J = 20.5 Hz, 1H), 4.77 (d, J = 20.4 Hz, 1H), 4.63 (s, 1H), 4.43 (s, 2H), 3.59-3.48 (m, 4H), 3.32-3.18 (m, 4H), 3.05-2.83 (m, 6H), 2.67-2.63 (m, 2H), 2.31-2.21 (m, 2H), 2.17-2.06 (m, 3H). LCMS (ESI) C 36 H 42 N 5 O 2 S + [M+H] + : calculated value 608.31, found value 608.3.

实施例41：3-(4-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09938)的制备Example 41: Preparation of 3-(4-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09938)

参照合成方案1的方法制备目标化合物GT-09938(8mg，白色固体，收率12％)。1H NMR(400MHz，DMSO)δ11.20(s，1H)，7.99(d，J＝7.6Hz，1H)，7.94(d，J＝7.4Hz，1H)，7.67(t，J＝7.8Hz，1H)，7.56-7.43(m，4H)，7.38-7.32(m，4H)，7.26-7.22(m，2H)，6.07-5.94(m，1H)，5.24(d，J＝20.0Hz，1H)，4.88(d，J＝20.6Hz，1H)，4.53-4.33(m，3H)，3.65-3.55(m，2H)，3.14-3.05(m，4H)，2.98-2.82(m，4H)，2.74-2.66(m，2H)，2.46-2.38(m，2H)，2.32-2.22(m，3H)，2.20-2.06(m，4H).LCMS(ESI)C36H42N5O2S+[M+H]+：计算值608.31，实测值608.3.The target compound GT-09938 (8 mg, white solid, yield 12%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.56-7.43 (m, 4H), 7.38-7.32 (m, 4H), 7.26-7.22 (m, 2H), 6.07-5.94 (m, 1H), 5.24 (d, J = 20.0 Hz, 1H) z, 1H), 4.88 (d, J = 20.6 Hz, 1H), 4.53-4.33 (m, 3H), 3.65-3.55 (m, 2H), 3.14-3.05 (m, 4H), 2.98-2.82 (m, 4H), 2.74-2.66 (m, 2H), 2.46-2.38 (m, 2H), 2.32-2.22 (m, 3H), 2.20-2.06 (m, 4H). LCMS (ESI) C 36 H 42 N 5 O 2 S + [M+H] + : calculated value 608.31, found value 608.3.

实施例42：3-(6-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09862)的制备Example 42: Preparation of 3-(6-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09862)

参照合成方案1的方法制备目标化合物GT-09862(8mg，白色固体，收率12％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，8.10(s，1H)，7.87(d，J＝7.3Hz，1H)，7.77(d，J＝8.1Hz，1H)，7.51-7.44(m，4H)，7.37-7.31(m，4H)，7.25-7.21(m，2H)，6.01-5.86(m，1H)，4.88(d，J＝20.7Hz，1H)，4.74(d，J＝20.2Hz，1H)，4.46(brs，3H)，3.56-3.51(m，2H)，3.13-3.04(m，2H)，3.03-2.92(m，4H)，2.89-2.80(m，2H)，2.67-2.62(m，2H)，2.45-2.42(m，3H)，2.34-2.26(m，2H)，2.14-1.98(m，4H).LCMS(ESI)C36H42N5O2S+[M+H]+：计算值608.31，实测值608.3.The target compound GT-09862 (8 mg, white solid, yield 12%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.51-7.44 (m, 4H), 7.37-7.31 (m, 4H), 7.25-7.21 (m, 2H), 6.01-5.86 (m, 1H), 4.88 (d, J = 20.7 Hz, 1H), 4.74 (d, J = 20.2 Hz, 1H), 4.46 (brs, 3H), 3.56-3.51 (m, 2H), 3.13-3.04 (m, 2H), 3.03-2.92 (m, 4H), 2.89-2.80 (m, 2H), 2.67-2.62 (m, 2H), 2.45-2.42 (m, 3H), 2.34-2.26 (m, 2H), 2.14-1.98 (m, 4H). LCMS (ESI) C 36 H 42 N 5 O 2 S + [M+H] + : calculated value 608.31, found value 608.3.

实施例43：3-(4-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09617)的制备Example 43: Preparation of 3-(4-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09617)

参照合成方案1的方法制备目标化合物GT-09617(12mg，白色固体，收率16％)。1H NMR(400MHz，DMSO)δ11.12(s，1H)，7.91-7.77(m，5H)，7.67-7.52(m，2H)，7.48-7.43(m，4H)，7.37-7.35(m，2H)，5.97(d，J＝10.5Hz，1H)，5.60(d，J＝7.3Hz，1H)，4.86(d，J＝19.2Hz，1H)，4.74(d，J＝18.1Hz，1H)，3.89-3.67(m，1H)，3.26-3.09(m，6H)，3.08-2.94(m，7H)，2.65(d，J＝16.8Hz，2H)，2.47-2.39(m，2H)，2.15-2.03(m，1H)，1.82-1.73(m，2H).LCMS(ESI)C36H40F2N5O2S+[M+H]+：计算值644.29，实测值644.3.The target compound GT-09617 (12 mg, white solid, yield 16%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 7.91-7.77 (m, 5H), 7.67-7.52 (m, 2H), 7.48-7.43 (m, 4H), 7.37-7.35 (m, 2H), 5.97 (d, J = 10.5 Hz, 1H), 5.60 (d, J = 7.3 Hz, 1H), 4.86 (d, J = 19.2 Hz, 1 3H), 4.74 (d, J = 18.1 Hz, 1H), 3.89-3.67 (m, 1H), 3.26-3.09 (m, 6H), 3.08-2.94 (m, 7H), 2.65 (d, J = 16.8 Hz, 2H), 2.47-2.39 (m, 2H), 2.15-2.03 (m, 1H), 1.82-1.73 (m, 2H). LCMS (ESI) C 36 H 40 F 2 N 5 O 2 S + [M+H] + : calculated value 644.29, found value 644.3.

实施例44：3-(6-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09691)的制备Example 44: Preparation of 3-(6-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09691)

参照合成方案1的方法制备目标化合物GT-09691(14mg，白色固体，收率20％)。1H NMR(400MHz，DMSO)δ11.06(s，1H)，7.95-7.84(m，1H)，7.81-7.66(m，4H)，7.61(s，2H)，7.44-7.33(m，4H)，7.34-7.23(m，2H)，5.93-5.82(m，1H)，5.57-5.47(m，1H)，4.77(d，J＝20.2Hz，1H)，4.63(d，J＝19.9Hz，1H)，4.01-3.68(m，2H)，3.65-3.38(m，6H)，3.13-3.02(m，5H)，3.07-2.92(m，5H)，2.61-2.55(m，2H)，2.08-1.96(m，1H)，1.89-1.70(m，1H).LCMS(ESI)C36H40F2N5O2S+[M+H]+：计算值644.29，实测值644.3.The target compound GT-09691 (14 mg, white solid, yield 20%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 7.95-7.84 (m, 1H), 7.81-7.66 (m, 4H), 7.61 (s, 2H), 7.44-7.33 (m, 4H), 7.34-7.23 (m, 2H), 5.93-5.82 (m, 1H), 5.57-5.47 (m, 1H), 4.77 (d, J=20.2 Hz, 1H), 4.63 (d, J=19.9 Hz, 1H), 4.01-3.68 (m, 2H), 3.65-3.38 (m, 6H), 3.13-3.02 (m, 5H), 3.07-2.92 (m, 5H), 2.61-2.55 (m, 2H), 2.08-1.96 (m, 1H), 1.89-1.70 (m, 1H). LCMS (ESI) C 36 H 40 F 2 N 5 O 2 S + [M+H] + : calculated value 644.29, found value 644.3.

实施例45：3-(4-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09618)的制备Example 45: Preparation of 3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09618)

参照合成方案1的方法制备目标化合物GT-09618(15mg，白色固体，收率20％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.74(d，J＝4.8Hz，1H)，7.93-7.90(m，2H)，7.68(d，J＝7.0Hz，3H)，7.61(dd，J＝13.9，7.5Hz，2H)，7.51-7.37(m，4H)，5.98(d，J＝8.0Hz，1H)，5.84(s，1H)，5.01(dd，J＝33.7，18.0Hz，1H)，4.80(d，J＝20.1Hz，1H)，4.29-3.92(m，2H)，3.27-2.90(m，13H)，2.66(d，J＝14.1Hz，2H)，2.47-2.38(m，1H)，2.17-2.05(m，1H)，2.06-1.82(m，2H).LCMS(ESI)C35H39F2N6O2S+[M+H]+：计算值645.28，实测值645.3.The target compound GT-09618 (15 mg, white solid, yield 20%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.93-7.90 (m, 2H), 7.68 (d, J = 7.0 Hz, 3H), 7.61 (dd, J = 13.9, 7.5 Hz, 2H), 7.51-7.37 (m, 4H), 5.98 (d, J = 8.0 Hz, 1H), 5.84 (s, 1H), 5. .01 (dd, J = 33.7, 18.0 Hz, 1H), 4.80 (d, J = 20.1 Hz, 1H), 4.29-3.92 (m, 2H), 3.27-2.90 (m, 13H), 2.66 (d, J = 14.1 Hz, 2H), 2.47-2.38 (m, 1H), 2.17-2.05 (m, 1H), 2.06-1.82 (m, 2H). LCMS (ESI) C 35 H 39 F 2 N 6 O 2 S + [M+H] + : calculated value 645.28, found value 645.3.

实施例46：3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09679)的制备Example 46: Preparation of 3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09679)

参照合成方案1的方法制备目标化合物GT-09679(11mg，白色固体，收率14％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，7.91(d，J＝7.5Hz，1H)，7.70-7.65(m，1H)，7.63-7.50(m，1H)，7.37(d，J＝8.4Hz，2H)，7.24(d，J＝8.5Hz，2H)，6.03-5.90(m，1H)，4.84(d，J＝19.7Hz，1H)，4.70(d，J＝20.2Hz，1H)，3.17-3.08(m，4H)，3.02-2.93(m，4H)，2.71-2.61(m，2H)，2.42-2.33(m，6H)，2.15-2.00(m，4H)，1.96-1.85(m，2H)，1.74-1.59(m，2H)，1.51-1.37(m，3H)，0.99(s，3H)，0.96(s，3H).LCMS(ESI)C38H45ClF2N5O3S+[M+H]+：计算值724.29，实测值724.3.The target compound GT-09679 (11 mg, white solid, yield 14%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.70-7.65 (m, 1H), 7.63-7.50 (m, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.03-5.90 (m, 1H), 4.84 (d, J = 19.7 Hz, 1H), 4.70 (d, J = 20.2 Hz, 1H), 3.17-3.08 (m, 4H), 3.02-2.93 (m, 4H), 2.71-2.61 (m, 2H), 2.42-2.33 (m, 6H), 2.15-2.00 (m, 4H), 1.96-1.85 (m, 2H), 1.74-1.59 (m, 2H), 1.51-1.37 (m, 3H), 0.99 (s, 3H), 0.96 (s, 3H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 3 S + [M+H] + : calculated value 724.29, found value 724.3.

实施例47：3-(4-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09619)的制备Example 47: Preparation of 3-(4-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09619)

参照合成方案1的方法制备目标化合物GT-09619(19mg，白色固体，收率23％)。1H NMR(400MHz，DMSO)δ11.15(d，J＝4.5Hz，1H)，7.87(d，J＝7.5Hz，1H)，7.67-7.50(m，2H)，7.37(d，J＝8.4Hz，2H)，7.24(d，J＝8.5Hz，2H)，6.07-5.91(m，1H)，4.86(d，J＝18.8Hz，1H)，4.75(d，J＝21.0Hz，1H)，3.91-3.74(m，1H)，3.27-3.19(m，7H)，3.05-2.86(m，4H)，2.72-2.62(m，2H)，2.44-2.29(m，4H)，2.19-2.00(m，3H)，1.90(d，J＝17.2Hz，1H)，1.80-1.57(m，2H)，1.52-1.36(m，2H)，0.98(d，J＝13.3Hz，6H).LCMS(ESI)C38H45ClF2N5O3S+[M+H]+：计算值724.29，实测值724.3.The target compound GT-09619 (19 mg, white solid, yield 23%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.15 (d, J = 4.5 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.67-7.50 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.07-5.91 (m, 1H), 4.86 (d, J = 18.8 Hz, 1H), 4.75 (d, J = 21.0 Hz, 1H), 3.91-3.3 .74 (m, 1H), 3.27-3.19 (m, 7H), 3.05-2.86 (m, 4H), 2.72-2.62 (m, 2H), 2.44-2.29 (m, 4H), 2.19-2.00 (m, 3H), 1.90 (d, J=17.2 Hz, 1H), 1.80-1.57 (m, 2H), 1.52-1.36 (m, 2H), 0.98 (d, J=13.3 Hz, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 3 S + [M+H] + : calculated value 724.29, found value 724.3.

实施例48：3-(6-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09692)的制备Example 48: Preparation of 3-(6-((4-(4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09692)

参照合成方案1的方法制备目标化合物GT-09692(10mg，白色固体，收率13％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，7.90-7.85(m，1H)，7.72-7.69(m，2H)，7.37(d，J＝8.3Hz，2H)，7.24(d，J＝8.5Hz，2H)，5.98-5.92(m，1H)，4.84(d，J＝20.9Hz，1H)，4.70(d，J＝20.1Hz，1H)，3.31-3.17(m，6H)，3.15-3.02(m，3H)，3.03-2.90(m，3H)，2.68-2.62(m，2H)，2.43-2.33(m，4H)，2.14-2.04(m，3H)，1.90(d，J＝15.5Hz，1H)，1.79-1.60(m，3H)，1.47-1.38(m，2H)，0.98(d，J＝12.9Hz，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound GT-09692 (10 mg, white solid, yield 13%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.90-7.85 (m, 1H), 7.72-7.69 (m, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 5.98-5.92 (m, 1H), 4.84 (d, J = 20.9 Hz, 1H), 4.70 (d, J = 20.1 Hz, 1H), 3.31-3.17 (m , 6H), 3.15-3.02 (m, 3H), 3.03-2.90 (m, 3H), 2.68-2.62 (m, 2H), 2.43-2.33 (m, 4H), 2.14-2.04 (m, 3H), 1.90 (d, J=15.5 Hz, 1H), 1.79-1.60 (m, 3H), 1.47-1.38 (m, 2H), 0.98 (d, J=12.9 Hz, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例49：3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09680)的制备Example 49: Preparation of 3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09680)

参照合成方案1的方法制备目标化合物GT-09680(21mg，白色固体，收率27％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，7.90(d，J＝8.0Hz，1H)，7.65-7.51(m，2H)，7.44(d，J＝8.4Hz，2H)，7.13(d，J＝8.4Hz，2H)，6.01-5.90(m，1H)，4.83(d，J＝18.0Hz，1H)，4.70(d，J＝20.4Hz，1H)，3.57-3.53(m，2H)，3.24-3.19(m，4H)，3.03-2.96(m，3H)，2.89-2.81(m，4H)，2.65-2.58(m，4H)，2.30-2.24(m，4H)，2.03(s，4H)，1.80-1.67(m，2H)，1.47-1.45(m，2H)，0.96(s，6H).LCMS(ESI)C38H47ClF2N5O2S+[M+H]+：计算值710.31，实测值710.3.The target compound GT-09680 (21 mg, white solid, yield 27%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.65-7.51 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.01-5.90 (m, 1H), 4.83 (d, J = 18.0 Hz, 1H), 4.70 (d, J = 20.4 Hz, 1H), 3 .57-3.53 (m, 2H), 3.24-3.19 (m, 4H), 3.03-2.96 (m, 3H), 2.89-2.81 (m, 4H), 2.65-2.58 (m, 4H), 2.30-2.24 (m, 4H), 2.03 (s, 4H), 1.80-1.67 (m, 2H), 1.47-1.45 (m, 2H), 0.96 (s, 6H). LCMS (ESI) C 38 H 47 ClF 2 N 5 O 2 S + [M+H] + : calculated value 710.31, found value 710.3.

实施例50：3-(4-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09576)的制备Example 50: Preparation of 3-(4-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09576)

参照合成方案1的方法制备目标化合物GT-09576(23mg，白色固体，收率28％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，7.86(d，J＝6.5Hz，1H)，7.84-7.77(m，1H)，7.60-7.55(m，1H)，7.44(d，J＝8.3Hz，2H)，7.14(d，J＝8.3Hz，2H)，5.97(s，1H)，4.90(d，J＝20.5Hz，1H)，4.78(d，J＝20.1Hz，1H)，3.94-3.64(m，2H)，3.55(brs，2H)，3.39-3.31(m，4H)，3.25-3.18(m，3H)，3.07-2.97(m，4H)，2.94-2.79(m，3H)，2.67-2.60(m，3H)，2.33-2.25(m，3H)，2.17-2.07(m，1H)，2.04(s，2H)，1.85-1.72(m，2H)，1.46(t，J＝6.1Hz，2H)，0.96(s，6H).LCMS(ESI)C38H47ClF2N5O2S+[M+H]+：计算值710.31，实测值710.3.The target compound GT-09576 (23 mg, white solid, yield 28%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ11.15 (s, 1H), 7.86 (d, J=6.5 Hz, 1H), 7.84-7.77 (m, 1H), 7.60-7.55 (m, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.3 Hz, 2H), 5.97 (s, 1H), 4.90 (d, J=20.5 Hz, 1H), 4.78 (d, J=20.1 Hz, 1H), 3.94-3.64 (m, 2H), 3.5 5 (brs, 2H), 3.39-3.31 (m, 4H), 3.25-3.18 (m, 3H), 3.07-2.97 (m, 4H), 2.94-2.79 (m, 3H), 2.67-2.60 (m, 3H), 2.33-2.25 (m, 3H), 2.17-2.07 (m, 1H), 2.04 (s, 2H), 1.85-1.72 (m, 2H), 1.46 (t, J=6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 7 ClF 2 N 5 O 2 S + [M+H] + : calculated value 710.31, found value 710.3.

实施例51：3-(6-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09863)的制备Example 51: Preparation of 3-(6-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09863)

参照合成方案1的方法制备目标化合物GT-09863(16mg，白色固体，收率21％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，7.99-7.92(m，1H)，7.75-7.62(m，2H)，7.44(d，J＝8.3Hz，2H)，7.13(d，J＝8.3Hz，2H)，5.98-5.94(m，1H)，4.84(d，J＝20.2Hz，1H)，4.69(d，J＝19.6Hz，1H)，3.54(s，2H)，3.25-3.17(m，4H)，3.07-2.96(m，4H)，2.93-2.75(m，4H)，2.71-2.53(m，6H)，2.33-2.25(m，3H)，2.15-2.07(m，1H)，2.03(s，3H)，1.92-1.63(m，2H)，0.96(s，6H).LCMS(ESI)C38H47ClF2N5O2S+[M+H]+：计算值710.31，实测值710.3.The target compound GT-09863 (16 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.99-7.92 (m, 1H), 7.75-7.62 (m, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 5.98-5.94 (m, 1H), 4.84 (d, J = 20.2 Hz, 1H), 4.69 (d, J = 19.6 Hz, 1H), 3.54 (s, 2H), 3.25-3.17 (m, 4H), 3.07-2.96 (m, 4H), 2.93-2.75 (m, 4H), 2.71-2.53 (m, 6H), 2.33-2.25 (m, 3H), 2.15-2.07 (m, 1H), 2.03 (s, 3H), 1.92-1.63 (m, 2H), 0.96 (s, 6H). LCMS (ESI) C 38 H 47 ClF 2 N 5 O 2 S + [M+H] + : calculated value 710.31, found value 710.3.

实施例52：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09934)的制备Example 52: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09934)

参照合成方案1的方法制备目标化合物GT-09934(8mg，白色固体，收率12％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.03-7.94(m，1H)，7.85(d，J＝8.0Hz，1H)，7.81-7.69(m，1H)，7.42-7.34(m，2H)，7.20(dd，J＝7.0，2.3Hz，1H)，6.04-5.88(m，1H)，4.86(d，J＝20.5Hz，1H)，4.76(d，J＝20.2Hz，1H)，4.52-4.40(m，1H)，3.68-3.61(m，2H)，3.29-3.23(m，4H)，3.21-3.13(m，4H)，3.05-2.90(m，4H)，2.67-2.61(m，2H)，2.41-2.36(m，2H)，2.18-2.03(m，4H).LCMS(ESI)C29H34Cl2N5O2S+[M+H]+：计算值586.18，实测值586.3.The target compound GT-09934 (8 mg, white solid, yield 12%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.03-7.94 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.81-7.69 (m, 1H), 7.42-7.34 (m, 2H), 7.20 (dd, J = 7.0, 2.3 Hz, 1H), 6.04-5.88 (m, 1H), 4.86 (d, J = 20.5 Hz, 1H), 4 .76 (d, J = 20.2 Hz, 1H), 4.52-4.40 (m, 1H), 3.68-3.61 (m, 2H), 3.29-3.23 (m, 4H), 3.21-3.13 (m, 4H), 3.05-2.90 (m, 4H), 2.67-2.61 (m, 2H), 2.41-2.36 (m, 2H), 2.18-2.03 (m, 4H). LCMS (ESI) C 29 H 34 Cl 2 N 5 O 2 S + [M+H] + : calculated value 586.18, found value 586.3.

实施例53：3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09939)的制备Example 53: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09939)

参照合成方案1的方法制备目标化合物GT-09939(14mg，白色固体，收率21％)。1H NMR(400MHz，DMSO)δ11.21(s，1H)，8.07-7.87(m，2H)，7.78-7.62(m，1H)，7.40-7.30(m，2H)，7.25-7.14(m，1H)，6.02-5.98(m，1H)，5.24(d，J＝18.2Hz，1H)，4.89(d，J＝18.3Hz，1H)，4.53-4.30(m，2H)，3.70-3.55(m，4H)，3.17-3.07(m，4H)，2.97-2.82(m，2H)，2.74-2.66(m，2H)，2.44-2.39(m，2H)，2.30-2.18(m，3H)，2.18-2.04(m，4H).LCMS(ESI)C29H34Cl2N5O2S+[M+H]+：计算值586.18，实测值586.3.The target compound GT-09939 (14 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.07-7.87 (m, 2H), 7.78-7.62 (m, 1H), 7.40-7.30 (m, 2H), 7.25-7.14 (m, 1H), 6.02-5.98 (m, 1H), 5.24 (d, J = 18.2 Hz, 1H), 4.89 (d, J = 18.3 Hz, 1H). z, 1H), 4.53-4.30 (m, 2H), 3.70-3.55 (m, 4H), 3.17-3.07 (m, 4H), 2.97-2.82 (m, 2H), 2.74-2.66 (m, 2H), 2.44-2.39 (m, 2H), 2.30-2.18 (m, 3H), 2.18-2.04 (m, 4H). LCMS (ESI) C 29 H 34 Cl 2 N 5 O 2 S + [M+H] + : calculated value 586.18, found value 586.3.

实施例54：3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09935)的制备Example 54: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09935)

参照合成方案1的方法制备目标化合物GT-09935(8mg，白色固体，收率12％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，8.14-8.10(m，1H)，7.93-7.86(m，1H)，7.82-7.74(m，1H)，7.42-7.35(m，2H)，7.22-7.18(m，1H)，5.96(d，J＝10.3Hz，2H)，4.89(d，J＝20.8Hz，1H)，4.75(d，J＝20.4Hz，2H)，4.55-4.42(m，2H)，3.65-3.54(m，4H)，3.24-3.16(m，6H)，3.03-2.92(m，4H)，2.67-2.63(m，2H)，2.44-2.33(m，2H)，2.18-2.04(m，3H).LCMS(ESI)C29H34Cl2N5O2S+[M+H]+：计算值586.18，实测值586.3.The target compound GT-09935 (8 mg, white solid, yield 12%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.14-8.10 (m, 1H), 7.93-7.86 (m, 1H), 7.82-7.74 (m, 1H), 7.42-7.35 (m, 2H), 7.22-7.18 (m, 1H), 5.96 (d, J = 10.3 Hz, 2H), 4.89 (d, J = 20.8 Hz, 1H), 4.75 (d, J = 20.4 Hz, 2H), 4.55-4.42 (m, 2H), 3.65-3.54 (m, 4H), 3.24-3.16 (m, 6H), 3.03-2.92 (m, 4H), 2.67-2.63 (m, 2H), 2.44-2.33 (m, 2H), 2.18-2.04 (m, 3H). LCMS (ESI) C 29 H 34 Cl 2 N 5 O 2 S + [M+H] + : calculated value 586.18, found value 586.3.

实施例55：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09687)的制备Example 55: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09687)

参照合成方案1的方法制备目标化合物GT-09687(13mg，白色固体，收率19％)。1H NMR(400MHz，DMSO)δ11.07(s，1H)，7.86(d，J＝8.0Hz，1H)，7.63(s，1H)，7.53(d，J＝7.6Hz，1H)，7.29-7.24(m，2H)，7.14-7.05(m，1H)，5.89(d，J＝11.3Hz，1H)，4.79(d，J＝20.5Hz，1H)，4.65(d，J＝20.6Hz，1H)，4.10-3.83(m，2H)，3.17-2.98(m，10H)，2.95-2.84(m，2H)，2.63-2.55(m，2H)，2.50-2.45(m，2H)，2.17-2.08(m，1H)，2.06-2.01(m，1H)，1.99-1.87(m，1H).LCMS(ESI)C29H32Cl2F2N5O2S+[M+H]+：计算值622.16，实测值622.2.The target compound GT-09687 (13 mg, white solid, yield 19%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.29-7.24 (m, 2H), 7.14-7.05 (m, 1H), 5.89 (d, J = 11.3 Hz, 1H), 4.79 (d, J = 20.5 Hz, 1H), 4.65 (d, J = 20.6 Hz, 1H), 4.10-3.83 (m, 2H), 3.17-2.98 (m, 10H), 2.95-2.84 (m, 2H), 2.63-2.55 (m, 2H), 2.50-2.45 (m, 2H), 2.17-2.08 (m, 1H), 2.06-2.01 (m, 1H), 1.99-1.87 (m, 1H ) . LCMS ( ESI ) C29H32Cl2F2N5O2S + [M+H] + : calculated value 622.16 , found value 622.2.

实施例56：3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09575)的制备Example 56: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09575)

参照合成方案1的方法制备目标化合物GT-09575(31mg，白色固体，收率43％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，7.87(d，J＝7.7Hz，1H)，7.70-7.61(m，1H)，7.58(d，J＝7.4Hz，1H)，7.34(d，J＝5.3Hz，2H)，7.21-7.15(m，1H)，6.01-5.95(m，1H)，4.89(d，J＝19.8Hz，1H)，4.77(d，J＝20.9Hz，1H)，3.97-3.72(m，2H)，3.24-3.14(m，9H)，3.06-2.86(m，4H)，2.70-2.64(m，2H)，2.18-2.07(m，2H)，2.03-1.84(m，2H).LCMS(ESI)C29H32Cl2F2N5O2S+[M+H]+：计算值622.16，实测值622.2.The target compound GT-09575 (31 mg, white solid, yield 43%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.70-7.61 (m, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 5.3 Hz, 2H), 7.21-7.15 (m, 1H), 6.01-5.95 (m, 1H), 4.89 (d , J = 19.8 Hz, 1H), 4.77 (d, J = 20.9 Hz, 1H), 3.97-3.72 (m, 2H), 3.24-3.14 (m, 9H), 3.06-2.86 (m, 4H), 2.70-2.64 (m, 2H), 2.18-2.07 (m, 2H), 2.03-1.84 (m, 2H). LCMS (ESI) C 29 H 32 Cl 2 F 2 N 5 O 2 S + [M+H] + : calculated value 622.16, found value 622.2.

实施例57：3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09693)的制备Example 57: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09693)

参照合成方案1的方法制备目标化合物GT-09693(11mg，白色固体，收率16％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，8.06-7.95(m，1H)，7.78-7.68(m，2H)，7.33(d，J＝4.7Hz，2H)，7.16(t，J＝4.8Hz，1H)，6.01-5.90(m，1H)，4.86(d，J＝20.7Hz，1H)，4.72(d，J＝20.1Hz，1H)，4.30-3.84(m，2H)，3.18-3.05(m，11H)，2.70-2.62(m，2H)，2.22-1.93(m，6H).LCMS(ESI)C29H32Cl2F2N5O2S+[M+H]+：计算值622.16，实测值622.2.The target compound GT-09693 (11 mg, white solid, yield 16%) was prepared by referring to the method of Synthesis Scheme 1. 1H NMR (400MHz, DMSO) δ11.13 (s, 1H), 8.06-7.95 (m, 1H), 7.78-7.68 (m, 2H), 7.33 (d, J=4.7Hz, 2H), 7.16 (t, J=4.8Hz, 1H), 6.01-5.90 (m, 1H), 4.86 (d, J=20.7Hz, 1H), 4.72 (d, J=20.1Hz, 1H), 4.30-3.84 (m, 2H), 3.18-3.05 (m, 11H), 2.70-2.62 (m, 2H), 2.22-1.93 (m, 6H). LCMS (ESI) C 29 H 32 Cl 2 F 2 N 5 O 2 S + [M+H] + : Calculated value 622.16, measured value 622.2.

实施例58：3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09688)的制备Example 58: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09688)

参照合成方案1的方法制备目标化合物GT-09688(12mg，白色固体，收率17％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，7.92(d，J＝7.8Hz，1H)，7.66(s，1H)，7.63-7.54(m，2H)，7.38(t，J＝7.7Hz，1H)，7.26(d，J＝6.2Hz，1H)，6.02-5.88(m，1H)，5.75(s，1H)，4.85(d，J＝20.1Hz，1H)，4.71(d，J＝19.7Hz，1H)，3.98-3.84(m，2H)，3.31-3.21(m，6H)，3.17-3.06(m，3H)，3.01-2.92(m，2H)，2.70-2.61(m，4H)，2.14-2.06(m，1H)，2.04-1.94(m，1H).LCMS(ESI)C30H31Cl2F2N4O2S+[M+H]+：计算值619.15，实测值619.2.The target compound GT-09688 (12 mg, white solid, yield 17%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.63-7.54 (m, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 6.2 Hz, 1H), 6.02-5.88 (m, 1H), 5.75 (s, 1H), 4.85 (d, J = 20 .1 Hz, 1H), 4.71 (d, J=19.7 Hz, 1H), 3.98-3.84 (m, 2H), 3.31-3.21 (m, 6H), 3.17-3.06 (m, 3H), 3.01-2.92 (m, 2H), 2.70-2.61 (m, 4H), 2.14-2.06 (m, 1H), 2.04-1.94 (m, 1H). LCMS (ESI) C 30 H 31 Cl 2 F 2 N 4 O 2 S + [M+H] + : calculated value 619.15, found value 619.2.

实施例59：3-(4-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09614)的制备Example 59: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09614)

参照合成方案1的方法制备目标化合物GT-09614(10mg，白色固体，收率14％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，7.87(d，J＝7.4Hz，1H)，7.68-7.54(m，3H)，7.39(t，J＝7.9Hz，1H)，7.26(dd，J＝7.6，1.2Hz，1H)，6.00(d，J＝11.0Hz，1H)，5.77(s，1H)，4.89(d，J＝18.7Hz，1H)，4.76(d，J＝20.2Hz，1H)，3.97-3.74(m，4H)，3.37-3.19(m，9H)，3.08-2.92(m，2H)，2.71-2.65(m，2H)，2.17-2.09(m，1H)，2.02-1.93(m，1H).LCMS(ESI)C30H31Cl2F2N4O2S+[M+H]+：计算值619.15，实测值619.2.The target compound GT-09614 (10 mg, white solid, yield 14%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.68-7.54 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.6, 1.2 Hz, 1H), 6.00 (d, J = 11.0 Hz, 1H), 5.77 (s, 1H), 4.89 (d, J = 18.7 Hz, 1H), 4.76 (d, J = 20.2 Hz, 1H), 3.97-3.74 (m, 4H), 3.37-3.19 (m, 9H), 3.08-2.92 (m, 2H), 2.71-2.65 (m, 2H), 2.17-2.09 (m, 1H), 2.02-1.93 (m, 1H). LCMS (ESI) C 30 H 31 Cl 2 F 2 N 4 O 2 S + [M+H] + : calculated value 619.15, found value 619.2.

实施例60：3-(6-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09694)的制备Example 60: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09694)

参照合成方案1的方法制备目标化合物GT-09694(10mg，白色固体，收率15％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，8.00-7.88(m，1H)，7.73-7.64(m，2H)，7.60(d，J＝8.0Hz，1H)，7.38(t，J＝7.8Hz，1H)，7.25(d，J＝7.7Hz，1H)，6.03-5.89(m，1H)，5.74(s，1H)，4.85(d，J＝20.6Hz，1H)，4.71(d，J＝20.2Hz，1H)，4.07-3.84(m，2H)，3.65-3.52(m，2H)，3.37-3.31(m，6H)，3.32-3.05(m，4H)，2.99-2.92(m，1H)，2.69-2.63(m，2H)，2.14-1.99(m，3H).LCMS(ESI)C30H31Cl2F2N4O2S+[M+H]+：计算值619.15，实测值619.2.The target compound GT-09694 (10 mg, white solid, yield 15%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.00-7.88 (m, 1H), 7.73-7.64 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 6.03-5.89 (m, 1H), 5.74 (s, 1H), 4.85 (d, J =20.6 Hz, 1H), 4.71 (d, J=20.2 Hz, 1H), 4.07-3.84 (m, 2H), 3.65-3.52 (m, 2H), 3.37-3.31 (m, 6H), 3.32-3.05 (m, 4H), 2.99-2.92 (m, 1H), 2.69-2.63 (m, 2H), 2.14-1.99 (m, 3H). LCMS (ESI) C 30 H 31 Cl 2 F 2 N 4 O 2 S + [M+H] + : calculated value 619.15, found value 619.2.

实施例61：3-(5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09861)的制备Example 61: Preparation of 3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09861)

参照合成方案1的方法制备目标化合物GT-09861(13mg，白色固体，收率21％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.09(dd，J＝8.8，5.2Hz，1H)，7.97(d，J＝8.0Hz，1H)，7.89(s，1H)，7.77(t，J＝6.8Hz，1H)，7.61(dd，J＝8.9，1.7Hz，1H)，7.26(t，J＝8.5Hz，1H)，5.97(d，J＝14.1Hz，1H)，4.88(d，J＝20.4Hz，1H)，4.74(d，J＝20.3Hz，1H)，4.45(brs，2H)，4.25-4.01(m，2H)，3.61-3.50(m，6H)，3.02-2.95(m，4H)，2.67-2.63(m，2H)，2.37-2.31(m，2H)，2.26-2.15(m，2H)，2.15-1.96(m，3H).LCMS(ESI)C30H34FN6O3S+[M+H]+：计算值577.24，实测值577.3.The target compound GT-09861 (13 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.09 (dd, J = 8.8, 5.2 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.77 (t, J = 6.8 Hz, 1H), 7.61 (dd, J = 8.9, 1.7 Hz, 1H), 7.26 (t, J = 8.5 Hz, 1H), 5.97 (d, J = 14.1 Hz, 1H), 4.88 ( d, J = 20.4 Hz, 1H), 4.74 (d, J = 20.3 Hz, 1H), 4.45 (brs, 2H), 4.25-4.01 (m, 2H), 3.61-3.50 (m, 6H), 3.02-2.95 (m, 4H), 2.67-2.63 (m, 2H), 2.37-2.31 (m, 2H), 2.26-2.15 (m, 2H), 2.15-1.96 (m, 3H). LCMS (ESI) C 30 H 34 FN 6 O 3 S + [M+H] + : calculated value 577.24, found value 577.3.

实施例62：3-(4-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09940)的制备Example 62: Preparation of 3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09940)

参照合成方案1的方法制备目标化合物GT-09940(10mg，白色固体，收率15％)。1H NMR(400MHz，DMSO)δ11.21(s，1H)，8.12-8.08(m，1H)，8.04-7.90(m，2H)，7.68(t，J＝7.7Hz，1H)，7.61(dd，J＝9.1，2.0Hz，1H)，7.26(td，J＝9.0，2.1Hz，1H)，6.05-6.00(m，1H)，5.25(d，J＝21.4Hz，1H)，4.88(d，J＝20.4Hz，1H)，4.49-4.36(m，1H)，4.22-4.00(m，2H)，3.64-3.50(m，6H)，3.21-3.07(m，4H)，3.02-2.89(m，2H)，2.74-2.66(m，2H)，2.40-2.33(m，2H)，2.29-2.19(m，2H)，2.18-2.06(m，2H).LCMS(ESI)C30H34FN6O3S+[M+H]+：计算值577.24，实测值577.3.The target compound GT-09940 (10 mg, white solid, yield 15%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.12-8.08 (m, 1H), 8.04-7.90 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.61 (dd, J = 9.1, 2.0 Hz, 1H), 7.26 (td, J = 9.0, 2.1 Hz, 1H), 6.05-6.00 (m, 1H), 5.25 (d, J = 21.4 Hz, 1H), 4.88 ( d, J = 20.4 Hz, 1H), 4.49-4.36 (m, 1H), 4.22-4.00 (m, 2H), 3.64-3.50 (m, 6H), 3.21-3.07 (m, 4H), 3.02-2.89 (m, 2H), 2.74-2.66 (m, 2H), 2.40-2.33 (m, 2H), 2.29-2.19 (m, 2H), 2.18-2.06 (m, 2H). LCMS (ESI) C 30 H 34 FN 6 O 3 S + [M+H] + : calculated value 577.24, found value 577.3.

实施例63：3-(6-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09864)的制备Example 63: Preparation of 3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09864)

参照合成方案1的方法制备目标化合物GT-09864(11mg，白色固体，收率16％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，8.14-8.05(m，2H)，7.90(d，J＝8.1Hz，1H)，7.78(d，J＝7.9Hz，1H)，7.61(dd，J＝9.0，2.0Hz，1H)，7.26(t，J＝9.0Hz，1H)，5.96(d，J＝9.3Hz，1H)，4.89(d，J＝20.5Hz，1H)，4.75(d，J＝20.5Hz，1H)，4.49(s，2H)，4.22-4.03(m，2H)，3.61-3.49(m，6H)，3.04-2.89(m，4H)，2.72-2.67(m，2H)，2.41-2.32(m，3H)，2.22-2.04(m，4H).LCMS(ESI)C30H34FN6O3S+[M+H]+：计算值577.24，实测值577.3.The target compound GT-09864 (11 mg, white solid, yield 16%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.14-8.05 (m, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.61 (dd, J = 9.0, 2.0 Hz, 1H), 7.26 (t, J = 9.0 Hz, 1H), 5.96 (d, J = 9.3 Hz, 1H), 4.89 (d , J = 20.5 Hz, 1H), 4.75 (d, J = 20.5 Hz, 1H), 4.49 (s, 2H), 4.22-4.03 (m, 2H), 3.61-3.49 (m, 6H), 3.04-2.89 (m, 4H), 2.72-2.67 (m, 2H), 2.41-2.32 (m, 3H), 2.22-2.04 (m, 4H). LCMS (ESI) C 30 H 34 FN 6 O 3 S + [M+H] + : calculated value 577.24, found value 577.3.

实施例64：3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09689)的制备Example 64: Preparation of 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09689)

参照合成方案1的方法制备目标化合物GT-09689(13mg，白色固体，收率19％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，8.05(dd，J＝8.9，5.3Hz，1H)，7.93(d，J＝7.6Hz，1H)，7.71(brs，1H)，7.62(brs，1H)，7.56(dd，J＝9.1，2.1Hz，1H)，7.21(t，J＝9.0Hz，1H)，6.04-5.87(m，1H)，4.85(d，J＝20.3Hz，1H)，4.72(d，J＝19.7Hz，1H)，4.19-3.89(m，2H)，3.70-3.56(m，3H)，3.58-3.48(m，6H)，3.20-3.03(m，3H)，3.01-2.93(m，2H)，2.71-2.61(m，2H)，2.19-1.92(m，3H).LCMS(ESI)C30H32F3N6O3S+[M+H]+：计算值613.22，实测值613.3.The target compound GT-09689 (13 mg, white solid, yield 19%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.05 (dd, J = 8.9, 5.3 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.71 (brs, 1H), 7.62 (brs, 1H), 7.56 (dd, J = 9.1, 2.1 Hz, 1H), 7.21 (t, J = 9.0 Hz, 1H), 6.04-5.87 (m, 1H), 4. 85 (d, J = 20.3 Hz, 1H), 4.72 (d, J = 19.7 Hz, 1H), 4.19-3.89 (m, 2H), 3.70-3.56 (m, 3H), 3.58-3.48 (m, 6H), 3.20-3.03 (m, 3H), 3.01-2.93 (m, 2H), 2.71-2.61 (m, 2H), 2.19-1.92 (m, 3H). LCMS (ESI) C 30 H 32 F 3 N 6 O 3 S + [M+H] + : calculated value 613.22, found value 613.3.

实施例65：3-(4-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09615)的制备Example 65: Preparation of 3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09615)

参照合成方案1的方法制备目标化合物GT-09615(15mg，白色固体，收率21％)。1H NMR(400MHz，DMSO)δ11.16(s，1H)，8.06(dd，J＝8.9，5.3Hz，1H)，7.88(d，J＝7.3Hz，1H)，7.65(s，1H)，7.57(dd，J＝9.1，2.1Hz，2H)，7.22(t，J＝8.0Hz，1H)，6.08-5.91(m，1H)，4.91(d，J＝23.1Hz，1H)，4.83-4.69(m，1H)，3.92-3.85(m，2H)，3.65-3.54(m，4H)，3.31-3.24(m，9H)，3.11-2.94(m，2H)，2.70-2.67(m，2H)，2.21-2.04(m，2H)，2.01-1.85(m，1H).LCMS(ESI)C30H32F3N6O3S+[M+H]+：计算值613.22，实测值613.3.The target compound GT-09615 (15 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 8.06 (dd, J = 8.9, 5.3 Hz, 1H), 7.88 (d, J = 7.3 Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J = 9.1, 2.1 Hz, 2H), 7.22 (t, J = 8.0 Hz, 1H), 6.08-5.91 (m, 1H), 4.91 (d, J = 7.3 Hz, 1H). =23.1 Hz, 1H), 4.83-4.69 (m, 1H), 3.92-3.85 (m, 2H), 3.65-3.54 (m, 4H), 3.31-3.24 (m, 9H), 3.11-2.94 (m, 2H), 2.70-2.67 (m, 2H), 2.21-2.04 (m, 2H), 2.01-1.85 (m, 1H). LCMS (ESI) C 30 H 32 F 3 N 6 O 3 S + [M+H] + : calculated value 613.22, found value 613.3.

实施例66：3-(6-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09695)的制备Example 66: Preparation of 3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09695)

参照合成方案1的方法制备目标化合物GT-09695(9mg，白色固体，收率13％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，8.04(dd，J＝8.9，5.3Hz，1H)，8.00-7.98(m，1H)，7.71(brs，2H)，7.56(dd，J＝9.1，2.2Hz，1H)，7.20(t，J＝7.9Hz，1H)，5.99-5.94(m，1H)，4.86(d，J＝20.4Hz，1H)，4.72(d，J＝20.2Hz，1H)，4.27-4.21(m，2H)，3.74-3.66(m，2H)，3.11-2.93(m，12H)，2.69-2.65(m，2H)，2.12-2.03(m，3H).LCMS(ESI)C30H32F3N6O3S+[M+H]+：计算值613.22，实测值613.3.The target compound GT-09695 (9 mg, white solid, yield 13%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.04 (dd, J = 8.9, 5.3 Hz, 1H), 8.00-7.98 (m, 1H), 7.71 (brs, 2H), 7.56 (dd, J = 9.1, 2.2 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 5.99-5.94 (m , 1H), 4.86 (d, J = 20.4 Hz, 1H), 4.72 (d, J = 20.2 Hz, 1H), 4.27-4.21 (m, 2H), 3.74-3.66 (m, 2H), 3.11-2.93 (m, 12H), 2.69-2.65 (m, 2H), 2.12-2.03 (m, 3H). LCMS (ESI) C 30 H 32 F 3 N 6 O 3 S + [M+H] + : calculated value 613.22, found value 613.3.

实施例67：3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09690)的制备Example 67: Preparation of 3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09690)

参照合成方案1的方法制备目标化合物GT-09690(14mg，白色固体，收率21％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，8.18(s，1H)，7.90(d，J＝7.9Hz，1H)，7.73(dd，J＝9.1，2.1Hz，1H)，7.63(s，1H)，7.54(d，J＝7.5Hz，1H)，7.35(dd，J＝10.0，8.1Hz，1H)，5.98-5.92(m，1H)，4.84(d，J＝19.6Hz，1H)，4.70(d，J＝20.1Hz，1H)，3.94-3.78(m，2H)，3.76-3.65(m，2H)，3.60-3.43(m，6H)，3.08-3.03(m，1H)，2.98-2.92(m，1H)，2.69-2.63(m，2H)，2.45-2.29(m，4H)，2.28-2.16(m，2H)，2.15-2.03(m，2H).LCMS(ESI)C31H33F3N5O3S+[M+H]+：计算值612.23，实测值612.2.The target compound GT-09690 (14 mg, white solid, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.18 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.73 (dd, J = 9.1, 2.1 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.35 (dd, J = 10.0, 8.1 Hz, 1H), 5.98-5.92 (m, 1H), 4.84 (d, J = 19.6 Hz, 1H), 4.70 (d, J = 20.1 Hz, 1H), 3.94-3.78 (m, 2H), 3.76-3.65 (m, 2H), 3.60-3.43 (m, 6H), 3.08-3.03 (m, 1H), 2.98-2.92 (m, 1H), 2.69-2.63 (m, 2H), 2.45-2.29 (m, 4H), 2.28-2.16 (m, 2H), 2.15-2.03 (m, 2H). LCMS (ESI) C 31 H 33 F 3 N 5 O 3 S + [M+H] + : calculated value 612.23, found value 612.2.

实施例68：3-(4-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09616)的制备Example 68: Preparation of 3-(4-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09616)

参照合成方案1的方法制备目标化合物GT-09616(13mg，白色固体，收率18％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，8.26-8.14(m，1H)，7.86(d，J＝7.4Hz，1H)，7.73(dd，J＝9.0，1.9Hz，1H)，7.66-7.53(m，2H)，7.39-7.30(m，1H)，6.06-5.89(m，1H)，4.95-4.83(m，1H)，4.75(d，J＝19.9Hz，1H)，4.16-3.94(m，1H)，3.89-3.61(m，4H)，3.60-3.44(m，4H)，3.26-3.12(m，2H)，3.01-2.95(m，2H)，2.75-2.62(m，2H)，2.46-2.33(m，3H)，2.27-2.19(m，2H)，2.17-1.95(m，2H).LCMS(ESI)C31H33F3N5O3S+[M+H]+：计算值612.23，实测值612.2.The target compound GT-09616 (13 mg, white solid, yield 18%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.26-8.14 (m, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.73 (dd, J = 9.0, 1.9 Hz, 1H), 7.66-7.53 (m, 2H), 7.39-7.30 (m, 1H), 6.06-5.89 (m, 1H), 4.95-4.83 (m, 1H), 4.75 (d, J = 19 .9 Hz, 1H), 4.16-3.94 (m, 1H), 3.89-3.61 (m, 4H), 3.60-3.44 (m, 4H), 3.26-3.12 (m, 2H), 3.01-2.95 (m, 2H), 2.75-2.62 (m, 2H), 2.46-2.33 (m, 3H), 2.27-2.19 (m, 2H), 2.17-1.95 (m, 2H). LCMS (ESI) C 31 H 33 F 3 N 5 O 3 S + [M+H] + : calculated value 612.23, found value 612.2.

实施例69：3-(6-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09936)的制备Example 69: Preparation of 3-(6-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione (GT-09936)

参照合成方案1的方法制备目标化合物GT-09936(12mg，白色固体，收率17％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，8.15-8.06(m，1H)，7.94-7.86(m，1H)，7.72(d，J＝8.9Hz，1H)，7.69-7.62(m，2H)，7.38-7.30(m，1H)，5.99-5.91(m，1H)，4.83(d，J＝20.6Hz，1H)，4.69(d，J＝20.3Hz，1H)，3.87-3.82(m，2H)，3.28-3.14(m，6H)，3.08-2.90(m，4H)，2.71-2.64(m，2H)，2.30-2.22(m，4H)，2.14-2.06(m，2H)，2.02-1.98(m，2H).LCMS(ESI)C31H33F3N5O3S+[M+H]+：计算值612.23，实测值612.2.The target compound GT-09936 (12 mg, white solid, yield 17%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.15-8.06 (m, 1H), 7.94-7.86 (m, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.69-7.62 (m, 2H), 7.38-7.30 (m, 1H), 5.99-5.91 (m, 1H), 4.83 (d, J = 20.6 Hz, 1 3H), 4.69 (d, J = 20.3 Hz, 1H), 3.87-3.82 (m, 2H), 3.28-3.14 (m, 6H), 3.08-2.90 (m, 4H), 2.71-2.64 (m, 2H), 2.30-2.22 (m, 4H), 2.14-2.06 (m, 2H), 2.02-1.98 (m, 2H). LCMS (ESI) C 31 H 33 F 3 N 5 O 3 S + [M+H] + : calculated value 612.23, found value 612.2.

实施例70：1-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-05334)的制备Example 70: Preparation of 1-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-05334)

参照合成方案1的方法制备目标化合物GT-05334(32mg，白色固体，收率30％)。1H NMR(400MHz，DMSO-d6)δ10.61(s，1H)，9.41(s，1H)，7.72(d，J＝7.7Hz，1H)，7.62-7.54(m，1H)，7.54-7.44(m，1H)，7.37(d，J＝8.3Hz，2H)，7.07(d，J＝8.3Hz，2H)，4.70(d，J＝16.2Hz，1H)，4.48(d，J＝16.3Hz，1H)，4.01-3.80(m，1H)，3.73-3.68(m，3H)，3.48(s，2H)，3.15(d，J＝10.1Hz，4H)，3.01-2.87(m，4H)，2.84-2.76(m，4H)，2.73-2.63(m，1H)，2.59-2.49(m，2H)，2.20(brs，2H)，1.97(s，2H)，1.86-1.74(m，1H)，1.72-1.65(m，1H)，1.39(t，J＝6.1Hz，2H)，0.89(s，6H).LCMS(ESI)C37H46ClF2N6O3 +[M+H]+：计算值695.33，实测值695.3.The target compound GT-05334 (32 mg, white solid, yield 30%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.41 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.62-7.54 (m, 1H), 7.54-7.44 (m, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 4.70 (d, J = 16.2 Hz, 1H), 4.48 (d, J = 16.3 Hz, 1H), 4.01-3.80 (m, 1H), 3.73-3.68 (m, 3H), 3.48 (s, 2H), 3.15 (d, J = 10.1 Hz, 4H), 3.01-2.87 (m, 4H), 2.84-2.76 (m, 4H), 2.73-2.63 (m, 1H), 2.59-2.49 (m, 2H), 2.20 (brs, 2H), 1.97 (s, 2H), 1.86-1.74 (m, 1H), 1.72-1.65 (m, 1H), 1.39 (t, J = 6.1 Hz, 2H), 0.89 (s, 6H). LCMS (ESI) C 3 7 H 4 6 ClF 2 N 6 O 3 + [M+H] + : calculated value 695.33, found value 695.3.

实施例71：1-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-09355)的制备Example 71: Preparation of 1-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-09355)

参照合成方案1的方法制备目标化合物GT-09355(11mg，白色固体，收率20％)。1H NMR(400MHz，DMSO)δ10.70(s，1H)，7.94-7.82(m，2H)，7.83-7.73(m，1H)，7.43-7.31(m，2H)，7.22-7.19(m，1H)，4.82(d，J＝16.1Hz，1H)，4.59(d，J＝16.6Hz，1H)，4.45(brs，1H)，3.79(t，J＝6.8Hz，2H)，3.67-3.58(m，2H)，3.51-3.43(m，4H)，3.25-3.17(m，4H)，3.04-2.95(m，2H)，2.94-2.82(m，2H)，2.81-2.76(m，1H)，2.40-2.30(m，2H)，2.29-2.12(m，2H)，2.06-1.92(m，1H).LCMS(ESI)C28H33Cl2N6O3 +[M+H]+：计算值571.20，实测值571.2.The target compound GT-09355 (11 mg, white solid, yield 20%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 7.94-7.82 (m, 2H), 7.83-7.73 (m, 1H), 7.43-7.31 (m, 2H), 7.22-7.19 (m, 1H), 4.82 (d, J = 16.1 Hz, 1H), 4.59 (d, J = 16.6 Hz, 1H), 4.45 (brs, 1H), 3.79 (t, J = 6.8H z, 2H), 3.67-3.58 (m, 2H), 3.51-3.43 (m, 4H), 3.25-3.17 (m, 4H), 3.04-2.95 (m, 2H), 2.94-2.82 (m, 2H), 2.81-2.76 (m, 1H), 2.40-2.30 (m, 2H), 2.29-2.12 (m, 2H), 2.06-1.92 (m, 1H). LCMS (ESI) C 2 8 H 3 3 Cl 2 N 6 O 3 + [M+H] + : calculated value 571.20, found value 571.2.

实施例72：5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-09357)的制备Example 72: Preparation of 5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-09357)

参照合成方案1的方法制备目标化合物GT-09357(17mg，白色固体，收率32％)。1H NMR(400MHz，DMSO)δ10.93(s，1H)，8.28(s，1H)，8.20-8.04(m，2H)，7.39-7.34(m，2H)，7.26-7.15(m，1H)，4.65-4.34(m，2H)，3.83(t，J＝6.8Hz，2H)，3.69-3.65(m，2H)，3.24-3.13(m，6H)，3.09-2.96(m，2H)，2.86(t，J＝6.8Hz，2H)，2.76(t，J＝6.8Hz，1H)，2.46-2.29(m，3H)，2.26-2.10(m，2H)，2.10-1.92(m，1H).LCMS(ESI)C28H31Cl2N6O4 +[M+H]+：计算值585.18，实测值585.2.The target compound GT-09357 (17 mg, white solid, yield 32%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.28 (s, 1H), 8.20-8.04 (m, 2H), 7.39-7.34 (m, 2H), 7.26-7.15 (m, 1H), 4.65-4.34 (m, 2H), 3.83 (t, J = 6.8 Hz, 2H), 3.69-3.65 ( m, 2H), 3.24-3.13 (m, 6H), 3.09-2.96 (m, 2H), 2.86 (t, J = 6.8 Hz, 2H), 2.76 (t, J = 6.8 Hz, 1H), 2.46-2.29 (m, 3H), 2.26-2.10 (m, 2H), 2.10-1.92 (m, 1H). LCMS (ESI) C 2 8 H 31 Cl 2 N 6 O 4 + [M+H] + : calculated value 585.18, found value 585.2.

实施例73：1-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-09205)的制备Example 73: Preparation of 1-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-09205)

参照合成方案1的方法制备目标化合物GT-09205(43mg，白色固体，收率57％)。1H NMR(400MHz，DMSO)δ10.68(s，1H)，7.82(d，J＝7.8Hz，1H)，7.71(s，1H)，7.62(d，J＝7.7Hz，1H)，7.40-7.32(m，2H)，7.17(dd，J＝5.7，3.8Hz，1H)，4.80(d，J＝16.6Hz，1H)，4.57(d，J＝16.5Hz，1H)，4.10(s，2H)，3.81-3.77(m，4H)，3.33-3.14(m，10H)，2.90-2.84(m，2H)，2.78(t，J＝5.3Hz，1H)，2.40-2.25(m，1H)，2.20-2.04(m，1H).LCMS(ESI)C28H31Cl2F2N6O3 +[M+H]+：计算值607.18，实测值607.2.The target compound GT-09205 (43 mg, white solid, yield 57%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.40-7.32 (m, 2H), 7.17 (dd, J = 5.7, 3.8 Hz, 1H), 4.80 (d, J = 16.6 Hz, 1H), 4 .57 (d, J = 16.5 Hz, 1H), 4.10 (s, 2H), 3.81-3.77 (m, 4H), 3.33-3.14 (m, 10H), 2.90-2.84 (m, 2H), 2.78 (t, J = 5.3 Hz, 1H), 2.40-2.25 (m, 1H), 2.20-2.04 (m, 1H). LCMS (ESI) C 2 8 H 31 Cl 2 F 2 N 6 O 3 + [M+H] + : calculated value 607.18, found value 607.2.

实施例74：1-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-09206)的制备Example 74: Preparation of 1-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-09206)

参照合成方案1的方法制备目标化合物GT-09206(31mg，白色固体，收率41％)。1H NMR(400MHz，DMSO)δ10.68(s，1H)，7.81(d，J＝7.8Hz，1H)，7.70-7.53(m，3H)，7.39(t，J＝7.9Hz，1H)，7.26(dd，J＝7.6，1.5Hz，1H)，5.75(s，1H)，4.79(d，J＝16.7Hz，1H)，4.56(d，J＝16.7Hz，1H)，4.12-3.88(m，4H)，3.88-3.77(m，5H)，3.56-3.33(m，3H)，3.26-3.11(m，1H)，2.95-2.82(m，2H)，2.81-2.70(m，2H)，2.40-2.33(m，1H)，2.21-2.05(m，1H).LCMS(ESI)C29H30Cl2F2N5O3 +[M+H]+：计算值604.17，实测值604.2.The target compound GT-09206 (31 mg, white solid, yield 41%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ10.68 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.70-7.53 (m, 3H), 7.39 (t, J=7.9 Hz, 1H), 7.26 (dd, J=7.6, 1.5 Hz, 1H), 5.75 (s, 1H), 4.79 (d, J=16.7 Hz, 1H), 4.56 (d, J=1 6.7 Hz, 1H), 4.12-3.88 (m, 4H), 3.88-3.77 (m, 5H), 3.56-3.33 (m, 3H), 3.26-3.11 (m, 1H), 2.95-2.82 (m, 2H), 2.81-2.70 (m, 2H), 2.40-2.33 (m, 1H), 2.21-2.05 (m, 1H). LCMS (ESI) C 2 9 H 3 0 Cl 2 F 2 N 5 O 3 + [M+H] + : calculated value 604.17, found value 604.2.

实施例75：5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-09358)的制备Example 75: Preparation of 5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-09358)

参照合成方案1的方法制备目标化合物GT-09358(17mg，白色固体，收率31％)。1H NMR(400MHz，DMSO)δ10.92(s，1H)，8.03-7.99(m，2H)，7.95-7.91(m，1H)，7.62(d，J＝8.0Hz，1H)，7.39(t，J＝7.9Hz，1H)，7.27(d，J＝6.6Hz，1H)，5.76(s，1H)，4.09-3.87(m，4H)，3.82(t，J＝6.7Hz，2H)，3.29-3.20(m，2H)，3.11-3.04(m，3H)，2.89(s，1H)，2.85(t，J＝6.8Hz，2H)，2.74(s，1H)，2.72-2.59(m，2H)，2.44-2.26(m，2H)，2.15-1.96(m，1H).LCMS(ESI)C29H28Cl2F2N5O4 +[M+H]+：计算值618.15，实测值618.2.The target compound GT-09358 (17 mg, white solid, yield 31%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.03-7.99 (m, 2H), 7.95-7.91 (m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 6.6 Hz, 1H), 5.76 (s, 1H), 4.09-3.87 (m, 4H), 3. 82 (t, J = 6.7 Hz, 2H), 3.29-3.20 (m, 2H), 3.11-3.04 (m, 3H), 2.89 (s, 1H), 2.85 (t, J = 6.8 Hz, 2H), 2.74 (s, 1H), 2.72-2.59 ( m , 2H), 2.44-2.26 (m, 2H), 2.15-1.96 (m, 1H ) . LCMS (ESI) C29H28Cl2F2N5O4 + [M+H] + : calculated value 618.15 , found value 618.2.

实施例76：1-(5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-09356)的制备Example 76: Preparation of 1-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-09356)

参照合成方案1的方法制备目标化合物GT-09356(19mg，白色固体，收率36％)。1H NMR(400MHz，DMSO)δ10.70(s，1H)，8.10(dd，J＝8.9，5.2Hz，1H)，7.88(d，J＝7.8Hz，2H)，7.77(d，J＝7.3Hz，1H)，7.61(dd，J＝9.0，2.0Hz，1H)，7.26(dd，J＝10.0，8.1Hz，1H)，4.82(d，J＝16.5Hz，1H)，4.58(d，J＝16.6Hz，1H)，4.44(s，1H)，4.11(brs，2H)，3.79(t，J＝6.9Hz，2H)，3.66-3.47(m，6H)，3.230-3.22(m，4H)，3.09-2.93(m，2H)，2.90-2.83(m，1H)，2.80-2.75(m，1H)，2.41-2.28(m，2H)，2.27-2.09(m，2H).LCMS(ESI)C29H33FN7O4 +[M+H]+：计算值562.26，实测值562.3.The target compound GT-09356 (19 mg, white solid, yield 36%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ10.70 (s, 1H), 8.10 (dd, J=8.9, 5.2 Hz, 1H), 7.88 (d, J=7.8 Hz, 2H), 7.77 (d, J=7.3 Hz, 1H), 7.61 (dd, J=9.0, 2.0 Hz, 1H), 7.26 (dd, J=10.0, 8.1 Hz, 1H), 4.82 (d, J=16.5 Hz, 1H), 4.58 (d, J=16.6 Hz, 1H), 4.44 (s, 1H), 4.11 (brs, 2H), 3.79 (t, J=6.9 Hz, 2H), 3.66-3.47 (m, 6H), 3.230-3.22 (m, 4H), 3.09-2.93 (m, 2H), 2.90-2.83 (m, 1H), 2.80-2.75 (m, 1H), 2.41-2.28 (m, 2H), 2.27-2.09 (m, 2H). LCMS (ESI) C 29 H 33 FN 7 O 4 + [M+H] + : calculated value 562.26, found value 562.3.

实施例77：2-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)异吲哚啉-1，3-二酮(GT-09359)的制备Example 77: Preparation of 2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione (GT-09359)

参照合成方案1的方法制备目标化合物GT-09359(17mg，白色固体，收率33％)。1H NMR(400MHz，DMSO)δ10.93(s，1H)，8.34-8.20(m，1H)，8.11-8.08(m，2H)，7.86-7.80(m，1H)，7.64-7.58(m，1H)，7.26(t，J＝8.9Hz，1H)，4.61-4.52(m，1H)，4.47-4.32(m，1H)，4.22-3.98(m，2H)，3.72-3.64(m，2H)，3.62-3.47(m，8H)，3.25-3.18(m，4H)，3.07-2.91(m，2H)，2.41-2.32(m，1H)，2.21-1.98(m，2H).LCMS(ESI)C29H31FN7O5 +[M+H]+：计算值576.24，实测值576.3.The target compound GT-09359 (17 mg, white solid, yield 33%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.34-8.20 (m, 1H), 8.11-8.08 (m, 2H), 7.86-7.80 (m, 1H), 7.64-7.58 (m, 1H), 7.26 (t, J = 8.9 Hz, 1H), 4.61-4.52 (m, 1H), 4.47- 4.32 (m, 1H), 4.22-3.98 (m, 2H), 3.72-3.64 (m, 2H), 3.62-3.47 (m, 8H), 3.25-3.18 (m, 4H), 3.07-2.91 (m, 2H), 2.41-2.32 (m, 1H), 2.21-1.98 (m, 2H). LCMS (ESI) C 29 H 31 FN 7 O 5 + [M+H] + : calculated value 576.24, found value 576.3.

实施例78：1-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-09207)的制备Example 78: Preparation of 1-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-09207)

参照合成方案1的方法制备目标化合物GT-09207(49mg，白色固体，收率65％)。1H NMR(400MHz，DMSO)δ10.68(s，1H)，8.06(dd，J＝8.9，5.3Hz，1H)，7.83(d，J＝7.7Hz，1H)，7.71(brs，1H)，7.63(brs，1H)，7.57(dd，J＝9.1，2.1Hz，1H)，7.21(td，J＝9.1，2.1Hz，1H)，4.79(d，J＝16.2Hz，1H)，4.57(d，J＝16.4Hz，1H)，4.32-3.97(m，2H)，3.81-3.77(m，4H)，3.57-3.44(m，4H)，3.40-2.98(m，6H)，2.90-2.84(m，2H)，2.81-2.73(m，1H)，2.26-1.92(m，2H).LCMS(ESI)C29H31F3N7O4 +[M+H]+：计算值598.24，实测值598.3.The target compound GT-09207 (49 mg, white solid, yield 65%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ10.68 (s, 1H), 8.06 (dd, J=8.9, 5.3 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.71 (brs, 1H), 7.63 (brs, 1H), 7.57 (dd, J=9.1, 2.1 Hz, 1H), 7.21 (td, J=9.1, 2.1 Hz, 1H), 4.79 (d, J =16.2 Hz, 1H), 4.57 (d, J=16.4 Hz, 1H), 4.32-3.97 (m, 2H), 3.81-3.77 (m, 4H), 3.57-3.44 (m, 4H), 3.40-2.98 (m, 6H), 2.90-2.84 (m, 2H), 2.81-2.73 (m, 1H), 2.26-1.92 (m, 2H). LCMS (ESI) C 2 9 H 3 1 F 3 N 7 O 4 + [M+H] + : calculated value 598.24, found value 598.3.

实施例79：5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-09360)的制备Example 79: Preparation of 5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-09360)

参照合成方案1的方法制备目标化合物GT-09360(38mg，白色固体，收率69％)。1H NMR(400MHz，DMSO)δ10.92(s，1H)，8.16-7.99(m，3H)，7.95(s，1H)，7.58(dd，J＝9.1，2.2Hz，1H)，7.22(td，J＝9.1，2.1Hz，1H)，4.04(brs，2H)，3.82(t，J＝6.8Hz，2H)，3.74-3.56(m，6H)，3.27-3.17(m，4H)，3.17-2.99(m，3H)，2.86(t，J＝6.8Hz，2H)，2.22-2.10(m，1H)，2.08-1.93(m，1H).LCMS(ESI)C29H29F3N7O5 +[M+H]+：计算值612.22，实测值612.2.The target compound GT-09360 (38 mg, white solid, yield 69%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400MHz, DMSO) δ10.92 (s, 1H), 8.16-7.99 (m, 3H), 7.95 (s, 1H), 7.58 (dd, J=9.1, 2.2Hz, 1H), 7.22 (td, J=9.1, 2.1Hz, 1H), 4.04 (brs, 2H), 3.82 ( t, J＝6.8Hz, 2H), 3.74-3.56(m, 6H), 3.27-3.17(m, 4H), 3.17-2.99(m, 3H) , 2.86 (t, J=6.8Hz, 2H), 2.22-2.10 (m, 1H), 2.08-1.93 (m, 1H).LCMS (ESI) C 29 H 29 F 3 N 7 O 5 + [M+H] + : Calculated 612.22, found 612.2.

实施例80：1-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮(GT-09208)的制备Example 80: Preparation of 1-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (GT-09208)

参照合成方案1的方法制备目标化合物GT-09208(34mg，白色固体，收率46％)。1H NMR(400MHz，DMSO)δ10.68(s，1H)，8.23(s，1H)，7.79(d，J＝7.8Hz，1H)，7.73(d，J＝9.0Hz，1H)，7.63(s，1H)，7.54(s，1H)，7.34(t，J＝9.0Hz，1H)，4.78(d，J＝16.7Hz，1H)，4.55(d，J＝16.7Hz，1H)，4.20-3.98(m，1H)，3.89(s，2H)，3.79(t，J＝7.4Hz，3H)，3.75-3.65(m，2H)，3.35-3.21(m，3H)，3.19-3.00(m，2H)，2.97-2.82(m，2H)，2.82-2.70(m，2H)，2.47-2.37(m，3H)，2.27-2.18(m，2H).LCMS(ESI)C30H32F3N6O4 +[M+H]+：计算值597.24，实测值597.3.The target compound GT-09208 (34 mg, white solid, yield 46%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ10.68 (s, 1H), 8.23 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.34 (t, J=9.0 Hz, 1H), 4.78 (d, J=16.7 Hz, 1H), 4.55 (d, J=16.7 Hz, 1H), 4.20 -3.98 (m, 1H), 3.89 (s, 2H), 3.79 (t, J=7.4 Hz, 3H), 3.75-3.65 (m, 2H), 3.35-3.21 (m, 3H), 3.19-3.00 (m, 2H), 2.97-2.82 (m, 2H), 2.82-2.70 (m, 2H), 2.47-2.37 (m, 3H), 2.27-2.18 (m, 2H). LCMS (ESI) C 30 H 32 F 3 N 6 O 4 + [M+H] + : calculated value 597.24, found value 597.3.

实施例81：5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮(GT-09361)的制备Example 81: Preparation of 5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-2-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)isoindoline-1,3-dione (GT-09361)

参照合成方案1的方法制备目标化合物GT-09361(22mg，白色固体，收率40％)。1H NMR(400MHz，DMSO)δ10.91(s，1H)，8.24(s，1H)，8.01(d，J＝7.7Hz，1H)，7.97(s，1H)，7.91(d，J＝7.7Hz，1H)，7.73(dd，J＝9.1，2.1Hz，1H)，7.34(td，J＝9.1，2.1Hz，1H)，4.18-3.99(m，1H)，3.92(s，2H)，3.83(t，J＝6.7Hz，2H)，3.78-3.65(m，2H)，3.61-3.54(m，4H)，3.33-3.20(m，2H)，3.10-3.02(m，1H)，2.85(t，J＝6.8Hz，2H)，2.48-2.42(m，2H)，2.39-2.33(m，1H)，2.23-2.19(m，2H)，2.12-2.05(m，1H).LCMS(ESI)C30H30F3N6O5 +[M+H]+：计算值611.22，实测值611.2.The target compound GT-09361 (22 mg, white solid, yield 40%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.24 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.73 (dd, J = 9.1, 2.1 Hz, 1H), 7.34 (td, J = 9.1, 2.1 Hz, 1H), 4.18-3.99 (m, 1H), 3.92 (s, 2H), 3.83 (t , J = 6.7 Hz, 2H), 3.78-3.65 (m, 2H), 3.61-3.54 (m, 4H), 3.33-3.20 (m, 2H), 3.10-3.02 (m, 1H), 2.85 (t, J = 6.8 Hz, 2H), 2.48-2.42 (m, 2H), 2.39-2.33 (m, 1H), 2.23-2.19 (m, 2H), 2.12-2.05 (m, 1H). LCMS (ESI) C 30 H 30 F 3 N 6 O 5 + [M+H] + : calculated value 611.22, found value 611.2.

实施例82：3-(6-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09188)的制备Example 82: Preparation of 3-(6-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09188)

参照合成方案1的方法制备目标化合物(GT-09188)(白色固体，27mg，收率46％)。1H NMR(400MHz，DMSO)δ11.95(s，1H)，11.01(s，1H)，7.96-7.83(m，5H)，7.79(d，J＝7.8Hz，1H)，7.70(d，J＝7.8Hz，1H)，7.43(t，J＝7.5Hz，4H)，7.35(t，J＝7.3Hz，2H)，5.60(s，1H)，5.13(dd，J＝13.2，5.0Hz，1H)，4.51(d，J＝17.7Hz，1H)，4.38(d，J＝17.4Hz，2H)，3.59(s，2H)，3.32-3.24(m，5H)，3.11(s，2H)，3.05-2.86(m，6H)，2.61(d，J＝17.4Hz，1H)，2.46-2.37(m，1H)，2.08-1.89(m，3H).LCMS(ESI)C36H40F2N5O3 +[M+H]+：计算值628.31，实测值628.3.The target compound (GT-09188) (white solid, 27 mg, yield 46%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 11.01 (s, 1H), 7.96-7.83 (m, 5H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.5 Hz, 4H), 7.35 (t, J = 7.3 Hz, 2H), 5.60 (s, 1H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.51 (d, J = 17.7 Hz, 1H), 4.38 (d, J = 17.4 Hz, 2H), 3.59 (s, 2H), 3.32-3.24 (m, 5H), 3.11 (s, 2H), 3.05-2.86 (m, 6H), 2.61 (d, J = 17.4 Hz, 1H), 2.46-2.37 (m, 1H), 2.08-1.89 (m, 3H). LCMS (ESI) C 36 H 40 F 2 N 5 O 3 + [M+H] + : calculated value 628.31, found value 628.3.

实施例83：3-(7-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09189)的制备Example 83: Preparation of 3-(7-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09189)

参照合成方案1的方法制备目标化合物(GT-09189)(白色固体，20mg，收率34％)。1H NMR(400MHz，DMSO)δ12.01(s，1H)，11.04(s，1H)，7.91(d，J＝7.3Hz，4H)，7.72(s，3H)，7.43(t，J＝7.6Hz，4H)，7.35(t，J＝7.3Hz，2H)，5.60(s，1H)，5.18-5.07(m，1H)，4.88(d，J＝37.2Hz，1H)，4.78-4.61(m，1H)，4.53(d，J＝18.0Hz，1H)，4.48-4.36(m，1H)，3.72(d，J＝30.8Hz，2H)，3.35-3.25(m，4H)，3.09(d，J＝17.8Hz，3H)，3.07-2.91(m，5H)，2.62(d，J＝16.9Hz，1H)，2.46-2.36(m，1H)，2.09-1.90(m，3H).LCMS(ESI)C36H40F2N5O3 +[M+H]+：计算值628.31，实测值628.3.The target compound (GT-09189) (white solid, 20 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 11.04 (s, 1H), 7.91 (d, J = 7.3 Hz, 4H), 7.72 (s, 3H), 7.43 (t, J = 7.6 Hz, 4H), 7.35 (t, J = 7.3 Hz, 2H), 5.60 (s, 1H), 5.18-5.07 (m, 1H), 4.88 (d, J = 37.2 Hz, 1H), 4.78-4.61 (m, 1H) , 4.53 (d, J = 18.0 Hz, 1H), 4.48-4.36 (m, 1H), 3.72 (d, J = 30.8 Hz, 2H), 3.35-3.25 (m, 4H), 3.09 (d, J = 17.8 Hz, 3H), 3.07-2.91 (m, 5H), 2.62 (d, J = 16.9 Hz, 1H), 2.46-2.36 (m, 1H), 2.09-1.90 (m, 3H). LCMS (ESI) C 36 H 40 F 2 N 5 O 3 + [M+H] + : calculated value 628.31, found value 628.3.

实施例84：3-(5-(2-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09190)的制备Example 84: Preparation of 3-(5-(2-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09190)

参照合成方案1的方法制备目标化合物(GT-09190)(白色固体，10mg，收率17％)。1H NMR(400MHz，DMSO)δ11.91(s，1H)，10.99(s，1H)，7.90(d，J＝6.9Hz，4H)，7.71(d，J＝7.8Hz，1H)，7.52(s，1H)，7.44(t，J＝7.6Hz，5H)，7.36(t，2H)，5.61(s，1H)，5.14-5.04(m，1H)，4.45(d，J＝17.6Hz，1H)，4.32(d，J＝17.5Hz，1H)，3.96(s，1H)，3.58(s，2H)，3.34-3.32(m，2H)，3.23-3.12(m，5H)，3.02(d，J＝10.8Hz，4H)，2.96-2.80(m，2H)，2.70-2.54(m，2H)，2.46-2.32(m，2H)，2.11-1.98(m，3H).LCMS(ESI)C37H42F2N5O3 +[M+H]+：计算值642.33，实测值642.4.The target compound (GT-09190) (white solid, 10 mg, yield 17%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 10.99 (s, 1H), 7.90 (d, J = 6.9 Hz, 4H), 7.71 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.44 (t, J = 7.6 Hz, 5H), 7.36 (t, 2H), 5.61 (s, 1H), 5.14-5.04 (m, 1H), 4.45 (d, J = 17.6 Hz, 1H), 4.32 (d, J = 17.5 Hz, 1H), 3.96 (s, 1H), 3.58 (s, 2H), 3.34-3.32 (m, 2H), 3.23-3.12 (m, 5H), 3.02 (d, J = 10.8 Hz, 4H), 2.96-2.80 (m, 2H), 2.70-2.54 (m, 2H), 2.46-2.32 (m, 2H), 2.11-1.98 (m, 3H). LCMS (ESI) C 3 7 H 4 2 F 2 N 5 O 3 + [M+H] + : calculated value 642.33, found value 642.4.

实施例85：3-(5-(3-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09191)的制备Example 85: Preparation of 3-(5-(3-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09191)

参照合成方案1的方法制备目标化合物(GT-09191)(白色固体，12mg，收率15％)。1H NMR(400MHz，DMSO)δ11.90(s，1H)，10.99(s，1H)，10.75(s，1H)，7.90(d，J＝7.2Hz，4H)，7.68(d，J＝7.8Hz，1H)，7.51-7.34(m，8H)，5.60(s，1H)，5.16-4.99(m，1H)，4.43(d，J＝17.3Hz，1H)，4.30(d，J＝17.3Hz，1H)，3.91(s，1H)，3.30(s，4H)，3.16-2.89(m，11H)，2.75(t，J＝7.4Hz，2H)，2.60(d，J＝17.6Hz，1H)，2.47-2.31(m，2H)，2.15-1.94(m，5H).LCMS(ESI)C38H44F2N5O3 +[M+H]+：计算值656.34，实测值656.4.The target compound (GT-09191) (white solid, 12 mg, yield 15%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 10.99 (s, 1H), 10.75 (s, 1H), 7.90 (d, J = 7.2 Hz, 4H), 7.68 (d, J = 7.8 Hz, 1H), 7.51-7.34 (m, 8H), 5.60 (s, 1H), 5.16-4.99 (m, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.91 (s, 1H), 3.30 (s, 4H), 3.16-2.89 (m, 11H), 2.75 (t, J = 7.4 Hz, 2H), 2.60 (d, J = 17.6 Hz, 1H), 2.47-2.31 (m, 2H), 2.15-1.94 (m, 5H). LCMS (ESI) C 38 H 44 F 2 N 5 O 3 + [M+H] + : calculated value 656.34, found value 656.4.

实施例86：5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09192)的制备Example 86: Preparation of 5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09192)

参照合成方案1的方法制备目标化合物(GT-09192)(白色固体，21mg，收率35％)。1H NMR(400MHz，DMSO)δ11.47(s，1H)，11.07(s，1H)，7.89(d，J＝7.8Hz，2H)，7.86-7.66(m，5H)，7.37(t，J＝7.4Hz，4H)，7.29(t，J＝7.3Hz，2H)，5.51(s，1H)，5.09(dd，J＝12.8，5.5Hz，1H)，4.01(s，2H)，3.16(s，3H)，2.99(d，J＝31.9Hz，8H)，2.88-2.76(m，2H)，2.61-2.47(m，3H)，2.04-1.95(m，1H)，1.81(s，2H).LCMS(ESI)C36H38F2N5O4 +[M+H]+：计算值642.29，实测值642.3.The target compound (GT-09192) (white solid, 21 mg, yield 35%) was prepared by referring to the method of Synthesis Scheme 1 . NMR (400MHz, DMSO) δ11.47 (s, 1H), 11.07 (s, 1H), 7.89 (d, J=7.8Hz, 2H), 7.86- 7.66 (m, 5H), 7.37 (t, J=7.4Hz, 4H), 7.29 (t, J=7.3Hz, 2H), 5.51 (s, 1H), 5.09 ( dd, J=12.8, 5.5Hz, 1H), 4.01 (s, 2H), 3.16 (s, 3H), 2.99 (d, J=31.9Hz, 8H), 2.8 8-2.76(m, 2H), 2.61-2.47(m, 3H), 2.04-1.95(m, 1H), 1.81(s, 2H).LCMS(ESI)C 36 H 38 F 2 N 5 O 4 + [M+H] + : calculated value 642.29, found value 642.3.

实施例87：4-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09193)的制备Example 87: Preparation of 4-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09193)

参照合成方案1的方法制备目标化合物(GT-09193)(白色固体，26mg，收率43％)。1H NMR(400MHz，DMSO)δ11.58(s，1H)，11.07(s，1H)，7.91(s，1H)，7.86-7.82(m，2H)，7.78(d，J＝5.9Hz，4H)，7.37(t，J＝7.5Hz，4H)，7.29(t，J＝7.3Hz，2H)，5.51(s，1H)，5.08(dd，J＝12.8，5.4Hz，1H)，4.25(s，2H)，3.18(s，4H)，3.09-2.89(m，8H)，2.88-2.78(m，2H)，2.62-2.51(m，2H)，2.02-1.92(m，1H)，1.90-1.73(m，2H).LCMS(ESI)C36H38F2N5O4 +[M+H]+：计算值642.29，实测值642.3.The target compound (GT-09193) (white solid, 26 mg, yield 43%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 11.07 (s, 1H), 7.91 (s, 1H), 7.86-7.82 (m, 2H), 7.78 (d, J = 5.9 Hz, 4H), 7.37 (t, J = 7.5 Hz, 4H), 7.29 (t, J = 7.3 Hz, 2H), 5.51 (s, 1H), 5.08 (dd, J=12.8, 5.4 Hz, 1H), 4.25 (s, 2H), 3.18 (s, 4H), 3.09-2.89 (m, 8H), 2.88-2.78 (m, 2H), 2.62-2.51 (m, 2H), 2.02-1.92 (m, 1H), 1.90-1.73 (m, 2H). LCMS (ESI) C 36 H 38 F 2 N 5 O 4 + [M+H] + : calculated value 642.29, found value 642.3.

实施例88：3-(7-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09194)的制备Example 88: Preparation of 3-(7-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09194)

参照合成方案1的方法制备目标化合物(GT-09194)(白色固体，21mg，收率34％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，10.55(s，1H)，7.91-7.61(m，7H)，7.39(t，J＝7.4Hz，4H)，7.29(t，J＝12.7Hz，2H)，5.12(dd，J＝13.2，5.1Hz，1H)，4.85(d，J＝11.6Hz，1H)，4.71(d，J＝12.6Hz，1H)，4.51(d，J＝17.8Hz，1H)，4.39(d，1H)，3.60-3.55(m，6H)，3.21-2.98(m，6H)，2.95-2.87(m，1H)，2.70-2.56(m，2H)，2.49-2.36(m，2H)，2.29(d，J＝11.1Hz，2H)，2.18-1.97(m，3H).LCMS(ESI)C36H42N5O3 +[M+H]+：计算值592.33，实测值592.4.The target compound (GT-09194) (white solid, 21 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 10.55 (s, 1H), 7.91-7.61 (m, 7H), 7.39 (t, J = 7.4 Hz, 4H), 7.29 (t, J = 12.7 Hz, 2H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.71 (d, J = 12.6 Hz, 1H ), 4.51 (d, J = 17.8 Hz, 1H), 4.39 (d, 1H), 3.60-3.55 (m, 6H), 3.21-2.98 (m, 6H), 2.95-2.87 (m, 1H), 2.70-2.56 (m, 2H), 2.49-2.36 (m, 2H), 2.29 (d, J = 11.1 Hz, 2H), 2.18-1.97 (m, 3H). LCMS (ESI) C 36 H 42 N 5 O 3 + [M+H] + : calculated value 592.33, found value 592.4.

实施例89：3-(5-(2-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09195)的制备Example 89: Preparation of 3-(5-(2-(4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09195)

参照合成方案1的方法制备目标化合物(GT-09195)(白色固体，20mg，收率32％)。1H NMR(400MHz，DMSO)δ10.92(s，1H)，10.75(s，1H)，7.65(d，J＝7.8Hz，1H)，7.50(d，J＝22.2Hz，4H)，7.46(s，1H)，7.37(d，J＝8.1Hz，1H)，7.29(t，J＝7.4Hz，5H)，7.20(t，J＝6.9Hz，2H)，5.07-4.98(m，1H)，4.38(d，J＝17.5Hz，1H)，4.25(d，J＝17.5Hz，1H)，3.65(d，J＝11.0Hz，2H)，3.26-3.18(m，6H)，3.16-3.11(m，3H)，3.00-2.88(m，4H)，2.86-2.78(m，2H)，2.52(d，2H)，2.39-2.23(m，4H)，2.12-2.00(m，2H)，1.96-1.90(m，1H).LCMS(ESI)C37H44N5O3 +[M+H]+：计算值606.34，实测值606.4.The target compound (GT-09195) (white solid, 20 mg, yield 32%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 10.75 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 22.2 Hz, 4H), 7.46 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.29 (t, J = 7.4 Hz, 5H), 7.20 (t, J = 6.9 Hz, 2H), 5.07-4.98 (m, 1H), 4.38 (d, J = 17.5 Hz, 4H). z, 1H), 4.25 (d, J = 17.5 Hz, 1H), 3.65 (d, J = 11.0 Hz, 2H), 3.26-3.18 (m, 6H), 3.16-3.11 (m, 3H), 3.00-2.88 (m, 4H), 2.86-2.78 (m, 2H), 2.52 (d, 2H), 2.39-2.23 (m, 4H), 2.12-2.00 (m, 2H), 1.96-1.90 (m, 1H). LCMS (ESI) C 3 7 H 4 4 N 5 O 3 + [M+H] + : calculated value 606.34, found value 606.4.

实施例90：3-(5-(3-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09196)的制备Example 90: Preparation of 3-(5-(3-(4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09196)

参照合成方案1的方法制备目标化合物(GT-09196)(黄色固体，16mg，收率19％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，10.56(s，1H)，7.68(d，J＝7.7Hz，5H)，7.49(s，1H)，7.44-7.33(m，6H)，7.30(t，J＝7.2Hz，2H)，5.11(dd，J＝13.2，5.0Hz，1H)，4.44(d，J＝17.3Hz，1H)，4.31(d，J＝17.4Hz，1H)，3.63(d，J＝11.8Hz，2H)，3.28-3.20(m，3H)，3.09-2.99(m，4H)，2.97-2.87(m，4H)，2.77(t，J＝7.2Hz，2H)，2.61(dd，J＝34.8，17.6Hz，2H)，2.46-2.36(m，2H)，2.35-2.21(m，3H)，2.19-1.94(m，6H).LCMS(ESI)C38H46N5O3 +[M+H]+：计算值620.36，实测值620.4.The target compound (GT-09196) (yellow solid, 16 mg, yield 19%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.56 (s, 1H), 7.68 (d, J = 7.7 Hz, 5H), 7.49 (s, 1H), 7.44-7.33 (m, 6H), 7.30 (t, J = 7.2 Hz, 2H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 3.63 (d, J = 11.8 Hz, 2H), 3.28-3.20 (m, 3H), 3.09-2.99 (m, 4H), 2.97-2.87 (m, 4H), 2.77 (t, J = 7.2 Hz, 2H), 2.61 (dd, J = 34.8, 17.6 Hz, 2H), 2.46-2.36 (m, 2H), 2.35-2.21 (m, 3H), 2.19-1.94 (m, 6H). LCMS (ESI) C 38 H 46 N 5 O 3 + [M+H] + : calculated value 620.36, found value 620.4.

实施例91：5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09334)的制备Example 91: Preparation of 5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09334)

参照合成方案1的方法制备目标化合物(GT-09334)(白色固体，19mg，收率31％)。1H NMR(400MHz，DMSO)δ11.08(s，2H)，8.14(s，1H)，8.02(d，J＝7.6Hz，1H)，7.96(d，J＝7.6Hz，1H)，7.56(s，4H)，7.30(t，J＝7.3Hz，4H)，7.23-7.17(m，2H)，5.12(dd，J＝12.7，5.4Hz，1H)，4.44(s，2H)，3.44(d，4H)，3.43-3.41(m，3H)，3.30-3.29(m，2H)，3.00-2.88(m，4H)，2.86-2.77(m，2H)，2.58-2.47(m，2H)，2.26-2.18(m，2H)，2.09-1.96(m，3H).LCMS(ESI)C36H40N5O4 +[M+H]+：计算值606.31，实测值606.3.The target compound (GT-09334) (white solid, 19 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.08 (s, 2H), 8.14 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.56 (s, 4H), 7.30 (t, J = 7.3 Hz, 4H), 7.23-7.17 (m, 2H), 5.12 (dd, J = 12.7, 5.4 Hz, 1 3H), 4.44 (s, 2H), 3.44 (d, 4H), 3.43-3.41 (m, 3H), 3.30-3.29 (m, 2H), 3.00-2.88 (m, 4H), 2.86-2.77 (m, 2H), 2.58-2.47 (m, 2H), 2.26-2.18 (m, 2H), 2.09-1.96 (m, 3H). LCMS (ESI) C 36 H 40 N 5 O 4 + [M+H] + : calculated value 606.31, found value 606.3.

实施例92：4-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09335)的制备Example 92: Preparation of 4-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09335)

参照合成方案1的方法制备目标化合物(GT-09335)(白色固体，23mg，收率37％)。1H NMR(400MHz，DMSO)δ11.09(s，1H)，10.83(s，1H)，8.10(d，J＝7.6Hz，1H)，7.96(d，J＝6.8Hz，1H)，7.89(t，J＝7.6Hz，1H)，7.51(s，4H)，7.29(t，J＝7.3Hz，4H)，7.20(t，J＝7.0Hz，2H)，5.11(dd，J＝12.7，5.4Hz，1H)，4.63(s，2H)，3.54(s，3H)，3.28-3.22(m，5H)，3.09-2.99(m，3H)，2.97-2.76(m，4H)，2.61-2.49(m，2H)，2.24-2.16(m，2H)，2.10-1.96(m，3H).LCMS(ESI)C36H40N5O4 +[M+H]+：计算值606.31，实测值606.3.The target compound (GT-09335) (white solid, 23 mg, yield 37%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 10.83 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 6.8 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.51 (s, 4H), 7.29 (t, J = 7.3 Hz, 4H), 7.20 (t, J = 7.0 Hz, 2H), 5.1 1 (dd, J = 12.7, 5.4 Hz, 1H), 4.63 (s, 2H), 3.54 (s, 3H), 3.28-3.22 (m, 5H), 3.09-2.99 (m, 3H), 2.97-2.76 (m, 4H), 2.61-2.49 (m, 2H), 2.24-2.16 (m, 2H), 2.10-1.96 (m, 3H). LCMS (ESI) C 36 H 40 N 5 O 4 + [M+H] + : calculated value 606.31, found value 606.3.

实施例93：3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09336)的制备Example 93: Preparation of 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09336)

参照合成方案1的方法制备目标化合物(GT-09336)(白色固体，27mg，收率45％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，8.74(d，J＝4.7Hz，1H)，7.92(t，1H)，7.80(s，1H)，7.70-7.61(m，4H)，7.49-7.38(m，4H)，5.85(s，1H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.59(d，J＝15.7Hz，1H)，4.43(d，J＝17.6Hz，1H)，4.27(s，2H)，3.36-3.28(m，3H)，3.16-3.00(m，9H)，2.94-2.82(m，2H)，2.61(d，J＝16.5Hz，1H)，2.46-2.40(m，1H)，2.06-1.91(m，3H).LCMS(ESI)C35H38F3N6O3 +[M+H]+：计算值647.30，实测值647.3.The target compound (GT-09336) (white solid, 27 mg, yield 45%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.74 (d, J = 4.7 Hz, 1H), 7.92 (t, 1H), 7.80 (s, 1H), 7.70-7.61 (m, 4H), 7.49-7.38 (m, 4H), 5.85 (s, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 15 .7 Hz, 1H), 4.43 (d, J = 17.6 Hz, 1H), 4.27 (s, 2H), 3.36-3.28 (m, 3H), 3.16-3.00 (m, 9H), 2.94-2.82 (m, 2H), 2.61 (d, J = 16.5 Hz, 1H), 2.46-2.40 (m, 1H), 2.06-1.91 (m, 3H). LCMS (ESI) C 35 H 38 F 3 N 6 O 3 + [M+H] + : calculated value 647.30, found value 647.3.

实施例94：3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09337)的制备Example 94: Preparation of 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09337)

参照合成方案1的方法制备目标化合物(GT-09337)(白色固体，16mg，收率27％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.74(d，J＝4.8Hz，1H)，7.99-7.83(m，2H)，7.72-7.60(m，4H)，7.50-7.36(m，4H)，5.86(s，1H)，5.13(dd，J＝13.3，5.1Hz，1H)，4.49(d，J＝17.4，3.8Hz，1H)，4.36(d，J＝17.5，4.7Hz，1H)，4.28(s，2H)，3.33-3.23(m，4H)，3.13-3.03(m，7H)，2.98-2.81(m，3H)，2.61(d，J＝17.4Hz，1H)，2.45-2.39(m，1H)，2.07-1.92(m，3H).LCMS(ESI)C35H38F3N6O3 +[M+H]+：计算值647.30，实测值647.3.The target compound (GT-09337) (white solid, 16 mg, yield 27%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.99-7.83 (m, 2H), 7.72-7.60 (m, 4H), 7.50-7.36 (m, 4H), 5.86 (s, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.4, 3.8 Hz, 1H). z, 1H), 4.36 (d, J = 17.5, 4.7 Hz, 1H), 4.28 (s, 2H), 3.33-3.23 (m, 4H), 3.13-3.03 (m, 7H), 2.98-2.81 (m, 3H), 2.61 (d, J = 17.4 Hz, 1H), 2.45-2.39 (m, 1H), 2.07-1.92 (m, 3H). LCMS (ESI) C 35 H 38 F 3 N 6 O 3 + [M+H] + : calculated value 647.30, found value 647.3.

实施例95：3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09338)的制备Example 95: Preparation of 3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09338)

参照合成方案1的方法制备目标化合物(GT-09338)(白色固体，20mg，收率33％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.74(d，J＝4.7Hz，1H)，7.91(t，J＝7.7，3.9Hz，1H)，7.68(d，J＝7.0Hz，2H)，7.64(d，J＝7.8Hz，1H)，7.59(s，1H)，7.54(d，J＝9.5Hz，1H)，7.50-7.39(m，4H)，5.86(s，1H)，5.10(dd，J＝13.2，5.0Hz，1H)，4.52(d，J＝17.5Hz，1H)，4.39(d，J＝18.1Hz，1H)，4.29(s，2H)，3.39-3.34(m，3H)，3.15-3.10(m，2H)，3.10-2.98(m，6H)，2.97-2.87(m，2H)，2.61(d，J＝17.3Hz，1H)，2.47-2.30(m，2H)，2.14-2.04(m，1H)，2.03-1.94(m，2H).LCMS(ESI)C35H38F3N6O3 +[M+H]+：计算值647.30，实测值647.3.The target compound (GT-09338) (white solid, 20 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.74 (d, J = 4.7 Hz, 1H), 7.91 (t, J = 7.7, 3.9 Hz, 1H), 7.68 (d, J = 7.0 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 9.5 Hz, 1H), 7.50-7.39 (m, 4H), 5.86 (s, 1H), 5.10 (dd, J = 13.2, 5.0 Hz, 1H), 4 .52 (d, J = 17.5 Hz, 1H), 4.39 (d, J = 18.1 Hz, 1H), 4.29 (s, 2H), 3.39-3.34 (m, 3H), 3.15-3.10 (m, 2H), 3.10-2.98 (m, 6H), 2.97-2.87 (m, 2H), 2.61 (d, J = 17.3 Hz, 1H), 2.47-2.30 (m, 2H), 2.14-2.04 (m, 1H), 2.03-1.94 (m, 2H). LCMS (ESI) C 35 H 38 F 3 N 6 O 3 + [M+H] + : calculated value 647.30, found value 647.3.

实施例96：3-(4-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09339)的制备Example 96: Preparation of 3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09339)

参照合成方案1的方法制备目标化合物(GT-09339)(黄色固体，19mg，收率32％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，8.75(d，J＝4.4Hz，1H)，7.91(t，J＝7.7，1.6Hz，1H)，7.76(d，J＝7.2Hz，2H)，7.66(d，J＝6.8Hz，2H)，7.59(d，J＝7.9Hz，2H)，7.49-7.37(m，5H)，5.82(s，1H)，5.20-5.13(m，1H)，4.63-4.57(m，1H)，4.40(d，1H)，4.08(s，2H)，3.14-3.01(m，10H)，2.96-2.88(m，2H)，2.65-2.60(m，1H)，2.41-2.28(m，2H)，1.98(d，J＝35.9Hz，4H).LCMS(ESI)C35H39F2N6O3 +[M+H]+：计算值629.30，实测值629.3.The target compound (GT-09339) (yellow solid, 19 mg, yield 32%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 7.91 (t, J = 7.7, 1.6 Hz, 1H), 7.76 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 6.8 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.49-7.37 (m, 5H), 5.82 (s, 1 3H), 5.20-5.13 (m, 1H), 4.63-4.57 (m, 1H), 4.40 (d, 1H), 4.08 (s, 2H), 3.14-3.01 (m, 10H), 2.96-2.88 (m, 2H), 2.65-2.60 (m, 1H), 2.41-2.28 (m, 2H), 1.98 (d, J=35.9 Hz, 4H). LCMS (ESI) C 35 H 39 F 2 N 6 O 3 + [M+H] + : calculated value 629.30, found value 629.3.

实施例97：3-(6-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09340)的制备Example 97: Preparation of 3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09340)

参照合成方案1的方法制备目标化合物(GT-09340)(白色固体，12mg，收率21％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，8.74(d，J＝4.5Hz，1H)，7.96(s，1H)，7.91(t，J＝7.6Hz，1H)，7.83(d，J＝6.9Hz，1H)，7.78-7.65(m，4H)，7.63(d，J＝7.9Hz，1H)，7.53-7.36(m，5H)，5.86(s，1H)，5.13(dd，J＝13.2，5.0Hz，1H)，4.51(d，J＝17.7Hz，1H)，4.41(s，1H)，4.36(d，1H)，3.34-3.30(m，2H)，3.14(s，3H)，3.06-3.00(m，6H)，2.96-2.86(m，2H)，2.61(d，J＝17.0Hz，2H)，2.45-2.32(m，2H)，2.08-1.95(m，3H).LCMS(ESI)C35H39F2N6O3 +[M+H]+：计算值629.30，实测值629.4.The target compound (GT-09340) (white solid, 12 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.74 (d, J = 4.5 Hz, 1H), 7.96 (s, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.83 (d, J = 6.9 Hz, 1H), 7.78-7.65 (m, 4H), 7.63 (d, J = 7.9 Hz, 1H), 7.53-7.36 (m, 5H), 5.86 (s, 1H), 5.13 (dd, J = 13.2 , 5.0 Hz, 1H), 4.51 (d, J=17.7 Hz, 1H), 4.41 (s, 1H), 4.36 (d, 1H), 3.34-3.30 (m, 2H), 3.14 (s, 3H), 3.06-3.00 (m, 6H), 2.96-2.86 (m, 2H), 2.61 (d, J=17.0 Hz, 2H), 2.45-2.32 (m, 2H), 2.08-1.95 (m, 3H). LCMS (ESI) C 35 H 39 F 2 N 6 O 3 + [M+H] + : calculated value 629.30, found value 629.4.

实施例98：3-(7-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09341)的制备Example 98: Preparation of 3-(7-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09341)

参照合成方案1的方法制备目标化合物(GT-09341)(黄色固体，13mg，收率22％)。1H NMR(400MHz，DMSO)δ11.04(s，1H)，8.74(d，J＝4.9Hz，1H)，7.91(t，J＝7.7，1.5Hz，1H)，7.74(s，3H)，7.69(d，J＝7.2Hz，2H)，7.64(d，J＝7.8Hz，1H)，7.49-7.39(m，4H)，5.87(s，1H)，5.16-5.09(m，1H)，4.98-4.81(m，1H)，4.77-4.64(m，1H)，4.53(d，J＝17.8Hz，1H)，3.75(s，2H)，3.42-3.40(m，2H)，3.19-2.98(m，10H)，2.89(t，J＝11.7Hz，1H)，2.62(d，J＝17.2Hz，1H)，2.45-2.39(m，1H)，2.03(s，3H).LCMS(ESI)C35H39F2N6O3 +[M+H]+：计算值629.30，实测值629.3.The target compound (GT-09341) (yellow solid, 13 mg, yield 22%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.74 (d, J = 4.9 Hz, 1H), 7.91 (t, J = 7.7, 1.5 Hz, 1H), 7.74 (s, 3H), 7.69 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.49-7.39 (m, 4H), 5.87 (s, 1H), 5.16-5.09 (m, 1H), 4.98- 4.81 (m, 1H), 4.77-4.64 (m, 1H), 4.53 (d, J = 17.8 Hz, 1H), 3.75 (s, 2H), 3.42-3.40 (m, 2H), 3.19-2.98 (m, 10H), 2.89 (t, J = 11.7 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.45-2.39 (m, 1H), 2.03 (s, 3H). LCMS (ESI) C 35 H 39 F 2 N 6 O 3 + [M+H] + : calculated value 629.30, found value 629.3.

实施例99：3-(5-(2-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09342)的制备Example 99: Preparation of 3-(5-(2-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09342)

参照合成方案1的方法制备目标化合物(GT-09342)(黄色固体，18mg，收率23％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，8.75(d，J＝4.6Hz，1H)，7.92(t，J＝7.8Hz，1H)，7.75-7.64(m，4H)，7.53(s，1H)，7.50-7.36(m，5H)，5.88(s，1H)，5.10(dd，J＝13.3，5.0Hz，1H)，4.45(d，J＝17.5Hz，1H)，4.32(d，J＝17.5Hz，1H)，4.00(s，2H)，3.43-3.35(m，4H)，3.27-3.15(m，5H)，3.10-3.04(m，4H)，2.95-2.88(m，1H)，2.60(d，J＝16.4Hz，2H)，2.39(dd，J＝17.5，8.8Hz，2H)，2.17-1.97(m，3H).LCMS(ESI)C36H41F2N6O3 +[M+H]+：计算值643.32，实测值643.3.The target compound (GT-09342) (yellow solid, 18 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.75 (d, J = 4.6 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.75-7.64 (m, 4H), 7.53 (s, 1H), 7.50-7.36 (m, 5H), 5.88 (s, 1H), 5.10 (dd, J = 13.3, 5.0 Hz, 1H), 4.45 (d, J = 17.5 Hz, 1H), 4.32 (d, J = 17.5 Hz, 1H), 4.00 (s, 2H), 3.43-3.35 (m, 4H), 3.27-3.15 (m, 5H), 3.10-3.04 (m, 4H), 2.95-2.88 (m, 1H), 2.60 (d, J = 16.4 Hz, 2H), 2.39 (dd, J = 17.5, 8.8 Hz, 2H), 2.17-1.97 (m, 3H). LCMS (ESI) C 3 6 H 4 1 F 2 N 6 O 3 + [M+H] + : calculated value 643.32, found value 643.3.

实施例100：3-(5-(3-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09343)的制备Example 100: Preparation of 3-(5-(3-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09343)

参照合成方案1的方法制备目标化合物(GT-09343)(黄色固体，18mg，收率23％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，10.99(s，1H)，8.74(d，J＝4.7Hz，1H)，7.91(t，J＝7.6Hz，1H)，7.75-7.61(m，4H)，7.52-7.35(m，6H)，5.88(s，1H)，5.11(dd，J＝13.3，5.0Hz，1H)，4.43(d，J＝17.2Hz，1H)，4.30(d，J＝17.4Hz，1H)，3.91(s，1H)，3.37-3.26(m，4H)，3.15-3.00(m，10H)，2.96-2.87(m，1H)，2.75(t，J＝7.2Hz，2H)，2.60(d，J＝16.6Hz，1H)，2.44-2.38(m，1H)，2.16-1.94(m，5H).LCMS(ES1)C37H43F2N6O3 +[M+H]+：计算值657.34，实测值657.4.The target compound (GT-09343) (yellow solid, 18 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 10.99 (s, 1H), 8.74 (d, J = 4.7 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.75-7.61 (m, 4H), 7.52-7.35 (m, 6H), 5.88 (s, 1H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1 3H), 4.30 (d, J = 17.4 Hz, 1H), 3.91 (s, 1H), 3.37-3.26 (m, 4H), 3.15-3.00 (m, 10H), 2.96-2.87 (m, 1H), 2.75 (t, J = 7.2 Hz, 2H), 2.60 (d, J = 16.6 Hz, 1H), 2.44-2.38 (m, 1H), 2.16-1.94 (m, 5H). LCMS (ES1) C 3 7 H 4 3 F 2 N 6 O 3 + [M+H] + : calculated value 657.34, found value 657.4.

实施例101：5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09344)的制备Example 101: Preparation of 5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09344)

参照合成方案1的方法制备目标化合物(GT-09344)(白色固体，14mg，收率24％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，8.74(d，J＝4.1Hz，1H)，8.11(s，1H)，8.05-7.97(m，2H)，7.95-7.88(m，1H)，7.72-7.62(m，3H)，7.50-7.36(m，4H)，5.86(s，1H)，5.18(dd，J＝12.7，5.4Hz，1H)，4.32(s，2H)，3.34-3.25(m，2H)，3.22-3.00(m，10H)，2.95-2.82(m，2H)，2.65-2.53(m，2H)，2.15-2.01(m，2H)，1.98(s，1H).LCMS(ESI)C35H37F2N6O4 +[M+H]+：计算值643.28，实测值643.3.The target compound (GT-09344) (white solid, 14 mg, yield 24%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.74 (d, J = 4.1 Hz, 1H), 8.11 (s, 1H), 8.05-7.97 (m, 2H), 7.95-7.88 (m, 1H), 7.72-7.62 (m, 3H), 7.50-7.36 (m, 4H), 5.86 (s, 1H), 5. 18 (dd, J = 12.7, 5.4 Hz, 1H), 4.32 (s, 2H), 3.34-3.25 (m, 2H), 3.22-3.00 (m, 10H), 2.95-2.82 (m, 2H), 2.65-2.53 (m, 2H), 2.15-2.01 (m, 2H), 1.98 (s, 1H). LCMS (ESI) C 35 H 37 F 2 N 6 O 4 + [M+H] + : calculated value 643.28, found value 643.3.

实施例102：4-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09345)的制备Example 102: Preparation of 4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09345)

参照合成方案1的方法制备目标化合物(GT-09345)(白色固体，23mg，收率38％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，8.74(d，J＝4.7Hz，1H)，8.05(s，1H)，7.98-7.86(m，3H)，7.73-7.57(m，3H)，7.50-7.33(m，4H)，5.84(s，1H)，5.16(dd，J＝12.7，5.4Hz，1H)，4.42(s，2H)，3.24(s，2H)，3.20-2.98(m，10H)，2.97-2.82(m，2H)，2.69-2.55(m，2H)，2.09-1.96(m，2H)，1.94(s，1H).LCMS(ESI)C35H37F2N6O4 +[M+H]+：计算值643.28，实测值643.3.The target compound (GT-09345) (white solid, 23 mg, yield 38%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400MHz, DMSO) δ11.14 (s, 1H), 8.74 (d, J=4.7Hz, 1H), 8.05 (s, 1H), 7.9 8-7.86(m, 3H), 7.73-7.57(m, 3H), 7.50-7.33(m, 4H), 5.84(s, 1H), 5.16(dd , J=12.7, 5.4Hz, 1H), 4.42 (s, 2H), 3.24 (s, 2H), 3.20-2.98 (m, 10H), 2.97-2 .82(m,2H),2.69-2.55(m,2H),2.09-1.96(m,2H),1.94(s,1H).LCMS(ESI)C 35 H 37 F 2 N 6 O 4 + [M+H] + : Calculated value 643.28, found value 643.3.

实施例103：3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09346)的制备Example 103: Preparation of 3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09346)

参照合成方案1的方法制备目标化合物(GT-09346)(白色固体，26mg，收率50％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.73(s，1H)，7.58(d，J＝8.6Hz，1H)，7.38(d，J＝8.5Hz，2H)，7.24(d，J＝8.5Hz，2H)，5.13(dd，J＝13.3，5.0Hz，1H)，4.45(s，1H)，4.35(d，J＝17.4Hz，1H)，3.99(s，2H)，3.27-3.22(m，2H)，3.14-3.02(m，3H)，2.95-2.89(m，1H)，2.61(d，J＝16.6Hz，2H)，2.44-2.32(m，4H)，2.12-1.97(m，2H)，1.96-1.65(m，4H)，1.48-1.37(m，2H)，0.98(d，J＝14.0Hz，6H).LCMS(ESI)C38H44ClF3N5O4 +[M+H]+：计算值726.30，实测值726.3.The target compound (GT-09346) (white solid, 26 mg, yield 50%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.73 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 5.13 (dd, J = 13.3, 5.0 Hz, 1H), 4.45 (s, 1H), 4.35 (d, J = 17.4 Hz, 1H), 3.99 (s, 2H) , 3.27-3.22 (m, 2H), 3.14-3.02 (m, 3H), 2.95-2.89 (m, 1H), 2.61 (d, J = 16.6 Hz, 2H), 2.44-2.32 (m, 4H), 2.12-1.97 (m, 2H), 1.96-1.65 (m, 4H), 1.48-1.37 (m, 2H), 0.98 (d, J = 14.0 Hz, 6H). LCMS (ESI) C 3 8 H 4 4 ClF 3 N 5 O 4 + [M+H] + : calculated value 726.30, found value 726.3.

实施例104：3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09347)的制备Example 104: Preparation of 3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09347)

参照合成方案1的方法制备目标化合物(GT-09347)(白色固体，22mg，收率42％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，7.47(s，1H)，7.38(d，J＝8.5Hz，3H)，7.25(d，J＝8.5Hz，2H)，5.09(dd，J＝13.2，5.1Hz，1H)，4.50(d，J＝17.6Hz，1H)，4.37(d，J＝17.9Hz，1H)，4.03(s，2H)，3.26-2.99(m，7H)，2.97-2.86(m，2H)，2.84-2.67(m，2H)，2.61(d，J＝17.0Hz，2H)，2.46-2.35(m，4H)，2.14-1.77(m，6H)，1.47-1.37(m，2H)，0.98(d，J＝13.9Hz，6H).LCMS(ESI)C38H44ClF3N5O4 +[M+H]+：计算值726.30，实测值726.3.The target compound (GT-09347) (white solid, 22 mg, yield 42%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.5 Hz, 3H), 7.25 (d, J = 8.5 Hz, 2H), 5.09 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 (d, J = 17.6 Hz, 1H), 4.37 (d, J = 17.9 Hz, 1H), 4.03 (s, 3H), 3.26-2.99 (m, 7H), 2.97-2.86 (m, 2H), 2.84-2.67 (m, 2H), 2.61 (d, J=17.0 Hz, 2H), 2.46-2.35 (m, 4H), 2.14-1.77 (m, 6H), 1.47-1.37 (m, 2H), 0.98 (d, J=13.9 Hz, 6H). LCMS (ESI) C 3 8 H 4 4 ClF 3 N 5 O 4 + [M+H] + : calculated value 726.30, found value 726.3.

实施例105：3-(4-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09348)的制备Example 105: Preparation of 3-(4-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09348)

参照合成方案1的方法制备目标化合物(GT-09348)(白色固体，14mg，收率28％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，7.77-7.69(m，1H)，7.64(s，1H)，7.55(t，J＝7.2Hz，1H)，7.37(d，J＝8.4Hz，2H)，7.24(d，J＝8.5Hz，2H)，5.15(dd，J＝13.2，5.1Hz，1H)，4.54(d，J＝16.9Hz，1H)，4.39(d，J＝17.3Hz，1H)，3.87(s，2H)，3.30-3.12(m，5H)，3.05(s，2H)，2.99-2.88(m，2H)，2.68(s，2H)，2.64(d，J＝17.3Hz，2H)，2.44-2.32(m，4H)，2.13-2.01(m，2H)，1.90(d，J＝17.0Hz，1H)，1.80(s，2H)，1.48-1.37(m，2H)，0.98(d，J＝13.9Hz，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound (GT-09348) (white solid, 14 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.77-7.69 (m, 1H), 7.64 (s, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 4.54 (d, J = 16.9 Hz, 1H), 4.39 (d, J = 17.3 Hz, 1H), 3.87 (s, 2 3H), 3.30-3.12 (m, 5H), 3.05 (s, 2H), 2.99-2.88 (m, 2H), 2.68 (s, 2H), 2.64 (d, J=17.3 Hz, 2H), 2.44-2.32 (m, 4H), 2.13-2.01 (m, 2H), 1.90 (d, J=17.0 Hz, 1H), 1.80 (s, 2H), 1.48-1.37 (m, 2H), 0.98 (d, J=13.9 Hz, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例106：3-(6-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09349)的制备Example 106: Preparation of 3-(6-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09349)

参照合成方案1的方法制备目标化合物(GT-09349)(白色固体，24mg，收率47％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，7.89(s，1H)，7.73(s，1H)，7.68(d，J＝7.7Hz，1H)，7.37(d，J＝8.5Hz，2H)，7.24(d，J＝8.5Hz，2H)，5.13(dd，J＝13.3，5.1Hz，1H)，4.50(d，J＝17.6Hz，1H)，4.37(d，J＝17.6Hz，1H)，4.27(s，2H)，3.25-3.08(m，6H)，3.01(s，2H)，2.96-2.87(m，2H)，2.61(d，J＝16.8Hz，2H)，2.45-2.34(m，4H)，2.31-2.22(m，1H)，2.13-1.96(m，3H)，1.95-1.80(m，3H)，1.46-1.36(m，2H)，0.98(d，J＝13.1Hz，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound (GT-09349) (white solid, 24 mg, yield 47%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 17.6 Hz, 1H), 4.37 (d, J = 17.6 Hz, 1H), 4.27 ( s, 2H), 3.25-3.08 (m, 6H), 3.01 (s, 2H), 2.96-2.87 (m, 2H), 2.61 (d, J=16.8 Hz, 2H), 2.45-2.34 (m, 4H), 2.31-2.22 (m, 1H), 2.13-1.96 (m, 3H), 1.95-1.80 (m, 3H), 1.46-1.36 (m, 2H), 0.98 (d, J=13.1 Hz, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例107：3-(7-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09350)的制备Example 107: Preparation of 3-(7-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09350)

参照合成方案1的方法制备目标化合物(GT-09350)(白色固体，22mg，收率43％)。1H NMR(400MHz，DMSO)δ11.04(s，1H)，7.70(s，3H)，7.37(d，J＝8.5Hz，2H)，7.24(d，J＝8.3Hz，2H)，5.21-5.04(m，1H)，4.77(s，1H)，4.55(s，1H)，4.52(d，J＝17.9Hz，1H)，4.45-4.36(m，1H)，3.37-3.27(m，3H)，3.18(s，3H)，3.07-2.86(m，4H)，2.62(d，J＝17.4Hz，3H)，2.45-2.32(m，4H)，2.19-1.99(m，3H)，1.90(d，J＝17.3Hz，3H)，1.49-1.36(m，2H)，0.98(d，J＝13.5Hz，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound (GT-09350) (white solid, 22 mg, yield 43%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 7.70 (s, 3H), 7.37 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 5.21-5.04 (m, 1H), 4.77 (s, 1H), 4.55 (s, 1H), 4.52 (d, J = 17.9 Hz, 1H), 4.45-4.36 (m, 1H), 3.37 -3.27 (m, 3H), 3.18 (s, 3H), 3.07-2.86 (m, 4H), 2.62 (d, J = 17.4 Hz, 3H), 2.45-2.32 (m, 4H), 2.19-1.99 (m, 3H), 1.90 (d, J = 17.3 Hz, 3H), 1.49-1.36 (m, 2H), 0.98 (d, J = 13.5 Hz, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例108：3-(5-(2-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09351)的制备Example 108: Preparation of 3-(5-(2-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09351)

参照合成方案1的方法制备目标化合物(GT-09351)(白色固体，23mg，收率33％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，7.71(d，J＝7.8Hz，1H)，7.51(s，1H)，7.42(d，J＝7.9Hz，1H)，7.38(d，J＝8.5Hz，2H)，7.26(d，J＝8.5Hz，2H)，5.11(dd，J＝13.3，5.0Hz，1H)，4.45(d，J＝17.4Hz，1H)，4.32(d，J＝17.5Hz，1H)，3.90(s，1H)，3.33-3.27(m，3H)，3.25-3.06(m，8H)，3.04-2.88(m，3H)，2.61(d，J＝16.2Hz，2H)，2.45-2.36(m，4H)，2.26(s，1H)，2.13-1.83(m，6H)，1.44(d，J＝7.8Hz，2H)，0.99(d，J＝13.3Hz，6H).LCMS(ESI)C39H47ClF2N5O4 +[M+H]+：计算值722.33，实测值722.4.The target compound (GT-09351) (white solid, 23 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.5 Hz, 2H). , 1H), 3.90 (s, 1H), 3.33-3.27 (m, 3H), 3.25-3.06 (m, 8H), 3.04-2.88 (m, 3H), 2.61 (d, J=16.2 Hz, 2H), 2.45-2.36 (m, 4H), 2.26 (s, 1H), 2.13-1.83 (m, 6H), 1.44 (d, J=7.8 Hz, 2H), 0.99 (d, J=13.3 Hz, 6H). LCMS (ESI) C 39 H 47 ClF 2 N 5 O 4 + [M+H] + : calculated value 722.33, found value 722.4.

实施例109：3-(5-(3-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09378)的制备Example 109: Preparation of 3-(5-(3-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09378)

参照合成方案1的方法制备目标化合物(GT-09378)(白色固体，14mg，收率20％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，10.65(s，1H)，7.71-7.64(m，1H)，7.48(s，1H)，7.42-7.33(m，3H)，7.25(d，J＝8.5Hz，2H)，5.11(dd，J＝13.3，5.0Hz，1H)，4.43(d，J＝17.3Hz，1H)，4.30(d，J＝17.3Hz，1H)，3.83(s，1H)，3.32-3.23(m，2H)，3.18-2.82(m，9H)，2.74(t，J＝7.3Hz，2H)，2.60(d，J＝17.5Hz，2H)，2.46-2.29(m，5H)，2.21(s，1H)，2.14-1.97(m，4H)，1.93-1.72(m，3H)，1.50-1.35(m，2H)，0.98(d，J＝12.4Hz，6H).LCMS(ESI)C40H49ClF2N5O4 +[M+H]+：计算值736.34，实测值736.3.The target compound (GT-09378) (white solid, 14 mg, yield 20%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.65 (s, 1H), 7.71-7.64 (m, 1H), 7.48 (s, 1H), 7.42-7.33 (m, 3H), 7.25 (d, J = 8.5 Hz, 2H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.83 (s, 1H ), 3.32-3.23 (m, 2H), 3.18-2.82 (m, 9H), 2.74 (t, J = 7.3 Hz, 2H), 2.60 (d, J = 17.5 Hz, 2H), 2.46-2.29 (m, 5H), 2.21 (s, 1H), 2.14-1.97 (m, 4H), 1.93-1.72 (m, 3H), 1.50-1.35 (m, 2H), 0.98 (d, J = 12.4 Hz, 6H). LCMS (ESI) C 40 H 49 ClF 2 N 5 O 4 + [M+H] + : calculated value 736.34, found value 736.3.

实施例110：5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09352)的制备Example 110: Preparation of 5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09352)

参照合成方案1的方法制备目标化合物(GT-09352)(白色固体，23mg，收率44％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，7.94(t，J＝11.4Hz，2H)，7.90(s，1H)，7.38(d，J＝8.5Hz，2H)，7.25(d，J＝8.5Hz，2H)，5.17(dd，J＝12.7，5.3Hz，1H)，4.06(s，2H)，3.26-2.96(m，7H)，2.95-2.83(m，2H)，2.83-2.67(m，2H)，2.67-2.57(m，3H)，2.43-2.33(m，3H)，2.11-2.00(m，2H)，1.97-1.58(m，4H)，1.52-1.39(m，2H)，0.98(d，J＝13.6Hz，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09352) (white solid, 23 mg, yield 44%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.94 (t, J = 11.4 Hz, 2H), 7.90 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.17 (dd, J = 12.7, 5.3 Hz, 1H), 4.06 (s, 2H), 3.26-2.96 (m, 7H), 2.95-2.83 (m, 2H), 2.83-2.67 (m, 2H), 2.67-2.57 (m, 3H), 2.43-2.33 (m, 3H), 2.11-2.00 (m, 2H), 1.97-1.58 (m, 4H), 1.52-1.39 (m, 2H), 0.98 (d, J=13.6 Hz, 6H). LCMS (ESI) C 38 H 43 ClF 2 N 5 O 5 + [M+H] + : calculated value 722.29, found value 722.3.

实施例111：4-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09353)的制备Example 111: Preparation of 4-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09353)

参照合成方案1的方法制备目标化合物(GT-09353)(白色固体，16mg，收率31％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，7.97-7.91(m，1H)，7.88(d，J＝4.9Hz，2H)，7.38(d，J＝8.5Hz，2H)，7.25(d，J＝8.5Hz，2H)，5.15(dd，J＝12.8，5.4Hz，1H)，4.21(s，2H)，3.33-3.11(m，7H)，3.06(s，2H)，2.96-2.84(m，2H)，2.82-2.65(m，2H)，2.61(d，J＝19.2Hz，2H)，2.44-2.35(m，3H)，2.12-2.01(m，2H)，1.90(d，J＝16.2Hz，1H)，1.77(s，2H)，1.50-1.40(m，2H)，0.98(d，J＝14.2Hz，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09353) (white solid, 16 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.97-7.91 (m, 1H), 7.88 (d, J = 4.9 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 4.21 (s, 2H), 3.33-3.11 (m, 7H), 3.06 (s, 2H ), 2.96-2.84 (m, 2H), 2.82-2.65 (m, 2H), 2.61 (d, J=19.2 Hz, 2H), 2.44-2.35 (m, 3H), 2.12-2.01 (m, 2H), 1.90 (d, J=16.2 Hz, 1H), 1.77 (s, 2H), 1.50-1.40 (m, 2H), 0.98 (d, J=14.2 Hz, 6H). LCMS (ESI) C 3 8 H 4 3 ClF 2 N 5 O 5 + [M+H] + : calculated value 722.29, found value 722.3.

实施例112：3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09379)的制备Example 112: Preparation of 3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09379)

参照合成方案1的方法制备目标化合物(GT-09379)(白色固体，18mg，收率33％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，10.05(s，1H)，7.71(s，1H)，7.63(d，1H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.13(dd，J＝13.2，5.0Hz，1H)，4.58(d，J＝17.8Hz，1H)，4.42(d，J＝17.4Hz，1H)，4.10(s，2H)，3.58-3.52(m，5H)，3.21(d，J＝10.5Hz，2H)，3.11-3.01(m，3H)，2.97-2.77(m，4H)，2.61(d，J＝13.8Hz，3H)，2.47-2.42(m，1H)，2.32(s，2H)，2.06-1.95(m，3H)，1.93-1.83(m，1H)，1.80(s，1H)，1.45(t，J＝6.1Hz，2H)，0.95(s，6H).LCMS(ESI)C38H46ClF3N5O3 +[M+H]+：计算值712.32，实测值712.4.The target compound (GT-09379) (white solid, 18 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 10.05 (s, 1H), 7.71 (s, 1H), 7.63 (d, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.58 (d, J = 17.8 Hz, 1H), 4.42 (d, J = 17.4 Hz, 1H), 4.10 (s, 2H), 3.58-3.52 ( m, 5H), 3.21 (d, J = 10.5 Hz, 2H), 3.11-3.01 (m, 3H), 2.97-2.77 (m, 4H), 2.61 (d, J = 13.8 Hz, 3H), 2.47-2.42 (m, 1H), 2.32 (s, 2H), 2.06-1.95 (m, 3H), 1.93-1.83 (m, 1H), 1.80 (s, 1H), 1.45 (t, J = 6.1 Hz, 2H), 0.95 (s, 6H). LCMS (ESI) C 3 8 H 4 6 ClF 3 N 5 O 3 + [M+H] + : calculated value 712.32, found value 712.4.

实施例113：3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09380)的制备Example 113: Preparation of 3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09380)

参照合成方案1的方法制备目标化合物(GT-09380)(白色固体，17mg，收率31％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，9.92(s，1H)，7.73(s，1H)，7.57(d，J＝8.6Hz，1H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.13(dd，J＝13.2，4.9Hz，1H)，4.47(d，J＝16.7Hz，1H)，4.34(d，J＝17.4Hz，1H)，3.96(s，2H)，3.53(s，3H)，3.21(d，J＝11.1Hz，2H)，3.09-2.99(m，3H)，2.98-2.76(m，4H)，2.66-2.54(m，4H)，2.47-2.37(m，2H)，2.30(s，2H)，2.02(s，3H)，1.90-1.65(m，2H)，1.46(t，J＝6.1Hz，2H)，0.95(s，6H).LCMS(ESI)C38H46ClF3N5O3 +[M+H]+：计算值712.32，实测值712.3.The target compound (GT-09380) (white solid, 17 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.92 (s, 1H), 7.73 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.13 (dd, J = 13.2, 4.9 Hz, 1H), 4.47 (d, J = 16.7 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 3.96 ( s, 2H), 3.53 (s, 3H), 3.21 (d, J=11.1 Hz, 2H), 3.09-2.99 (m, 3H), 2.98-2.76 (m, 4H), 2.66-2.54 (m, 4H), 2.47-2.37 (m, 2H), 2.30 (s, 2H), 2.02 (s, 3H), 1.90-1.65 (m, 2H), 1.46 (t, J=6.1 Hz, 2H), 0.95 (s, 6H). LCMS (ESI) C 3 8 H 4 6 ClF 3 N 5 O 3 + [M+H] + : calculated value 712.32, found value 712.3.

实施例114：3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09381)的制备Example 114: Preparation of 3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09381)

参照合成方案1的方法制备目标化合物(GT-09381)(白色固体，16mg，收率29％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，9.98(s，1H)，7.55-7.46(m，1H)，7.44(d，J＝8.4Hz，3H)，7.14(d，J＝8.4Hz，2H)，5.09(dd，J＝13.3，5.1Hz，1H)，4.50(d，J＝17.8Hz，1H)，4.37(d，J＝17.9Hz，1H)，4.05(s，2H)，3.52(d，J＝10.4Hz，4H)，3.22(d，J＝10.9Hz，3H)，3.07(d，J＝10.5Hz，3H)，2.92-2.77(m，3H)，2.60(d，J＝13.8Hz，3H)，2.47-2.35(m，2H)，2.31(s，2H)，2.05-1.97(m，3H)，1.97-1.68(m，2H)，1.46(t，J＝6.1Hz，2H)，0.96(s，6H).LCMS(ESI)C38H46ClF3N5O3 +[M+H]+：计算值712.32，实测值712.3.The target compound (GT-09381) (white solid, 16 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.98 (s, 1H), 7.55-7.46 (m, 1H), 7.44 (d, J = 8.4 Hz, 3H), 7.14 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 17.8 Hz, 1H), 4.37 (d, J = 17.9 Hz, 1H), 4.05 (s, 2H), 3.52 (d, J = 10. 4 Hz, 4H), 3.22 (d, J = 10.9 Hz, 3H), 3.07 (d, J = 10.5 Hz, 3H), 2.92-2.77 (m, 3H), 2.60 (d, J = 13.8 Hz, 3H), 2.47-2.35 (m, 2H), 2.31 (s, 2H), 2.05-1.97 (m, 3H), 1.97-1.68 (m, 2H), 1.46 (t, J = 6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 6 ClF 3 N 5 O 3 + [M+H] + : calculated value 712.32, found value 712.3.

实施例115：3-(4-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09382)的制备Example 115: Preparation of 3-(4-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09382)

参照合成方案1的方法制备目标化合物(GT-09382)(白色固体，20mg，收率37％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，9.93(s，1H)，7.87-7.59(m，2H)，7.57-7.48(m，1H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.15(dd，J＝13.2，5.0Hz，1H)，4.65-4.51(m，1H)，4.40(d，J＝17.5Hz，1H)，3.83(s，1H)，3.52(s，3H)，3.22(d，J＝10.8Hz，2H)，3.01(d，J＝23.7Hz，4H)，2.97-2.78(m，4H)，2.68-2.54(m，4H)，2.44-2.25(m，4H)，2.03(s，3H)，1.91-1.62(m，2H)，1.46(t，J＝6.1Hz，2H)，0.96(s，6H).LCMS(ESI)C38H47ClF2N5O3 +[M+H]+：计算值694.33，实测值694.4.The target compound (GT-09382) (white solid, 20 mg, yield 37%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.93 (s, 1H), 7.87-7.59 (m, 2H), 7.57-7.48 (m, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.15 (dd, J = 13.2, 5.0 Hz, 1H), 4.65-4.51 (m, 1H), 4.40 (d, J = 17.5 Hz, 1H), 3.8 3 (s, 1H), 3.52 (s, 3H), 3.22 (d, J = 10.8 Hz, 2H), 3.01 (d, J = 23.7 Hz, 4H), 2.97-2.78 (m, 4H), 2.68-2.54 (m, 4H), 2.44-2.25 (m, 4H), 2.03 (s, 3H), 1.91-1.62 (m, 2H), 1.46 (t, J = 6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 7 ClF 2 N 5 O 3 + [M+H] + : calculated value 694.33, found value 694.4.

实施例116：3-(6-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09383)的制备Example 116: Preparation of 3-(6-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09383)

参照合成方案1的方法制备目标化合物(GT-09383)(白色固体，24mg，收率45％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，10.14(s，1H)，7.90(s，1H)，7.82-7.72(m，1H)，7.71-7.63(m，1H)，7.44(d，J＝8.3Hz，2H)，7.14(d，J＝8.3Hz，2H)，5.13(dd，J＝13.2，4.8Hz，1H)，4.50(d，J＝17.6Hz，1H)，4.37(d，1H)，4.32-4.18(m，1H)，3.53(s，3H)，3.21(d，J＝11.0Hz，3H)，3.08(d，J＝10.0Hz，3H)，2.97-2.76(m，4H)，2.68-2.53(m，4H)，2.48-2.37(m，2H)，2.32(s，2H)，2.11-1.95(m，4H)，1.87(s，1H)，1.45(t，J＝6.1Hz，2H)，0.95(s，6H).LCMS(ESI)C38H47ClF2N5O3 +[M+H]+：计算值694.33，实测值694.4.The target compound (GT-09383) (white solid, 24 mg, yield 45%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 10.14 (s, 1H), 7.90 (s, 1H), 7.82-7.72 (m, 1H), 7.71-7.63 (m, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.13 (dd, J = 13.2, 4.8 Hz, 1H), 4.50 (d, J = 17.6 Hz, 1H), 4.37 (d, 1H), 4.32-4. 18 (m, 1H), 3.53 (s, 3H), 3.21 (d, J = 11.0 Hz, 3H), 3.08 (d, J = 10.0 Hz, 3H), 2.97-2.76 (m, 4H), 2.68-2.53 (m, 4H), 2.48-2.37 (m, 2H), 2.32 (s, 2H), 2.11-1.95 (m, 4H), 1.87 (s, 1H), 1.45 (t, J = 6.1 Hz, 2H), 0.95 (s, 6H). LCMS (ESI) C 38 H 47 ClF 2 N 5 O 3 + [M+H] + : calculated value 694.33, found value 694.4.

实施例117：3-(7-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09384)的制备Example 117: Preparation of 3-(7-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09384)

参照合成方案1的方法制备目标化合物(GT-09384)(白色固体，23mg，收率43％)。1H NMR(400MHz，DMSO)δ11.04(s，1H)，10.19(s，1H)，7.71(s，3H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.3Hz，2H)，5.16-5.06(m，1H)，5.01-4.56(m，2H)，4.51(d，J＝18.0Hz，1H)，4.45-4.35(m，1H)，3.53(s，3H)，3.22(d，J＝10.4Hz，3H)，3.09(s，2H)，2.93-2.76(m，3H)，2.68-2.57(m，3H)，2.48-2.36(m，2H)，2.33(s，2H)，2.03(s，4H)，1.89(s，1H)，1.45(t，J＝6.1Hz，2H)，0.95(s，6H).LCMS(ESI)C38H47ClF2N5O3 +[M+H]+：计算值694.33，实测值694.4.The target compound (GT-09384) (white solid, 23 mg, yield 43%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 10.19 (s, 1H), 7.71 (s, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.16-5.06 (m, 1H), 5.01-4.56 (m, 2H), 4.51 (d, J = 18.0 Hz, 1H), 4.45-4.35 (m, 1H), 3. 53 (s, 3H), 3.22 (d, J = 10.4 Hz, 3H), 3.09 (s, 2H), 2.93-2.76 (m, 3H), 2.68-2.57 (m, 3H), 2.48-2.36 (m, 2H), 2.33 (s, 2H), 2.03 (s, 4H), 1.89 (s, 1H), 1.45 (t, J = 6.1 Hz, 2H), 0.95 (s, 6H). LCMS (ESI) C 3 8 H 4 7 ClF 2 N 5 O 3 + [M+H] + : calculated value 694.33, found value 694.4.

实施例118：3-(5-(2-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09385)的制备Example 118: Preparation of 3-(5-(2-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09385)

参照合成方案1的方法制备目标化合物(GT-09385)(黄色固体，22mg，收率31％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，10.12(s，1H)，7.71(d，J＝7.8Hz，1H)，7.51(s，1H)，7.44(t，J＝8.5Hz，3H)，7.15(d，J＝8.4Hz，2H)，5.11(dd，J＝13.2，5.1Hz，1H)，4.45(d，J＝17.5Hz，1H)，4.32(d，J＝17.4Hz，1H)，3.92(s，1H)，3.55(s，4H)，3.24(d，J＝11.2Hz，6H)，3.15-3.06(m，3H)，2.94-2.83(m，3H)，2.68-2.57(m，4H)，2.43-2.38(m，1H)，2.34(s，2H)，2.08-1.93(m，5H)，1.46(t，J＝6.1Hz，2H)，0.96(s，6H).LCMS(ESI)C39H49ClF2N5O3 +[M+H]+：计算值708.35，实测值708.4.The target compound (GT-09385) (yellow solid, 22 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 10.12 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.44 (t, J = 8.5 Hz, 3H), 7.15 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.45 (d, J = 17.5 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H) , 3.92 (s, 1H), 3.55 (s, 4H), 3.24 (d, J = 11.2 Hz, 6H), 3.15-3.06 (m, 3H), 2.94-2.83 (m, 3H), 2.68-2.57 (m, 4H), 2.43-2.38 (m, 1H), 2.34 (s, 2H), 2.08-1.93 (m, 5H), 1.46 (t, J = 6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 39 H 49 ClF 2 N 5 O 3 + [M+H] + : calculated value 708.35, found value 708.4.

实施例119：3-(5-(3-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09386)的制备Example 119: Preparation of 3-(5-(3-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09386)

参照合成方案1的方法制备目标化合物(GT-09386)(黄色固体，24mg，收率32％)。1H NMR(400MHz，DMSO)δ11.21(s，1H)，10.99(s，1H)，10.41(s，1H)，7.73-7.63(m，1H)，7.52-7.42(m，3H)，7.39(d，J＝7.9Hz，1H)，7.15(d，J＝8.4Hz，2H)，5.11(dd，J＝13.3，5.1Hz，1H)，4.43(d，J＝17.4Hz，1H)，4.31(d，1H)，3.90(s，1H)，3.46-3.27(m，4H)，3.22(d，J＝11.0Hz，3H)，3.17-3.02(m，5H)，2.97-2.79(m，3H)，2.78-2.73(m，2H)，2.65-2.55(m，3H)，2.47-2.39(m，1H)，2.36(s，2H)，2.16-2.01(m，5H)，2.01-1.88(m，2H)，1.45(t，J＝6.1Hz，2H)，0.96(s，6H).LCMS(ESI)C40H51ClF2N5O3 +[M+H]+：计算值722.36，实测值722.4.The target compound (GT-09386) (yellow solid, 24 mg, yield 32%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 10.99 (s, 1H), 10.41 (s, 1H), 7.73-7.63 (m, 1H), 7.52-7.42 (m, 3H), 7.39 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.4 Hz, 1H), 4.31 (d, 1H), 3.90 (s, 1H), 3.46 -3.27 (m, 4H), 3.22 (d, J = 11.0 Hz, 3H), 3.17-3.02 (m, 5H), 2.97-2.79 (m, 3H), 2.78-2.73 (m, 2H), 2.65-2.55 (m, 3H), 2.47-2.39 (m, 1H), 2.36 (s, 2H), 2.16-2.01 (m, 5H), 2.01-1.88 (m, 2H), 1.45 (t, J = 6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 40 H 51 ClF 2 N 5 O 3 + [M+H] + : calculated value 722.36, found value 722.4.

实施例120：5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09387)的制备Example 120: Preparation of 5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09387)

参照合成方案1的方法制备目标化合物(GT-09387)(白色固体，15mg，收率28％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，9.96(s，1H)，8.04-7.87(m，3H)，7.44(d，J＝8.3Hz，2H)，7.14(d，J＝8.3Hz，2H)，5.17(dd，J＝12.8，5.4Hz，1H)，4.08(s，2H)，3.54(s，3H)，3.21(d，J＝10.6Hz，3H)，3.06(d，J＝10.4Hz，4H)，2.92-2.81(m，3H)，2.68-2.54(m，5H)，2.31(s，2H)，2.10-1.99(m，3H)，1.89(s，1H)，1.78(s，1H)，1.46(t，J＝6.1Hz，2H)，0.96(s，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound (GT-09387) (white solid, 15 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.96 (s, 1H), 8.04-7.87 (m, 3H), 7.44 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.17 (dd, J = 12.8, 5.4 Hz, 1H), 4.08 (s, 2H), 3.54 (s, 3H), 3.21 (d, J = 1 0.6 Hz, 3H), 3.06 (d, J=10.4 Hz, 4H), 2.92-2.81 (m, 3H), 2.68-2.54 (m, 5H), 2.31 (s, 2H), 2.10-1.99 (m, 3H), 1.89 (s, 1H), 1.78 (s, 1H), 1.46 (t, J=6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例121：4-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09388)的制备Example 121: Preparation of 4-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09388)

参照合成方案1的方法制备目标化合物(GT-09388)(白色固体，12mg，收率22％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，9.98(s，1H)，7.98(s，1H)，7.93-7.85(m，2H)，7.44(d，J＝8.3Hz，2H)，7.14(d，J＝8.3Hz，2H)，5.15(dd，J＝12.8，5.4Hz，1H)，4.27(s，2H)，3.54(s，3H)，3.22(d，J＝10.6Hz，3H)，3.08(s，4H)，2.91-2.81(m，3H)，2.68-2.53(m，5H)，2.31(s，2H)，2.08-1.99(m，3H)，1.95-1.81(m，1H)，1.76(s，1H)，1.46(t，J＝6.1Hz，2H)，0.96(s，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound (GT-09388) (white solid, 12 mg, yield 22%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.98 (s, 1H), 7.98 (s, 1H), 7.93-7.85 (m, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 4.27 (s, 2H), 3.54 (s, 3H), 3. 22 (d, J = 10.6 Hz, 3H), 3.08 (s, 4H), 2.91-2.81 (m, 3H), 2.68-2.53 (m, 5H), 2.31 (s, 2H), 2.08-1.99 (m, 3H), 1.95-1.81 (m, 1H), 1.76 (s, 1H), 1.46 (t, J = 6.1 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例122：3-(7-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09389)的制备Example 122: Preparation of 3-(7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09389)

参照合成方案1的方法制备目标化合物(GT-09389)(白色固体，23mg，收率38％)。1H NMR(400MHz，DMSO)δ11.67(s，1H)，11.02(s，1H)，10.64(s，1H)，7.90-7.67(m，3H)，7.41-7.35(m，2H)，7.23-7.14(m，1H)，5.13(dd，J＝13.1，5.0Hz，1H)，4.86(d，J＝11.5Hz，1H)，4.73(d，J＝12.6Hz，1H)，4.52(d，J＝17.9Hz，1H)，4.39(d，1H)，3.63-3.54(m，4H)，3.49-3.45(m，2H)，3.29-3.25(m，2H)，3.19-3.05(m，4H)，3.00-2.84(m，2H)，2.64(d，J＝16.5Hz，1H)，2.46-2.35(m，3H)，2.22-1.99(m，3H).LCMS(ESI)C29H34Cl2N5O3 +[M+H]+：计算值570.20，实测值570.3.The target compound (GT-09389) (white solid, 23 mg, yield 38%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 11.02 (s, 1H), 10.64 (s, 1H), 7.90-7.67 (m, 3H), 7.41-7.35 (m, 2H), 7.23-7.14 (m, 1H), 5.13 (dd, J = 13.1, 5.0 Hz, 1H), 4.86 (d, J = 11.5 Hz, 1H), 4.73 (d, J = 12.6 Hz, 1H), 4.5 2 (d, J = 17.9 Hz, 1H), 4.39 (d, 1H), 3.63-3.54 (m, 4H), 3.49-3.45 (m, 2H), 3.29-3.25 (m, 2H), 3.19-3.05 (m, 4H), 3.00-2.84 (m, 2H), 2.64 (d, J = 16.5 Hz, 1H), 2.46-2.35 (m, 3H), 2.22-1.99 (m, 3H). LCMS (ESI) C 29 H 34 Cl 2 N 5 O 3 + [M+H] + : calculated value 570.20, found value 570.3.

实施例123：3-(5-(2-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09390)的制备Example 123: Preparation of 3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09390)

参照合成方案1的方法制备目标化合物(GT-09390)(白色固体，9mg，收率11％)。1H NMR(400MHz，DMSO)δ11.45(s，1H)，10.99(s，1H)，10.78(s，1H)，7.73(d，J＝7.7Hz，1H)，7.54(s，1H)，7.46-7.36(m，2H)，7.21(d，J＝4.4Hz，1H)，5.17-5.03(m，1H)，4.46(d，J＝17.4Hz，1H)，4.33(d，J＝17.6Hz，1H)，3.78-3.72(m，1H)，3.61(s，2H)，3.54-3.44(m，3H)，3.30-3.08(m，8H)，3.05-2.83(m，3H)，2.70-2.57(m，2H)，2.46-2.34(m，3H)，2.33-2.10(m，2H)，2.04-1.94(m，1H).LCMS(ESI)C30H36Cl2N5O3 +[M+H]+：计算值584.22，实测值584.3.The target compound (GT-09390) (white solid, 9 mg, yield 11%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 10.99 (s, 1H), 10.78 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.46-7.36 (m, 2H), 7.21 (d, J = 4.4 Hz, 1H), 5.17-5.03 (m, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.33 (d, 3H), 3.78-3.72 (m, 1H), 3.61 (s, 2H), 3.54-3.44 (m, 3H), 3.30-3.08 (m, 8H), 3.05-2.83 (m, 3H), 2.70-2.57 (m, 2H), 2.46-2.34 (m, 3H), 2.33-2.10 (m, 2H), 2.04-1.94 (m, 1H). LCMS (ESI) C 30 H 36 Cl 2 N 5 O 3 + [M+H] + : calculated value 584.22, found value 584.3.

实施例124：3-(5-(3-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09391)的制备Example 124: Preparation of 3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09391)

参照合成方案1的方法制备目标化合物(GT-09391)(白色固体，31mg，收率37％)。1H NMR(400MHz，DMSO)δ11.57(s，1H)，10.99(s，1H)，10.73(s，1H)，7.69(d，J＝7.8Hz，1H)，7.50(s，1H)，7.44-7.36(m，3H)，7.23-7.17(m，1H)，5.11(dd，J＝13.3，5.1Hz，1H)，4.43(d，J＝17.2，8.4Hz，1H)，4.31(d，1H)，3.69-3.57(m，4H)，3.47-3.40(m，4H)，3.28-3.19(m，3H)，3.05(s，2H)，2.99-2.86(m，3H)，2.81-2.71(m，2H)，2.61(d，J＝18.2Hz，2H)，2.44-2.32(m，3H)，2.24-2.18(m，1H)，2.12-1.97(m，3H).LCMS(ESI)C31H38Cl2N5O3 +[M+H]+：计算值598.23，实测值598.3.The target compound (GT-09391) (white solid, 31 mg, yield 37%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.57 (s, 1H), 10.99 (s, 1H), 10.73 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.44-7.36 (m, 3H), 7.23-7.17 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.2, 8.4 Hz, 1H), 4.31 (d, 1 3H), 3.69-3.57 (m, 4H), 3.47-3.40 (m, 4H), 3.28-3.19 (m, 3H), 3.05 (s, 2H), 2.99-2.86 (m, 3H), 2.81-2.71 (m, 2H), 2.61 (d, J=18.2 Hz, 2H), 2.44-2.32 (m, 3H), 2.24-2.18 (m, 1H), 2.12-1.97 (m, 3H). LCMS (ESI) C 31 H 38 Cl 2 N 5 O 3 + [M+H] + : calculated value 598.23, found value 598.3.

实施例125：5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09392)的制备Example 125: Preparation of 5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09392)

参照合成方案1的方法制备目标化合物(GT-09392)(白色固体，15mg，收率25％)。1H NMR(400MHz，DMSO)δ11.51(s，1H)，11.26(s，1H)，11.16(s，1H)，8.23(s，1H)，8.11(d，J＝7.0Hz，1H)，8.04(d，J＝7.6Hz，1H)，7.43-7.27(m，2H)，7.24-7.10(m，1H)，5.19(dd，J＝12.8，5.4Hz，1H)，4.52(s，2H)，3.62-3.50(m，4H)，3.44(s，2H)，3.30-3.11(m，5H)，3.11-2.94(m，2H)，2.94-2.86(m，1H)，2.65-2.53(m，2H)，2.42-2.31(m，2H)，2.30-2.13(m，2H)，2.12-2.03(m，1H).LCMS(ESI)C29H32Cl2N5O4 +[M+H]+：计算值584.18，实测值584.2.The target compound (GT-09392) (white solid, 15 mg, yield 25%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 11.26 (s, 1H), 11.16 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 7.0 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.43-7.27 (m, 2H), 7.24-7.10 (m, 1H), 5.19 (dd, J = 12.8, 5.4 Hz, 1H), 4.52 (s, 2H), 3.62-3.50 (m, 4H), 3.44 (s, 2H), 3.30-3.11 (m, 5H), 3.11-2.94 (m, 2H), 2.94-2.86 (m, 1H), 2.65-2.53 (m, 2H), 2.42-2.31 (m, 2H), 2.30-2.13 (m, 2H), 2.12-2.03 (m, 1H). LCMS (ESI) C 2 9 H 3 2 Cl 2 N 5 O 4 + [M+H] + : calculated value 584.18, found value 584.2.

实施例126：4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09393)的制备Example 126: Preparation of 4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09393)

参照合成方案1的方法制备目标化合物(GT-09393)(黄色固体，20mg，收率33％)。1H NMR(400MHz，DMSO)δ11.47(s，1H)，11.17(s，1H)，10.97(s，1H)，8.15(d，J＝8.5Hz，1H)，8.03(d，J＝7.3Hz，1H)，8.01-7.95(m，1H)，7.48-7.32(m，2H)，7.26-7.14(m，1H)，5.19(dd，J＝12.8，5.4Hz，1H)，4.71(s，2H)，3.68-3.55(m，4H)，3.47-3.43(m，2H)，3.27-3.08(m，6H)，2.94-2.85(m，2H)，2.73(s，1H)，2.69-2.55(m，2H)，2.42-2.33(m，2H)，2.23-2.14(m，1H)，2.12-2.03(m，1H).LCMS(ESI)C29H32Cl2N5O4 +[M+H]+：计算值584.18，实测值584.2.The target compound (GT-09393) (yellow solid, 20 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 11.17 (s, 1H), 10.97 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 7.3 Hz, 1H), 8.01-7.95 (m, 1H), 7.48-7.32 (m, 2H), 7.26-7.14 (m, 1H), 5.19 (dd, J = 12.8, 5.4 Hz, 1H ), 4.71 (s, 2H), 3.68-3.55 (m, 4H), 3.47-3.43 (m, 2H), 3.27-3.08 (m, 6H), 2.94-2.85 (m, 2H), 2.73 (s, 1H), 2.69-2.55 (m, 2H), 2.42-2.33 (m, 2H), 2.23-2.14 (m, 1H), 2.12-2.03 (m, 1H). LCMS (ESI) C 2 9 H 3 2 Cl 2 N 5 O 4 + [M+H] + : calculated value 584.18, found value 584.2.

实施例127：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09417)的制备Example 127: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09417)

参照合成方案1的方法制备目标化合物(GT-09417)(白色固体，35mg，收率59％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，7.72-7.62(m，2H)，7.38-7.31(m，2H)，7.21-7.13(m，1H)，5.14(dd，J＝13.2，5.0Hz，1H)，4.59(d，J＝17.5Hz，1H)，4.43(d，J＝17.4Hz，1H)，4.00(s，2H)，3.83-3.71(m，3H)，3.32-3.21(m，6H)，3.15(s，2H)，2.95-2.89(m，1H)，2.83-2.71(m，1H)，2.61(d，J＝17.3Hz，2H)，2.47-2.41(m，1H)，2.33(s，1H)，2.12-2.00(m，2H).LCMS(ESI)C29H31Cl2F3N5O3 +[M+H]+：计算值624.18，实测值624.2.The target compound (GT-09417) (white solid, 35 mg, yield 59%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.72-7.62 (m, 2H), 7.38-7.31 (m, 2H), 7.21-7.13 (m, 1H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.59 (d, J = 17.5 Hz, 1H), 4.43 (d, J = 17.4 Hz, 1H), 4.00 (s, 2 3H), 3.83-3.71 (m, 3H), 3.32-3.21 (m, 6H), 3.15 (s, 2H), 2.95-2.89 (m, 1H), 2.83-2.71 (m, 1H), 2.61 (d, J=17.3 Hz, 2H), 2.47-2.41 (m, 1H), 2.33 (s, 1H), 2.12-2.00 (m, 2H). LCMS (ESI) C 29 H 31 Cl 2 F 3 N 5 O 3 + [M+H] + : calculated value 624.18, found value 624.2.

实施例128：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09418)的制备Example 128: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09418)

参照合成方案1的方法制备目标化合物(GT-09418)(白色固体，31mg，收率52％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.74(d，J＝5.5Hz，1H)，7.58(d，J＝8.6Hz，1H)，7.41-7.28(m，2H)，7.23-7.11(m，1H)，5.13(dd，J＝13.3，5.1Hz，1H)，4.49(d，J＝17.4Hz，1H)，4.36(d，J＝17.4Hz，1H)，3.96(s，2H)，3.82-3.61(m，3H)，3.31-3.20(m，6H)，3.12(s，2H)，2.97-2.89(m，1H)，2.68(s，1H)，2.66-2.59(m，1H)，2.49-2.39(m，2H)，2.29(s，1H)，2.11-1.98(m，2H).LCMS(ES1)C29H31Cl2F3N5O3 +[M+H]+：计算值624.18，实测值624.2.The target compound (GT-09418) (white solid, 31 mg, yield 52%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ11.02 (s, 1H), 7.74 (d, J=5.5 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.41-7.28 (m, 2H), 7.23-7.11 (m, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.49 (d, J=17.4 Hz, 1H), 4.36 (d, J=17.4 Hz, 1H), 3.96 (s, 2H), 3.82-3.61 (m, 3H), 3.31-3.20 (m, 6H), 3.12 (s, 2H), 2.97-2.89 (m, 1H), 2.68 (s, 1H), 2.66-2.59 (m, 1H), 2.49-2.39 (m, 2H), 2.29 (s, 1H), 2.11-1.98 (m, 2H). LCMS (ES1) C 29 H 31 Cl 2 F 3 N 5 O 3 + [M+H] + : calculated value 624.18, found value 624.2.

实施例129：3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09419)的制备Example 129: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09419)

参照合成方案1的方法制备目标化合物(GT-09419)(白色固体，24mg，收率40％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.48(s，1H)，7.42-7.30(m，3H)，7.22-7.14(m，1H)，5.09(dd，J＝13.3，5.1Hz，1H)，4.51(d，J＝17.9Hz，1H)，4.38(d，J＝17.9Hz，1H)，4.00(s，2H)，3.65(s，3H)，3.34-3.16(m，9H)，2.95-2.88(m，1H)，2.85-2.71(m，1H)，2.63-2.57(m，1H)，2.45-2.35(m，1H)，2.35-2.25(m，1H)，2.15-2.06(m，1H)，2.06-1.95(m，1H).LCMS(ESI)C29H31Cl2F3N5O3 +[M+H]+：计算值624.18，实测值624.2.The target compound (GT-09419) (white solid, 24 mg, yield 40%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.48 (s, 1H), 7.42-7.30 (m, 3H), 7.22-7.14 (m, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.9 Hz, 1H), 4.38 (d, J = 17.9 Hz, 1H), 4.00 (s, 2H), 3.65 (s, 3H), 3.34-3.16 (m, 9H), 2.95-2.88 (m, 1H), 2.85-2.71 (m, 1H), 2.63-2.57 (m, 1H), 2.45-2.35 (m, 1H), 2.35-2.25 (m, 1H), 2.15-2.06 (m, 1H), 2.06-1.95 (m, 1H). LCMS (ESI) C 29 H 31 Cl 2 F 3 N 5 O 3 + [M+H] + : calculated value 624.18, found value 624.2.

实施例130：3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09420)的制备Example 130: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09420)

参照合成方案1的方法制备目标化合物(GT-09420)(白色固体，31mg，收率54％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，7.72(d，J＝7.4Hz，1H)，7.66(s，1H)，7.55(t，J＝7.4Hz，1H)，7.39-7.31(m，2H)，7.21-7.14(m，1H)，5.16(dd，J＝13.1，5.0Hz，1H)，4.63-4.51(m，1H)，4.41(d，J＝17.6Hz，1H)，3.89(s，3H)，3.67-3.58(m，3H)，3.42-3.37(m，2H)，3.36-3.20(m，6H)，3.09(s，1H)，2.98-2.89(m，1H)，2.63(d，J＝16.9Hz，1H)，2.43-2.24(m，2H)，2.15-1.99(m，2H).LCMS(ES1)C29H32Cl2F2N5O3 +[M+H]+：计算值606.18，实测值606.2.The target compound (GT-09420) (white solid, 31 mg, yield 54%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.66 (s, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.39-7.31 (m, 2H), 7.21-7.14 (m, 1H), 5.16 (dd, J = 13.1, 5.0 Hz, 1H), 4.63-4.51 (m, 1H), 4.41 (d, J = 7.4 Hz, 1H). =17.6 Hz, 1H), 3.89 (s, 3H), 3.67-3.58 (m, 3H), 3.42-3.37 (m, 2H), 3.36-3.20 (m, 6H), 3.09 (s, 1H), 2.98-2.89 (m, 1H), 2.63 (d, J=16.9 Hz, 1H), 2.43-2.24 (m, 2H), 2.15-1.99 (m, 2H). LCMS (ES1) C 29 H 32 Cl 2 F 2 N 5 O 3 + [M+H] + : calculated value 606.18, found value 606.2.

实施例131：3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09421)的制备Example 131: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09421)

参照合成方案1的方法制备目标化合物(GT-09421)(白色固体，39mg，收率67％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.90(s，1H)，7.78(d，J＝6.9Hz，1H)，7.69(d，J＝7.8Hz，1H)，7.33(d，J＝6.8Hz，2H)，7.16(t，1H)，5.14(dd，J＝13.2，5.0Hz，1H)，4.51(d，J＝17.6Hz，1H)，4.38(d，J＝17.6Hz，1H)，4.26(s，2H)，3.80-3.73(m，2H)，3.35(s，2H)，3.27-3.10(m，8H)，2.96-2.88(m，1H)，2.81(s，1H)，2.62(d，J＝17.1Hz，1H)，2.45-2.36(m，1H)，2.32(d，J＝10.2Hz，1H)，2.20(s，1H)，2.06-1.95(m，1H).LCMS(ESI)C29H32Cl2F2N5O3 +[M+H]+：计算值606.18，实测值606.2.The target compound (GT-09421) (white solid, 39 mg, yield 67%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.90 (s, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 6.8 Hz, 2H), 7.16 (t, 1H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.51 (d, J = 17.6 Hz, 1H), 4.38 (d, J = 17.6 Hz, 1H), 4.26 (s, 2H), 3.80-3.73 (m, 2H), 3.35 (s, 2H), 3.27-3.10 (m, 8H), 2.96-2.88 (m, 1H), 2.81 (s, 1H), 2.62 (d, J=17.1 Hz, 1H), 2.45-2.36 (m, 1H), 2.32 (d, J=10.2 Hz, 1H), 2.20 (s, 1H), 2.06-1.95 (m, 1H). LCMS (ESI) C 29 H 32 Cl 2 F 2 N 5 O 3 + [M+H] + : calculated value 606.18, found value 606.2.

实施例132：3-(7-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09422)的制备Example 132: Preparation of 3-(7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09422)

参照合成方案1的方法制备目标化合物(GT-09422)(白色固体，27mg，收率47％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，7.77-7.62(m，3H)，7.40-7.25(m，2H)，7.20-7.09(m，1H)，5.17-5.08(m，1H)，4.85-4.38(m，4H)，3.71-3.66(m，2H)，3.41-3.37(m，2H)，3.18(s，8H)，2.98-2.86(m，2H)，2.62(d，J＝17.6Hz，1H)，2.47-2.37(m，1H)，2.35-2.26(m，1H)，2.23-2.11(m，1H)，2.08-1.99(m，1H).LCMS(ESI)C29H32Cl2F2N5O3 +[M+H]+：计算值606.18，实测值606.2.The target compound (GT-09422) (white solid, 27 mg, yield 47%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.77-7.62 (m, 3H), 7.40-7.25 (m, 2H), 7.20-7.09 (m, 1H), 5.17-5.08 (m, 1H), 4.85-4.38 (m, 4H), 3.71-3.66 (m, 2H), 3.41-3 .37 (m, 2H), 3.18 (s, 8H), 2.98-2.86 (m, 2H), 2.62 (d, J=17.6 Hz, 1H), 2.47-2.37 (m, 1H), 2.35-2.26 (m, 1H), 2.23-2.11 (m, 1H), 2.08-1.99 (m, 1H). LCMS (ESI) C 29 H 32 Cl 2 F 2 N 5 O 3 + [M+H] + : calculated value 606.18, found value 606.2.

实施例133：3-(5-(2-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09430)的制备Example 133: Preparation of 3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09430)

参照合成方案1的方法制备目标化合物(GT-09430)(白色固体，23mg，收率39％)。1H NMR(400MHz，DMSO)δ11.00(s，1H)，7.72(d，J＝7.8Hz，1H)，7.53(s，1H)，7.44(d，J＝7.8Hz，1H)，7.39-7.31(m，2H)，7.22-7.12(m，1H)，5.12(dd，J＝13.2，5.1Hz，1H)，4.46(d，J＝17.5Hz，1H)，4.33(d，J＝17.5Hz，1H)，4.03(s，1H)，3.66(s，3H)，3.39-3.32(m，3H)，3.23-3.09(m，10H)，2.97-2.89(m，1H)，2.61(d，J＝16.9Hz，1H)，2.44-2.20(m，3H)，2.06-1.97(m，1H).LCMS(ESI)C30H34Cl2F2N5O3 +[M+H]+：计算值620.20，实测值620.3.The target compound (GT-09430) (white solid, 23 mg, yield 39%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.39-7.31 (m, 2H), 7.22-7.12 (m, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 (d, J = 17.5 Hz, 1H) , 4.33 (d, J = 17.5 Hz, 1H), 4.03 (s, 1H), 3.66 (s, 3H), 3.39-3.32 (m, 3H), 3.23-3.09 (m, 10H), 2.97-2.89 (m, 1H), 2.61 (d, J = 16.9 Hz, 1H), 2.44-2.20 (m, 3H), 2.06-1.97 (m, 1H). LCMS (ESI) C 30 H 34 Cl 2 F 2 N 5 O 3 + [M+H] + : calculated value 620.20, found value 620.3.

实施例134：3-(5-(3-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09431)的制备Example 134: Preparation of 3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09431)

参照合成方案1的方法制备目标化合物(GT-09431)(白色固体，18mg，收率31％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，7.68(d，J＝7.8Hz，1H)，7.50(s，1H)，7.41(d，J＝8.0Hz，1H)，7.35-7.30(m，2H)，7.19-7.13(m，1H)，5.14-5.05(m，1H)，4.44(d，J＝17.4Hz，1H)，4.31(d，J＝17.4Hz，1H)，3.96(s，1H)，3.65-3.64(m，1H)，3.08(s，10H)，2.98-2.84(m，2H)，2.77(t，J＝7.4Hz，2H)，2.67-2.53(m，2H)，2.49-2.30(m，2H)，2.29-2.16(m，2H)，2.15-2.05(m，2H)，2.04-1.97(m，1H).LCMS(ESI)C31H36Cl2F2N5O3 +[M+H]+：计算值634.22，实测值634.3.The target compound (GT-09431) (white solid, 18 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.19-7.13 (m, 1H), 5.14-5.05 (m, 1H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H) , 3.96 (s, 1H), 3.65-3.64 (m, 1H), 3.08 (s, 10H), 2.98-2.84 (m, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.67-2.53 (m, 2H), 2.49-2.30 (m, 2H), 2.29-2.16 (m, 2H), 2.15-2.05 (m, 2H), 2.04-1.97 (m, 1H). LCMS (ESI) C 31 H 36 Cl 2 F 2 N 5 O 3 + [M+H] + : calculated value 634.22, found value 634.3.

实施例135：5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09432)的制备Example 135: Preparation of 5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09432)

参照合成方案1的方法制备目标化合物(GT-09432)(白色固体，27mg，收率46％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，7.96(d，J＝7.4Hz，2H)，7.90(d，J＝7.6Hz，1H)，7.37-7.32(m，2H)，7.20-7.15(m，1H)，5.17(dd，J＝12.8，5.3Hz，1H)，4.03(s，2H)，3.82-3.60(m，3H)，3.29-3.20(m，6H)，3.17-3.08(m，2H)，2.94-2.86(m，1H)，2.77(s，1H)，2.67-2.53(m，3H)，2.27(s，1H)，2.13-2.01(m，2H).LCMS(ESI)C29H30Cl2F2N5O4 +[M+H]+：计算值620.16，实测值620.2.The target compound (GT-09432) (white solid, 27 mg, yield 46%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 7.96 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.37-7.32 (m, 2H), 7.20-7.15 (m, 1H), 5.17 (dd, J = 12.8, 5.3 Hz, 1H), 4.03 (s, 2H), 3.82-3.60 (m, 3H), 3.29-3.20 (m, 6H), 3.17-3.08 (m, 2H), 2.94-2.86 (m, 1H), 2.77 (s, 1H), 2.67-2.53 (m, 3H), 2.27 (s, 1H), 2.13-2.01 (m, 2H). LCMS (ESI) C 29 H 30 Cl 2 F 2 N 5 O 4 + [M+H] + : calculated value 620.16, found value 620.2.

实施例136：4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09433)的制备Example 136: Preparation of 4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09433)

参照合成方案1的方法制备目标化合物(GT-09433)(白色固体，30mg，收率51％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，7.99-7.92(m，1H)，7.92-7.85(m，2H)，7.38-7.33(m，2H)，7.20-7.14(m，1H)，5.16(dd，J＝12.7，5.4Hz，1H)，4.23(s，2H)，3.97-3.61(m，3H)，3.28(s，6H)，3.12(s，2H)，2.95-2.86(m，1H)，2.67(s，1H)，2.65-2.54(m，2H)，2.49-2.37(m，1H)，2.33(s，1H)，2.11-2.01(m，2H).LCMS(ESI)C29H30Cl2F2N5O4 +[M+H]+：计算值620.16，实测值620.2.The target compound (GT-09433) (white solid, 30 mg, yield 51%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.99-7.92 (m, 1H), 7.92-7.85 (m, 2H), 7.38-7.33 (m, 2H), 7.20-7.14 (m, 1H), 5.16 (dd, J = 12.7, 5.4 Hz, 1H), 4.23 (s, 2H), 3. 97-3.61 (m, 3H), 3.28 (s, 6H), 3.12 (s, 2H), 2.95-2.86 (m, 1H), 2.67 (s, 1H), 2.65-2.54 (m, 2H), 2.49-2.37 (m, 1H), 2.33 (s, 1H), 2.11-2.01 (m, 2H). LCMS (ESI) C 29 H 30 Cl 2 F 2 N 5 O 4 + [M+H] + : calculated value 620.16, found value 620.2.

实施例137：3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09599)的制备Example 137: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09599)

参照合成方案1的方法制备目标化合物(GT-09599)(白色固体，20mg，收率34％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.68-7.58(m，3H)，7.39(t，J＝7.9Hz，1H)，7.26(dd，J＝7.7，1.5Hz，1H)，5.76(s，1H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.59(d，J＝17.5Hz，1H)，4.42(d，J＝17.4Hz，1H)，3.96(s，5H)，3.45-3.35(m，3H)，3.11(s，1H)，2.97-2.88(m，1H)，2.77-2.69(m，1H)，2.61(d，J＝16.6Hz，2H)，2.48-2.32(m，3H)，2.12-1.97(m，2H).LCMS(ESI)C30H30Cl2F3N4O3 +[M+H]+：计算值621.16，实测值621.2.The target compound (GT-09599) (white solid, 20 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.68-7.58 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.7, 1.5 Hz, 1H), 5.76 (s, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 17.5 Hz, 1H), 4.42 (d, J = 17.4 Hz, 1H), 3.96 (s, 5H), 3.45-3.35 (m, 3H), 3.11 (s, 1H), 2.97-2.88 (m, 1H), 2.77-2.69 (m, 1H), 2.61 (d, J = 16.6 Hz, 2H), 2.48-2.32 (m, 3H), 2.12-1.97 (m, 2H). LCMS (ESI) C 30 H 30 Cl 2 F 3 N 4 O 3 + [M+H] + : calculated value 621.16, found value 621.2.

实施例138：3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09600)的制备Example 138: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09600)

参照合成方案1的方法制备目标化合物(GT-09600)(白色固体，20mg，收率34％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.72(d，J＝5.6Hz，1H)，7.65-7.54(m，2H)，7.39(t，J＝7.9Hz，1H)，7.30-7.21(m，1H)，5.76(s，1H)，5.19-5.06(m，1H)，4.49(d，J＝17.4Hz，1H)，4.36(d，J＝17.2Hz，1H)，3.93(s，5H)，3.36-3.25(m，2H)，3.10(s，1H)，2.96-2.87(m，1H)，2.83-2.66(m，2H)，2.65-2.55(m，2H)，2.47-2.31(m，3H)，2.14-1.98(m，2H).LCMS(ESI)C30H30Cl2F3N4O3 +[M+H]+：计算值621.16，实测值621.2.The target compound (GT-09600) (white solid, 20 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.65-7.54 (m, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.30-7.21 (m, 1H), 5.76 (s, 1H), 5.19-5.06 (m, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4 .36 (d, J = 17.2 Hz, 1H), 3.93 (s, 5H), 3.36-3.25 (m, 2H), 3.10 (s, 1H), 2.96-2.87 (m, 1H), 2.83-2.66 (m, 2H), 2.65-2.55 (m, 2H), 2.47-2.31 (m, 3H), 2.14-1.98 (m, 2H). LCMS (ESI) C 30 H 30 Cl 2 F 3 N 4 O 3 + [M+H] + : calculated value 621.16, found value 621.2.

实施例139：3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09601)的制备Example 139: Preparation of 3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09601)

参照合成方案1的方法制备目标化合物(GT-09601)(白色固体，16mg，收率28％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.64-7.59(m，1H)，7.45(s，1H)，7.39(t，J＝7.9Hz，1H)，7.32(d，J＝10.0Hz，1H)，7.29-7.24(m，1H)，5.76(s，1H)，5.09(dd，J＝13.3，5.1Hz，1H)，4.51(d，J＝17.6Hz，1H)，4.37(d，J＝17.9Hz，1H)，3.91(s，5H)，3.19-3.00(m，2H)，2.98-2.83(m，2H)，2.82-2.56(m，4H)，2.44-2.23(m，3H)，2.15-1.96(m，2H).LCMS(ESI)C30H30Cl2F3N4O3 +[M+H]+：计算值621.16，实测值621.2.The target compound (GT-09601) (white solid, 16 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.64-7.59 (m, 1H), 7.45 (s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 7.29-7.24 (m, 1H), 5.76 (s, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1 3H), 4.51 (d, J = 17.6 Hz, 1H), 4.37 (d, J = 17.9 Hz, 1H), 3.91 (s, 5H), 3.19-3.00 (m, 2H), 2.98-2.83 (m, 2H), 2.82-2.56 (m, 4H), 2.44-2.23 (m, 3H), 2.15-1.96 (m, 2H). LCMS (ESI) C 30 H 30 Cl 2 F 3 N 4 O 3 + [M+H] + : calculated value 621.16, found value 621.2.

实施例140：3-(4-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09602)的制备Example 140: Preparation of 3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09602)

参照合成方案1的方法制备目标化合物(GT-09602)(白色固体，6mg，收率11％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.70(d，J＝7.5Hz，1H)，7.66-7.58(m，2H)，7.54(t，J＝7.5Hz，1H)，7.40(t，J＝10.2，5.4Hz，1H)，7.32-7.19(m，1H)，5.76(s，1H)，5.16(dd，J＝13.2，5.1Hz，1H)，4.63-4.48(m，1H)，4.40(d，J＝17.7Hz，1H)，4.17-3.58(m，6H)，3.30-3.15(m，2H)，3.14-2.87(m，3H)，2.63(d，J＝17.5Hz，2H)，2.44-2.27(m，3H)，2.09-1.95(m，2H).LCMS(ESI)C30H31Cl2F2N4O3 +[M+H]+：计算值603.17，实测值603.2.The target compound (GT-09602) (white solid, 6 mg, yield 11%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.66-7.58 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 10.2, 5.4 Hz, 1H), 7.32-7.19 (m, 1H), 5.76 (s, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.63-4.48 (m, 1H), 4.40 (d, J=17.7 Hz, 1H), 4.17-3.58 (m, 6H), 3.30-3.15 (m, 2H), 3.14-2.87 (m, 3H), 2.63 (d, J=17.5 Hz, 2H), 2.44-2.27 (m, 3H), 2.09-1.95 (m, 2H). LCMS (ESI) C 30 H 31 Cl 2 F 2 N 4 O 3 + [M+H] + : calculated value 603.17, found value 603.2.

实施例141：3-(6-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09635)的制备Example 141: Preparation of 3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09635)

参照合成方案1的方法制备目标化合物(GT-09635)(白色固体，18mg，收率31％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，7.90-7.78(m，1H)，7.76-7.65(m，2H)，7.60(d，J＝8.1Hz，1H)，7.38(t，J＝7.8Hz，1H)，7.30-7.19(m，1H)，5.74(s，1H)，5.14(dd，J＝13.2，5.0Hz，1H)，4.50(d，J＝17.6Hz，1H)，4.37(d，J＝17.5Hz，1H)，4.14(s，2H)，3.91-3.79(m，3H)，3.42-3.18(m，4H)，2.98-2.82(m，2H)，2.67-2.57(m，3H)，2.45-2.34(m，2H)，2.19(s，1H)，2.05-1.93(m，1H).LCMS(ESI)C30H31Cl2F2N4O3 +[M+H]+：计算值603.17，实测值603.3.The target compound (GT-09635) (white solid, 18 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.90-7.78 (m, 1H), 7.76-7.65 (m, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.30-7.19 (m, 1H), 5.74 (s, 1H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.50 (d, J = 13.3, 11.9 Hz, 1H), 4.70 (d, J = 13.1, 11.9 Hz, 1H), 4.91 (d, J = 13.3, 11.9 Hz, 1H), 4.85 (d, J = 13. =17.6 Hz, 1H), 4.37 (d, J=17.5 Hz, 1H), 4.14 (s, 2H), 3.91-3.79 (m, 3H), 3.42-3.18 (m, 4H), 2.98-2.82 (m, 2H), 2.67-2.57 (m, 3H), 2.45-2.34 (m, 2H), 2.19 (s, 1H), 2.05-1.93 (m, 1H). LCMS (ESI) C 30 H 31 Cl 2 F 2 N 4 O 3 + [M+H] + : calculated value 603.17, found value 603.3.

实施例142：3-(7-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09636)的制备Example 142: Preparation of 3-(7-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09636)

参照合成方案1的方法制备目标化合物(GT-09636)(白色固体，23mg，收率41％)。1H NMR(400MHz，DMSO)δ11.02(d，J＝5.3Hz，1H)，9.31(d，J＝6.6Hz，1H)，8.45(d，J＝6.9Hz，1H)，7.68-7.64(m，2H)，7.61-7.57(m，2H)，5.74(s，1H)，5.14-5.10(m，1H)，4.51-4.33(m，4H)，3.81(s，3H)，3.40-3.14(m，4H)，2.95-2.85(m，2H)，2.81-2.73(m，1H)，2.69-2.56(m，3H)，2.46-2.38(m，2H)，2.05-2.00(m，1H).LCMS(ES1)C30H31Cl2F2N4O3 +[M+H]+：计算值603.17，实测值603.3.The target compound (GT-09636) (white solid, 23 mg, yield 41%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (d, J = 5.3 Hz, 1H), 9.31 (d, J = 6.6 Hz, 1H), 8.45 (d, J = 6.9 Hz, 1H), 7.68-7.64 (m, 2H), 7.61-7.57 (m, 2H), 5.74 (s, 1H), 5.14-5.10 (m, 1H) , 4.51-4.33 (m, 4H), 3.81 (s, 3H), 3.40-3.14 (m, 4H), 2.95-2.85 (m, 2H), 2.81-2.73 (m, 1H), 2.69-2.56 (m, 3H), 2.46-2.38 (m, 2H), 2.05-2.00 (m, 1H). LCMS (ES1) C 30 H 31 Cl 2 F 2 N 4 O 3 + [M+H] + : calculated value 603.17, found value 603.3.

实施例143：3-(5-(2-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09637)的制备Example 143: Preparation of 3-(5-(2-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09637)

参照合成方案1的方法制备目标化合物(GT-09637)(白色固体，14mg，收率25％)。1H NMR(400MHz，DMSO)δ11.00(s，1H)，9.33(d，J＝6.6Hz，1H)，8.48(d，J＝9.5Hz，1H)，7.74-7.58(m，3H)，7.53(s，1H)，7.47-7.43(m，1H)，5.74(s，1H)，5.12(dd，J＝13.2，5.1Hz，1H)，4.45(d，J＝17.2Hz，1H)，4.33(d，1H)，3.94-3.60(m，5H)，3.35-3.14(m，5H)，3.08-2.86(m，5H)，2.64-2.55(m，2H)，2.46-2.35(m，2H)，2.03-1.96(m，1H).LCMS(ESI)C31H33Cl2F2N4O3 +[M+H]+：计算值617.19，实测值617.3.The target compound (GT-09637) (white solid, 14 mg, yield 25%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.33 (d, J = 6.6 Hz, 1H), 8.48 (d, J = 9.5 Hz, 1H), 7.74-7.58 (m, 3H), 7.53 (s, 1H), 7.47-7.43 (m, 1H), 5.74 (s, 1H), 5.12 (dd, J = 13.2, 5.1 Hz , 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.33 (d, 1H), 3.94-3.60 (m, 5H), 3.35-3.14 (m, 5H), 3.08-2.86 (m, 5H), 2.64-2.55 (m, 2H), 2.46-2.35 (m, 2H), 2.03-1.96 (m, 1H). LCMS (ESI) C 31 H 33 Cl 2 F 2 N 4 O 3 + [M+H] + : calculated value 617.19, found value 617.3.

实施例144：3-(5-(3-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09638)的制备Example 144: Preparation of 3-(5-(3-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09638)

参照合成方案1的方法制备目标化合物(GT-09638)(白色固体，17mg，收率29％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，9.31(d，J＝6.4Hz，1H)，8.47(d，J＝6.8Hz，1H)，7.73-7.63(m，2H)，7.64-7.57(m，1H)，7.50(s，1H)，7.44-7.40(m，1H)，5.72(s，1H)，5.11(dd，J＝13.2，5.0Hz，1H)，4.44(d，J＝17.1Hz，1H)，4.31(d，J＝17.3Hz，1H)，3.93(s，1H)，3.72-3.55(m，6H)，3.09(s，3H)，2.96-2.87(m，2H)，2.82-2.73(m，3H)，2.61(d，J＝17.7Hz，2H)，2.46-2.34(m，2H)，2.12-2.05(m，1H)，2.04-1.96(m，2H).LCMS(ESI)C32H35Cl2F2N4O3 +[M+H]+：计算值631.20，实测值631.3.The target compound (GT-09638) (white solid, 17 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.31 (d, J = 6.4 Hz, 1H), 8.47 (d, J = 6.8 Hz, 1H), 7.73-7.63 (m, 2H), 7.64-7.57 (m, 1H), 7.50 (s, 1H), 7.44-7.40 (m, 1H), 5.72 (s, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.93 (s, 1H), 3.72-3.55 (m, 6H), 3.09 (s, 3H), 2.96-2.87 (m, 2H), 2.82-2.73 (m, 3H), 2.61 (d, J = 17.7 Hz, 2H), 2.46-2.34 (m, 2H), 2.12-2.05 (m, 1H), 2.04-1.96 (m, 2H). LCMS (ESI) C 3 2 H 3 5 Cl 2 F 2 N 4 O 3 + [M+H] + : calculated value 631.20, found value 631.3.

实施例145：5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09639)的制备Example 145: Preparation of 5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09639)

参照合成方案1的方法制备目标化合物(GT-09639)(白色固体，10mg，收率18％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，7.97-7.91(m，2H)，7.88(s，1H)，7.61(d，J＝7.7Hz，1H)，7.39(t，J＝7.9Hz，1H)，7.26(dd，J＝7.7，1.5Hz，1H)，5.75(s，1H)，5.17(dd，J＝12.9，5.3Hz，1H)，3.97(d，J＝7.7Hz，5H)，3.10(d，J＝27.5Hz，2H)，2.90(ddd，J＝30.4，16.3，9.4Hz，2H)，2.68-2.53(m，4H)，2.49-2.27(m，3H)，2.10-2.00(m，2H).LCMS(ESI)C30H29Cl2F2N4O4 +[M+H]+：计算值617.15，实测值617.2.The target compound (GT-09639) (white solid, 10 mg, yield 18%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.97-7.91 (m, 2H), 7.88 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.7, 1.5 Hz, 1H), 5.75 (s, 1H), 5.17 (dd, J = 12 .9, 5.3 Hz, 1H), 3.97 (d, J = 7.7 Hz, 5H), 3.10 (d, J = 27.5 Hz, 2H), 2.90 (ddd, J = 30.4, 16.3, 9.4 Hz, 2H), 2.68-2.53 (m, 4H), 2.49-2.27 (m, 3H), 2.10-2.00 (m, 2H). LCMS (ESI) C 30 H 29 Cl 2 F 2 N 4 O 4 + [M+H] + : calculated value 617.15, found value 617.2.

实施例146：4-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09640)的制备Example 146: Preparation of 4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09640)

参照合成方案1的方法制备目标化合物(GT-09640)(白色固体，12mg，收率21％)。1H NMR(400MHz，DMSO)δ11.14(s，1H)，7.94-7.85(m，3H)，7.64-7.55(m，1H)，7.39(t，J＝7.8Hz，1H)，7.26(d，J＝7.5Hz，1H)，5.76(s，1H)，5.15(dd，J＝12.7，5.4Hz，1H)，4.20(d，J＝23.9Hz，2H)，3.93(s，2H)，3.36-3.20(m，4H)，3.06(s，1H)，2.93-2.86(m，1H)，2.71-2.53(m，4H)，2.46-2.24(m，2H)，2.12-1.98(m，2H).LCMS(ESI)C30H29Cl2F2N4O4 +[M+H]+：计算值617.15，实测值617.2.The target compound (GT-09640) (white solid, 12 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.94-7.85 (m, 3H), 7.64-7.55 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 5.76 (s, 1H), 5.15 (dd, J = 12.7, 5.4 Hz, 1H ), 4.20 (d, J = 23.9 Hz, 2H), 3.93 (s, 2H), 3.36-3.20 (m, 4H), 3.06 (s, 1H), 2.93-2.86 (m, 1H), 2.71-2.53 (m, 4H), 2.46-2.24 (m, 2H), 2.12-1.98 (m, 2H). LCMS (ESI) C 30 H 29 Cl 2 F 2 N 4 O 4 + [M+H] + : calculated value 617.15, found value 617.2.

实施例147：3-(4-氟-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09641)的制备Example 147: Preparation of 3-(4-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09641)

参照合成方案1的方法制备目标化合物(GT-09641)(白色固体，16mg，收率26％)。1H NMR(400MHz，DMSO)δ11.59(s，1H)，11.02(d，J＝13.9Hz，2H)，8.14-8.06(m，1H)，7.88(s，1H)，7.71(d，J＝7.6Hz，1H)，7.63-7.59(m，1H)，7.31-7.21(m，1H)，5.18-5.11(m，1H)，4.66-4.56(m，2H)，4.55-4.40(m，3H)，4.11(s，2H)，3.67-3.53(m，6H)，3.15-3.00(m，3H)，2.96-2.90(m，1H)，2.65-2.56(m，2H)，2.47-2.39(m，2H)，2.38-2.31(m，2H)，2.18(s，1H)，2.03-1.99(m，1H).LCMS(ESI)C30H33F2N6O4 +[M+H]+：计算值579.25，实测值579.3.The target compound (GT-09641) (white solid, 16 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.59 (s, 1H), 11.02 (d, J = 13.9 Hz, 2H), 8.14-8.06 (m, 1H), 7.88 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.31-7.21 (m, 1H), 5.18-5.11 (m, 1H), 4.66-4.56 (m, 2H), 4.55-4.40 (m, 3H), 4.11 (s, 2H), 3.67-3.53 (m, 6H), 3.15-3.00 (m, 3H), 2.96-2.90 (m, 1H), 2.65-2.56 (m, 2H), 2.47-2.39 (m, 2H), 2.38-2.31 (m, 2H), 2.18 (s, 1H), 2.03-1.99 (m, 1H). LCMS (ESI) C 30 H 33 F 2 N 6 O 4 + [M+H] + : calculated value 579.25, found value 579.3.

实施例148：3-(6-氟-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09642)的制备Example 148: Preparation of 3-(6-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09642)

参照合成方案1的方法制备目标化合物(GT-09642)(白色固体，27mg，收率43％)。1H NMR(400MHz，DMSO)δ11.82(s，1H)，11.26(s，1H)，11.02(d，J＝13.2Hz，1H)，8.10(dd，J＝8.8，5.1Hz，1H)，7.98(dd，J＝17.1，5.3Hz，1H)，7.68(d，J＝8.5Hz，1H)，7.61(d，J＝9.0Hz，1H)，7.26(t，J＝9.1Hz，1H)，5.18-5.11(m，1H)，4.88(s，1H)，4.52-4.33(m，4H)，4.11(s，2H)，3.64-3.47(m，6H)，3.14-3.01(m，3H)，2.96-2.89(m，1H)，2.69-2.55(m，2H)，2.47-2.34(m，3H)，2.20(s，2H)，2.04-1.98(m，1H).LCMS(ESI)C30H33F2N6O4 +[M+H]+：计算值579.25，实测值579.3.The target compound (GT-09642) (white solid, 27 mg, yield 43%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 11.26 (s, 1H), 11.02 (d, J = 13.2 Hz, 1H), 8.10 (dd, J = 8.8, 5.1 Hz, 1H), 7.98 (dd, J = 17.1, 5.3 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H), 5 .18-5.11 (m, 1H), 4.88 (s, 1H), 4.52-4.33 (m, 4H), 4.11 (s, 2H), 3.64-3.47 (m, 6H), 3.14-3.01 (m, 3H), 2.96-2.89 (m, 1H), 2.69-2.55 (m, 2H), 2.47-2.34 (m, 3H), 2.20 (s, 2H), 2.04-1.98 (m, 1H). LCMS (ESI) C 30 H 33 F 2 N 6 O 4 + [M+H] + : calculated value 579.25, found value 579.3.

实施例149：3-(7-氟-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09643)的制备Example 149: Preparation of 3-(7-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09643)

参照合成方案1的方法制备目标化合物(GT-09643)(白色固体，11mg，收率18％)。1H NMR(400MHz，DMSO)δ11.56(s，1H)，11.26(s，1H)，11.02(s，1H)，8.10(dd，J＝8.8，5.2Hz，1H)，7.72-7.55(m，3H)，7.26(t，J＝8.9Hz，1H)，5.11(dd，J＝13.2，5.1Hz，1H)，4.60-4.38(m，4H)，4.12(s，2H)，3.62-3.48(m，6H)，3.32-3.28(m，2H)，3.07-2.87(m，3H)，2.70-2.55(m，2H)，2.45-2.31(m，3H)，2.24(d，J＝18.5Hz，2H)，2.05-1.97(m，1H).LCMS(ESI)C30H33F2N6O4 +[M+H]+：计算值579.25，实测值579.3.The target compound (GT-09643) (white solid, 11 mg, yield 18%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 11.26 (s, 1H), 11.02 (s, 1H), 8.10 (dd, J = 8.8, 5.2 Hz, 1H), 7.72-7.55 (m, 3H), 7.26 (t, J = 8.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.60-4.3 8 (m, 4H), 4.12 (s, 2H), 3.62-3.48 (m, 6H), 3.32-3.28 (m, 2H), 3.07-2.87 (m, 3H), 2.70-2.55 (m, 2H), 2.45-2.31 (m, 3H), 2.24 (d, J=18.5 Hz, 2H), 2.05-1.97 (m, 1H). LCMS (ESI) C 30 H 33 F 2 N 6 O 4 + [M+H] + : calculated value 579.25, found value 579.3.

实施例150：3-(4-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09644)的制备Example 150: Preparation of 3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09644)

参照合成方案1的方法制备目标化合物(GT-09644)(白色固体，14mg，收率23％)。1H NMR(400MHz，DMSO)δ11.07(s，1H)，10.99(s，1H)，8.10(dd，J＝8.9，5.2Hz，1H)，7.94(s，1H)，7.84(d，J＝7.2Hz，1H)，7.68-7.56(m，3H)，7.31-7.22(m，1H)，5.25-5.16(m，1H)，4.79(d，J＝17.6Hz，1H)，4.62(s，1H)，4.55-4.42(m，2H)，4.36(d，J＝17.3Hz，2H)，4.12(s，2H)，3.62-3.55(m，4H)，3.11(s，2H)，3.01-2.86(m，2H)，2.65(d，J＝17.0Hz，2H)，2.39-2.29(m，3H)，2.23(s，2H)，2.12-1.94(m，2H).LCMS(ESI)C30H34FN6O4 +[M+H]+：计算值561.26，实测值561.3.The target compound (GT-09644) (white solid, 14 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 10.99 (s, 1H), 8.10 (dd, J = 8.9, 5.2 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.68-7.56 (m, 3H), 7.31-7.22 (m, 1H), 5.25-5.16 (m, 1H), 4.79 (d, J = 17.6 Hz, 1H), 4.62 ( s, 1H), 4.55-4.42 (m, 2H), 4.36 (d, J=17.3 Hz, 2H), 4.12 (s, 2H), 3.62-3.55 (m, 4H), 3.11 (s, 2H), 3.01-2.86 (m, 2H), 2.65 (d, J=17.0 Hz, 2H), 2.39-2.29 (m, 3H), 2.23 (s, 2H), 2.12-1.94 (m, 2H). LCMS (ESI) C 30 H 34 FN 6 O 4 + [M+H] + : calculated value 561.26, found value 561.3.

实施例151：3-(6-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09645)的制备Example 151: Preparation of 3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09645)

参照合成方案1的方法制备目标化合物(GT-09645)(白色固体，12mg，收率20％)。1H NMR(400MHz，DMSO)δ11.47(s，1H)，11.02(s，1H)，10.83(s，1H)，8.09(dd，J＝9.0，5.3Hz，1H)，8.03-7.96(m，1H)，7.85(d，J＝7.6Hz，1H)，7.73(d，J＝7.7Hz，1H)，7.62(d，J＝9.1Hz，1H)，7.26(t，J＝8.3Hz，1H)，5.13(dd，J＝13.3，5.1Hz，1H)，4.54-4.37(m，4H)，4.11(s，1H)，3.53(d，J＝22.9Hz，6H)，3.28-3.13(m，3H)，3.01-2.87(m，4H)，2.62(d，J＝16.2Hz，2H)，2.40-2.31(m，2H)，2.16(s，2H)，2.05-1.99(m，1H).LCMS(ESI)C30H34FN6O4 +[M+H]+：计算值561.26，实测值561.3.The target compound (GT-09645) (white solid, 12 mg, yield 20%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 11.02 (s, 1H), 10.83 (s, 1H), 8.09 (dd, J = 9.0, 5.3 Hz, 1H), 8.03-7.96 (m, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.26 (t, J = 8.3 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.54-4.37 (m, 4H), 4.11 (s, 1H), 3.53 (d, J = 22.9 Hz, 6H), 3.28-3.13 (m, 3H), 3.01-2.87 (m, 4H), 2.62 (d, J = 16.2 Hz, 2H), 2.40-2.31 (m, 2H), 2.16 (s, 2H), 2.05-1.99 (m, 1H). LCMS (ESI) C 30 H 34 FN 6 O 4 + [M+H] + : calculated value 561.26, found value 561.3.

实施例152：3-(7-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09646)的制备Example 152: Preparation of 3-(7-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09646)

参照合成方案1的方法制备目标化合物(GT-09646)(白色固体，14mg，收率23％)。1H NMR(400MHz，DMSO)δ11.78(s，1H)，11.03(s，1H)，10.65(s，1H)，8.10(dd，J＝8.9，5.2Hz，1H)，7.81-7.70(m，3H)，7.62(dd，J＝9.1，2.2Hz，1H)，7.29-7.23(m，1H)，5.17-5.08(m，1H)，4.86(d，J＝12.1Hz，1H)，4.73(d，J＝12.8Hz，1H)，4.47(dd，J＝42.8，17.9Hz，2H)，4.11(d，J＝12.9Hz，1H)，3.65-3.53(m，6H)，3.34-3.23(m，4H)，3.14-3.04(m，2H)，2.92-2.85(m，1H)，2.63(d，J＝17.6Hz，1H)，2.45-2.31(m，3H)，2.17(s，2H)，2.07-1.98(m，1H).LCMS(ES1)C30H34FN6O4 +[M+H]+：计算值561.26，实测值561.3.The target compound (GT-09646) (white solid, 14 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 11.03 (s, 1H), 10.65 (s, 1H), 8.10 (dd, J = 8.9, 5.2 Hz, 1H), 7.81-7.70 (m, 3H), 7.62 (dd, J = 9.1, 2.2 Hz, 1H), 7.29-7.23 (m, 1H), 5.17-5.08 (m, 1H), 4.86 (d, J = 12.1 Hz, 1H), 4.73 (d, J = 12.8 Hz, 1 H), 4.47 (dd, J=42.8, 17.9 Hz, 2H), 4.11 (d, J=12.9 Hz, 1H), 3.65-3.53 (m, 6H), 3.34-3.23 (m, 4H), 3.14-3.04 (m, 2H), 2.92-2.85 (m, 1H), 2.63 (d, J=17.6 Hz, 1H), 2.45-2.31 (m, 3H), 2.17 (s, 2H), 2.07-1.98 (m, 1H). LCMS (ES1) C 30 H 34 FN 6 O 4 + [M+H] + : calculated value 561.26, found value 561.3.

实施例153：3-(5-(2-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09647)的制备Example 153: Preparation of 3-(5-(2-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09647)

参照合成方案1的方法制备目标化合物(GT-09647)(白色固体，15mg，收率24％)。1H NMR(400MHz，DMSO)δ11.68(s，1H)，11.00(s，1H)，10.92(s，1H)，8.11(dd，J＝8.8，5.2Hz，1H)，7.72(d，J＝7.8Hz，1H)，7.64-7.59(m，1H)，7.54(s，1H)，7.45(d，J＝7.7Hz，1H)，7.31-7.22(m，1H)，5.12(dd，J＝13.2，5.1Hz，1H)，4.46(d，J＝17.4Hz，1H)，4.33(d，J＝17.4Hz，1H)，4.13(s，1H)，3.75(d，J＝11.7Hz，2H)，3.70-3.48(m，5H)，3.36(s，5H)，3.25-3.20(m，2H)，3.10-2.96(m，2H)，2.94-2.85(m，1H)，2.61(d，J＝16.6Hz，1H)，2.47-2.34(m，3H)，2.28-2.09(m，2H)，2.05-1.94(m，1H).LCMS(ESI)C31H36FN6O4 +[M+H]+：计算值575.28，实测值575.3.The target compound (GT-09647) (white solid, 15 mg, yield 24%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 11.00 (s, 1H), 10.92 (s, 1H), 8.11 (dd, J = 8.8, 5.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.64-7.59 (m, 1H), 7.54 (s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.31-7.22 (m, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 4.13 (s, 1H), 3.75 (d, J = 11.7 Hz, 2H), 3.70-3.48 (m, 5H), 3.36 (s, 5H), 3.25-3.20 (m, 2H), 3.10-2.96 (m, 2H), 2.94-2.85 (m, 1H), 2.61 (d, J = 16.6 Hz, 1H), 2.47-2.34 (m, 3H), 2.28-2.09 (m, 2H), 2.05-1.94 (m, 1H). LCMS (ESI) C 31 H 36 FN 6 O 4 + [M+H] + : calculated value 575.28, found value 575.3.

实施例154：3-(5-(3-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09648)的制备Example 154: Preparation of 3-(5-(3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09648)

参照合成方案1的方法制备目标化合物(GT-09648)(白色固体，18mg，收率15％)。1H NMR(400MHz，DMSO)δ11.62(s，1H)，10.99(s，1H)，10.67(s，1H)，8.10(dd，J＝8.9，5.2Hz，1H)，7.69(d，J＝7.8Hz，1H)，7.65-7.58(m，1H)，7.50(s，1H)，7.41(d，J＝7.8Hz，1H)，7.30-7.22(m，1H)，5.11(dd，J＝13.2，5.0Hz，1H)，4.44(d，J＝17.4Hz，1H)，4.31(d，J＝17.3Hz，1H)，4.16-4.09(m，1H)，3.70-3.52(m，6H)，3.41(s，2H)，3.30-3.24(m，2H)，3.05(s，2H)，2.99-2.86(m，3H)，2.78(t，J＝7.4Hz，2H)，2.61(d，J＝17.2Hz，1H)，2.45-2.31(m，3H)，2.29-2.14(m，2H)，2.13-2.05(m，2H)，2.04-1.96(m，1H).LCMS(ESI)C32H38FN6O4 +[M+H]+：计算值589.29，实测值589.3.The target compound (GT-09648) (white solid, 18 mg, yield 15%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.62 (s, 1H), 10.99 (s, 1H), 10.67 (s, 1H), 8.10 (dd, J = 8.9, 5.2 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.65-7.58 (m, 1H), 7.50 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.30-7.22 (m, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 1 =17.3Hz, 1H), 4.16-4.09(m, 1H), 3.70-3.52(m, 6H), 3.41(s, 2H), 3.30-3.24(m, 2H), 3.05(s, 2H), 2.99-2.86(m, 3H), 2.78(t, J＝7.4Hz, 2H), 2.61(d, J＝17.2Hz, 1H), 2.45-2.31(m, 3H), 2.29-2.14(m, 2H), 2.13-2.05(m, 2H), 2.04-1.96(m, 1H).LCMS(ESI)C 32 H 38 FN 6 O 4 + [M+H] + : calculated value 589.29, found value 589.3.

实施例155：2-(2，6-二氧代哌啶-3-基)-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)异吲哚啉-1，3-二酮(GT-09649)的制备Example 155: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione (GT-09649)

参照合成方案1的方法制备目标化合物(GT-09649)(白色固体，10mg，收率16％)。1H NMR(400MHz，DMSO)δ11.61(s，1H)，11.26(s，1H)，11.16(s，1H)，8.22(s，1H)，8.13-7.99(m，3H)，7.62(d，J＝9.1Hz，1H)，7.26(t，J＝9.0Hz，1H)，5.19(dd，J＝12.8，5.3Hz，1H)，4.52(s，1H)，4.11(s，1H)，3.78-3.46(m，8H)，3.30-3.23(m，2H)，3.17-3.08(m，1H)，3.07-2.84(m，3H)，2.59(d，J＝23.0，11.0Hz，4H)，2.33(s，2H)，2.19(s，2H)，2.12-2.05(m，1H).LCMS(ESI)C30H32FN6O5 +[M+H]+：计算值575.24，实测值575.3.The target compound (GT-09649) (white solid, 10 mg, yield 16%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.61 (s, 1H), 11.26 (s, 1H), 11.16 (s, 1H), 8.22 (s, 1H), 8.13-7.99 (m, 3H), 7.62 (d, J = 9.1 Hz, 1H), 7.26 (t, J = 9.0 Hz, 1H), 5.19 (dd, J = 12.8, 5.3 Hz, 1H), 4.52 (s, 1 3H), 4.11 (s, 1H), 3.78-3.46 (m, 8H), 3.30-3.23 (m, 2H), 3.17-3.08 (m, 1H), 3.07-2.84 (m, 3H), 2.59 (d, J=23.0, 11.0 Hz, 4H), 2.33 (s, 2H), 2.19 (s, 2H), 2.12-2.05 (m, 1H). LCMS (ESI) C 30 H 32 FN 6 O 5 + [M+H] + : calculated value 575.24, found value 575.3.

实施例156：2-(2，6-二氧代哌啶-3-基)-4-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)异吲哚啉-1，3-二酮(GT-09650)的制备Example 156: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione (GT-09650)

参照合成方案1的方法制备目标化合物(GT-09650)(黄色固体，10mg，收率16％)。1H NMR(400MHz，DMSO)δ11.67(s，1H)，11.16(s，1H)，11.08(s，1H)，8.22-8.15(m，1H)，8.10(dd，J＝8.8，5.3Hz，1H)，8.03(d，J＝7.1Hz，1H)，7.97(t，J＝7.5Hz，1H)，7.62(dd，J＝9.1，2.1Hz，1H)，7.30-7.22(m，1H)，5.19(dd，J＝12.7，5.3Hz，1H)，4.71(s，2H)，4.10(s，2H)，3.58(s，6H)，3.31-3.20(m，3H)，3.18-3.03(m，2H)，2.94-2.85(m，1H)，2.66-2.56(m，2H)，2.40-2.30(m，2H)，2.30-2.11(m，2H)，2.12-2.02(m，1H).LCMS(ESI)C30H32FN6O5 +[M+H]+：计算值575.24，实测值575.3.The target compound (GT-09650) (yellow solid, 10 mg, yield 16%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 11.16 (s, 1H), 11.08 (s, 1H), 8.22-8.15 (m, 1H), 8.10 (dd, J=8.8, 5.3 Hz, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.97 (t, J=7.5 Hz, 1H), 7.62 (dd, J=9.1, 2.1 Hz, 1H), 7.30-7.22 (m, 1H), 5.19 (dd, J = 12.7, 5.3 Hz, 1H), 4.71 (s, 2H), 4.10 (s, 2H), 3.58 (s, 6H), 3.31-3.20 (m, 3H), 3.18-3.03 (m, 2H), 2.94-2.85 (m, 1H), 2.66-2.56 (m, 2H), 2.40-2.30 (m, 2H), 2.30-2.11 (m, 2H), 2.12-2.02 (m, 1H). LCMS (ESI) C 30 H 32 FN 6 O 5 + [M+H] + : calculated value 575.24, found value 575.3.

实施例157：3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09655)的制备Example 157: Preparation of 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09655)

参照合成方案1的方法制备目标化合物(GT-09655)(白色固体，35mg，收率59％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，8.07(dd，J＝8.9，5.2Hz，1H)，7.78-7.68(m，1H)，7.65(d，J＝7.7Hz，1H)，7.58(dd，J＝9.1，2.2Hz，1H)，7.27-7.17(m，1H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.60(d，J＝17.5Hz，1H)，4.43(d，J＝17.5Hz，1H)，4.09(s，2H)，3.67-3.62(m，4H)，3.54-3.46(m，3H)，3.32(s，4H)，3.22(s，1H)，3.00-2.82(m，2H)，2.61(d，J＝17.2Hz，1H)，2.48-2.39(m，1H)，2.34-2.23(m，1H)，2.16-2.06(m，1H)，2.05-1.97(m，1H).LCMS(ESI)C30H31F4N6O4 +[M+H]+：计算值615.23，实测值615.3.The target compound (GT-09655) (white solid, 35 mg, yield 59%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ11.03 (s, 1H), 8.07 (dd, J=8.9, 5.2 Hz, 1H), 7.78-7.68 (m, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.58 (dd, J=9.1, 2.2 Hz, 1H), 7.27-7.17 (m, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.60 (d, J=17.5 Hz, 1H), 4.43 (d, J=17 .5 Hz, 1H), 4.09 (s, 2H), 3.67-3.62 (m, 4H), 3.54-3.46 (m, 3H), 3.32 (s, 4H), 3.22 (s, 1H), 3.00-2.82 (m, 2H), 2.61 (d, J=17.2 Hz, 1H), 2.48-2.39 (m, 1H), 2.34-2.23 (m, 1H), 2.16-2.06 (m, 1H), 2.05-1.97 (m, 1H). LCMS (ESI) C 30 H 31 F 4 N 6 O 4 + [M+H] + : calculated value 615.23, found value 615.3.

实施例158：3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09656)的制备Example 158: Preparation of 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09656)

参照合成方案1的方法制备目标化合物(GT-09656)(白色固体，26mg，收率44％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.07(dd，J＝8.9，5.2Hz，1H)，7.77(d，J＝4.9Hz，1H)，7.64-7.52(m，2H)，7.23(t，J＝9.1，2.2Hz，1H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.49(d，J＝17.3Hz，1H)，4.36(d，J＝17.5Hz，1H)，4.03(s，2H)，3.69(s，6H)，3.33-3.23(m，4H)，3.18(s，1H)，3.00-2.83(m，2H)，2.68-2.54(m，2H)，2.45-2.36(m，1H)，2.30-2.17(m，1H)，2.10-1.98(m，2H).LCMS(ESI)C30H31F4N6O4 +[M+H]+：计算值615.23，实测值615.3.The target compound (GT-09656) (white solid, 26 mg, yield 44%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.07 (dd, J = 8.9, 5.2 Hz, 1H), 7.77 (d, J = 4.9 Hz, 1H), 7.64-7.52 (m, 2H), 7.23 (t, J = 9.1, 2.2 Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 4 .36 (d, J = 17.5 Hz, 1H), 4.03 (s, 2H), 3.69 (s, 6H), 3.33-3.23 (m, 4H), 3.18 (s, 1H), 3.00-2.83 (m, 2H), 2.68-2.54 (m, 2H), 2.45-2.36 (m, 1H), 2.30-2.17 (m, 1H), 2.10-1.98 (m, 2H). LCMS (ESI) C 30 H 31 F 4 N 6 O 4 + [M+H] + : calculated value 615.23, found value 615.3.

实施例159：3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09657)的制备Example 159: Preparation of 3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09657)

参照合成方案1的方法制备目标化合物(GT-09657)(白色固体，28mg，收率47％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.07(dd，J＝8.9，5.3Hz，1H)，7.58(dd，J＝9.1，2.1Hz，1H)，7.52(s，1H)，7.43(d，J＝9.4Hz，1H)，7.23(t，J＝9.0，2.1Hz，1H)，5.10(dd，J＝13.3，5.1Hz，1H)，4.52(d，J＝17.9Hz，1H)，4.39(d，J＝18.0Hz，1H)，4.11(s，2H)，3.66(d，J＝13.0Hz，8H)，3.27(s，5H)，2.96-2.87(m，1H)，2.61(d，J＝17.2Hz，1H)，2.44-2.34(m，1H)，2.27(s，1H)，2.18-2.07(m，1H)，2.05-1.97(m，1H).LCMS(ES1)C30H31F4N6O4 +[M+H]+：计算值615.23，实测值615.3.The target compound (GT-09657) (white solid, 28 mg, yield 47%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.07 (dd, J = 8.9, 5.3 Hz, 1H), 7.58 (dd, J = 9.1, 2.1 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 9.4 Hz, 1H), 7.23 (t, J = 9.0, 2.1 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 (d, J = 17.9 Hz, 1H), 4.39 (d, J = 18.0 Hz, 1H), 4.11 (s, 2H), 3.66 (d, J = 13.0 Hz, 8H), 3.27 (s, 5H), 2.96-2.87 (m, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.44-2.34 (m, 1H), 2.27 (s, 1H), 2.18-2.07 (m, 1H), 2.05-1.97 (m, 1H). LCMS (ES1) C 30 H 31 F 4 N 6 O 4 + [M+H] + : calculated value 615.23, found value 615.3.

实施例160：3-(4-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09658)的制备Example 160: Preparation of 3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09658)

参照合成方案1的方法制备目标化合物(GT-09658)(白色固体，36mg，收率62％)。1H NMR(400MHz，DMSO)δ11.04(s，1H)，8.07(dd，J＝8.9，5.2Hz，1H)，7.83-7.65(m，2H)，7.62-7.52(m，2H)，7.23(t，J＝9.0，2.0Hz，1H)，5.16(dd，J＝13.2，5.1Hz，1H)，4.68-4.54(m，1H)，4.43(d，J＝17.5Hz，1H)，3.95(s，2H)，3.77-3.66(m，6H)，3.34(s，6H)，3.14(s，1H)，2.98-2.90(m，1H)，2.64(d，J＝17.2Hz，1H)，2.43-2.34(m，1H)，2.27(s，1H)，2.14-1.98(m，2H).LCMS(ESI)C30H32F3N6O4 +[M+H]+：计算值597.24，实测值597.3.The target compound (GT-09658) (white solid, 36 mg, yield 62%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.07 (dd, J = 8.9, 5.2 Hz, 1H), 7.83-7.65 (m, 2H), 7.62-7.52 (m, 2H), 7.23 (t, J = 9.0, 2.0 Hz, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.68-4.54 (m, 1H), 4.43 (d, J = 17.5 Hz, 1H), 3.95 (s, 2H), 3.77-3.66 (m, 6H), 3.34 (s, 6H), 3.14 (s, 1H), 2.98-2.90 (m, 1H), 2.64 (d, J = 17.2 Hz, 1H), 2.43-2.34 (m, 1H), 2.27 (s, 1H), 2.14-1.98 (m, 2H). LCMS (ESI) C 30 H 32 F 3 N 6 O 4 + [M+H] + : calculated value 597.24, found value 597.3.

实施例161：3-(6-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09659)的制备Example 161: Preparation of 3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09659)

参照合成方案1的方法制备目标化合物(GT-09659)(白色固体，28mg，收率499％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.06(dd，J＝8.9，5.3Hz，1H)，7.95(s，1H)，7.82(d，J＝7.6Hz，1H)，7.71(d，J＝7.8Hz，1H)，7.57(dd，J＝9.1，2.2Hz，1H)，7.21(t，J＝9.1，2.2Hz，1H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.50(d，J＝14.8Hz，1H)，4.43-4.28(m，3H)，3.63(s，8H)，3.42(s，1H)，3.18(s，4H)，2.96-2.88(m，1H)，2.62(d，J＝16.7Hz，1H)，2.48-2.36(m，1H)，2.35-2.15(m，2H)，2.05-1.98(m，1H).LCMS(ESI)C30H32F3N6O4 +[M+H]+：计算值597.24，实测值597.3.The target compound (GT-09659) (white solid, 28 mg, yield 499%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.06 (dd, J = 8.9, 5.3 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 9.1, 2.2 Hz, 1H), 7.21 (t, J = 9.1, 2.2 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H). z, 1H), 4.50 (d, J=14.8 Hz, 1H), 4.43-4.28 (m, 3H), 3.63 (s, 8H), 3.42 (s, 1H), 3.18 (s, 4H), 2.96-2.88 (m, 1H), 2.62 (d, J=16.7 Hz, 1H), 2.48-2.36 (m, 1H), 2.35-2.15 (m, 2H), 2.05-1.98 (m, 1H). LCMS (ESI) C 30 H 32 F 3 N 6 O 4 + [M+H] + : calculated value 597.24, found value 597.3.

实施例162：3-(7-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09660)的制备Example 162: Preparation of 3-(7-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09660)

参照合成方案1的方法制备目标化合物(GT-09660)(白色固体，24mg，收率42％)。1H NMR(400MHz，DMSO)δ11.04(s，1H)，8.06(dd，J＝8.9，5.3Hz，1H)，7.72(s，3H)，7.57(dd，J＝9.1，2.2Hz，1H)，7.21(t，J＝9.1，2.2Hz，1H)，5.19-5.10(m，1H)，4.82(d，J＝37.2Hz，1H)，4.71-4.58(m，1H)，4.52(d，J＝17.9Hz，1H)，4.47-4.38(m，1H)，3.65-3.55(m，6H)，3.45(s，2H)，3.15(s，4H)，3.03-2.84(m，2H)，2.63(d，J＝17.0Hz，1H)，2.47-2.37(m，1H)，2.30-2.10(m，2H)，2.09-2.00(m，1H).LCMS(ESI)C30H32F3N6O4 +[M+H]+：计算值597.24，实测值597.3.The target compound (GT-09660) (white solid, 24 mg, yield 42%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.06 (dd, J = 8.9, 5.3 Hz, 1H), 7.72 (s, 3H), 7.57 (dd, J = 9.1, 2.2 Hz, 1H), 7.21 (t, J = 9.1, 2.2 Hz, 1H), 5.19-5.10 (m, 1H), 4.82 (d, J = 37.2 Hz, 1H), 4.71-4.58 (m, 1H), 4. 52 (d, J = 17.9 Hz, 1H), 4.47-4.38 (m, 1H), 3.65-3.55 (m, 6H), 3.45 (s, 2H), 3.15 (s, 4H), 3.03-2.84 (m, 2H), 2.63 (d, J = 17.0 Hz, 1H), 2.47-2.37 (m, 1H), 2.30-2.10 (m, 2H), 2.09-2.00 (m, 1H). LCMS (ESI) C 30 H 32 F 3 N 6 O 4 + [M+H] + : calculated value 597.24, found value 597.3.

实施例163：3-(5-(2-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09661)的制备Example 163: Preparation of 3-(5-(2-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09661)

参照合成方案1的方法制备目标化合物(GT-09661)(白色固体，24mg，收率41％)。1H NMR(400MHz，DMSO)δ11.00(s，1H)，8.06(dd，J＝8.9，5.3Hz，1H)，7.72(d，J＝7.8Hz，1H)，7.61-7.50(m，2H)，7.44(d，J＝7.8Hz，1H)，7.21(t，J＝9.1，2.2Hz，1H)，5.12(dd，J＝13.3，5.1Hz，1H)，4.46(d，J＝17.5Hz，1H)，4.33(d，J＝17.4Hz，1H)，4.02(s，1H)，3.66(s，3H)，3.36(s，3H)，3.29-3.12(m，4H)，3.07(s，4H)，2.96-2.88(m，1H)，2.69-2.53(m，2H)，2.49-2.30(m，2H)，2.23(s，2H)，2.05-1.96(m，1H).LCMS(ESI)C31H34F3N6O4 +[M+H]+：计算值611.26，实测值611.3.The target compound (GT-09661) (white solid, 24 mg, yield 41%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.06 (dd, J = 8.9, 5.3 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.61-7.50 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 9.1, 2.2 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.5 Hz, 1H). , 1H), 4.33 (d, J = 17.4 Hz, 1H), 4.02 (s, 1H), 3.66 (s, 3H), 3.36 (s, 3H), 3.29-3.12 (m, 4H), 3.07 (s, 4H), 2.96-2.88 (m, 1H), 2.69-2.53 (m, 2H), 2.49-2.30 (m, 2H), 2.23 (s, 2H), 2.05-1.96 (m, 1H). LCMS (ESI) C 31 H 34 F 3 N 6 O 4 + [M+H] + : calculated value 611.26, found value 611.3.

实施例164：3-(5-(3-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09662)的制备Example 164: Preparation of 3-(5-(3-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09662)

参照合成方案1的方法制备目标化合物(GT-09662)(白色固体，47mg，收率39％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，8.05(dd，J＝8.8，5.3Hz，1H)，7.69(d，J＝7.8Hz，1H)，7.57(dd，J＝9.1，2.1Hz，1H)，7.50(s，1H)，7.41(d，J＝7.8Hz，1H)，7.21(t，J＝9.0，2.1Hz，1H)，5.11(dd，J＝13.3，5.1Hz，1H)，4.44(d，J＝17.3Hz，1H)，4.31(d，J＝17.3Hz，1H)，3.97(s，1H)，3.69(s，3H)，3.55(s，6H)，3.16-3.00(m，6H)，2.95-2.87(m，1H)，2.77(t，J＝7.2Hz，2H)，2.66-2.56(m，1H)，2.44-2.34(m，1H)，2.21(s，1H)，2.17-2.05(m，2H)，2.04-1.95(m，1H).LCMS(ESI)C32H36F3N6O4 +[M+H]+：计算值625.27，实测值625.3.The target compound (GT-09662) (white solid, 47 mg, yield 39%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ10.99 (s, 1H), 8.05 (dd, J=8.8, 5.3 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.57 (dd, J=9.1, 2.1 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.21 (t, J=9.0, 2.1 Hz, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.44 (d, J=17.3 Hz, 1 3H), 4.31 (d, J = 17.3 Hz, 1H), 3.97 (s, 1H), 3.69 (s, 3H), 3.55 (s, 6H), 3.16-3.00 (m, 6H), 2.95-2.87 (m, 1H), 2.77 (t, J = 7.2 Hz, 2H), 2.66-2.56 (m, 1H), 2.44-2.34 (m, 1H), 2.21 (s, 1H), 2.17-2.05 (m, 2H), 2.04-1.95 (m, 1H). LCMS (ESI) C 3 2 H 3 6 F 3 N 6 O 4 + [M+H] + : calculated value 625.27, found value 625.3.

实施例165：5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09663)的制备Example 165: Preparation of 5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09663)

参照合成方案1的方法制备目标化合物(GT-09663)(白色固体，32mg，收率54％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.07(dd，J＝8.9，5.3Hz，1H)，8.04-7.89(m，3H)，7.58(dd，J＝9.1，2.1Hz，1H)，7.22(t，J＝9.1，2.1Hz，1H)，5.18(dd，J＝12.8，5.3Hz，1H)，4.13(s，2H)，3.66(s，6H)，3.27(s，5H)，2.98-2.82(m，2H)，2.69-2.54(m，3H)，2.23(s，1H)，2.14-2.02(m，2H).LCMS(ESI)C30H30F3N6O5 +[M+H]+：计算值611.22，实测值611.3.The target compound (GT-09663) (white solid, 32 mg, yield 54%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400MHz, DMSO) δ11.15 (s, 1H), 8.07 (dd, J=8.9, 5.3Hz, 1H), 8.04-7.89 (m, 3H), 7.58 (dd, J=9.1, 2.1Hz, 1H), 7.22 (t, J=9.1, 2.1Hz, 1H), 5.18 ( dd, J=12.8, 5.3Hz, 1H), 4.13(s, 2H), 3.66(s, 6H), 3.27(s, 5H), 2.98-2.8 2(m, 2H), 2.69-2.54(m, 3H), 2.23(s, 1H), 2.14-2.02(m, 2H).LCMS(ESI)C 30 H 30 F 3 N 6 O 5 + [M+H] + : Calculated 611.22, found 611.3.

实施例166：4-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09664)的制备Example 166: Preparation of 4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09664)

参照合成方案1的方法制备目标化合物(GT-09664)(白色固体，34mg，收率57％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.08(dd，J＝8.9，5.2Hz，1H)，8.02-7.95(m，1H)，7.92(d，J＝6.2Hz，2H)，7.59(dd，J＝9.1，2.1Hz，1H)，7.23(t，J＝9.1，2.0Hz，1H)，5.19-5.14(m，1H)，4.29(s，2H)，3.84-3.71(m，6H)，3.37(s，6H)，3.16(s，1H)，2.93-2.87(m，1H)，2.66-2.56(m，2H)，2.34-2.24(m，1H)，2.15-2.03(m，2H).LCMS(ESI)C30H30F3N6O5 +[M+H]+：计算值611.22，实测值611.3.The target compound (GT-09664) (white solid, 34 mg, yield 57%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.08 (dd, J = 8.9, 5.2 Hz, 1H), 8.02-7.95 (m, 1H), 7.92 (d, J = 6.2 Hz, 2H), 7.59 (dd, J = 9.1, 2.1 Hz, 1H), 7.23 (t, J = 9.1, 2.0 Hz, 1H), 5. 19-5.14 (m, 1H), 4.29 (s, 2H), 3.84-3.71 (m, 6H), 3.37 (s, 6H), 3.16 (s, 1H), 2.93-2.87 (m, 1H), 2.66-2.56 (m, 2H), 2.34-2.24 (m, 1H), 2.15-2.03 (m, 2H). LCMS (ESI) C 30 H 30 F 3 N 6 O 5 + [M+H] + : calculated value 611.22, found value 611.3.

实施例167：3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09665)的制备Example 167: Preparation of 3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09665)

参照合成方案1的方法制备目标化合物(GT-09665)(白色固体，20mg，收率34％)。1H NMR(400MHz，DMSO)δ11.64(s，1H)，11.03(s，1H)，8.28(s，1H)，7.73(dd，J＝9.0，2.0Hz，1H)，7.68-7.62(m，2H)，7.34(t，J＝9.1，2.1Hz，1H)，5.14(dd，J＝13.2，5.0Hz，1H)，4.59(d，J＝17.5Hz，1H)，4.42(d，J＝17.5Hz，1H)，4.09(s，1H)，3.93(s，2H)，3.73(s，2H)，3.51-3.32(m，4H)，3.11(d，J＝9.7Hz，1H)，2.97-2.87(m，1H)，2.79-2.56(m，4H)，2.48-2.36(m，3H)，2.19(s，3H)，2.04-1.96(m，1H).LCMS(ESI)C31H32F4N5O4 +[M+H]+：计算值614.24，实测值614.3.The target compound (GT-09665) (white solid, 20 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 11.03 (s, 1H), 8.28 (s, 1H), 7.73 (dd, J = 9.0, 2.0 Hz, 1H), 7.68-7.62 (m, 2H), 7.34 (t, J = 9.1, 2.1 Hz, 1H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.59 (d, J = 17.5 Hz, 1H), 4.42 (d , J = 17.5 Hz, 1H), 4.09 (s, 1H), 3.93 (s, 2H), 3.73 (s, 2H), 3.51-3.32 (m, 4H), 3.11 (d, J = 9.7 Hz, 1H), 2.97-2.87 (m, 1H), 2.79-2.56 (m, 4H), 2.48-2.36 (m, 3H), 2.19 (s, 3H), 2.04-1.96 (m, 1H). LCMS (ESI) C 31 H 32 F 4 N 5 O 4 + [M+H] + : calculated value 614.24, found value 614.3.

实施例168：3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09666)的制备Example 168: Preparation of 3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09666)

参照合成方案1的方法制备目标化合物(GT-09666)(白色固体，20mg，收率34％)。1H NMR(400MHz，DMSO)δ11.50(s，1H)，11.02(s，1H)，8.27(s，1H)，7.76-7.66(m，2H)，7.57(d，J＝8.7Hz，1H)，7.34(t，J＝9.1，2.1Hz，1H)，5.13(dd，J＝13.2，5.0Hz，1H)，4.49(d，J＝17.2Hz，1H)，4.35(d，J＝17.4Hz，1H)，4.06(s，1H)，3.89(s，2H)，3.79-3.70(m，2H)，3.55-3.30(m，6H)，3.08(s，1H)，2.96-2.85(m，1H)，2.75-2.56(m，3H)，2.43-2.34(m，2H)，2.20(s，2H)，2.14-1.98(m，2H).LCMS(ESI)C31H32F4N5O4 +[M+H]+：计算值614.24，实测值614.3.The target compound (GT-09666) (white solid, 20 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.50 (s, 1H), 11.02 (s, 1H), 8.27 (s, 1H), 7.76-7.66 (m, 2H), 7.57 (d, J = 8.7 Hz, 1H), 7.34 (t, J = 9.1, 2.1 Hz, 1H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.49 (d, J = 17.2 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 4.06 (s, 1H), 3.89 (s, 2H), 3.79-3.70 (m, 2H), 3.55-3.30 (m, 6H), 3.08 (s, 1H), 2.96-2.85 (m, 1H), 2.75-2.56 (m, 3H), 2.43-2.34 (m, 2H), 2.20 (s, 2H), 2.14-1.98 (m, 2H). LCMS (ESI) C 31 H 32 F 4 N 5 O 4 + [M+H] + : calculated value 614.24, found value 614.3.

实施例169：3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09667)的制备Example 169: Preparation of 3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09667)

参照合成方案1的方法制备目标化合物(GT-09667)(白色固体，16mg，收率28％)。1H NMR(400MHz，DMSO)δ11.56(s，1H)，11.02(s，1H)，8.28(s，1H)，7.73(dd，J＝9.1，2.0Hz，1H)，7.46(s，1H)，7.38-7.26(m，2H)，5.09(dd，J＝13.3，5.1Hz，1H)，4.51(d，J＝17.9Hz，1H)，4.37(d，J＝17.9Hz，1H)，4.07(s，1H)，3.90(s，3H)，3.75(s，2H)，3.53-3.33(m，5H)，3.11(s，1H)，2.98-2.86(m，1H)，2.75-2.57(m，3H)，2.44-2.32(m，2H)，2.28-2.12(m，3H)，2.05-1.96(m，1H).LCMS(ESI)C31H32F4N5O4 +[M+H]+：计算值614.24，实测值614.3.The target compound (GT-09667) (white solid, 16 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 11.02 (s, 1H), 8.28 (s, 1H), 7.73 (dd, J = 9.1, 2.0 Hz, 1H), 7.46 (s, 1H), 7.38-7.26 (m, 2H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.51 (d, J = 17.9 Hz, 1H), 4.37 (d, J = 17 .9 Hz, 1H), 4.07 (s, 1H), 3.90 (s, 3H), 3.75 (s, 2H), 3.53-3.33 (m, 5H), 3.11 (s, 1H), 2.98-2.86 (m, 1H), 2.75-2.57 (m, 3H), 2.44-2.32 (m, 2H), 2.28-2.12 (m, 3H), 2.05-1.96 (m, 1H). LCMS (ESI) C 31 H 32 F 4 N 5 O 4 + [M+H] + : calculated value 614.24, found value 614.3.

实施例170：3-(4-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09668)的制备Example 170: Preparation of 3-(4-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09668)

参照合成方案1的方法制备目标化合物(GT-09668)(白色固体，23mg，收率40％)。1H NMR(400MHz，DMSO)δ11.58(s，1H)，11.02(s，1H)，8.28(s，1H)，7.77-7.67(m，2H)，7.62(d，J＝7.2Hz，1H)，7.54(t，J＝7.5Hz，1H)，7.34(t，J＝9.0，1.9Hz，1H)，5.15(dd，J＝13.2，5.1Hz，1H)，4.63-4.50(m，1H)，4.40(d，J＝17.5Hz，1H)，4.13(s，1H)，3.85-3.69(m，5H)，3.48-3.42(m，2H)，3.26(s，1H)，3.04(s，1H)，3.00-2.89(m，1H)，2.81-2.70(m，1H)，2.69-2.56(m，3H)，2.48-2.32(m，3H)，2.21(s，2H)，2.14-1.97(m，2H).LCMS(ESI)C31H33F3N5O4 +[M+H]+：计算值596.25，实测值596.3.The target compound (GT-09668) (white solid, 23 mg, yield 40%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 11.02 (s, 1H), 8.28 (s, 1H), 7.77-7.67 (m, 2H), 7.62 (d, J = 7.2 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 9.0, 1.9 Hz, 1H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 4.63-4.50 (m, 1H), 4.40 (d, J = 7. =17.5 Hz, 1H), 4.13 (s, 1H), 3.85-3.69 (m, 5H), 3.48-3.42 (m, 2H), 3.26 (s, 1H), 3.04 (s, 1H), 3.00-2.89 (m, 1H), 2.81-2.70 (m, 1H), 2.69-2.56 (m, 3H), 2.48-2.32 (m, 3H), 2.21 (s, 2H), 2.14-1.97 (m, 2H). LCMS (ESI) C 31 H 33 F 3 N 5 O 4 + [M+H] + : calculated value 596.25, found value 596.3.

实施例171：3-(6-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09669)的制备Example 171: Preparation of 3-(6-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09669)

参照合成方案1的方法制备目标化合物(GT-09669)(白色固体，19mg，收率34％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，8.24(s，1H)，7.82(s，1H)，7.76-7.63(m，3H)，7.38-7.29(m，1H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.49(d，J＝17.5Hz，1H)，4.36(d，J＝17.5Hz，1H)，4.06(s，3H)，3.73-3.63(m，5H)，3.25(s，2H)，2.99-2.84(m，2H)，2.68-2.53(m，4H)，2.48-2.38(m，2H)，2.22(s，3H)，2.06-1.98(m，1H).LCMS(ESI)C31H33F3N5O4 +[M+H]+：计算值596.25，实测值596.3.The target compound (GT-09669) (white solid, 19 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.76-7.63 (m, 3H), 7.38-7.29 (m, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.49 (d, J=17.5 Hz, 1H), 4.36 (d, J = 17.5 Hz, 1H), 4.06 (s, 3H), 3.73-3.63 (m, 5H), 3.25 (s, 2H), 2.99-2.84 (m, 2H), 2.68-2.53 (m, 4H), 2.48-2.38 (m, 2H), 2.22 (s, 3H), 2.06-1.98 (m, 1H). LCMS (ESI) C 31 H 33 F 3 N 5 O 4 + [M+H] + : calculated value 596.25, found value 596.3.

实施例172：3-(7-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09670)的制备Example 172: Preparation of 3-(7-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09670)

参照合成方案1的方法制备目标化合物(GT-09670)(白色固体，26mg，收率45％)。1H NMR(400MHz，DMSO)δ11.45(s，1H)，11.02(s，1H)，8.24(s，1H)，7.72(dd，J＝9.1，2.0Hz，1H)，7.70-7.64(m，1H)，7.64-7.54(m，2H)，7.34(t，J＝9.2，2.1Hz，1H)，5.11(d，J＝10.9Hz，1H)，4.56-4.27(m，4H)，4.12(s，1H)，3.75-3.58(m，5H)，3.36-3.07(m，4H)，2.98-2.77(m，2H)，2.62(d，J＝17.3Hz，2H)，2.45-2.32(m，2H)，2.20(s，3H)，2.08-1.97(m，1H).LCMS(ESI)C31H33F3N5O4 +[M+H]+：计算值596.25，实测值596.3.The target compound (GT-09670) (white solid, 26 mg, yield 45%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 11.02 (s, 1H), 8.24 (s, 1H), 7.72 (dd, J = 9.1, 2.0 Hz, 1H), 7.70-7.64 (m, 1H), 7.64-7.54 (m, 2H), 7.34 (t, J = 9.2, 2.1 Hz, 1H), 5.11 (d, J = 10.9 Hz, 1H ), 4.56-4.27 (m, 4H), 4.12 (s, 1H), 3.75-3.58 (m, 5H), 3.36-3.07 (m, 4H), 2.98-2.77 (m, 2H), 2.62 (d, J=17.3 Hz, 2H), 2.45-2.32 (m, 2H), 2.20 (s, 3H), 2.08-1.97 (m, 1H). LCMS (ESI) C 31 H 33 F 3 N 5 O 4 + [M+H] + : calculated value 596.25, found value 596.3.

实施例173：3-(5-(2-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09671)的制备Example 173: Preparation of 3-(5-(2-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09671)

参照合成方案1的方法制备目标化合物(GT-09671)(白色固体，12mg，收率21％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，8.20(s，1H)，7.78-7.64(m，2H)，7.52(s，1H)，7.43(d，J＝8.0Hz，1H)，7.34(t，J＝9.1，2.1Hz，1H)，5.17-5.06(m，1H)，4.45(d，J＝17.4Hz，1H)，4.32(d，J＝17.3Hz，1H)，3.70-3.54(m，5H)，3.36-3.19(m，6H)，3.10(s，3H)，2.95-2.88(m，1H)，2.61(d，J＝17.0Hz，2H)，2.48-2.31(m，3H)，2.22(s，3H)，2.07-1.97(m，1H).LCMS(ESI)C32H35F3N5O4 +[M+H]+：计算值610.26，实测值610.3.The target compound (GT-09671) (white solid, 12 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.20 (s, 1H), 7.78-7.64 (m, 2H), 7.52 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 9.1, 2.1 Hz, 1H), 5.17-5.06 (m, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.3 2 (d, J = 17.3 Hz, 1H), 3.70-3.54 (m, 5H), 3.36-3.19 (m, 6H), 3.10 (s, 3H), 2.95-2.88 (m, 1H), 2.61 (d, J = 17.0 Hz, 2H), 2.48-2.31 (m, 3H), 2.22 (s, 3H), 2.07-1.97 (m, 1H). LCMS (ESI) C 3 2 H 3 5 F 3 N 5 O 4 + [M+H] + : calculated value 610.26, found value 610.3.

实施例174：3-(5-(3-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09672)的制备Example 174: Preparation of 3-(5-(3-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09672)

参照合成方案1的方法制备目标化合物(GT-09672)(白色固体，35mg，收率29％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，8.14(s，1H)，7.76-7.62(m，2H)，7.50(s，1H)，7.41(d，J＝7.9Hz，1H)，7.33(t，J＝9.1，1.9Hz，1H)，5.11(dd，J＝13.2，5.1Hz，1H)，4.44(d，J＝17.3Hz，1H)，4.31(d，J＝17.3Hz，1H)，4.00(s，2H)，3.71-3.54(m，6H)，3.03(s，3H)，2.98-2.83(m，2H)，2.77(t，J＝7.4Hz，2H)，2.61(d，J＝17.6Hz，2H)，2.48-2.28(m，4H)，2.21(s，2H)，2.12-1.95(m，3H).LCMS(ESI)C33H37F3N5O4 +[M+H]+：计算值624.28，实测值624.3.The target compound (GT-09672) (white solid, 35 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.14 (s, 1H), 7.76-7.62 (m, 2H), 7.50 (s, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.33 (t, J = 9.1, 1.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d , J = 17.3 Hz, 1H), 4.00 (s, 2H), 3.71-3.54 (m, 6H), 3.03 (s, 3H), 2.98-2.83 (m, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.61 (d, J = 17.6 Hz, 2H), 2.48-2.28 (m, 4H), 2.21 (s, 2H), 2.12-1.95 (m, 3H). LCMS (ESI) C 33 H 37 F 3 N 5 O 4 + [M+H] + : calculated value 624.28, found value 624.3.

实施例175：5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09673)的制备Example 175: Preparation of 5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09673)

参照合成方案1的方法制备目标化合物(GT-09673)(白色固体，13mg，收率22％)。1H NMR(400MHz，DMSO)δ11.14(s，2H)，8.23(s，1H)，7.99-7.88(m，2H)，7.84(d，J＝7.6Hz，1H)，7.73(dd，J＝9.1，2.0Hz，1H)，7.34(t，J＝9.1，2.1Hz，1H)，5.17(dd，J＝12.9，5.4Hz，1H)，4.07(s，1H)，3.89(s，2H)，3.72(s，2H)，3.63-3.47(m，3H)，3.32-3.20(m，2H)，3.03(s，1H)，2.94-2.85(m，1H)，2.66-2.54(m，3H)，2.48-2.33(m，3H)，2.22(s，2H)，2.13-2.01(m，2H).LCMS(ESI)C31H31F3N5O5 +[M+H]+：计算值610.23，实测值610.3.The target compound (GT-09673) (white solid, 13 mg, yield 22%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 2H), 8.23 (s, 1H), 7.99-7.88 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 9.1, 2.0 Hz, 1H), 7.34 (t, J = 9.1, 2.1 Hz, 1H), 5.17 (dd, J = 12.9, 5.4 Hz, 1H), 4.07 (s, 3H), 3.89 (s, 2H), 3.72 (s, 2H), 3.63-3.47 (m, 3H), 3.32-3.20 (m, 2H), 3.03 (s, 1H), 2.94-2.85 (m, 1H), 2.66-2.54 (m, 3H), 2.48-2.33 (m, 3H), 2.22 (s, 2H), 2.13-2.01 (m, 2H). LCMS (ESI) C 31 H 31 F 3 N 5 O 5 + [M+H] + : calculated value 610.23, found value 610.3.

实施例176：4-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09674)的制备Example 176: Preparation of 4-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09674)

参照合成方案1的方法制备目标化合物(GT-09674)(白色固体，11mg，收率19％)。1H NMR(400MHz，DMSO)δ11.14(s，2H)，8.23(s，1H)，7.92-7.83(m，3H)，7.73(dd，J＝9.1，2.0Hz，1H)，7.34(t，J＝9.1，2.1Hz，1H)，5.15(dd，J＝12.7，5.4Hz，1H)，4.21-4.10(m，2H)，3.68(s，2H)，3.64-3.47(m，3H)，3.32-3.26(m，2H)，3.04(s，1H)，2.95-2.82(m，2H)，2.69-2.54(m，3H)，2.47-2.33(m，3H)，2.22(s，2H)，2.12-1.96(m，2H).LCMS(ESI)C31H31F3N5O5 +[M+H]+：计算值610.23，实测值610.3.The target compound (GT-09674) (white solid, 11 mg, yield 19%) was prepared by referring to the method of Synthesis Scheme 1. 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 2H), 8.23 (s, 1H), 7.92-7.83 (m, 3H), 7.73 (dd, J = 9.1, 2.0 Hz, 1H), 7.34 (t, J = 9.1, 2.1 Hz, 1H), 5.15 (dd, J = 12.7, 5.4 Hz, 1H), 4.21-4.10 (m, 2 3H), 3.68 (s, 2H), 3.64-3.47 (m, 3H), 3.32-3.26 (m, 2H), 3.04 (s, 1H), 2.95-2.82 (m, 2H), 2.69-2.54 (m, 3H), 2.47-2.33 (m, 3H), 2.22 (s, 2H), 2.12-1.96 (m, 2H). LCMS (ESI) C 31 H 31 F 3 N 5 O 5 + [M+H] + : calculated value 610.23, found value 610.3.

实施例177：3-(5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09675)的制备Example 177: Preparation of 3-(5-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09675)

参照合成方案4的方法制备目标化合物(GT-09675)(白色固体，16mg，收率43％)。1H NMR(400MHz，DMSO)δ11.75(s，1H)，11.01(s，1H)，7.87(d，J＝7.0Hz，4H)，7.80(d，J＝7.8Hz，1H)，7.63(s，1H)，7.49(d，J＝7.7Hz，1H)，7.44(t，J＝7.5Hz，4H)，7.36(t，J＝7.3Hz，2H)，5.60(s，1H)，5.14(dd，J＝13.3，5.0Hz，1H)，4.76-4.48(m，2H)，4.42-4.34(m，1H)，3.36-3.21(m，4H)，3.15-3.00(m，6H)，2.99-2.88(m，2H)，2.61(d，J＝16.8Hz，1H)，2.45-2.33(m，1H)，2.04-1.97(m，1H)，1.92-1.61(m，2H)，1.26-1.09(m，1H).LCMS(ESI)C36H38F2N5O4 +[M+H]+：计算值642.29，实测值642.3.The target compound (GT-09675) (white solid, 16 mg, yield 43%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 11.01 (s, 1H), 7.87 (d, J = 7.0 Hz, 4H), 7.80 (d, J = 7.8 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.44 (t, J = 7.5 Hz, 4H), 7.36 (t, J = 7.3 Hz, 2H), 5.60 (s, 1H), 5.14 (dd, J = 13.3, 5.0 Hz , 1H), 4.76-4.48 (m, 2H), 4.42-4.34 (m, 1H), 3.36-3.21 (m, 4H), 3.15-3.00 (m, 6H), 2.99-2.88 (m, 2H), 2.61 (d, J=16.8 Hz, 1H), 2.45-2.33 (m, 1H), 2.04-1.97 (m, 1H), 1.92-1.61 (m, 2H), 1.26-1.09 (m, 1H). LCMS (ESI) C 36 H 38 F 2 N 5 O 4 + [M+H] + : calculated value 642.29, found value 642.3.

实施例178：3-(5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09676)的制备Example 178: Preparation of 3-(5-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09676)

参照合成方案4的方法制备目标化合物(GT-09676)(白色固体，10mg，收率26％)。1H NMR(400MHz，DMSO)δ11.69(s，1H)，11.02(s，1H)，7.87(d，J＝6.6Hz，4H)，7.44(t，J＝7.5Hz，5H)，7.40-7.30(m，3H)，5.61(d，J＝8.1Hz，1H)，5.10(dd，J＝13.3，5.1Hz，1H)，4.53(d，J＝18.3Hz，1H)，4.40(d，J＝18.1，4.2Hz，1H)，3.83-3.58(m，2H)，3.31-3.17(m，4H)，3.15-3.09(m，2H)，3.07-2.95(m，5H)，2.60(d，J＝16.6Hz，1H)，2.43-2.30(m，1H)，2.05-1.96(m，1H)，1.92-1.66(m，2H).LCMS(ESI)C36H37F3N5O4 +[M+H]+：计算值660.28，实测值660.3.The target compound (GT-09676) (white solid, 10 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 11.02 (s, 1H), 7.87 (d, J = 6.6 Hz, 4H), 7.44 (t, J = 7.5 Hz, 5H), 7.40-7.30 (m, 3H), 5.61 (d, J = 8.1 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.53 (d, J = 18.3 Hz, 1H), 4.4 0 (d, J = 18.1, 4.2 Hz, 1H), 3.83-3.58 (m, 2H), 3.31-3.17 (m, 4H), 3.15-3.09 (m, 2H), 3.07-2.95 (m, 5H), 2.60 (d, J = 16.6 Hz, 1H), 2.43-2.30 (m, 1H), 2.05-1.96 (m, 1H), 1.92-1.66 (m, 2H). LCMS (ESI) C 36 H 37 F 3 N 5 O 4 + [M+H] + : calculated value 660.28, found value 660.3.

实施例179：3-(6-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09677)的制备Example 179: Preparation of 3-(6-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09677)

参照合成方案4的方法制备目标化合物(GT-09677)(白色固体，6mg，收率17％)。1H NMR(400MHz，DMSO)δ11.44(s，1H)，11.01(s，1H)，7.83(d，J＝7.1Hz，4H)，7.72(d，J＝7.8Hz，1H)，7.68-7.61(m，2H)，7.44(t，J＝7.4Hz，4H)，7.37(t，J＝7.1Hz，2H)，5.61(d，J＝8.9Hz，1H)，5.13(dd，J＝13.3，5.1Hz，1H)，4.53(d，J＝17.9Hz，1H)，4.39(d，J＝17.8Hz，1H)，3.30-3.09(m，7H)，3.08-2.98(m，5H)，2.98-2.84(m，2H)，2.61(d，J＝17.1Hz，1H)，2.47-2.36(m，1H)，2.05-1.98(m，1H)，1.77(s，2H).LCMS(ESI)C36H38F2N5O4 +[M+H]+：计算值642.29，实测值642.3.The target compound (GT-09677) (white solid, 6 mg, yield 17%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.44 (s, 1H), 11.01 (s, 1H), 7.83 (d, J = 7.1 Hz, 4H), 7.72 (d, J = 7.8 Hz, 1H), 7.68-7.61 (m, 2H), 7.44 (t, J = 7.4 Hz, 4H), 7.37 (t, J = 7.1 Hz, 2H), 5.61 (d, J = 8.9 Hz, 1H), 5.13 (dd, J = 13.3, 5. 1 Hz, 1H), 4.53 (d, J = 17.9 Hz, 1H), 4.39 (d, J = 17.8 Hz, 1H), 3.30-3.09 (m, 7H), 3.08-2.98 (m, 5H), 2.98-2.84 (m, 2H), 2.61 (d, J = 17.1 Hz, 1H), 2.47-2.36 (m, 1H), 2.05-1.98 (m, 1H), 1.77 (s, 2H). LCMS (ESI) C 36 H 38 F 2 N 5 O 4 + [M+H] + : calculated value 642.29, found value 642.3.

实施例180：3-(4-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09678)的制备Example 180: Preparation of 3-(4-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09678)

参照合成方案4的方法制备目标化合物(GT-09678)(白色固体，13mg，收率35％)。1H NMR(400MHz，DMSO)δ11.77(s，1H)，10.98(d，J＝4.7Hz，1H)，7.90-7.84(m，4H)，7.66-7.56(m，2H)，7.44(t，J＝7.5Hz，4H)，7.36(t，J＝7.3Hz，2H)，5.61(d，J＝8.2Hz，1H)，5.19-5.07(m，1H)，4.72-4.15(m，3H)，3.70-3.57(m，2H)，3.38-3.20(m，4H)，3.14-2.95(m，6H)，2.89(t，1H)，2.57(d，J＝17.7Hz，1H)，2.47-2.33(m，1H)，2.03-1.95(m，1H)，1.94-1.67(m，2H).LCMS(ESI)C36H38F2N5O4 +[M+H]+：计算值642.29，实测值642.4.The target compound (GT-09678) (white solid, 13 mg, yield 35%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 10.98 (d, J = 4.7 Hz, 1H), 7.90-7.84 (m, 4H), 7.66-7.56 (m, 2H), 7.44 (t, J = 7.5 Hz, 4H), 7.36 (t, J = 7.3 Hz, 2H), 5.61 (d, J = 8.2 Hz, 1H), 5.19-5.07 (m, 1H) , 4.72-4.15 (m, 3H), 3.70-3.57 (m, 2H), 3.38-3.20 (m, 4H), 3.14-2.95 (m, 6H), 2.89 (t, 1H), 2.57 (d, J=17.7 Hz, 1H), 2.47-2.33 (m, 1H), 2.03-1.95 (m, 1H), 1.94-1.67 (m, 2H). LCMS (ESI) C 36 H 38 F 2 N 5 O 4 + [M+H] + : calculated value 642.29, found value 642.4.

实施例181：3-(5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09710)的制备Example 181: Preparation of 3-(5-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09710)

参照合成方案4的方法制备目标化合物(GT-09710)(白色固体，7mg，收率19％)。1H NMR(400MHz，DMSO)δ11.46(s，1H)，11.02(s，1H)，7.84(d，J＝6.6Hz，4H)，7.67(d，J＝7.5Hz，1H)，7.44(t，J＝7.4Hz，4H)，7.37(t，J＝7.3Hz，2H)，5.60(d，J＝8.9Hz，1H)，5.14(dd，J＝13.3，4.7Hz，1H)，4.81-4.54(m，1H)，4.42(dd，J＝48.5，17.2Hz，2H)，3.62-3.45(m，2H)，3.30-3.17(m，4H)，3.16-3.10(m，2H)，3.07-2.98(m，4H)，2.94-2.87(m，1H)，2.60(d，J＝17.7Hz，1H)，2.49-2.29(m，2H)，2.05-1.98(m，1H)，1.76-1.70(m，1H).LCMS(ESI)C36H37F3N5O4 +[M+H]+：计算值660.28，实测值660.3.The target compound (GT-09710) (white solid, 7 mg, yield 19%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.46 (s, 1H), 11.02 (s, 1H), 7.84 (d, J = 6.6 Hz, 4H), 7.67 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.4 Hz, 4H), 7.37 (t, J = 7.3 Hz, 2H), 5.60 (d, J = 8.9 Hz, 1H), 5.14 (dd, J = 13.3, 4.7 Hz, 1H), 4.81-4.54 (m, 1H), 4.4 2 (dd, J = 48.5, 17.2 Hz, 2H), 3.62-3.45 (m, 2H), 3.30-3.17 (m, 4H), 3.16-3.10 (m, 2H), 3.07-2.98 (m, 4H), 2.94-2.87 (m, 1H), 2.60 (d, J = 17.7 Hz, 1H), 2.49-2.29 (m, 2H), 2.05-1.98 (m, 1H), 1.76-1.70 (m, 1H). LCMS (ESI) C 36 H 37 F 3 N 5 O 4 + [M+H] + : calculated value 660.28, found value 660.3.

实施例182：3-(7-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09711)的制备Example 182: Preparation of 3-(7-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09711)

参照合成方案4的方法制备目标化合物(GT-09711)(白色固体，11mg，收率29％)。1H NMR(400MHz，DMSO)δ11.35(s，1H)，10.99(s，1H)，7.82(d，J＝6.6Hz，4H)，7.70-7.66(m，2H)，7.44(t，J＝7.3Hz，4H)，7.37(d，J＝7.2Hz，2H)，7.33-7.29(m，1H)，5.60(d，J＝9.5Hz，1H)，5.09-4.96(m，1H)，4.79-4.65(m，1H)，4.54-4.38(m，2H)，3.36-3.22(m，4H)，3.22-3.08(m，6H)，3.02(s，4H)，2.94-2.82(m，2H)，2.61(d，J＝16.5Hz，1H)，2.48-2.30(m，2H)，2.03-1.93(m，1H)，1.93-1.77(m，1H)，1.69-1.55(m，1H).LCMS(ESI)C36H38F2N5O4 +[M+H]+：计算值642.29，实测值642.4.The target compound (GT-09711) (white solid, 11 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 10.99 (s, 1H), 7.82 (d, J = 6.6 Hz, 4H), 7.70-7.66 (m, 2H), 7.44 (t, J = 7.3 Hz, 4H), 7.37 (d, J = 7.2 Hz, 2H), 7.33-7.29 (m, 1H), 5.60 (d, J = 9.5 Hz, 1H), 5.09-4.96 (m, 1H), 4.79-4.65 ( m, 1H), 4.54-4.38 (m, 2H), 3.36-3.22 (m, 4H), 3.22-3.08 (m, 6H), 3.02 (s, 4H), 2.94-2.82 (m, 2H), 2.61 (d, J=16.5 Hz, 1H), 2.48-2.30 (m, 2H), 2.03-1.93 (m, 1H), 1.93-1.77 (m, 1H), 1.69-1.55 (m, 1H). LCMS (ESI) C 36 H 38 F 2 N 5 O 4 + [M+H] + : calculated value 642.29, found value 642.4.

实施例183：4-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09712)的制备Example 183: Preparation of 4-(4-(4-diphenylmethylpiperazine-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09712)

参照合成方案4的方法制备目标化合物(GT-09712)(白色固体，8mg，收率21％)。1H NMR(400MHz，DMSO)δ11.29(s，1H)，11.17-11.05(m，1H)，8.01-7.91(m，2H)，7.85-7.64(m，5H)，7.45(t，J＝7.4Hz，4H)，7.37(t，J＝7.1Hz，2H)，5.60(d，J＝9.3Hz，1H)，5.13(dd，J＝12.5，5.3Hz，1H)，4.79-4.59(m，1H)，3.31-3.22(m，2H)，3.21-3.08(m，5H)，3.07-2.96(m，4H)，2.96-2.76(m，2H)，2.60(d，J＝17.2Hz，1H)，2.45(s，1H)，2.05(s，1H)，1.90-1.63(m，2H).LCMS(ESI)C36H36F2N5O5 +[M+H]+：计算值656.27，实测值656.3.The target compound (GT-09712) (white solid, 8 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.29 (s, 1H), 11.17-11.05 (m, 1H), 8.01-7.91 (m, 2H), 7.85-7.64 (m, 5H), 7.45 (t, J = 7.4 Hz, 4H), 7.37 (t, J = 7.1 Hz, 2H), 5.60 (d, J = 9.3 Hz, 1H), 5.13 (dd, J = 12.5, 5.3 Hz, 1H), 4.79-4.59 (m, 1H), 3.31-3.22 (m, 2H), 3.21-3.08 (m, 5H), 3.07-2.96 (m, 4H), 2.96-2.76 (m, 2H), 2.60 (d, J=17.2 Hz, 1H), 2.45 (s, 1H), 2.05 (s, 1H), 1.90-1.63 (m, 2H). LCMS (ESI) C 36 H 36 F 2 N 5 O 5 + [M+H] + : calculated value 656.27, found value 656.3.

实施例184：5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09713)的制备Example 184: Preparation of 5-(4-(4-diphenylmethylpiperazine-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09713)

参照合成方案4的方法制备目标化合物(GT-09713)(白色固体，9mg，收率24％)。1H NMR(400MHz，DMSO)δ11.53(s，1H)，11.15(s，1H)，8.01(d，J＝8.1Hz，1H)，7.85(d，J＝7.0Hz，6H)，7.44(t，J＝7.4Hz，4H)，7.37(t，J＝7.2Hz，2H)，5.61(d，J＝9.2Hz，1H)，5.18(dd，J＝12.7，5.4Hz，1H)，4.79-4.47(m，1H)，3.66-3.56(m，1H)，3.29-3.18(m，4H)，3.14-3.09(m，2H)，3.03(s，4H)，2.94-2.87(m，1H)，2.65-2.53(m，2H)，2.10-2.01(m，1H)，1.92-1.72(m，2H).LCMS(ESI)C36H36F2N5O5 +[M+H]+：计算值656.27，实测值656.3.The target compound (GT-09713) (white solid, 9 mg, yield 24%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 11.15 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.0 Hz, 6H), 7.44 (t, J = 7.4 Hz, 4H), 7.37 (t, J = 7.2 Hz, 2H), 5.61 (d, J = 9.2 Hz, 1H), 5.18 (dd, J = 12.7, 5.4H). z, 1H), 4.79-4.47 (m, 1H), 3.66-3.56 (m, 1H), 3.29-3.18 (m, 4H), 3.14-3.09 (m, 2H), 3.03 (s, 4H), 2.94-2.87 (m, 1H), 2.65-2.53 (m, 2H), 2.10-2.01 (m, 1H), 1.92-1.72 (m, 2H). LCMS (ESI) C 36 H 36 F 2 N 5 O 5 + [M+H] + : calculated value 656.27, found value 656.3.

实施例185：3-(5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09714)的制备Example 185: Preparation of 3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09714)

参照合成方案4的方法制备目标化合物(GT-09714)(白色固体，11mg，收率29％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.74(d，J＝4.8Hz，1H)，7.92(t，J＝12.1，4.4Hz，1H)，7.85-7.77(m，1H)，7.69(d，J＝7.0Hz，2H)，7.64(d，J＝7.6Hz，2H)，7.52-7.39(m，5H)，5.86(s，1H)，5.14(dd，J＝13.2，5.0Hz，1H)，4.79-4.55(m，1H)，4.51(d，J＝17.7Hz，1H)，4.39(d，J＝17.6，4.2Hz，1H)，3.96-3.84(m，2H)，3.44-3.27(m，2H)，3.18-2.99(m，8H)，2.95-2.88(m，1H)，2.61(d，J＝17.2Hz，1H)，2.46-2.35(m，1H)，2.06-1.99(m，1H)，1.95-1.71(m，2H).LCMS(ESI)C35H37F2N6O4 +[M+H]+：计算值643.28，实测值643.3.The target compound (GT-09714) (white solid, 11 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.92 (t, J = 12.1, 4.4 Hz, 1H), 7.85-7.77 (m, 1H), 7.69 (d, J = 7.0 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.52-7.39 (m, 5H), 5.86 (s, 1H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.79-4.55 (m, 1H), 4.51 (d, J = 17.7 Hz, 1H), 4.39 (d, J = 17.6, 4.2 Hz, 1H), 3.96-3.84 (m, 2H), 3.44-3.27 (m, 2H), 3.18-2.99 (m, 8H), 2.95-2.88 (m, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.46-2.35 (m, 1H), 2.06-1.99 (m, 1H), 1.95-1.71 (m, 2H). LCMS (ESI) C 35 H 37 F 2 N 6 O 4 + [M+H] + : calculated value 643.28, found value 643.3.

实施例186：3-(5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09715)的制备Example 186: Preparation of 3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09715)

参照合成方案4的方法制备目标化合物(GT-09715)(白色固体，11mg，收率29％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.75(d，J＝4.8Hz，1H)，7.91(t，J＝7.8，6.5Hz，1H)，7.66(d，J＝8.2Hz，2H)，7.59(d，J＝7.8Hz，1H)，7.51-7.37(m，5H)，7.28(s，1H)，5.85(s，1H)，5.10(dd，J＝13.3，4.7Hz，1H)，4.76-4.47(m，2H)，4.39(d，J＝18.0Hz，1H)，3.79-3.65(m，2H)，3.38-3.27(m，2H)，3.16-2.98(m，8H)，2.95-2.87(m，1H)，2.60(d，J＝17.1Hz，1H)，2.43-2.30(m，1H)，2.05-1.95(m，1H)，1.84(d，J＝60.3Hz，2H).LCMS(ESI)C35H36F3N6O4 +[M+H]+：计算值661.27，实测值661.3.The target compound (GT-09715) (white solid, 11 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.91 (t, J = 7.8, 6.5 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.51-7.37 (m, 5H), 7.28 (s, 1H), 5.85 (s, 1H), 5.10 (dd, J = 13.3, 4.7 Hz, 1H), 4.76- 4.47 (m, 2H), 4.39 (d, J = 18.0 Hz, 1H), 3.79-3.65 (m, 2H), 3.38-3.27 (m, 2H), 3.16-2.98 (m, 8H), 2.95-2.87 (m, 1H), 2.60 (d, J = 17.1 Hz, 1H), 2.43-2.30 (m, 1H), 2.05-1.95 (m, 1H), 1.84 (d, J = 60.3 Hz, 2H). LCMS (ESI) C 35 H 36 F 3 N 6 O 4 + [M+H] + : calculated value 661.27, found value 661.3.

实施例187：3-(5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09716)的制备Example 187: Preparation of 3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09716)

参照合成方案4的方法制备目标化合物(GT-09716)(白色固体，15mg，收率39％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.75(d，J＝6.7Hz，1H)，7.92(t，J＝7.7，1.3Hz，1H)，7.72-7.60(m，5H)，7.51-7.36(m，4H)，5.86(s，1H)，5.14(dd，J＝13.2，4.8Hz，1H)，4.75-4.58(m，1H)，4.49(d，J＝17.6Hz，1H)，4.36(d，J＝17.4Hz，1H)，3.92-3.89(m，1H)，3.57-3.50(m，1H)，3.39-3.24(m，2H)，3.19-2.97(m，8H)，2.96-2.87(m，1H)，2.61(d，J＝17.4Hz，1H)，2.46-2.35(m，1H)，2.08-1.98(m，1H)，1.96-1.63(m，2H).LCMS(ESI)C35H36F3N6O4 +[M+H]+：计算值661.27，实测值661.3.The target compound (GT-09716) (white solid, 15 mg, yield 39%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.75 (d, J = 6.7 Hz, 1H), 7.92 (t, J = 7.7, 1.3 Hz, 1H), 7.72-7.60 (m, 5H), 7.51-7.36 (m, 4H), 5.86 (s, 1H), 5.14 (dd, J = 13.2, 4.8 Hz, 1H), 4.75-4.58 (m, 1H), 4.49 (d, J = 17.6 Hz, 1H), 4 .36 (d, J = 17.4 Hz, 1H), 3.92-3.89 (m, 1H), 3.57-3.50 (m, 1H), 3.39-3.24 (m, 2H), 3.19-2.97 (m, 8H), 2.96-2.87 (m, 1H), 2.61 (d, J = 17.4 Hz, 1H), 2.46-2.35 (m, 1H), 2.08-1.98 (m, 1H), 1.96-1.63 (m, 2H). LCMS (ESI) C 35 H 36 F 3 N 6 O 4 + [M+H] + : calculated value 661.27, found value 661.3.

实施例188：3-(4-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09717)的制备Example 188: Preparation of 3-(4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09717)

参照合成方案4的方法制备目标化合物(GT-09717)(白色固体，13mg，收率35％)。1H NMR(400MHz，DMSO)δ10.98(d，J＝4.6Hz，1H)，8.74(d，J＝4.9Hz，1H)，7.93(t，J＝7.7Hz，1H)，7.85(d，J＝8.6Hz，1H)，7.72-7.58(m，5H)，7.50-7.38(m，4H)，5.87(s，1H)，5.20-5.06(m，1H)，4.77-4.30(m，3H)，3.74-3.53(m，2H)，3.47-3.26(m，2H)，3.21-3.02(m，8H)，2.94-2.83(m，1H)，2.57(d，J＝17.0Hz，1H)，2.46-2.30(m，1H)，2.04-1.70(m，3H).LCMS(ESI)C35H37F2N6O4 +[M+H]+：计算值643.28，实测值643.3.The target compound (GT-09717) (white solid, 13 mg, yield 35%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 10.98 (d, J = 4.6 Hz, 1H), 8.74 (d, J = 4.9 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.72-7.58 (m, 5H), 7.50-7.38 (m, 4H), 5.87 (s, 1H), 5.20-5.06 ( m, 1H), 4.77-4.30 (m, 3H), 3.74-3.53 (m, 2H), 3.47-3.26 (m, 2H), 3.21-3.02 (m, 8H), 2.94-2.83 (m, 1H), 2.57 (d, J=17.0 Hz, 1H), 2.46-2.30 (m, 1H), 2.04-1.70 (m, 3H). LCMS (ESI) C 35 H 37 F 2 N 6 O 4 + [M+H] + : calculated value 643.28, found value 643.3.

实施例189：3-(6-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09718)的制备Example 189: Preparation of 3-(6-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09718)

参照合成方案4的方法制备目标化合物(GT-09718)(白色固体，5mg，收率14％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.75(d，J＝4.7Hz，1H)，7.91(t，J＝7.7，3.9Hz，1H)，7.74-7.61(m，6H)，7.48-7.33(m，4H)，5.86(s，1H)，5.13(dd，J＝13.2，5.1Hz，1H)，4.90-4.56(m，1H)，4.53(d，J＝17.8Hz，1H)，4.40(d，J＝17.8Hz，1H)，4.00-3.83(m，2H)，3.41-3.26(m，2H)，3.17-3.00(m，8H)，2.96-2.87(m，1H)，2.61(d，J＝17.1Hz，1H)，2.46-2.38(m，1H)，2.06-1.75(m，3H).LCMS(ESI)C35H37F2N6O4 +[M+H]+：计算值643.28，实测值643.4.The target compound (GT-09718) (white solid, 5 mg, yield 14%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.75 (d, J = 4.7 Hz, 1H), 7.91 (t, J = 7.7, 3.9 Hz, 1H), 7.74-7.61 (m, 6H), 7.48-7.33 (m, 4H), 5.86 (s, 1H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.90-4.56 (m, 1H), 4.53 ( d, J = 17.8 Hz, 1H), 4.40 (d, J = 17.8 Hz, 1H), 4.00-3.83 (m, 2H), 3.41-3.26 (m, 2H), 3.17-3.00 (m, 8H), 2.96-2.87 (m, 1H), 2.61 (d, J = 17.1 Hz, 1H), 2.46-2.38 (m, 1H), 2.06-1.75 (m, 3H). LCMS (ESI) C 35 H 37 F 2 N 6 O 4 + [M+H] + : calculated value 643.28, found value 643.4.

实施例190：3-(7-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09719)的制备Example 190: Preparation of 3-(7-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09719)

参照合成方案4的方法制备目标化合物(GT-09719)(白色固体，12mg，收率32％)。1H NMR(400MHz，DMSO)δ10.98(d，J＝18.3Hz，1H)，8.74(d，J＝4.7Hz，1H)，7.90(t，J＝11.0，5.5Hz，1H)，7.73-7.64(m，4H)，7.61(d，J＝7.5Hz，1H)，7.49-7.38(m，4H)，7.35-7.28(m，1H)，5.83(s，1H)，5.09-4.93(m，1H)，4.78-4.65(m，1H)，4.54-4.34(m，2H)，3.44-3.17(m，4H)，3.16-3.00(m，8H)，2.92-2.83(m，1H)，2.61(d，J＝15.5Hz，1H)，2.47-2.33(m，1H)，2.04-1.58(m，3H).LCMS(ESI)C35H37F2N6O4 +[M+H]+：计算值643.28，实测值643.3.The target compound (GT-09719) (white solid, 12 mg, yield 32%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 10.98 (d, J = 18.3 Hz, 1H), 8.74 (d, J = 4.7 Hz, 1H), 7.90 (t, J = 11.0, 5.5 Hz, 1H), 7.73-7.64 (m, 4H), 7.61 (d, J = 7.5 Hz, 1H), 7.49-7.38 (m, 4H), 7.35-7.28 (m, 1H), 5.83 (s, 1H) , 5.09-4.93 (m, 1H), 4.78-4.65 (m, 1H), 4.54-4.34 (m, 2H), 3.44-3.17 (m, 4H), 3.16-3.00 (m, 8H), 2.92-2.83 (m, 1H), 2.61 (d, J=15.5 Hz, 1H), 2.47-2.33 (m, 1H), 2.04-1.58 (m, 3H). LCMS (ESI) C 35 H 37 F 2 N 6 O 4 + [M+H] + : calculated value 643.28, found value 643.3.

实施例191：4-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09720)的制备Example 191: Preparation of 4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09720)

参照合成方案4的方法制备目标化合物(GT-09720)(白色固体，8mg，收率21％)。1H NMR(400MHz，DMSO)δ11.19-11.09(m，1H)，11.07-10.38(m，1H)，8.75(d，J＝6.6Hz，1H)，8.02-7.88(m，3H)，7.77-7.64(m，3H)，7.61(d，J＝7.7Hz，1H)，7.49-7.39(m，4H)，5.84(s，1H)，5.18-5.06(m，1H)，4.79-4.59(m，1H)，3.49-3.21(m，4H)，3.16-2.98(m，8H)，2.91-2.82(m，1H)，2.60(d，J＝17.5Hz，1H)，2.49-2.41(m，1H)，2.09-1.99(m，1H)，1.97-1.64(m，2H).LCMS(ESI)C35H35F2N6O5 +[M+H]+：计算值657.26，实测值657.3.The target compound (GT-09720) (white solid, 8 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.19-11.09 (m, 1H), 11.07-10.38 (m, 1H), 8.75 (d, J = 6.6 Hz, 1H), 8.02-7.88 (m, 3H), 7.77-7.64 (m, 3H), 7.61 (d, J = 7.7 Hz, 1H), 7.49-7.39 (m, 4H), 5.84 (s, 1H), 5.18 -5.06 (m, 1H), 4.79-4.59 (m, 1H), 3.49-3.21 (m, 4H), 3.16-2.98 (m, 8H), 2.91-2.82 (m, 1H), 2.60 (d, J=17.5 Hz, 1H), 2.49-2.41 (m, 1H), 2.09-1.99 (m, 1H), 1.97-1.64 (m, 2H). LCMS (ESI) C 3 5 H 3 5 F 2 N 6 O 5 + [M+H] + : calculated value 657.26, found value 657.3.

实施例192：5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09721)的制备Example 192: Preparation of 5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazine-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09721)

参照合成方案4的方法制备目标化合物(GT-09721)(白色固体，9mg，收率24％)。1H NMR(400MHz，DMSO)δ11.13(s，1H)，8.74(d，J＝4.2Hz，1H)，8.01(d，J＝8.1Hz，1H)，7.96-7.79(m，3H)，7.69(d，J＝6.9Hz，2H)，7.63(d，J＝7.9Hz，1H)，7.49-7.37(m，4H)，5.85(s，1H)，5.18(dd，J＝12.7，5.4Hz，1H)，4.62(d，J＝53.8Hz，1H)，3.60-3.51(m，2H)，3.43-3.27(m，2H)，3.17-3.00(m，8H)，2.96-2.86(m，1H)，2.58(d，2H)，2.13-2.02(m，1H)，2.01-1.64(m，2H).LCMS(ESI)C35H35F2N6O5 +[M+H]+：计算值657.26，实测值657.3.The target compound (GT-09721) (white solid, 9 mg, yield 24%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.74 (d, J = 4.2 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.96-7.79 (m, 3H), 7.69 (d, J = 6.9 Hz, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.49-7.37 (m, 4H), 5.85 (s, 1H), 5.18 (dd , J = 12.7, 5.4 Hz, 1H), 4.62 (d, J = 53.8 Hz, 1H), 3.60-3.51 (m, 2H), 3.43-3.27 (m, 2H), 3.17-3.00 (m, 8H), 2.96-2.86 (m, 1H), 2.58 (d, 2H), 2.13-2.02 (m, 1H), 2.01-1.64 (m, 2H). LCMS (ESI) C 35 H 35 F 2 N 6 O 5 + [M+H] + : calculated value 657.26, found value 657.3.

实施例193：3-(5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09722)的制备Example 193: Preparation of 3-(5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09722)

参照合成方案4的方法制备目标化合物(GT-09722)(白色固体，18mg，收率55％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，7.80(d，J＝12.0Hz，1H)，7.64(s，1H)，7.51(d，J＝7.7Hz，1H)，7.39(d，J＝8.5Hz，2H)，7.25(d，J＝8.5Hz，2H)，5.14(dd，J＝13.2，5.0Hz，1H)，4.73-4.37(m，3H)，3.46-3.01(m，6H)，2.97-2.86(m，2H)，2.78(s，1H)，2.61(d，J＝17.2Hz，1H)，2.49-2.31(m，4H)，2.16-1.62(m，6H)，1.53-1.35(m，2H)，0.98(d，J＝14.3Hz，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09722) (white solid, 18 mg, yield 55%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.64 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.73-4. 37 (m, 3H), 3.46-3.01 (m, 6H), 2.97-2.86 (m, 2H), 2.78 (s, 1H), 2.61 (d, J=17.2 Hz, 1H), 2.49-2.31 (m, 4H), 2.16-1.62 (m, 6H), 1.53-1.35 (m, 2H), 0.98 (d, J=14.3 Hz, 6H). LCMS (ESI) C 38 H 43 ClF 2 N 5 O 5 + [M+H] + : calculated value 722.29, found value 722.3.

实施例194：3-(5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09723)的制备Example 194: Preparation of 3-(5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09723)

参照合成方案4的方法制备目标化合物(GT-09723)(白色固体，6mg，收率19％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.45(s，1H)，7.38(d，J＝8.4Hz，2H)，7.35-7.27(m，1H)，7.25(d，J＝8.5Hz，2H)，5.10(dd，J＝13.3，5.0Hz，1H)，4.68-4.35(m，3H)，3.37-3.08(m，6H)，3.07-2.85(m，3H)，2.81-2.55(m，4H)，2.43-2.34(m，3H)，2.14-1.98(m，2H)，1.91(d，J＝17.4Hz，1H)，1.78-1.57(m，3H)，1.51-1.41(m，2H)，0.98(d，J＝12.9Hz，6H).LCMS(ESI)C38H42ClF3N5O5 +[M+H]+：计算值740.28，实测值740.3.The target compound (GT-09723) (white solid, 6 mg, yield 19%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.45 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.35-7.27 (m, 1H), 7.25 (d, J = 8.5 Hz, 2H), 5.10 (dd, J = 13.3, 5.0 Hz, 1H), 4.68-4.35 (m, 3H), 3.37-3.08 (m, 6 3H), 3.07-2.85 (m, 3H), 2.81-2.55 (m, 4H), 2.43-2.34 (m, 3H), 2.14-1.98 (m, 2H), 1.91 (d, J=17.4 Hz, 1H), 1.78-1.57 (m, 3H), 1.51-1.41 (m, 2H), 0.98 (d, J=12.9 Hz, 6H). LCMS (ESI) C 3 8 H 4 2 ClF 3 N 5 O 5 + [M+H] + : calculated value 740.28, found value 740.3.

实施例195：3-(5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09724)的制备Example 195: Preparation of 3-(5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09724)

参照合成方案4的方法制备目标化合物(GT-09724)(白色固体，13mg，收率39％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.75-7.58(m，2H)，7.38(d，J＝8.0Hz，2H)，7.25(d，J＝8.3Hz，2H)，5.14(dd，J＝13.2，4.9Hz，1H)，4.69-4.34(m，3H)，3.16(s，4H)，3.01-2.88(m，2H)，2.74-2.54(m，4H)，2.46-2.26(m，4H)，2.12-2.00(m，2H)，1.90(d，J＝16.9Hz，1H)，1.73-1.54(m，2H)，1.50-1.39(m，2H)，0.98(d，J＝13.3Hz，6H).LCMS(ESI)C38H42ClF3N5O5 +[M+H]+：计算值740.28，实测值740.3.The target compound (GT-09724) (white solid, 13 mg, yield 39%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.75-7.58 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 5.14 (dd, J = 13.2, 4.9 Hz, 1H), 4.69-4.34 (m, 3H), 3.16 (s, 4H), 3.01- 2.88 (m, 2H), 2.74-2.54 (m, 4H), 2.46-2.26 (m, 4H), 2.12-2.00 (m, 2H), 1.90 (d, J=16.9 Hz, 1H), 1.73-1.54 (m, 2H), 1.50-1.39 (m, 2H), 0.98 (d, J=13.3 Hz, 6H). LCMS (ESI) C 3 8 H 4 2 ClF 3 N 5 O 5 + [M+H] + : calculated value 740.28, found value 740.3.

实施例196：3-(4-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09733)的制备Example 196: Preparation of 3-(4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09733)

参照合成方案4的方法制备目标化合物(GT-09733)(白色固体，14mg，收率43％)。1H NMR(400MHz，DMSO)δ11.00(d，J＝4.1Hz，1H)，7.86(d，J＝8.3Hz，1H)，7.68-7.54(m，2H)，7.38(d，J＝8.4Hz，2H)，7.25(d，J＝8.5Hz，2H)，5.19-5.08(m，1H)，4.68-4.25(m，3H)，3.84-3.64(m，4H)，3.21(s，4H)，3.06(s，1H)，2.96-2.88(m，1H)，2.80-2.68(m，1H)，2.59(d，J＝17.1Hz，2H)，2.47-2.26(m，4H)，2.12-1.98(m，2H)，1.90(d，J＝17.0Hz，1H)，1.79-1.60(m，2H)，1.51-1.38(m，2H)，0.98(d，J＝13.8Hz，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09733) (white solid, 14 mg, yield 43%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.00 (d, J = 4.1 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.68-7.54 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.19-5.08 (m, 1H), 4.68-4.25 (m, 3H), 3.84-3.64 (m, 4H), 3.21 (s, 4H), 3.06 (s, 1H), 2.96-2.88 (m, 1H), 2.80-2.68 (m, 1H), 2.59 (d, J = 17.1 Hz, 2H), 2.47-2.26 (m, 4H), 2.12-1.98 (m, 2H), 1.90 (d, J = 17.0 Hz, 1H), 1.79-1.60 (m, 2H), 1.51-1.38 (m, 2H), 0.98 (d, J = 13.8 Hz, 6H). LCMS (ESI) C 3 8 H 4 3 ClF 2 N 5 O 5 + [M+H] + : calculated value 722.29, found value 722.3.

实施例197：3-(6-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09725)的制备Example 197: Preparation of 3-(6-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09725)

参照合成方案4的方法制备目标化合物(GT-09725)(白色固体，15mg，收率46％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.73(d，J＝7.7Hz，1H)，7.69-7.60(m，2H)，7.39(d，J＝6.5Hz，2H)，7.25(d，J＝8.4Hz，2H)，5.14(dd，J＝13.2，5.0Hz，1H)，4.75-4.48(m，2H)，4.40(d，J＝17.8Hz，1H)，3.34-3.21(m，3H)，3.07(s，1H)，3.00-2.85(m，2H)，2.81(s，1H)，2.61(d，J＝16.8Hz，2H)，2.45-2.34(m，3H)，2.15-2.01(m，2H)，1.90(d，J＝16.9Hz，1H)，1.78-1.58(m，4H)，1.50-1.40(m，2H)，1.32-1.04(m，3H)，0.98(d，J＝14.1Hz，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09725) (white solid, 15 mg, yield 46%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.69-7.60 (m, 2H), 7.39 (d, J = 6.5 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 5.14 (dd, J = 13.2, 5.0 Hz, 1H), 4.75-4.48 (m, 2H), 4.40 (d, J = 17.8 Hz, 1H), 3.34-3.21 (m, 3H), 3.07 (s, 1H), 3.00-2.85 (m, 2H), 2.81 (s, 1H), 2.61 (d, J = 16.8 Hz, 2H), 2.45-2.34 (m, 3H), 2.15-2.01 (m, 2H), 1.90 (d, J = 16.9 Hz, 1H), 1.78-1.58 (m, 4H), 1.50-1.40 (m, 2H), 1.32-1.04 (m, 3H), 0.98 (d, J = 14.1 Hz, 6H). LCMS (ESI) C 3 8 H 4 3 ClF 2 N 5 O 5 + [M+H] + : calculated value 722.29, found value 722.3.

实施例198：3-(7-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09726)的制备Example 198: Preparation of 3-(7-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09726)

参照合成方案4的方法制备目标化合物(GT-09726)(白色固体，16mg，收率49％)。1H NMR(400MHz，DMSO)δ11.00(s，1H)，7.76-7.65(m，2H)，7.40-7.30(m，3H)，7.27-7.21(m，2H)，5.08-4.94(m，1H)，4.77-4.60(m，1H)，4.55-4.37(m，2H)，3.34-2.95(m，8H)，2.90-2.81(m，1H)，2.61(d，3H)，2.36(d，4H)，2.10-1.86(m，3H)，1.83-1.40(m，5H)，0.98(d，J＝13.5Hz，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09726) (white solid, 16 mg, yield 49%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.00 (s, 1H), 7.76-7.65 (m, 2H), 7.40-7.30 (m, 3H), 7.27-7.21 (m, 2H), 5.08-4.94 (m, 1H), 4.77-4.60 (m, 1H), 4.55-4.37 (m , 2H), 3.34-2.95 (m, 8H), 2.90-2.81 (m, 1H), 2.61 (d, 3H), 2.36 (d, 4H), 2 .10-1.86(m, 3H), 1.83-1.40(m, 5H), 0.98(d, J=13.5Hz, 6H).LCMS(ESI)C 38 H 43 ClF 2 N 5 O 5 + [M+H] + : Calculated 722.29, found 722.3.

实施例199：4-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09727)的制备Example 199: Preparation of 4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09727)

参照合成方案4的方法制备目标化合物(GT-09727)(白色固体，11mg，收率33％)。1H NMR(400MHz，DMSO)δ11.20-11.04(m，1H)，8.04-7.91(m，2H)，7.78-7.63(m，1H)，7.41-7.33(m，2H)，7.25(d，J＝8.4Hz，2H)，5.19-5.06(m，1H)，4.80-4.53(m，1H)，3.44-3.00(m，8H)，2.97-2.80(m，2H)，2.78-2.56(m，3H)，2.37(d，J＝16.6Hz，3H)，2.15-2.00(m，2H)，1.98-1.50(m，4H)，1.50-1.36(m，2H)，0.98(d，J＝13.9Hz，6H).LCMS(ESI)C38H41ClF2N5O6 +[M+H]+：计算值736.27，实测值736.3.The target compound (GT-09727) (white solid, 11 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.20-11.04 (m, 1H), 8.04-7.91 (m, 2H), 7.78-7.63 (m, 1H), 7.41-7.33 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 5.19-5.06 (m, 1H), 4.80-4.53 (m, 1H), 3.44-3 .00 (m, 8H), 2.97-2.80 (m, 2H), 2.78-2.56 (m, 3H), 2.37 (d, J=16.6 Hz, 3H), 2.15-2.00 (m, 2H), 1.98-1.50 (m, 4H), 1.50-1.36 (m, 2H), 0.98 (d, J=13.9 Hz, 6H). LCMS (ESI) C 38 H 41 ClF 2 N 5 O 6 + [M+H] + : calculated value 736.27, found value 736.3.

实施例200：5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09728)的制备Example 200: Preparation of 5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazine-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09728)

参照合成方案4的方法制备目标化合物(GT-09728)(白色固体，11mg，收率33％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.01(d，J＝7.4Hz，1H)，7.85(s，2H)，7.38(d，J＝8.2Hz，2H)，7.25(d，J＝8.4Hz，2H)，5.19(dd，J＝12.7，5.4Hz，1H)，4.59(d，J＝43.1Hz，1H)，3.50-3.30(m，5H)，3.26-3.10(m，3H)，3.04(s，1H)，2.94-2.86(m，1H)，2.79-2.54(m，4H)，2.47-2.22(m，3H)，2.15-2.02(m，2H)，1.90(d，J＝16.7Hz，1H)，1.80-1.62(m，2H)，1.50-1.37(m，2H)，0.98(d，J＝13.6Hz，6H).LCMS(ESI)C38H41ClF2N5O6 +[M+H]+：计算值736.27，实测值736.3.The target compound (GT-09728) (white solid, 11 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.01 (d, J = 7.4 Hz, 1H), 7.85 (s, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 5.19 (dd, J = 12.7, 5.4 Hz, 1H), 4.59 (d, J = 43.1 Hz, 1H), 3.50-3.30 (m, 5H), 3.26-3. 10 (m, 3H), 3.04 (s, 1H), 2.94-2.86 (m, 1H), 2.79-2.54 (m, 4H), 2.47-2.22 (m, 3H), 2.15-2.02 (m, 2H), 1.90 (d, J=16.7 Hz, 1H), 1.80-1.62 (m, 2H), 1.50-1.37 (m, 2H), 0.98 (d, J=13.6 Hz, 6H). LCMS (ESI) C 3 8 H 4 1 ClF 2 N 5 O 6 + [M+H] + : calculated value 736.27, found value 736.3.

实施例201：3-(5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09729)的制备Example 201: Preparation of 3-(5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09729)

参照合成方案4的方法制备目标化合物(GT-09729)(白色固体，10mg，收率29％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，10.02(s，1H)，7.81(d，J＝7.8Hz，1H)，7.63(s，1H)，7.50(d，J＝7.7Hz，1H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.74-4.48(m，2H)，4.45-4.34(m，1H)，3.57(s，3H)，3.31-3.17(m，4H)，3.16-2.83(m，6H)，2.61(d，J＝15.7Hz，3H)，2.46-2.36(m，1H)，2.32(s，2H)，2.02(s，3H)，1.88-1.60(m，2H)，1.46(t，J＝6.2Hz，2H)，0.96(s，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.4.The target compound (GT-09729) (white solid, 10 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 10.02 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.74-4.48 (m, 2H), 4. 45-4.34 (m, 1H), 3.57 (s, 3H), 3.31-3.17 (m, 4H), 3.16-2.83 (m, 6H), 2.61 (d, J=15.7 Hz, 3H), 2.46-2.36 (m, 1H), 2.32 (s, 2H), 2.02 (s, 3H), 1.88-1.60 (m, 2H), 1.46 (t, J=6.2 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 38 H 45 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.4.

实施例202：3-(5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09730)的制备Example 202: Preparation of 3-(5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09730)

参照合成方案4的方法制备目标化合物(GT-09730)(白色固体，13mg，收率36％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，10.05(s，1H)，7.44(d，J＝8.4Hz，3H)，7.32(s，1H)，7.14(d，J＝8.4Hz，2H)，5.11(dd，J＝13.2，5.1Hz，1H)，4.76-4.50(m，2H)，4.46-4.36(m，1H)，3.66(s，1H)，3.31-3.04(m，7H)，2.96-2.82(m，4H)，2.69-2.56(m，4H)，2.44-2.36(m，1H)，2.33(s，2H)，2.09-1.98(m，3H)，1.86-1.64(m，2H)，1.46(t，J＝6.2Hz，2H)，0.96(s，6H).LCMS(ESI)C38H44ClF3N5O4 +[M+H]+：计算值726.30，实测值726.3.The target compound (GT-09730) (white solid, 13 mg, yield 36%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 10.05 (s, 1H), 7.44 (d, J = 8.4 Hz, 3H), 7.32 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.76-4.50 (m, 2H), 4.46-4.36 (m, 1H), 3.66 ( s, 1H), 3.31-3.04 (m, 7H), 2.96-2.82 (m, 4H), 2.69-2.56 (m, 4H), 2.44-2.36 (m, 1H), 2.33 (s, 2H), 2.09-1.98 (m, 3H), 1.86-1.64 (m, 2H), 1.46 (t, J=6.2 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 4 ClF 3 N 5 O 4 + [M+H] + : calculated value 726.30, found value 726.3.

实施例203：3-(5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09731)的制备Example 203: Preparation of 3-(5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09731)

参照合成方案4的方法制备目标化合物(GT-09731)(白色固体，10mg，收率28％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，9.88(s，1H)，7.72-7.55(m，2H)，7.44(d，J＝8.4Hz，2H)，7.14(d，2H)，5.14(dd，J＝13.1，5.0Hz，1H)，4.72-4.31(m，3H)，3.59-3.51(m，3H)，3.30-3.18(m，4H)，3.15-2.76(m，6H)，2.65-2.55(m，3H)，2.43-2.25(m，3H)，2.04(s，3H)，1.87-1.60(m，2H)，1.46(t，J＝6.2Hz，2H)，0.96(s，6H).LCMS(ESI)C38H44ClF3N5O4 +[M+H]+：计算值726.30，实测值726.3.The target compound (GT-09731) (white solid, 10 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.88 (s, 1H), 7.72-7.55 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, 2H), 5.14 (dd, J = 13.1, 5.0 Hz, 1H), 4.72-4.31 (m, 3H), 3.59-3.51 ( m, 3H), 3.30-3.18 (m, 4H), 3.15-2.76 (m, 6H), 2.65-2.55 (m, 3H), 2.43-2.25 (m, 3H), 2.04 (s, 3H), 1.87-1.60 (m, 2H), 1.46 (t, J=6.2 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 4 ClF 3 N 5 O 4 + [M+H] + : calculated value 726.30, found value 726.3.

实施例204：3-(4-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09732)的制备Example 204: Preparation of 3-(4-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09732)

参照合成方案4的方法制备目标化合物(GT-09732)(白色固体，11mg，收率31％)。1H NMR(400MHz，DMSO)δ10.99(d，J＝4.0Hz，1H)，9.92(s，1H)，7.85(d，J＝8.6Hz，1H)，7.66-7.55(m，2H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.20-5.06(m，1H)，4.75-4.27(m，3H)，3.55(s，3H)，3.30-3.16(m，4H)，3.10-3.01(m，2H)，2.92-2.80(m，3H)，2.66-2.54(m，4H)，2.47-2.37(m，1H)，2.31(s，2H)，2.07-1.96(m，3H)，1.74(s，2H)，1.46(t，J＝6.2Hz，2H)，0.96(s，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.4.The target compound (GT-09732) (white solid, 11 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 10.99 (d, J = 4.0 Hz, 1H), 9.92 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.66-7.55 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.20-5.06 (m, 1H), 4.75-4.27 (m, 3H), 3.55 (s, 3 3H), 3.30-3.16 (m, 4H), 3.10-3.01 (m, 2H), 2.92-2.80 (m, 3H), 2.66-2.54 (m, 4H), 2.47-2.37 (m, 1H), 2.31 (s, 2H), 2.07-1.96 (m, 3H), 1.74 (s, 2H), 1.46 (t, J=6.2 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.4.

实施例205：3-(6-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09828)的制备Example 205: Preparation of 3-(6-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09828)

参照合成方案4的方法制备目标化合物(GT-09828)(白色固体，11mg，收率32％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，9.90(s，1H)，7.72(d，J＝7.8Hz，1H)，7.69-7.62(m，2H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.13(dd，J＝13.3，5.1Hz，1H)，4.80-4.49(m，2H)，4.40(d，J＝17.8Hz，1H)，3.66-3.58(m，4H)，3.31-3.17(m，4H)，3.10-3.01(m，2H)，2.95-2.82(m，3H)，2.65-2.57(m，3H)，2.47-2.36(m，1H)，2.31(s，2H)，2.06-1.98(m，3H)，1.83-1.62(m，2H)，1.46(t，J＝6.2Hz，2H)，0.96(s，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.4.The target compound (GT-09828) (white solid, 11 mg, yield 32%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.90 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.69-7.62 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.80-4.49 (m, 2H), 4.40 (d, J = 17.8 Hz, 1H), 3. 66-3.58 (m, 4H), 3.31-3.17 (m, 4H), 3.10-3.01 (m, 2H), 2.95-2.82 (m, 3H), 2.65-2.57 (m, 3H), 2.47-2.36 (m, 1H), 2.31 (s, 2H), 2.06-1.98 (m, 3H), 1.83-1.62 (m, 2H), 1.46 (t, J=6.2 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 38 H 45 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.4.

实施例206：3-(7-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09829)的制备Example 206: Preparation of 3-(7-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09829)

参照合成方案4的方法制备目标化合物(GT-09829)(白色固体，10mg，收率29％)。1H NMR(400MHz，DMSO)δ11.00(d，J＝4.3Hz，1H)，9.94(s，1H)，7.74-7.63(m，2H)，7.49-7.38(m，2H)，7.37-7.27(m，1H)，7.14(d，J＝7.1Hz，2H)，5.11-4.93(m，1H)，4.80-4.61(m，1H)，4.61-4.35(m，2H)，3.60(s，2H)，3.42-3.16(m，5H)，3.13-2.98(m，3H)，2.93-2.79(m，3H)，2.61(d，J＝15.1Hz，3H)，2.47-2.36(m，1H)，2.31(s，2H)，2.12-1.94(m，3H)，1.87-1.67(m，1H)，1.57(s，1H)，1.46(t，J＝6.1Hz，2H)，0.95(s，6H).LCMS(ESI)C38H45ClF2N5O4 +[M+H]+：计算值708.31，实测值708.3.The target compound (GT-09829) (white solid, 10 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.00 (d, J = 4.3 Hz, 1H), 9.94 (s, 1H), 7.74-7.63 (m, 2H), 7.49-7.38 (m, 2H), 7.37-7.27 (m, 1H), 7.14 (d, J = 7.1 Hz, 2H), 5.11-4.93 (m, 1H), 4.80-4.61 (m, 1H), 4.61-4.35 (m, 2H), 3.60 (s, 2H), 3. 42-3.16 (m, 5H), 3.13-2.98 (m, 3H), 2.93-2.79 (m, 3H), 2.61 (d, J=15.1 Hz, 3H), 2.47-2.36 (m, 1H), 2.31 (s, 2H), 2.12-1.94 (m, 3H), 1.87-1.67 (m, 1H), 1.57 (s, 1H), 1.46 (t, J=6.1 Hz, 2H), 0.95 (s, 6H). LCMS (ESI) C 3 8 H 4 5 ClF 2 N 5 O 4 + [M+H] + : calculated value 708.31, found value 708.3.

实施例207：4-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09830)的制备Example 207: Preparation of 4-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09830)

参照合成方案4的方法制备目标化合物(GT-09830)(白色固体，9mg，收率26％)。1H NMR(400MHz，DMSO)δ11.17-11.08(m，1H)，9.75(s，1H)，8.12-7.87(m，2H)，7.81-7.59(m，1H)，7.43(d，J＝8.3Hz，2H)，7.14(d，J＝8.3Hz，2H)，5.20-5.07(m，1H)，4.81-4.48(m，1H)，3.59-3.51(m，2H)，3.33-3.09(m，6H)，3.06-2.96(m，2H)，2.94-2.80(m，3H)，2.60(d，J＝13.9Hz，3H)，2.34-2.25(m，2H)，2.09-1.99(m，3H)，1.88-1.56(m，2H)，1.46(t，J＝6.1Hz，2H)，1.28(dd，J＝11.1，6.5Hz，1H)，0.96(s，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09830) (white solid, 9 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.17-11.08 (m, 1H), 9.75 (s, 1H), 8.12-7.87 (m, 2H), 7.81-7.59 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.20-5.07 (m, 1H), 4.81-4.48 (m, 1H), 3.59-3.51 (m, 2H), 3.33-3.0 9 (m, 6H), 3.06-2.96 (m, 2H), 2.94-2.80 (m, 3H), 2.60 (d, J = 13.9 Hz, 3H), 2.34-2.25 (m, 2H), 2.09-1.99 (m, 3H), 1.88-1.56 (m, 2H), 1.46 (t, J = 6.1 Hz, 2H), 1.28 (dd, J = 11.1, 6.5 Hz, 1H), 0.96 (s, 6H). LCMS (ESI) C 38 H 43 ClF 2 N 5 O 5 + [M+H] + : calculated value 722.29, found value 722.3.

实施例208：5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09831)的制备Example 208: Preparation of 5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09831)

参照合成方案4的方法制备目标化合物(GT-09831)(白色固体，9mg，收率26％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，9.62(s，1H)，8.01(d，J＝8.1Hz，1H)，7.85(d，2H)，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.19(dd，J＝12.8，5.4Hz，1H)，4.60(d，J＝52.1Hz，1H)，3.63-3.50(m，3H)，3.22(d，J＝9.0Hz，4H)，3.08-2.97(m，2H)，2.96-2.85(m，3H)，2.70-2.53(m，4H)，2.33-2.25(m，2H)，2.13-2.00(m，3H)，1.83-1.68(m，2H)，1.66-1.57(m，1H)，1.46(t，J＝6.2Hz，2H)，0.96(s，6H).LCMS(ESI)C38H43ClF2N5O5 +[M+H]+：计算值722.29，实测值722.3.The target compound (GT-09831) (white solid, 9 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 9.62 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.85 (d, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.19 (dd, J = 12.8, 5.4 Hz, 1H), 4.60 (d, J = 52.1 Hz, 1H), 3.63-3.50 (m, 3H), 3 .22 (d, J = 9.0 Hz, 4H), 3.08-2.97 (m, 2H), 2.96-2.85 (m, 3H), 2.70-2.53 (m, 4H), 2.33-2.25 (m, 2H), 2.13-2.00 (m, 3H), 1.83-1.68 (m, 2H), 1.66-1.57 (m, 1H), 1.46 (t, J = 6.2 Hz, 2H), 0.96 (s, 6H). LCMS (ESI) C 38 H 43 ClF 2 N 5 O 5 + [M+H] + : calculated value 722.29, found value 722.3.

实施例209：3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09832)的制备Example 209: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09832)

参照合成方案4的方法制备目标化合物(GT-09832)(白色固体，8mg，收率21％)。1H NMR(400MHz，DMSO)δ11.04(d，J＝15.2Hz，2H)，7.81(d，J＝7.8Hz，1H)，7.66(s，1H)，7.55(d，J＝8.8Hz，1H)，7.43-7.31(m，2H)，7.28-7.17(m，1H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.66(s，1H)，4.52(d，J＝17.6Hz，1H)，4.40(d，J＝17.6Hz，1H)，3.75-3.53(m，4H)，3.47(d，J＝9.7Hz，2H)，3.28-3.11(m，5H)，2.98-2.78(m，2H)，2.61(d，J＝16.2Hz，1H)，2.46-2.36(m，1H)，2.32(dd，J＝11.6，9.8Hz，1H)，2.19-2.06(m，1H)，2.06-1.97(m，1H)，1.86-1.70(m，2H).LCMS(ESI)C29H32Cl2N5O4 +[M+H]+：计算值584.18，实测值584.2.The target compound (GT-09832) (white solid, 8 mg, yield 21%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.04 (d, J = 15.2 Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.43-7.31 (m, 2H), 7.28-7.17 (m, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.66 (s, 1H), 4.52 (d, J = 17.6 Hz, 1H), 4.40 (d, J = 17.6 Hz, 1H). , 1H), 3.75-3.53 (m, 4H), 3.47 (d, J = 9.7 Hz, 2H), 3.28-3.11 (m, 5H), 2.98-2.78 (m, 2H), 2.61 (d, J = 16.2 Hz, 1H), 2.46-2.36 (m, 1H), 2.32 (dd, J = 11.6, 9.8 Hz, 1H), 2.19-2.06 (m, 1H), 2.06-1.97 (m, 1H), 1.86-1.70 (m, 2H). LCMS (ESI) C 29 H 32 Cl 2 N 5 O 4 + [M+H] + : calculated value 584.18, found value 584.2.

实施例210：3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09833)的制备Example 210: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09833)

参照合成方案4的方法制备目标化合物(GT-09833)(白色固体，10mg，收率25％)。1H NMR(400MHz，DMSO)δ11.11(s，1H)，11.03(s，1H)，7.49(s，1H)，7.43-7.31(m，3H)，7.26-7.17(m，1H)，5.11(dd，J＝13.2，5.1Hz，1H)，4.79-4.59(m，1H)，4.54(d，J＝18.1Hz，1H)，4.41(d，J＝18.1Hz，1H)，3.72-3.53(m，4H)，3.47(d，J＝10.2Hz，2H)，3.29-3.13(m，5H)，2.98-2.79(m，2H)，2.61(d，J＝16.6Hz，1H)，2.45-2.26(m，2H)，2.14-1.97(m，2H)，1.86-1.71(m，2H).LCMS(ESI)C29H31Cl2FN5O4 +[M+H]+：计算值602.17，实测值602.2.The target compound (GT-09833) (white solid, 10 mg, yield 25%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 11.03 (s, 1H), 7.49 (s, 1H), 7.43-7.31 (m, 3H), 7.26-7.17 (m, 1H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 4.79-4.59 (m, 1H), 4.54 (d, J=18.1 Hz, 1H), 4.41 (d, J=1 8.1 Hz, 1H), 3.72-3.53 (m, 4H), 3.47 (d, J=10.2 Hz, 2H), 3.29-3.13 (m, 5H), 2.98-2.79 (m, 2H), 2.61 (d, J=16.6 Hz, 1H), 2.45-2.26 (m, 2H), 2.14-1.97 (m, 2H), 1.86-1.71 (m, 2H). LCMS (ESI) C 29 H 31 Cl 2 FN 5 O 4 + [M+H] + : calculated value 602.17, found value 602.2.

实施例211：3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09834)的制备Example 211: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09834)

参照合成方案4的方法制备目标化合物(GT-09834)(白色固体，11mg，收率28％)。1H NMR(400MHz，DMSO)δ11.50-10.74(m，2H)，7.78-7.59(m，2H)，7.44-7.34(m，2H)，7.21(dd，J＝7.1，2.4Hz，1H)，5.23-5.03(m，1H)，4.69(d，J＝12.1Hz，1H)，4.50(d，J＝17.4Hz，1H)，4.37(d，J＝17.6Hz，1H)，3.58(s，4H)，3.46(d，J＝10.2Hz，2H)，3.28-3.10(m，5H)，2.97-2.81(m，2H)，2.61(d，J＝17.4Hz，1H)，2.47-2.38(m，1H)，2.35-2.27(m，1H)，2.13(s，1H)，2.07-1.99(m，1H)，1.70(s，2H).LCMS(ESI)C29H31Cl2FN5O4 +[M+H]+：计算值602.17，实测值602.2.The target compound (GT-09834) (white solid, 11 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.50-10.74 (m, 2H), 7.78-7.59 (m, 2H), 7.44-7.34 (m, 2H), 7.21 (dd, J = 7.1, 2.4 Hz, 1H), 5.23-5.03 (m, 1H), 4.69 (d, J = 12.1 Hz, 1H), 4.50 (d, J = 17.4 Hz, 1H), 4.37 (d, J = 17.6 Hz, 1H ), 3.58 (s, 4H), 3.46 (d, J = 10.2 Hz, 2H), 3.28-3.10 (m, 5H), 2.97-2.81 (m, 2H), 2.61 (d, J = 17.4 Hz, 1H), 2.47-2.38 (m, 1H), 2.35-2.27 (m, 1H), 2.13 (s, 1H), 2.07-1.99 (m, 1H), 1.70 (s, 2H). LCMS (ESI) C 29 H 31 Cl 2 FN 5 O 4 + [M+H] + : calculated value 602.17, found value 602.2.

实施例212：3-(4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09835)的制备Example 212: Preparation of 3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09835)

参照合成方案4的方法制备目标化合物(GT-09835)(白色固体，5mg，收率14％)。1H NMR(400MHz，DMSO)δ11.16-10.91(m，2H)，7.85(dd，J＝7.0，1.5Hz，1H)，7.69-7.56(m，2H)，7.43-7.29(m，2H)，7.26-7.13(m，1H)，5.15(dd，J＝13.2，4.9Hz，1H)，4.80-4.17(m，3H)，3.66-3.53(m，3H)，3.50-3.42(m，2H)，3.29-3.02(m，6H)，2.97-2.78(m，2H)，2.58(d，J＝17.4Hz，1H)，2.47-2.36(m，1H)，2.19(s，2H)，2.04-1.96(m，1H)，1.85-1.69(m，2H).LCMS(ESI)C29H32Cl2N5O4 +[M+H]+：计算值584.18，实测值584.3.The target compound (GT-09835) (white solid, 5 mg, yield 14%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.16-10.91 (m, 2H), 7.85 (dd, J = 7.0, 1.5 Hz, 1H), 7.69-7.56 (m, 2H), 7.43-7.29 (m, 2H), 7.26-7.13 (m, 1H), 5.15 (dd, J = 13.2, 4.9 Hz, 1H), 4.80-4.17 (m, 3H), 3. 66-3.53 (m, 3H), 3.50-3.42 (m, 2H), 3.29-3.02 (m, 6H), 2.97-2.78 (m, 2H), 2.58 (d, J=17.4 Hz, 1H), 2.47-2.36 (m, 1H), 2.19 (s, 2H), 2.04-1.96 (m, 1H), 1.85-1.69 (m, 2H). LCMS (ESI) C 29 H 32 Cl 2 N 5 O 4 + [M+H] + : calculated value 584.18, found value 584.3.

实施例213：3-(6-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09836)的制备Example 213: Preparation of 3-(6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09836)

参照合成方案4的方法制备目标化合物(GT-09836)(白色固体，9mg，收率24％)。1H NMR(400MHz，DMSO)δ11.10(s，1H)，11.02(s，1H)，7.73(d，J＝8.3Hz，2H)，7.70-7.65(m，1H)，7.40-7.34(m，2H)，7.21(dd，J＝7.1，2.5Hz，1H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.66(s，1H)，4.53(d，J＝17.8Hz，1H)，4.40(d，J＝17.8Hz，1H)，3.79-3.53(m，4H)，3.46(d，J＝9.9Hz，2H)，3.30-3.16(m，5H)，2.99-2.78(m，2H)，2.62(d，J＝16.7Hz，1H)，2.46-2.36(m，1H)，2.34-2.08(m，2H)，2.06-2.00(m，1H)，1.84-1.70(m，2H).LCMS(ESI)C29H32Cl2N5O4 +[M+H]+：计算值584.18，实测值584.3.The target compound (GT-09836) (white solid, 9 mg, yield 24%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 11.02 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.70-7.65 (m, 1H), 7.40-7.34 (m, 2H), 7.21 (dd, J = 7.1, 2.5 Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.66 (s, 1H), 4.53 (d, J = 17.8 Hz, 1H), 4.40 (d, J = 17.8 Hz, 1H), 3.79-3.53 (m, 4H), 3.46 (d, J = 9.9 Hz, 2H), 3.30-3.16 (m, 5H), 2.99-2.78 (m, 2H), 2.62 (d, J = 16.7 Hz, 1H), 2.46-2.36 (m, 1H), 2.34-2.08 (m, 2H), 2.06-2.00 (m, 1H) , 1.84-1.70 (m, 2H) . LCMS (ESI) C29H32Cl2N5O4 + [ M+H] + : calculated value 584.18, found value 584.3.

实施例214：3-(7-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09837)的制备Example 214: Preparation of 3-(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09837)

参照合成方案4的方法制备目标化合物(GT-09837)(白色固体，6mg，收率16％)。1H NMR(400MHz，DMSO)δ11.20-10.58(m，2H)，7.76-7.60(m，2H)，7.45-7.29(m，3H)，7.26-7.10(m，1H)，5.09-4.86(m，1H)，4.73(t，1H)，4.56-4.48(m，1H)，4.46-4.34(m，1H)，3.64-3.53(m，2H)，3.50-3.41(m，3H)，3.30-3.14(m，5H)，3.05-2.91(m，1H)，2.91-2.71(m，2H)，2.61(d，J＝17.3Hz，1H)，2.46-2.36(m，1H)，2.27(dd，J＝31.4，13.4Hz，1H)，2.13-1.91(m，2H)，1.91-1.62(m，2H).LCMS(ESI)C29H32Cl2N5O4 +[M+H]+：计算值584.18，实测值584.3.The target compound (GT-09837) (white solid, 6 mg, yield 16%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.20-10.58 (m, 2H), 7.76-7.60 (m, 2H), 7.45-7.29 (m, 3H), 7.26-7.10 (m, 1H), 5.09-4.86 (m, 1H), 4.73 (t, 1H), 4.56-4.48 (m, 1H), 4.46-4.34 (m, 1H), 3.64-3.53 (m, 2H), 3.50- 3.41 (m, 3H), 3.30-3.14 (m, 5H), 3.05-2.91 (m, 1H), 2.91-2.71 (m, 2H), 2.61 (d, J=17.3 Hz, 1H), 2.46-2.36 (m, 1H), 2.27 (dd, J=31.4, 13.4 Hz, 1H), 2.13-1.91 (m, 2H), 1.91-1.62 (m, 2H). LCMS (ESI) C 2 9 H 3 2 Cl 2 N 5 O 4 + [M+H] + : calculated value 584.18, found value 584.3.

实施例215：4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09838)的制备Example 215: Preparation of 4-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09838)

参照合成方案4的方法制备目标化合物(GT-09838)(白色固体，7mg，收率18％)。1H NMR(400MHz，DMSO)δ11.23-10.57(m，2H)，8.07-7.91(m，2H)，7.90-7.70(m，1H)，7.43-7.30(m，2H)，7.26-7.12(m，1H)，5.23-5.05(m，1H)，4.72(d，J＝12.6Hz，1H)，3.65-3.40(m，6H)，3.30-2.96(m，6H)，2.94-2.79(m，2H)，2.64-2.56(m，1H)，2.34-2.24(m，1H)，2.13-1.94(m，2H)，1.81-1.45(m，2H).LCMS(ESI)C29H30Cl2N5O5 +[M+H]+：计算值598.16，实测值598.2.The target compound (GT-09838) (white solid, 7 mg, yield 18%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.23-10.57 (m, 2H), 8.07-7.91 (m, 2H), 7.90-7.70 (m, 1H), 7.43-7.30 (m, 2H), 7.26-7.12 (m, 1H), 5.23-5.05 (m, 1H), 4.72 (d, J=12.6 Hz, 1H), 3.65-3.40 (m, 6H), 3.30-2.96 (m, 6H), 2.94-2.79 (m, 2H), 2.64-2.56 (m, 1H), 2.34-2.24 (m, 1H), 2.13-1.94 (m, 2H), 1.81-1.45 (m, 2H). LCMS (ESI) C 2 9 H 3 0 Cl 2 N 5 O 5 + [M+H] + : calculated value 598.16, found value 598.2.

实施例216：5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09839)的制备Example 216: Preparation of 5-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09839)

参照合成方案4的方法制备目标化合物(GT-09839)(白色固体，13mg，收率33％)。1H NMR(400MHz，DMSO)δ11.22(s，1H)，11.16(s，1H)，8.02(d，J＝7.7Hz，1H)，7.95(s，1H)，7.93-7.87(m，1H)，7.42-7.33(m，2H)，7.25-7.19(m，1H)，5.19(dd，J＝12.8，5.4Hz，1H)，4.64(s，1H)，3.59(s，4H)，3.46(d，J＝10.0Hz，2H)，3.29-3.10(m，5H)，2.97-2.81(m，2H)，2.69-2.53(m，2H)，2.35-2.21(m，1H)，2.13-2.02(m，2H)，1.81(d，J＝9.7Hz，2H).LCMS(ESI)C29H30Cl2N5O5 +[M+H]+：计算值598.16，实测值598.2.The target compound (GT-09839) (white solid, 13 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 11.16 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.95 (s, 1H), 7.93-7.87 (m, 1H), 7.42-7.33 (m, 2H), 7.25-7.19 (m, 1H), 5.19 (dd, J = 12.8, 5.4 Hz, 1H), 4.6 4 (s, 1H), 3.59 (s, 4H), 3.46 (d, J = 10.0 Hz, 2H), 3.29-3.10 (m, 5H), 2.97-2.81 (m, 2H), 2.69-2.53 (m, 2H), 2.35-2.21 (m, 1H), 2.13-2.02 (m, 2H), 1.81 (d, J = 9.7 Hz, 2H). LCMS (ESI) C 2 9 H 3 0 Cl 2 N 5 O 5 + [M+H] + : calculated value 598.16, found value 598.2.

实施例217：3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09840)的制备Example 217: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09840)

参照合成方案4的方法制备目标化合物(GT-09840)(白色固体，22mg，收率60％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.83(d，J＝7.8Hz，1H)，7.67(s，1H)，7.54(d，J＝7.8Hz，1H)，7.32(d，J＝6.7Hz，2H)，7.22-7.09(m，1H)，5.15(dd，J＝13.4，4.6Hz，1H)，4.69(d，J＝70.8Hz，1H)，4.57-4.49(m，1H)，4.46-4.34(m，1H)，3.91-3.56(m，4H)，3.15(s，8H)，2.95-2.87(m，1H)，2.61(d，J＝17.1Hz，1H)，2.45-2.33(m，1H)，2.06-1.86(m，2H).LCMS(ESI)C29H30Cl2F2N5O4 +[M+H]+：计算值620.16，实测值620.2.The target compound (GT-09840) (white solid, 22 mg, yield 60%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 6.7 Hz, 2H), 7.22-7.09 (m, 1H), 5.15 (dd, J = 13.4, 4.6 Hz, 1H), 4.69 (d, J = 70.8 Hz, 1H), 4.57-4.49 (m, 1H), 4.46-4.34 (m, 1H), 3.91-3.56 (m, 4H), 3.15 (s, 8H), 2.95-2.87 (m, 1H), 2.61 (d, J=17.1 Hz, 1H), 2.45-2.33 (m, 1H), 2.06-1.86 (m, 2H). LCMS (ESI) C 29 H 30 Cl 2 F 2 N 5 O 4 + [M+H] + : calculated value 620.16, found value 620.2.

实施例218：3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09841)的制备Example 218: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09841)

参照合成方案4的方法制备目标化合物(GT-09841)(白色固体，21mg，收率56％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，7.50(s，1H)，7.43-7.25(m，3H)，7.17(t，1H)，5.11(dd，J＝13.2，3.9Hz，1H)，4.83-4.38(m，3H)，3.76(d，J＝63.6Hz，2H)，3.34-2.98(m，10H)，2.97-2.85(m，1H)，2.61(d，J＝16.8Hz，1H)，2.44-2.32(m，1H)，2.31-1.85(m，3H).LCMS(ESI)C29H29Cl2F3N5O4 +[M+H]+：计算值638.15，实测值638.2.The target compound (GT-09841) (white solid, 21 mg, yield 56%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.03 (s, 1H), 7.50 (s, 1H), 7.43-7.25 (m, 3H), 7.17 (t, 1H), 5.11 (dd, J=13.2, 3.9Hz, 1H), 4.83-4.38 (m, 3H), 3.7 6 (d, J=63.6Hz, 2H), 3.34-2.98 (m, 10H), 2.97-2.85 (m, 1H), 2.61 (d, J=16.8Hz, 1H), 2.44-2.32 (m, 1H), 2.31-1.85 (m, 3H). LCMS (ESI) C 29 H 29 Cl 2 F 3 N 5 O 4 + [M+H] + : Calculated value 638.15, measured value 638.2.

实施例219：3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09842)的制备Example 219: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09842)

参照合成方案4的方法制备目标化合物(GT-09842)(白色固体，17mg，收率45％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，7.78-7.60(m，2H)，7.32(d，J＝6.6Hz，2H)，7.17(t，J＝4.8Hz，1H)，5.15(dd，J＝13.3，4.9Hz，1H)，4.85-4.60(m，1H)，4.50(d，J＝17.4Hz，1H)，4.38(d，J＝17.4Hz，1H)，3.79-3.63(m，2H)，3.34-2.99(m，10H)，2.96-2.86(m，1H)，2.61(d，J＝16.8Hz，1H)，2.45-2.30(m，1H)，2.30-1.97(m，2H)，1.91(s，1H).LCMS(ESI)C29H29Cl2F3N5O4 +[M+H]+：计算值638.15，实测值638.2.The target compound (GT-09842) (white solid, 17 mg, yield 45%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.78-7.60 (m, 2H), 7.32 (d, J = 6.6 Hz, 2H), 7.17 (t, J = 4.8 Hz, 1H), 5.15 (dd, J = 13.3, 4.9 Hz, 1H), 4.85-4.60 (m, 1H), 4.50 (d, J = 17.4 Hz, 1H) , 4.38 (d, J = 17.4 Hz, 1H), 3.79-3.63 (m, 2H), 3.34-2.99 (m, 10H), 2.96-2.86 (m, 1H), 2.61 (d, J = 16.8 Hz, 1H), 2.45-2.30 (m, 1H), 2.30-1.97 (m, 2H), 1.91 (s, 1H). LCMS (ESI) C 29 H 29 Cl 2 F 3 N 5 O 4 + [M+H] + : calculated value 638.15, found value 638.2.

实施例220：3-(4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09843)的制备Example 220: Preparation of 3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09843)

参照合成方案4的方法制备目标化合物(GT-09843)(白色固体，15mg，收率41％)。1H NMR(400MHz，DMSO)δ11.00(d，J＝2.6Hz，1H)，7.87(t，1H)，7.65(d，J＝5.0Hz，2H)，7.32(d，J＝6.7Hz，2H)，7.18(t，J＝9.1，4.4Hz，1H)，5.21-5.08(m，1H)，4.91-4.27(m，3H)，3.58(s，3H)，3.28-2.99(m，8H)，2.96-2.86(m，1H)，2.58(d，J＝17.5Hz，1H)，2.47-2.34(m，1H)，2.31-1.84(m，3H).LCMS(ESI)C29H30Cl2F2N5O4 +[M+H]+：计算值620.16，实测值620.2.The target compound (GT-09843) (white solid, 15 mg, yield 41%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.00 (d, J=2.6Hz, 1H), 7.87 (t, 1H), 7.65 (d, J=5.0Hz, 2H), 7.32 (d, J=6.7Hz, 2H), 7.18 (t, J=9.1, 4.4Hz, 1H), 5.21-5.08 (m, 1H ), 4.91-4.27(m, 3H), 3.58(s, 3H), 3.28-2.99(m, 8H), 2.96-2.86(m, 1H), 2.58(d, J=17.5Hz, 1H), 2.47-2.34(m, 1H), 2.31-1.84(m, 3H).LCMS(ESI)C 29 H 30 Cl 2 F 2 N 5 O 4 + [M+H] + : Calculated value 620.16, found value 620.2.

实施例221：3-(6-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09844)的制备Example 221: Preparation of 3-(6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09844)

参照合成方案4的方法制备目标化合物(GT-09844)(白色固体，20mg，收率55％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.77-7.63(m，3H)，7.33(d，J＝7.3，6.2Hz，2H)，7.18(t，J＝9.3，4.2Hz，1H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.87-4.37(m，3H)，3.66(s，2H)，3.08(d，J＝79.5Hz，10H)，2.96-2.87(m，1H)，2.62(d，J＝16.6Hz，1H)，2.47-2.32(m，1H)，2.20(s，1H)，2.08-1.87(m，2H).LCMS(ESI)C29H30Cl2F2N5O4 +[M+H]+：计算值620.16，实测值620.3.The target compound (GT-09844) (white solid, 20 mg, yield 55%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.02 (s, 1H), 7.77-7.63 (m, 3H), 7.33 (d, J=7.3, 6.2Hz , 2H), 7.18 (t, J=9.3, 4.2Hz, 1H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 4.87-4.37 ( m, 3H), 3.66 (s, 2H), 3.08 (d, J=79.5Hz, 10H), 2.96-2.87 (m, 1H), 2.62 (d, J= 16.6Hz, 1H), 2.47-2.32(m, 1H), 2.20(s, 1H), 2.08-1.87(m, 2H).LCMS(ESI)C 29H 30 Cl 2 F 2 N 5 O 4 + [M+H] + : calculated value 620.16, found value 620.3.

实施例222：3-(7-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09845)的制备Example 222: Preparation of 3-(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09845)

参照合成方案4的方法制备目标化合物(GT-09845)(白色固体，18mg，收率49％)。1H NMR(400MHz，DMSO)δ11.06-10.95(m，1H)，7.80-7.65(m，2H)，7.41-7.28(m，3H)，7.21-7.10(m，1H)，5.10-4.98(m，1H)，4.93-4.69(m，1H)，4.55-4.36(m，2H)，3.42-3.04(m，13H)，2.92-2.83(m，1H)，2.61(d，J＝17.0Hz，1H)，2.46-2.36(m，1H)，2.05-1.84(m，2H).LCMS(ESI)C29H30Cl2F2N5O4 +[M+H]+：计算值620.16，实测值620.2.The target compound (GT-09845) (white solid, 18 mg, yield 49%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.06-10.95 (m, 1H), 7.80-7.65 (m, 2H), 7.41-7.28 (m, 3H), 7.21-7.10 (m, 1H), 5.10-4.98 (m, 1H), 4.93-4.69 (m, 1H) ), 4.55-4.36(m, 2H), 3.42-3.04(m, 13H), 2.92-2.83(m, 1H), 2.61(d, J=17.0Hz, 1H), 2.46-2.36(m, 1H), 2.05-1.84(m, 2H).LCMS(ESI)C 29 H 30 Cl 2 F 2 N 5 O 4 + [M+H] + : Calculated value 620.16, measured value 620.2.

实施例223：4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09846)的制备Example 223: Preparation of 4-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09846)

参照合成方案4的方法制备目标化合物(GT-09846)(白色固体，13mg，收率35％)。1H NMR(400MHz，DMSO)δ11.14(d，J＝4.9Hz，1H)，8.07-7.89(m，2H)，7.83-7.64(m，1H)，7.33(d，J＝4.6Hz，2H)，7.22-7.12(m，1H)，5.23-5.09(m，1H)，4.93-4.61(m，1H)，3.58(s，2H)，3.36-2.96(m，11H)，2.94-2.84(m，1H)，2.61(d，J＝17.8Hz，1H)，2.37-1.95(m，2H)，1.95-1.76(m，1H).LCMS(ESI)C29H28Cl2F2N5O5 +[M+H]+：计算值634.14，实测值634.2.The target compound (GT-09846) (white solid, 13 mg, yield 35%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.14 (d, J=4.9Hz, 1H), 8.07-7.89 (m, 2H), 7.83-7.64 (m, 1H), 7.33 (d, J=4.6Hz, 2H), 7.22-7.12 (m, 1H), 5.23-5.09 (m, 1H), 4 .93-4.61(m, 1H), 3.58(s, 2H), 3.36-2.96(m, 11H), 2.94-2.84(m, 1H), 2 .61(d, J＝17.8Hz, 1H), 2.37-1.95(m, 2H), 1.95-1.76(m, 1H).LCMS(ESI)C 29 H 28 Cl 2 F 2 N 5 O 5 + [M+H] + : calculated value 634.14, found value 634.2.

实施例224：5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09847)的制备Example 224: Preparation of 5-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09847)

参照合成方案4的方法制备目标化合物(GT-09847)(白色固体，15mg，收率40％)。1H NMR(400MHz，DMSO)δ11.16(s，1H)，8.00(t，J＝18.3Hz，1H)，7.89(s，2H)，7.32(t，J＝6.6Hz，2H)，7.17(t，J＝4.8Hz，1H)，5.20(dd，J＝12.7，5.4Hz，1H)，4.68(d，J＝57.1Hz，1H)，3.61(s，2H)，3.11(s，10H)，2.95-2.85(m，1H)，2.70-2.53(m，2H)，2.36-1.84(m，3H).LCMS(ESI)C29H28Cl2F2N5O5 +[M+H]+：计算值634.14，实测值634.2.The target compound (GT-09847) (white solid, 15 mg, yield 40%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.16 (s, 1H), 8.00 (t, J=18.3Hz, 1H), 7.89 (s, 2H), 7.32 (t, J=6.6Hz, 2H), 7.17 (t, J=4.8Hz, 1H), 5.20 (dd, J=12.7 , 5.4Hz, 1H), 4.68 (d, J=57.1Hz, 1H), 3.61 (s, 2H), 3.11 (s, 10H), 2.95-2.85 (m, 1H), 2.70-2.53 (m, 2H), 2.36-1.84 (m, 3H).LCMS (ESI) C 29 H 28 Cl 2 F 2 N 5 O 5 + [M+H] + : Calculated value 634.14, measured value 634.2.

实施例225：3-(5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09848)的制备Example 225: Preparation of 3-(5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09848)

参照合成方案4的方法制备目标化合物(GT-09848)(白色固体，11mg，收率23％)。1H NMR(400MHz，DMSO)δ11.37(s，1H)，11.02(s，1H)，8.09(dd，J＝8.9，5.2Hz，1H)，7.81(d，J＝7.8Hz，1H)，7.66(s，1H)，7.62(dd，J＝9.1，2.2Hz，1H)，7.54(d，J＝7.7Hz，1H)，7.32-7.20(m，1H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.66(s，1H)，4.52(d，J＝17.6Hz，1H)，4.39(d，J＝17.6Hz，1H)，4.13(d，J＝13.0Hz，2H)，3.77-3.51(m，6H)，3.30(d，J＝10.9Hz，2H)，3.15(d，J＝15.7Hz，1H)，2.98-2.77(m，2H)，2.61(d，J＝16.9Hz，1H)，2.45-2.31(m，1H)，2.30-1.97(m，3H)，1.76(s，2H).LCMS(ESI)C30H32FN6O5 +[M+H]+：计算值575.24，实测值575.3.The target compound (GT-09848) (white solid, 11 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.37 (s, 1H), 11.02 (s, 1H), 8.09 (dd, J = 8.9, 5.2 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.62 (dd, J = 9.1, 2.2 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.32-7.20 (m, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.66 (s, 1H), 4.52 (d, 3H), 1.76 (s, 2H). LCMS (ESI) C 30 H 32 FN 6 O 5 + [ M + H ] + : calculated value 575.24, found value 575.3.

实施例226：3-(7-氟-5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09849)的制备Example 226: Preparation of 3-(7-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09849)

参照合成方案4的方法制备目标化合物(GT-09849)(白色固体，13mg，收率26％)。1H NMR(400MHz，DMSO)δ11.47(s，1H)，11.03(s，1H)，8.09(dd，J＝8.9，5.2Hz，1H)，7.62(dd，J＝9.1，2.2Hz，1H)，7.49(s，1H)，7.36(d，J＝8.3Hz，1H)，7.31-7.20(m，1H)，5.11(dd，J＝13.3，5.1Hz，1H)，4.75-4.58(m，1H)，4.54(d，1H)，4.43(d，J＝14.6Hz，1H)，4.13(d，J＝13.3Hz，2H)，3.68-3.50(m，6H)，3.33-3.24(m，2H)，3.13(s，1H)，2.95-2.73(m，2H)，2.61(d，J＝16.8Hz，1H)，2.45-2.33(m，1H)，2.26(s，1H)，2.12-1.96(m，2H)，1.84-1.68(m，2H).LCMS(ESI)C30H31F2N6O5 +[M+H]+：计算值593.23，实测值593.3.The target compound (GT-09849) (white solid, 13 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 11.03 (s, 1H), 8.09 (dd, J = 8.9, 5.2 Hz, 1H), 7.62 (dd, J = 9.1, 2.2 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.31-7.20 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.75-4.58 (m, 1H), 4.54 (d, 1H), 4.43 (d, J = 14.6 Hz, 1H), 4.13 (d, J = 13.3 Hz, 2H), 3.68-3.50 (m, 6H), 3.33-3.24 (m, 2H), 3.13 (s, 1H), 2.95-2.73 (m, 2H), 2.61 (d, J = 16.8 Hz, 1H), 2.45-2.33 (m, 1H), 2.26 (s, 1H), 2.12-1.96 (m, 2H), 1.84-1.68 (m, 2H). LCMS (ESI) C 30 H 31 F 2 N 6 O 5 + [M+H] + : calculated value 593.23, found value 593.3.

实施例227：3-(6-氟-5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09850)的制备Example 227: Preparation of 3-(6-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09850)

参照合成方案4的方法制备目标化合物(GT-09850)(白色固体，7mg，收率15％)。1H NMR(400MHz，DMSO)δ11.20(d，J＝75.5Hz，1H)，11.03(s，1H)，8.09(dd，J＝8.9，5.2Hz，1H)，7.76-7.65(m，2H)，7.62(dd，J＝9.1，2.2Hz，1H)，7.31-7.21(m，1H)，5.15(dd，J＝13.1，4.9Hz，1H)，4.69(d，J＝12.3Hz，1H)，4.50(d，J＝17.3Hz，1H)，4.37(d，J＝15.4Hz，1H)，4.13(d，J＝13.0Hz，2H)，3.70-3.48(m，6H)，3.31-3.23(m，2H)，3.14(s，1H)，2.98-2.78(m，2H)，2.61(d，J＝16.9Hz，1H)，2.46-2.25(m，2H)，2.17-1.95(m，2H)，1.68(s，2H).LCMS(ESI)C30H31F2N6O5 +[M+H]+：计算值593.23，实测值593.3.The target compound (GT-09850) (white solid, 7 mg, yield 15%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.20 (d, J = 75.5 Hz, 1H), 11.03 (s, 1H), 8.09 (dd, J = 8.9, 5.2 Hz, 1H), 7.76-7.65 (m, 2H), 7.62 (dd, J = 9.1, 2.2 Hz, 1H), 7.31-7.21 (m, 1H), 5.15 (dd, J = 13.1, 4.9 Hz, 1H), 4.69 (d, J = 12.3 Hz, 1H), 4.50 (d, J = 13.7 Hz, 1H). =17.3 Hz, 1H), 4.37 (d, J=15.4 Hz, 1H), 4.13 (d, J=13.0 Hz, 2H), 3.70-3.48 (m, 6H), 3.31-3.23 (m, 2H), 3.14 (s, 1H), 2.98-2.78 (m, 2H), 2.61 (d, J=16.9 Hz, 1H), 2.46-2.25 (m, 2H), 2.17-1.95 (m, 2H), 1.68 (s, 2H). LCMS (ESI) C 30 H 31 F 2 N 6 O 5 + [M+H] + : calculated value 593.23, found value 593.3.

实施例228：3-(4-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09851)的制备Example 228: Preparation of 3-(4-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09851)

参照合成方案4的方法制备目标化合物(GT-09851)(白色固体，10mg，收率19％)。1H NMR(400MHz，DMSO)δ11.38(s，1H)，11.00(s，1H)，8.18-8.03(m，1H)，7.89-7.76(m，1H)，7.72-7.55(m，3H)，7.30-7.17(m，1H)，5.15(dd，J＝13.2，5.1Hz，1H)，4.77-4.29(m，3H)，4.13(d，J＝13.0Hz，2H)，3.84-3.49(m，6H)，3.29(d，J＝9.9Hz，2H)，3.15(s，1H)，2.98-2.69(m，2H)，2.59(d，J＝16.9Hz，1H)，2.49-2.38(m，1H)，2.34-2.06(m，2H)，2.04-1.96(m，1H)，1.86-1.67(m，2H).LCMS(ESI)C30H32FN6O5 +[M+H]+：计算值575.24，实测值575.3.The target compound (GT-09851) (white solid, 10 mg, yield 19%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 11.00 (s, 1H), 8.18-8.03 (m, 1H), 7.89-7.76 (m, 1H), 7.72-7.55 (m, 3H), 7.30-7.17 (m, 1H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 4.77-4.29 (m, 3H), 4.13 (d, J = 13.0 Hz , 2H), 3.84-3.49 (m, 6H), 3.29 (d, J = 9.9 Hz, 2H), 3.15 (s, 1H), 2.98-2.69 (m, 2H), 2.59 (d, J = 16.9 Hz, 1H), 2.49-2.38 (m, 1H), 2.34-2.06 (m, 2H), 2.04-1.96 (m, 1H), 1.86-1.67 (m, 2H). LCMS (ESI) C 30 H 32 FN 6 O 5 + [M+H] + : calculated value 575.24, found value 575.3.

实施例229：3-(6-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09896)的制备Example 229: Preparation of 3-(6-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09896)

参照合成方案4的方法制备目标化合物(GT-09896)(白色固体，17mg，收率35％)。1H NMR(400MHz，DMSO)δ11.24(s，1H)，11.02(s，1H)，8.10(dd，J＝8.9，5.2Hz，1H)，7.78-7.70(m，2H)，7.69-7.65(m，1H)，7.62(dd，J＝9.1，2.2Hz，1H)，7.31-7.20(m，1H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.68-4.33(m，3H)，4.13(d，J＝13.0Hz，2H)，3.69-3.53(m，6H)，3.30(d，J＝10.0Hz，2H)，3.19-3.08(m，1H)，2.97-2.80(m，2H)，2.61(d，J＝17.6Hz，1H)，2.45-2.36(m，1H)，2.26-2.00(m，3H)，1.77(d，J＝8.0Hz，2H).LCMS(ESI)C30H32FN6O5 +[M+H]+：计算值575.24，实测值575.3.The target compound (GT-09896) (white solid, 17 mg, yield 35%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 11.02 (s, 1H), 8.10 (dd, J = 8.9, 5.2 Hz, 1H), 7.78-7.70 (m, 2H), 7.69-7.65 (m, 1H), 7.62 (dd, J = 9.1, 2.2 Hz, 1H), 7.31-7.20 (m, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.68-4.33 (m , 3H), 4.13 (d, J = 13.0 Hz, 2H), 3.69-3.53 (m, 6H), 3.30 (d, J = 10.0 Hz, 2H), 3.19-3.08 (m, 1H), 2.97-2.80 (m, 2H), 2.61 (d, J = 17.6 Hz, 1H), 2.45-2.36 (m, 1H), 2.26-2.00 (m, 3H), 1.77 (d, J = 8.0 Hz, 2H). LCMS (ESI) C 30 H 32 FN 6 O 5 + [M+H] + : calculated value 575.24, found value 575.3.

实施例230：3-(7-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09897)的制备Example 230: Preparation of 3-(7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09897)

参照合成方案4的方法制备目标化合物(GT-09897)(白色固体，8mg，收率17％)。1H NMR(400MHz，DMSO)δ11.37-10.86(m，2H)，8.14-8.05(m，1H)，7.74-7.65(m，2H)，7.64-7.59(m，1H)，7.29-7.21(m，1H)，5.12-4.94(m，1H)，4.72(s，1H)，4.59-4.36(m，2H)，4.20-4.02(m，2H)，3.58(t，J＝13.1Hz，4H)，3.49-3.44(m，2H)，3.29(d，J＝10.3Hz，3H)，3.09-2.75(m，3H)，2.67-2.58(m，1H)，2.48-2.35(m，1H)，2.30-2.14(m，1H)，2.05-1.98(m，1H)，1.92-1.65(m，2H).LCMS(ESI)C30H32FN6O5 +[M+H]+：计算值575.24，实测值575.3.The target compound (GT-09897) (white solid, 8 mg, yield 17%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.37-10.86 (m, 2H), 8.14-8.05 (m, 1H), 7.74-7.65 (m, 2H), 7.64-7.59 (m, 1H), 7.29-7.21 (m, 1H), 5.12-4.94 (m, 1H), 4.72 (s, 1H), 4.59-4.36 (m, 2H), 4.20-4.02 (m, 2H), 3. 58 (t, J = 13.1 Hz, 4H), 3.49-3.44 (m, 2H), 3.29 (d, J = 10.3 Hz, 3H), 3.09-2.75 (m, 3H), 2.67-2.58 (m, 1H), 2.48-2.35 (m, 1H), 2.30-2.14 (m, 1H), 2.05-1.98 (m, 1H), 1.92-1.65 (m, 2H). LCMS (ESI) C 30 H 32 FN 6 O 5 + [M+H] + : calculated value 575.24, found value 575.3.

实施例231：2-(2，6-二氧代哌啶-3-基)-4-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)异吲哚啉-1，3-二酮(GT-09898)的制备Example 231: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione (GT-09898)

参照合成方案4的方法制备目标化合物(GT-09898)(白色固体，14mg，收率28％)。1H NMR(400MHz，DMSO)δ11.52-11.06(m，2H)，8.14-8.03(m，1H)，8.03-7.89(m，2H)，7.85-7.71(m，1H)，7.62(dd，J＝9.1，2.1Hz，1H)，7.26(t，J＝9.0，1.9Hz，1H)，5.24-5.03(m，1H)，4.72(d，J＝11.4Hz，1H)，4.12(d，J＝13.0Hz，2H)，3.70-3.51(m，4H)，3.50-3.38(m，2H)，3.31-3.19(m，2H)，3.13-2.94(m，1H)，2.94-2.79(m，2H)，2.69-2.52(m，2H)，2.34-2.20(m，1H)，2.13-1.91(m，2H)，1.82-1.42(m，2H).LCMS(ESI)C30H30FN6O6 +[M+H]+：计算值589.22，实测值589.3.The target compound (GT-09898) (white solid, 14 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.52-11.06 (m, 2H), 8.14-8.03 (m, 1H), 8.03-7.89 (m, 2H), 7.85-7.71 (m, 1H), 7.62 (dd, J = 9.1, 2.1 Hz, 1H), 7.26 (t, J = 9.0, 1.9 Hz, 1H), 5.24-5.03 (m, 1H), 4.72 (d, J = 11.4 Hz, 1H), 4.12 (d, J = 13.0 Hz, 2H), 3.70-3.51 (m, 4H), 3.50-3.38 (m, 2H), 3.31-3.19 (m, 2H), 3.13-2.94 (m, 1H), 2.94-2.79 (m, 2H), 2.69-2.52 (m, 2H), 2.34-2.20 (m, 1H), 2.13-1.91 (m, 2H), 1.82-1.42 (m, 2H). LCMS (ESI) C 30 H 30 FN 6 O 6 + [M+H] + : calculated value 589.22, found value 589.3.

实施例232：2-(2，6-二氧代哌啶-3-基)-5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)异吲哚啉-1，3-二酮(GT-09899)的制备Example 232: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione (GT-09899)

参照合成方案4的方法制备目标化合物(GT-09899)(白色固体，15mg，收率30％)。1H NMR(400MHz，DMSO)δ11.15(s，2H)，8.08(dd，J＝20.2，10.1Hz，1H)，8.02(d，J＝7.7Hz，1H)，7.95(s，1H)，7.93-7.87(m，1H)，7.62(dd，J＝9.1，2.1Hz，1H)，7.32-7.15(m，1H)，5.19(dd，J＝12.8，5.4Hz，1H)，4.64(s，1H)，4.14(d，J＝12.6Hz，2H)，3.83-3.49(m，6H)，3.33-3.29(m，2H)，3.16(s，1H)，2.97-2.78(m，2H)，2.65-2.52(m，2H)，2.35-2.17(m，1H)，2.15-1.96(m，2H)，1.78(s，2H).LCMS(ESI)C30H30FN6O6 +[M+H]+：计算值589.22，实测值589.3.The target compound (GT-09899) (white solid, 15 mg, yield 30%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 2H), 8.08 (dd, J = 20.2, 10.1 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.95 (s, 1H), 7.93-7.87 (m, 1H), 7.62 (dd, J = 9.1, 2.1 Hz, 1H), 7.32-7.15 (m, 1H), 5.19 (dd, J = 12.8, 5.4 Hz, 3H), 4.64 (s, 1H), 4.14 (d, J=12.6 Hz, 2H), 3.83-3.49 (m, 6H), 3.33-3.29 (m, 2H), 3.16 (s, 1H), 2.97-2.78 (m, 2H), 2.65-2.52 (m, 2H), 2.35-2.17 (m, 1H), 2.15-1.96 (m, 2H), 1.78 (s, 2H). LCMS (ESI) C 30 H 30 FN 6 O 6 + [M+H] + : calculated value 589.22, found value 589.3.

实施例233：3-(5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09900)的制备Example 233: Preparation of 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09900)

参照合成方案4的方法制备目标化合物(GT-09900)(白色固体，27mg，收率58％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.07(dd，J＝8.9，5.3Hz，1H)，7.83(d，J＝7.8Hz，1H)，7.67(s，1H)，7.61-7.49(m，2H)，7.28-7.12(m，1H)，5.15(dd，J＝12.9，4.8Hz，1H)，4.81-4.33(m，3H)，3.72(s，6H)，3.29(s，6H)，2.96-2.89(m，1H)，2.62(d，J＝16.9Hz，1H)，2.46-2.37(m，1H)，2.33-2.08(m，1H)，2.07-1.91(m，2H).LCMS(ESI)C30H30F3N6O5 +[M+H]+：计算值611.22，实测值611.3.The target compound (GT-09900) (white solid, 27 mg, yield 58%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.07 (dd, J = 8.9, 5.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.61-7.49 (m, 2H), 7.28-7.12 (m, 1H), 5.15 (dd, J = 12.9, 4.8 Hz, 1H), 4.81-4.33 (m, 3H), 3.72 (s, 6H), 3.29 (s, 6H), 2.96-2.89 (m, 1H), 2.62 (d, J=16.9 Hz, 1H), 2.46-2.37 (m, 1H), 2.33-2.08 (m, 1H), 2.07-1.91 (m, 2H). LCMS (ESI) C 30 H 30 F 3 N 6 O 5 + [M+H] + : calculated value 611.22, found value 611.3.

实施例234：3-(5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09901)的制备Example 234: Preparation of 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09901)

参照合成方案4的方法制备目标化合物(GT-09901)(白色固体，27mg，收率57％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，8.07(dd，J＝8.9，5.3Hz，1H)，7.58(dd，J＝9.1，2.2Hz，1H)，7.50(s，1H)，7.36(s，1H)，7.22(t，J＝9.1，2.2Hz，1H)，5.11(dd，J＝13.3，4.1Hz，1H)，4.80-4.37(m，3H)，3.90-3.72(m，5H)，3.41-3.09(m，6H)，2.98-2.83(m，2H)，2.61(d，J＝17.3Hz，1H)，2.43-2.31(m，1H)，2.30-2.06(m，1H)，2.05-1.88(m，2H).LCMS(ESI)C30H29F4N6O5 +[M+H]+：计算值629.21，实测值629.3.The target compound (GT-09901) (white solid, 27 mg, yield 57%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.07 (dd, J = 8.9, 5.3 Hz, 1H), 7.58 (dd, J = 9.1, 2.2 Hz, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.22 (t, J = 9.1, 2.2 Hz, 1H), 5.11 (dd, J = 13.3, 4.1 Hz, 1 3H), 4.80-4.37 (m, 3H), 3.90-3.72 (m, 5H), 3.41-3.09 (m, 6H), 2.98-2.83 (m, 2H), 2.61 (d, J=17.3 Hz, 1H), 2.43-2.31 (m, 1H), 2.30-2.06 (m, 1H), 2.05-1.88 (m, 2H). LCMS (ESI) C 30 H 29 F 4 N 6 O 5 + [M+H] + : calculated value 629.21, found value 629.3.

实施例235：3-(5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09902)的制备Example 235: Preparation of 3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09902)

参照合成方案4的方法制备目标化合物(GT-09902)(白色固体，21mg，收率45％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，8.10-7.95(m，1H)，7.75-7.61(m，2H)，7.57(dd，J＝9.1，2.1Hz，1H)，7.21(t，J＝9.1，2.1Hz，1H)，5.15(dd，J＝13.2，5.0Hz，1H)，4.86-4.59(m，1H)，4.44(dd，J＝49.1，17.6Hz，2H)，3.78-3.63(m，4H)，3.43-3.29(m，4H)，3.16(s，3H)，3.09-2.99(m，1H)，2.96-2.86(m，1H)，2.61(d，J＝17.0Hz，1H)，2.46-2.36(m，1H)，2.22-1.98(m，2H)，1.88(s，1H).LCMS(ESI)C30H29F4N6O5 +[M+H]+：计算值629.21，实测值629.3.The target compound (GT-09902) (white solid, 21 mg, yield 45%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.10-7.95 (m, 1H), 7.75-7.61 (m, 2H), 7.57 (dd, J=9.1, 2.1 Hz, 1H), 7.21 (t, J=9.1, 2.1 Hz, 1H), 5.15 (dd, J=13.2, 5.0 Hz, 1H), 4.86-4.59 (m, 1H), 4.44 (dd, J=49 .1, 17.6 Hz, 2H), 3.78-3.63 (m, 4H), 3.43-3.29 (m, 4H), 3.16 (s, 3H), 3.09-2.99 (m, 1H), 2.96-2.86 (m, 1H), 2.61 (d, J=17.0 Hz, 1H), 2.46-2.36 (m, 1H), 2.22-1.98 (m, 2H), 1.88 (s, 1H). LCMS (ESI) C 30 H 29 F 4 N 6 O 5 + [M+H] + : calculated value 629.21, found value 629.3.

实施例236：3-(4-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09903)的制备Example 236: Preparation of 3-(4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09903)

参照合成方案4的方法制备目标化合物(GT-09903)(白色固体，23mg，收率50％)。1H NMR(400MHz，DMSO)δ11.01(d，J＝4.1Hz，1H)，8.06(dd，J＝8.9，5.3Hz，1H)，7.93-7.81(m，1H)，7.65(d，J＝5.0Hz，2H)，7.58(dd，J＝9.1，2.2Hz，1H)，7.22(t，J＝9.1，2.2Hz，1H)，5.18-5.11(m，1H)，4.83-4.48(m，1H)，4.49-4.21(m，2H)，3.95-3.66(m，6H)，3.36-3.04(m，6H)，2.97-2.85(m，1H)，2.59(d，J＝17.3Hz，1H)，2.47-2.37(m，1H)，2.25-1.86(m，3H).LCMS(ESI)C30H30F3N6O5 +[M+H]+：计算值611.22，实测值611.3.The target compound (GT-09903) (white solid, 23 mg, yield 50%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.01 (d, J = 4.1 Hz, 1H), 8.06 (dd, J = 8.9, 5.3 Hz, 1H), 7.93-7.81 (m, 1H), 7.65 (d, J = 5.0 Hz, 2H), 7.58 (dd, J = 9.1, 2.2 Hz, 1H), 7.22 (t, J = 9.1, 2.2 Hz, 1H), 5.18-5. 11 (m, 1H), 4.83-4.48 (m, 1H), 4.49-4.21 (m, 2H), 3.95-3.66 (m, 6H), 3.36-3.04 (m, 6H), 2.97-2.85 (m, 1H), 2.59 (d, J=17.3 Hz, 1H), 2.47-2.37 (m, 1H), 2.25-1.86 (m, 3H). LCMS (ESI) C 30 H 30 F 3 N 6 O 5 + [M+H] + : calculated value 611.22, found value 611.3.

实施例237：3-(6-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09904)的制备Example 237: Preparation of 3-(6-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09904)

参照合成方案4的方法制备目标化合物(GT-09904)(白色固体，30mg，收率53％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.06(dd，J＝8.9，5.3Hz，1H)，7.78-7.62(m，3H)，7.58(dd，J＝9.1，2.2Hz，1H)，7.22(t，J＝9.1，2.2Hz，1H)，5.15(dd，J＝13.3，5.1Hz，1H)，4.48(dd，J＝52.3，17.8Hz，3H)，3.71-3.62(m，6H)，3.35-3.05(m，6H)，2.99-2.88(m，1H)，2.62(d，J＝16.6Hz，1H)，2.47-2.34(m，1H)，2.28-1.88(m，3H).LCMS(ESI)C30H30F3N6O5 +[M+H]+：计算值611.22，实测值611.3.The target compound (GT-09904) (white solid, 30 mg, yield 53%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.06 (dd, J = 8.9, 5.3 Hz, 1H), 7.78-7.62 (m, 3H), 7.58 (dd, J = 9.1, 2.2 Hz, 1H), 7.22 (t, J = 9.1, 2.2 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1 3H), 4.48 (dd, J=52.3, 17.8 Hz, 3H), 3.71-3.62 (m, 6H), 3.35-3.05 (m, 6H), 2.99-2.88 (m, 1H), 2.62 (d, J=16.6 Hz, 1H), 2.47-2.34 (m, 1H), 2.28-1.88 (m, 3H). LCMS (ESI) C 30 H 30 F 3 N 6 O 5 + [M+H] + : calculated value 611.22, found value 611.3.

实施例238：3-(7-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09905)的制备Example 238: Preparation of 3-(7-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09905)

参照合成方案4的方法制备目标化合物(GT-09905)(白色固体，31mg，收率55％)。1H NMR(400MHz，DMSO)δ11.00(s，1H)，8.12-7.99(m，1H)，7.78-7.66(m，2H)，7.62-7.51(m，1H)，7.44-7.31(m，1H)，7.22(t，1H)，5.13-4.95(m，1H)，4.92-4.69(m，1H)，4.56-4.34(m，2H)，3.74-3.61(m，6H)，3.35-3.15(m，6H)，2.96-2.85(m，1H)，2.62(d，J＝17.1Hz，1H)，2.49-2.13(m，2H)，2.02-1.63(m，2H).LCMS(ESI)C30H30F3N6O5 +[M+H]+：计算值611.22，实测值611.3.The target compound (GT-09905) (white solid, 31 mg, yield 55%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.12-7.99 (m, 1H), 7.78-7.66 (m, 2H), 7.62-7.51 (m, 1H), 7.44-7.31 (m, 1H), 7.22 (t, 1H), 5.13-4.95 (m, 1H), 4.92-4.69 (m , 1H), 4.56-4.34 (m, 2H), 3.74-3.61 (m, 6H), 3.35-3.15 (m, 6H), 2.96-2.85 (m, 1H), 2.62 (d, J=17.1 Hz, 1H), 2.49-2.13 (m, 2H), 2.02-1.63 (m, 2H). LCMS (ESI) C 30 H 30 F 3 N 6 O 5 + [M+H] + : calculated value 611.22, found value 611.3.

实施例239：4-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09906)的制备Example 239: Preparation of 4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09906)

参照合成方案4的方法制备目标化合物(GT-09906)(白色固体，28mg，收率49％)。1H NMR(400MHz，DMSO)δ11.23-11.10(m，1H)，8.13-7.91(m，3H)，7.85-7.67(m，1H)，7.64-7.49(m，1H)，7.22(t，J＝9.0Hz，1H)，5.21-5.08(m，1H)，4.90-4.62(m，1H)，3.84-3.64(m，6H)，3.39-3.13(m，6H)，3.12-2.97(m，1H)，2.95-2.83(m，1H)，2.61(d，J＝17.8Hz，1H)，2.26-1.76(m，3H).LCMS(ESI)C30H28F3N6O6 +[M+H]+：计算值625.20，实测值625.3.The target compound (GT-09906) (white solid, 28 mg, yield 49%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.23-11.10 (m, 1H), 8.13-7.91 (m, 3H), 7.85-7.67 (m, 1H), 7.64-7.49 (m, 1H), 7.22 (t, J=9.0Hz, 1H), 5.21-5.08 (m, 1H), 4.90 -4.62(m, 1H), 3.84-3.64(m, 6H), 3.39-3.13(m, 6H), 3.12-2.97(m, 1H), 2 .95-2.83(m, 1H), 2.61(d, J=17.8Hz, 1H), 2.26-1.76(m, 3H).LCMS(ESI)C 30 H 28 F 3 N 6 O 6 + [M+H] + : calculated value 625.20, found value 625.3.

实施例240：5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09907)的制备Example 240: Preparation of 5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09907)

参照合成方案4的方法制备目标化合物(GT-09907)(白色固体，25mg，收率44％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.11-7.97(m，2H)，7.89(s，2H)，7.57(dd，J＝9.1，2.2Hz，1H)，7.21(t，J＝9.1，2.2Hz，1H)，5.20(dd，J＝12.7，5.4Hz，1H)，4.68(d，J＝53.2Hz，1H)，3.78-3.67(m，2H)，3.49-2.97(m，10H)，2.95-2.84(m，1H)，2.67-2.54(m，2H)，2.25-1.85(m，3H).LCMS(ESI)C30H28F3N6O6 +[M+H]+：计算值625.20，实测值625.3.The target compound (GT-09907) (white solid, 25 mg, yield 44%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.15 (s, 1H), 8.11-7.97 (m, 2H), 7.89 (s, 2H), 7.57 (dd, J=9.1, 2.2Hz, 1H), 7.21 (t, J=9.1, 2.2Hz, 1H), 5.20 (dd, J=12.7, 5 .4Hz, 1H), 4.68(d, J=53.2Hz, 1H), 3.78-3.67(m, 2H), 3.49-2.97(m, 10H), 2.95-2.84(m, 1H), 2.67-2.54(m, 2H), 2.25-1.85(m, 3H).LCMS(ESI)C 30 H 28 F 3 N 6 O 6 + [M+H] + : calculated value 625.20, found value 625.3.

实施例241：3-(5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09908)的制备Example 241: Preparation of 3-(5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09908)

参照合成方案4的方法制备目标化合物(GT-09908)(白色固体，16mg，收率29％)。1H NMR(400MHz，DMSO)δ11.56(s，1H)，11.02(s，1H)，8.24(s，1H)，7.84(d，J＝7.8Hz，1H)，7.75-7.64(m，2H)，7.57(d，J＝7.8Hz，1H)，7.34(t，J＝9.1，2.0Hz，1H)，5.17-5.11(m，1H)，4.89-4.25(m，5H)，4.06-3.45(m，10H)，2.96-2.89(m，1H)，2.59(d，1H)，2.44-2.40(m，1H)，2.25-2.01(m，4H).LCMS(ESI)C31H31F3N5O5 +[M+H]+：计算值610.23，实测值610.3.The target compound (GT-09908) (white solid, 16 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.56 (s, 1H), 11.02 (s, 1H), 8.24 (s, 1H), 7.84 (d, J=7.8Hz, 1H), 7.75-7.64 (m, 2H), 7.57 (d, J=7.8Hz, 1H), 7.34 (t, J=9.1, 2.0H z, 1H), 5.17-5.11 (m, 1H), 4.89-4.25 (m, 5H), 4.06-3.45 (m, 10H), 2.96-2. 89(m,1H),2.59(d,1H),2.44-2.40(m,1H),2.25-2.01(m,4H).LCMS(ESI)C 31 H 31 F 3 N 5 O 5 + [M+H] + : calculated value 610.23, found value 610.3.

实施例242：3-(5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09909)的制备Example 242: Preparation of 3-(5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09909)

参照合成方案4的方法制备目标化合物(GT-09909)(白色固体，24mg，收率42％)。1H NMR(400MHz，DMSO)δ11.58(s，1H)，11.03(s，1H)，8.23(s，1H)，7.73(d，1H)，7.52-7.30(m，3H)，5.12(dd，J＝13.1，4.9Hz，1H)，4.73(d，J＝83.3Hz，1H)，4.59-4.36(m，3H)，4.12-3.44(m，9H)，3.12-2.85(m，2H)，2.59(d，1H)，2.42-2.37(m，1H)，2.31-1.97(m，5H).LCMS(ESI)C31H30F4N5O5 +[M+H]+：计算值628.22，实测值628.3.The target compound (GT-09909) (white solid, 24 mg, yield 42%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.58 (s, 1H), 11.03 (s, 1H), 8.23 (s, 1H), 7.73 (d, 1H), 7.52-7.30 (m, 3H), 5.12 (dd, J=13.1, 4.9Hz, 1H), 4.73 (d, J =83.3Hz, 1H), 4.59-4.36(m, 3H), 4.12-3.44(m, 9H), 3.12-2.85(m, 2H), 2.59(d, 1H), 2.42-2.37(m, 1H), 2.31-1.97(m, 5H).LCMS(ESI)C 31 H 30 F 4 N 5 O 5 + [M+H] + : Calculated value 628.22, measured value 628.3.

实施例243：3-(5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09910)的制备Example 243: Preparation of 3-(5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09910)

参照合成方案4的方法制备目标化合物(GT-09910)(白色固体，13mg，收率23％)。1HNMR(400MHz，DMSO)δ11.55(s，1H)，11.03(s，1H)，8.19(s，1H)，7.77-7.64(m，3H)，7.34(t，J＝8.9Hz，1H)，5.15(dd，1H)，4.94-4.66(m，1H)，4.61-4.30(m，3H)，3.97-3.45(m，8H)，3.10-2.83(m，2H)，2.66-2.56(m，2H)，2.43-2.38(m，1H)，2.27-1.87(m，5H).LCMS(ESI)C31H30F4N5O5 +[M+H]+：计算值628.22，实测值628.3.The target compound (GT-09910) (white solid, 13 mg, yield 23%) was prepared by referring to the method of Synthesis Scheme 4. 1HNMR (400MHz, DMSO) δ 11.55 (s, 1H), 11.03 (s, 1H), 8.19 (s, 1H), 7.77-7.64 (m, 3H), 7.34 (t, J=8.9Hz, 1H), 5.15 (dd, 1H), 4.94-4.66 ( m, 1H), 4.61-4.30 (m, 3H), 3.97-3.45 (m, 8H), 3.10-2.83 (m, 2H), 2.66-2.56 (m, 2H), 2.43-2.38 (m, 1H), 2.27-1.87 (m, 5H). LCMS (ESI) C 31 H 30 F 4 N 5 O 5 + [M+H] + : Calculated value 628.22, measured value 628.3.

实施例244：3-(4-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09911)的制备Example 244: Preparation of 3-(4-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09911)

参照合成方案4的方法制备目标化合物(GT-09911)(白色固体，17mg，收率31％)。1H NMR(400MHz，DMSO)δ11.68(s，1H)，11.00(d，J＝3.8Hz，1H)，8.24(s，1H)，7.88(d，J＝8.5Hz，1H)，7.78-7.51(m，3H)，7.34(t，J＝9.1，2.1Hz，1H)，5.23-5.08(m，1H)，4.95-4.21(m，4H)，4.02-3.45(m，8H)，3.24-3.05(m，1H)，2.90(t，J＝20.2，8.7Hz，1H)，2.59(d，J＝17.7Hz，2H)，2.48-2.35(m，2H)，2.26-1.94(m，4H).LCMS(ESI)C31H31F3N5O5 +[M+H]+：计算值610.23，实测值610.3.The target compound (GT-09911) (white solid, 17 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 11.00 (d, J = 3.8 Hz, 1H), 8.24 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.78-7.51 (m, 3H), 7.34 (t, J = 9.1, 2.1 Hz, 1H), 5.23-5.08 (m, 1H), 4.95-4.21 (m, 4H), 4.02-3.45 (m, 8H), 3.24-3.05 (m, 1H), 2.90 (t, J = 20.2, 8.7 Hz, 1H), 2.59 (d, J = 17.7 Hz, 2H), 2.48-2.35 (m, 2H), 2.26-1.94 (m, 4H). LCMS (ESI) C 31 H 31 F 3 N 5 O 5 + [M+H] + : calculated value 610.23, found value 610.3.

实施例245：3-(6-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09912)的制备Example 245: Preparation of 3-(6-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09912)

参照合成方案4的方法制备目标化合物(GT-09912)(白色固体，20mg，收率36％)。1H NMR(400MHz，DMSO)δ11.49-10.96(m，2H)，8.21(s，1H)，7.77-7.69(m，4H)，7.35(t，J＝9.1Hz，1H)，5.16(dd，1H)，4.58-4.38(m，3H)，4.08-3.46(m，8H)，3.21-3.02(m，1H)，2.95-2.88(m，1H)，2.68-2.58(m，2H)，2.46-2.37(m，2H)，2.26-1.96(m，5H).LCMS(ESI)C31H31F3N5O5 +[M+H]+：计算值610.23，实测值610.3.The target compound (GT-09912) (white solid, 20 mg, yield 36%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.49-10.96 (m, 2H), 8.21 (s, 1H), 7.77-7.69 (m, 4H), 7.35 (t, J=9.1Hz, 1H), 5.16 (dd, 1H), 4.58-4.38 (m, 3H ), 4.08-3.46(m, 8H), 3.21-3.02(m, 1H), 2.95-2.88(m, 1H), 2.68-2.58(m, 2H), 2.46-2.37(m, 2H), 2.26-1.96(m, 5H).LCMS(ESI)C 31 H 31 F 3 N 5 O 5 + [M+H] + : Calculated value 610.23, measured value 610.3.

实施例246：3-(7-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09913)的制备Example 246: Preparation of 3-(7-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09913)

参照合成方案4的方法制备目标化合物(GT-09913)(白色固体，25mg，收率45％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.21(s，1H)，7.80-7.64(m，4H)，7.41-7.31(m，2H)，5.11-4.65(m，3H)，4.57-4.39(m，3H)，3.75-3.52(m，4H)，2.99-2.82(m，2H)，2.63(d，J＝14.2Hz，2H)，2.47-2.32(m，3H)，2.29-1.86(m，6H).LCMS(ESI)C31H31F3N5O5 +[M+H]+：计算值610.23，实测值610.3.The target compound (GT-09913) (white solid, 25 mg, yield 45%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.21 (s, 1H), 7.80-7.64 (m, 4H), 7.41-7.31 (m, 2H), 5.11-4.65 (m, 3H), 4.57-4.39 (m, 3H), 3.75-3.52 (m, 4H), 2.99-2.82 (m, 2H), 2.63 (d, J=14.2 Hz, 2H), 2.47-2.32 (m, 3H), 2.29-1.86 (m, 6H). LCMS (ESI) C 31 H 31 F 3 N 5 O 5 + [M+H] + : calculated value 610.23, found value 610.3.

实施例247：4-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09914)的制备Example 247: Preparation of 4-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09914)

参照合成方案4的方法制备目标化合物(GT-09914)(白色固体，20mg，收率36％)。1HNMR(400MHz，DMSO)δ11.88-10.99(m，2H)，8.21(s，1H)，8.05-7.92(m，2H)，7.85-7.66(m，2H)，7.33(t，J＝8.2Hz，1H)，5.21-5.12(m，1H)，4.81(d，J＝64.4Hz，1H)，4.38(s，1H)，3.84-3.46(m，6H)，3.32-2.82(m，4H)，2.61(d，J＝18.6Hz，2H)，2.44-1.85(m，6H).LCMS(ESI)C31H29F3N5O6 +[M+H]+：计算值624.21，实测值624.3.The target compound (GT-09914) (white solid, 20 mg, yield 36%) was prepared by referring to the method of Synthesis Scheme 4. 1HNMR (400MHz, DMSO) δ 11.88-10.99 (m, 2H), 8.21 (s, 1H), 8.05-7.92 (m, 2H), 7.85-7.66 (m, 2H), 7.33 (t, J=8.2Hz, 1H), 5.21-5.12 (m, 1 H), 4.81 (d, J = 64.4Hz, 1H), 4.38 (s, 1H), 3.84-3.46 (m, 6H), 3.32-2.82 (m, 4H), 2.61 (d, J = 18.6Hz, 2H), 2.44-1.85 (m, 6H). LCMS (ESI) C 31 H 29 F 3 N 5 O 6 + [M+H] + : Calculated value 624.21, measured value 624.3.

实施例248：5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09915)的制备Example 248: Preparation of 5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09915)

参照合成方案4的方法制备目标化合物(GT-09915)(白色固体，24mg，收率42％)。1H NMR(400MHz，DMSO)δ12.05-11.01(m，2H)，8.37-8.11(m，1H)，8.04(d，J＝7.6Hz，1H)，7.99-7.84(m，2H)，7.72(d，J＝9.0，1.9Hz，1H)，7.34(t，1H)，5.20(dd，J＝12.8，5.4Hz，1H)，4.74(d，J＝79.7Hz，1H)，4.57-4.08(m，1H)，4.02-3.42(m，8H)，3.17-2.98(m，1H)，2.93-2.88(m，1H)，2.67-2.53(m，3H)，2.46-2.30(m，1H)，2.27-2.03(m，4H).LCMS(ESI)C31H29F3N5O6 +[M+H]+：计算值624.21，实测值624.3.The target compound (GT-09915) (white solid, 24 mg, yield 42%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 12.05-11.01 (m, 2H), 8.37-8.11 (m, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.99-7.84 (m, 2H), 7.72 (d, J = 9.0, 1.9 Hz, 1H), 7.34 (t, 1H), 5.20 (dd, J = 12.8, 5.4 Hz, 1H ), 4.74 (d, J = 79.7 Hz, 1H), 4.57-4.08 (m, 1H), 4.02-3.42 (m, 8H), 3.17-2.98 (m, 1H), 2.93-2.88 (m, 1H), 2.67-2.53 (m, 3H), 2.46-2.30 (m, 1H), 2.27-2.03 (m, 4H). LCMS (ESI) C 31 H 29 F 3 N 5 O 6 + [M+H] + : calculated value 624.21, found value 624.3.

实施例249：3-(5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09944)的制备Example 249: Preparation of 3-(5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09944)

参照合成方案4的方法制备目标化合物(GT-09944)(白色固体，22mg，收率37％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，7.90-7.59(m，5H)，7.52(d，J＝8.2Hz，1H)，7.49-7.14(m，7H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.71-4.45(m，2H)，4.38(d，J＝17.6Hz，1H)，3.79-3.57(m，4H)，3.47-3.30(m，4H)，3.11(s，3H)，2.98-2.86(m，2H)，2.81(s，1H)，2.61(d，J＝17.2Hz，1H)，2.44-2.37(m，1H)，2.21(s，1H)，2.08-1.94(m，2H)，1.71(s，2H).LCMS(ESI)C36H40N5O4 +[M+H]+：计算值606.31，实测值606.4.The target compound (GT-09944) (white solid, 22 mg, yield 37%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.90-7.59 (m, 5H), 7.52 (d, J = 8.2 Hz, 1H), 7.49-7.14 (m, 7H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.71-4.45 (m, 2H), 4.38 (d, J = 17.6 Hz, 1H), 3.79-3 .57 (m, 4H), 3.47-3.30 (m, 4H), 3.11 (s, 3H), 2.98-2.86 (m, 2H), 2.81 (s, 1H), 2.61 (d, J=17.2 Hz, 1H), 2.44-2.37 (m, 1H), 2.21 (s, 1H), 2.08-1.94 (m, 2H), 1.71 (s, 2H). LCMS (ESI) C 36 H 40 N 5 O 4 + [M+H] + : calculated value 606.31, found value 606.4.

实施例250：3-(5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09945)的制备Example 250: Preparation of 3-(5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09945)

参照合成方案4的方法制备目标化合物(GT-09945)(白色固体，16mg，收率26％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.09-7.48(m，4H)，7.46(s，1H)，7.45-7.23(m，8H)，5.10(dd，J＝13.3，5.1Hz，1H)，4.62-4.37(m，3H)，3.69-3.55(m，3H)，3.44-3.21(m，4H)，3.11(t，3H)，2.97-2.87(m，2H)，2.84-2.76(m，1H)，2.58(d，1H)，2.47-2.29(m，2H)，2.20(s，1H)，2.05-1.95(m，2H)，1.77-1.65(m，2H).LCMS(ESI)C36H39FN5O4 +[M+H]+：计算值624.30，实测值624.4.The target compound (GT-09945) (white solid, 16 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.09-7.48 (m, 4H), 7.46 (s, 1H), 7.45-7.23 (m, 8H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.62-4.37 (m, 3H), 3.69-3.55 (m, 3H), 3.44-3.2 1 (m, 4H), 3.11 (t, 3H), 2.97-2.87 (m, 2H), 2.84-2.76 (m, 1H), 2.58 (d, 1H), 2.47-2.29 (m, 2H), 2.20 (s, 1H), 2.05-1.95 (m, 2H), 1.77-1.65 (m, 2H). LCMS (ESI) C36H39FN5O4 + [M+H] + : calculated value 624.30 , found value 624.4.

实施例251：3-(5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09946)的制备Example 251: Preparation of 3-(5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09946)

参照合成方案4的方法制备目标化合物(GT-09946)(白色固体，20mg，收率33％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，8.01-7.57(m，5H)，7.56-7.20(m，7H)，5.18-5.09(m，1H)，4.65(d，J＝12.3Hz，1H)，4.54-4.32(m，2H)，3.65-3.53(m，4H)，3.42-3.22(m，3H)，3.13(s，3H)，2.98-2.78(m，3H)，2.61(d，J＝16.6Hz，1H)，2.49-2.30(m，2H)，2.28-2.18(m，1H)，2.09-1.94(m，2H)，1.78-1.55(m，2H).LCMS(ESI)C36H39FN5O4 +[M+H]+：计算值624.30，实测值624.3.The target compound (GT-09946) (white solid, 20 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.01-7.57 (m, 5H), 7.56-7.20 (m, 7H), 5.18-5.09 (m, 1H), 4.65 (d, J = 12.3 Hz, 1H), 4.54-4.32 (m, 2H), 3.65-3.53 (m, 4H), 3.42 -3.22 (m, 3H), 3.13 (s, 3H), 2.98-2.78 (m, 3H), 2.61 (d, J=16.6 Hz, 1H), 2.49-2.30 (m, 2H), 2.28-2.18 (m, 1H), 2.09-1.94 (m, 2H), 1.78-1.55 (m, 2H). LCMS (ESI) C 36 H 39 FN 5 O 4 + [M+H] + : calculated value 624.30, found value 624.3.

实施例252：3-(4-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09947)的制备Example 252: Preparation of 3-(4-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09947)

参照合成方案4的方法制备目标化合物(GT-09947)(白色固体，17mg，收率29％)。1H NMR(400MHz，DMSO)δ10.99(s，1H)，7.83(dd，J＝6.3，2.3Hz，1H)，7.80-7.44(m，6H)，7.44-7.21(m，7H)，5.13(dd，J＝12.8，4.6Hz，1H)，4.66-4.52(m，1H)，4.47-4.30(m，2H)，3.74-3.57(m，4H)，3.47-3.32(m，3H)，3.29-2.97(m，4H)，2.95-2.85(m，2H)，2.54(d，1H)，2.47-2.39(m，1H)，2.36-1.91(m，4H)，1.77-1.65(m，2H).LCMS(ESI)C36H40N5O4 +[M+H]+：计算值606.31，实测值606.4.The target compound (GT-09947) (white solid, 17 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.83 (dd, J = 6.3, 2.3 Hz, 1H), 7.80-7.44 (m, 6H), 7.44-7.21 (m, 7H), 5.13 (dd, J = 12.8, 4.6 Hz, 1H), 4.66-4.52 (m, 1H), 4.47-4.30 (m , 2H), 3.74-3.57 (m, 4H), 3.47-3.32 (m, 3H), 3.29-2.97 (m, 4H), 2.95-2.85 (m, 2H), 2.54 (d, 1H), 2.47-2.39 (m, 1H), 2.36-1.91 (m, 4H), 1.77-1.65 (m, 2H). LCMS (ESI) C 36 H 40 N 5 O 4 + [M+H] + : calculated value 606.31, found value 606.4.

实施例253：3-(6-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09948)的制备Example 253: Preparation of 3-(6-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09948)

参照合成方案4的方法制备目标化合物(GT-09948)(白色固体，19mg，收率35％)。1H NMR(400MHz，DMSO)δ11.01(s，1H)，8.16-7.45(m，7H)，7.43-7.18(m，6H)，5.14(dd，J＝13.3，5.1Hz，1H)，4.67-4.36(m，3H)，3.76-3.55(m，4H)，3.46-3.24(m，4H)，3.23-2.98(m，3H)，2.97-2.71(m，3H)，2.61(d，J＝16.9Hz，1H)，2.46-2.35(m，1H)，2.24-1.92(m，3H)，1.73(s，2H).LCMS(ESI)C36H40N5O4 +[M+H]+：计算值606.31，实测值606.3.The target compound (GT-09948) (white solid, 19 mg, yield 35%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.01 (s, 1H), 8.16-7.45 (m, 7H), 7.43-7.18 (m, 6H), 5.14 (dd, J=13.3, 5.1Hz, 1H), 4.67-4.36 (m, 3H), 3.76-3.55 (m, 4H), 3 .46-3.24(m, 4H), 3.23-2.98(m, 3H), 2.97-2.71(m, 3H), 2.61(d, J=16.9 Hz, 1H), 2.46-2.35(m, 1H), 2.24-1.92(m, 3H), 1.73(s, 2H).LCMS(ESI)C 36 H 40 N 5 O 4 + [M+H] + : calculated value 606.31, found value 606.3.

实施例254：3-(7-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09949)的制备Example 254: Preparation of 3-(7-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09949)

参照合成方案4的方法制备目标化合物(GT-09949)(白色固体，17mg，收率29％)。1H NMR(400MHz，DMSO)δ10.99(d，J＝7.2Hz，1H)，8.17-7.44(m，6H)，7.44-7.25(m，7H)，5.14-4.91(m，1H)，4.68(t，J＝11.6Hz，1H)，4.56-4.33(m，2H)，3.59(s，4H)，3.46-3.12(m，5H)，3.11-2.70(m，5H)，2.61(d，J＝16.6Hz，1H)，2.41-2.31(m，1H)，2.23-2.14(m，1H)，2.02-1.91(m，1H)，1.90-1.44(m，3H).LCMS(ESI)C36H40N5O4 +[M+H]+：计算值606.31，实测值606.4.The target compound (GT-09949) (white solid, 17 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4 . NMR (400MHz, DMSO) δ10.99 (d, J=7.2Hz, 1H), 8.17-7.44 (m, 6H), 7.44-7.25 (m , 7H), 5.14-4.91 (m, 1H), 4.68 (t, J=11.6Hz, 1H), 4.56-4.33 (m, 2H), 3.59 (s, 4 H), 3.46-3.12 (m, 5H), 3.11-2.70 (m, 5H), 2.61 (d, J=16.6Hz, 1H), 2.41-2.31 (m, 1H), 2.23-2.14 (m, 1H), 2.02-1.91 (m, 1H), 1.90-1.44 (m, 3H).LCMS (ESI) C 36 H 40 N 5 O 4 + [M+H] + : calculated value 606.31, found value 606.4.

实施例255：4-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09950)的制备Example 255: Preparation of 4-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09950)

参照合成方案4的方法制备目标化合物(GT-09950)(白色固体，22mg，收率36％)。1H NMR(400MHz，DMSO)δ11.18-11.07(m，1H)，8.01-7.92(m，2H)，7.82-7.48(m，4H)，7.46-7.10(m，7H)，5.17-5.09(m，1H)，4.68(d，J＝9.8Hz，1H)，3.62-3.48(m，6H)，3.36-2.76(m，8H)，2.60(d，J＝17.7Hz，1H)，2.49-2.41(m，1H)，2.23(d，J＝10.2Hz，1H)，2.10-1.90(m，2H)，1.77-1.42(m，2H).LCMS(ESI)C36H38N5O5 +[M+H]+：计算值620.29，实测值620.3.The target compound (GT-09950) (white solid, 22 mg, yield 36%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.18-11.07(m, 1H), 8.01-7.92(m, 2H), 7.82-7.48(m , 4H), 7.46-7.10 (m, 7H), 5.17-5.09 (m, 1H), 4.68 (d, J=9.8Hz, 1H), 3.62-3 .48(m, 6H), 3.36-2.76(m, 8H), 2.60(d, J=17.7Hz, 1H), 2.49-2.41(m, 1H), 2.23(d, J=10.2Hz, 1H), 2.10-1.90(m, 2H), 1.77-1.42(m, 2H).LCMS(ESI)C 36 H 38 N 5 O 5 + [M+H] + : calculated value 620.29, found value 620.3.

实施例256：5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09951)的制备Example 256: Preparation of 5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09951)

参照合成方案4的方法制备目标化合物(GT-09951)(白色固体，16mg，收率27％)。1H NMR(400MHz，DMSO)δ11.15(s，1H)，8.01(d，J＝7.6Hz，1H)，7.93-7.85(m，2H)，7.70-7.19(m，9H)，5.19(dd，J＝12.7，5.4Hz，1H)，4.86-4.11(m，2H)，3.68-3.54(m，4H)，3.45-3.38(m，2H)，3.36-2.97(m，4H)，2.96-2.75(m，3H)，2.66-2.55(m，2H)，2.26-2.14(m，1H)，2.10-1.94(m，2H)，1.74(s，2H).LCMS(ESI)C36H38N5O5 +[M+H]+：计算值620.29，实测值620.4.The target compound (GT-09951) (white solid, 16 mg, yield 27%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.15 (s, 1H), 8.01 (d, J=7.6Hz, 1H), 7.93-7.85 (m, 2H) , 7.70-7.19 (m, 9H), 5.19 (dd, J=12.7, 5.4Hz, 1H), 4.86-4.11 (m, 2H), 3.68-3 .54(m, 4H), 3.45-3.38(m, 2H), 3.36-2.97(m, 4H), 2.96-2.75(m, 3H), 2.66- 2.55(m, 2H), 2.26-2.14(m, 1H), 2.10-1.94(m, 2H), 1.74(s, 2H).LCMS(ESI)C 36 H 38 N 5 O 5 + [M+H] + : calculated value 620.29, found value 620.4.

实施例257：3-(5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09952)的制备Example 257: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09952)

参照合成方案4的方法制备目标化合物(GT-09952)(白色固体，18mg，收率33％)。1H NMR(400MHz，DMSO)δ11.02(s，1H)，7.84(d，J＝7.8Hz，1H)，7.72-7.51(m，3H)，7.38(t，J＝7.8Hz，1H)，7.26(d，J＝14.0，7.0Hz，1H)，5.76(s，1H)，5.15(dd，1H)，4.85-4.39(m，3H)，4.00-3.60(m，5H)，3.43-3.26(m，3H)，3.13-2.84(m，2H)，2.66-2.56(m，2H)，2.44-2.36(m，1H)，2.11-1.96(m，2H).LCMS(ESI)C30H29Cl2F2N4O4 +[M+H]+：计算值617.15，实测值617.2.The target compound (GT-09952) (white solid, 18 mg, yield 33%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400MHz, DMSO) δ11.02 (s, 1H), 7.84 (d, J=7.8Hz, 1H), 7.72-7.51 (m, 3H) , 7.38 (t, J=7.8Hz, 1H), 7.26 (d, J=14.0, 7.0Hz, 1H), 5.76 (s, 1H), 5.15 (dd, 1H), 4.85-4.39(m, 3H), 4.00-3.60(m, 5H), 3.43-3.26(m, 3H), 3.13-2.84(m , 2H), 2.66-2.56(m, 2H), 2.44-2.36(m, 1H), 2.11-1.96(m, 2H).LCMS(ESI)C 30H 29 Cl 2 F 2 N 4 O 4 + [M+H] + : calculated value 617.15, found value 617.2.

实施例258：3-(5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09953)的制备Example 258: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09953)

参照合成方案4的方法制备目标化合物(GT-09953)(白色固体，19mg，收率34％)。1HNMR(400MHz，DMSO)δ11.03(s，1H)，7.61(d，J＝8.0，1.2Hz，1H)，7.51(s，1H)，7.42-7.31(m，2H)，7.30-7.22(m，1H)，5.76(s，1H)，5.12(dd，J＝13.3，4.3Hz，1H)，4.93-4.59(m，1H)，4.55(d，J＝18.2Hz，1H)，4.42(d，J＝18.0，3.1Hz，1H)，4.16-3.60(m，6H)，3.39-3.22(m，2H)，3.07(s，1H)，2.96-2.87(m，1H)，2.61(d，J＝16.7Hz，2H)，2.46-2.37(m，1H)，2.15-1.94(m，2H).LCMS(ESI)C30H28Cl2F3N4O4 +[M+H]+：计算值635.14，实测值635.2.The target compound (GT-09953) (white solid, 19 mg, yield 34%) was prepared by referring to the method of Synthesis Scheme 4. 1HNMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.61 (d, J = 8.0, 1.2 Hz, 1H), 7.51 (s, 1H), 7.42-7.31 (m, 2H), 7.30-7.22 (m, 1H), 5.76 (s, 1H), 5.12 (dd, J = 13.3, 4.3 Hz, 1H), 4.93-4.59 (m, 1H), 4.55 (d, J = 13.3, 4.3 Hz, 1H). =18.2 Hz, 1H), 4.42 (d, J=18.0, 3.1 Hz, 1H), 4.16-3.60 (m, 6H), 3.39-3.22 (m, 2H), 3.07 (s, 1H), 2.96-2.87 (m, 1H), 2.61 (d, J=16.7 Hz, 2H), 2.46-2.37 (m, 1H), 2.15-1.94 (m, 2H). LCMS (ESI) C 30 H 28 Cl 2 F 3 N 4 O 4 + [M+H] + : calculated value 635.14, found value 635.2.

实施例259：3-(5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09954)的制备Example 259: Preparation of 3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09954)

参照合成方案4的方法制备目标化合物(GT-09954)(白色固体，12mg，收率22％)。1H NMR(400MHz，DMSO)δ11.03(s，1H)，7.74-7.63(m，2H)，7.63-7.58(m，1H)，7.38(t，J＝7.9Hz，1H)，7.31-7.19(m，1H)，5.76(s，1H)，5.15(dd，J＝13.2，5.0Hz，1H)，4.91-4.61(m，1H)，4.45(dd，J＝48.4，17.4Hz，2H)，4.21-3.55(m，7H)，3.22-3.01(m，1H)，2.97-2.87(m，1H)，2.61(d，J＝16.7Hz，2H)，2.48-2.20(m，2H)，2.11-1.89(m，2H).LCMS(ESI)C30H28Cl2F3N4O4 +[M+H]+：计算值635.14，实测值635.2.The target compound (GT-09954) (white solid, 12 mg, yield 22%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.74-7.63 (m, 2H), 7.63-7.58 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.31-7.19 (m, 1H), 5.76 (s, 1H), 5.15 (dd, J = 13.2, 5.0 Hz, 1H), 4.91-4.61 ( m, 1H), 4.45 (dd, J=48.4, 17.4 Hz, 2H), 4.21-3.55 (m, 7H), 3.22-3.01 (m, 1H), 2.97-2.87 (m, 1H), 2.61 (d, J=16.7 Hz, 2H), 2.48-2.20 (m, 2H), 2.11-1.89 (m, 2H). LCMS (ESI) C 30 H 28 Cl 2 F 3 N 4 O 4 + [M+H] + : calculated value 635.14, found value 635.2.

实施例260：3-(4-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09955)的制备Example 260: Preparation of 3-(4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09955)

参照合成方案4的方法制备目标化合物(GT-09955)(白色固体，17mg，收率31％)。1H NMR(400MHz，DMSO)δ11.00(d，J＝3.2Hz，1H)，7.94-7.82(m，1H)，7.74-7.51(m，3H)，7.39(t，J＝7.8Hz，1H)，7.27(d，J＝7.6，1.4Hz，1H)，5.76(s，1H)，5.24-5.06(m，1H)，4.52-4.34(m，2H)，3.86(s，3H)，3.70-3.60(m，2H)，3.45-3.09(m，4H)，2.99-2.84(m，2H)，2.59(d，J＝17.5Hz，2H)，2.41(d，J＝13.5Hz，1H)，2.13-1.93(m，2H).LCMS(ESI)C30H29Cl2F2N4O4 +[M+H]+：计算值617.15，实测值617.3.The target compound (GT-09955) (white solid, 17 mg, yield 31%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.00 (d, J = 3.2 Hz, 1H), 7.94-7.82 (m, 1H), 7.74-7.51 (m, 3H), 7.39 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.6, 1.4 Hz, 1H), 5.76 (s, 1H), 5.24-5.06 (m, 1H), 4 .52-4.34 (m, 2H), 3.86 (s, 3H), 3.70-3.60 (m, 2H), 3.45-3.09 (m, 4H), 2.99-2.84 (m, 2H), 2.59 (d, J=17.5 Hz, 2H), 2.41 (d, J=13.5 Hz, 1H), 2.13-1.93 (m, 2H). LCMS (ESI) C 30 H 29 Cl 2 F 2 N 4 O 4 + [M+H] + : calculated value 617.15, found value 617.3.

实施例261：3-(6-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09956)的制备Example 261: Preparation of 3-(6-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09956)

参照合成方案4的方法制备目标化合物(GT-09956)(白色固体，14mg，收率26％)。1HNMR(400MHz，DMSO)δ11.02(s，1H)，7.80-7.65(m，3H)，7.61(d，J＝8.0，1.4Hz，1H)，7.39(t，J＝7.8Hz，1H)，7.27(d，J＝7.7，1.5Hz，1H)，5.76(s，1H)，5.15(dd，J＝13.2，5.1Hz，1H)，4.48(dd，J＝52.1，17.8Hz，2H)，4.02-3.69(m，4H)，3.65-3.55(m，3H)，3.32-3.03(m，2H)，3.01-2.87(m，2H)，2.69-2.56(m，2H)，2.46-2.38(m，1H)，2.14-1.99(m，2H).LCMS(ESI)C30H29Cl2F2N4O4 +[M+H]+：计算值617.15，实测值617.2.The target compound (GT-09956) (white solid, 14 mg, yield 26%) was prepared by referring to the method of Synthesis Scheme 4. 1HNMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.80-7.65 (m, 3H), 7.61 (d, J = 8.0, 1.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.7, 1.5 Hz, 1H), 5.76 (s, 1H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 4.48 (dd, J=52.1, 17.8 Hz, 2H), 4.02-3.69 (m, 4H), 3.65-3.55 (m, 3H), 3.32-3.03 (m, 2H), 3.01-2.87 (m, 2H), 2.69-2.56 (m, 2H), 2.46-2.38 (m, 1H), 2.14-1.99 (m, 2H). LCMS (ESI) C 30 H 29 Cl 2 F 2 N 4 O 4 + [M+H] + : calculated value 617.15, found value 617.2.

实施例262：3-(7-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(GT-09957)的制备Example 262: Preparation of 3-(7-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (GT-09957)

参照合成方案4的方法制备目标化合物(GT-09957)(白色固体，15mg，收率28％)。1H NMR(400MHz，DMSO)δ11.01(d，J＝5.0Hz，1H)，7.80-7.66(m，2H)，7.60(d，J＝8.0Hz，1H)，7.46-7.32(m，2H)，7.26(d，J＝7.5Hz，1H)，5.74(s，1H)，5.09-4.97(m，1H)，4.95-4.70(m，1H)，4.56-4.37(m，2H)，4.26-3.70(m，3H)，3.52(s，2H)，3.40-3.19(m，4H)，2.93-2.84(m，1H)，2.62(d，J＝16.8Hz，2H)，2.46-2.36(m，1H)，2.12-1.90(m，2H).LCMS(ESI)C30H29Cl2F2N4O4 +[M+H]+：计算值617.15，实测值617.2.The target compound (GT-09957) (white solid, 15 mg, yield 28%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.01 (d, J = 5.0 Hz, 1H), 7.80-7.66 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.46-7.32 (m, 2H), 7.26 (d, J = 7.5 Hz, 1H), 5.74 (s, 1H), 5.09-4.97 (m, 1H), 4.95-4.70 (m, 1H), 4.56-4.37 (m, 2H), 4.26-3.70 (m, 3H), 3.52 (s, 2H), 3.40-3.19 (m, 4H), 2.93-2.84 (m, 1H), 2.62 (d, J=16.8 Hz, 2H), 2.46-2.36 (m, 1H), 2.12-1.90 (m, 2H). LCMS (ESI) C 30 H 29 Cl 2 F 2 N 4 O 4 + [M+H] + : calculated value 617.15, found value 617.2.

实施例263：4-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09958)的制备Example 263: Preparation of 4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridine-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09958)

参照合成方案4的方法制备目标化合物(GT-09958)(白色固体，20mg，收率36％)。1H NMR(400MHz，DMSO)δ11.14(d，J＝5.5Hz，1H)，8.09-7.89(m，2H)，7.83-7.70(m，1H)，7.60(d，J＝8.0Hz，1H)，7.37(t，J＝7.8Hz，1H)，7.26(d，J＝6.9Hz，1H)，5.74(s，1H)，5.27-5.05(m，1H)，4.95-4.62(m，1H)，4.33-3.52(m，6H)，3.36-2.99(m，4H)，2.96-2.84(m，1H)，2.61(d，J＝18.9Hz，2H)，2.14-1.88(m，2H).LCMS(ESI)C30H27Cl2F2N4O5 +[M+H]+：计算值631.13，实测值631.2.The target compound (GT-09958) (white solid, 20 mg, yield 36%) was prepared by referring to the method of Synthesis Scheme 4. 1 H NMR (400 MHz, DMSO) δ 11.14 (d, J = 5.5 Hz, 1H), 8.09-7.89 (m, 2H), 7.83-7.70 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 6.9 Hz, 1H), 5.74 ( s, 1H), 5.27-5.05 (m, 1H), 4.95-4.62 (m, 1H), 4.33-3.52 (m, 6H), 3.36-2.99 (m, 4H), 2.96-2.84 (m, 1H), 2.61 (d, J=18.9 Hz, 2H), 2.14-1.88 (m, 2H). LCMS (ESI) C 30 H 27 Cl 2 F 2 N 4 O 5 + [M+H] + : calculated value 631.13, found value 631.2.

实施例264：5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮(GT-09959)的制备Example 264: Preparation of 5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GT-09959)

参照合成方案4的方法制备目标化合物(GT-09959)(白色固体，16mg，收率29％)。1H NMR(400MHz，DMSO)δ11.16(s，1H)，8.04(d，J＝7.8Hz，1H)，7.91(s，2H)，7.60(d，J＝8.0Hz，1H)，7.38(t，J＝7.8Hz，1H)，7.31-7.21(m，1H)，5.75(s，1H)，5.20(dd，J＝12.7，5.4Hz，1H)，4.72(d，J＝76.6Hz，1H)，4.05-3.59(m，5H)，3.41-3.19(m，3H)，3.14-2.84(m，2H)，2.66-2.53(m，3H)，2.13-1.96(m，2H).LCMS(ESI)C30H27Cl2F2N4O5 +[M+H]+：计算值631.13，实测值631.2.
生物活性检测实验The target compound (GT-09959) (white solid, 16 mg, yield 29%) was prepared by referring to the method of Synthesis Scheme 4 . NMR (400MHz, DMSO) δ11.16 (s, 1H), 8.04 (d, J=7.8Hz, 1H), 7.91 (s, 2H), 7.60 ( d, J=8.0Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.31-7.21 (m, 1H), 5.75 (s, 1H), 5.20 ( dd, J=12.7, 5.4Hz, 1H), 4.72 (d, J=76.6Hz, 1H), 4.05-3.59 (m, 5H), 3.41-3.19 (m, 3H), 3.14-2.84 (m, 2H), 2.66-2.53 (m, 3H), 2.13-1.96 (m, 2H).LCMS (ESI) C 30 H 27 Cl 2 F 2 N 4 O 5 + [M+H] + : calculated value 631.13, found value 631.2.
Biological activity detection experiment

实验试剂和材料：
Experimental reagents and materials:

实验方法：Experimental methods:

细胞培养Cell culture

在表2的细胞培养基中、在含5％CO2的37℃培养箱中分别培养本公开使用的肿瘤细胞。所有细胞在实验前均经STR鉴定为正确细胞并经支原体检测试剂盒检测为支原体阴性。
表2本公开使用的肿瘤细胞和细胞培养基
The tumor cells used in the present disclosure were cultured in the cell culture medium in Table 2 in a 37°C incubator containing 5% CO 2. All cells were identified as correct cells by STR before the experiment and tested as mycoplasma negative by a mycoplasma detection kit.
Table 2 Tumor cells and cell culture medium used in the present disclosure

I.本公开化合物对肿瘤细胞的半数抑制浓度(IC50)测定I. Determination of the half-maximal inhibitory concentration (IC 50 ) of the disclosed compounds on tumor cells

本公开化合物(包括表1化合物和实施例化合物)的IC50采用美仑生物公司的CellTiter-Meiluncell发光法细胞活力检测试剂盒进行测定。具体步骤如下：肿瘤细胞以表3的接种密度分别接种在96孔细胞培养板中。第二天，将本公开待测化合物进行系列稀释。稀释操作可遵循以下两种方式之一进行：
(1)第一种稀释方法：将本公开待测化合物(包括表1化合物和实施例化合物)从最高浓度
2000μM开始进行5倍梯度稀释，从高到低共设置9个浓度(2000、400、80、16、3.2、0.64、0.128、0.0256、0.00512μM)。随后，吸取本公开待测化合物0.5μL，分别加入到含有待测细胞的96孔板中，每个孔含细胞培养基100μL，每孔中待测化合物的最终测试浓度分别达到10、2、0.4、0.08、0.016、0.0032、0.00064、0.000128、0.0000256μM。或
(2)作为替代方案，可以采用第二种稀释方法：将本公开待测化合物(包括表1化合物和实
施例化合物)从最高浓度100μM开始进行50倍梯度稀释，共设置2个浓度(100μM、2μM)。在96孔板中，向每孔加入稀释好的本公开待测化合物与相应的检测试剂，确保每孔中待测化合物的最终测试浓度分别达到500nM、10nM，旨在评估这两个浓度水平下待测化合物对肿瘤细胞增殖的抑制活性。以下将以稀释好的2μM的待测化合物为例说明试验流程(100μM浓度的操作步骤和第一种稀释方法获得的梯度浓度的操作步骤与之相似)。The IC50 of the disclosed compounds (including the compounds in Table 1 and the compounds in the examples) was determined using the CellTiter-Meiluncell luminescent cell viability detection kit of Meilun Biotech. The specific steps are as follows: Tumor cells were inoculated in 96-well cell culture plates at the inoculation density in Table 3. On the second day, the disclosed compounds to be tested were serially diluted. The dilution operation can be performed in one of the following two ways:
(1) The first dilution method: dilute the compounds to be tested in the present disclosure (including the compounds in Table 1 and the compounds in the examples) from the highest concentration to
5-fold gradient dilution was performed starting from 2000 μM, and 9 concentrations were set from high to low (2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512 μM). Subsequently, 0.5 μL of the test compound of the present disclosure was taken and added to the 96-well plate containing the cells to be tested, each well containing 100 μL of cell culture medium, and the final test concentration of the test compound in each well reached 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256 μM, respectively. Or
(2) As an alternative, a second dilution method can be used: the test compounds of the present disclosure (including the compounds in Table 1 and the example compounds) are diluted 50 times from the highest concentration of 100 μM, and a total of 2 concentrations (100 μM, 2 μM) are set. In a 96-well plate, the diluted test compounds of the present disclosure and the corresponding detection reagents are added to each well to ensure that the final test concentrations of the test compounds in each well reach 500 nM and 10 nM, respectively, in order to evaluate the inhibitory activity of the test compounds on tumor cell proliferation at these two concentration levels. The following will take the diluted 2 μM test compound as an example to illustrate the test process (the operating steps of the 100 μM concentration and the gradient concentration obtained by the first dilution method are similar).

取上述稀释好的本公开化合物(包括表1化合物和实施例化合物)0.5μL加入接种好的100μL细胞中，最终检测化合物浓度为10nM。本公开化合物处理细胞一段时间后，按照试剂盒的操作说明书将细胞活性检测试剂加入培养基中进行细胞活性测定。阴性对照为DMSO，对照药为对应的商品化的免疫调节药物(包括来那度胺(1enalidomide)和泊马度胺(pomalidomide))，均采用与本公开化合物相同的处理方式处理细胞。本公开化合物对细胞的生长抑制通过Prism Graphpad软件进行绘制并从中统计本公开化合物IC50。
表3：肿瘤细胞的接种程序和处理时间
Take 0.5 μL of the diluted compounds of the present invention (including compounds in Table 1 and example compounds) and add them to 100 μL of inoculated cells, and the final concentration of the detected compound is 10 nM. After the cells are treated with the compounds of the present invention for a period of time, the cell activity detection reagent is added to the culture medium according to the operating instructions of the kit for cell activity determination. The negative control is DMSO, and the control drug is the corresponding commercial immunomodulatory drug (including lenalidomide and pomalidomide), and the cells are treated in the same manner as the compounds of the present invention. The inhibition of cell growth by the compounds of the present invention is plotted by Prism Graphpad software and the IC 50 of the compounds of the present invention is calculated therefrom.
Table 3: Tumor cell inoculation procedure and treatment time

抑制肿瘤细胞增殖的结果列于表I-1至表I-8中。
表I-1：本公开化合物对人髓性单核细胞白血病细胞MV-4-11增殖的抑制活性(抑制率％)


在表I-1中，符号1a1、1a2、1a3、1a4、1a5、1a6、1a7、1a8、1a9、1a10和1a11的含义如下：
0＜1a1＜5％，5％≤1a2＜10％，10％≤1a3＜20％，20％≤1a4＜30％，30％≤1a5≤40％，40％＜1a6＜50％，50％≤1a7＜60％，60％≤1a8＜70％，70％≤1a9＜80％，80％≤1a10＜100％，100％≤1a11≤105％。
表I-2：本公开化合物对人多发性骨髓瘤细胞MM.1S增殖的抑制活性(抑制率％)

在表I-2中，符号1b1、1b2、1b3、1b4、1b5、1b6、1b7、1b8、1b9和1b10的含义如下：0＜
1b1＜5％，5％≤1b2＜10％，10％≤1b3＜20％，20％≤1b4＜32％，32％≤1b5＜42％，42％≤1b6＜50％，50％≤1b7＜60％，60％≤1b8＜70％，70％≤1b9＜80％，80％≤1b10≤100％。
表I-3：本公开化合物对人急性T淋巴细胞白血病细胞Molt4增殖的抑制活性(抑制率％)


在表I-3中，符号1c1、1c2、1c3、1c4、1c5、1c6、1c7、1c8、1c9、1c10、1c11和1c12的含
义如下：-7％＜1c1＜0，0＜1c2＜5％，5％≤1c3＜10％，10％≤1c4＜20％，20％≤1c5＜30％，30％≤1c6＜40％，40％≤1c7＜50％，50％≤1c8＜60％，60％≤1c9＜70％，70％≤1c10＜80％，80％≤1c11≤100％，100％＜1c12≤105％。
表I-4：本公开化合物对人结肠癌细胞SW620增殖的抑制活性(抑制率％)

在表I-4中，符号1d1、1d2、1d3、1d4、1d5、1d6、1d7、1d8、1d9和1d10的含义如下：0＜
1d1＜5％，5％≤1d2＜10％，10％≤1d3＜20％，20％≤1d4＜30％，30％≤1d5＜40％，40％≤1d6＜50％，50％≤1d7＜60％，60％≤1d8＜70％，70％≤1d9＜80％，80％≤1d10≤100％。
表I-5：本公开化合物对人乳腺癌细胞MCF-7增殖的抑制活性(抑制率％)

在表I-5中，符号1e1、1e2、1e3、1e4、1e5、1e6、1e7、1e8、1e9、1e10和1e11的含义如下：
-10％＜1e1＜0，0＜1e2＜5％，5％≤1e3＜10％，10％≤1e4＜20％，20％≤1e5＜30％，30％≤1e6＜40％，40％≤1e7＜50％，50％≤1e8＜60％，60％≤1e9＜70％，70％≤1e10＜80％，80％≤1e11≤100％。
表I-6：本公开化合物对人弥漫性大B淋巴瘤细胞TMD8增殖的抑制活性(抑制率％)


在表I-6中，符号1f1、1f2、1f3、1f4、1f5、1f6、1f7、1f8、1f9和1f10的含义如下：0＜1f1＜
5％，5％≤1f2＜10％，10％≤1f3＜20％，20％≤1f4＜30％，30％≤1f5＜40％，40％≤1f6＜50％，50％≤1f7＜60％，60％≤1f8＜70％，70％≤1f9＜80％，80％≤1f10≤100％。
表I-7：本公开化合物对人套细胞淋巴瘤细胞JEKO-1增殖的抑制活性(抑制率％)

在表I-7中，符号1g1、1g2、1g3、1g4、1g5、1g6、1g7、1g8、1g9和1g10的含义如下：0＜
1g1＜5％，5％≤1g2＜10％，10％≤1g3＜20％，20％≤1g4＜30％，30％≤1g5＜40％，40％≤1g6＜50％，50％≤1g7＜60％，60％≤1g8＜70％，70％≤1g9＜80％，80％≤1g10≤100％。
表I-8：本公开化合物对肿瘤细胞增殖的抑制活性(IC50，nM)

注：在表I-8中，符号A+++、A++、A+、A、B、C、D、E、F和G指示如下：0nM＜A++++
≤2nM；2nM＜A+++≤5nM；5nM＜A++≤10nM；10nM＜A+≤20nM；20nM＜A≤50nM；50nM＜B≤100nM；100nM＜C≤200nM；200nM＜D≤500nM；500nM＜E≤1000nM；1000nM＜F≤5000nM；5000nM＜G≤10000nM；10000nM＜H。符号“-”表示未检测。The results of inhibiting tumor cell proliferation are listed in Table I-1 to Table I-8.
Table I-1: Inhibitory activity of the disclosed compounds on proliferation of human myelomonocytic leukemia cells MV-4-11 (inhibition rate %)


In Table I-1, the symbols 1a1, 1a2, 1a3, 1a4, 1a5, 1a6, 1a7, 1a8, 1a9, 1a10 and 1a11 have the following meanings:
0<1a1<5%, 5%≤1a2<10%, 10%≤1a3<20%, 20%≤1a4<30%, 30%≤1a5≤40%, 40%<1a6<50 %, 50%≤1a7<60%, 60%≤1a8<70%, 70%≤1a9<80%, 80%≤1a10<100%, 100%≤1a11≤105%.
Table I-2: Inhibitory activity of the disclosed compounds on proliferation of human multiple myeloma cells MM.1S (inhibition rate %)

In Table I-2, the symbols 1b1, 1b2, 1b3, 1b4, 1b5, 1b6, 1b7, 1b8, 1b9 and 1b10 have the following meanings: 0<
1b1＜5%, 5%≤1b2＜10%, 10%≤1b3＜20%, 20%≤1b4＜32%, 32%≤1b5＜42%, 42%≤ 1b6<50%, 50%≤1b7<60%, 60%≤1b8<70%, 70%≤1b9<80%, 80%≤1b10≤100%.
Table I-3: Inhibitory activity of the disclosed compounds on the proliferation of human acute T lymphoblastic leukemia cells Molt4 (inhibition rate %)


In Table I-3, the symbols 1c1, 1c2, 1c3, 1c4, 1c5, 1c6, 1c7, 1c8, 1c9, 1c10, 1c11 and 1c12 have the following meanings: -7%＜1c1＜0, 0＜1c2＜5%, 5%≤1c3＜10%, 10%≤1c4＜20%, 20%≤1c5＜30%, 30%≤1c6＜40%, 40%≤1c7＜50%, 50%≤1c8＜60%, 60%≤1c9＜70%, 70%≤1c10＜80%, 80%≤1c11≤100%, 100%＜1c12≤105%.
Table I-4: Inhibitory activity of the disclosed compounds on proliferation of human colon cancer cell SW620 (inhibition rate %)

In Table I-4, the symbols 1d1, 1d2, 1d3, 1d4, 1d5, 1d6, 1d7, 1d8, 1d9 and 1d10 have the following meanings: 0<
1d1<5%, 5%≤1d2<10%, 10%≤1d3<20%, 20%≤1d4<30%, 30%≤1d5<40%, 40%≤ 1d6<50%, 50%≤1d7<60%, 60%≤1d8<70%, 70%≤1d9<80%, 80%≤1d10≤100%.
Table I-5: Inhibitory activity of the disclosed compounds on proliferation of human breast cancer cells MCF-7 (inhibition rate %)

In Table I-5, the symbols 1e1, 1e2, 1e3, 1e4, 1e5, 1e6, 1e7, 1e8, 1e9, 1e10, and 1e11 have the following meanings:
-10%<1e1<0, 0<1e2<5%, 5%≤1e3<10%, 10%≤1e4<20%, 20%≤1e5<30%, 30%≤1e6<40 %, 40%≤1e7<50%, 50%≤1e8<60%, 60%≤1e9<70%, 70%≤1e10<80%, 80%≤1e11≤100%.
Table I-6: Inhibitory activity of the disclosed compounds on proliferation of human diffuse large B-cell lymphoma TMD8 cells (inhibition rate %)


In Table I-6, the symbols 1f1, 1f2, 1f3, 1f4, 1f5, 1f6, 1f7, 1f8, 1f9, and 1f10 have the following meanings: 0＜1f1＜
5%, 5%≤1f2＜10%, 10%≤1f3＜20%, 20%≤1f4＜30%, 30%≤1f5＜40%, 40%≤1f6＜50%, 50%≤1f7＜60%, 60%≤1f8＜70%, 70%≤1f9＜80%, 80%≤1f10≤100%.
Table I-7: Inhibitory activity of the disclosed compounds on proliferation of human mantle cell lymphoma JEKO-1 cells (inhibition rate %)

In Table I-7, the symbols 1g1, 1g2, 1g3, 1g4, 1g5, 1g6, 1g7, 1g8, 1g9 and 1g10 have the following meanings: 0<
1g1＜5%, 5%≤1g2＜10%, 10%≤1g3＜20%, 20%≤1g4＜30%, 30%≤1g5＜40%, 40%≤ 1g6<50%, 50%≤1g7<60%, 60%≤1g8<70%, 70%≤1g9<80%, 80%≤1g10≤100%.
Table I-8: Inhibitory activity of the disclosed compounds on tumor cell proliferation (IC 50 , nM)

Note: In Table I-8, the symbols A+++, A++, A+, A, B, C, D, E, F, and G indicate the following: 0nM < A++++
≤2nM; 2nM＜A+++≤5nM; 5nM＜A++≤10nM; 10nM＜A+≤20nM; 20nM＜A≤50nM; 50nM＜B≤100nM; 100nM＜C≤200nM; 200nM＜D≤500nM; 500nM＜E≤1000nM; 1000nM＜F≤5000nM; 5000nM＜G≤10000nM; 10000nM＜H. The symbol “-” means not detected.

结果显示，本公开的化合物(包括表1化合物和实施例化合物)可以抑制肿瘤细胞的增殖(如表I-1至表I-8所示)，抑制效果显著优于对应的阳性对照药。The results show that the compounds disclosed in the present invention (including the compounds in Table 1 and the example compounds) can inhibit the proliferation of tumor cells (as shown in Tables I-1 to I-8), and the inhibitory effect is significantly better than that of the corresponding positive control drugs.

II.蛋白质免疫印迹(Western Blot)测定II. Protein immunoblotting (Western Blot) assay

使用常规蛋白质免疫印迹法(Western Blot)检测本公开化合物对细胞中靶蛋白表达的影响。Conventional protein immunoblotting (Western Blot) was used to detect the effects of the disclosed compounds on the expression of target proteins in cells.

(1)细胞种板和收集蛋白：将细胞密度为1×106个/mL的hPBMC细胞按照PBMC细胞复苏操作说明书(妙顺(上海)生物科技有限公司)进行复苏后，用浓度为500nM和50nM的本公开化合物(包括表1化合物和各实施例化合物)处理。同时设置阴性对照组(DMSO)，和阳性对照组：对应的商品化的免疫调节药物(来那度胺(1enalidomide))，其均采用与本公开化合物相同的处理方式处理细胞。化合物处理细胞24小时后，收集细胞，加入含有蛋白酶抑制剂的RIPA蛋白裂解液裂解细胞，并置于冰上30分钟，离心。收集上清液，所得上清液为提取的细胞总蛋白。用常规BCA法(Bicinchoninc acid procedure)测定上清液的蛋白浓度。(1) Cell seeding and protein collection: hPBMC cells with a cell density of 1×10 6 cells/mL were revived according to the PBMC cell resuscitation operating instructions (Miaoshun (Shanghai) Biotechnology Co., Ltd.), and then treated with the compounds of the present disclosure (including the compounds in Table 1 and the compounds of each example) at concentrations of 500nM and 50nM. A negative control group (DMSO) and a positive control group were also set up: the corresponding commercial immunomodulatory drugs (lenalidomide), which were treated with the same treatment method as the compounds of the present disclosure. After the cells were treated with the compounds for 24 hours, the cells were collected, RIPA protein lysis buffer containing protease inhibitors was added to lyse the cells, and the cells were placed on ice for 30 minutes and centrifuged. The supernatant was collected, and the resulting supernatant was the extracted total cell protein. The protein concentration of the supernatant was determined by the conventional BCA method (Bicinchoninc acid procedure).

(2)向收集的上清液加入5X含SDS上样缓冲液，95℃下5分钟变性处理后，进行聚丙烯酰胺凝胶SDS-PAGE电泳，然后转移到硝酸纤维素膜(0.45μM NC膜)上，经封闭液常温封闭1小时，随后按照Cell Signaling Technology公司的抗体说明书进行抗体孵育和显影等操作方法。(2) Add 5X SDS-containing loading buffer to the collected supernatant, denature at 95°C for 5 minutes, perform polyacrylamide gel SDS-PAGE electrophoresis, and then transfer to a nitrocellulose membrane (0.45μM NC membrane). Block with blocking solution at room temperature for 1 hour, and then perform antibody incubation and development according to the antibody instructions of Cell Signaling Technology.

半数降解浓度(蛋白降解至50％所对应的药物浓度，即，DC50)读取方法：对比药物处理后对应Western blotting条带的灰度值与空白DMSO处理后对应Western blotting条带的灰度值，读取灰度值是空白DMSO处理后对应Western blotting条带的灰度值一半时的药物浓度范围。Method for reading half degradation concentration (drug concentration corresponding to 50% protein degradation, i.e. DC 50 ): Compare the gray value of the Western blotting band after drug treatment with the gray value of the Western blotting band after blank DMSO treatment, and read the drug concentration range when the gray value is half of the gray value of the Western blotting band after blank DMSO treatment.

DC50值的计算可以采用ImageJ软件读取药物处理后对应Western blotting条带的灰度值。拟合药物浓度与灰度值之间的关系曲线推算对应灰度值一半时的药物浓度。The DC 50 value can be calculated by using ImageJ software to read the gray value of the corresponding Western blotting band after drug treatment, and the relationship curve between drug concentration and gray value can be fitted to estimate the drug concentration corresponding to half of the gray value.

蛋白剩余含量％是指用蛋白降解剂化合物处理细胞后细胞中剩余目的蛋白的含量。The % remaining protein content refers to the amount of target protein remaining in the cells after the cells are treated with a protein degrading compound.

蛋白剩余含量％的计算方法：利用Image J软件读取药物(蛋白降解剂)处理后对应Western blotting条带的灰度值。将药物处理后对应Western blotting条带的灰度值除以内参蛋白对应Western blotting条带的灰度值，所得的商值进行归一化处理，得到经过蛋白降解剂处理后的目的蛋白的相对剩余含量％。Calculation method of protein residual content %: Use Image J software to read the gray value of the corresponding Western blotting band after drug (protein degrader) treatment. Divide the gray value of the corresponding Western blotting band after drug treatment by the gray value of the corresponding Western blotting band of the internal reference protein, and normalize the obtained quotient to obtain the relative residual content % of the target protein after protein degrader treatment.

目的蛋白降解率％＝1-目的蛋白剩余含量％Target protein degradation rate % = 1-target protein remaining content %

本公开化合物(包括表1化合物和各实施例化合物)对细胞中底物蛋白表达的影响结果列于以下表II-1中。
表II-1本公开化合物对底物蛋白WEE1、IKZF1、IKZF2、IKZF3、CK1α和GSPT1的降解结
果






注：在表II-1中，A表示0％≤底物蛋白剩余含量≤80％，B表示80％＜底物蛋白剩余含量≤
100％。The results of the effects of the compounds disclosed herein (including the compounds in Table 1 and the compounds in the examples) on the expression of substrate proteins in cells are listed in the following Table II-1.
Table II-1 Degradation results of the disclosed compounds on substrate proteins WEE1, IKZF1, IKZF2, IKZF3, CK1α and GSPT1






Note: In Table II-1, A means 0% ≤ substrate protein remaining content ≤ 80%, B means 80% < substrate protein remaining content ≤
100%.

本发明化合物对目标底物蛋白的降解效果如表II-1以及图1所示。从表II-1的实验结果和图1可知，本发明化合物能显著降解底物蛋白(例如WEE1蛋白、IKZF1/2/3蛋白、CK1α蛋白、GSPT1蛋白等)。相比于来那度胺，本发明化合物在诱导底物蛋白的降解效率方面有显著性的提升，也可以选择性地诱导降解底物蛋白，从而可以用于治疗与底物蛋白相关的适应症。The degradation effect of the compounds of the present invention on the target substrate protein is shown in Table II-1 and Figure 1. From the experimental results in Table II-1 and Figure 1, it can be seen that the compounds of the present invention can significantly degrade substrate proteins (such as WEE1 protein, IKZF1/2/3 protein, CK1α protein, GSPT1 protein, etc.). Compared with lenalidomide, the compounds of the present invention have a significant improvement in the efficiency of inducing the degradation of substrate proteins, and can also selectively induce the degradation of substrate proteins, so that they can be used to treat indications related to substrate proteins.

III.本公开化合物对CRBN的结合亲和力检测实验：III. Binding affinity test of the disclosed compounds to CRBN:

采用CEREBLON BINDING KITS试剂盒(规格10，000tests；试剂货号：64BDCRBNPEH；供应商CISBIO公司)、通过HTRF(均相时间分辨荧光技术，homogeneous time-resolved fluorescence)方法检测待测化合物的CRBN结合能力，具体方法如下：
1.根据CEREBLON BINDING KITS试剂盒的说明书，对本公开待测化合物(包括表1化合物
和实施例化合物)和来那度胺进行系列稀释，具体采用diluent#9(1X)溶液作为稀释剂，并设定多个浓度梯度。稀释操作可遵循以下两种方式之一进行：
(1)第一种稀释方法：将本公开待测化合物(包括表1化合物和实施例化合物)从最高
浓度40μM开始进行5倍梯度稀释，从高到低共设置7个浓度(40、8、1.6、0.32、0.064、0.0128、0.00256μM)。随后，在96孔板的每个孔中分别加入已稀释好的本公开待测化合物与相应的检测试剂，每孔中待测化合物的最终测试浓度分别达到10、2、0.4、0.08、0.016、0.0032、0.00064μM。
(2)作为替代方案，可以采用第二种稀释方法：将本公开待测化合物(包括表1化合物
和实施例化合物)从最高浓度8μM开始进行4倍梯度稀释，共设置2个浓度(8μM、2μM)。在96孔板中，每孔加入稀释好的本公开待测化合物与相应的检测试剂，每孔中待测化合物的最终测试浓度分别达到2μM、0.5μM。试验操作以稀释好的8μM的待测化合物和来那度胺溶液为例介绍如下。
2.取2.5μL上述稀释好的8μM的待测化合物和来那度胺溶液以及相同体积的diluent#9(1X)
溶液(溶剂对照组，Std0)分别加入到96孔板的各孔中。然后，各孔中分别加入2.5μL的人Cereblon WT GST-tagged蛋白溶液。最后，取5μL已均匀混合的Thalidomide-Red试剂和GST Eu抗体工作液加入上述各孔中。各孔中待测化合物和来那度胺的最终测试浓度为2μM。
3.空白对照孔按顺序分别加入2.5μL的diluent#9(1X)溶液，2.5μL的binding buffer溶液以
及5μL已均匀混合的Thalidomide-Red试剂和GST Eu抗体工作液。
4.将上述各孔的溶液在室温下密封抚育3小时后用Spark酶标仪(V3.1 SP1)的HTRF方法分
别检测各孔在发射波长为620nm和665nm时的吸光度值。The CEREBLON BINDING KITS kit (specification 10,000 tests; reagent number: 64BDCRBNPEH; supplier CISBIO) was used to detect the CRBN binding ability of the test compound by HTRF (homogeneous time-resolved fluorescence) method. The specific method is as follows:
1. According to the instructions of the CEREBLON BINDING KITS kit, the compounds to be tested in the present disclosure (including the compounds in Table 1 and the example compounds) and lenalidomide were serially diluted, specifically using diluent #9 (1X) solution as the diluent, and setting multiple concentration gradients. The dilution operation can be performed in one of the following two ways:
(1) The first dilution method: The test compounds of the present disclosure (including the compounds in Table 1 and the example compounds) were diluted 5-fold from the highest concentration of 40 μM, and a total of 7 concentrations were set from high to low (40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256 μM). Subsequently, the diluted test compounds of the present disclosure and the corresponding detection reagents were added to each well of the 96-well plate, and the final test concentrations of the test compounds in each well reached 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064 μM, respectively.
(2) As an alternative, a second dilution method can be used: the test compound of the present disclosure (including the compounds in Table 1 and the example compounds) is diluted 4 times from the highest concentration of 8 μM, and a total of 2 concentrations (8 μM, 2 μM) are set. In a 96-well plate, the diluted test compound of the present disclosure and the corresponding detection reagent are added to each well, and the final test concentration of the test compound in each well reaches 2 μM and 0.5 μM, respectively. The experimental operation is described as follows using the diluted 8 μM test compound and lenalidomide solution as an example.
2. Take 2.5 μL of the above diluted 8 μM test compound and lenalidomide solution and the same volume of diluent #9 (1X)
The solution (solvent control group, Std0) was added to each well of a 96-well plate. Then, 2.5 μL of human Cereblon WT GST-tagged protein solution was added to each well. Finally, 5 μL of the evenly mixed Thalidomide-Red reagent and GST Eu antibody working solution were added to each well. The final test concentration of the test compound and lenalidomide in each well was 2 μM.
3. Add 2.5 μL of diluent #9 (1X) solution, 2.5 μL of binding buffer solution, and 5 μL of evenly mixed Thalidomide-Red reagent and GST Eu antibody working solution to the blank control wells in sequence.
4. After the solutions in the above wells were sealed and incubated at room temperature for 3 hours, the absorbance values of each well at emission wavelengths of 620 nm and 665 nm were detected using the HTRF method of Spark microplate reader (V3.1 SP1).

采用如下方法计算相应的CRBN结合抑制率：
R化合物＝OD 665nm化合物/OD 620nm化合物-OD 665nm对照/OD 620nm对照
RStd0＝OD 665nm Std0/OD 620nm Std0-OD 665nm对照/OD 620nm对照
抑制率(％)＝(1-R化合物/RStd0)＊100
注：OD 665nm化合物是待测化合物各孔在发射波长665nm时的吸光度值
OD 620nm化合物是待测化合物各孔在发射波长620nm时的吸光度值
OD 665nm对照是空白对照孔在发射波长665nm时的吸光度值
OD 620nm对照是空白对照孔在发射波长620nm时的吸光度值
OD 665nm Std0是溶剂对照孔在发射波长665nm时的吸光度值
OD 620nm Std0是溶剂对照孔在发射波长620nm时的吸光度值The corresponding CRBN binding inhibition rate was calculated as follows:
R compound = OD 665nm compound / OD 620nm compound - OD 665nm control / OD 620nm control
R Std0 = OD 665nm Std0 / OD 620nm Std0 - OD 665nm control / OD 620nm control
Inhibition rate (%) = (1-R compound /R Std0 ) * 100
Note: OD 665nm compound is the absorbance value of each well of the test compound at an emission wavelength of 665nm
OD 620nm Compound is the absorbance value of each well of the test compound at an emission wavelength of 620nm
OD 665nm control is the absorbance value of the blank control well at an emission wavelength of 665nm
OD 620nm control is the absorbance value of the blank control well at an emission wavelength of 620nm
OD 665nm Std0 is the absorbance value of the solvent control well at an emission wavelength of 665nm
OD 620nm Std0 is the absorbance value of the solvent control well at an emission wavelength of 620nm

结果列于以下表III-1和表III-2中。
表III-1：本发明化合物(包括但不限于表1化合物和各实施例化合物)的HTRF的抑制活性
(IC50，μM)

在表III-1中，符号a1、a、b、c、d和e的含义如下：0＜a0≤0.1μM，0.1μM＜a≤0.5μM，
0.5μM＜b≤1μM，1μM＜c≤1.5μM，1.5μM＜d＜1.9μM，1.9μM≤e≤10μM，10μM＜f。
表III-2：本发明化合物(包括但不限于表1化合物和实施例化合物)在2μM、0.5μM浓度下的
CRBN结合亲和力筛选


在表III-2中，符号a1、a2、a3、a4、a5、a6和a7的含义如下：0％＜a≤10％，10％＜a1≤
20％，20％＜a2≤30％，30％＜a3≤40％，40％＜a4≤53％，53％＜a5≤60％，60％＜a6≤70％，70％＜a7≤80％，80％＜a8≤100％。The results are shown in the following Table III-1 and Table III-2.
Table III-1: HTRF inhibitory activity of the compounds of the present invention (including but not limited to the compounds in Table 1 and the compounds of the examples)
(IC 50 , μM)

In Table III-1, the symbols a1, a, b, c, d and e have the following meanings: 0＜a0≤0.1μM, 0.1μM＜a≤0.5μM,
0.5μM<b≤1μM, 1μM<c≤1.5μM, 1.5μM<d<1.9μM, 1.9μM≤e≤10μM, 10μM<f.
Table III-2: Compounds of the present invention (including but not limited to compounds in Table 1 and Example compounds) at 2 μM and 0.5 μM concentrations
CRBN binding affinity screening


In Table III-2, the symbols a1, a2, a3, a4, a5, a6 and a7 have the following meanings: 0%＜a≤10%, 10%＜a1≤
20%, 20%＜a2≤30%, 30%＜a3≤40%, 40%＜a4≤53%, 53%＜a5≤60%, 60%＜a6≤70%, 70%＜a7≤80%, 80%＜a8≤100%.

表III-1和III-2的结果表明本发明化合物(包括但不限于表1化合物和各实施例化合物)相比于来那度胺具有更低或相当的IC50值，或者具有更高的抑制率，表现出更强的对CRBN的结合力。The results in Tables III-1 and III-2 show that the compounds of the present invention (including but not limited to the compounds in Table 1 and the compounds of the examples) have lower or equivalent IC 50 values than lenalidomide, or have higher inhibition rates, and exhibit stronger binding affinity to CRBN.

IV.TNF-α活性抑制实验IV. TNF-α Activity Inhibition Experiment

将PBMCs细胞于37℃，5％CO2下培养，然后以1×107细胞/每孔接种于96孔板中。测试化合物(包括表1化合物和实施例化合物)溶解于DMSO中，并稀释至相应的浓度，使得最终加入细胞培养中DMSO的浓度不超过0.5％。在含有化合物或者不含有化合物的培养基孵育1h后，细胞用脂多糖(LPS；1ng/ml)进行刺激，并继续培养18～20h，然后收集上清液，用无血清的培养基稀释，用ELISA试剂盒测试TNF-α水平，然后Graphpad Prism 7.0计算IC50。PBMCs were cultured at 37°C, 5% CO2 , and then seeded in 96-well plates at 1× 107 cells/well. Test compounds (including compounds in Table 1 and Example compounds) were dissolved in DMSO and diluted to the corresponding concentrations, so that the final concentration of DMSO added to the cell culture did not exceed 0.5%. After incubation in the medium containing or not containing the compound for 1 hour, the cells were stimulated with lipopolysaccharide (LPS; 1 ng/ml) and continued to be cultured for 18-20 hours, and then the supernatant was collected, diluted with serum-free medium, and the TNF-α level was tested using an ELISA kit, and then Graphpad Prism 7.0 was used to calculate the IC50 .

TNF-α表达下调是免疫调剂剂发挥抗肿瘤作用的重要因素。经本发明的化合物处理后，TNF-α水平受到剂量依赖性抑制。Down-regulation of TNF-α expression is an important factor in the anti-tumor effect of immunomodulators. After treatment with the compounds of the present invention, TNF-α levels are inhibited in a dose-dependent manner.

V.本公开化合物的药代动力学研究V. Pharmacokinetic Studies of the Disclosed Compounds

使用常规药代动力学实验方法检测本公开化合物的药代动力学性质。The pharmacokinetic properties of the disclosed compounds are tested using conventional pharmacokinetic experimental methods.

将本公开待测化合物(包括表1化合物和实施例化合物)口服给药至实验动物，评价本公开化合物的药代动力学性质。采用的实验动物可以是药代动力学实验常用的成年健康的啮齿类动物(例如小鼠、大鼠(例如Sprague-Dawley(SD)大鼠)、豚鼠)或非啮齿类动物(兔、犬和猴)等。在本公开中采用的实验动物是小鼠。The test compounds of the present disclosure (including the compounds in Table 1 and the example compounds) are orally administered to experimental animals to evaluate the pharmacokinetic properties of the compounds of the present disclosure. The experimental animals used can be adult healthy rodents (e.g., mice, rats (e.g., Sprague-Dawley (SD) rats), guinea pigs) or non-rodents (rabbits, dogs, and monkeys) commonly used in pharmacokinetic experiments. The experimental animals used in the present disclosure are mice.

实验动物分2组，分别为对照组(采集空白血浆)和口服给药组(给药剂量为10mg/kg或30mg/kg)。给药后在预定采样时间点采集血液样本，例如采血时间点为：给药后0.25h、0.5h、1h、2h、4h、8h、24h。对照组采集空白血浆。The experimental animals were divided into two groups, a control group (blank plasma was collected) and an oral administration group (dosage was 10 mg/kg or 30 mg/kg). Blood samples were collected at predetermined sampling time points after administration, for example, the blood collection time points were: 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration. Blank plasma was collected from the control group.

分析前对血浆样品进行前处理：向10μL血浆样品中加入10μL 50％乙腈以及200μL内标溶液(内标溶液为含50ng/ml地塞米松的乙腈溶液)。空白对照组的血浆样品不加内标，补加同体积乙腈。将处理后样品涡旋混匀，离心后，取上清液进行LC-MS/MS进样分析。The plasma samples were pre-treated before analysis: 10 μL 50% acetonitrile and 200 μL internal standard solution (the internal standard solution was an acetonitrile solution containing 50 ng/ml dexamethasone) were added to 10 μL plasma sample. The plasma samples of the blank control group were not added with internal standard, but with the same volume of acetonitrile. The treated samples were vortexed and centrifuged, and the supernatant was taken for LC-MS/MS injection analysis.

制备标准曲线和QC样品后，用LC-MS/MS分析测定待测血浆样品中化合物浓度。根据LC-MS/MS分析测定的血药浓度数据，使用药代动力学计算软件WinNonlinv8.1非房室模型分别计算待测化合物的药代动力学参数。After preparing the standard curve and QC samples, the concentration of the compound in the plasma sample to be tested was determined by LC-MS/MS analysis. According to the blood drug concentration data determined by LC-MS/MS analysis, the pharmacokinetic parameters of the test compound were calculated using the pharmacokinetic calculation software WinNonlinv8.1 non-compartmental model.

结果显示，经口服给药途径施用的本公开化合物具有良好的药代动力学(DMPK)特性，可以用作为肿瘤病人的治疗药物。The results show that the compounds of the present disclosure administered via oral administration have good pharmacokinetic (DMPK) properties and can be used as therapeutic drugs for tumor patients.

VI.本公开化合物对植物血凝素或eBioscienceTM细胞刺激混合物(PMA+Ionomycin)诱导PBMC释放包括TNF-α、IL-2、IL-5、IL-10、IL-1α、IL-1β、GM-CSF在内的炎症因子的影响VI. Effects of the compounds disclosed herein on the release of inflammatory factors including TNF-α, IL-2, IL-5, IL-10, IL-1α, IL-1β, and GM-CSF from PBMC induced by phytohemagglutinin or eBioscience TM cell stimulation mixture (PMA+Ionomycin)

本发明人检测了本发明化合物对于由植物血凝素或eBioscienceTM细胞刺激复合物(包含PMA与Ionomycin)所触发的外周血单个核细胞(PBMC)释放一系列炎症因子的影响，这些炎症因子包括TNF-α、IL-2、IL-5、IL-10、IL-1α、IL-6、IL-1β、粒细胞-巨噬细胞集落刺激因子(GM-CSF)等。已报道研究提示这些炎症因子在癌症、自身免疫疾病、感染性疾病和炎症性疾病的发生和发展中可能扮演着重要角色。在类风湿性关节炎(RA)、银屑病关节炎(PsA)、强直性脊柱炎(AS)等自身免疫性疾病中，TNF-α的表达水平明显升高，并通过刺激滑膜细胞增殖和促进炎症反应而发挥作用。IL-1α与癌症、自身免疫性疾病、感染性疾病和其他炎性疾病有关，参与自身免疫性疾病的炎症过程。在类风湿性关节炎、系统性红斑狼疮等疾病中，IL-1β的升高可以反映炎症反应的程度和活性。IL-2、IL-5、IL-10、GM-CSF也可能与多种炎症性疾病和自身免疫疾病相关。The inventors have detected the effects of the compounds of the present invention on the release of a series of inflammatory factors from peripheral blood mononuclear cells (PBMCs) triggered by phytohemagglutinin or eBioscience TM cell stimulation complex (comprising PMA and Ionomycin), including TNF-α, IL-2, IL-5, IL-10, IL-1α, IL-6, IL-1β, granulocyte-macrophage colony stimulating factor (GM-CSF), etc. Reported studies have suggested that these inflammatory factors may play an important role in the occurrence and development of cancer, autoimmune diseases, infectious diseases, and inflammatory diseases. In autoimmune diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), the expression level of TNF-α is significantly increased, and it exerts its effects by stimulating synovial cell proliferation and promoting inflammatory responses. IL-1α is associated with cancer, autoimmune diseases, infectious diseases, and other inflammatory diseases, and is involved in the inflammatory process of autoimmune diseases. In diseases such as rheumatoid arthritis and systemic lupus erythematosus, the increase of IL-1β can reflect the degree and activity of inflammatory response. IL-2, IL-5, IL-10, and GM-CSF may also be associated with a variety of inflammatory diseases and autoimmune diseases.

本研究使用了以下材料：The following materials were used in this study:

VI.1试剂和耗材
VI.1 Reagents and consumables

VI.2方法VI.2 Methods

VI.2.1细胞复苏与铺板VI.2.1 Cell recovery and plating

准备完全培养基，37℃预热备用；从液氮罐取出细胞，用镊子夹取冻存管盖子与瓶身交界线恰好下面位置，浸入37℃温水中，并不时摇动令其尽快融化；吸出细胞悬液，加到含有10mL完全培养基的离心管中，混匀；室温下400g离心10min；弃去上清液，加入完全培养基，计数并调整细胞密度，以75μL/孔接种到96孔板中至每孔细胞数为1×105，在高湿度，37℃，5％CO2培养箱中静置培养2h。Prepare complete culture medium and preheat it at 37℃ for later use; take out cells from liquid nitrogen tank, use tweezers to grab the position just below the junction of cryotube cover and bottle body, immerse in 37℃ warm water, and shake from time to time to melt it as quickly as possible; aspirate cell suspension, add to centrifuge tube containing 10mL complete culture medium, mix; centrifuge at 400g for 10min at room temperature; discard supernatant, add complete culture medium, count and adjust cell density, inoculate into 96-well plate at 75μL/well until the number of cells in each well is 1× 105 , and culture in a high humidity, 37℃, 5% CO2 incubator for 2h.

VI.2.2化合物的配制及在细胞板中的添加
1)测试化合物(包括表1化合物和实施例化合物)用DMSO配制成10mM的储存液。
2)测试化合物以1mM为最高浓度，用DMSO稀释10倍，得到2个浓度梯度的化合物。
3)用培养基将测试化合物稀释至所设置的相应作用终浓度的5倍。
4)按25μL/孔将稀释好的化合物，根据以下布局加入相应细胞孔中。化合物作用终浓度从
1μM开始，10倍稀释，共2个浓度点。
5)1h后按25μL/孔将PHA或PMA+Ionomycin分别加入到细胞孔中至PHA的终浓度分别
为1μg/mL(TNF-α、IL-10、IL-6、IL-1β、IFN-γ、IL-2、IL-12p40、IL-1α、IL-8)，或PMA的终浓度为81nM/mL(IL-4、IL-5、IL-13、GM-CSF和IL-17A)，或Ionomycin的终浓度为1.34μM/mL(IL-4、IL-5、IL-13、GM-CSF和IL-17A)。
6)细胞板放入高湿度，37℃，5％CO2培养箱中共孵育24h。
细胞板布局：
VI.2.2 Preparation of compounds and addition to cell plates
1) Test compounds (including compounds in Table 1 and compounds in Examples) were prepared into 10 mM stock solutions using DMSO.
2) The test compound was diluted 10 times with DMSO with 1 mM as the highest concentration to obtain compounds with 2 concentration gradients.
3) Dilute the test compound with culture medium to 5 times the final concentration of the corresponding effect.
4) Add the diluted compound to the corresponding cell wells according to the following layout at 25 μL/well. The final concentration of the compound is
Start with 1 μM and dilute 10 times, with a total of 2 concentration points.
5) After 1 h, PHA or PMA + Ionomycin was added to the cell wells at 25 μL/well to a final concentration of PHA of 1 μg/mL (TNF-α, IL-10, IL-6, IL-1β, IFN-γ, IL-2, IL-12p40, IL-1α, IL-8), or a final concentration of PMA of 81 nM/mL (IL-4, IL-5, IL-13, GM-CSF and IL-17A), or a final concentration of Ionomycin of 1.34 μM/mL (IL-4, IL-5, IL-13, GM-CSF and IL-17A).
6) The cell plate was placed in a high humidity, 37°C, 5% CO2 incubator and incubated for 24 hours.
Cell Plate Layout:

VI.2.3检测
(1)离心，吸取培养液上清，按照流式CBA实验操作说明检测培养液上清中的TNF-α、IL-
10、IL-6、IL-1β、IFN-γ、IL-2、IL-12p40、IL-1α、IL-8、IL-4、IL-5、IL-13、GM-CSF和IL-17A细胞因子。
(2)流式CBA实验操作如下：标准品和样本的稀释：将标准品和样本按照一定的比例稀释，
以便在检测中进行准确的定量分析。微球混合：将捕捉微球和样本或标准品混合，避光反应1H。抗体混合：将捕获抗体和样本或标准品混合，避光反应2H。这两步是流式CBA技术的核心，通过微球与目标分子的结合，实现对细胞因子的定量检测。流式细胞仪检测：使用流式细胞仪对混合物进行检测。流式细胞仪通过激光激发微球上的荧光标记，收集并分析荧光信号，从而定量测定样本中的细胞因子浓度。
(3)根据通过流式细胞仪收集的数据需要进行进一步的分析，通常使用专门的软件FACP进
行数据处理，生成详细的细胞因子浓度(TNF-α、IL-10、IL-6、IL-1β、IFN-γ、IL-2、IL-12p40、IL-1α、IL-8、IL-4、IL-5、IL-13、GM-CSF和IL-17A)报告，抑制率％＝[(Ac-As)/(Ac-Ab)]×100％
As：样品的OA(细胞+PHA/PMA+Ionomycin+待测化合物)
Ac：阳性细胞对照的OA(细胞+PHA/PMA+Ionomycin+DMSO)
Ab：空白对照的OA(细胞+培养基+DMSO)
(4)运用软件Graphpad Prism 6并采用计算公式XY-analysis/Nonlinear regression(curve 
fit)/Dose response-Inhibition/log(inhibitor)vs.response-Variable slope(four parameters)进行IC50曲线拟合并计算出IC50值。VI.2.3 Detection
(1) Centrifuge, aspirate the culture supernatant, and detect TNF-α and IL-
10. IL-6, IL-1β, IFN-γ, IL-2, IL-12p40, IL-1α, IL-8, IL-4, IL-5, IL-13, GM-CSF and IL-17A cytokines.
(2) The flow CBA experiment is performed as follows: Dilution of standards and samples: dilute the standards and samples in a certain ratio.
In order to perform accurate quantitative analysis in the test. Microsphere mixing: Mix the capture microspheres and samples or standards, and react in the dark for 1H. Antibody mixing: Mix the capture antibodies and samples or standards, and react in the dark for 2H. These two steps are the core of flow CBA technology. Through the combination of microspheres and target molecules, quantitative detection of cytokines is achieved. Flow cytometer detection: Use a flow cytometer to detect the mixture. The flow cytometer excites the fluorescent markers on the microspheres with lasers, collects and analyzes the fluorescent signals, and thus quantitatively determines the cytokine concentration in the sample.
(3) Further analysis is required based on the data collected by flow cytometry. FACP is usually used for data processing to generate detailed cytokine concentration (TNF-α, IL-10, IL-6, IL-1β, IFN-γ, IL-2, IL-12p40, IL-1α, IL-8, IL-4, IL-5, IL-13, GM-CSF and IL-17A) reports. Inhibition rate % = [(Ac-As)/(Ac-Ab)] × 100%
As: OA of sample (cells + PHA/PMA + Ionomycin + test compound)
Ac: OA of positive cell control (cells + PHA/PMA + Ionomycin + DMSO)
Ab: OA of blank control (cells + culture medium + DMSO)
(4) Using the software Graphpad Prism 6 and the calculation formula XY-analysis/Nonlinear regression (curve
IC50 curve fitting was performed using the data from the R-squared fitting method (fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters) and the IC50 value was calculated.

结果列于以下表IV中。
表IV：本发明化合物(包括但不限于表1化合物和实施例化合物)在1μM、0.1μM浓度下对
炎症因子的抑制率％



注：在表IV中，符号IV1、IV2、IV3、IV4、IV5、IV6、IV7、IV8、IV9、IV10、IV11、IV12、IV13
和IV14的含义如下：-320％≤IV1＜-200％，-200％≤IV2＜-100％，-100％≤IV3＜-50％，-50％≤IV4＜0％，0％＜IV5≤10％，10％＜IV6≤20％，20％＜IV7≤30％，30％＜IV8≤40％，40％＜IV9≤50％，50％＜IV10≤60％，60％＜IV11≤70％，70％＜IV12≤80％，80％＜IV13≤90％，90％＜IV14≤100％。符号“-”表示未检测。The results are listed in Table IV below.
Table IV: Inhibition rate of the compounds of the present invention (including but not limited to the compounds in Table 1 and the compounds in the examples) on inflammatory factors at concentrations of 1 μM and 0.1 μM (%)



Note: In Table IV, symbols IV1, IV2, IV3, IV4, IV5, IV6, IV7, IV8, IV9, IV10, IV11, IV12, IV13
The meanings of IV1 and IV14 are as follows: -320%≤IV1＜-200%, -200%≤IV2＜-100%, -100%≤IV3＜-50%, -50%≤IV4＜0%, 0%＜IV5≤10%, 10%＜IV6≤20%, 20%＜IV7≤30%, 30%＜IV8≤40%, 40%＜IV9≤50%, 50%＜IV10≤60%, 60%＜IV11≤70%, 70%＜IV12≤80%, 80%＜IV13≤90%, 90%＜IV14≤100%. The symbol "-" means not detected.

实验结果表明，本公开化合物(包括表1化合物和实施例化合物)在调节与炎症性疾病、自身免疫性疾病相关的细胞因子生成水平方面展现出了优异的调控能力，其抑制效果相较于阳性对照药物来那度胺更为显著。阳性对照药物来那度胺对IL-2或者IL-10是升高作用，会产生炎症反应，在临床中患者有发生皮疹等毒作用的风险，本公开化合物对IL-2和IL-10有抑制或者无明显刺激作用，对治疗免疫系统疾病有更大的优势。本公开化合物(包括表1化合物和实施例化合物)具备成为治疗多种炎症性疾病、自身免疫性疾病(诸如类风湿性关节炎、强直性脊柱炎、银屑病及其关节炎、系统性红斑狼疮、特应性皮炎、以及化脓性汗腺炎等)潜在疗法的广阔前景。The experimental results show that the disclosed compounds (including compounds in Table 1 and Example compounds) show excellent regulatory ability in regulating the level of cytokine production associated with inflammatory diseases and autoimmune diseases, and their inhibitory effect is more significant than that of the positive control drug lenalidomide. The positive control drug lenalidomide has an increasing effect on IL-2 or IL-10, which will produce an inflammatory reaction. In clinical practice, patients have the risk of toxic effects such as rashes. The disclosed compounds have an inhibitory or no obvious stimulating effect on IL-2 and IL-10, which has a greater advantage in treating immune system diseases. The disclosed compounds (including compounds in Table 1 and Example compounds) have a broad prospect of becoming a potential therapy for treating a variety of inflammatory diseases, autoimmune diseases (such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and its arthritis, systemic lupus erythematosus, atopic dermatitis, and suppurative hidradenitis, etc.).

VII.本公开化合物对咪喹莫特诱导小鼠背部银屑病样皮损的药效实验VII. Pharmacological efficacy of the disclosed compounds on imiquimod-induced psoriasis-like lesions on the back of mice

将本公开化合物(受试物，包括表1化合物和实施例化合物)每天1次连续7天经口灌胃给予至咪喹莫特诱导小鼠，研究本公开化合物对咪喹莫特诱导小鼠背部皮肤银屑病样皮损的药效作用。The compounds of the present invention (test substances, including compounds in Table 1 and example compounds) were orally administered to imiquimod-induced mice once a day for 7 consecutive days to study the pharmacodynamic effects of the compounds of the present invention on psoriasis-like lesions on the back skin of imiquimod-induced mice.

将60只C57BL/6J雌性小鼠(购自上海斯莱克实验动物有限责任公司)按照体重平均分成6组，每组10只：

注：ig.经口灌胃；sc.皮下注射；qd.每天一次。Sixty C57BL/6J female mice (purchased from Shanghai Slake Laboratory Animal Co., Ltd.) were divided into 6 groups according to their body weight, with 10 mice in each group:

Note: ig. oral gavage; sc. subcutaneous injection; qd. once a day.

实验动物分组后，所有小鼠背部剃毛，除Control组以外，其余各组动物使用咪喹莫特乳膏局部涂抹，每天1次，连续7天。同时按照上述表格各组分别给予溶剂对照、阳性对照药或受试物，每天1次，连续7天。After the experimental animals were grouped, the backs of all mice were shaved, and except for the Control group, the animals in the other groups were topically applied with imiquimod cream once a day for 7 consecutive days. At the same time, according to the above table, each group was given solvent control, positive control drug or test substance once a day for 7 consecutive days.

观察实验开始和实验过程中每个动物所有的临床症状。2天1次称量动物体重并记录。Observe all clinical symptoms of each animal at the beginning and during the experiment. Weigh the animal's body weight once every two days and record it.

评分
皮损大体观评分(PASI法)：造模给药的最后3天，每天1次，观察各组小鼠皮损的变化情
况。PASI法：分别对皮损处红斑、鳞屑和浸润增厚程度评分，三者积分相加为总积分。PASI评分标准：0分，无；1分，轻度；2分，中度；3分，重度；4分，极重度。Scoring of gross lesion score (PASI method): During the last 3 days of modeling and drug administration, the changes in skin lesions of mice in each group were observed once a day. PASI method: The erythema, scaling and infiltration thickening of the skin lesions were scored separately, and the three scores were added together to form the total score. PASI scoring standard: 0 points, none; 1 point, mild; 2 points, moderate; 3 points, severe; 4 points, extremely severe.

造模给药的最后3天，每天1次对皮损处拍照。During the last 3 days of modeling and drug administration, the skin lesions were photographed once a day.

实验结束后小鼠采用吸入过量CO2法安乐死处死。采用6mm打孔器取背部皮损处3个不同部位的皮肤称重并记录，计算平均重量。At the end of the experiment, the mice were euthanized by inhalation of excessive CO 2. The skin from three different parts of the back lesions was taken with a 6 mm punch and weighed and recorded, and the average weight was calculated.

皮损处皮肤组织匀浆，检测IL-23p19、IL-12p40、IL-17、TNF-α的含量。Skin tissue homogenates from lesions were used to detect the levels of IL-23p19, IL-12p40, IL-17, and TNF-α.

局部皮损部取材固定后HE染色，并进行病理评分(表皮厚度、表皮细胞角化程度、基层细胞厚度、真皮炎症细胞浸润程度)，评分标准：0分，无；1分，轻度；2分，中度；3分，重度；4分，极重度。The local skin lesions were fixed and stained with HE, and pathological scoring (epidermal thickness, degree of epidermal cell keratinization, basal cell thickness, and degree of dermal inflammatory cell infiltration) was performed. The scoring criteria were: 0 point, none; 1 point, mild; 2 points, moderate; 3 points, severe; 4 points, extremely severe.

实验数据以Mean±SD表示；两组间数据使用SPSS统计分析，p＜0.05认为是有显著性差异。The experimental data were expressed as Mean±SD. The data between the two groups were analyzed using SPSS statistics, and p<0.05 was considered to be a significant difference.

实验结果表明，本公开化合物对咪喹莫特诱导小鼠背部皮肤银屑病样病变具有改善作用，可用于治疗银屑病。The experimental results show that the disclosed compound has an improving effect on imiquimod-induced psoriasis-like lesions on the back skin of mice, and can be used to treat psoriasis.

VIII.本公开化合物对II型胶原诱导的CIA模型大鼠的药效实验VIII. Pharmacological efficacy of the disclosed compounds on type II collagen-induced CIA model rats

将本公开化合物(受试物，包括表1化合物和实施例化合物)每天1次连续21天经口灌胃给予至牛II型胶原(Chondrex公司)诱导的Wistar大鼠，研究本公开化合物对该大鼠关节炎模型(CIA)的药效作用。The compounds of the present invention (test substances, including compounds in Table 1 and example compounds) were orally administered to Wistar rats induced with bovine type II collagen (Chondrex) once a day for 21 consecutive days to study the pharmacodynamic effects of the compounds of the present invention on the rat arthritis model (CIA).

造模剂配制：
将10mg CII(Immunization Grade Bovine Type II Collagen，购自Chondrex公司)溶解于5mL 
0.05M醋酸溶液中，使之充分溶解，制成浓度为2mg/mL的溶液，4℃避光放置过夜。试验时在冰浴条件下将2mg/mL的CII溶液与4mg/mL的完全弗氏佐剂(Complete Freund′s Adjuvant，CFA，购自Chondrex公司)溶液等体积混合充分乳化成乳剂。Modeling agent preparation:
Dissolve 10 mg of CII (Immunization Grade Bovine Type II Collagen, purchased from Chondrex) in 5 mL
0.05M acetic acid solution, fully dissolved to make a solution with a concentration of 2mg/mL, and placed in the dark at 4℃ overnight. During the experiment, 2mg/mL CII solution and 4mg/mL Complete Freund's Adjuvant (CFA, purchased from Chondrex) solution were mixed in equal volumes under ice bath conditions to fully emulsify into an emulsion.

在第0天随机选取10只Wistar大鼠(购自北京维通利华实验动物技术有限公司)作为空白对照Control组，不进行免疫。剩余100只Wistar大鼠尾根部皮内注射等体积混合CII(2mg/mL)和CFA(4mg/mL)制备的乳剂进行第一次免疫。在第7天进行第二次增强免疫。在第10～14天，即在第二次增强免疫后3～7天，发病足AI(Arthritis Index)评分在1～2分时，从造模动物中选取50只，根据体重、足容积和AI评分分成5组，每组10只：

注：ig.经口灌胃；sc.皮下注射On day 0, 10 Wistar rats (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were randomly selected as the blank control group and were not immunized. The remaining 100 Wistar rats were intradermally injected with an emulsion prepared by mixing equal volumes of CII (2 mg/mL) and CFA (4 mg/mL) at the base of the tail for the first immunization. The second booster immunization was performed on day 7. On days 10 to 14, that is, 3 to 7 days after the second booster immunization, when the AI (Arthritis Index) score of the onset foot was 1 to 2 points, 50 rats were selected from the modeling animals and divided into 5 groups according to body weight, foot volume and AI score, with 10 rats in each group:

Note: ig. oral gavage; sc. subcutaneous injection

第二次增强免疫后3～7天，待发病足AI评分达到1～2分时开始根据上述表格各组动物经口灌胃(或皮下注射)分别给予溶剂对照、阳性对照药或受试物，每天1次，连续21天。3 to 7 days after the second booster immunization, when the AI score of the diseased foot reaches 1 to 2 points, each group of animals is given solvent control, positive control drug or test substance by oral gavage (or subcutaneous injection) according to the above table, once a day for 21 consecutive days.

第二次增强免疫后3天开始，每周2次测量双侧后足足趾容积并记录。Starting from 3 days after the second booster immunization, the volume of bilateral hind paws was measured and recorded twice a week.

足容积测量：测量前，用记号笔在大鼠踝关节处画线标记位置，仪器内加入干净清水后仪器数值清零准备测量。将大鼠后肢放入水中使踝关节处的标记线位于液体表面，此时踩下脚踏读数，为大鼠足容积。测量结束后再次踩下脚踏清零准备测量下一只。Foot volume measurement: Before measurement, use a marker to draw a line at the ankle joint of the rat to mark the position. After adding clean water to the instrument, the instrument value is reset to zero and ready for measurement. Put the rat's hind limbs into the water so that the marked line at the ankle joint is on the surface of the liquid. At this time, step on the pedal to read the value, which is the rat's foot volume. After the measurement is completed, step on the pedal again to reset to zero and prepare for the next measurement.

评分
关节炎指数(AI)：每周2次测量足容积同时对四个足趾肿胀进行评分，每只足0～4分，每只
大鼠最高评分为16分。
关节炎指数(Arthritis Index)评分标准：
Scoring Arthritis Index (AI): The paw volume was measured twice a week and the swelling of the four toes was scored, with each foot ranging from 0 to 4 points, and the highest score for each rat was 16 points.
Arthritis Index scoring criteria:

开始给药记为第0天，给药5天后，即在第5天给药后2h，实验动物颈静脉采集血液，静置30min以上，离心分离血清，-80℃冻存，ELISA法检测血清TNF-α、IL-1β、IL-6。The start of drug administration was recorded as day 0. Five days after drug administration, i.e., 2 hours after drug administration on the fifth day, blood was collected from the jugular vein of the experimental animals, allowed to stand for more than 30 minutes, centrifuged to separate serum, and stored at -80°C. Serum TNF-α, IL-1β, and IL-6 were detected by ELISA.

实验结束后，动物采用吸入过量CO2法安乐死。采集动物脾脏和胸腺，称重并计算脏器系数。After the experiment, the animals were euthanized by inhalation of excessive CO 2. The spleen and thymus of the animals were collected, weighed, and the organ coefficient was calculated.

病理检测：取一侧足关节组织于10％中性福尔马林溶液中固定，脱钙后石蜡包埋，用于制备病理切片，HE染色进行病理观察。
观察指标：
1.滑膜炎性细胞(淋巴细胞，浆细胞)浸润；
2.滑膜组织增生；
3.滑膜血管翳；
4.滑膜表面纤维素样坏死物。
评分计数方法：0，1，2，3，4五个级别：“0”未见；“1”轻度；“2”中度；“3”重度；
“4”极重度。Pathological examination: The foot joint tissue of one side was fixed in 10% neutral formalin solution, decalcified and embedded in paraffin for preparation of pathological sections and HE staining for pathological observation.
Observation indicators:
1. Infiltration of synovial inflammatory cells (lymphocytes, plasma cells);
2. Synovial tissue hyperplasia;
3. Synovial pannus;
4. Fibrinoid necrosis on the synovial surface.
Scoring method: 0, 1, 2, 3, 4 five levels: "0" not seen; "1"mild;"2"moderate;"3"severe;
“4”: Extremely severe.

实验数据以Mean±SEM表示；两组间数据采用Excel-T test分析，p＜0.05认为是有显著性差异。评分数据使用SPSS非参数检验Mann-Whitney U test分析，p＜0.05认为是有显著性差异。The experimental data were expressed as Mean ± SEM. The data between the two groups were analyzed using Excel-T test, and p < 0.05 was considered to be significantly different. The scoring data were analyzed using SPSS non-parametric test Mann-Whitney U test, and p < 0.05 was considered to be significantly different.

实验结果表明，本公开化合物可以调节牛II型胶原诱导的CIA模型大鼠的血清炎性因子水平，对大鼠四肢肿胀具有明显的改善作用，可以用于治疗关节炎。The experimental results show that the disclosed compounds can regulate the levels of serum inflammatory factors in CIA model rats induced by bovine type II collagen, have a significant improvement effect on swelling of the rat limbs, and can be used to treat arthritis.

以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本领域技术人员应了解，本发明不受上述实施例的限制，在不脱离本发明精神和范围的前提下，本发明还可进行各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and various changes and improvements may be made to the present invention without departing from the spirit and scope of the present invention, and these changes and improvements all fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims (25)

式(I)化合物或其盐、对映异构体、立体异构体、同位素富集类似物、溶剂化物或多晶型物，
A compound of formula (I) or a salt, enantiomer, stereoisomer, isotopically enriched analog, solvate or polymorph thereof,
其中in Z1表示C(O)、C(S)、CH2或CD2，Z2、Z3和Z4各自独立地表示C(O)或C(S)；Z 1 represents C(O), C(S), CH 2 or CD 2 , and Z 2 , Z 3 and Z 4 each independently represent C(O) or C(S); Z5表示CH或N；Z 5 represents CH or N; Ra1、Ra2、Ra3和Ra4各自独立地表示氢、氘、卤素、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基或卤代C1-6烷氧基； Ra1 , Ra2 , Ra3 and Ra4 each independently represent hydrogen, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, deuterated C1-6 alkoxy or halogenated C1-6 alkoxy; (Ra5)m表示与其连接的异吲哚啉环可选地被m个Ra5取代，各Ra5相同或不同且各自独立地表示氘、卤素、羟基、巯基、硝基、氨基、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基或C2-6炔基；(R a5 ) m represents that the isoindoline ring connected thereto is optionally substituted by m R a5 , each R a5 being the same or different and independently representing deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl; m表示整数0、1、2或3；m represents an integer 0, 1, 2 or 3; R表示C(O)或可选取代的直链或支链的C1-5亚烷基；R represents C(O) or an optionally substituted linear or branched C 1-5 alkylene group; X表示：
X means:
其中环A表示含氮亚杂环基，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0-20的整数；wherein ring A represents a nitrogen-containing heterocyclic group, (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterium, halogen, amino, hydroxyl, thiol, nitro, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0-20; 环B表示含氮亚杂环基，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0-20的整数；Ring B represents a nitrogen-containing heterocyclic group, (R d2 ) n2 represents that Ring B is optionally substituted by n2 R d2 groups, each R d2 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n2 represents an integer of 0-20; Rc表示C(O)、CRc1Rc2或键，其中Rc1和Rc2各自独立地表示H、氘、卤素、可选经取代的直链或支链烷基、可选经取代的环烷基、可选经取代的杂环基、可选经取代的芳基或可选经取代的杂芳基；R c represents C(O), CR c1 R c2 or a bond, wherein R c1 and R c2 each independently represent H, deuterium, halogen, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; 环C表示亚环烷基、亚杂环基、亚芳基或亚杂芳基，m1表示0或1的整数，(Rd3)n3表示环C可选地被n3个Rd3基团取代，各Rd3各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0-20的整数；和Ring C represents a cycloalkylene group, a heterocyclylene group, an arylene group or a heteroarylene group, m1 represents an integer of 0 or 1, (R d3 ) n3 represents that Ring C is optionally substituted by n3 R d3 groups, each R d3 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n3 represents an integer of 0-20; and 环D表示杂环基、环烷基、芳基或杂芳基，(Rd4)n4表示环D可选地被n4个Rd4基团取代，各Rd4各自独立地表示氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0-20的整数。Ring D represents a heterocyclyl group, a cycloalkyl group, an aryl group or a heteroaryl group, (R d4 ) n4 represents that ring D is optionally substituted by n4 R d4 groups, each R d4 independently represents deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n4 represents an integer of 0-20. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物，其中The compound of formula (I) or its salt, enantiomer, stereoisomer, solvate or polymorph as claimed in claim 1, wherein (i)Ra1、Ra2、Ra3和Ra4各自独立地表示H；和/或(i) Ra1 , Ra2 , Ra3 and Ra4 each independently represent H; and/or (ii)R表示C(O)或可选取代的直链或支链的C1-3亚烷基；和/或(ii) R represents C(O) or an optionally substituted linear or branched C 1-3 alkylene group; and/or (iii)X表示：
(iii) X represents:
其中环A表示4至30元含氮亚杂环基(包括4至20元含氮亚杂环基和4至15元含氮亚杂环基)，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0-20的整数；wherein ring A represents a 4- to 30-membered nitrogen-containing heterocyclylene group (including a 4- to 20-membered nitrogen-containing heterocyclylene group and a 4- to 15-membered nitrogen-containing heterocyclylene group), (R d1 ) n1 represents that ring A is optionally substituted by n1 R d1 groups, each R d1 is independently deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n1 represents an integer of 0-20; 环B表示4至30元含氮亚杂环基，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0-20的整数；Ring B represents a 4- to 30-membered nitrogen-containing heterocyclic group, (R d2 ) n2 represents that Ring B is optionally substituted by n2 R d2 groups, each R d2 is independently deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n2 represents an integer of 0-20; Rc表示C(O)、CRc1Rc2或键，其中Rc1和Rc2各自独立地表示H、氘、卤素、可选经取代的直链或支链C1-10烷基、可选经取代的C3-30环烷基、可选经取代的C5-30芳基、可选经取代的4至30元杂环基或可选经取代的5至30元杂芳基；R c represents C(O), CR c1 R c2 or a bond, wherein R c1 and R c2 each independently represent H, deuterium, halogen, optionally substituted straight or branched C 1-10 alkyl, optionally substituted C 3-30 cycloalkyl, optionally substituted C 5-30 aryl , optionally substituted 4 to 30 membered heterocyclyl, or optionally substituted 5 to 30 membered heteroaryl; 环C表示4至30元亚杂环基、C3-30亚环烷基、C5-30亚芳基或5至30元亚杂芳基，m1表示整数0或1，(Rd3)n3表示环C可选地被n3个Rd3基团取代，各Rd3各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0-20的整数；和/或Ring C represents a 4- to 30-membered heterocyclylene group, a C 3-30 cycloalkylene group, a C 5-30 arylene group or a 5- to 30-membered heteroarylene group, m1 represents an integer of 0 or 1, (R d3 ) n3 represents that Ring C is optionally substituted by n3 R d3 groups, each R d3 is independently deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n3 represents an integer of 0-20; and/or 环D表示C3-30环烷基、4至30元杂环基、C5-30芳基或5至30元杂芳基，(Rd4)n4表示环D可选地被n4个Rd4基团取代，各Rd4各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0-20的整数。Ring D represents a C 3-30 cycloalkyl group, a 4- to 30-membered heterocyclyl group, a C 5-30 aryl group or a 5- to 30-membered heteroaryl group, (R d4 ) n4 represents that ring D is optionally substituted by n4 R d4 groups, each R d4 is each independently deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 2-6 alkynyl or C 2-6 alkenyl, and n4 represents an integer of 0-20. 如权利要求1或2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物，其中The compound of formula (I) or its salt, enantiomer, stereoisomer, solvate or polymorph as claimed in claim 1 or 2, wherein (i)所述环A表示4至20元含氮亚杂环基(包括4至15元含氮亚杂环基)，(Rd1)n1表示环A可选地被n1个Rd1基团取代，各Rd1各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1- 6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n1表示0-20的整数；和/或(i) Ring A represents a 4- to 20-membered nitrogen-containing heterocyclic group (including a 4- to 15-membered nitrogen-containing heterocyclic group), ( Rd1 ) n1 represents that Ring A is optionally substituted by n1 Rd1 groups, each Rd1 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl , C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl or C2-6 alkenyl, and n1 represents an integer of 0-20; and/or (ii)所述环B表示4至20元含氮亚杂环基(包括4至15元含氮亚杂环基)，(Rd2)n2表示环B可选地被n2个Rd2基团取代，各Rd2各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1- 6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n2表示0-20的整数；和/或(ii) Ring B represents a 4- to 20-membered nitrogen-containing heterocyclic group (including a 4- to 15-membered nitrogen-containing heterocyclic group), ( Rd2 ) n2 represents that Ring B is optionally substituted by n2 Rd2 groups, each Rd2 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl , C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl or C2-6 alkenyl, and n2 represents an integer of 0-20; and/or (iii)所述Rc1和Rc2各自独立地表示H、氘、卤素、可选经取代的直链或支链C1-6烷基、可选经取代的C3-20环烷基(包括可选经取代的C3-15环烷基)、可选经取代的C5-20芳基(包括可选经取代的C5-15芳基)、可选经取代的4至20元杂环基(包括可选经取代的4至15元杂环基)或可选经取代的5至20元杂芳基(包括可选经取代的5至15元杂芳基)；和/或(iii) said R c1 and R c2 each independently represent H, deuterium, halogen, optionally substituted straight or branched C 1-6 alkyl, optionally substituted C 3-20 cycloalkyl (including optionally substituted C 3-15 cycloalkyl), optionally substituted C 5-20 aryl (including optionally substituted C 5-15 aryl), optionally substituted 4 to 20 membered heterocyclyl (including optionally substituted 4 to 15 membered heterocyclyl), or optionally substituted 5 to 20 membered heteroaryl (including optionally substituted 5 to 15 membered heteroaryl); and/or (iv)所述环C表示4至20元亚杂环基(包括4至15元亚杂环基)、C3-20亚环烷基(包括C3-15亚环烷基)、C5-20亚芳基(包括C5-15亚芳基)或5至20元亚杂芳基(包括5至15元亚杂芳基)，m1表示整数0或1，(Rd3)n3表示环C可选地被n3个Rd3基团取代，各Rd3各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n3表示0-20的整数；和/或(iv) the ring C represents a 4- to 20-membered heterocyclylene (including a 4- to 15-membered heterocyclylene), a C3-20 cycloalkylene (including a C3-15 cycloalkylene), a C5-20 arylene (including a C5-15 arylene) or a 5- to 20-membered heteroarylene (including a 5- to 15-membered heteroarylene), m1 represents an integer of 0 or 1, ( Rd3 ) n3 represents that the ring C is optionally substituted by n3 Rd3 groups, each Rd3 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl or C2-6 alkenyl, and n3 represents an integer of 0-20; and/or (v)环D表示C3-20环烷基(包括C3-15环烷基)、4至20元杂环基(包括4至15元杂环基)、C5-20芳基(包括C5-15芳基)或5至20元杂芳基(包括5至15元杂芳基)，(Rd4)n4表示环D可选地被n4个Rd4基团取代，各Rd4各自独立地为氘、C1-6烷基、氘代C1-6烷基、卤代C1- 6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基或C2-6烯基，和n4表示0-20的整数。(v) Ring D represents C3-20 cycloalkyl (including C3-15 cycloalkyl), 4- to 20-membered heterocyclyl (including 4- to 15-membered heterocyclyl), C5-20 aryl (including C5-15 aryl) or 5- to 20-membered heteroaryl (including 5- to 15-membered heteroaryl), ( Rd4 ) n4 represents that Ring D is optionally substituted by n4 Rd4 groups, each Rd4 is independently deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl or C2-6 alkenyl, and n4 represents an integer of 0-20. 如权利要求1-3中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物，其中A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof as claimed in any one of claims 1 to 3, wherein (i)R表示C(O)或可选取代的亚甲基；和/或(i) R represents C(O) or optionally substituted methylene; and/or (ii)所述环A和环B各自独立地表示亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚哌啶基、亚哌嗪基、氮杂环庚亚基、二氮杂环庚亚基、氮杂环辛亚基、二氮杂环辛亚基、氮杂双环[3.1.1]庚烷亚基、氮杂双环[2.2.1]庚烷亚基、氮杂双环[3.2.1]辛烷亚基、氮杂双环[2.2.2]辛烷亚基、二氮杂双环[3.1.1]庚烷亚基、二氮杂双环[2.2.1]庚烷亚基、二氮杂双环[3.2.1]辛烷亚基、二氮杂双环[2.2.2]辛烷亚基、亚奎宁环基、2，6-二氮杂螺[3.3]庚烷亚基、2，7-二氮杂螺[3.5]壬烷亚基、2，8-二氮杂螺[4.5]癸烷亚基、3，9-二氮杂螺[5.5]十一烷亚基、3-氮杂螺[5.5]十一烷亚基、7-氮杂螺[3.5]壬烷亚基、8-氮杂螺[4.5]癸烷亚基或八氢吡咯并[3，4-c]吡咯亚基，其可选地被一或多个(例如1-10个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代；和/或(ii) Ring A and Ring B each independently represent an azetidinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidinyl group, a piperazinyl group, an azepanylidene group, an azacyclooctanylidene group, a diazacyclooctanylidene group, an azabicyclo[3.1.1]heptanylidene group, an azabicyclo[2.2.1]heptanylidene group, an azabicyclo[3.2.1]octanylidene group, an azabicyclo[2.2.2]octanylidene group, a diazabicyclo[3.1.1]heptanylidene group, a diazabicyclo[2.2.1]heptanylidene group, a diazabicyclo[3.2 .1] octanyl, diazabicyclo[2.2.2]octanyl, quinuclidinyl, 2,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonanyl, 8-azaspiro[4.5]decanyl or octahydropyrrolo[3,4-c]pyrroleyl, which may be optionally substituted by one or more (e.g. 1-10) selected from deuterium, C substituted with a substituent selected from the group consisting of C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C 2-6 alkynyl and C 2-6 alkenyl; and/or (iii)Rc1和Rc2各自独立地表示：(iii) R c1 and R c2 each independently represent: H、氘、卤素或可选经取代的直链或支链C1-10烷基；或H, deuterium, halogen or optionally substituted straight or branched C 1-10 alkyl; or 环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、螺环烷基(例如C5-C20螺环基，例如螺[3.3]庚烷基、螺[2.5]辛烷基、螺[3.5]壬烷基、螺[4.4]壬烷基、螺[4.5]癸烷基、螺[5.5]十一烷基)、对薄荷烷基、间薄荷烷基、或桥环烷基(例如C6-C20桥环基，例如金刚烷基、降金刚烷基、冰片基、降冰片基、二环[2.2.1]庚烷基、2-氧代二环[2.2.1]庚烷基或二环[2.2.1]庚烯基)，其可选地被一或多个(例如1-10个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代；或cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl (e.g. C5 - C20 spirocyclyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl (e.g. C6 - C20 bridged cycloalkyl, such as adamantyl, noradamantyl, bornyl, norbornyl, bicyclo[2.2.1]heptyl, 2-oxobicyclo[2.2.1]heptyl or bicyclo[2.2.1]heptenyl), which may be optionally substituted by one or more (e.g. 1-10) selected from deuterium, C substituted with a substituent selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C 2-6 alkynyl and C 2-6 alkenyl; or 氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、四氢吡啶基、二羟基哌啶基、二氟哌啶基、吗啉基、硫代吗啉基、氮杂环庚烷基、氮杂环辛烷基、二氧杂环己基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1，4-二氮杂环庚烷基，4，5-二氮杂环庚烷基，1，3-二氮杂环庚烷基)、二氮杂环辛烷基、桥杂环基(例如6至20元桥杂环基，例如6-氮杂双环[3.1.1]庚烷基、2，5-二氮杂双环[2.2.1]庚烷基、3，6-二氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、2，5-二氮杂双环[2.2.2]辛烷基和奎宁环基)、和氮杂螺环基(例如5至20元氮杂螺环基，例如2，6-二氮杂螺[3.3]庚烷基、2，7-二氮杂螺[3.5]壬烷基、2，8-二氮杂螺[4.5]癸烷基、3，9-二氮杂螺[5.5]十一烷基、3-氮杂螺[5.5]十一烷基和7-氮杂螺[3.5]壬烷基)、或八氢吡咯并[3，4-c]吡咯基，其可选地被一或多个(例如1-10个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代；或azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxypiperidinyl, difluoropiperidinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanyl, dioxanyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepanyl, 4,5-diazepanyl, 1,3-diazepanyl), diazepanyl, bridged heterocyclic radical (e.g., 6 to 20 membered bridged heterocyclic radicals such as 6-azabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[ 3.1.1]heptyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl and quinuclidine), and azaspirocyclyl (e.g., a 5- to 20-membered azaspirocyclyl, such as 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 3,9-diazaspiro[5.5]undecyl, 3-azaspiro[5.5]undecyl and 7-azaspiro[3.5]nonyl), or octahydropyrrolo[3,4-c]pyrrolyl, which may be optionally substituted by one or more (e.g., 1-10) selected from deuterium, C substituted with a substituent selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C 2-6 alkynyl and C 2-6 alkenyl; or 苯基或萘基，其可选地被一或多个(例如1-7个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、C2-6炔基和C2-6烯基的取代基取代；或Phenyl or naphthyl, which is optionally substituted with one or more (e.g. 1-7) substituents selected from deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C 2-6 alkynyl and C 2-6 alkenyl; or 呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲哚啉基、苯并呋喃基、苯并二氢吡喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2，1，3]噁二唑基、苯并[2，1，3]噻二唑基、苯并[1，2，3]噻二唑基、2-氧代-2，3-二氢-1H-苯并[d]咪唑基、苯并[b][1，4]噁嗪基、3，4-二氢-2H-苯并[b][1，4]噁嗪基、喹啉基、异喹啉基、1，2，3，4-四氢喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、1，2，3，4-四氢喹喔啉基、酞嗪基、5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪基、4，5，6，7-四氢噻吩并[3，2-c]吡啶基、5-氧代-6，7-二氢噻吩并[3，2-d]嘧啶基、噻吩并[2，3-d]嘧啶基、噻吩并[3，2-d]嘧啶基、异噁唑并[4，5-c]吡啶基、异噁唑并[4，5-c]嘧啶基、异噁唑并[4，5-d]嘧啶基、吡唑并[1，5-a]吡啶基、吡唑并[1，5-a]嘧啶基、咪唑并[1，2-a]吡啶基、1H-吡咯并[3，2-b]吡啶基、1H-吡咯并[2，3-b]吡啶基、吡咯并[2，1-b]噻唑基、咪唑并[2，1-b]噻唑基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶基、或6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶基，其可选地被一或多个(例如1-10个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、C2-6炔基和C2-6烯基的取代基取代；和/或furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl oxazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimidinyl, isoxazolo[4,5-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, which may be optionally substituted by one or more (e.g., 1-10) selected from deuterium, C The present invention is substituted with a substituent selected from the group consisting of C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C 2-6 alkynyl and C 2-6 alkenyl; and/or (iv)所述环C表示：(iv) the ring C represents: 亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、亚螺环烷基(例如C5-C20亚螺环烷基，例如螺[3.3]庚烷亚基、螺[2.5]辛烷亚基、螺[3.5]壬烷亚基、螺[4.4]壬烷亚基、螺[4.5]癸烷亚基、螺[5.5]十一烷亚基)、亚对薄荷烷基、亚间薄荷烷基、或亚桥环烷基(例如C6-C20亚桥环烷基，例如亚金刚烷基、亚降金刚烷基、亚冰片基、亚降冰片基、二环[2.2.1]庚烷亚基、2-氧代二环[2.2.1]庚烷亚基或二环[2.2.1]庚烯亚基)，其可选地被一或多个(例如1-20个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代；或cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decahydronaphthylene, octahydropentalenylene, octahydro-1H-indenylene, spirocycloalkylene (e.g., C5- C20 spirocycloalkylene, such as spiro [3.3 ]heptaneylene, spiro[2.5]octanylene, spiro[3.5]nonaneylene, spiro[4.4]nonaneylene, spiro[4.5]decaneylene, spiro[5.5]undecaneylene), p-menthanylene, m-menthanylene, or bridged cycloalkylene (e.g., C6-C20 spirocycloalkylene, such as spiro[3.3]heptaneylene, spiro[2.5]octanylene, spiro[3.5]nonaneylene, spiro[4.4]nonaneylene, spiro[4.5]decaneylene, spiro[5.5]undecaneylene), p-menthanylene, m-menthanylene, or bridged cycloalkylene (e.g., C6 -C20 20 bridged cycloalkylene, for example adamantylene, noradamantylene, bornylene, norbornylene, bicyclo[2.2.1]heptanylene, 2-oxobicyclo[2.2.1]heptanylene or bicyclo[2.2.1]heptenylene), which is optionally substituted with one or more (e.g. 1-20) substituents selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, oxo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl , amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo-substituted C 1-6 alkoxy , C 2-6 alkenyl and C 2-6 alkynyl; or 亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚四氢吡啶基、二羟基哌啶亚基、二氟哌啶亚基、亚吗啉基、亚硫代吗啉基、亚氮杂环庚烷基、亚氮杂环辛烷基、亚二氧杂环己基、亚氮杂环庚烷基、亚氮杂环辛烷基、二氮杂环庚烷亚基(例如1，4-二氮杂环庚烷亚基，4，5-二氮杂环庚烷亚基，1，3-二氮杂环庚烷亚基)、二氮杂环辛烷亚基、亚桥杂环基(例如6至20元亚桥杂环基，例如6-氮杂双环[3.1.1]庚烷亚基、2，5-二氮杂双环[2.2.1]庚烷亚基、3，6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、3，8-二氮杂双环[3.2.1]辛烷亚基、2，5-二氮杂双环[2.2.2]辛烷亚基和亚奎宁环基)、亚氮杂螺环基(例如5至20元亚氮杂螺环基，例如2，6-二氮杂螺[3.3]庚烷亚基、2，7-二氮杂螺[3.5]壬烷亚基、2，8-二氮杂螺[4.5]癸烷亚基、3，9-二氮杂螺[5.5]十一烷亚基、3-氮杂螺[5.5]十一烷亚基和7-氮杂螺[3.5]壬烷亚基)、或八氢吡咯并[3，4-c]吡咯亚基，其可选地被一或多个(例如1-20个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、氧代基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代；或Azobutylene, oxebutylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, tetrahydropyridinylene, dihydroxypiperidinylene, difluoropiperidinylene, morpholinylene, thiomorpholinylene, azepanylene, octanylene, dioxanylene, azepanylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, tetrahydropyridinylene, dihydroxypiperidinylene, difluoropiperidinylene, morpholinylene, thiomorpholinylene, azepanylene, octanylene, dioxanylene, azepanylene heptyl, azacyclooctanyl, diazacycloheptanediyl (e.g., 1,4-diazacycloheptanediyl, 4,5-diazacycloheptanediyl, 1,3-diazacycloheptanediyl), diazacyclooctanyl, subbridged heterocyclic groups (e.g., 6- to 20-membered subbridged heterocyclic groups, such as 6-azabicyclo[3.1.1]heptandiyl, 2,5-diazabicyclo[2.2.1]heptandiyl, 3,6-diazabicyclo[3. 1.1] heptanediyl, 3-azabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 3,8-diazabicyclo[3.2.1]octanylidene, 2,5-diazabicyclo[2.2.2]octanylidene and quinuclidinyl), azaspirocyclyl (e.g., 5- to 20-membered azaspirocyclyl, such as 2,6-diazaspiro[3.3]heptanediyl, 2,7-diazaspiro[3.4]heptanediyl, 2,8-diazabicyclo[3.2.1]octanylidene, 2,5-diazabicyclo[2.2.2]octanylidene and quinuclidinyl), substituted C 1-6 alkyl, C 1-6 alkyl substituted with hydroxyl, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 1-6 alkyl substituted with deuterium, C 2-6 alkenyl and C 2-6 alkynyl; or 亚苯基或亚萘基，其可选地被一或多个(例如1-6个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代；或Phenylene or naphthylene, which is optionally substituted with one or more (e.g. 1-6) substituents selected from deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; or 亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚三嗪基、亚吲哚基、亚异吲哚基、亚吲哚啉基、亚苯并呋喃基、亚苯并二氢吡喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2，1，3]噁二唑基、亚苯并[2，1，3]噻二唑基、亚苯并[1，2，3]噻二唑基、2-氧代-2，3-二氢-1H-苯并[d]咪唑亚基、亚苯并[b][1，4]噁嗪基、3，4-二氢-2H-苯并[b][1，4]噁嗪亚基、亚喹啉基、亚异喹啉基、1，2，3，4-四氢喹啉亚基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、1，2，3，4-四氢喹喔啉亚基、亚酞嗪基、5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪亚基、4，5，6，7-四氢噻吩并[3，2-c]吡啶亚基、5-氧代-6，7-二氢噻吩并[3，2-d]嘧啶亚基、噻吩并[2，3-d]嘧啶亚基、噻吩并[3，2-d]嘧啶亚基、异噁唑并[4，5-c]吡啶亚基、异噁唑并[4，5-c]嘧啶亚基、异噁唑并[4，5-d]嘧啶亚基、吡唑并[1，5-a]吡啶亚基、吡唑并[1，5-a]嘧啶亚基、咪唑并[1，2-a]吡啶亚基、1H-吡咯并[3，2-b]吡啶亚基、1H-吡咯并[2，3-b]吡啶亚基、吡咯并[2，1-b]噻唑亚基、咪唑并[2，1-b]噻唑亚基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶亚基、或6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶亚基，其可选地被一或多个(例如1-20个)选自氘、卤素、羟基、巯基、硝基、氨基、氰基、C1-6烷基、卤代C1-6烷基、氘代C1-6烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基的取代基取代；和/或furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, triazinylene, indolylene, isoindolylene, indolylene, benzofuranylene, chromanylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolylene, benzo[b][1,4]oxazinylene, 3,4-dihydro-2H-benzo[b][1,4]oxazinylene, quinolylene, isoquinolylene, 1,2,3,4-tetrahydroquinolylene, naphthyridinylene, cinnolinylene, quinazolinylene, quinoxalinylene, 1,2,3,4-tetrahydroquinoxalinylene, phthalazinylene, 5,6,7,8- Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine subunit, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl subunit, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl subunit, thieno[2,3-d]pyrimidinyl subunit, thieno[3,2-d]pyrimidinyl subunit, isoxazolo[4,5-c]pyridinyl subunit, isoxazolo[4,5-c]pyrimidinyl subunit, isoxazolo[4,5-d]pyrimidinyl subunit, pyrazolo[1,5-a]pyridinyl subunit, pyrazolo[1,5-a]pyrimidinyl subunit, imidazole pyrimidine, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine, or 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine, which may be substituted by one or more (e.g., 1-20) selected from deuterium, halogen, hydroxyl, thiol, nitro, amino, cyano, C substituted with a substituent selected from C 1-6 alkyl, C 1-6 halogenated alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxy substituted alkyl, C 1-6 amino substituted alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 halogenated alkoxy, C 2-6 alkenyl and C 2-6 alkynyl; and/or (v)所述环D表示：(v) The ring D represents: 环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、螺环烷基(例如C5-C20螺环基，例如螺[3.3]庚烷基、螺[2.5]辛烷基、螺[3.5]壬烷基、螺[4.4]壬烷基、螺[4.5]癸烷基、螺[5.5]十一烷基)、对薄荷烷基、间薄荷烷基、或桥环烷基(例如C6-C20桥环基，例如金刚烷基、降金刚烷基、冰片基、降冰片基、二环[2.2.1]庚烷基、2-氧代二环[2.2.1]庚烷基或二环[2.2.1]庚烯基)，其可选地被一或多个(例如1-20个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代；或cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl (e.g. C5 - C20 spirocyclyl, such as spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl), p-menthanyl, m-menthanyl, or bridged cycloalkyl (e.g. C6 - C20 bridged cycloalkyl, such as adamantyl, noradamantyl, bornyl, norbornyl, bicyclo[2.2.1]heptyl, 2-oxobicyclo[2.2.1]heptyl or bicyclo[2.2.1]heptenyl), which may be optionally substituted by one or more (e.g. 1-20) selected from deuterium, C substituted with a substituent selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C 2-6 alkynyl and C 2-6 alkenyl; or 氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、四氢吡啶基、二羟基哌啶基、二氟哌啶基、吗啉基、硫代吗啉基、氮杂环庚烷基、氮杂环辛烷基、二氧杂环己基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1，4-二氮杂环庚烷基，4，5-二氮杂环庚烷基，1，3-二氮杂环庚烷基)、二氮杂环辛烷基、桥杂环基(例如6至20元桥杂环基，例如6-氮杂双环[3.1.1]庚烷基、2，5-二氮杂双环[2.2.1]庚烷基、3，6-二氮杂双环[3.1.1]庚烷基、3-氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、3，8-二氮杂双环[3.2.1]辛烷基、2，5-二氮杂双环[2.2.2]辛烷基和奎宁环基)、和氮杂螺环基(例如5至20元氮杂螺环基，例如2，6-二氮杂螺[3.3]庚烷基、2，7-二氮杂螺[3.5]壬烷基、2，8-二氮杂螺[4.5]癸烷基、3，9-二氮杂螺[5.5]十一烷基、3-氮杂螺[5.5]十一烷基和7-氮杂螺[3.5]壬烷基)、或八氢吡咯并[3，4-c]吡咯基，其可选地被一或多个(例如1-20个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代；或azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydroxypiperidinyl, difluoropiperidinyl, morpholinyl, thiomorpholinyl, azepanyl, azocanyl, dioxanyl, azepanyl, azocanyl, diazepanyl (e.g., 1,4-diazepanyl, 4,5-diazepanyl, 1,3-diazepanyl), diazepanyl, bridged heterocyclic radical (e.g., 6 to 20 membered bridged heterocyclic radicals such as 6-azabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[ 3,1.1]heptyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl and quinuclidine), and azaspirocyclyl (e.g., a 5- to 20-membered azaspirocyclyl, such as 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 3,9-diazaspiro[5.5]undecyl, 3-azaspiro[5.5]undecyl and 7-azaspiro[3.5]nonyl), or octahydropyrrolo[3,4-c]pyrrolyl, which may be optionally substituted by one or more (e.g., 1-20) selected from deuterium, C substituted with a substituent selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, oxo, C 2-6 alkynyl and C 2-6 alkenyl; or 苯基或萘基，其可选地被一或多个(例如1-7个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、C2-6炔基和C2-6烯基的取代基取代；或Phenyl or naphthyl, which is optionally substituted with one or more (e.g. 1-7) substituents selected from deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, amino, hydroxy, mercapto, cyano, C 2-6 alkynyl and C 2-6 alkenyl; or 呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲哚啉基、苯并呋喃基、苯并二氢吡喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2，1，3]噁二唑基、苯并[2，1，3]噻二唑基、苯并[1，2，3]噻二唑基、2-氧代-2，3-二氢-1H-苯并[d]咪唑基、苯并[b][1，4]噁嗪基、3，4-二氢-2H-苯并[b][1，4]噁嗪基、喹啉基、异喹啉基、1，2，3，4-四氢喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、1，2，3，4-四氢喹喔啉基、酞嗪基、5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪基、4，5，6，7-四氢噻吩并[3，2-c]吡啶基、5-氧代-6，7-二氢噻吩并[3，2-d]嘧啶基、噻吩并[2，3-d]嘧啶基、噻吩并[3，2-d]嘧啶基、异噁唑并[4，5-c]吡啶基、异噁唑并[4，5-c]嘧啶基、异噁唑并[4，5-d]嘧啶基、吡唑并[1，5-a]吡啶基、吡唑并[1，5-a]嘧啶基、咪唑并[1，2-a]吡啶基、1H-吡咯并[3，2-b]吡啶基、1H-吡咯并[2，3-b]吡啶基、吡咯并[2，1-b]噻唑基、咪唑并[2，1-b]噻唑基、5，6，7，8-四氢苯并[4，5]噻吩并[2，3-d]嘧啶基、或6，7-二氢-5H-环戊熳并[4，5]噻吩并[2，3-d]嘧啶基，其可选地被一或多个(例如1-20个)选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、C2-6炔基和C2-6烯基的取代基取代。furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolyl, benzofuranyl, chromanyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl oxazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, phthalazinyl, 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, isoxazolo[4,5-c]pyridinyl, isoxazolo[4,5-c]pyrimidinyl, isoxazolo[4,5-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-b]thiazolyl, 1H-pyrrolo[2,1-b]thiazolyl, 1H-pyrrolo[2,1-b]thiazolyl, 1H-pyrrolo[2,3-d]pyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H- pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H- pyrrolo[2,3-b]thiazolyl, 1H -pyrrolo[ 2,3- b]thiazolyl, 1H-pyrrolo[2,3 -b]pyrimidinyl ...d]pyrimidinyl, 1H-pyrrolo[ 2,3- d]pyrimidinyl, 1H- pyrrolo[2,3 如权利要求1-4中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物，其中R表示：
-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-或-(CH2)5-；A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof as claimed in any one of claims 1 to 4, wherein R represents:
-CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 - or -(CH 2 ) 5 -; 其中上述基团可选地被选自氘、C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、卤素、氨基、羟基、巯基、氰基、氧代基、C2-6炔基和C2-6烯基的取代基取代。The above groups are optionally substituted by substituents selected from deuterium, C1-6 alkyl, deuterated C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, halogen, amino, hydroxyl, thiol, cyano, oxo, C2-6 alkynyl and C2-6 alkenyl. 如权利要求1-5中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物，其中X表示：

A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof as claimed in any one of claims 1 to 5, wherein X represents:

如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物，其选自：The compound of formula (I) or its salt, enantiomer, stereoisomer, solvate or polymorph as claimed in claim 1, which is selected from: 3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-氟-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-fluoro-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2，6-二氧代哌啶-3-基)-4-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)异吲哚啉-1，3-二酮；2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione; 2-(2，6-二氧代哌啶-3-基)-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)异吲哚啉-1，3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione; 3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(2-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)乙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(2-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)丙基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(4-二苯基甲基哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(4-(4-diphenylmethylpiperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-氟-5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-氟-5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-fluoro-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(2，6-二氧代哌啶-3-基)-4-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)异吲哚啉-1，3-二酮；2-(2,6-dioxopiperidin-3-yl)-4-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione; 2-(2，6-二氧代哌啶-3-基)-5-(4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)异吲哚啉-1，3-二酮；2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)isoindoline-1,3-dione; 3-(5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(6-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮；3-(7-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；4-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 5-(3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-羰基)-2-(2，6-二氧代哌啶-3-基)异吲哚啉-1，3-二酮；5-(3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-carbonyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(4-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(4-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 3-(6-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-硫代异吲哚啉-2-基)哌啶-2，6-二酮；3-(6-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-thioisoindolin-2-yl)piperidine-2,6-dione; 1-(5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((4-(4-二苯基甲基哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((4-(4-diphenylmethylpiperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((4-(4-二苯基甲基哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((4-(4-diphenylmethylpiperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((3，3-二氟-4-(4-(苯基(吡啶-2-基)甲基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((3,3-difluoro-4-(4-(phenyl(pyridin-2-yl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((4-(4-(4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-羰基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((4-(4-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbonyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((4-(4-((4′-氯-5，5-二甲基-3，4，5，6-四氢-[1，1′-联苯]-2-基)甲基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((4-(4-(2，3-二氯苯基)哌嗪-1-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((4-(4-(2，3-二氯苯基)-3，6-二氢吡啶-1(2H)-基)-3，3-二氟哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((4-(4-(2,3-dichlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3,3-difluoropiperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-((4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)异吲哚啉-1，3-二酮；2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-((4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindoline-1,3-dione; 1-(5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；1-(5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-((3，3-二氟-4-(4-(6-氟苯并[d]异噁唑-3-基)哌嗪-1-基)哌啶-1-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮；5-((3,3-difluoro-4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)piperidin-1-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione; 1-(5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-1-氧代异吲哚啉-2-基)二氢嘧啶-2，4(1H，3H)-二酮；和1-(5-((3′,3′-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4′-bipiperidinyl]-1′-yl)methyl)-1-oxoisoindolin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione; and 5-((3′，3′-二氟-4-(6-氟苯并[d]异噁唑-3-基)-[1，4′-联哌啶]-1′-基)甲基)-2-(2，4-二氧代四氢嘧啶-1(2H)-基)异吲哚啉-1，3-二酮。5-((3',3'-difluoro-4-(6-fluorobenzo[d]isoxazol-3-yl)-[1,4'-bipiperidinyl]-1'-yl)methyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoindoline-1,3-dione. 如权利要求1至7中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物或多晶型物，其是式(I)化合物的硫酸盐、氢卤酸盐(包括盐酸盐、氢溴酸盐)、马来酸盐、磺酸盐、柠檬酸盐/枸橼酸盐、乳酸盐、乳糖酸盐、L-酒石酸盐、富马酸盐、L-苹果酸盐、L-乳酸盐、ɑ-酮戊二酸盐、马尿酸盐、D-葡萄糖醛酸盐、D-葡萄糖酸盐、ɑ-D-葡庚糖酸盐、乙醇酸盐、粘酸盐、L-抗坏血酸盐、乳清酸盐、苦味酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、月桂酸盐、帕莫酸盐、癸二酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、乙二磺酸盐、甲酸盐、乙酸盐、2，2-二氯乙酸盐、三甲基乙酸盐、丙酸盐、戊酸盐、棕榈酸盐、三苯基乙酸盐、2-乙基-丁二酸盐、碘酸盐、烟酸盐、L-焦谷氨酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、硝酸盐、龙胆酸盐、胆酸盐、水杨酸盐、对苯二酸盐、戊二酸盐、己二酸盐、硬脂酸盐、油酸盐、十一烯酸盐、樟脑酸盐、樟脑磺酸盐、十二基磺酸盐、磷酸盐、硫氰酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、碳酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、丙酮酸盐、对氯苯磺酸盐、1，5-萘二磺酸盐、3-羟基-2-萘甲酸盐、1-羟基-2-萘甲酸盐、2-萘磺酸盐、羟乙酸盐、三氟乙酸盐、对苯二甲酸盐和对甲苯磺酸盐。A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof as described in any one of claims 1 to 7, which is a sulfate, hydrohalide (including hydrochloride, hydrobromide), maleate, sulfonate, citrate/citrate, lactate, lactobionate, L-tartrate, fumarate, L-malate, L-lactate, α-ketoglutarate, hippurate, D-glucuronate, D-gluconate, α-D-glucoheptonate, glycolate, mucate, L-ascorbate, orotate, picrate, glycinate, alanine, arginine, cinnamate, laurate, pamoate, sebacate, benzenesulfonate, methanesulfonate, ethanesulfonate, edisylate, formate, acetate, 2,2-dichloroacetate of a compound of formula (I). , trimethylacetate, propionate, valerate, palmitate, triphenylacetate, 2-ethyl-succinate, iodate, nicotinate, L-pyroglutamate, L-proline salt, ferulate, 2-hydroxyethanesulfonate, nitrate, gentisate, cholate, salicylate, terephthalate, glutarate, adipate, stearate, oleate, undecylenate, camphorate, camphorsulfonate, dodecylsulfonate, phosphate, thiocyanate, dihydrogenphosphate, pyrophosphate, metaphosphate, oxalate, carbonate, malonate, benzoate, mandelate, succinate, pyruvate, p-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, 3-hydroxy-2-naphthoate, 1-hydroxy-2-naphthoate, 2-naphthalenesulfonate, glycolate, trifluoroacetate, terephthalate, and p-toluenesulfonate. 药物组合物，其包含如权利要求1至8中任一项所述的式(I)化合物或其医药学上可接受的盐，及至少一种医药学上可接受的载体或辅料。A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, and at least one pharmaceutically acceptable carrier or excipient. 如权利要求9所述的药物组合物，进一步包括第二治疗剂，例如抗癌剂。The pharmaceutical composition of claim 9, further comprising a second therapeutic agent, such as an anticancer agent. 如权利要求1至8中任一项所述的式(I)化合物或其药学上可接受的盐，其用于预防或治疗与cereblon蛋白相关的疾病或病症。A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, for use in preventing or treating a disease or condition associated with cereblon protein. 如权利要求1至8中任一项所述的式(I)化合物或其药学上可接受的盐，其用于预防或治疗选自以下的疾病或病症：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome，RS)、急性肝功能衰竭和糖尿病。A compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, for use in preventing or treating a disease or condition selected from the following: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes. 如权利要求11或12所述的式(I)化合物或其药学上可接受的盐，其中所述疾病或病症选自由以下组成的群组：骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性髓性白血病(CML)、慢性粒细胞白血病、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML)、急性淋巴细胞白血病(包括急性B淋巴细胞白血病、T淋巴细胞白血病、急性T淋巴细胞白血病、慢性淋巴细胞白血病、淋巴瘤细胞白血病、T淋巴细胞白血病、单核细胞白血病、髓性单核细胞白血病)；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、免疫母细胞T细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤(FL)、Burkitt′s淋巴瘤、边缘区淋巴瘤(MZL)、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤；伯基特淋巴瘤(Burkitt′s淋巴瘤)；甲状腺癌；黑色素瘤；肺癌，包括肺腺癌、肺鳞癌、非小细胞肺癌、小细胞肺癌；炎症性肌纤维母细胞瘤；结直肠癌；肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括三阴性乳腺癌、偶发性乳腺癌、乳腺管癌和考登病患者；胰腺癌；中枢神经系统癌症；神经母细胞瘤；神经胶质瘤；外周神经上皮瘤；髓外浆细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；子宫癌；头颈癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；皮肤癌；里希特氏综合征(Richter syndrome，RS)；脓毒综合征；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、银屑病关节炎、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎、化脓性汗腺炎、痛风、I型糖尿病、荨麻疹、炎症性肠病(包括克罗恩病和溃疡性结肠炎)；角结膜干燥症；炎症性疾病，包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎；脑型疟疾；感染性疾病，包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等；感染性休克；结核病；细菌性脑膜炎；慢性阻塞性肺疾病；哮喘；出血性休克；器官(包括肾、心脏、肺)或组织移植排斥反应；糖尿病；类肉瘤病；成人呼吸窘迫综合征；贫血；小儿再生障碍性贫血；心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症)；恶病质和败血症休克所致的多器官功能衰竭；和急性肝功能衰竭。A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 11 or 12, wherein the disease or condition is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia (CML), Chronic myeloid leukemia, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (including acute B-lymphocytic leukemia, T-lymphocytic leukemia, acute T-lymphocytic leukemia, chronic lymphocytic leukemia, lymphoma cell leukemia, T-lymphocytic leukemia, monocytic leukemia, myelomonocytic leukemia); lymphoma, including diffuse Non-Hodgkin's lymphoma, Hodgkin's lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, immunoblastic T-cell lymphoma, CD20-positive lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Burkitt's lymphoma, marginal zone lymphoma (MZL), primary lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) ) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma; Burkitt's lymphoma; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; brain glioma; glioblastoma astrocytoma ; ovarian cancer; bronchogenic cancer; prostate cancer; breast cancer, including triple-negative breast cancer, incidental breast cancer, ductal carcinoma, and patients with Cowden's disease; pancreatic cancer; central nervous system cancer; neuroblastoma; glioma; peripheral neuroepithelial tumor; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; head and neck cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose tumors, especially Ewing sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct cancer; bone cancer; cervical cancer; skin cancer; Richter syndrome (RS); sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Sichuan schisis, polymyositis/dermatomyositis, Sjögren's syndrome, atopic dermatitis, hidradenitis suppurativa, gout, type 1 diabetes, urticaria, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); keratoconjunctivitis sicca; inflammatory diseases, including Crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, HIV/AIDS, COVID-19 novel coronavirus infection, Gram-negative Gram-negative bacterial infection, Gram-positive bacterial infection, tuberculosis, etc.; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplant rejection; diabetes; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia in children; cardiovascular disease (such as coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure caused by cachexia and septic shock; and acute liver failure. 如权利要求1至8中任一项所述的式(I)化合物或其药学上可接受的盐或如权利要求9或10所述的药物组合物的用途，其用于制备用以预防或治疗与cereblon蛋白相关的疾病或病症的药物。Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 or a pharmaceutical composition as claimed in claim 9 or 10 for preparing a medicament for preventing or treating a disease or condition associated with cereblon protein. 如权利要求1至8中任一项所述的式(I)化合物或其药学上可接受的盐或如权利要求9或10所述的药物组合物的用途，其用于制备用以预防或治疗选自以下的疾病或病症的药物：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome，RS)、急性肝功能衰竭和糖尿病。Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, or a pharmaceutical composition as described in claim 9 or 10, for preparing a medicament for preventing or treating a disease or condition selected from the following: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes. 治疗或预防受试者中与cereblon蛋白相关的疾病或病症的方法，其包括向受试者施用治疗有效量的如权利要求1-8中任一项所述的式(I)化合物或其药学上可接受的盐，或如权利要求9或10所述的药物组合物。A method for treating or preventing a disease or condition associated with cereblon protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, or a pharmaceutical composition as described in claim 9 or 10. 治疗或预防受试者中的疾病或病症的方法，其包括向所述受试者施用治疗有效量的如权利要求1-8中任一项所述的式(I)化合物或其药学上可接受的盐，或如权利要求9或10所述的药物组合物，其中所述疾病或病症是选自：肿瘤、感染性疾病、炎性疾病、自身免疫性疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、心血管疾病、里希特氏综合征(Richter syndrome，RS)、急性肝功能衰竭和糖尿病。A method for treating or preventing a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9 or 10, wherein the disease or condition is selected from: tumors, infectious diseases, inflammatory diseases, autoimmune diseases, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, Richter syndrome (RS), acute liver failure and diabetes. 如权利要求14或15所述的用途或如权利要求16或17所述的方法，其中所述疾病或病症选自由以下组成的群组：骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性髓性白血病(CML)、慢性粒细胞白血病、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性B淋巴细胞白血病、T淋巴细胞白血病、急性T淋巴细胞白血病、淋巴瘤细胞白血病、单核细胞白血病、髓性单核细胞白血病；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、免疫母细胞T细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤(FL)、Burkitt′s淋巴瘤、边缘区淋巴瘤(MZL)、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤；伯基特淋巴瘤(Burkitt′s淋巴瘤)；甲状腺癌；黑色素瘤；肺癌，包括肺腺癌、肺鳞癌、非小细胞肺癌、小细胞肺癌；炎症性肌纤维母细胞瘤；结直肠癌；肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括三阴性乳腺癌、偶发性乳腺癌、乳腺管癌和考登病患者；胰腺癌；中枢神经系统癌症；神经母细胞瘤；神经胶质瘤；外周神经上皮瘤；髓外浆细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；子宫癌；头颈癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；皮肤癌；里希特氏综合征(Richter syndrome，RS)；脓毒综合征；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、银屑病关节炎、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎、化脓性汗腺炎、痛风、I型糖尿病、荨麻疹、炎症性肠病(包括克罗恩病和溃疡性结肠炎)；角结膜干燥症；炎症性疾病，包括肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎；脑型疟疾；感染性疾病，包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等；感染性休克；结核病；细菌性脑膜炎；慢性阻塞性肺疾病；哮喘；出血性休克；器官(包括肾、心脏、肺)或组织移植排斥反应；类肉瘤病；成人呼吸窘迫综合征；贫血；小儿再生障碍性贫血；心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症)；恶病质和败血症休克所致的多器官功能衰竭；和急性肝功能衰竭。The use of claim 14 or 15 or the method of claim 16 or 17, wherein the disease or condition is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, CML, chronic myeloid leukemia, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute B-cell leukemia, T-cell leukemia, acute T-cell leukemia, lymphoma cell leukemia, monocytic leukemia, myelomonocytic leukemia; lymphoma, including diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, anaplastic lymphoma lymphoma, anaplastic large cell lymphoma, immunoblastic T-cell lymphoma, CD20-positive lymphoma, mantle cell lymphoma, follicular lymphoma (FL), Burkitt's lymphoma, marginal zone lymphoma (MZL), primary lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma , refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma; Burkitt's lymphoma; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; brain glioma; glioblastoma astrocytoma; ovarian cancer; bronchial cancer; prostate cancer ; breast cancer, including triple-negative breast cancer, incidental breast cancer, ductal carcinoma, and patients with Cowden disease; pancreatic cancer; central nervous system cancers; neuroblastoma; glioma; peripheral neuroepithelial tumors; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumors; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; head and neck cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose tumors, Ewing sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct cancer; bone cancer; cervical cancer; skin cancer; Richter syndrome (RS); sepsis syndrome; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis/dermatomyositis, Sjögren's syndrome, atopic dermatitis, hidradenitis suppurativa, gout, type 1 diabetes, urticaria, inflammatory bowel disease (including Crohn's disease and ulcerative colitis); keratoconjunctivitis sicca; inflammatory diseases, including pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases, including viral pneumonia, AIDS, COVID-19 novel coronavirus infection, Gram-negative Bacterial infection, Gram-positive bacterial infection, tuberculosis, etc.; septic shock; tuberculosis; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue transplant rejection; sarcoidosis; adult respiratory distress syndrome; anemia; aplastic anemia in children; cardiovascular disease (such as coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); multiple organ failure caused by cachexia and septic shock; and acute liver failure. 制备如权利要求1所述的式(I)化合物的方法，其包括使式(M1)化合物与式(M2)化合物反应制备得到式(I)化合物：
A method for preparing a compound of formula (I) as claimed in claim 1, comprising reacting a compound of formula (M1) with a compound of formula (M2) to obtain a compound of formula (I):
其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5、(Rd1)n1、环B、(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D、和(Rd4)n4如权利要求1中所定义；wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2, Z3 , Z4 , Z5 , ( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc , ring C, m1, ( Rd3 ) n3 , ring D, and ( Rd4 ) n4 are as defined in claim 1; 含氮杂环A表示4至30元含氮杂环(优选地，4至20元含氮杂环；更优选地，4至15元含氮杂环)；The nitrogen-containing heterocycle A represents a 4- to 30-membered nitrogen-containing heterocycle (preferably, a 4- to 20-membered nitrogen-containing heterocycle; more preferably, a 4- to 15-membered nitrogen-containing heterocycle); R表示可选取代的直链或支链的C1-5亚烷基；R represents an optionally substituted straight or branched C 1-5 alkylene group; LE表示Cl、Br、I、甲磺酰氧基、对甲苯磺酰氧基、邻硝基苯磺酰基、C(O)Cl或COOH；和LE represents Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, o-nitrobenzenesulfonyl, C(O)Cl or COOH; and 式(I)化合物的Xa相应地表示由以下通式表示的结构：
 Xa of the compound of formula (I) correspondingly represents a structure represented by the following general formula:
其中含氮亚杂环基A是所述含氮杂环A去除N上的氢原子获得的二价基团，所述含氮亚杂环基A表示4至30元含氮亚杂环基(优选地，4至20元含氮亚杂环基；更优选地，4至15元含氮亚杂环基)，以及wherein the nitrogen-containing heterocyclic group A is a divalent group obtained by removing a hydrogen atom from N of the nitrogen-containing heterocyclic ring A, and the nitrogen-containing heterocyclic group A represents a 4- to 30-membered nitrogen-containing heterocyclic group (preferably, a 4- to 20-membered nitrogen-containing heterocyclic group; more preferably, a 4- to 15-membered nitrogen-containing heterocyclic group), and (Rd1)n1、环B、(Rd2)n2、Rc、环C、m1、(Rd3)n3、环D、和(Rd4)n4如权利要求1-8中任一项中所定义。( Rd1 ) n1 , ring B, ( Rd2 ) n2 , Rc , ring C, m1, ( Rd3 ) n3 , ring D, and ( Rd4 ) n4 are as defined in any one of claims 1 to 8. 如权利要求19所述的方法，其中(1)当基团LE表示甲磺酰氧基时，通过使式(M3)化合物与甲烷磺酸酐或甲烷磺酰氯发生反应制备得到式(M1)化合物：
The method of claim 19, wherein (1) when the group LE represents a methanesulfonyloxy group, the compound of formula (M1) is prepared by reacting a compound of formula (M3) with methanesulfonic anhydride or methanesulfonyl chloride:
其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4、Z5和R如权利要求19中所定义；或wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 , Z5 and R are as defined in claim 19; or 其中(2)当基团LE表示Cl、Br或I时，通过使所述式(M3)化合物与氢卤酸发生卤代反应制备得到式(M1)化合物。Wherein (2) when the group LE represents Cl, Br or I, the compound of formula (M1) is prepared by subjecting the compound of formula (M3) to a halogenation reaction with a hydrohalic acid. 如权利要求20或21所述的方法，其中式(M1)化合物、式(I)化合物和式(M3)化合物的R表示CH2。The method according to claim 20 or 21, wherein R of the compound of formula (M1), the compound of formula (I) and the compound of formula (M3) represents CH 2 . 如权利要求21所述的方法，其中通过使式(M4)化合物与(三丁基锡)甲醇在钯催化剂催化下发生偶联反应制备得到式(M3)化合物：
The method of claim 21, wherein the compound of formula (M3) is prepared by coupling reaction of the compound of formula (M4) with (tributyltin)methanol under a palladium catalyst:
其中基团Ra1、Ra2、Ra3、Ra4、(Ra5)m、Z1、Z2、Z3、Z4和Z5如权利要求19中所定义。wherein the groups Ra1 , Ra2 , Ra3 , Ra4 , ( Ra5 ) m , Z1 , Z2 , Z3 , Z4 and Z5 are as defined in claim 19. 如权利要求22所述的方法，其中当式(M4)化合物中的Z5表示N，且Z1表示C(O)、CH2或CD2，Z2、Z3和Z4各自独立地表示C(O)时，通过使式(M5)化合物与式(M6)化合物发生胺酯交换反应制备得到式(M4)化合物：
The method of claim 22, wherein when Z 5 in the compound of formula (M4) represents N, and Z 1 represents C(O), CH 2 or CD 2 , and Z 2 , Z 3 and Z 4 each independently represent C(O), the compound of formula (M4) is prepared by subjecting the compound of formula (M5) to an amine ester exchange reaction with the compound of formula (M6):
其中基团Ra1、Ra2、Ra3、Ra4和(Ra5)m如权利要求19中所定义。wherein the groups Ra1 , Ra2 , Ra3 , Ra4 and ( Ra5 ) m are as defined in claim 19. 如权利要求22所述的方法，其中当式(M4)化合物中的Z1表示C(O)、C(S)、CH2或CD2，Z2、Z3和Z4各自独立地表示C(O)或C(S)，且Z1、Z2、Z3和Z4中至少一个表示C(S)时，通过使式(M7)的化合物与硫化试剂发生硫化作用来制备得到式(M4)的化合物：
The method of claim 22, wherein when Z 1 in the compound of formula (M4) represents C(O), C(S), CH 2 or CD 2 , Z 2 , Z 3 and Z 4 each independently represent C(O) or C(S), and at least one of Z 1 , Z 2 , Z 3 and Z 4 represents C(S), the compound of formula (M4) is prepared by subjecting the compound of formula (M7) to a sulfiding agent to sulfidation:
其中式(M7)的化合物的Z6表示C(O)、CH2或CD2；以及wherein Z 6 of the compound of formula (M7) represents C(O), CH 2 or CD 2 ; and 基团Ra1、Ra2、Ra3、Ra4和(Ra5)m如权利要求19中所定义。The groups Ra1 , Ra2 , Ra3 , Ra4 and ( Ra5 ) m are as defined in claim 19. 如权利要求24所述的方法，其中所述硫化试剂包括二硫化碳，六甲基二硅硫烷，硫，硫脲，硫化氢，五硫化二磷，劳森试剂(Lawesson′s Reagent)，Belleau’s试剂，和Davy’s试剂。A method as claimed in claim 24, wherein the sulfiding reagent includes carbon disulfide, hexamethyldisilathane, sulfur, thiourea, hydrogen sulfide, phosphorus pentasulfide, Lawesson's Reagent, Belleau’s Reagent, and Davy’s Reagent.
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