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WO2025113665A1 - Fused tetraheterocyclic derivative, pharmaceutical composition thereof, and use thereof - Google Patents

Fused tetraheterocyclic derivative, pharmaceutical composition thereof, and use thereof Download PDF

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Publication number
WO2025113665A1
WO2025113665A1 PCT/CN2024/135781 CN2024135781W WO2025113665A1 WO 2025113665 A1 WO2025113665 A1 WO 2025113665A1 CN 2024135781 W CN2024135781 W CN 2024135781W WO 2025113665 A1 WO2025113665 A1 WO 2025113665A1
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Prior art keywords
ring
alkyl
alkoxy
halogenated
substituted
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French (fr)
Chinese (zh)
Inventor
李鑫
周鹏飞
江斌
王如伟
马前
刘阳
郝生雷
童忠安
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
Original Assignee
Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Publication of WO2025113665A1 publication Critical patent/WO2025113665A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/22—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 four or more hetero rings
    • 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
    • C07D491/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to the field of medical technology, and in particular to a fused tetraheterocyclic derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition and medical uses thereof.
  • the Polycomb group (PcG) protein Polycomb repressive complex 2 plays the core function of transcriptional repression in the body, and achieves gene silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27me3); in tumors, it can promote the occurrence and development of tumors by inhibiting the expression of tumor suppressor genes.
  • the catalytic subunit EZH2 of PRC2 is an important representative of the third generation epidemic genetic regulation precision therapy targets. Compared with the first and second generation pan epigenetic regulation targets, current therapeutic targets can target tumors with specific mutation types, and the efficacy and safety have been greatly improved.
  • EZH2 is an ideal target for directly shutting down the abnormal activity of PRC2, as a complex protein, the function and activity of PRC2 is highly dependent on the regulation of the skeleton and another core subunit EED.
  • the methyltransferase activity of the PRC2 complex can also be inhibited by interfering with the protein-protein interaction (PPI) between EZH2 and EED.
  • PPI protein-protein interaction
  • TPD targeted protein degradation
  • PROTACs proteolysis targeting chimeras
  • Protein degraders can target "undruggable" targets, improve the selectivity and inhibitory activity of targets, prolong the duration of drug action and drug-resistant mutations; they are particularly suitable for drug development against traditionally undruggable targets (such as transcription factors and scaffold proteins), targets that are prone to acquired drug-resistant mutations during tumor targeted therapy, targets with gene amplification and/or protein overexpression, targets with different protein subtypes, scaffold proteins, protein polymers, etc.
  • small molecule inhibitors targeting EZH2 have been approved for marketing, and the feasibility of PRC2 as an anti-tumor drug target has been verified clinically, but the effect of EZH2 small molecule inhibitors in solid tumors is still limited, and multiple small molecule inhibitors of EZH2 and EED are still under clinical research.
  • the use of protein degradation technology for drug development of this target may bring new directions and breakthroughs to drug development of this target.
  • the object of the present invention is to provide a PROTAC compound, which can degrade and/or inhibit EED protein, has excellent degradation/inhibition effect on EED protein and excellent tumor cell proliferation inhibition effect, and has excellent pharmacokinetic characteristics, good CYP450 effect, good safety, and is more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: POI—(L) n0 —ULM (I)
  • POI is the ligand that binds to the EED protein
  • L is the connection link between POI and ULM
  • ULM is the group that binds to the E3 ligase
  • n0 is 0 or 1.
  • n0 is 0.
  • n0 is 1.
  • POI is a structure represented by formula (A-1) or an isomer thereof
  • W 4 and W 5 are each independently selected from -CH-, -N- and -C-;
  • the A1 ring is selected from a C3-15 cycloalkyl ring (preferably a C3-12 cycloalkyl ring, more preferably a C3-10 cycloalkyl ring, further preferably a C3-8 cycloalkyl ring, further preferably a C3-6 cycloalkyl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 4- to 12-membered heterocycloalkyl ring, more preferably a 4- to 10-membered heterocycloalkyl ring, further preferably a 4- to 8-membered heterocycloalkyl ring, further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 15-membered heteroaryl ring (preferably a 5- to 12-membered heteroaryl ring, more preferably a 5- to 10-membered heteroaryl ring, further preferably a 5- to 6-membered heteroaryl ring) and a C6-14
  • R 1 p1 represents that the hydrogen on the A1 ring is replaced by p1 R 1s , p1 is 0, 1, 2 or 3, each R 1 is the same or different and is independently selected from X 1 , hydrogen, deuterium, cyano, carboxyl, nitro, formyl, sulfonic acid , halogen (preferably fluorine, chlorine or bromine), C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-6 alkyl, and further preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-8 alkyl, more preferably halogenated C 1-6 alkyl, and further preferably halogenated C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, and further preferably C 1-3 alkoxy), halogenated C 1-10 alkoxy (preferably halogenated C 1-8 alkoxy, more preferably halogenated C 1-8 al
  • each R 2 is the same or different and is independently selected from X 1 , hydrogen, deuterium, C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-6 alkyl, and further preferably C 1-3 alkyl ), C 1-10 alkoxy (preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, and further preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-8 alkyl, more preferably halogenated C 1-6 alkyl, and further preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-8 alkoxy, more preferably halogenated C 1-6 alkoxy, and further preferably halogenated C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C The C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-6 alkyl, and further preferably C 1-3 alkyl ), C 1-10
  • each R 3 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -COC 1-8 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -COOC 1-8 alkyl (preferably -COOC 1-6 alkyl (preferably -COOC 1-6 alkyl (preferably -COOC 1-6 alkyl (preferably -COOC 1-6 alkyl (preferably -COOC 1-6 alky
  • R 4 p4 represents that the hydrogen on the imidazo[1,5-c]pyrimidine ring is replaced by p4 R 4 , p4 is 0, 1 or 2, each R 4 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -COC 1-8 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -COOC 1-8 alkyl (preferably -COOC 1-6 alkyl
  • X 1 is the connection site between POI and L or ULM, and at least one of R 1 and R 2 is X 1 .
  • W 1 , W 2 , W 3 are each independently selected from a bond, -CH 2 -, -C(O)NH-, and -NHC(O)-.
  • W 4 , W 5 are each independently selected from -CH- and -C-.
  • the structure represented by formula (A-1) is the structure represented by formula (A-2) or an isomer thereof,
  • p1 is zero.
  • p1 is 1.
  • R 1 is selected from Xi 1 , hydrogen, cyano, carboxyl, nitro, formyl, sulfonic acid, methyl, ethyl, propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, tetrahydropyrrolyl, tetrahydrofur
  • R 1 is selected from the group consisting of F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 OH, -CH 2 CH 2 OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -SOCH 3 , -SO 2 CH 3 , -SO 2 NH 2 , -SO 2 NHCH 3 and -SO 2 N(CH 3 ) 2 .
  • R1 is selected from Xi , hydrogen, -CH3, -CHF2 , -CF3 , -CH2OH, -OCH3 , -OCH2CH3 , -COCH3 , -COOCH3 , -CONH2 , -CONHCH3 , -CON ( CH3 ) 2 , -SOCH3 , -SO2CH3 , -SO2NH2 , -SO2NHCH3 , and -SO2N ( CH3 ) 2 .
  • R 1 is selected from the group consisting of X 1 , —CH 3 , and —CF 3 .
  • R 1 is selected from X 1 and —CF 3 .
  • p1 is 1, and R 1 is X 1 or -CF 3 .
  • p1 is 1 and R 1 is X 1 .
  • p1 is 1 and R1 is -CF3 .
  • p2 is 0.
  • p2 is 1.
  • R 2 is selected from X 1 , hydrogen, deuterium, C 1-3 alkyl (preferably methyl, ethyl, isopropyl), halogenated C 1-3 alkyl (preferably trifluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl), C 3-6 cycloalkyl (preferably cyclopropyl, cyclobutyl) and 4 to 6 membered heterocycloalkyl; the C 1-3 alkyl, halogenated C 1-3 alkyl, C The 3-6- membered cycloalkyl and 4- to 6-membered heterocycloalkyl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, carboxyl, nitro, formyl, sulfonic acid, methyl, ethyl, isopropyl, methoxy, ethoxy, is
  • R2 is selected from Xi , hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, -CH2 -cyclopropyl, -CH2-azetidine, -CH2 -tetrahydropyrrole, -CH2 -piperidine, -CH2 -piperazine, tetrahydro-2H-pyran, and -CH2- (tetrahydro-2H-pyran ) .
  • R2 is selected from Xi , hydrogen, deuterium, -CH3, -CH2CH3 , -CH2CH2CH3 , -CH( CH3 ) 2 , -C( CH3 ) 3 , -CH2F , -CHF2 , -CF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -CH2CF2CH3 , cyclopropyl , cyclobutyl , cyclopentyl, cyclohexyl , azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl , -CH2 - cyclopropyl , -CH2-azetidine, -CH2 -tetrahydropyrrole, -CH2-piperidine, -CH2 -piperazine, tetrahydro - 2H -pyr
  • R 2 is selected from the group consisting of X 1 , -CH 3 , -CH 2 CHF 2 , -CH 2 CF 2 CH 3 , and -CH(CH 3 ) 2 .
  • R 2 is selected from X 1 and -CH(CH 3 ) 2 .
  • R 2 is X 1 .
  • R 2 is -CH(CH 3 ) 2 .
  • p2 is 1 and R 2 is X 1 or -CH(CH 3 ) 2 .
  • p2 is 1 and R 2 is X 1 .
  • p2 is 1 and R 2 is -CH(CH 3 ) 2 .
  • p3 is 0.
  • p3 is 1.
  • p3 is 3.
  • R 3 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl, quinolyl, naphthyl, -CH 2 -cyclopropyl, -CH 2 -
  • R3 is selected from hydrogen, deuterium, fluorine, chlorine , bromine, iodine , -CH3 , -CH2CH3, -CH( CH3 ) 2 , -CH2CH2CH3 , -CH2F , -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH ( CH3 ) 2 , -OCH2F , -OCHF2 , -OCF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -OCH2CH2F , -OCH2CHF2 , and -OCH2CF3 .
  • p3 is 1 and R3 is fluoro.
  • two adjacent R 3 and the carbon atom to which they are attached form a C 3-6 cycloalkyl ring, a 3- to 6-membered heterocycloalkyl ring, or a 5- to 6-membered heteroaryl ring.
  • two adjacent R3 and the carbon atom to which they are attached form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cyclohexene ring, a cyclopentene ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, a thiazole ring, a pyrazole ring, an imidazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring or a triazine ring.
  • two adjacent R 3 and the carbon atom to which they are attached form a cyclopropane ring.
  • p3 is 3, wherein one R 3 is fluorine, and the other two R 3 and the carbon atom to which they are attached form a cyclopropane ring.
  • the C 3-15 cycloalkyl ring in the A1 ring is selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a bicyclopentane ring, a cyclohexane ring, a spiro[3.3]heptane ring, a spiro[3.4]octane ring, a spiro[3.5]nonane ring, a decalin ring, a tetradecahydroanthracene ring, an octahydro-1'H-spiro[cyclopentane-1,2'-naphthalene] ring, a cyclohexene ring and a spiro[4.5]dec-6-ene ring.
  • the 3- to 15-membered heterocycloalkyl ring in the A1 ring is selected from an azetidine ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a piperazine ring, a 2,5-dihydro-1H-pyrrole ring, a 2,3-dihydro-1H-pyrrole ring, a 1,2,3,6-tetrahydropyridine ring, a 1,2,3,4-tetrahydropyridine ring, a 3,4-dihydro-2H-1,4-oxazine ring, a 1,3-dioxole ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ...azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ring
  • the 5- to 15-membered heteroaryl ring in the A1 ring is selected from a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a benzopyrrole ring, a benzofuran ring, a benzothiophene ring, a benzopyrazole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a pyridine ring,
  • a pyridopyrrole ring a pyridofuran ring, a pyridothiophene ring, a pyridopyrazole ring, a pyridoimidazole ring, a pyridothiazole ring, a pyridooxazole ring, a pyrimidopyrrole ring, a pyridazinopyrrole ring, a pyrazinopyrrole ring, a pyrimidopyrazole ring, a pyridazinopyrazole ring, a pyrazinopyrazole ring, a pyrimidoimidazole ring, a pyridazinoimidazole ring, a pyrazinoimidazole ring, a quinoline ring, an isoquinoline ring and a 9H-pyrido[2,3-b]indole ring.
  • the C 6-14 aromatic ring in the A1 ring is selected from a benzene ring and a naphthalene ring.
  • the A1 ring is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, and a thiazole ring.
  • the A1 ring is selected from a benzene ring, a pyridine ring, and a pyrazole ring.
  • the A1 ring is selected from a benzene ring and a pyridine ring.
  • R 1 , R 2 , and p1 are as defined in the specification, and at least one of R 1 and R 2 is X 1 .
  • the structure Selected from:
  • the structure Selected from Wherein Y 1 , Y 2 , and Y 3 are each independently CH or N, (R 1 ) p1 , R 2 , and A1 are as described in the specification, and X 1 is the connection site between POI and L or ULM.
  • Y 1 , Y 2 , and Y 3 are each independently CH.
  • Y 2 and Y 3 are each independently CH, and Y 1 is N.
  • Y 1 and Y 3 are each independently CH, and Y 2 is N.
  • Y 1 and Y 2 are each independently CH, and Y 3 is N.
  • Y 1 and Y 2 are each independently N, and Y 3 is CH.
  • Y 2 and Y 3 are each independently N, and Y 1 is CH.
  • Y 1 , Y 2 , and Y 3 are each independently N.
  • the structure Selected from Where X1 is the connection site between POI and L or ULM.
  • the structure Selected from Where X1 is the connection site between POI and L or ULM.
  • the structure Selected from: Where X1 is the connection site between POI and L or ULM.
  • the structure Selected from: Where X1 is the connection site between POI and L or ULM.
  • the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.
  • the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.
  • the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.
  • the compound represented by formula (I) is represented by formula (IC),
  • R 1 , R 2 , R 3 , W 4 , W 5 A1 ring, R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p2, p3, p4 and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .
  • the compound represented by formula (I) is represented by formula (ID),
  • R 1 , R 2 , R 3 , W 4 , W 5 A1 ring, R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p2, p3, p4 and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .
  • the compound represented by formula (I) is represented by formula (IE),
  • R 1 , R 3 , R 4 , L, ULM, p1, p3, p4 and n0 are as defined in the specification, and R 1 is not X 1 .
  • the compound represented by formula (I) is represented by formula (IF),
  • R 2 is not X 1 .
  • the compound represented by formula (I) is represented by formula (IA),
  • R 1 , R 3 , R 4 , L, ULM, p1, p3, p4 and n0 are as defined in the specification, and R 1 is not X 1 .
  • the compound represented by formula (I) is represented by formula (IB),
  • R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p3, p4 and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .
  • the compound represented by formula (I) is represented by formula (IB-1),
  • R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p3, p4, n0, Y 1 , Y 2 , and Y 3 are as defined in the specification, and R 1 and R 2 are not X 1 .
  • the compound represented by formula (I) is selected from the following structures: wherein R 1 , R 2 , R 3 , L, ULM, p1, p3, and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .
  • the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, and n0 are as defined in the specification.
  • the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, and n0 are as defined in the specification.
  • the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, and n0 are as defined in the specification.
  • L is a structure represented by formula (L-1) or an isomer thereof, -(L a ) m1 - (L-1),
  • n1 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • Each occurrence of L a is independently selected from a bond, -C(O)-, -C(O)NR L1 -, -NR L1 -, -O-, -S-, C 1-10 alkylene (preferably C 1-8 alkylene, more preferably C 1-6 alkylene, and further preferably C 1-3 alkylene), C 1-10 alkyleneoxy (preferably C 1-8 alkyleneoxy, more preferably C 1-6 alkyleneoxy, and further preferably C 1-3 alkyleneoxy), C 2-10 alkenylene (preferably C 2-8 alkenylene, more preferably C 2-6 alkenylene, and further preferably C 2-4 alkenylene), C 2-10 alkynylene (preferably C 2-8 alkynylene, more preferably C 2-6 alkynylene, and further preferably C 2-4 alkynylene), C 3-15 cycloalkyl ring (preferably C 3-10 cycloalkyl ring, more preferably C 3-8 cycloalkyl ring, and
  • Each occurrence of RL1 is independently selected from hydrogen, deuterium, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), halo-substituted C1-8 alkoxy (preferably halo-substituted C1-6 alkoxy, more preferably halo-substituted C1-3 alkoxy) and halo-substituted C1-8 alkyl (preferably halo-substituted C1-6 alkyl, more preferably halo-substituted C1-3 alkyl).
  • each occurrence of R is independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoroethoxy, difluoroethoxy, and monofluoroethoxy.
  • each occurrence of R L1 is independently selected from hydrogen, methyl, ethyl, difluoromethyl, and monofluoromethyl.
  • R L1 is hydrogen
  • each RL is independently selected from deuterium, halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, amino, carboxyl, hydroxymethyl, hydroxyethyl, methyl, ethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
  • each RL2 is independently selected from deuterium, -F, -Cl , -Br , -OH , -CN , -CHO, -COOH, -NH2 , -CH2OH , -CH2CH2OH , -CH3 , -CH2CH3 , -CH2F, -CHF2 , -CF3 , -CH2CH2F, -CH2CHF2 , -CH2CF3 , -OCH3 , -OCH2CH3, -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2, -OCH2CF3 , -COCH3 , -CH2 - cyclopropyl , cyclopropyl , -CONH2 , -COOCH3 , -OCOCH3, -CONHCH3 , -
  • each RL2 is independently selected from deuterium, -F, -Cl , -Br , -OH , -CN , -COOH , -NH2, -CH2OH , -CH2CH2OH, -CH3 , -CH2CH3 , -CH2F , -CHF2 , -CF3, -CH2CH2F, -CH2CHF2 , -CH2CF3 , -OCH3 , -OCH2CH3 , -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2 , -OCH2CF3 , -COCH3 , -CH2 - cyclopropyl, cyclopropyl , and -CONH2 .
  • R L2 are each independently selected from fluoro, chloro, bromo, methyl, hydroxy, and hydroxymethyl.
  • the La is each independently selected from the following structures or isomers thereof: -C(O)-, -C(O)NH-, -O-, -S-, -NH-, C1-10 alkylene, C1-10 alkyleneoxy, C3-12 cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring; the C3-12 cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring are unsubstituted or substituted with 1, 2, 3 or 4 RL2 , and the RL2 is selected from fluorine, methyl, hydroxyl and hydroxymethyl.
  • the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH 2 ) m2 -, -O(CH 2 ) m2 -, -(CH 2 ) m2 O-, cyclopropane ring, cyclobutane ring, bicyclopentane ring, cyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, 2-azaspiro[3.3]heptane ring, 6-azaspiro[3.4]octan
  • the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH 2 ) m2 -, -O(CH 2 ) m2 -, -(CH 2 ) m2 O-, cyclopropane ring, cyclobutane ring, cyclopentane ring, bicyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, 2-azaspiro[3.3]heptane ring, 7-azaspiro[3.5]nonan
  • the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH2-, -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4- , - ( CH2 ) 5- , - ( CH2 ) 7- , -( CH2 ) 8- , -OCH2- , -OCH2CH2-, -CH2O- , -CH2CH2 O-, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, cyclobutane ring, cyclopentan
  • the La is each independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -CH 2 CH 2 O-,
  • the La is each independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -CH 2 CH 2 O-,
  • the La is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -NH-, -CH 2 -,
  • the La is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -CH 2 -, -NH-,
  • the La is independently selected from the following structures or isomers thereof: -CONH-, -CH2- , -NH-, -CO-,
  • the La is independently selected from the following structures or isomers thereof: -CH2- , -NH-, -CONH-, -CO-,
  • L is selected from the following structures or isomers thereof: -( CH2 ) m3- , -C(O)-( CH2 ) m3- , -C(O)NH-( CH2 ) m3- , -C(O)NH-( CH2 ) m3 -O-, -Cy0 -NH-( CH2 ) m3- , -C(O)NH- Cy0- , -C(O)-Cy0-, -(CH2) m3 -C(O)-Cy0-, -( CH2 ) m3 - C (O)-Cy0-, -( CH2 ) m3 - Cy0- , -( CH2 ) m3 -C(O)NH-( CH2 ) m3 O-Cy0-O( CH2 ) m3- , -Cy0 - Cy0-, -Cy0 - CH2- Cy0- ,
  • the Cy O is each independently selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a bicyclopentane ring, a cyclohexane ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a hydroxy-substituted piperidine ring, a hydroxymethyl-substituted piperidine ring, a piperazine ring, a 2-azaspiro[3.3]heptane ring, a 6-azaspiro[3.4]octane ring, a 7-azaspiro[3.5]nonane ring, a 2,6-diazaspiro[3.3]heptane ring, a 2,6-diazaspiro[3.4]octane ring, a 2,7-diazaspiro[3.5]nonane ring,
  • azine ring a triazine ring, a thiophene ring, a furan ring, a pyrrole ring, a thiazole ring, an oxazole ring, a pyrazole ring, an imidazole ring, a triazole ring, (2S,6R)-2,6-dimethylpiperazine, 3-azabicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane and 3,9-diazaspiro[5.5]undecane, 1,1,3,3-tetramethylcyclobutane, 3-fluoropiperidine, (S)-3-fluoropiperidine
  • the Cy O is each independently selected from the following structures or isomers thereof: piperidine ring, piperazine ring, 3,3,5,5-tetramethylpiperidine, cyclohexane ring, cyclobutane ring, 1,1,3,3-tetramethylcyclobutane, azetidine ring, 3,3-difluoropiperidine, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,5-dimethylpiperidine, 2,6-dimethylpiperazine, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 3-azabicyclo[3.2.1]octane.
  • the Cy O is each independently selected from the following structures or isomers thereof: piperidine ring, piperazine ring, 3,3,5,5-tetramethylpiperidine, 3,3-difluoropiperidine, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,3-dimethylpiperidine, 2,6-dimethylpiperazine, azetidine ring, 1,1,3,3-tetramethylcyclobutane, cyclohexane ring, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.2.1]octane.
  • the Cy O is independently selected from the following structures or isomers thereof: piperidine ring, 3,3-difluoropiperidine, 3,9-diazaspiro[5.5]undecane, 7-azaspiro[3.5]nonane, 3-azabicyclo[3.2.1]octane.
  • the Cy 0 is each independently selected from the following structures or isomers thereof: piperidine ring, 3,3-difluoropiperidine, 3,9-diazaspiro[5.5]undecane, 7-azaspiro[3.5]nonane.
  • the Cy O is each independently selected from the following structures or isomers thereof:
  • the Cy O is each independently selected from the following structures or isomers thereof:
  • the Cy O is each independently selected from the following structures or isomers thereof:
  • the Cy O is each independently selected from the following structures or isomers thereof:
  • the Cy O is each independently selected from the following structures or isomers thereof:
  • L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.
  • L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.
  • L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.
  • L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.
  • L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.
  • ULM is a compound represented by formula (U-1) or an isomer thereof:
  • U0 is a bond, -N(R U0 )-, -CON(R U0 )-, -CH 2 - or -(CH 2 ) 2 -;
  • R U0 is independently hydrogen or C 1-3 alkyl
  • Ring B is absent or is selected from a 5- to 15-membered heteroaryl ring (preferably a 6- to 12-membered heteroaryl ring, more preferably a 6- to 10-membered heteroaryl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 5- to 12-membered heterocycloalkyl ring, more preferably a 5- to 10-membered heterocycloalkyl ring), a C 3-15 cycloalkyl ring, and a C 6-10 aromatic ring (preferably a benzene ring);
  • a 5- to 15-membered heteroaryl ring preferably a 6- to 12-membered heteroaryl ring, more preferably a 6- to 10-membered heteroaryl ring
  • a 3- to 15-membered heterocycloalkyl ring preferably a 5- to 12-membered heterocycloalkyl ring, more preferably a 5- to 10-membered heterocycloalkyl ring
  • S 2 and S 4 are each independently selected from -N-, -NH-, -CH- and -CH 2 -;
  • S 6 is selected from C, -CH- and N;
  • R B1 b1 represents that the hydrogen on the B ring is replaced by b1 R B1s , b1 is 0, 1, 2 or 3, each R B1 is the same or different and is independently selected from X 2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, -NR a1 R b1 , C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl),
  • each RB2 is the same or different and is independently selected from X2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, -NRa1Rb1 , C1-6 alkyl , C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl , -CONRa2Rb2, C1-6 alkyl substituted with -OC (O) C1-6 alkyl and C1-6 alkyl substituted with -COOC1-6 alkyl;
  • halogen preferably fluorine, chlorine or bromine
  • Ra1 , Rb1 , Ra2 , and Rb2 are each independently selected from hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, cyano-substituted C1-6 alkyl, carboxyl-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, -COC1-6 alkyl, and -COOC1-6 alkyl;
  • X2 is the connection site between ULM and L or POI, and at least one of RB1 and RB2 is X2 .
  • RB1 and RB2 are not both X2 .
  • the B ring is absent.
  • the 5- to 15-membered heteroaryl ring in Ring B is selected from a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a benzopyrrole ring, a benzofuran ring, a benzothiophene ring, a benzopyrazole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a pyridine ring, a The rings
  • the 5- to 15-membered heteroaryl ring in Ring B is selected from a pyridine ring and a benzopyrazole ring.
  • the 5- to 15-membered heteroaryl ring in Ring B is selected from: in Indicates covalent attachment to U 0 .
  • the 5- to 15-membered heteroaryl ring in Ring B is selected from: in Indicates covalent attachment to U 0 .
  • the C 6-10 aromatic ring in Ring B is selected from a benzene ring and a naphthalene ring.
  • the C 6-10 aromatic ring in Ring B is a benzene ring.
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from: in Indicates covalent attachment to U 0 .
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from —CH—, N, and NO; S 7 and S 8 are each independently selected from a bond, —O—, —NH—, —CH 2 —, —C(O)—, —C(O)O—, —C(O)S—, —CH 2 C(O)—, —CH 2 C(S)—, —C(S)—, —CONH—, —CH ⁇ N—, —N ⁇ N—, —CH ⁇ CH—, —SO—, and —SO 2 —; Indicates covalent attachment to U 0 .
  • Q 1 , Q 2 , Q 3 , and Q 4 are each independently -CH-.
  • S 7 and S 8 are each independently selected from -CH 2 - and -C(O)-.
  • S7 is -CH2- and S8 is -C(O)-.
  • S7 is -C(O)- and S8 is -C(O)-.
  • S7 is -CH2- and S8 is -C(S)-.
  • S7 is -C(O)- and S8 is -C(S)-.
  • S7 is a bond and S8 is -CONH-.
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B1 and Ring B2 are each independently selected from a C 4-8 cycloalkyl ring, a 4- to 8-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring and a benzene ring; S 9 and S 10 are each independently selected from a bond, -CH 2 - and -C(O)-; Indicates covalent attachment to U 0 .
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from wherein Ring B3, Ring B4 and Ring B5 are each independently selected from a C 5-7 cycloalkyl ring and a 5- to 7-membered heterocycloalkyl ring, Q 1 , Q 2 , Q 3 , Q 4 , S 7 and S 8 are as described in the specification, Indicates covalent attachment to U 0 .
  • Ring B3, Ring B4, and Ring B5 are each independently selected from a partially unsaturated C 5-7 cycloalkyl ring and a partially unsaturated 5- to 7-membered heterocycloalkyl ring.
  • Ring B3, Ring B4, Ring B5 are each independently selected from 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-1,4-oxazine, 1,3-dioxole, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine and 2,3,4,5-tetrahydro-1H-azepine.
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from in Indicates covalent attachment to U 0 .
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is in Indicates covalent attachment to U 0 .
  • Ring B3 is a 5- to 7-membered nitrogen-containing heterocycloalkyl ring.
  • Ring B3 is a partially unsaturated 5- to 7-membered nitrogen-containing heterocycloalkyl ring.
  • Ring B3 is selected from 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine, and 2,3,4,5-tetrahydro-1H-azepine.
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B7 is a 5- to 10-membered heterocycloalkyl ring, Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently selected from C, -CH-, and N, Indicates covalent attachment to U 0 .
  • Ring B7 is 1,3-dioxole.
  • the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B6 is selected from a 5- to 6-membered heteroaryl ring and a benzene ring; Q 11 , Q 12 , Q 13 are each independently selected from -C-, -N-, -S-, -O-, -NH-; S 7 and S 8 are as described in the specification, Indicates covalent attachment to U 0 .
  • Ring B6 is a benzene ring.
  • Q 11 is selected from -S-, -O-, and -NH-, and Q 12 and Q 13 are each independently selected from -C-.
  • the structure Selected from: in Indicates covalent attachment to U 0 .
  • Ring B is selected from: in Indicates covalent attachment to U 0 .
  • Ring B is selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 .
  • Ring B is selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 .
  • each R B1 is independently X 2 , deuterium, fluorine, chlorine, bromine, cyano, carboxyl, hydroxyl, nitro, -NH 2 , -N(CH 3 ) 2 , -NHCH 3 , -NHCOCH 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, -SCH 3 , -SOCH 3 , -SO 2 CH 3 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -CH 2 CN , -(CH 2 ) 2 CN , -(CH 2 ) 3 CN , -CH 2 OH , -(CH 2 ) 2 OH
  • R B1 is selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and methoxy.
  • b1 is 1 and R B1 is fluoro.
  • b1 is 1 and RB1 is X2 .
  • X2 is the connection site between ULM and L or POI, Indicates covalent attachment to U 0 .
  • X2 is the connection site between ULM and L or POI, Indicates covalent attachment to U 0 .
  • U 0 is a bond, -NH-, -CONH-, or -CH 2 -.
  • U 0 is a bond
  • U 0 is -NH-.
  • U 0 is -CONH-.
  • U 0 is -CH 2 -.
  • S 1 and S 3 are -C(O)-
  • S 2 is -NH-
  • S 4 and S 5 are -CH 2 -.
  • S6 is CH.
  • S6 is N.
  • b2 is 0.
  • the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.
  • the ULM is selected from the following structures or isomers thereof: Wherein X2 is the connection site between ULM and L or POI.
  • the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.
  • the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.
  • the ULM is selected from the following structures or isomers thereof: Wherein X2 is the connection site between ULM and L or POI.
  • ULM is a structure represented by formula (U-2) or an isomer thereof:
  • R U7 represents that the hydrogen on the tetrahydropyrrole ring is replaced by r1 R U7 , r1 is 0, 1, 2 or 3, each R U7 is the same or different, and each is independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, amino, C 1-3 alkoxy, halogenated C 1-3 alkoxy and -OCOC 1-3 alkyl;
  • halogen preferably fluorine, chlorine or bromine
  • RU1 is -C ( RU3RU4 ) -U1 ;
  • U 1 is selected from the following structures or isomers thereof: X 2 , -NHCO-X 2 , -NHCOCH 3 , 5- to 6-membered heteroaryl ring, The 5- to 6-membered heteroaryl ring, is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X 2 , halogen, hydroxy, cyano, amino, carboxyl, C 1-6 alkyl (preferably methyl, ethyl, isopropyl), C 1-6 alkoxy (preferably methoxy, ethoxy, isopropoxy), halogenated C 1-6 alkyl (preferably trifluoromethyl), halogenated C 1-6 alkoxy (preferably trifluoromethoxy), -COC 1-6 alkyl (preferably -COCH 3 ), -COOC 1-6 alkyl (preferably -COOCH 3 ), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHCH 3 ),
  • R Ua is selected from hydrogen, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxyl, carboxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 ;
  • R U3 and R U4 are each independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably C 1-3 alkoxy), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy) and -SC 1-6 alkyl (preferably -SC 1-3 alkyl); or R U3 and R U4 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl (preferably C 3-6 cycloalkyl) and a 3 to 7 membered heterocycloalkyl (preferably 4 to 6 membered heterocycloalkyl); the C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -SC 1-6 alkyl, C 3-7 -membered
  • R U5 and R U6 are each independently selected from X 2 , hydrogen, deuterium, halogen, amino, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (halogenated C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), C 1-6 alkyl substituted by CONHC 1-6 alkyl, C 1-6 alkyl substituted by CON(C 1-6 alkyl) 2 , C 1-6 alkyl substituted by carboxyl, and C 1-6 alkyl substituted by COOC 1-6 alkyl;
  • R U2 r2 represents that the hydrogen on the D ring is replaced by r2 R U2 , r2 is 0, 1, 2 or 3, each R U2 is the same or different and is independently selected from X 2 , hydrogen, deuterium, halogen (preferably fluorine, chlorine), nitro, cyano, carboxyl, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkyl substituted with hydroxyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NR a3 R b3 , -COC 1-6 alkyl, -COOC 1-6 alkyl, -OCOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SC
  • halogen preferably fluor
  • the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-10 cycloalkyl ring (preferably a C 3-8 cycloalkyl ring, more preferably a C 3-6 cycloalkyl ring) and a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring);
  • R a3 and R b3 are each independently selected from hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHC 1-3 alkyl), -CON(C 1-6 alkyl) 2 (preferably -CON(C 1-3 alkyl) 2 ), 5- to 6-membered heteroaryl and phenyl; wherein the 5- to 6-membered heteroaryl and phenyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, C 1-6 alky
  • X 2 is the connection site between ULM and L or POI, and at least one of U 1 , RU5 , RU6 and RU2 is X 2 , or RU1 contains at least one X 2 .
  • one of U 1 , RU5 , RU6 , and RU2 is X 2 .
  • R U1 contains one X 2 .
  • R1 is 2, and R U7 is selected from fluoro and hydroxy.
  • the structure represented by formula (U-2) is the structure represented by formula (U-2-1) or an isomer thereof:
  • R U7 is selected from hydroxy, amino, -OCH 3 , -OCF 3 , and -OCOCH 3 .
  • R U7 is hydroxy
  • R Ua is selected from fluoro, cyano, methyl, ethyl, trifluoromethyl, and trifluoromethoxy.
  • R Ua is selected from fluoro and cyano.
  • U 1 is selected from X 2 , -NHCO-X 2 , -NHCOCH 3 , Where X2 is the connection site between ULM and L or POI.
  • U is selected from -NHCO-X and Where X2 is the connection site between ULM and L or POI.
  • R U3 and R U4 are each independently hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy; or R U3 and R U4 and the carbon atom to which they are attached form a C 3-6 cycloalkyl ring.
  • R U3 and R U4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, fluoroisopropyl or fluorotert-butyl; or R U3 and R U4 and the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.
  • R U3 and R U4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 ; or R U3 and R U4 and the carbon atom to which they are attached form a cyclopropyl ring.
  • R U3 , R U4 are each independently hydrogen, -CH(CH 3 ) 2 , or -C(CH 3 ) 3 .
  • R U1 is selected from the following structures or isomers thereof: Wherein X2 is the connection site between ULM and L or POI.
  • R U1 is selected from the following structures: Where X2 is the connection site between ULM and L or POI.
  • R U1 is selected from the following structures: Wherein X2 is the connection site between ULM and L or POI.
  • R U5 and R U6 are each independently X 2 , hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl or halogenated C 1-3 alkoxy.
  • R U5 and R U6 are each independently hydrogen, C 1-3 alkyl, or halogenated C 1-3 alkyl.
  • R U5 , R U6 are each independently hydrogen, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 , -CHF 2 , -CH 2 F, -OCHF 2 , or -OCH 2 F.
  • R U5 , R U6 are each independently hydrogen or -CH 3 .
  • r2 is 0.
  • r2 is 1.
  • r2 is 2.
  • R U2 is a 5- to 6-membered heteroaryl or phenyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -NH 2 , -NHCOC 1-3 alkyl, -COC 1-3 alkyl, -COOC 1-3 alkyl, -OCOC 1-3 alkyl, -CONH 2 , -NHCONH 2 , -CONHC 1-3 alkyl, -NHCONHC 1-3 alkyl, -SOC 1-3 alkyl, -SO 2 C 1-3 alkyl and -SC 1-3 alkyl.
  • halogen preferably fluorine, chlorine
  • cyano carboxyl, hydroxyl, C 1-3 alkyl,
  • the 5- to 6-membered heteroaryl is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazolyl.
  • the 5- to 6-membered heteroaryl is selected from
  • the 5- to 6-membered heteroaryl is N-(2-membered heteroaryl)
  • the 5- to 6-membered heteroaryl ring is selected from a thiazole ring, an oxazole ring, a pyrazole ring, an imidazole ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a tetrazole ring, and a triazole ring.
  • R U2 is cyano
  • R a3 and R b3 are each independently selected from hydrogen, 5- to 6-membered heteroaryl and phenyl; the 5- to 6-membered heteroaryl is thiazolyl, oxazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, pyrrolyl, triazolyl and tetrazolyl; the 5- to 6-membered heteroaryl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, -COCH 3 and -CONH 2 .
  • R U2 is -NHR a3 , wherein R a3 is a 5- to 6-membered heteroaryl or phenyl group, wherein the 5- to 6-membered heteroaryl group is selected from thiazolyl, imidazolyl, pyrazolyl, oxazolyl, pyridinyl and pyrimidinyl; and the 5- to 6-membered heteroaryl or phenyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkyl, halo C 1-3 alkyl, -SC 1-3 alkyl and -OCOC 1-3 alkyl.
  • R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl is substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy and trifluoroethoxy.
  • R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl being substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl and isopropyl.
  • R U2 is selected from the following structures: cyano,
  • R2 is 1, R U2 is selected from cyano,
  • r2 is 1, R U2 is
  • r2 is 2, R and U2 are X2 and Where X2 is the connection site between ULM and L or POI.
  • the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-6 cycloalkyl ring, and a 3- to 6-membered heterocycloalkyl ring.
  • the D ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring.
  • the D ring is selected from a benzene ring, a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a triazole ring, a thiazole ring, an oxazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a piperidine ring, a piperazine ring and a tetrahydropyrrole ring.
  • the D ring is selected from a benzene ring and a pyridine ring.
  • X2 is the connection site between ULM and L or POI.
  • the ULM is selected from the following structures or isomers thereof: ; wherein X 2 is the connection site between ULM and L or POI.
  • the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.
  • the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.
  • ULM is a structure represented by formula (U-3) or an isomer thereof:
  • R n1 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -SC 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5 to 10 membered heteroaryl; the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5 to 10 membered heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, C 1-6 alkyl, -SC 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alky
  • R n2 , R n3 and the connected N together form a 4- to 12-membered heterocycloalkyl ring;
  • the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the following group: X 2 , halogen, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, C 1-6 alkyl, -SC 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -COC 1-6 alkyl, -COOC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5- to 10-membere
  • R n1 is selected from tert-butyl, tert-butyl substituted with morpholinyl, thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane; the thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the following group: halogen, cyano, hydroxyl, nitro, trifluoromethyl, difluoromethyl, monofluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, -SCH 3 , -SOCH 3 , -SO 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -COCH 3 .
  • R n1 is selected from tert-butyl, pyridinyl, and the pyridinyl is substituted with bromine.
  • R n2 , R n3 and the attached N together form a 4- to 12-membered heterocycloalkyl ring, wherein the 4- to 12-membered heterocycloalkyl ring is selected from a tetrahydropyrrole ring, a piperidine ring, a morpholine ring, a piperazine ring, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, (1R,5S)-3,8-diazabicyclo[3.2.1]octane, 1,4-diazapine, 3,9-diazaspiro[5.5]undecane, 4,7-diazaspiro[2.5]octane; the 4- to 12-membered heterocycloalkyl ring is unsubstituted or substituted with 1,2,3 or 4 substituents selected from the group consisting of: X 2 , fluorine, chlorine
  • R n2 , R n3 and the attached N together form a piperidine ring.
  • the ULM is selected from the following structures:
  • the compound of formula (I) is a specific compound selected from the Examples.
  • the compound of formula (I) is a compound selected from the following or a stereoisomer thereof:
  • the compound of formula (I) is a compound selected from the following or a stereoisomer thereof:
  • the second aspect of the present application provides a pharmaceutical composition, comprising the compound represented by formula (I) described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.
  • the third aspect of the present application provides the use of the compound shown in (I) described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition provided in the second aspect of the present application in the preparation of a drug for treating EED-mediated diseases.
  • the EED-mediated disease is a tumor or an autoimmune disease.
  • the EED-mediated disease is cancer.
  • the cancer is selected from multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.
  • the fourth aspect of the present application provides a method for preventing and/or treating EED-mediated diseases, comprising administering to a subject a therapeutically effective amount of a compound represented by formula (I) as described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition as described in the second aspect of the present application.
  • the EED-mediated disease is a tumor or an autoimmune disease.
  • the EED-mediated disease is cancer.
  • the cancer is selected from multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.
  • the fifth aspect of the present application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof for use as a medicine or for treatment.
  • FIG1 is a Western blot showing the degradation of EED protein by compound H39 in Karpas-422 cells
  • FIG2 is a graph showing the dose-degradation activity of compound H39 on EED protein in Karpas-422 cells
  • FIG3 is a graph showing the in vivo anti-tumor activity results of compound D1 and compound H39;
  • FIG4 is a graph showing the effects of compound D1 and compound H39 on mouse body weight
  • FIG5 is a graph showing the in vivo anti-tumor activity results of compound D1 and compound H80;
  • FIG6 is a graph showing the effects of compound D1 and compound H80 on the body weight of mice.
  • the inventor unexpectedly discovered a bifunctional compound that targets degradation and/or inhibits EED protein, which has excellent EED protein degradation, excellent tumor cell (such as wsuDLCL-2 cells, Pfeiffer cells, etc.) proliferation inhibition, excellent pharmacokinetic characteristics, good CYP450 effect, good safety, and is more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).
  • EED protein degradation e.g., wsuDLCL-2 cells, Pfeiffer cells, etc.
  • the present application provides a bifunctional compound or PROTAC compound having a POI-ULM structure or a POI-L-ULM structure, wherein POI is a ligand targeted by the EED protein (or a ligand bound to the EED protein), ULM is an E3 ligase linker (or a binding group), and L is a linker chain connecting POI and ULM.
  • the PROTAC compound can bind to the EED protein through the POI portion, thereby pulling the EED protein toward the E3 ligase, thereby inducing the degradation (and/or inhibition) of the EED protein.
  • E3 ligase ligands include VHL (Von Hippel-Lindau) E3 ubiquitin ligase linker (abbreviated as VLM), CRBN (cereblon) E3 ubiquitin ligase linker (abbreviated as CLM), MDM2 (mouse double minute 2 homologue) E3 ubiquitin ligase linker (abbreviated as MLM), cIAP (cellular inhibitor of apoptosis) E3 ubiquitin ligase linker (abbreviated as ILM), etc.
  • VHL Volt-Lindau
  • VLM VL
  • CLM CLM
  • MDM2 mimouse double minute 2 homologue
  • MLM cIAP
  • ILM cellular inhibitor of apoptosis
  • ILM cellular inhibitor of apoptosis
  • POI is a ligand targeting EED protein and can bind to EED protein.
  • Alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group.
  • C 1-10 alkyl refers to an alkyl group having 1 to 10 carbon atoms, preferably a C 1-8 alkyl group; more preferably a C 1-6 alkyl group; and further preferably a C 1-3 alkyl; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2, 2,
  • C2-10 alkenyl refers to an alkenyl group having 2 to 10 carbon atoms, preferably a C2-8 alkenyl group, more preferably a C2-6 alkenyl group, further preferably a C2-4 alkenyl group, and the definition is similar; non-limiting examples of alkenyl include ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl and the like.
  • Alkynyl refers to a straight chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon triple bonds;
  • C2-10 alkynyl refers to an alkynyl group having 2 to 10 carbon atoms, preferably a C2-8 alkynyl group, more preferably a C2-6 alkynyl group, further preferably a C2-4 alkynyl group, and the definition is similar; non-limiting examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl and the like.
  • Alkylene is divalent and requires two binding partners. Formally, the second valence is generated by removing a hydrogen atom from an alkyl group, such as -CH3 and -CH2- , -CH2CH3 and -CH2CH2- or -CH ( CH3 )-, etc.
  • alkyl group such as -CH3 and -CH2- , -CH2CH3 and -CH2CH2- or -CH ( CH3 )-, etc.
  • C1-10 alkylene is preferred, C1-8 alkylene is more preferred, C1-6 alkylene is further preferred, and C1-3 alkylene is most preferred.
  • C1-3 alkylene includes -CH2-, - ( CH2 ) 2- , -CH( CH3 )-, -( CH2 ) 3- , -CH( CH2CH3 ) - , -CH2CH ( CH3 )- and -C( CH3 ) 2- .
  • the alkylene group may be methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, etc.
  • propylene includes 1-methylethylene
  • butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.
  • Alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond, and the carbon atom can only be part of one C-C double bond.
  • alkylene defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, forming the corresponding alkenylene.
  • it is preferably C 2-10 alkenylene, more preferably C 2-8 alkenylene, further preferably C 2-6 alkenylene, and most preferably C 2-4 alkenylene.
  • the alkenylene can be vinylene, propenylene, 1-methylvinylene, butenylene, 1-methylpropenylene, 1,1-dimethylvinylene, 1,2-dimethylvinylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene, etc.
  • the generic terms propenylene, butenylene, pentenylene, hexenylene and the like are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e.
  • propenylene includes 1-methylpropenylene
  • butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylvinylene and 1,2-dimethylvinylene.
  • Alkenylene may optionally be present in cis or trans or in E or Z form for one or more double bonds.
  • Alkynylidene refers to a group consisting of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C triple bond.
  • alkylene group defined above two hydrogen atoms are removed from two adjacent carbon atoms and the free valence is saturated to form two additional bonds, thereby forming the corresponding alkynylene group.
  • it is preferably a C 2-10 alkynylene group, more preferably a C 2-8 alkynylene group, further preferably a C 2-6 alkynylene group, and most preferably a C 2-4 alkynylene group.
  • the alkynylene group can be ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, etc.
  • propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.
  • Alkyleneoxy refers to a divalent alkoxy group. In certain embodiments, it is preferably a C 1-10 alkyleneoxy group, more preferably a C 1-8 alkyleneoxy group, further preferably a C 1-6 alkyleneoxy group, and most preferably a C 1-3 alkyleneoxy group. In certain embodiments, the alkyleneoxy group may be -OCH 2 -, -OCH(CH 3 )CH 2 -, -OCH 2 CH 2 O-, -CH 2 CH 2 O-, and the like.
  • propyleneoxy includes -O( CH2 ) 3O- , -O(CH2) 3- , -OCH2CH( CH3 )-, -OC(CH3) 2- , -OCH( CH3 ) CH2- , -OCH2CH( CH3 ) O- , -OC( CH3 ) 2O- and -OCH( CH3 ) CH2O- .
  • Cycloalkyl and “cycloalkyl ring” are used interchangeably and refer to monocyclic or polycyclic cyclic hydrocarbon groups, which may be fused to aryl or heteroaryl groups.
  • the cycloalkyl ring may be optionally substituted.
  • the cycloalkyl ring is a spiro ring or a bridged ring.
  • the cycloalkyl ring contains one or more carbonyl groups, such as an oxo group.
  • C 3-15 cycloalkyl refers to a monocyclic or polycyclic cycloalkyl group having 3 to 15 carbon atoms, such as spiro[4.5]decane, spiro[3.3]heptane, spiro[5.5]undecane, dispiro[5.2.59.26]hexadecane, decahydroazulene, 1,2-diethylcyclopent-1-ene, bicyclo[3.3.2]decane.
  • C 3-8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. It is preferably a C 3-7 cycloalkyl group, such as cycloheptane, spiro[3.3]heptane, etc., and more preferably a C 3-6 cycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • It may be a saturated cycloalkyl group, such as cyclohexyl, cyclopropyl, etc. It may be a partially unsaturated cycloalkyl group, such as cyclohexene, 1,2-diethylcyclopent-1-ene, etc.
  • Spiro refers to a polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system. Spirocycles are divided into bispirocycles or polyspirocycles according to the number of rings, preferably bispirocycles. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispirocycle. For example:
  • Spiro heterocycle refers to a polycyclic hydrocarbon in which one atom (called spiro atom) is shared between the monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system.
  • Spiro heterocycles are divided into bispiro heterocycles or polyspiro heterocycles according to the number of rings, preferably bispiro heterocycles. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocycle. For example:
  • Bridged ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atoms are called bridgehead carbons.
  • the two bridgehead carbons can be a carbon chain or a bond, called a bridge. These can contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • Bicyclic or tricyclic bridged rings are preferred. For example:
  • Bridged heterocycle refers to a polycyclic group that shares two or more atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system.
  • the bridged heterocycle is bicyclic or tricyclic. For example:
  • Heterocycloalkyl and “heterocycloalkyl ring” are used interchangeably and refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which group may be fused with an aryl or heteroaryl group.
  • the heterocycloalkyl ring may be a saturated heterocycloalkyl ring or a partially unsaturated heterocycloalkyl ring.
  • the heterocycloalkyl ring may be optionally substituted.
  • the heterocycloalkyl ring is a spiro heterocycle or a bridged heterocycle.
  • the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thio.
  • "3 to 15-membered heterocycloalkyl” refers to a group having 3 to 15 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • it is a 3 to 10-membered heterocycloalkyl, more preferably a 3 to 7-membered heterocycloalkyl, further more preferably a 3 to 7-membered heterocycloalkyl, further preferably a 3 to 6-membered heterocycloalkyl.
  • heterocycloalkyl examples include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-onyl, oxetan-2-onyl, dihydrofuran- 2(3H)-one, pyrrolidine-2-one, pyrrolidine-2,5-dione, dihydrofuran-2,5-dione, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazine-2-one, morpholin-3-one, 2,3
  • Aryl and “aromatic ring” are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 or 14 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms.
  • the aromatic ring may be optionally substituted.
  • C 6-14 aryl refers to an aryl group having 6 to 14 ring carbon atoms.
  • C 6-10 aryl refers to an aryl group having 6 to 10 ring carbon atoms. Non-limiting examples include phenyl, naphthyl, anthracenyl.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 or 14 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings.
  • the heteroaryl ring may be optionally substituted.
  • 5 to 15-membered heteroaryl refers to a monocyclic heteroaryl having 5 to 15 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • 5 to 6-membered heteroaryl refers to a monocyclic heteroaryl having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • Non-limiting examples include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinolyl, benzopyrrolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benz
  • Heteroatom refers to nitrogen, oxygen or sulfur. In heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings.
  • Halo means that one or more (eg, 1, 2, 3 or all) hydrogen atoms in a group are replaced by halogen.
  • Haloalkyl refers to an alkyl group substituted with one or more (e.g., 1, 2, 3 or all) halogens, wherein the definition of alkyl is as described above. Preferably, it is a halogenated C 1-8 alkyl group, more preferably a halogenated C 1-6 alkyl group, and more preferably a halogenated C 1-3 alkyl group.
  • haloalkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
  • Alkoxy refers to -O-alkyl, wherein alkyl is as defined above. Preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, most preferably C 1-3 alkoxy. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
  • Alkoxyalkyl refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above . Preferably , it is C1-6alkoxyC1-6alkyl , more preferably C1-3alkoxyC1-3alkyl .
  • alkoxyalkyl include -CH2OCH3 , -CH2OCH2CH3 , -CH2CH2OCH3 , etc.
  • Alkenylalkyl refers to an alkyl group substituted with one or more alkenyl groups, wherein the definitions of alkyl and alkenyl are as described above. Preferably, it is C2-8 alkenyl C1-10 alkyl, more preferably C2-8 alkenyl C1-8 alkyl, further preferably C2-8 alkenyl C1-6 alkyl, further preferably C2-8 alkenyl C1-3 alkyl.
  • Non-limiting examples of cycloalkylalkyl include wait.
  • Alkynylalkyl refers to an alkyl group substituted with one or more alkynyl groups, wherein the definitions of alkyl and alkynyl are as described above. Preferably, it is C2-8alkynylC1-10alkyl , more preferably C2-8alkynylC1-8alkyl , further preferably C2-8alkynylC1-6alkyl , further preferably C2-8alkynylC1-3alkyl .
  • Non - limiting examples of cycloalkylalkyl include wait.
  • Heterocycloalkylalkyl refers to an alkyl group substituted by one or more heterocycloalkyl groups, wherein alkyl and heterocycloalkyl are as defined above.
  • it is a 4- to 10-membered heterocycloalkylC 1-6 alkyl group, more preferably a 4- to 8-membered heterocycloalkylC 1-3 alkyl group, further preferably a 3- to 6-membered heterocycloalkylC 1-3 alkyl group, further preferably a 4- to 6 - membered heterocycloalkylC 1-3 alkyl group.
  • heterocycloalkylalkyl groups include -CH 2 -tetrahydropyrrolyl, -CH 2 -azetidinyl, -CH 2 -piperidinyl, -CH 2 -piperazinyl, and the like.
  • “Hydroxy-substituted alkyl” refers to an alkyl group substituted with one or more hydroxy groups, wherein the definition of alkyl is as described above. Preferably, it is a C 1-10 alkyl group substituted with hydroxy groups, more preferably a C 1-8 alkyl group substituted with hydroxy groups, further preferably a C 1-6 alkyl group substituted with hydroxy groups, and more preferably a C 1-3 alkyl group substituted with hydroxy groups.
  • Non-limiting examples of "hydroxy-substituted alkyl group” include -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , and the like.
  • Cyano-substituted alkyl refers to an alkyl group substituted with one or more cyano groups, wherein the definition of alkyl is as described above. Preferably, it is a cyano-substituted C 1-10 alkyl group, more preferably a cyano-substituted C 1-8 alkyl group, further preferably a cyano-substituted C 1-6 alkyl group, further preferably a cyano-substituted C 1-3 alkyl group.
  • Non-limiting examples of "cyano-substituted alkyl” include -CH 2 CN, -CH 2 CH 2 CN, -CH(CN)CH 3 , and the like.
  • Carboxyl-substituted alkyl refers to an alkyl group substituted with one or more carboxyl groups, wherein the alkyl group is as defined above. Preferably, it is a carboxyl-substituted C 1-10 alkyl group, more preferably a carboxyl-substituted C 1-8 alkyl group, further preferably a carboxyl-substituted C 1-6 alkyl group, further preferably a carboxyl-substituted C 1-3 alkyl group.
  • Non-limiting examples of "carboxyl-substituted alkyl” include -CH 2 COOH, -CH 2 CH 2 COOH, -CH(COOH)CH 3 , and the like.
  • Amino-substituted alkyl refers to an alkyl group substituted by one or more amino groups, wherein the definition of alkyl is as described above. Preferably, it is an amino-substituted C 1-10 alkyl group, more preferably an amino-substituted C 1-8 alkyl group, further preferably an amino-substituted C 1-6 alkyl group, further preferably an amino-substituted C 1-3 alkyl group.
  • Non-limiting examples of "amino-substituted alkyl” include -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(NH 2 )CH 3 , and the like.
  • Haloalkoxy refers to an alkoxy group substituted by one or more (e.g., 1, 2, 3, 4 or 5) halogens, wherein the definition of alkoxy is as described above.
  • it is a halogenated C 1-10 alkoxy group, more preferably a halogenated C 1-8 alkoxy group, further preferably a halogenated C 1-6 alkoxy group, further preferably a halogenated C 1-3 alkoxy group.
  • Halogenated alkoxy groups include (but are not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • Amino refers to -NH 2
  • cyano refers to -CN
  • nitro refers to -NO 2
  • benzyl refers to -CH 2 -phenyl
  • oxo O
  • carboxy refers to -C(O)OH
  • acetyl refers to -C(O)CH 3
  • acetamido refers to -C(O)NH 2
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxy refers to -OH
  • thiol refers to -SH
  • formyl refers to -CHO
  • sulfonate refers to -SO 3 H.
  • the attachment site as used herein refers to the point at which one group is connected to another group through a covalent bond.
  • X 1 is the attachment site of POI and L or ULM
  • X 1 is the attachment point to L or ULM.
  • This definition is similar to "a structure having "wherein X1 is the connection site between POI and L or ULM” has the same meaning as that expressed.
  • the connecting chain structure X 10 indicates the connection point with POI
  • X 20 indicates the connection point with ULM. Its meaning is the same as the structure. The meaning expressed is the same.
  • Substituted means that one or more hydrogen atoms, preferably 1 to 5 hydrogen atoms, are independently replaced by a corresponding number of substituents in a group, and more preferably 1 to 3 hydrogen atoms are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (such as olefinic) bonds.
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 groups or less, independently selected from deuterium, halogen (preferably fluorine, chlorine), cyano, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), cyano-substituted C 1-8 alkyl (preferably cyano-substituted C 1-6 alkyl, more preferably cyano-substituted C 1-3 alkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably
  • R A10 and R B10 are each independently hydrogen or C 1-3 alkyl; or R A10 , R B10 and the nitrogen atom to which they are connected together form a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl,
  • R A0 and R B0 are each independently hydrogen, C 1-3 alkyl or acetyl; or R A0 , R B0 and the nitrogen atom to which they are connected together form a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -C(O)OC
  • any two “preferably” may be independent of each other.
  • any two substituents may be the same or different.
  • they may be substituted by two halogens that are the same or different, or by one halogen and one hydroxyl.
  • dosage forms can be used in suitable dosage forms with one or more pharmaceutical carriers.
  • These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules and syrups.
  • “Pharmaceutically acceptable carrier” refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient that is compatible with a patient, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to a target site without terminating the activity of the agent.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.
  • Patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • Treatment means to lessen, slow the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other adverse effects.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts with inorganic bases and salts with organic bases.
  • the compounds of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • the compound comprises enantiomers.
  • diastereomers may exist.
  • the present invention includes both stereoisomers and mixtures of both stereoisomers, such as racemates, diastereomeric mixtures, etc. Unless otherwise indicated, the compounds are represented by wedge-shaped bonds. Represents the absolute configuration of a stereocenter.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of this application.
  • Enantiomers, diastereomers and mixtures of these isomers of the compounds of the present invention are all within the protection scope of the present invention. Enantiomers and diastereomers can be separated by methods known in the art, such as crystallization and chiral chromatography.
  • the present invention provides methods for preparing compounds of formula (I), which can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein.
  • the solvents, temperatures and other reaction conditions provided herein can be varied according to the art.
  • the reactions can be used in sequence to provide compounds of the present invention, or they can be used to synthesize fragments, which are subsequently added by the methods described herein and/or methods known in the art.
  • the compounds described in the present invention can be synthesized using appropriate optional starting materials using methods similar to the following or the exemplary methods described in the examples, or related open literature used by those skilled in the art.
  • the starting materials or intermediates used to synthesize the compounds described in the present invention can be synthesized or can be obtained from commercial sources. If the existing literature is not reported or cannot be obtained from commercial sources, similar existing preparation methods of analogs or similar preparation methods recorded in the present invention can be used to prepare.
  • Compounds such as described in the present invention and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art.
  • the general method for preparing the compounds disclosed in the present invention can be from reactions known in the art, and the reaction can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various parts into the molecules provided by the present invention.
  • the main advantages of the present invention are that the compounds of the present invention have excellent EED protein degradation effect and tumor cell proliferation inhibition effect, and have excellent pharmacokinetic characteristics, have a good effect on cytochrome P450 (CYP450), have good safety, and are more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).
  • CYP450 cytochrome P450
  • LC-MS Agilent 1290 HPLC System/6130/6150MS liquid chromatography-mass spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50 ⁇ 2.1 mm, 1.7 ⁇ m.
  • ISCO Combiflash-Rf75 or Rf200 automatic column analyzer Use ISCO Combiflash-Rf75 or Rf200 automatic column analyzer and Agela 4g, 12g, 20g, 40g, 80g, and 120g disposable silica gel columns.
  • the reaction progress can be monitored by thin layer chromatography (TLC), and the compound purification can be performed by column chromatography.
  • TLC thin layer chromatography
  • the developing solvent system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc.
  • the volume ratio of the solvent is adjusted according to the different polarities of the compound.
  • PE petroleum ether
  • EA ethyl acetate
  • THF tetrahydrofuran
  • H 2 O water
  • DMF N,N-dimethylformamide
  • DME dimethyl ether
  • DCM dichloromethane
  • MeOH methanol
  • EtOH ethanol
  • DMSO dimethyl sulfoxide
  • ACN acetonitrile
  • DIPEA N,N-diisopropylethylamine
  • TEA/Et 3 N triethylamine
  • TFA trifluoroacetic acid
  • FA formic acid
  • SOCl 2 thionyl chloride
  • CCl 4 carbon tetrachloride
  • AcOH/CH 3 COOH acetic acid
  • p-TsOH p-toluenesulfonic acid
  • NMI N-methylimidazole
  • NMP N-methylpyrrolidone
  • LiOH lithium hydroxide
  • TCF N-methylpyrroli
  • the percentage content involved in this article unless otherwise specified, for solid-liquid mixing and solid-solid mixing, it refers to mass percentage, and for liquid-liquid mixing, it refers to volume percentage. Unless otherwise specified, the solvent is water.
  • room temperature refers to about 20-30°C.
  • overnight means about 10 to 16 hours.
  • Step 1 Dissolve methyl 4-bromo-3-formylbenzoate (5 g, 20.57 mmol) and propan-2-amine (2.43 g, 41.14 mmol) in ethanol (60 mL), then add acetic acid (3.09 g, 51.43 mmol, 2.94 mL). The reaction was stirred at 20 ° C for 18 h, then the temperature was lowered to 0 ° C, Na (CN) BH 3 (2.59 g, 41.14 mmol) was added, and stirred at 0 ° C for 3 h.
  • Step 2 Z1-a (5.4 g, 18.87 mmol) was dissolved in DCM (60 mL), and then Et 3 N (7.64 g, 75.48 mmol) was added thereto, the temperature was lowered to 0°C, and (Boc) 2 O (6.18 g, 28.31 mmol) was added dropwise to the reaction solution. The reaction was heated to room temperature at 0°C and stirred for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (40 g, 0-35% EA/PE) to obtain the product Z1-b (4.7 g, colorless oil), yield: 64.48%. MS m/z (ESI): 286.1 [M-100+H] + .
  • Step 3 Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 g, 2.30 mmol) and Z1-b (1.77 g, 4.60 mmol) were dissolved in DME (20 mL) and water (2 mL), then Pd(OAc) 2 (51.58 mg, 229.75 ⁇ mol), CataCXium A (164.75 mg, 459.51 ⁇ mol), K 2 CO 3 (1.27 g, 9.19 mmol) and (Pin) 2 B 2 (1.17 g, 4.60 mmol) were added.
  • Step 4 Z1-c (950 mg, 1.44 mmol) was dissolved in DCM (15 mL), and then TFA (163.70 mg, 1.44 mmol, 2.5 mL) was added. The reaction was stirred at 20°C for 3 h. After the reaction was completed, the reaction solution was concentrated to obtain Z1-d (806 mg, oil, crude product), yield: 99.97%. MS m/z (ESI): 562.2 [M+H] + .
  • Step 5 Dissolve Z1-d (806 mg, 1.44 mmol) in THF (20 mL) and water (5 mL), then add LiOH (1.03 g, 43.06 mmol). The reaction was stirred at 75 °C for 18 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was adjusted to pH 2-3 with dilute hydrochloric acid (3 mol/L), and concentrated to obtain intermediate Z1 (2.1 g, brown solid, crude product). MS m/z (ESI): 520.2 [M+H] + .
  • Step 1 Dissolve 5-bromo-4-methylpicolinic acid (12.5 g, 57.86 mmol) in MeOH (250 mL), then add SOCl 2 (17.15 g, 144.14 mmol, 10.47 mL) and stir at 84°C for 2 h. After the reaction is completed, cool to room temperature, quench with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate (3 ⁇ 500 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain Z2-a (13 g, white solid, crude product), yield: 97.66%. MS m/z (ESI): 230.0 [M+H] + .
  • Step 2 Z2-a (5 g, 21.73 mmol) was dissolved in CCl 4 (70 mL), and then NBS (11.60 g, 65.20 mmol) and AIBN (356.88 mg, 2.17 mmol) were added, and stirred at 80° C. for 18 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated to obtain Z2-b (8.43 g, light yellow oil, crude product), yield: 100.00%. MS m/z (ESI): 385.8 [M+H] + .
  • Step 3 Dissolve Z2-b (8 g, 20.63 mmol) in THF (100 mL), cool to 0-5°C, add diethyl phosphite (3.11 g, 22.69 mmol) and DIPEA (4 g, 30.94 mmol, 5.39 mL) dropwise, and react at 25°C for 1 h. After the reaction, concentrate the reaction solution and purify it with CombiFlash (120 g, 0-50% PE/EA) to obtain Z2-c (4.2 g, white solid), yield: 65.91%. MS m/z (ESI): 307.9 [M+H] + .
  • Step 4 Dissolve Z2-c (2 g, 6.47 mmol) in EtOH (1 mL), cool the reaction mixture to 0°C, add isopropylamine (1.91 g, 32.37 mmol), warm to room temperature and continue stirring for 2 h. Concentrate the reaction mixture to obtain Z2-d (1.86 g, colorless oil, crude product), yield: 100.00%. MS m/z (ESI): 287.0 [M+H] + .
  • Step 5 Z2-d (1.86 g, 6.48 mmol) was dissolved in DCM (20 mL), and Et 3 N (3.28 g, 32.39 mmol) was added under ice water, and then (Boc) 2 O (3.53 g, 9.72 mmol, purity 60%) was added, and the mixture was naturally warmed to room temperature and stirred for 18 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-50% EA/PE) to obtain Z2-e (2.4 g, colorless oil), yield: 95.68%. MS m/z (ESI): 387.1 [M+H] + .
  • Step 6 Z2-e (500 mg, 1.15 mmol) and ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (667.33 mg, 1.72 mmol) were dissolved in DME (10 mL) and water (1 mL), and then Pd(OAc) 2 (77.37 mg, 344.63 ⁇ mol), CataCXium A (205.94 mg, 574.39 ⁇ mol), K 2 CO 3 (793.86 mg, 5.74 mmol) and (Pin) 2 B 2 (875.15 mg, 3.45 mmol) were added and stirred at 70° C.
  • Step 7 Z2-f (300 mg, 452.69 ⁇ mol) was dissolved in DCM (15 mL), and then TFA (4 mL) was added and stirred at room temperature for 18 h. After the reaction was completed, it was neutralized with sodium bicarbonate aqueous solution, and then extracted with a mixed solution of dichloromethane and methanol (10:1; 3 ⁇ 70 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain Z2-g (248 mg, light yellow solid, crude product), yield: 99.87%. MS m/z (ESI): 563.3 [M+H] + .
  • Step 8 Z2-g (248.44 mg, 441.59 ⁇ mol) was dissolved in THF (20 mL) and water (5 mL), and then LiOH (317.26 mg, 13.25 mmol) was added and stirred at 75°C for 18 h. After the reaction was completed, it was cooled to room temperature and filtered. The filtrate was adjusted to pH 2-3 with dilute hydrochloric acid (3 mol/L), concentrated and freeze-dried to obtain intermediate Z2 (763 mg, khaki solid, 30% content), yield: 99.63%. MS m/z (ESI): 521.2 [M+H] + .
  • Step 1 2-Bromo-5-nitrobenzaldehyde (5.0 g, 21.74 mmol) and propan-2-amine (1.67 g, 28.26 mmol) were dissolved in DCM (40 mL) and methanol (4 mL) at room temperature, followed by the addition of acetic acid (1.69 g, 28.69 mmol) and stirring at 25°C for 16 hours. Then NaBH 4 (1.64 g, 43.47 mmol) was added and stirring continued at 25°C for 2 hours.
  • Step 3 Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (350 mg, 4.60 mmol) and Z3-b (600 mg, 1.61 mmol) were dissolved in ethylene glycol dimethyl ether (5 mL) and water (0.5 mL), and Pd(OAc) 2 (36 mg, 0.20 mmol), CataCXium A (115 mg, 0.40 mmol), potassium carbonate (556 mg, 5.00 mmol) and (Pin) 2 B 2 (613 mg, 2.41 mmol) were added, and the mixture was stirred at 70° C.
  • Step 4 Dissolve Z3-c (200 mg, 0.31 mmol) in DCM (5 mL), add TFA (2.5 mL), and stir at 25° C. for 2 hours. After the reaction is completed, the reaction solution is concentrated to obtain Z3-d (165 mg, yellow oil), yield: 97.56%. MS m/z (ESI): 549.4 [M+H] + .
  • Step 6 Z3-e (60 mg, 0.12 mmol) was dissolved in DMF (3 mL), HATU (88 mg, 0.23 mmol) and DIPEA (74 mg, 0.58 mmol) were added in sequence, and stirred at 25°C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give Z3-f (50 mg, yellow solid, crude product), yield: 86.33%. MS m/z (ESI): 503.2 [M+H] + .
  • Step 7 Dissolve Z3-f (50 mg, 0.10 mmol) in THF (6 mL), methanol (2 mL) and acetic acid (2 mL), add zinc powder (65 mg, 1.00 mmol), and stir at 45 ° C for 1 hour.
  • the reaction solution is filtered through diatomaceous earth, the filter cake is washed with methanol (6 mL ⁇ 2), the filtrate is diluted with water (20 mL), extracted with ethyl acetate (20 mL ⁇ 2), the organic phases are combined and dried over anhydrous sodium sulfate, and concentrated to obtain intermediate Z3 (40 mg, yellow solid, crude product), yield: 85.08%.
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1 g, 2.32 mmol) and 4-(tert-butoxycarbonylamino)butyric acid (542.83 mg, 2.67 mmol) were dissolved in DMF (10 mL), and NMI (1.01 g, 12.31 mmol) was added. The reaction was stirred at 20 ° C for 10 minutes, and then TCHF (781.99 mg, 2.79 mmol) was added and stirred at room temperature for 3 hours.
  • Step 2 H1-a (1.3 g, 2.11 mmol) was dissolved in DCM (12 mL), and then TFA (2.41 g, 21.11 mmol) was added. The reaction was stirred at 20 °C for 18 h. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane and methanol (10:1; 3 ⁇ 150 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give H1-b (1 g, viscous light yellow, crude product), yield: 91.86%. MS m/z (ESI): 516.3 [M+H] + .
  • Step 3 Dissolve intermediate Z1 (300 mg) in THF (20 mL), then add DIPEA (1.04 g, 8.08 mmol, 1.41 mL) and HATU (980.35 mg, 2.60 mmol). The reaction was stirred at 20°C for 18 h, then H1-b (387.11 mg, 750.70 ⁇ mol) was added and stirred for 3 h.
  • reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 35%-68% acetonitrile change) to obtain H1 (123.78 mg), yield: 21.45%. MS m/z(ESI):500.3[M/2+H] + .
  • Step 1 Dissolve 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (5 g, 19.68 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (9.07 g, 45.27 mmol) in EtOH (80 mL), add TFA (5.91 g, 98.42 mmol), stir at room temperature for 18 h, then cool to -10°C, add Na(CN)BH 3 (2.72 g, 43.31 mmol), and stir at 0°C for 2 h.
  • Step 2 H2-a (6.6 g, 15.06 mmol) and (Boc) 2 O (4.93 g, 22.59 mmol) were dissolved in DCM (100 mL), Et 3 N (6.10 g, 60.24 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (80 g, 0-70% EA/PE) to obtain H2-b (4.7 g, colorless solid), yield: 57.97%. MS m/z (ESI): 560.2 [M+Na] + .
  • Step 3 Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (2 g, 4.60 mmol) and H2-b (4.7 g, 8.73 mmol) were dissolved in DME (40 mL) and water (4 mL), and Pd(OAc) 2 (103.16 mg, 459.51 ⁇ mol), CataCXium A (329.50 mg, 919.02 ⁇ mol), K 2 CO 3 (2.54 g, 18.38 mmol) and (Pin) 2 B 2 (2.33 g, 9.19 mmol) were added and stirred at 70° C.
  • Step 4 H2-c (2 g, 2.46 mmol) was dissolved in DCM (25 mL), TFA (2.80 g, 24.57 mmol) was added, and the mixture was stirred at room temperature for 36 h. After the reaction was completed, sodium bicarbonate aqueous solution was added for neutralization, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (10:1). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain H2-d (1.2 g, light yellow solid, crude product), with a yield of 79.58%. MS m/z (ESI): 614.3 [M+H] + .
  • Step 5 H2-d (1.2 g, 1.96 mmol) was dissolved in THF (20 mL) and water (5 mL), LiOH (1.41 g, 58.67 mmol) was added, and the mixture was stirred at 75°C for 18 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was adjusted to pH 2-3 with dilute hydrochloric acid (3 mol/L), and concentrated to obtain H2-e (3.3 g). MS m/z (ESI): 586.2 [M+H] + .
  • Step 6 H2-e (3.3 g) was dissolved in THF (20 mL) and DMF (5 mL), and DIPEA (4.11 g, 31.76 mmol, 5.53 mL) and HATU (1.20 g, 3.18 mmol) were added, and stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with aqueous solution, and then extracted three times with dichloromethane and methanol (10:1), and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (24 g, 0-23%, MeOH/DCM+1% Et 3 N) to obtain H2-f (270 mg, light yellow solid), yield: 29.95%. MS m/z (ESI): 568.2 [M+H] + .
  • Step 7 H2-f (70 mg, 123.34 ⁇ mol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (91.12 mg, 246.68 ⁇ mol) were dissolved in DMSO (3 mL) and EtOH (1 mL), and NaBH 3 CN (62.01 mg, 986.72 ⁇ mol) and acetic acid (37.03 mg, 616.70 ⁇ mol) were added, and stirred in microwave at 90° C. for 0.5 h.
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (540 mg, 1.21 mmol) and cis-3-(tert-butyloxycarbonylamino)cyclobutanecarboxylic acid (522.88 mg, 2.43 mmol) were dissolved in DMF (7 mL), and then DIPEA (313.96 mg, 2.43 mmol, 423.12 ⁇ L) and HATU (641.53 mg, 1.70 mmol) were added.
  • Step 2 H3-a (430 mg, 669.97 ⁇ mol) was dissolved in EtOH (5 mL), and then diluted hydrochloric acid (4 mol/L, 2 mL) was added. The reaction was stirred at room temperature for 18 h. After the reaction was completed, the reaction solution was concentrated to obtain H3-b (320 mg, yellow solid, crude product), yield: 88.17%. MS m/z (ESI): 542.3 [M+H] + .
  • Step 3 Intermediate Z1 (100 mg, 192.48 ⁇ mol) was dissolved in DMF (5 mL), and then DIPEA (348.28 mg, 2.69 mmol, 469.38 ⁇ L) and HATU (326.78 mg, 866.18 ⁇ mol) were added, and the reaction was stirred at room temperature for 18 h. H3-b (312.80 mg, 577.44 ⁇ mol) was then added, and the reaction was stirred at room temperature for 2 h.
  • reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 35%-68% acetonitrile change) to obtain H3 (14.19 mg, purity: 100%), yield: 7.19%.
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (900 mg, 2.02 mmol) and 6-(tert-butoxycarbonylamino)hexanoic acid (515.03 mg, 2.23 mmol) were dissolved in DMF (10 mL), and then DIPEA (784.90 mg, 6.07 mmol, 1.06 mL) and HATU (1.15 g, 3.04 mmol) were added. The reaction was stirred at room temperature for 1 h.
  • Step 2 H4-a (0.89 g, 1.35 mmol) was dissolved in DCM (10 mL), and then diluted hydrochloric acid (4 mol/L, 3 mL) was added. The reaction was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated to obtain H4-b (800 mg, light yellow solid, hydrochloride), yield: 99.52%. MS m/z (ESI): 558.3 [M+H] + .
  • Step 3 Intermediate Z1 (100 mg, 192.48 ⁇ mol) was dissolved in DMF (10 mL), and then DIPEA (995.09 mg, 7.70 mmol, 1.34 mL) and HATU (290.47 mg, 769.94 ⁇ mol) were added. The reaction was stirred at room temperature for 18 h, then H4-b (343.13 mg, 577.45 ⁇ mol, hydrochloride) was added and stirred for 1 h.
  • reaction solution was concentrated and purified by CombiFlash (12 g, 0-13% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 40%-48% acetonitrile change) to obtain H4 (7.9 mg, purity 100%), yield: 3.94%.
  • Step 1 Compound 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.35 g, 5.57 mmol) and compound (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide (2 g, 4.6 mmol) were added to DMF (2 mL), and then HATU (2.12 g, 5.57 mmol) and DIPEA (2 mL) were added, stirred at room temperature for 10 minutes, and purified by silica gel column chromatography (DCM/MeOH 0-10%) to obtain H5-a (2.27 g), yield: 75.4%. MS m/z (ESI): 670 [M+H] + .
  • Step 2 H5-a (2.27 g, 3.4 mmol) was dissolved in ethyl acetate, and then a hydrochloric acid ethyl acetate solution (20 mL, 4 mol/L) was added dropwise, stirred at room temperature for 1 h, and concentrated to obtain H5-b (1.76 g), yield: 95.6%.
  • Step 3 Z1 (100 mg, 0.192 mmol) was dissolved in DMF (3 mL), and then DIPEA (2 mL) was added, followed by HATU (218 mg, 0.576 mmol), and the mixture was stirred at room temperature for 10 minutes. H5-b (109 mg, 0.192 mmol) was then added and stirred for 20 minutes. After concentration, the mixture was purified by high pressure liquid chromatography (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid aqueous solution) to obtain H5 (3.76 mg), yield: 2.9%. MS m/z (ESI): 527.3 [M/2+H] + .
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 1.12 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (256.12 mg, 1.46 mmol) were dissolved in DMF (5 mL), HATU (636.43 mg, 1.69 mmol) and DIPEA (363.38 mg, 2.81 mmol, 489.73 ⁇ L) were added with stirring at room temperature, and the mixture was stirred at room temperature for 5 h.
  • Step 2 H6-a (600 mg, 997.08 ⁇ mol) was dissolved in DCM (10 mL), diluted hydrochloric acid (4 mol/L, 5 mL) was added with stirring at room temperature, and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to obtain H6-b (500.18 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 502 [M+H] + .
  • Step 3 H10-a (100 mg, 192.48 ⁇ mol) was dissolved in DMF (5 mL), HATU (290.47 mg, 769.94 ⁇ mol) and DIPEA (746.32 mg, 5.77 mmol, 1.01 mL) were added with stirring at room temperature, and the mixture was stirred at room temperature overnight. H6-b (193.12 mg, 384.97 ⁇ mol) was added and the mixture was stirred at room temperature for 5 hours.
  • Step 1 Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 9.99 mmol) and azetidine-3-ol (1.46 g, 13.33 mmol, HCl) in DMF (10 mL), add K 2 CO 3 (4.14 g, 29.98 mmol), and stir at 80° C. for 18 h. After the reaction is completed, filter, concentrate the filtrate, and purify it with CombiFlash (40 g, 0-10% DCM/ACN) to obtain H7-a (1.1 g, yellow viscous material), yield: 33.43%. MS m/z (ESI): 330.1 [M+H] + .
  • Step 2 H7-a (0.9 g, 2.73 mmol) was dissolved in DCM (30 mL), and Dess-Martin periodinane (2.32 g, 5.47 mmol) was added and stirred at room temperature for 4 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated and purified by CombiFlash (20 g, 0-10% DCM/THF) to obtain H7-b (250 mg, yellow solid), yield: 27.95%. MS m/z (ESI): 328.0 [M+H] + .
  • Step 3 H2-f (66 mg, 116.29 ⁇ mol) and H7-b (133.21 mg, 407.02 ⁇ mol) were dissolved in DMSO (3 mL) and EtOH (1 mL), acetic acid (20.95 mg, 348.88 ⁇ mol) was added, and the mixture was stirred for 1 hour, and then Na(CN)BH 3 (58.46 mg, 930.34 ⁇ mol) was added, and the mixture was stirred at room temperature for 18 hours.
  • reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 35%-68% acetonitrile change) to obtain H7 (47.40 mg), yield: 44.96%.
  • Step 1 Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 9.99 mmol) and azetidine-3-ylmethanol (2.47 g, 19.98 mmol, hydrochloride) in DMF (10 mL), add K 2 CO 3 (5.52 g, 39.97 mmol), and stir at 70° C. for 18 h. After the reaction is completed, filter, concentrate the filtrate, and purify it with CombiFlash (40 g, 0-50% DCM/ACN) to obtain H8-a (230 mg, yellow solid), yield: 6.70%. MS m/z (ESI): 344.1 [M+H] + .
  • Step 2 H8-a (0.23 g, 669.90 ⁇ mol) was dissolved in DCM (30 mL), Dess-Martin periodinane (852.40 mg, 2.01 mmol) was added, stirred at room temperature for 18 h, filtered, and the filtrate was concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H8-b (130 mg, yellow solid), yield: 56.86%. MS m/z (ESI): 342.1 [M+H] + .
  • Step 3 H2-f (65 mg, 114.53 ⁇ mol) and H8-b (78.18 mg, 229.06 ⁇ mol) were dissolved in DMSO (3 mL) and EtOH (1 mL), acetic acid (20.63 mg, 343.59 ⁇ mol) was added, and the mixture was stirred for 1 hour, and then Na(CN)BH 3 (57.58 mg, 916.24 ⁇ mol) was added, and the mixture was stirred at room temperature for 18 hours.
  • reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 26%-56% acetonitrile change) to obtain H8 (48.90 mg), yield: 46.62%.
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 1.12 mmol) and 4-(tert-butoxycarbonylamino)butyric acid (251.42 mg, 1.24 mmol) were dissolved in DMF (5 mL), and then DIPEA (436.05 mg, 3.37 mmol, 587.67 ⁇ L) and HATU (636.43 mg, 1.69 mmol) were added and stirred at room temperature for 1 h.
  • DIPEA 436.05 mg, 3.37 mmol, 587.67 ⁇ L
  • HATU (636.43 mg, 1.69 mmol
  • Step 2 H9-a (430 mg, 682.75 ⁇ mol) was dissolved in DCM (10 mL), and then diluted hydrochloric acid (4 mol/L, 3 mL) was added and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated to obtain H9-b (386 mg, yellow solid, hydrochloride), yield: 99.86%. MS m/z (ESI): 530.3 [M+H] + .
  • Step 3 Dissolve the intermediate Z2 (210 mg, 30% content, 134.48 ⁇ mol) in DMF (5 mL), add DIPEA (1.48 g, 11.48 mmol, 2 mL) and (202.95 mg, 537.93 mmol), stir at room temperature for 0.5 h, then add H9-b (110 mg, 194.29 ⁇ mol, hydrochloride), and continue stirring at room temperature for 1 h.
  • reaction solution is concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mm NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 46%-57% acetonitrile change) to obtain H9 (4.26 mg), yield: 3.06%.
  • Step 2 H10-a (570 mg, 1.14 mmol) and 1-methylimidazole (280 mg, 3.41 mmol) were dissolved in acetonitrile (10 mL), TCFH (383 mg, 1.36 mmol) was added, and after stirring for 10 minutes, methyl 4-aminobenzoate (344 mg, 2.27 mmol) was added, and stirring was continued at room temperature for 20 hours.
  • Step 4 H10-c (23 mg, 0.037 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (33 mg, 0.074 mmol) were dissolved in DMF (5 mL), and DIPEA (15 mg, 0.11 mmol) and HATU (21 mg, 0.056 mmol) were added and stirred at room temperature for 4 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 1 Dissolve the intermediate Z1 (100 mg, 192.48 ⁇ mol) in DMF (5 mL), add DIPEA (1.48 g, 11.48 mmol, 2 mL) to completely dissolve it, and then add HATU (217.86 mg, 577.45 ⁇ mol). The reaction was stirred at room temperature for half an hour. After the raw materials reacted completely, tert-butyl 4-aminopiperidine-1-carboxylate (192.75 mg, 962.42 ⁇ mol) was added and reacted at room temperature for another hour. The reaction solution was concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H11-a (100 mg, light yellow solid), yield: 75.98%. MS m/z (ESI): 683.8 [M+H] + .
  • Step 2 H11-a (100 mg, 146.25 ⁇ mol) was dissolved in DCM (5 mL), TFA (146.25 ⁇ mol, 0.8 mL) was added, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, it was neutralized with saturated NaHCO 3 , extracted with a mixed solvent of dichloromethane and methanol (10:1; 3 ⁇ 50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain H11-b (85 mg, light yellow oil, crude product), yield: 99.58%. MS m/z (ESI): 584.3 [M+H] + .
  • Step 3 H11-b (60 mg, 102.80 ⁇ mol) and H8-b (105.26 mg, 308.40 ⁇ mol) were dissolved in DMSO (3 mL) and EtOH (1 mL), stirred at 80°C for 30 minutes, cooled to room temperature, and then NaBH 3 CN (58.14 mg, 925.20 ⁇ mol) was added, and stirred at room temperature for 0.5 h.
  • reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 38%-40% acetonitrile change) to obtain H11 (4.83 mg, purity 99.04%), yield: 5.12%.
  • Step 1 Dissolve intermediate Z1 (100 mg, 192.48 ⁇ mol) in DMF (5 mL), add DIPEA (1.48 g, 11.48 mmol, 2 mL) to completely dissolve it, then add HATU (217.86 mg, 577.45 ⁇ mol) and stir at room temperature for 0.5 h. After the reaction of the raw materials is complete, add tert-butyl piperazine-1-carboxylate (107.55 mg, 577.45 ⁇ mol) and continue to react at room temperature for 1 h. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H12-a (70 mg, light yellow solid), yield: 54.30%. MS m/z (ESI): 670.3 [M+H] + .
  • Step 2 H12-a (70 mg, 104.52 ⁇ mol) was dissolved in DCM (5.80 mL), TFA (3 mL) was added, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, the reaction solution was concentrated, neutralized with sodium bicarbonate, extracted with a mixed solvent of dichloromethane and methanol (10:1; 3 ⁇ 50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H12-b (57 mg, light yellow oil, crude product), yield: 95.74%. MS m/z (ESI): 570.2 [M+H] + .
  • Step 3 H12-b (57.00 mg, 100.07 ⁇ mol) and H8-b (60 mg, 175.79 ⁇ mol) were dissolved in DMSO (3 mL) and EtOH (1 mL), stirred at 80°C for 30 minutes, cooled to room temperature, and then NaBH 3 CN (60 mg, 954.78 ⁇ mol) was added and stirred at room temperature for 0.5 hours.
  • reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 40%-48% acetonitrile change) to obtain H12 (14.06 mg), yield: 15.06%.
  • reaction solution was purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 0.04% FA H 2 O-acetonitrile; wavelength: 254/214nm; gradient: 38%-48% acetonitrile change) to obtain H13 (2.43mg, purity: 94.41%), yield: 2.90%.
  • Step 2 H14-a (350 mg, 543.62 ⁇ mol) was dissolved in DCM (5 mL), and diluted hydrochloric acid (4 mol/L, 3 mL) was added with stirring at room temperature, and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to obtain H14-b (295.58 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 544 [M+H] + .
  • Step 3 H10-a (100 mg, 192.48 ⁇ mol) was dissolved in DMF (5 mL), and HATU (363.09 mg, 962.42 ⁇ mol) and DIPEA (746.32 mg, 5.77 mmol, 1.01 mL) were added under stirring at room temperature, and the mixture was stirred at room temperature for 2 hours, and H14-b (209.31 mg, 384.97 ⁇ mol) was added, and the mixture was stirred at room temperature overnight.
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 1.12 mmol) and 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid (515.70 mg, 2.25 mmol) were dissolved in DMF (10 mL), and DIPEA (726.76 mg, 5.62 mmol, 979.45 ⁇ L) and HATU (848.58 mg, 2.25 mmol) were added and stirred at room temperature for 1 h.
  • DIPEA 7.26.76 mg, 5.62 mmol, 979.45 ⁇ L
  • HATU 848.58 mg, 2.25 mmol
  • Step 2 H16-a (354 mg, 539.76 ⁇ mol) was dissolved in DCM (10 mL), diluted hydrochloric acid (4 mol/L, 2 mL) was added, and stirred at 20°C for 1 h. After the reaction was completed, the reaction solution was concentrated to obtain H16-b (299.96 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 556.3 [M+H] + .
  • Step 3 Dissolve intermediate Z1 (100 mg, 192.48 ⁇ mol) and DIPEA (1.48 g, 11.48 mmol, 2 mL) in DMF (5 mL), add HATU (254.16 mg, 673.69 ⁇ mol), stir at room temperature for 0.5 h, then add H16-b (213.94 mg, 384.97 ⁇ mol), and continue stirring at room temperature for 0.5 h. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H16 (18.29 mg), yield: 9.14%. MS m/z (ESI): 520.3 [M/2+H] + .
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.85 g, 1.97 mmol) and 5-tert-butoxy-5-oxo-pentanoic acid (427.31 mg, 2.27 mmol) were dissolved in DCM (10 mL), and DIPEA (1 g, 7.29 mmol) and HATU (1.33 g, 3.5 mmol) were added and stirred at room temperature for 30 minutes.
  • Step 2 H17-a (1.1 g, 1.83 mmol) was dissolved in THF (10 mL), diluted hydrochloric acid (4 mol/L, 12 mL) was added, and stirred at room temperature for 30 minutes. After the reaction was completed, it was neutralized with a saturated sodium bicarbonate aqueous solution, extracted with a mixed solvent of dichloromethane and methanol (10:1, 30 mL ⁇ 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H17-b (412 mg, colorless viscous substance, crude product), yield: 41.31%. MS m/z (ESI): 545.3 [M+H] + .
  • Step 3 H2-f (70 mg, 123.34 ⁇ mol) and H17-b (80.61 mg, 148.01 ⁇ mol) were dissolved in DMF (4 mL), and DIPEA (71.73 mg, 555.03 ⁇ mol) and HATU (69.80 mg, 185.01 ⁇ mol) were added, and stirred at room temperature for 1 h.
  • reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 44%-74% acetonitrile change) to obtain H17 (33.57 mg), yield: 24.87%.
  • Step 1 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1 g, 3.65 mmol) and tert-butyl N-(8-bromooctyl)carbamate (1 g, 3.24 mmol) were dissolved in DMF (10 mL), K 2 CO 3 (2.02 g, 14.59 mmol) was added, and stirred at 50° C. for 18 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by CombiFlash (12 g, 0-100% EA/PE) to obtain H18-a (335 mg, colorless oil), yield: 18.32%. MS m/z (ESI): 402.2 [M-100+H] + .
  • Step 2 H18-a (335 mg, 667.90 ⁇ mol) was dissolved in DCM (20 mL), HCl (4 mol/L ethyl acetate solution, 3 mL) was added, and stirred at room temperature for 18 h. After the reaction was completed, the reaction solution was concentrated to obtain H18-b (268 mg, white solid), yield: 99.95%. MS m/z (ESI): 402.2 [M+H] + .
  • Step 3 Dissolve intermediate Z1 (100 mg, 192.48 ⁇ mol) in DMF (1.02 mL), add DIPEA (199.02 mg, 1.54 mmol, 268.22 ⁇ L) and HATU (363.09 mg, 962.42 ⁇ mol), stir at room temperature for 18 hours, then add H18-b (149.18 mg, 371.61 ⁇ mol), and continue stirring at room temperature for 2 hours.
  • reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% ACN/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 47%-78% acetonitrile change) to obtain H18 (34.59 mg), yield: 19.12%.
  • Step 1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (600 mg, 1.35 mmol) and N-tert-butoxycarbonyl-8-aminooctanoic acid (385.00 mg, 1.48 mmol) were dissolved in DMF (15 mL), HATU (1.02 g, 2.70 mmol) and DIPEA (523.26 mg, 4.05 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours.
  • Step 2 H20-a (565 mg, 823.72 ⁇ mol) was dissolved in THF (5 mL), and dioxane hydrochloride solution (4 mol/L, 5.01 mL) was added under ice bath (0°C), and stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated to obtain H20-b (482 mg, yellow solid, crude product), which was directly used in the next step.
  • Step 3 H10-a (96.53 mg, 192.48 ⁇ mol) and H20-b (172.33 mg, 251.24 ⁇ mol) were dissolved in DMF (5 mL), HATU (157.98 mg, 418.74 ⁇ mol) and DIPEA (27.06 mg, 209.37 ⁇ mol, 36.47 ⁇ L) were added at room temperature, and stirred at room temperature for 3 hours.
  • Step 2 H11-a (195 mg, 285.18 ⁇ mol) was dissolved in 1,4-dioxane (4.00 mL), and a hydrochloric acid ethyl acetate solution (2 mol/L, 2 mL) was added at room temperature, and stirred at room temperature for 16 hours. After the reaction was completed, DCM (20 mL) was added to the reaction solution, and then a saturated sodium bicarbonate aqueous solution (50 mL) was added, and stirred for 5 minutes. Solids precipitated, filtered, and the filter cake was concentrated to obtain H11-b (95 mg, yellow solid, crude product) without further purification, and directly used in the next step. MS m/z (ESI): 583.8 [M+H] + .
  • Step 3 H11-b (40 mg, 68.53 ⁇ mol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (37.97 mg, 102.80 ⁇ mol) were dissolved in a mixed solution of DMSO (3 mL) and EtOH (1 mL), stirred at 80 °C for 0.5 h in a microwave reactor, cooled naturally to room temperature, NaBH 3 CN (43.07 mg, 685.34 ⁇ mol) was added at room temperature, and stirring was continued at room temperature for 2 h.
  • Step 1 (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300 mg, 674.78 ⁇ mol) and 3-(tert-butoxycarbonylamino)propionic acid (153.21 mg, 809.74 ⁇ mol) were dissolved in DMF (5 mL), and HATU (381.86 mg, 1.01 mmol) and DIPEA (436.05 mg, 3.37 mmol, 587.67 ⁇ L) were added successively under stirring at room temperature, and stirred at room temperature for 4 hours.
  • HATU 381.86 mg, 1.01 mmol
  • DIPEA 436.05 mg, 3.37 mmol, 587.67 ⁇ L
  • Step 2 H22-a (260 mg, 422.23 ⁇ mol) was dissolved in DCM (5 mL), and HCl in ethyl acetate (4.0 mol/L, 3 mL) was added under stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H22-b (217.73 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 516 [M+H] + .
  • Step 3 H10-a (100 mg, 192.48 ⁇ mol) and H22-b (198.52 mg, 384.97 ⁇ mol) were dissolved in DMF (5 mL), and HATU (363.09 mg, 962.42 ⁇ mol) and DIPEA (746.32 mg, 5.77 mmol, 1.01 mL) were added in sequence under stirring at room temperature, and stirred overnight at room temperature.
  • Step 1 (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.5 g, 1.12 mmol) and 1-tert-butoxycarbonylazetidine-3-carboxylic acid (452.60 mg, 2.25 mmol) were dissolved in DMF (10 mL), and DIPEA (581.40 mg, 4.50 mmol, 783.56 ⁇ L) and HATU (848.58 mg, 2.25 mmol) were added and stirred at room temperature for 1 hour.
  • DIPEA 581.40 mg, 4.50 mmol, 783.56 ⁇ L
  • HATU 848.58 mg, 2.25 mmol
  • Step 2 H23-a (170 mg, 270.79 ⁇ mol) was dissolved in DCM (10 mL), and HCl in ethyl acetate (4 M, 2 mL) was added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain H23-b (142 mg, yellow solid, HCl), yield: 92.95%. MS m/z (ESI): 528.3 [M+H] + .
  • Step 3 Dissolve intermediate Z1 (100 mg, 192.48 ⁇ mol) and DIPEA (1.48 g, 11.48 mmol, 2 mL) in DMF (5 mL), add HATU (290.47 mg, 769.94 ⁇ mol), stir at room temperature for 0.5 hours, then add H23-b (142 mg, 251.71 ⁇ mol, HCl), and continue stirring at room temperature for 0.5 hours.
  • reaction solution is concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 40%-45% acetonitrile change) to obtain H23 (1.93 mg), yield: 0.99%.
  • Step 1 (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S,-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (400 mg, 0.90 mmol) was dissolved in DCM (3 mL), triethylamine (273 mg, 2.70 mmol) and dihydro-2H-pyran-2,6(3H)-dione (103 mg, 0.90 mmol) were added at 0°C, and the reaction solution was stirred at 25°C for 1 hour.
  • Step 2 The intermediate Z3 (18 mg, 0.04 mmol) and H24-a (26 mg, 0.05 mmol) were dissolved in DMF (1.5 mL), HATU (22 mg, 0.06 mmol) and DIPEA (15 mg, 0.11 mmol) were added, and the mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative HPLC (Waters-Xbridge-C18-10 ⁇ m-19*250 mm column (mobile phase: 38%-68% (v/v) acetonitrile and water (containing 0.1% formic acid)) to obtain H24 (6 mg), yield: 15.54%.
  • reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3H2O - acetonitrile; wavelength: 254/214nm; gradient: 0%-70% acetonitrile change) to obtain H25 (14.64mg), yield: 25.3%.
  • reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 48%-55% acetonitrile change) to obtain H26 (20.43 mg), yield: 11.81%.
  • Step 1 Dissolve 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (2.8 g, 11.02 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (2.85 g, 16.54 mmol) in EtOH (30 mL), add AcOH (132.40 mg, 2.20 mmol, 0.4 mL), stir at room temperature for 18 hours, then add NaBH 3 CN (3.46 g, 55.12 mmol), and continue stirring at room temperature for 3 hours.
  • Step 2 H27-a (4.5 g, 10.97 mmol) and Et 3 N (7.77 g, 76.79 mmol, 11.10 mL) were dissolved in DCM (88.90 mL), (Boc) 2 O (7.18 g, 32.91 mmol) was added, and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (40 g, 0-15% EA/PE) to obtain H27-b (3 g, colorless oil), yield: 53.59%. MS m/z (ESI): 398.0 [M-112+H] + .
  • Step 3 Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1.5 g, 3.45 mmol) and H27-b (3 g, 5.88 mmol) were dissolved in DME (30 mL) and water (3 mL), and Pd(OAc) 2 (77.37 mg, 344.63 ⁇ mol), CataCXium A (247.13 mg, 689.26 ⁇ mol), K 2 CO 3 (1.91 g, 13.79 mmol) and (Pin) 2 B 2 (1.75 g, 6.89 mmol) were added, and the mixture was stirred at 70° C.
  • Step 5 H27-d (460 mg, 785.58 ⁇ mol) was dissolved in EtOH (3 mL), CH 3 ONa (424.40 mg, 7.86 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution, filtered, and the filter cake was dried to obtain the product H27-e (360 mg, white solid), yield: 84.94%. MS m/z (ESI): 540.2 [M+H] + .
  • Step 6 H27-e (100 mg, 185.36 ⁇ mol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde (273.87 mg, 741.45 ⁇ mol) were dissolved in DMSO (1 mL) and EtOH (3 mL), stirred at 90 °C in a microwave for 0.5 h, then cooled to room temperature, and then NaBH 3 CN (69.89 mg, 1.11 mmol) was added and stirring was continued at room temperature for 0.5 h.
  • the combined organic phases were dried over anhydrous sodium sulfate, concentrated, purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 55%-60% acetonitrile change) to obtain H27 (2.01 mg), yield: 1.13%.
  • reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA/H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 42%-62% acetonitrile change) to obtain H28 (21.30 mg), yield: 12.61%.
  • Step 1 Compound 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (1.0 g, 3.94 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (1.47 g, 7.87 mmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (2.50 g, 11.81 mmol) was added under stirring at room temperature, and stirred at room temperature for 1 hour. NaBH 3 CN (1.24 g, 19.68 mmol) was added, and stirring was continued at room temperature for 1 hour.
  • Step 3 Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (0.5 g, 1.15 mmol) and H29-b (903.58 mg, 1.72 mmol) were dissolved in DME (10 mL) and H 2 O (1 mL), and Pd(OAc) 2 (25.79 mg, 114.88 ⁇ mol), CataCXium A (82.38 mg, 229.75 ⁇ mol), potassium carbonate (635.09 mg, 4.60 mmol), (Pin) 2 B 2 , (583.43 mg, 2.30 mmol) were added, and the mixture was stirred at 70° C.
  • Step 4 H29-c (250 mg, 312.57 ⁇ mol) was dissolved in DCM (10 mL), and 2,2,2-trifluoroacetic acid (35.64 mg, 312.57 ⁇ mol, 3 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H29-d (187.41 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 600 [M+H] + .
  • Step 5 H29-d (540.62 mg, 10.01 mmol) was dissolved in methanol (20 mL), sodium methoxide (540.62 mg, 10.01 mmol) was added, and the temperature was raised to 70°C and stirred overnight. The reaction solution was poured into saturated sodium carbonate, extracted with EA (30 mL ⁇ 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give H29-e (184.63 mg, yellow solid, crude product), yield: 100.00%, which was used directly in the next step. MS m/z (ESI): 554 [M+H] + .
  • Step 6 H29-e (200 mg, 361.33 ⁇ mol) and H8-b (246.66 mg, 722.66 ⁇ mol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (382.90 mg, 1.81 mmol) was added with stirring at room temperature, and stirred at room temperature overnight. The reaction solution was poured into water and extracted with DCM (30 mL ⁇ 2).
  • Step 1 Compound 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (1.0 g, 3.94 mmol) and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (1.00 g, 4.72 mmol) were dissolved in DCM (15 mL), and NaBH(OAc) 3 (2.50 g, 11.81 mmol) was added with stirring at room temperature, and stirred at room temperature overnight.
  • Step 2 H30-a (1.7 g, 3.78 mmol) was dissolved in DCM (20 mL), triethylamine (1.14 g, 11.33 mmol) and (Boc) 2 O (1.03 g, 4.73 mmol) were added under stirring at room temperature, and stirred overnight at room temperature.
  • Step 3 Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (0.7 g, 1.61 mmol) and H30-b (1.77 g, 3.22 mmol) were dissolved in DME (20 mL) and water (2 mL), and Pd(OAc) 2 (36.11 mg, 160.83 ⁇ mol), CataCXium A (115.33 mg, 321.66 ⁇ mol), potassium carbonate (889.12 mg, 6.43 mmol), (Pin) 2 B 2 (816.81 mg, 3.22 mmol) were added, and the mixture was stirred at 70° C.
  • Step 4 H30-c (700 mg, 847.62 ⁇ mol, 1 mL) was dissolved in DCM (10 mL), trifluoroacetic acid (96.65 mg, 847.62 ⁇ mol, 3 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H30-d (530.28 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 626 [M+H] + .
  • Step 5 H30-d (600 mg, 959.06 ⁇ mol) was dissolved in methanol (25 mL), sodium methoxide (1.55 g, 28.77 mmol) was added, and the mixture was heated to 70°C and stirred overnight. After the reaction was completed, the reaction solution was poured into saturated sodium carbonate, extracted with EA (30 mL ⁇ 2), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H30-e (555.82 mg, crude product, yellow solid), yield: 100.00%, which was used directly in the next step. MS m/z (ESI): 580 [M+H] + .
  • Step 6 H30-e (300 mg, 517.65 ⁇ mol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carboxaldehyde (382.41 mg, 1.04 mmol) were dissolved in DCM (20 mL), and sodium acetate borohydride (548.55 mg, 2.59 mmol) was added under stirring at room temperature, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into water and extracted with DCM (30 mL ⁇ 2).
  • Step 1 Compound 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (1.0 g, 3.94 mmol) and tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (1.00 g, 4.17 mmol) were dissolved in DCM (15 mL), and NaBH(OAc) 3 (2.50 g, 11.81 mmol) was added with stirring at room temperature, and stirred at room temperature for 1 hour. NaBH 3 CN (1.24 g, 19.68 mmol) was added, and stirred at room temperature for 2 hours.
  • Step 3 Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (0.7 g, 1.61 mmol) and H31-b (1.86 g, 3.22 mmol) were dissolved in DME (20 mL) and Water (2 mL), and Pd(OAc) 2 (36.11 mg, 160.83 ⁇ mol), CataCXium A (115.33 mg, 321.66 ⁇ mol), K 2 CO 3 (889.12 mg, 6.43 mmol) and (Pin) 2 B 2 (816.81 mg, 3.22 mmol) were added, and the mixture was stirred at 70° C.
  • Step 4 H31-c (700 mg, 819.77 ⁇ mol) was dissolved in DCM (10 mL), and 2,2,2-trifluoroacetic acid (93.47 mg, 819.77 ⁇ mol, 3.0 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H31-d (512.86 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 654 [M+H] + .
  • Step 5 H31-d (600 mg, 917.90 ⁇ mol) was dissolved in methanol (25 mL), sodium methoxide (1.49 g, 27.54 mmol) was added, and the mixture was heated to 70°C and stirred overnight. After the reaction was completed, the reaction solution was poured into saturated sodium carbonate, extracted with EA (30 mL ⁇ 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H31-e (557.71 mg, crude product, yellow solid), yield: 100.00%, which was used directly in the next step. MS m/z (ESI): 608 [M+H] + .
  • Step 6 H31-e (300 mg, 493.75 ⁇ mol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carboxaldehyde (364.75 mg, 987.49 ⁇ mol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (523.22 mg, 2.47 mmol) was added with stirring at room temperature, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into water and extracted with DCM (30 mL ⁇ 2).
  • Step 1 Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (300 mg, 1.09 mmol) and 4-tert-butyloxycarbonylaminopiperidine (326 mg, 1.63 mmol) in DMF (3 mL), and add DIPEA (702 mg, 5.43 mmol). Heat the reaction solution to 80°C and stir overnight.
  • Step 2 H32-a (240 mg, 0.53 mmol) was dissolved in DCM (10 mL), and HCl in ethyl acetate (4 mol/L, 5.26 mmol) was added, and stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated to obtain H32-b (185 mg, crude product), yield: 98.74%, which was directly used for the next step. MS m/z (ESI): 357.1 [M+H] + .
  • Step 3 Dissolve the intermediate Z1 (30 mg, 0.058 mmol) in DMF (5 mL), add DIPEA (223 mg, 1.72 mmol) and HATU (100 mg, 0.27 mmol), stir at room temperature for 0.5 hours, then add H32-b (31 mg, 0.087 mmol), and continue to stir the reaction solution at room temperature for 20 hours.
  • reaction solution is concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H32 (4.99 mg), yield: 9.86%.
  • Step 1 Dissolve intermediate Z1 (200 mg, 384.97 ⁇ mol) and ethyl piperidine-4-carboxylate (302.60 mg, 1.92 mmol) in DMF (8 mL), add DIPEA (298.53 mg, 2.31 mmol, 402.33 ⁇ L) and HATU (290.47 mg, 769.94 ⁇ mol), and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H33-a (220 mg, light yellow solid), yield: 89.20%. MS m/z (ESI): 641.3 [M+H] + .
  • Step 2 H33-a (220 mg, 343.37 ⁇ mol) was dissolved in THF (4 mL) and water (1 mL), LiOH (65.79 mg, 2.75 mmol) was added, and the mixture was stirred at 75°C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and the pH was adjusted to 3-4 with dilute hydrochloric acid (2 mol/L), extracted with dichloromethane (60 mL ⁇ 3), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, H33-b (145 mg, light yellow solid, crude product) was obtained, with a yield of 68.93%. MS m/z (ESI): 613.3 [M+H] + .
  • Step 3 H33-b (60 mg, 97.94 ⁇ mol) and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (27.74 mg, 82.62 ⁇ mol) were dissolved in DMF (5 mL), and DIPEA (101.26 mg, 783.48 ⁇ mol, 136.47 ⁇ L) was added. The mixture was stirred at room temperature for 0.5 h, and then HATU (110.84 mg, 293.81 ⁇ mol) was added. The mixture was stirred at room temperature for 1 h.
  • reaction solution was purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 0.04% FA/H 2 O-acetonitrile; wavelength: 254/214nm; gradient: 40%-60% acetonitrile change) to obtain H33 (2.02mg), yield: 2.16%.
  • Step 1 Dissolve intermediate Z1 (200 mg, 384.97 ⁇ mol) and 4-(dimethoxymethyl)piperidine (306.48 mg, 1.92 mmol) in DMF (8 mL), add DIPEA (298.53 mg, 2.31 mmol, 402.33 ⁇ L) and HATU (290.47 mg, 769.94 ⁇ mol), and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H35-a (220 mg, light yellow solid), yield: 89.20%. MS m/z (ESI): 643.3 [M+H] + .
  • Step 2 H35-a (220 mg, 342.30 ⁇ mol) was dissolved in EtOH (4 mL) and H 2 O (2 mL), p-TsOH (176.83 mg, 1.03 mmol) was added, and the mixture was stirred at 90°C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was concentrated, and water was added to dilute the mixture to 30 mL. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 8, and the mixture was extracted with dichloromethane (60 mL ⁇ 3).
  • Step 3 H35-b (100 mg, 167.60 ⁇ mol) and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (50.16 mg, 167.60 ⁇ mol) were dissolved in EtOH (10 mL), and DIPEA (32.49 mg, 251.40 ⁇ mol, 43.79 ⁇ L) was added, and the mixture was stirred at 90°C in a microwave for 0.5 hour, and then CH 3 COOH (20.13 mg, 335.20 ⁇ mol) was added, and the mixture was stirred at 90°C in a microwave for 0.5 hour.
  • Step 4 H35-c (107 mg, 121.74 ⁇ mol) was dissolved in EtOH (10 mL), and NaBH 3 CN (76.50 mg, 1.22 mmol) was added, and the mixture was stirred at 20° C. for 4 hours. After the reaction was completed, the reaction solution was purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H35 (1.03 mg, white solid), yield: 0.84%. MS m/z (ESI): 880.3 [M+H] + .
  • Step 1 tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (717 mg, 3 mmol) was added to dioxane (1 mL), and then dioxane hydrochloride solution (4 mol/L, 10 mL) was added and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with dichloromethane (5 mL), and the filter cake was dried naturally to obtain H36-a (525 mg), yield: 100%. MS m/z (ESI): 176 [M + H] + .
  • Step 2 Add H36-a (525 mg, 3 mmol) and compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (828 mg, 3 mmol) to DMF (2 mL), add DIPEA (1 mL), heat to 125°C and stir at 125°C for 2 hours. After the reaction is completed, pour the reaction solution into water (100 mL), extract with ethyl acetate (30 mL ⁇ 3), combine the organic phases, concentrate and purify by silica gel column chromatography (PE/EA 0-60%) to obtain H36-b (790 mg), yield: 66.7%. MS m/z (ESI): 396 [M+H] + .
  • Step 3 H36-b (790 mg, 2 mmol) was dissolved in ammonia dioxane solution (10 mL, 1.6 mol/L), tetraisopropyl titanate (1136 mg, 4 mmol) was added, and the mixture was stirred at room temperature for 2 hours, and then NaBH (150 mg) was added and stirred for 30 minutes. After the reaction was completed, the reaction solution was purified by silica gel column chromatography (0-5% DCM/MeOH) to obtain H36-c (475 mg), yield: 75%. MS m/z (ESI): 397.2 [M+H] + .
  • Step 4 H36-c (100 mg, 250 umol) and H10-a (126 mg, 250 umol) were dissolved in DMF (2 mL), TCFH (16 mg, 55 ummol) and N-methylimidazole (1 mL) were added and stirred at room temperature. The resulting mixture was pumped dry and sent to the preparation, and the filtrate was purified by high pressure liquid phase (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid water) to obtain H36 (14 mg), yield: 6%. MS m/z (ESI): 880.4 [M+H] + .
  • Step 2 H37-a (30 mg, 0.05 mmol) was dissolved in methanol (1 mL), and hydrochloric acid/methanol solution (1 mL, 4 mol/L) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain H37-b (25 mg, yellow oil), with a yield of 98.35%. MS m/z (ESI): 556.2 [M+H] + .
  • Step 1 At 0°C, 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (8 g, 31.5 mmol) and acetic acid (0.1 mL, 1.75 mmol) were added to a solution of tert-butyl 4-aminopiperidine-1-carboxylate (6 g, 29.9 mmol) in DCM (100 mL), and the mixture was stirred at 25°C for 1.5 hours under a nitrogen atmosphere. Then NaBH(OAc) 3 (12.7 g, 59.9 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 25°C for 2 hours under a nitrogen atmosphere.
  • Step 3 H2-b (4.45 g, 8.27 mmol) was dissolved in DME (40 mL) and water (4 mL), and 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (2 g, 4.60 mmol), bis(Pin) 2 B 2 (2.33 g, 9.19 mmol), CataCXium A (329 mg, 0.92 mmol), Pd(OAc) 2 (103 mg, 0.46 mmol) and K 2 CO 3 (2.54 g, 18.4 mmol) were added, and the mixture was stirred at 70° C.
  • Step 4 To a solution of H2-c (2 g, 2.46 mmol) in EA (15 mL) was added a hydrochloric acid ethyl acetate solution (4 mol/L, 15 mL), and stirred at 25° C. for 2 hours. After the reaction was completed, the mixture was concentrated to give H2-d (1.8 g, yellow solid), yield: 95.9%. MS m/z (ESI): 614.2 [M+H] + .
  • Step 6 HATU (194 mg, 0.51 mmol) and DIPEA (276 mg, 2.13 mmol) were added to a solution of H2-e (250 mg, 0.43 mmol) in DMF (4 mL) and THF (20 mL), and stirred at 25° C. for 30 minutes under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated and diluted with water (10 mL), filtered and the filter cake was dried to obtain H2-f (150 mg, red solid), yield: 30.9%. MS m/z (ESI): 568.2 [M+H] + .
  • Step 7 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylic acid (16 mg, 0.04 mmol), HATU (25 mg, 0.07 mmol) and DIPEA (17 mg, 0.13 mmol) were added to a solution of H2-f (50 mg, 0.04 mmol) in DMF (2 mL), and stirred at 25 ° C for 30 minutes under a nitrogen atmosphere.
  • Step 1 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (278 mg, 0.820 mmol), XPhos (76.7 mg, 0.160 mmol), Ruphos-Pd-G3 (138 mg, 0.160 mmol), 4-(dimethoxymethyl)-piperidine (170 mg, 1.07 mmol) and toluene (6 mL) were added to a single-necked bottle at room temperature, and LiHMDS (1 mol/L, 4.11 mL, 4.11 mmol) was added with stirring at room temperature under nitrogen atmosphere, and the mixture was reacted at 80 °C for 2 hours.
  • LiHMDS (1 mol/L, 4.11 mL, 4.11 mmol
  • Step 2 Add H39-a (218 mg, 0.520 mmol) and THF (1.5 mL) to a single-mouth bottle at room temperature, add dilute hydrochloric acid (2 mol/L, 1.50 mL, 3.00 mmol) under stirring at room temperature, and react at 70°C for 1 hour. After the reaction is completed, add water (20 mL) to the reaction system, adjust the pH to 7 with saturated NaHCO 3 aqueous solution, extract with ethyl acetate (30 mL ⁇ 3), wash the combined organic phases with saturated brine (10 mL), dry over anhydrous sodium sulfate, and concentrate to obtain H39-b (140 mg, yellow solid), yield: 72.69%. MS m/z (ESI): 371.0 [M+H] + .
  • Step 3 H39-b (70.0 mg, 0.190 mmol), H2-f (91.0 mg, 0.160 mmol), DMSO (3 mL) and ethanol (1 mL) were added to a single-mouth bottle at room temperature, and NaBH 3 CN (76.7 mg, 1.28 mmol) and acetic acid (45.9 ⁇ L, 0.800 mmol) were added under stirring at room temperature, and the mixture was reacted under microwave conditions at 90° C. for 1 hour.
  • Step 1 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol) and 4-(dimethoxymethyl)piperidine (432 mg, 2.72 mmol) were dissolved in DMSO (10 mL) at room temperature, and DIPEA (702 mg, 5.43 mmol) was added and stirred at 120°C for 2 hours.
  • Step 2 H40-a (690 mg, 1.66 mmol) was dissolved in THF (4 mL), and aqueous hydrochloric acid solution (2 mol/L, 4 mL) was added, and the temperature was raised to 70°C and stirred for reaction for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (30 mL ⁇ 3), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain H40-b (450 mg, yellow solid, purity 80%), with a yield of 73.35%. MS m/z (ESI): 370.2 [M+H] + .
  • Step 3 H40-b (34 mg, 0.07 mmol, purity 80%) and H2-f (30 mg, 0.04 mmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), and NaBH 3 CN (18 mg, 0.30 mmol) and acetic acid (11 mg, 0.19 mmol) were added, and microwave reaction was performed at 95° C. for 1 hour.
  • H43 was prepared according to the above synthetic route.
  • the purification conditions of the preparative HPLC were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change), H43 (14.68mg, purity 98.93%), yield: 30.29%.
  • Step 1 Dissolve bis(trichloromethyl) carbonate (8.69 mg, 29.29 ⁇ mol) in DCM (5 mL), add tert-butyl piperazine-1-carboxylate (21.82 mg, 117.18 ⁇ mol) under ice bath (0°C), slowly warm the mixed solution to room temperature and stir at room temperature for 1 hour, continue to add 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindoline-1,3-dione (20 mg, 58.59 ⁇ mol) at 0°C, continue to stir at room temperature for 16 hours. After the reaction is completed, the reaction solution is concentrated to obtain H45-a (105 mg, 189.67 ⁇ mol). MS m/z (ESI): 453.9 [M-100+H] + .
  • Step 2 H45-a (105 mg, 189.67 ⁇ mol) was dissolved in DCM (5 mL), TFA (6.92 mg, 60.65 ⁇ mol, 1 mL) was added at room temperature, and the mixed solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H45-b (86 mg, white solid, crude product), which was directly used in the next step without further purification. MS m/z (ESI): 453.9 [M-100+H] + .
  • Step 3 H10-a (50 mg, 99.70 ⁇ mol) and H45-b (90.43 mg, 199.40 ⁇ mol) were dissolved in DMF (5 mL), HATU (75.23 mg, 199.40 ⁇ mol) and DIPEA (64.43 mg, 498.50 ⁇ mol, 86.83 ⁇ L) were added at room temperature, and the mixture was stirred for 16 hours at room temperature.
  • Step 1 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (1 g, 2.00 mmol) and 4-(dimethoxymethyl)piperidine (636.41 mg, 4.00 mmol) were dissolved in 1,4-dioxane (15 mL), Pd 2 (dba) 3 (183.00 mg, 199.85 ⁇ mol) and XPhos (190.54 mg, 399.69 ⁇ mol) and Cs 2 CO 3 (1.30 g, 4.00 mmol) were added under argon protection, and the temperature was raised to 100° C. and stirred overnight.
  • Step 2 H46-a (0.9 g, 1.56 mmol) was dissolved in CF 3 CH 2 OH (20 mL), TFA (212.80 mg, 1.87 mmol) and Pd/C (165.51 mg, 155.52 ⁇ mol, 10% purity) were added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated and dissolved in THF, and the pH value was adjusted to weak alkalinity with triethylamine. After concentration, it was purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H46-b (0.35 g, brown oil), yield: 56.20%. MS m/z (ESI): 401.3 [M+H] + .
  • Step 3 H46-b (300 mg, 749.12 ⁇ mol) was dissolved in DCM (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 5 mL) was added, and stirred at room temperature for 20 minutes. After the reaction was completed, the reaction mixture was concentrated and dissolved in dichloromethane, and a small amount of triethylamine was added. Purification by CombiFlash (4 g, 0-10% MeOH/DCM) gave H46-c (0.2 g, light yellow solid), yield: 75.33%. MS m/z (ESI): 355.2 [M+H] + .
  • Step 4 H2-f (50 mg, 88.10 ⁇ mol) and H46-c (46.83 mg, 132.15 ⁇ mol) were dissolved in DMSO (1 mL) and EtOH (0.5 mL), and NaBH 3 CN (27.68 mg, 440.50 ⁇ mol) and acetic acid (10.58 mg, 176.20 ⁇ mol) were added, and the mixture was heated to 90° C. and stirred for 45 minutes in a microwave.
  • Step 1 Dissolve 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (1.1 g, 4.33 mmol) and tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (1 g, 4.58 mmol) in EtOH (10 mL), add CH 3 COOH (312.08 mg, 5.20 mmol), stir at room temperature for 18 hours, then cool to 0°C, add NaBH 3 CN (598.72 mg, 9.53 mmol), and stir at 0°C for 2 hours.
  • Step 2 H47-a (1.98 g, 4.34 mmol) was dissolved in DCM (30 mL), Et 3 N (1.76 g, 17.36 mmol) and (Boc) 2 O (1.89 g, 8.68 mmol) were added, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-10% EA/PE) to obtain H47-b (2.1 g, colorless oil), yield: 86.98%. MS m/z (ESI): 444.0 [M-56-56+H] + .
  • Step 3 Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (2.2 g, 5.05 mmol) and H47-b (1.65 g, 2.97 mmol) were dissolved in water (10 mL) and DME (100 mL), and then Pd(OAc) 2 (453.92 mg, 2.02 mmol), CataCXium A (724.91 mg, 2.02 mmol), K 2 CO 3 (3.49 g, 25.27 mmol) and (Pin) 2 B 2 (3.21 g, 12.64 mmol) were added and stirred at 70° C.
  • Step 4 H47-c (2.8 g, 3.37 mmol) was dissolved in DCM (20 mL), HCl/1,4-dioxane (4 mol/L, 10.10 mL) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated to obtain H47-d (2.13 g, light yellow solid), yield: 100.00%. MS m/z (ESI): 632.3 [M+H] + .
  • Step 5 H47-d (2.1 g, 3.32 mmol) was dissolved in DCM (25 mL), (Boc) 2 O (870.78 mg, 3.99 mmol) and Et 3 N (336.45 mg, 3.32 mmol) were added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-40% DCM/EA) to obtain H47-e (2.2 g, light yellow solid), yield: 90.43%. MS m/z (ESI): 733.3 [M+H] + .
  • Step 6 H47-e (2.4 g, 3.28 mmol) was dissolved in THF (30 mL) and water (10 mL), LiOH (500 mg, 20.88 mmol) was added, and the mixture was stirred at 80°C for 18 hours. After the reaction was completed, the reaction solution was concentrated and adjusted to pH 5-6 with dilute hydrochloric acid (1 mol/L), filtered, and the filter cake was vacuum dried to obtain H47-f (1.7 g, yellow solid), yield: 73.66%. MS m/z (ESI): 704.3 [M+H] + .
  • Step 7 H47-f (1.7 g, 2.42 mmol) was dissolved in DMF (10 mL), Et 3 N (2.44 g, 24.16 mmol) and HATU (1.82 g, 4.83 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H47-g (320 mg, light yellow solid), yield: 19.32%. MS m/z (ESI): 630.2 [M-56+H] + .
  • Step 8 H47-g (320 mg, 466.72 ⁇ mol) was dissolved in MeOH (1 mL) and DCM (12 mL), HCl/1,4-dioxane (4 mol/L, 2 mL) was added, and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was neutralized with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (80 mL ⁇ 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H47-h (270 mg, light yellow solid), yield: 98.80%. MS m/z (ESI): 586.2 [M+H] + .
  • Step 9 H47-h (450 mg, 768.54 ⁇ mol) and H39-b (413.33 mg, 1.12 mmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (488.65 mg, 2.31 mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: water + 0.04% FA, acetonitrile; wavelength: 254/214 nm; gradient: 40%-70% acetonitrile change) to obtain H47 (50.26 mg), MS m/z (ESI): 470.7 [M/2+H] + .
  • Step 1 3-Fluoroisonicotinaldehyde (12 g, 95.92 mmol) was dissolved in toluene (200 mL), PTSA (1.65 g, 9.59 mmol) and MeOH (19.98 g, 575.54 mmol, 25.22 mL) were added, and the mixture was refluxed and stirred at 120°C for 18 hours.
  • reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (300 mL ⁇ 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-50% EA/PE) to obtain H49-a (11.3 g, colorless oil), yield: 68.82%.
  • Step 2 H49-a (11.3 g, 66.02 mmol) was dissolved in acetone (100 mL), BnBr (12.98 g, 75.92 mmol) was added, and the mixture was stirred at 70°C for 18 hours. After the reaction was completed, the reaction solution was concentrated and ethyl acetate (70 ml) was added for slurrying, filtered, and the filter cake was vacuum dried to obtain H49-b (16 g, white solid, HBr), yield: 70.62%. MS m/z (ESI): 262.1 [M-Br] + .
  • Step 3 H49-b (15 g, 57.19 mmol, HBr) was dissolved in MeOH (120 mL), the temperature was lowered to 0°C, NaBH 4 (4.33 g, 114.37 mmol) was added in batches, and the mixture was stirred at 0°C for 4 hours. After the reaction was completed, the reaction solution was concentrated and water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL ⁇ 3).
  • Step 4 H49-c (11.7 g, 44.10 mmol) was dissolved in EtOH (120 mL), PdOH/C (10.89 g, 20% purity) and ammonium formate (55.61 g, 881.95 mmol) were added, and stirred at 90°C for 18 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain H49-d (5.5 g, viscous oil), yield: 70.38%. MS m/z (ESI): 178.1 [M+H] + .
  • Step 5 H49-d (1 g, 2.96 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (890.91 mg, 5.03 mmol), Ruphos (275.99 mg, 591.44 ⁇ mol) and Ruphos-Pd-G3 (495.26 mg, 591.44 ⁇ mol) were dissolved in toluene (40 mL), and LiHMDS (1 mol/L, THF solution, 14.79 mmol, 14.79 mL) was added under nitrogen protection, and the mixture was stirred at 80 °C for 2 hours.
  • Step 6 H49-e (146.05 mg, 336.16 ⁇ mol) was dissolved in formic acid (8.54 g, 185.55 mmol, 7.00 mL) and stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H49-f (130 mg, red viscous product), yield: 99.57%. MS m/z (ESI): 389.2 [M+H] + .
  • Step 7 H2-f (100 mg, 176.20 ⁇ mol) and H49-f (130 mg, 334.71 ⁇ mol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (224.06 mg, 1.06 mmol) was added, and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: water + 0.04% FA, acetonitrile; wavelength: 254/214 nm; gradient: 40%-70% acetonitrile change) to obtain H49 (3.94 mg), yield: 2.24%. MS m/z (ESI): 470.7 [M/2+H] + .
  • Step 1 Compound 3,3-difluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.98 mmol) was dissolved in DCM (20 mL), and hydrogen chloride ethyl acetate solution (4.0 mol/L, 10 mL) was added under stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H51-a (601.56 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 152 [M+H] + .
  • Step 5 H51-d (830 mg, 2.52 mmol) was dissolved in MeOH (20 mL), Pd/C (576.39 mg, 541.62 ⁇ mol, 10% purity) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain H51-e (300 mg, colorless oil), yield: 60.98%. MS m/z (ESI): 196 [M+H] + .
  • Step 6-Step 8 Referring to the preparation method of Example 39, H51 was prepared according to the above synthetic route, MS m/z (ESI): 958 [M+H] + .
  • Step 1 to Step 5 refer to the preparation method of Example 88, and prepare H56-e according to the above synthetic route.
  • Step 7 H56-f (25 mg, 50.15 ⁇ mol) and H39-b (27.86 mg, 75.22 ⁇ mol) were dissolved in EtOH (0.5 mL) and DMSO (1 mL), heated to 85°C and stirred for 30 min under microwave, then NaBH(OAc) 3 (31.88 mg, 150.44 ⁇ mol) was added, and finally heated to 85°C and stirred for 30 min under microwave.
  • reaction solution was concentrated and initially purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H56 (1.9 mg, purity 95.3%), yield: 4.23%. MS m/z (ESI): 427.3 [M/2+H] + .
  • Example 39 compound H61 was prepared according to the above synthetic route.
  • the preparative HPLC purification conditions were: waters-sunfire-10um-19 ⁇ 150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid/water). MS m/z (ESI): 962 [M+H] + .
  • Step 1 H31-e (50 mg, 82.29 ⁇ mol) and H46-c (46.66 mg, 131.67 ⁇ mol) were dissolved in DMSO (1.5 mL) and EtOH (0.6 mL), AcOH (9.88 mg, 164.58 ⁇ mol) was added, and the mixture was heated to 90°C and stirred for 30 minutes under microwave. Then NaBH 3 CN (51.71 mg, 822.91 ⁇ mol) was added, and the mixture was heated to 90°C and stirred for 20 minutes under microwave.
  • Step 1 Compound 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1239 mg, 3.5 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (1460 mg, 3.5 mmol), Pd(dppf)Cl 2 (120 mg, 0.16 mmol), and Cs 2 CO 3 (3.41 g, 10.47 mmol) were added to 1,4-dioxane (10 mL) in sequence, and then water (2 mL) was added, nitrogen was replaced three times, and the mixture was heated to 110° C. and stirred for 15 hours.
  • Step 2 H65-a (1036 mg, 2 mmol) was added to MeOH (5 mL), and then Pd/C (200 mg, 10 wt%) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain H65-b (680 mg), with a yield of 100%. MS m/z (ESI): 340 [M+H] + .
  • Step 3 H65-b (680 mg, 2 mmol), 4-(dimethoxymethyl)piperidine (477 mg, 3 mmol), Ruphos-Pd-G3 (340 mg, 0.41 mmol) and Cs 2 CO 3 (1952 mg, 6 mmol) were added to 1,4-dioxane (10 mL) in sequence, and the nitrogen was replaced three times, and then heated at 120°C and stirred for 15 hours.
  • Step 4 H65-c (84 mg, 0.2 mmol) was added to DCM (5 mL), and then TFA (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, H65-d (74.5 mg) was obtained by concentration, with a yield of 100%. MS m/z (ESI): 373 [M+H] + .
  • Step 5 H2-f (113 mg, 0.2 mmol) was added to DMSO (5 mL), 3 drops of acetic acid and H65-d (74.5 mg, 0.2 mmol) were added, microwave heating was carried out at 90°C for 1 hour, and then NaBH(OAc) 3 (100 mg) was added, and microwave heating was continued at 90°C for 1 hour. After the reaction was completed, it was purified by preparative HPLC (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid/water), H65 (2 mg), yield: 10.5%. MS m/z (ESI): 924 [M+H] + .
  • Step 1 Compound 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1011 mg, 3 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1524 mg, 6 mmol), Ruphos-Pd-G3 (450 mg, 0.54 mmol) and Cs 2 CO 3 (2928 mg, 1.5 mmol) were added to 1,4-dioxane (15 mL) in sequence, and the nitrogen was replaced three times and then heated to 120° C. and stirred for 15 hours.
  • Step 2 Add H66-a (100 mg, 0.2 mmol) to DCM (5 mL), add TFA (2 mL), and stir at room temperature for 1 hour. After the reaction is completed, concentrate to obtain H66-b (82 mg). Yield: 100%. MS m/z (ESI): 412 [M+H] + .
  • Step 3 H66-b (100 mg, 0.2 mmol) was added to DMF (5 mL), and DIPEA (1 mL) and HATU (76 mg, 0.2 mmol) were added. After stirring at room temperature for 10 minutes, H10-a (82 mg, 0.2 mmol) was added and the reaction was continued for 1 hour. After the reaction was completed, the reaction solution was purified by preparative HPLC (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid/water) to obtain H66 (2 mg). Yield: 1%. MS m/z (ESI): 895 [M+H] + .
  • Step 1 Dissolve 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (1.5 g, 3.00 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.53 g, 6.00 mmol) in dioxane (20 mL), add Pd 2 (dba) 3 (274.50 mg, 299.77 ⁇ mol) and X-Phos (285.81 mg, 599.54 ⁇ mol) and Cs 2 CO 3 (1.95 g, 6.00 mmol) under argon protection, and heat to 100° C. and stir overnight.
  • Step 2 H67-a (2 g, 2.97 mmol) was dissolved in EtOH (30 mL) and THF (20 mL), and Pd/C (315.86 mg, 296.81 ⁇ mol, 10% purity) was added, and stirred at 40°C overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered to remove the catalyst and concentrated to obtain H67-b (1 g, gray solid, crude product), yield: 67.98%, and was directly used for the next step without purification. MS m/z (ESI): 496.3 [M+H] + .
  • Step 3 H67-b (1 g, 2.02 mmol) was dissolved in 1,4-dioxane (4 mol/L, 15 mL) of hydrogen chloride and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H67-c (0.7 g, gray solid, crude product, HCl), yield: 80.32%. It was directly reacted in the next step without purification. MS m/z (ESI): 396.2 [M+H] + .
  • Step 4 Dissolve intermediate Z1 (833.33 mg, 481.21 ⁇ mol) in DMF (5 mL), add HATU (907.73 mg, 2.41 mmol) and DIPEA (1.24 g, 9.62 mmol, 1.68 mL), stir at room temperature for 20 min, add H67-c (285.48 mg, 721.82 ⁇ mol), and continue stirring at room temperature for 2 hours. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and ethyl acetate was used for extraction three times.
  • Example 66 compound H68 was prepared according to the above synthetic route.
  • the purification conditions of its preparative HPLC were (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change).
  • Example 66 compound H69 was prepared according to the above synthetic route.
  • the purification conditions of preparative HPLC were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change.
  • Step 1 Dissolve 2-bromo-5-iodobenzaldehyde (10 g, 32.16 mmol) and propan-2-amine (2.28 g, 38.60 mmol, 3.35 mL) in DCM (150 mL), add NaBH(OAc) 3 (13.63 g, 64.33 mmol) with stirring at room temperature, and stir at room temperature for 16 hours. After the reaction is completed, pour the reaction solution into water, extract with DCM (100 ml ⁇ 2), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain H70-a (11 g, light yellow oil), yield: 96.61%. Directly react in the next step without purification. MS m/z (ESI): 354.0 [M+H] + .
  • Step 3 H70-b and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.29 g, 4.18 mmol) were dissolved in a mixed solution of 1,4-dioxane (30 mL), water (6 mL) and DMSO (3 mL), and Pd(dppf)Cl 2 (322.24 mg, 440.39 ⁇ mol) and K 2 CO 3 (1.22 g, 8.81 mmol) were added under argon protection, and the temperature was raised to 80°C and stirred for 16 hours.
  • Step 4 H70-c and (Pin) 2 B 2 (1.20 g, 4.71 mmol) were dissolved in 1,4-dioxane (30 mL), KOAc (924.64 mg, 9.42 mmol) and Pd(dppf)Cl 2 (229.79 mg, 314.05 ⁇ mol) were added, and the mixture was heated to 95°C and stirred overnight under an argon atmosphere. After the reaction was completed, the solid was filtered off, and the filtrate was concentrated and purified by CombiFlash (20 g, 0-20% EA/PE) to obtain H70-d (1.5 g, light brown solid), yield: 85.82%. MS m/z (ESI): 401.3 [M-156+H] + .
  • Step 5 H70-d (1.45 g, 2.61 mmol) was dissolved in MeOH (20 mL), Pd/C (277.27 mg, 260.54 ⁇ mol, 10% purity) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the catalyst was filtered off, and the filtrate was concentrated to obtain H70-e (1.3 g, light yellow solid), yield: 89.33%. The mixture was directly reacted in the next step without purification. MS m/z (ESI): 403.3 [M-156+H] + .
  • Step 6 H70-e (1.3 g, 2.33 mmol) and ethyl 8-bromo-5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (810.41 mg, 1.86 mmol) were dissolved in a mixed solution of DMSO (2 mL), water (3 mL) and 1,4-dioxane (20 mL), and Pd(dppf)Cl 2 (170.30 mg, 232.74 ⁇ mol) and K 2 CO 3 (643.35 mg, 4.65 mmol) were added under argon protection, and the temperature was raised to 95° C.
  • Step 7 H70-f (1.4 g, 1.78 mmol) was dissolved in DCM (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL) was slowly added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and slurried with PE and EA to obtain H70-g (1 g, light yellow solid, crude product), yield: 95.81%, and was directly used for the next step without purification. MS m/z (ESI): 587.3 [M+H] + .
  • Step 8 H70-g (0.4 g, 641.89 ⁇ mol, HCl) was dissolved in MeOH (5 mL), sodium methoxide (2.31 g, 12.84 mmol, purity 30%) was added, and the temperature was raised to 80°C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated and water and dichloromethane were added. The dichloromethane was extracted three times, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain H70-h (0.2 g, light yellow solid, crude product), yield: 57.63%, and the product was directly used for the next step without purification. MS m/z (ESI): 541.3 [M+H] + .
  • Step 9 H70-h (60 mg, 110.98 ⁇ mol) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (91.97 mg, 332.95 ⁇ mol) were dissolved in DMSO (2 mL), and DIPEA (71.72 mg, 554.91 ⁇ mol, 96.65 ⁇ L) was added, and the mixture was heated to 100° C. and stirred for 2 hours.
  • DIPEA 71.72 mg, 554.91 ⁇ mol, 96.65 ⁇ L
  • Step 2 H71-a (250 mg, 466.07 ⁇ mol) and tert-butyl piperazine-1-carboxylate (434.03 mg, 2.33 mmol) were dissolved in 1,4-dioxane (10 mL) and DMSO (2 mL), and Pd 2 (dba) 3 (85.36 mg, 93.21 ⁇ mol), Xantphos (53.94 mg, 93.21 ⁇ mol), t-BuONa (223.96 mg, 2.33 mmol) were added in sequence under argon protection, and the mixture was heated to 120° C. and stirred for 2 hours.
  • Step 3 H71-b (130 mg, 202.58 ⁇ mol) was dissolved in DCM (9.96 mL) and MeOH (2.99 mL), and a solution of hydrogen chloride in ethyl acetate (4.0 mol/L, 5 mL) was added with stirring at room temperature, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain H71-c (109.72 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 542 [M+H] + .
  • Step 4 H71-c (100 mg, 184.63 ⁇ mol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoroisoindole-1,3-dione (102.00 mg, 369.26 ⁇ mol) were dissolved in NMP (5 mL), and DIPEA (477.25 mg, 3.69 mmol, 643.19 ⁇ L) was added, and the mixture was heated to 120° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC to obtain H71 (4.54 mg, purity 100%), with a yield of 3.08%. MS m/z (ESI): 798 [M+H] + .
  • Step 1 H71-a (200 mg, 372.86 ⁇ mol) and 4-(dimethoxymethyl)piperidine (296.84 mg, 1.86 mmol) were dissolved in 1,4-dioxane (20 mL) and DMSO (4 mL), and Pd 2 (dba) 3 (68.29 mg, 74.57 ⁇ mol), Xantphos (43.15 mg, 74.57 ⁇ mol), t-BuONa (215.00 mg, 2.24 mmol) were added under argon protection, and the mixture was heated to 120° C. and stirred for 3 hours.
  • Step 2 H74-a (20 mg, 32.54 ⁇ mol) was dissolved in DCM (5 mL), TFA (3.71 mg, 32.54 ⁇ mol, 2 mL) was added with stirring at room temperature, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain H74-b (18.50 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 569 [M+H] + .
  • Step 3 H74-b (20 mg, 35.17 ⁇ mol) and H99-b (24.08 mg, 70.34 ⁇ mol) were dissolved in DCM (5 mL), and NaBH(OAc) 3 (7.45 mg, 35.17 ⁇ mol) was added with stirring at room temperature, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC to obtain H74 (1.67 mg, purity 94.53%), yield: 5.02%. MS m/z (ESI): 895 [M+H] + .
  • Step 1 H10-a (337 mg, 0.67 mmol) was dissolved in DMF (10 mL), and DIPEA (522.42 mg, 4.04 mmol) and HA TU (508 mg, 1.35 mmol) were added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (0-10% MeOH/DCM) to obtain H76-a (300 mg, yellow solid), yield: 81.77%. MS m/z (ESI): 545.3 [M+H] + .
  • Step 2 H76-a (300 mg, 0.55 mmol) was dissolved in THF (30 mL), LAH (2.5 mol/L, 0.88 mL) was added at -78 °C, and stirred for 2 hours under argon protection. After the reaction was completed, sodium sulfate decahydrate was added to the reaction solution for quenching, filtration was performed, and the filtrate was concentrated to obtain H76-b (225 mg), yield: 84.12%, which was directly used for the next step reaction. MS m/z (ESI): 486.2 [M+H] + .
  • Step 3 H76-b (80 mg, 0.16 mmol) and H67-b (65 mg, 0.16 mmol) were dissolved in DCM (15 mL), acetic acid (10 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then NaBH(OAc) 3 (70 mg, 0.33 mmol) was added, and stirring was continued overnight.
  • Step 1 3,3,5,5-tetramethylpiperidin-4-one (3.7 g, 19.30 mmol, HCl) and K 2 CO 3 (8.00 g, 57.90 mmol) were dissolved in DMF (40.00 mL), BnBr (4.95 g, 28.95 mmol, 3.44 mL) was added, and the temperature was raised to 60°C and stirred overnight. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, and ethyl acetate was extracted three times.
  • Step 2 H78-a (4.7 g, 19.16 mmol) and hydroxylamine (3.99 g, 57.47 mmol, HCl) were dissolved in MeOH (80 mL), NaOAc (7.86 g, 95.78 mmol) was added, and the temperature was raised to 70°C and stirred for 72 hours. After the reaction was completed, the reaction solution was concentrated and water and dichloromethane were added, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain H78-b (4.99 g, white solid, crude product), yield: 100.00%, and the mixture was directly used for the next step without purification. MS m/z (ESI): 261.2 [M+H] + .
  • Step 3 H78-b (4.5 g, 17.28 mmol) was dissolved in THF (80 mL), LiAlH 4 (3.94 g, 103.70 mmol) was added, and the temperature was raised to 70°C and stirred for 3 hours.
  • Step 5 H78-d (1 g, 2.89 mmol) was dissolved in THF (20 mL), Pd/C (305.91 mg, 288.60 ⁇ mol, 10% purity) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 16 hours under a hydrogen balloon. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain H78-e (0.6 g, light white solid, crude product), yield: 81.09%, which was directly used for the next step without purification. MS m/z (ESI): 257.2 [M+H] + .
  • Step 6 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (0.5 g, 999.23 ⁇ mol) and H78-e (256.19 mg, 999.23 ⁇ mol) were dissolved in 1,4-dioxane (15 mL), Pd 2 (dba) 3 (91.50 mg, 99.92 ⁇ mol), X-Phos (95.27 mg, 199.85 ⁇ mol) and Cs 2 CO 3 (651.14 mg, 2.00 mmol) were added under argon protection, and the temperature was raised to 100° C. and stirred overnight.
  • Step 7 H78-f (250 mg, 369.90 ⁇ mol) and Pd/C (393.65 mg, 369.90 ⁇ mol, 10% purity) were dissolved in EtOH (5 mL) and THF (5 mL), and the mixture was heated to 40°C and stirred for 4 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain H78-g (180 mg, light yellow solid), with a yield of 97.79%. The mixture was directly used for the next step without purification. MS m/z (ESI): 498.3 [M+H] + .
  • Step 8 H78-g (180 mg, 361.72 ⁇ mol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain H78-h (0.1 g, light yellow solid, crude product), yield: 69.55%. It was directly used for the next step without purification. MS m/z (ESI): 398.3 [M+H] + .
  • Step 9 H10-a (50 mg, 99.70 ⁇ mol) and H78-h (47.56 mg, 119.64 ⁇ mol) were dissolved in DMF (3 mL), HATU (75.23 mg, 199.40 ⁇ mol) and DIPEA (38.66 mg, 299.10 ⁇ mol, 52.10 ⁇ L) were added, and stirred at room temperature for 1 hour. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate three times.
  • Step 1 H70-h (1.3 g, 2.40 mmol) and H39-b (1.07 g, 2.89 mmol) were dissolved in DCM (30 mL) and DMSO (10 mL), stirred at room temperature for 0.5 hours, then NaBH(OAc) 3 (1.53 g, 7.21 mmol) was added, and stirred at room temperature for 1 hour.
  • the solvent was removed by concentration under reduced pressure, ethyl acetate and sodium bicarbonate aqueous solution were added, the solid was filtered out, the mother liquor was extracted with ethyl acetate three times, the organic phases were combined, and the crude product was obtained by concentration under reduced pressure.
  • Step 2 H80 (1.1 g, 1.23 mmol) was dissolved in DCM (100 mL), and HCl/dioxane (4 M, 6.15 mL) was slowly added dropwise at 0°C. Stir at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain a light yellow solid, which was then ultrasonically dissolved in purified water and freeze-dried to obtain a light yellow solid product H80-a (1.14 g, 1.20 mmol, 97.52% yield, 97.52% purity, hydrochloride), a light yellow product.
  • Step 1 H78-e (1.39 g, 5.43 mmol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoroisoindole-1,3-dione (1 g, 3.62 mmol) were dissolved in DMF (15 mL), and DIPEA (1.87 g, 14.48 mmol, 2.52 mL) was added, and the temperature was raised to 100°C and stirred for 18 hours. After the reaction was completed, the reaction was concentrated and water and ethyl acetate (80 mL) were added to separate the organic phase, and the aqueous phase was extracted with ethyl acetate (80 mL ⁇ 2).
  • Step 2 H88-a (0.48 g, 936.41 ⁇ mol) was dissolved in DCM (12 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 6 mL) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H88-b (420 mg, yellow solid, HCl), yield: 99.91%. MS m/z (ESI): 413.3 [M-HCl+H] + .
  • Step 3 Dissolve methyl 4-bromo-3-formylbenzoate (7.2 g, 29.62 mmol) and 2,2-difluoroethane-1-amine (2.64 g, 32.59 mmol) in DCM (40 mL), stir at room temperature for 18 hours, add NaBH(OAc) 3 (12.56 g, 59.25 mmol), and continue stirring at room temperature for 4 hours. After the reaction is completed, the reaction solution is quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (80 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated to obtain H88-c (9 g, light yellow oil), yield: 98.60%. MS m/z (ESI): 308.0 [M+H] + .
  • Step 4 H88-c (9 g, 29.21 mmol) and Et 3 N (19.12 g, 87.63 mmol) were dissolved in DCM (50 mL), stirred at room temperature, and (Boc) 2 O (19.12 g, 87.63 mmol) was added, and the temperature was raised to 45°C and stirred overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (120 g, 0-40% DCM/PE) to obtain H88-d (7.2 g, yellow oil), yield: 60.38%. MS m/z (ESI): 352.0 [M-56+H] + .
  • Step 5 H88-d (7.2 g, 17.64 mmol), KOAc (6.06 g, 61.73 mmol), B 2 (pin) 2 (8.96 g, 35.27 mmol) and Pd(dppf) 2 Cl 2 (1.29 g, 1.76 mmol) were dissolved in 1,4-dioxane (100 mL) and stirred at 95°C for 6 hours.
  • reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (300 mL ⁇ 3), and the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-20% DCM/PE) to obtain H88-e (6.2 g, colorless oil), yield: 77.21%.
  • Step 6 Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (3 g, 6.89 mmol) and H88-e (4.71 g, 10.34 mmol) were dissolved in a mixed solution of water (8 mL), DMSO (5 mL) and 1,4-dioxane (40 mL), Pd(dppf) 2 Cl 2 (504.34 mg, 689.26 ⁇ mol) and K 2 CO 3 (1.91 g, 13.79 mmol) were added, and the mixture was stirred at 100 °C under nitrogen atmosphere for 4 hours.
  • Step 7 H88-f (4.2 g, 6.14 mmol) was dissolved in DCM (30 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H88-g (3.8 g, yellow solid, HCl), yield: 99.76%. MS m/z (ESI): 584.2 [M-HCl+H] + .
  • Step 8 H88-g (3.8 g, 6.51 mmol) was dissolved in a mixed solution of THF (40 mL) and water (10 mL), LiOH (3.12 g, 130.24 mmol) was added, and the mixture was stirred at 80°C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, pH was adjusted to 2-3 with dilute hydrochloric acid (2 mol/L), and then filtered, the filter cake was washed with water, and the filter cake was vacuum dried to obtain H88-h (3.1 g, yellow solid), yield: 87.92%. MS m/z (ESI): 542.2 [M+H] + .
  • Step 9 H88-h (100 mg, 184.68 ⁇ mol) and DIPEA (716.06 mg, 5.54 mmol, 965.04 ⁇ L) were dissolved in DMF (6 mL), HATU (140.35 mg, 369.36 ⁇ mol) was added, and the mixture was stirred at room temperature for 10 minutes. H88-b (99.49 mg, 221.62 ⁇ mol, HCl) was added, and the mixture was stirred at room temperature overnight.
  • Step 1 Dissolve 6-bromo-3-iodo-2-methyl-2H-indole (1.3 g, 3.86 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.45 g, 3.47 mmol) in THF (30 mL) and water (5 mL), add Pd(dppf)Cl 2 (282.30 mg, 385.81 ⁇ mol) and Cs 2 CO 3 (2.51 g, 7.72 mmol) under argon protection, heat to 80°C and stir overnight.
  • Step 2-Step 5 Referring to the preparation method of Example 46, compound H91 was prepared according to the above synthetic route.
  • the preparative HPLC purification conditions were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O -acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change.
  • Step 1-Step 2 Referring to the preparation method of Example 46, H92-b was prepared according to the above synthetic route, MS m/z (ESI): 311.1 [M+H] + .
  • Step 3 H92-b (150 mg, 483.41 ⁇ mol) was dissolved in EA (5 mL), and IBX (270.73 mg, 966.82 ⁇ mol) was added, and the mixture was heated to 70°C and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and purified by CombiFlash (4 g, 0-10% MeOH/DCM) to obtain H92-c (90 mg, light yellow solid), yield: 60.39%. MS m/z (ESI): 309.1 [M+H] + .
  • Step 4 Referring to the preparation method of Example 46, H92 was prepared according to the above synthetic route.
  • the purification conditions of the preparative HPLC were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile.
  • Step 1-Step 2 Referring to the preparation method of Example 78, according to the above synthetic route, H93-b was prepared, MS m/z (ESI): 229 [M+H] + .
  • Step 3-Step 5 Referring to the preparation method of Example 67, H93 was prepared according to the above synthetic route. MS m/z (ESI): 868 [M+H] + .
  • Step 2 H94-a (90 mg, 174.23 ⁇ mol) was dissolved in MeOH (5 mL), palladium carbon (185.42 mg, 174.23 ⁇ mol, 10% purity) was added, and stirred at room temperature for 6 hours under hydrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain H94-b (50 mg, yellow solid), yield: 75.04%. MS m/z (ESI): 383 [M+H] + .
  • Step 1 Dissolve the intermediate Z1 (120 mg, 0.23 mmol) in DMF (2.82 mL), add DIPEA (180 mg, 1.39 mmol) and HA TU (261.43 mg, 692.94 ⁇ mol), stir at room temperature for 0.5 hours, then add (3S, 5R)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (74 mg, 0.35 mmol), and continue stirring at room temperature overnight.
  • Step 2 H96-a (30 mg, 0.043 mmol) was dissolved in DCM (5 mL), HCl/EA (4 mol/L, 0.5 mL) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H96-b (25 mg, crude product), yield: 97.3%. It was directly used for the next step reaction. MS m/z (ESI): 598.3 [M+H] + .
  • Step 3 H96-b (23.54 mg, 39.39 ⁇ mol) was dissolved in DCM (8 mL), acetic acid (6.76 mg, 112.55 ⁇ mol) was added, and the mixture was stirred at room temperature for 1 hour, and then NaBH(OAc) 3 (23.85 mg, 112.55 ⁇ mol) was added, and stirring was continued overnight. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H96 (1.39 mg), yield: 2.55%.
  • Step 1 Dissolve the intermediate Z1 (150 mg, 288.73 ⁇ mol) in DMF (4.50 mL), add HATU (326.78 mg, 866.18 ⁇ mol) and DIPEA (373.16 mg, 2.89 mmol, 502.91 ⁇ L) at room temperature, stir at room temperature for 5 minutes, add 4-amino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (272.86 mg, 1.15 mmol), and stir at room temperature for 2 hours.
  • Step 2 H98-a (180 mg, 250.09 ⁇ mol) was dissolved in MeOH (5 mL) and DCM (10 mL), and hydrogen chloride ethyl acetate solution (4.0 mol/L, 7.50 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and dissolved with a small amount of methanol, and saturated sodium carbonate aqueous solution was added, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain H98-b (100 mg, yellow solid), yield: 64.53%. MS m/z (ESI): 620 [M+H] + .
  • Step 3 H98-b (120 mg, 193.66 ⁇ mol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoroisoindole-1,3-dione (267.47 mg, 968.31 ⁇ mol) were dissolved in NMP (5 mL), and DIPEA (500.59 mg, 3.87 mmol, 674.65 ⁇ L) was added, and the mixture was heated to 120° C. and stirred for 24 hours.
  • NMP 5 mL
  • DIPEA 500.59 mg, 3.87 mmol, 674.65 ⁇ L
  • H99 was prepared according to the above synthetic route.
  • the purification conditions of its preparation HPLC were as follows: preparation column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change.
  • Step 1 Dissolve N-(2-bromo-5-iodobenzyl)propan-2-amine (11 g, 31.07 mmol) in DCM (100 mL), add (Boc) 2 O (40.69 g, 186.43 mmol), triethylamine (22.01 g, 217.50 mmol, 30.34 mL), and react at room temperature overnight. After the reaction is completed, water is added to the reaction solution, and ethyl acetate is extracted twice.
  • Step 2 H101-a (5.5 g, 12.11 mmol) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (3.39 g, 12.11 mmol) were dissolved in a mixed solution of 1,4-dioxane (50 mL), water (10 mL) and DMSO (5 mL), and Pd(dppf)Cl 2 (1.33 g, 1.82 mmol) and K 2 CO 3 (3.35 g, 24.22 mmol) were added under argon protection. The temperature was raised to 80°C and stirred for 16 hours.
  • Step 3 H101-b (1 g, 2.08 mmol) was dissolved in 1,4-dioxane (10 mL), and Pd(dppf)Cl 2 (228.23 mg, 312.22 ⁇ mol), (Pin) 2 B 2 (687.13 mg, 2.71 mmol), and KOAc (407.96 mg, 4.16 mmol) were added. The mixture was reacted at 100°C for 16 h under an argon atmosphere. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate twice.
  • Step 4 H101-c (1 g, 1.90 mmol) was dissolved in EtOH (10 mL), palladium/carbon (100 mg, 189.57 ⁇ mol) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain H101-d (1 g, yellow solid), with a yield of 99.62%. MS m/z (ESI): 430.3 [M+H] + .
  • Step 5 H101-d (1 g, 1.89 mmol) was dissolved in THF (15 mL), and borane dimethyl sulfide (130.64 mg, 9.44 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, methanol was slowly added dropwise to the reaction solution until no bubbles were generated, and the mixture was stirred at 60°C for 1 hour. After concentration, it was purified by CombiFlash (12 g, 0-100% EA/PE) to obtain H101-e (800 mg, white solid), with a yield of 86.90%. MS m/z (ESI): 388.3 [M-100+H] + .
  • Step 6 H101-e (940 mg 1.93 mmol), 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (700 mg, 1.61 mmol) were dissolved in a mixed solution of water (3 mL) and 1,4-dioxane (15 mL), Pd(dppf)Cl 2 (176.35 mg, 241.24 ⁇ mol), K 2 CO 3 (444.56 mg, 3.22 mmol) were added, argon was replaced 3 times, and the reaction was carried out at 90° C. for 3 h.
  • Step 8 H101-g (340 mg, 552.18 ⁇ mol) was dissolved in MeOH (5 mL) and NaOH (110.43 mg, 2.76 mmol) in water (2 mL) was added. The reaction was allowed to react overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain H101-h (320 mg, light yellow solid), yield: 98.61%. MS m/z (ESI): 588.3 [M+H] + .
  • Step 9 H101-h (320 mg, 544.51 ⁇ mol) was dissolved in DMF (5 mL), HATU (267.06 mg, 707.86 ⁇ mol) and DIPEA (175.94 mg, 1.36 mmol) were added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (12 g, 0-40% MeOH/DCM) to obtain H101-i (240 mg, yellow solid), with a yield of 77.37%. MS m/z (ESI): 570.3 [M+H] + .
  • Step 10 H101-i (230 mg, 403.74 ⁇ mol) was dissolved in DCM (10 mL) and Dess-Martin periodinane (171.24 mg, 403.74 ⁇ mol) was added and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (4 g, 0-10% MeOH/DCM) to obtain H101-j (130 mg, yellow solid), yield: 56.72%. MS m/z (ESI): 568.3 [M+H] + .
  • Step 11 H101-j (50 mg, 88.08 ⁇ mol) and 2-(2,6-dioxo-3-piperidinyl)-5-(4-piperidinyl)isoindole-1,3-dione (39.09 mg, 114.51 ⁇ mol) were dissolved in a mixed solvent of EtOH (0.5 mL) and DMSO (2 mL), heated to 85°C under microwave and stirred for 30 min, then NaBH(OAc) 3 (74.67 mg, 352.33 ⁇ mol) was added, and finally heated to 85° under microwave and stirred for 30 min.
  • reaction solution was concentrated and initially purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H101 (1.23 mg, purity 93%), yield: 1.45%.
  • Step 1 Dissolve tert-butyl 3-hydroxy-2,2,4,4-(tetramethoxy)cyclobutylcarbamate (3.43 g, 14.11 mmol) in DMF (30 mL), add NaH (1.41 g, 35.26 mmol, 60% purity) at 0°C, stir at low temperature for 0.5 hours, then add 5-fluoro-N-methyl-2-nitroaniline (2 g, 11.75 mmol) and DMF (5 mL), return to room temperature and stir for 2 hours.
  • Step 2 H102-a (2 g, 5.08 mmol) was dissolved in MeOH (20 mL), THF (20 mL) and saturated NH 4 Cl aqueous solution (10 mL), iron powder (2.84 g, 50.83 mmol) was added, and the temperature was raised to 70°C and stirred overnight. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, ethyl acetate and water were added, and ethyl acetate was extracted three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain H102-b (1.7 g, yellow solid), yield: 92.01%, and the next step reaction was carried out directly without purification. MS m/z (ESI): 364.3 [M+H] + .
  • Step 3 H102-b (1.7 g, 4.68 mmol), CDI (834.18 mg, 5.14 mmol) and DIPEA (906.67 mg, 7.02 mmol, 1.22 mL) were dissolved in THF (30 mL), heated to 75 ° C and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, and ethyl acetate was extracted 3 times.
  • Step 4 t-BuOK (216.08 mg, 1.93 mmol) was added to a solution of H102-c (0.5 g, 1.28 mmol) in THF (10 mL) at 0°C under an argon atmosphere, and the mixture was reacted at 0°C for 0.5 hours. Then, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (734.28 mg, 1.93 mmol) in THF (5 mL) was added at 0°C, and the reaction was continued at 0°C for 0.5 hours.
  • Step 5 H102-d (0.5 g, 805.50 ⁇ mol) was dissolved in toluene (10 mL), and methanesulfonic acid (774.13 mg, 8.05 mmol, 552.95 ⁇ L) was added, and the temperature was raised to 110° C. and stirred for 10 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM FA/H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H102-e (40 mg), yield: 12.40%. MS m/z (ESI): 401.2 [M+H] + .
  • Step 6 H102-e (38.33 mg, 95.71 ⁇ mol) and H10-a (40 mg, 79.76 ⁇ mol) were dissolved in DMF (3 mL), HATU (45.14 mg, 119.64 ⁇ mol) and DIPEA (30.92 mg, 239.28 ⁇ mol, 41.68 ⁇ L) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate three times.
  • Step 1 H101-j (30 mg, 52.85 ⁇ mol) and H99-b (36.19 mg, 105.70 ⁇ mol) were dissolved in a mixed solvent of DCM (5 mL) and DMSO (1 mL), stirred at room temperature for 0.5 hours, and NaBH(OAc) 3 (33.60 mg, 158.55 ⁇ mol) was added, and the reaction was continued at room temperature for 3 hours.
  • reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 67%-72% acetonitrile change) to obtain H103 (2.07 mg, purity 99.54%), yield: 4.36%.
  • Step 1 H70-h (10 mg, 18.50 ⁇ mol) and H51-g (16.39 mg, 55.49 ⁇ mol) were dissolved in DCM (3 mL), stirred at room temperature for 2 h, then NaBH(OAc) 3 (15.68 mg, 73.99 ⁇ mol) was added, and stirred at room temperature overnight.
  • reaction solution was concentrated and preliminarily purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95 acetonitrile change) to obtain H105 (1.14 mg, purity 93.6%), yield: 6.20%.
  • Step 1 Dissolve 4-bromo-2-methylpyrazole-3-carboxaldehyde (5 g, 26.45 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (5.83 g, 29.10 mmol) in TFA (1 mL), add MeOH (60 mL), stir at room temperature for 30 min, add NaBH 3 CN (3.49 g, 55.55 mmol), and react at room temperature for 1.5 h.
  • Step 2 H106-a (9 g, 24.11 mmol) was dissolved in DCM (100 mL), (Boc) 2 O (10.52 g, 48.22 mmol), TEA (7.32 g, 72.33 mmol, 10.09 mL) and DMAP (294.55 mg, 2.41 mmol) were added, and the mixture was reacted at room temperature overnight. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate twice.
  • Step 3 H106-b (2.18 g, 4.6 mmol) and 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (1 g, 2.30 mmol) were dissolved in water (2 mL) and ethylene glycol dimethyl ether (15 mL), and Pd(OAc) 2 (103.16 mg, 459.51 ⁇ mol), n-butyldi(1-adamantyl)phosphine (164.96 mg, 459.51 ⁇ mol), K 2 CO 3 (1.27 g, 9.19 mmol) and (Pin) 2 B 2 (1.22 g, 4.82 mmol) were added, and the reaction was carried out at 75° C.
  • Step 4 H106-c (800 mg, 1.07 mmol) was dissolved in DCM (10 mL), TFA (5 mL) was added, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated, TEA and DCM were added to dissolve the solution, and the mixture was purified by CombiFlash (12 g, 0-50% MeOH/DCM) to obtain H106-d (400 mg, yellow solid), yield: 68.25%. MS m/z (ESI): 549.3 [M+H] + .
  • Step 6 H106-e (30 mg, 59.70 ⁇ mol) and H51-g (24.26 mg, 59.70 ⁇ mol) were dissolved in DCM (4 mL), stirred at room temperature for 2 h, then NaBH(OAc) 3 (37.96 mg, 179.09 ⁇ mol) was added, and stirred at room temperature overnight.
  • reaction solution was concentrated and preliminarily purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95 acetonitrile change) to obtain H106 (7.82 mg, purity 99.4%), yield: 14.58%. MS m/z(ESI):447.2[M/2+H] + .
  • Step 1 tert-Butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (12 g, 51.01 mmol) and benzylamine (5.47 g, 51.01 mmol) were dissolved in DCM (100 mL), and then NaBH(OAc) 3 (21.62 g, 102.03 mmol) was added and stirred at room temperature for 18 hours.
  • Step 2 H107-a (16.65 g, 51.01 mmol) and benzaldehyde (8.12 g, 76.52 mmol) were dissolved in DCM (100 mL), and then NaBH(OAc) 3 (21.62 g, 102.03 mmol) was added and stirred at room temperature for 18 hours.
  • Step 3 H107-b (6.4 g, 15.37 mmol) was dissolved in DCM (35 mL), and then HCl/1,4-dioxane (4 mol/L, 25 mL) was added and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated, then neutralized with saturated NaHCO 3 aqueous solution, extracted with ethyl acetate (150 mL ⁇ 3), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H107-c (4.6 g, white solid), yield: 94.62%. MS m/z (ESI): 317.2 [M+H] + .
  • Step 4 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol) and H107-c (1.50 g, 4.73 mmol) were dissolved in toluene (60 mL), and then Ruphos (275.99 mg, 591.44 ⁇ mol) and Ruphos-Pd-G3 (495.26 mg, 591.44 ⁇ mol) were added, and LiHMDS (1 mol/L THF solution, 14.79 mL) was added under nitrogen, and stirred at 90 ° C for 2 hours.
  • Step 5 H107-d (1.1 g, 1.92 mmol) and Pd/C (300 mg, 10% purity and 50% water) were dissolved in THF (30 mL) and stirred at 50° C. under a hydrogen atmosphere for 6 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with a small amount of methanol, and the filtrate was concentrated to obtain H107-e (690 mg, light yellow solid), yield: 91.47%. MS m/z (ESI): 394.1 [M+H] + .
  • Step 6 H10-a (30 mg, 59.82 ⁇ mol) and H107-e (35.30 mg, 89.73 ⁇ mol) were dissolved in DMF (2 mL), HATU (45.14 mg, 119.64 ⁇ mol) and DIPEA (23.19 mg, 179.46 ⁇ mol, 31.26 ⁇ L) were added, and stirred at room temperature for 1 hour. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and ethyl acetate was used for extraction three times.
  • Step 1 2-bromo-5-iodobenzaldehyde (10 g, 32.1 mmol) and 2,2-difluoroethylamine (3.52 g, 43.42 mmol) were dissolved in DCM (80 mL), stirred at room temperature for 18 hours, and NaBH(OAc) 3 (13.63 g, 64.33 mmol) was added, and stirred at room temperature for 24 hours. After the reaction was completed, it was quenched with saturated aqueous NaHCO 3 solution, and then extracted with dichloromethane (150 mL ⁇ 3). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to give H108-a (12 g, light yellow oil), yield: 99.23%. MS m/z (ESI): 375.9 [M+H] + .
  • Step 2 H108-a (12 g, 31.92 mmol) and Et 3 N (16.12 g, 159.58 mmol) were dissolved in DCM (50 mL), and Boc 2 O (20.90 g, 95.75 mmol) was added under stirring at room temperature, and the reaction solution was heated to 45°C and stirred overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (120 g, 0-40% EA/PE) to obtain H108-b (15 g, yellow oil), yield: 98.71%. MS m/z (ESI): 419.9 [M-56+H] + .
  • Step 3 H108-b (15 g, 31.51 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9.74 g, 31.51 mmol) were dissolved in 1,4-dioxane (90 mL), H 2 O (16 mL) and DMSO (9 mL), Pd(dppf)Cl 2 (2.31 g, 3.15 mmol) and K 2 CO 3 (8.71 g, 63.01 mmol) were added, and the mixture was stirred at 80° C. for 16 hours.
  • reaction solution was poured into water (150 mL) for quenching, extracted with ethyl acetate (250 mL ⁇ 3), the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-40% EA/PE) to obtain H108-c (10 g, colorless viscous oil), yield: 59.73%.
  • Step 4 H108-c (10 g, 18.82 mmol) and Pd(dppf)Cl 2 (1.38 g, 1.88 mmol) were dissolved in 1,4-dioxane (120 mL), and B 2 (pin) 2 (7.17 g, 28.23 mmol) and KOAc (4.62 g, 47.04 mmol) were added. The mixture was heated to 95°C and stirred for 6 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by CombiFlash (80 g, 0-20% EA/PE) to obtain H108-d (8 g, light yellow oil), yield: 73.49%. MS m/z (ESI): 423.2 [M-156+H] + .
  • Step 5 H108-d (8 g, 13.83 mmol) and Pd/C (2.2 g, 10% purity and 50% water) were dissolved in MeOH (100 mL) and stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with a small amount of methanol, and the filtrate was concentrated to obtain H108-e (6 g, light yellow solid), yield: 74.74%. MS m/z (ESI): 425.2 [M-156+H] + .
  • Step 6 H108-e (3.52 g, 6.07 mmol) and ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (2.2 g, 5.05 mmol) were dissolved in 1,4-dioxane (33 mL), H 2 O (6 mL) and DMSO (3.3 mL). Pd(dppf)Cl 2 (369.85 mg, 505.46 ⁇ mol) and K 2 CO 3 (1.40 g, 10.11 mmol) were added under argon protection. The reaction solution was heated to 95° C.
  • Step 7 H108-f (3 g, 3.71 mmol) was dissolved in DCM (30 mL), HCl/1,4-dioxane (4 mol/L, 15 mL) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and quenched with saturated sodium bicarbonate aqueous solution, the organic phase was washed with dichloromethane, the aqueous phase was filtered, and the filter cake was dried to obtain H108-g (2.31 g, yellow solid, HCl), yield: 96.55%. MS m/z (ESI): 609.3 [M+H] + .
  • Step 8 H108-g (2.31 g, 3.58 mmol, HCl) was dissolved in THF (40 mL) and H 2 O (8 mL), LiOH (1.61 g, 67.06 mmol) was added, and the mixture was stirred at 80° C. for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with dichloromethane (250 mL ⁇ 3), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H108-h (1.4 g), with a yield of 69.50%. MS m/z (ESI): 563.2 [M+H] + .
  • Step 9 H108-h (150 mg, 266.63 ⁇ mol) and H39-b (197.52 mg, 533.25 ⁇ mol) were dissolved in DCM (10 mL), and then NaBH(OAc) 3 (226.04 mg, 1.07 mmol) was added and stirred at room temperature for 3 hours.
  • reaction solution was concentrated and preliminarily purified by CombiFlash (4 g, 0-14% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H108 (39.69 mg), yield: 16.09%.
  • Step 1-Step 7 Referring to the preparation method of Example 70, according to the above synthetic route, H109-g was prepared, MS m/z (ESI): 623.3 [M+H] + .
  • Step 8 H109-g (2.45 g, 3.93 mmol) was dissolved in THF (40 mL) and water (20 mL), LiOH (1.41 g, 59.02 mmol) was added, and the mixture was stirred at 80°C for 20 hours. After the reaction was completed, the reaction solution was adjusted to pH 3-4 with dilute hydrochloric acid (1 mol/L), concentrated, and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA, acetonitrile; wavelength: 254/214 nm; gradient: 48%-58% acetonitrile change) to obtain H109-h (300 mg, white solid), yield: 12.82%. MS m/z (ESI): 595.3 [M+H] + .
  • Step 10 H109-i (90 mg, 156.08 ⁇ mol) and H39-b (115.63 mg, 312.17 ⁇ mol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (99.24 mg, 468.25 ⁇ mol) was added, and the mixture was stirred at room temperature (25° C.) for 2 hours.
  • Step 1 NaH (5.0 g, 125.5 mmol) was added to anhydrous DMSO (70 mL) and the temperature was lowered to 0°C. A solution of ethyl 2-(diphenylmethyleneamino)acetate (18.4 g, 69 mmol) in DMSO (50 mL) was added dropwise to the above mixture. After 10 minutes, a solution of 5-bromo-4-chloro-2-(methylthio)pyrimidine (15 g, 62.7 mmol) in DMSO (50 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours.
  • Step 3 H163-b (11.3 g, 36.91 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (8.46 g, 36.91 mmol) were dissolved in DMF (60 mL), and DIPEA (14.31 g, 110.72 mmol) and HATU (18.10 g, 47.98 mmol) were added. The reaction solution was stirred at room temperature for 20 hours.
  • Step 4 H163-c (8.8 g, 17.01 mmol) was dissolved in DCM (80 mL), cooled to 0°C, and m-chloroperbenzoic acid (8.29 g, 85% purity) was added. The reaction solution was stirred at 0°C for 2 hours. After the reaction was completed, a reaction solution containing H163-d was obtained. The reaction solution was filtered, the filter cake was washed, and the filtrate was directly used for the next reaction. MS m/z (ESI): 433.0 [M+H-100] + .
  • Step 5 H163-d (9 g, 16.87 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (3.67 g, 21.93 mmol) were dissolved in DCM (60 mL), and DIPEA (21.81 g, 168.72 mmol, 29.39 mL) was added. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash separation (0-100% EA/PE) to obtain H163-e (10.46 g, yellow solid), yield: 97.40%. MS m/z (ESI): 580.1 [M+H-56] + .
  • Step 6 H163-e (4 g, 6.28 mmol) was dissolved in DCE (100 mL), pyridine (25.53 g, 322.75 mmol) and trichlorophosphine (21.39 g, 139.47 mmol) were added, and the reaction solution was heated to 100 ° C and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into water, saturated NaHCO 3 aqueous solution was added for neutralization, filtered, the filter cake was washed, and the filtrate was extracted with ethyl acetate.

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Abstract

Provided is a bifunctional compound represented by formula (I). Further disclosed are a pharmaceutically acceptable salt of the compound, or a stereoisomer thereof, a pharmaceutical composition thereof, and use thereof. The compound has an excellent degradation effect on EED, and has an excellent inhibitory effect on tumor cell proliferation, thus demonstrating a potential therapeutic effect on tumors. POI—(L) n0—ULM (I).

Description

稠四杂环衍生物及其药物组合物和用途Condensed tetracyclic heterocyclic derivatives and pharmaceutical compositions and uses thereof

本申请要求于2023年11月30日提交中国专利局、申请号为202311632052.6发明名称为“稠四杂环衍生物及其药物组合物和用途”的中国专利申请、2023年12月29日提交中国专利局、申请号为202311861488.2发明名称为“稠四杂环衍生物及其药物组合物和用途”的中国专利申请、2024年6月27日提交中国专利局、申请号为202410854815.X发明名称为“稠四杂环衍生物及其药物组合物和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of the Chinese patent application filed with the China Patent Office on November 30, 2023, with application number 202311632052.6 and the invention name “Fused tetra-heterocyclic derivatives and their pharmaceutical compositions and uses”, the Chinese patent application filed with the China Patent Office on December 29, 2023, with application number 202311861488.2 and the invention name “Fused tetra-heterocyclic derivatives and their pharmaceutical compositions and uses”, and the Chinese patent application filed with the China Patent Office on June 27, 2024, with application number 202410854815.X and the invention name “Fused tetra-heterocyclic derivatives and their pharmaceutical compositions and uses”, the entire contents of which are incorporated by reference into this application.

技术领域Technical Field

本发明涉及医药技术领域，特别涉及一种稠四杂环衍生物、其药学上可接受的盐、立体异构体、药物组合物及其医药上的用途。The present invention relates to the field of medical technology, and in particular to a fused tetraheterocyclic derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition and medical uses thereof.

背景技术Background Art

多梳家族(the Polycomb group，PcG)蛋白多梳抑制复合体2(the Polycomb repressive complex 2，PRC2)在机体中行使转录抑制的核心功能，通过催化组蛋白3赖氨酸27的三甲基化(H3K27me3)，实现基因沉默；在肿瘤中可通过抑制抑癌基因表达等作用促进肿瘤的发生发展。PRC2的催化亚基EZH2是第三代表观遗传调控精准治疗靶点的重要代表，相较于第一代和第二代泛表观遗传调控的靶点，当前的治疗靶点可以针对特定突变类型的肿瘤，从疗效和安全性上都得到了较大提升。虽然EZH2是直接关闭PRC2异常活动的理想靶点，但作为一个复合蛋白，PRC2的功能和活性高度依赖骨架和另一个核心亚基EED的调节作用，通过干扰EZH2和EED之间的蛋白-蛋白相互作用(PPI)同样可以抑制PRC2复合体的甲基转移酶活性。诺华公司率先通过高通量筛选证明了EED的H3K27me3识别腔具有“成药性”，并发现靶向EED可以变构抑制EZH2的催化活性。The Polycomb group (PcG) protein Polycomb repressive complex 2 (PRC2) plays the core function of transcriptional repression in the body, and achieves gene silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27me3); in tumors, it can promote the occurrence and development of tumors by inhibiting the expression of tumor suppressor genes. The catalytic subunit EZH2 of PRC2 is an important representative of the third generation epidemic genetic regulation precision therapy targets. Compared with the first and second generation pan epigenetic regulation targets, current therapeutic targets can target tumors with specific mutation types, and the efficacy and safety have been greatly improved. Although EZH2 is an ideal target for directly shutting down the abnormal activity of PRC2, as a complex protein, the function and activity of PRC2 is highly dependent on the regulation of the skeleton and another core subunit EED. The methyltransferase activity of the PRC2 complex can also be inhibited by interfering with the protein-protein interaction (PPI) between EZH2 and EED. Novartis was the first to demonstrate through high-throughput screening that the H3K27me3 recognition cavity of EED is "druggable" and found that targeting EED can allosterically inhibit the catalytic activity of EZH2.

靶向蛋白降解(targeted protein degradation，TPD)技术的兴起，为小分子药物开发提供了新路径。其中，蛋白水解靶向嵌合体(proteolysis targeting chimeras，PROTACs)是研究最为成熟的系统。其作用机制是将小分子抑制剂和E3泛素连接酶的配体通过连接链进行连接，形成一种靶向诱导蛋白降解联合体；在生物体内，这种双功能分子的抑制剂部分可以识别靶蛋白，而E3酶配体部分可以识别泛素连接酶，最终通过泛素-蛋白酶体途径降解目标蛋白。蛋白降解药可以靶向“不可成药”的靶点，提高对靶点的选择性和抑制活性，延长药物的作用时间和耐药突变；尤其适用于针对传统意义上不可成药的靶点(如转录因子和支架蛋白)、肿瘤靶向治疗过程中易产生获得性耐药突变的靶点、基因扩增和/或蛋白过表达的靶点、有不同蛋白亚型的靶点、支架蛋白、蛋白聚合物等进行药物开发。目前，靶向EZH2的小分子抑制剂已获批上市，在临床上验证了PRC2作为抗肿瘤药物靶点的可行性，但在实体瘤中EZH2小分子抑制剂的效果仍然有限，多个EZH2和EED的小分子抑制剂仍在临床研究的探索中。考虑到PRC2的结构和功能特点，以及蛋白降解药物的优势，利用蛋白降解技术进行该靶点的药物研发或将为该靶点的药物开发带来新方向和新突破。The rise of targeted protein degradation (TPD) technology has provided a new path for the development of small molecule drugs. Among them, proteolysis targeting chimeras (PROTACs) are the most mature systems. Its mechanism of action is to connect small molecule inhibitors and E3 ubiquitin ligase ligands through a linker chain to form a targeted induced protein degradation consortium; in vivo, the inhibitor part of this bifunctional molecule can recognize the target protein, while the E3 enzyme ligand part can recognize the ubiquitin ligase, and finally degrade the target protein through the ubiquitin-proteasome pathway. Protein degraders can target "undruggable" targets, improve the selectivity and inhibitory activity of targets, prolong the duration of drug action and drug-resistant mutations; they are particularly suitable for drug development against traditionally undruggable targets (such as transcription factors and scaffold proteins), targets that are prone to acquired drug-resistant mutations during tumor targeted therapy, targets with gene amplification and/or protein overexpression, targets with different protein subtypes, scaffold proteins, protein polymers, etc. At present, small molecule inhibitors targeting EZH2 have been approved for marketing, and the feasibility of PRC2 as an anti-tumor drug target has been verified clinically, but the effect of EZH2 small molecule inhibitors in solid tumors is still limited, and multiple small molecule inhibitors of EZH2 and EED are still under clinical research. Considering the structural and functional characteristics of PRC2 and the advantages of protein degradation drugs, the use of protein degradation technology for drug development of this target may bring new directions and breakthroughs to drug development of this target.

尽管已有文献(Cell Chemical Biology 2020,27:41-46.)报道EED的蛋白降解剂，但其降解活性和成药性仍有较大的改进空间，因此，仍需要开发具有高活性的EED降解剂用于临床研究。Although protein degraders for EED have been reported in the literature (Cell Chemical Biology 2020, 27:41-46.), there is still much room for improvement in their degradation activity and drugability. Therefore, there is still a need to develop highly active EED degraders for clinical research.

发明内容Summary of the invention

本发明的目的是提供一种PROTAC化合物，本发明的化合物能够降解和/或抑制EED蛋白，对EED蛋白具有优异的降解/抑制作用并具有优异的肿瘤细胞增殖抑制作用，且具有优异的药代动力学特征，较好的CYP450作用，安全性好，更适于治疗EED蛋白活性异常的疾病或病症(如癌症等增殖性疾病)。The object of the present invention is to provide a PROTAC compound, which can degrade and/or inhibit EED protein, has excellent degradation/inhibition effect on EED protein and excellent tumor cell proliferation inhibition effect, and has excellent pharmacokinetic characteristics, good CYP450 effect, good safety, and is more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).

本发明第一方面提供了一种式(I)所示化合物、或其药学上可接受的盐、或其立体异构体：
POI—(L)n0—ULM
(I)，The first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
POI—(L) n0 —ULM
(I)

其中，POI为与EED蛋白结合的配体；Among them, POI is the ligand that binds to the EED protein;

L为连接POI和ULM的连接链；L is the connection link between POI and ULM;

ULM为与E3连接酶结合的基团；ULM is the group that binds to the E3 ligase;

n0为0或1。n0 is 0 or 1.

在一些实施方案中，n0为0。In some embodiments, n0 is 0.

在一些实施方案中，n0为1。In some embodiments, n0 is 1.

在一些实施方案中，POI为式(A-1)所示的结构或其异构体，
In some embodiments, POI is a structure represented by formula (A-1) or an isomer thereof,

其中，in,

表示(双键)或(单键)； express (double bond) or (single bond);

W1、W2、W3各自独立地选自键、-CH2-、-(CH2)2-、-CH＝CH-、-CH＝N-、-N＝N-、-(CH2)3-、-C(O)NH-、-NHC(O)-、-C(O)-、-NH-、-CH-和-N-；W 1 , W 2 , and W 3 are each independently selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -CH=CH-, -CH=N-, -N=N-, -(CH 2 ) 3 -, -C(O)NH-, -NHC(O)-, -C(O)-, -NH-, -CH-, and -N-;

W4、W5各自独立地选自-CH-、-N-和-C-；W 4 and W 5 are each independently selected from -CH-, -N- and -C-;

A1环选自C3-15环烷基环(优选为C3-12环烷基环，更优选为C3-10环烷基环，进一步优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环，进一步优选为4至6元杂环烷基环)、5至15元杂芳基环(优选为5至12元杂芳基环，更优选为5至10元杂芳基环，进一步优选为5至6元杂芳基环)和C6-14芳环；The A1 ring is selected from a C3-15 cycloalkyl ring (preferably a C3-12 cycloalkyl ring, more preferably a C3-10 cycloalkyl ring, further preferably a C3-8 cycloalkyl ring, further preferably a C3-6 cycloalkyl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 4- to 12-membered heterocycloalkyl ring, more preferably a 4- to 10-membered heterocycloalkyl ring, further preferably a 4- to 8-membered heterocycloalkyl ring, further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 15-membered heteroaryl ring (preferably a 5- to 12-membered heteroaryl ring, more preferably a 5- to 10-membered heteroaryl ring, further preferably a 5- to 6-membered heteroaryl ring) and a C6-14 aromatic ring;

(R1)p1表示A1环上的氢被p1个R1取代，p1为0、1、2或3，每个R1相同或不同，各自独立地选自X1、氢、氘、氰基、羧基、硝基、甲酰基、磺酸基、卤素(优选为氟、氯或溴)、C1-10烷基(优选为C1-8烷基，更优选为C1-6烷基，进一步优选为C1-3烷基)、卤代C1-10烷基(优选为卤代C1-8烷基，更优选为卤代C1-6烷基，进一步优选为卤代C1-3烷基)、C1-10烷氧基(优选为C1-8烷氧基，更优选为C1-6烷氧基，进一步优选为C1-3烷氧基)、卤代C1-10烷氧基(优选为卤代C1-8烷氧基，更优选为卤代C1-6烷氧基，进一步优选为卤代C1-3烷氧基)、-COC1-10烷基(优选为-COC1-8烷基，更优选为-COC1-6烷基，进一步优选为-COC1-3烷基)、-COOC1-10烷基(优选为-COOC1-8烷基，更优选为-COOC1-6烷基，进一步优选为-COOC1-3烷基)、-CONH2、-CONHC1-10烷基(优选为-CONHC1-8烷基，更优选为-CONHC1-6烷基，进一步优选为-CONHC1-3烷基)、-CON(C1-10烷基)2(优选为-CON(C1-8烷基)2，更优选为-CON(C1-6烷基)2，进一步优选为-CON(C1-3烷基)2)、-SOC1-10烷基(优选为-SOC1-8烷基，更优选为-SOC1-6烷基，进一步优选为-SOC1-3烷基)、-SO2C1-10烷基(优选为-SO2C1-8烷基，更优选为-SO2C1-6烷基，进一步优选为-SO2C1-3烷基)、-SO2NH2、-SO2NHC1-10烷基(优选为-SO2NHC1-8烷基，更优选为-SO2NHC1-6烷基，进一步优选为-SO2NHC1-3烷基)、-SO2N(C1-10烷基)2(优选为-SO2N(C1-8烷基)2，更优选为-SO2N(C1-6烷基)2，进一步优选为-SO2N(C1-3烷基)2)、C3-8环烷基(优选为C3-6环烷基)、3至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基；所述的C1-10烷基、卤代C1-10烷基、C1-10烷氧基、卤代C1-10烷氧基、-COC1-10烷基、-COOC1-10烷基、-CONH2、-CONHC1-10烷基、-CON(C1-10烷基)2、-SOC1-10烷基、-SO2C1-10烷基、-SO2NH2、-SO2NHC1-10烷基、-SO2N(C1-10烷基)2、C3-8环烷基、3至15元杂环烷基、5至10元杂芳基、C6-14芳基为未取代或被1、2或3个选自下组的取代基取代：氰基、羟基、羧基、硝基、甲酰基、磺酸基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、C3-6环烷基、3至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)、苯基和萘基；(R 1 ) p1 represents that the hydrogen on the A1 ring is replaced by p1 R 1s , p1 is 0, 1, 2 or 3, each R 1 is the same or different and is independently selected from X 1 , hydrogen, deuterium, cyano, carboxyl, nitro, formyl, sulfonic acid , halogen (preferably fluorine, chlorine or bromine), C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-6 alkyl, and further preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-8 alkyl, more preferably halogenated C 1-6 alkyl, and further preferably halogenated C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, and further preferably C 1-3 alkoxy), halogenated C 1-10 alkoxy (preferably halogenated C 1-8 alkoxy, more preferably halogenated C 1-6 alkoxy, and further preferably halogenated C -COC 1-10 alkyl (preferably -COC 1-8 alkyl, more preferably -COC 1-6 alkyl, further preferably -COC 1-3 alkyl), -COOC 1-10 alkyl (preferably -COOC 1-8 alkyl, more preferably -COOC 1-6 alkyl, further preferably -COOC 1-3 alkyl), -CONH 2 , -CONHC 1-10 alkyl (preferably -CONHC 1-8 alkyl, more preferably -CONHC 1-6 alkyl, further preferably -CONHC 1-3 alkyl), -CON(C 1-10 alkyl ) 2 (preferably -CON(C 1-8 alkyl) 2 , more preferably -CON(C 1-6 alkyl) 2 , further preferably -CON(C 1-3 alkyl) 2 ), -SOC 1-10 alkyl (preferably -SOC 1-8 alkyl, more preferably -SOC 1-6 alkyl, further preferably -SOC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-8 alkyl, more preferably -SO 2 C 1-6 alkyl, further preferably -SO 2 C 1-3 alkyl), -SO 2 NH 2 , -SO 2 NHC 1-10 alkyl (preferably -SO 2 NHC 1-8 alkyl, more preferably -SO 2 NHC 1-6 alkyl, further preferably -SO 2 NHC 1-3 alkyl), -SO 2 N(C 1-10 alkyl) 2 (preferably -SO 2 N(C 1-8 alkyl) 2 , more preferably -SO 2 N(C 1-6 alkyl) 2 , further preferably -SO 2 N(C 1-3 alkyl) 2 ), C 3-8 cycloalkyl (preferably C 3-8 cycloalkyl) 2 The C 1-10 alkyl, the halogenated C 1-10 alkyl, the C 1-10 alkoxy, the halogenated C 1-10 alkoxy, -COC 1-10 alkyl, -COOC 1-10 alkyl, -CONH 2 , -CONHC 1-10 alkyl, -CON(C 1-10 alkyl) 2 , -SOC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-10 alkyl, -SO 2 N(C 1-10 alkyl) 2 , C 1-10 alkyl, -COC 1-10 alkyl, -COOC 1-10 alkyl, -CONH 2 , -CONHC 1-10 alkyl, -CON(C 1-10 alkyl) 2 , -SOC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-10 alkyl, -SO 2 N(C 1-10 alkyl) 2 , C the C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 3-6 -membered cycloalkyl, 3- to 15-membered heterocycloalkyl (preferably 4- to 12-membered heterocycloalkyl, more preferably 4- to 8-membered heterocycloalkyl, and further preferably 4- to 6-membered heterocycloalkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl), phenyl and naphthyl;

(R2)p2表示A2环上的氢被p2个R2取代，p2为0、1、2或3，每个R2相同或不同，各自独立地选自X1、氢、氘、C1-10烷基(优选为C1-8烷基，更优选为C1-6烷基，进一步优选为C1-3烷基)、C1-10烷氧基(优选为C1-8烷氧基，更优选为C1-6烷氧基，进一步优选为C1-3烷氧基)、卤代C1-10烷基(优选为卤代C1-8烷基，更优选为卤代C1-6烷基，进一步优选为卤代C1-3烷基)、卤代C1-10烷氧基(优选为卤代C1-8烷氧基，更优选为卤代C1-6烷氧基，进一步优选为卤代C1-3烷氧基)、C3-8环烷基(优选为C3-6环烷基)、3至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)和5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；所述的C1-10烷基、C1-10烷氧基、卤代C1-10烷基、卤代C1-10烷氧基、5至10元杂芳基、C3-8环烷基、3至15元杂环烷基、C6-14芳基为未取代或被1、2、3或4个选自下组的取代基取代：卤素(优选为氟、氯或溴)、羟基、羧基、硝基、甲酰基、磺酸基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、5至6元杂芳基、C3-8环烷基、4至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)和C6-14芳基(优选为C6-12芳基)；(R 2 ) p2 represents that the hydrogen on the A2 ring is replaced by p2 R 2 , p2 is 0, 1, 2 or 3, each R 2 is the same or different and is independently selected from X 1 , hydrogen, deuterium, C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-6 alkyl, and further preferably C 1-3 alkyl ), C 1-10 alkoxy (preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, and further preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-8 alkyl, more preferably halogenated C 1-6 alkyl, and further preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-8 alkoxy, more preferably halogenated C 1-6 alkoxy, and further preferably halogenated C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C The C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-15 membered heterocycloalkyl, C 6-14 aryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), hydroxyl, carboxyl , nitro, formyl, sulfonic acid, C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkyl , halogenated C 1-6 alkoxy , C 1-6 alkoxy, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl, 4- to 15-membered heterocycloalkyl (preferably 4- to 12-membered heterocycloalkyl, more preferably 4- to 8-membered heterocycloalkyl, further preferably 4- to 6-membered heterocycloalkyl) and C 6-14 aryl (preferably C 6-12 aryl);

(R3)p3表示2,3-二氢苯并呋喃环上的氢被p3个R3取代，p3为0、1或2，每个R3相同或不同，各自独立地选自氢、氘、卤素(优选为氟、氯或溴)、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、-COC1-8烷基(优选为-COC1-6烷基，更优选为-COC1-3烷基)、-COOC1-8烷基(优选为-COOC1-6烷基，更优选为-COOC1-3烷基)、-CONH2、-CONHC1-8烷基(优选为-CONHC1-6烷基，更优选为-CONHC1-3烷基)、-CON(C1-8烷基)2(优选为-CON(C1-6烷基)2，更优选为-CON(C1-3烷基)2)、-SOC1-8烷基(优选为-SOC1-6烷基，更优选为-SOC1-3烷基)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、-SO2NH2、-SO2NHC1-8烷基(优选为-SO2NHC1-6烷基，更优选为-SO2NHC1-3烷基)、-SO2N(C1-8烷基)2(优选为-SO2N(C1-6烷基)2，更优选为-SO2N(C1-3烷基)2)、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；和/或相邻的两个R3以及与其相连的碳原子形成C3-8环烷基环(优选为C3-6环烷基环)、3至8元杂环烷基环(优选为3至6元杂环烷基环、4至5元杂环烷基环)、5至10元杂芳基环(优选为5至6元杂芳基环)、苯环；所述的C1-8烷基、卤代C1-8烷基、C1-8烷氧基、卤代C1-8烷氧基、-COC1-8烷基、-COOC1-8烷基、-CONH2、-CONHC1-8烷基、-CON(C1-8烷基)2、-SOC1-8烷基、-SO2C1-8烷基、-SO2NH2、-SO2NHC1-8烷基、-SO2N(C1-8烷基)2、C3-8环烷基、3至12元杂环烷基、5至10元杂芳基、C6-14芳基、C3-8环烷基环、3至8元杂环烷基环、5至10元杂芳基环、苯环为未取代或被1、2或3个选自下组的取代基取代：卤素、氰基、羟基、羧基、硝基、甲酰基、磺酸基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)和5至10元杂芳基(优选为5至6元杂芳基)；(R 3 ) p3 represents that the hydrogen on the 2,3-dihydrobenzofuran ring is replaced by p3 R 3 , p3 is 0, 1 or 2, each R 3 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -COC 1-8 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -COOC 1-8 alkyl (preferably -COOC 1-6 alkyl, more preferably -COOC 1-3 alkyl), -CONH 2 , -CONHC 1-8 alkyl (preferably -CONHC 1-6 alkyl, more preferably -CONHC 1-3 alkyl), -CON(C 1-8 alkyl) 2 (preferably -CON(C 1-6 alkyl) 2 , more preferably -CON(C 1-3 alkyl) 2 ), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NH 2 , -SO 2 NHC 1-8 alkyl (preferably -SO 2 NHC 1-6 alkyl, more preferably -SO 2 NHC 1-3 alkyl), -SO 2 N(C 1-8 alkyl) 2 (preferably -SO 2 N(C 1-6 alkyl) 2 , more preferably -SO 2 N(C 1-3 alkyl) 2 ), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 12 membered heterocycloalkyl (preferably 4 to 8 membered heterocycloalkyl, more preferably 4 to 6 membered heterocycloalkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl) and C 6-14 aryl (preferably C 6-12 aryl); and/or two adjacent R 3 and the carbon atom connected thereto form a C 3-8 cycloalkyl ring (preferably a C 3-6 cycloalkyl ring), a 3 to 8 membered heterocycloalkyl ring (preferably a 3 to 6 membered heterocycloalkyl ring, a 4 to 5 membered heterocycloalkyl ring), a 5 to 10 membered heteroaryl ring (preferably a 5 to 6 membered heteroaryl ring), a benzene ring; the C 1-8 alkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, -COC 1-8 alkyl, -COOC 1-8 alkyl, -CONH 2 , -CONHC 1-8 alkyl, -CON( C wherein the alkyl group is unsubstituted or substituted by 1 , 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy , carboxyl, nitro , formyl , sulfonic acid, C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-8 alkyl) 2 , C 3-8 cycloalkyl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, C 6-14 aryl, C 3-8 cycloalkyl ring, 3 to 8 membered heterocycloalkyl ring, 5 to 10 membered heteroaryl ring, and benzene ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C -SOC 1-6 alkyl), -SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N (C 1-6 alkyl) 2 , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 12 membered heterocycloalkyl (preferably 4 to 8 membered heterocycloalkyl, more preferably 4 to 6 membered heterocycloalkyl) and 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl);

(R4)p4表示咪唑并[1,5-c]嘧啶环上的氢被p4个R4取代，p4为0、1或2，每个R4相同或不同，各自独立地选自氢、氘、卤素(优选为氟、氯或溴)、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、-COC1-8烷基(优选为-COC1-6烷基，更优选为-COC1-3烷基)、-COOC1-8烷基(优选为-COOC1-6烷基，更优选为-COOC1-3烷基)、-CONH2、-CONHC1-8烷基(优选为-CONHC1-6烷基，更优选为-CONHC1-3烷基)、-CON(C1-8烷基)2(优选为-CON(C1-6烷基)2，更优选为-CON(C1-3烷基)2)、-SOC1-8烷基(优选为-SOC1-6烷基，更优选为-SOC1-3烷基)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、-SO2NH2、-SO2NHC1-8烷基(优选为-SO2NHC1-6烷基，更优选为-SO2NHC1-3烷基)、-SO2N(C1-8烷基)2(优选为-SO2N(C1-6烷基)2，更优选为-SO2N(C1-3烷基)2)、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；所述的C1-8烷基、卤代C1-8烷基、C1-8烷氧基、卤代C1-8烷氧基、-COC1-8烷基、-COOC1-8烷基、-CONH2、-CONHC1-8烷基、-CON(C1-8烷基)2、-SOC1-8烷基、-SO2C1-8烷基、-SO2NH2、-SO2NHC1-8烷基、-SO2N(C1-8烷基)2、C3-8环烷基、3至12元杂环烷基、5至10元杂芳基、C6-14芳基为未取代或被1、2或3个选自下组的取代基取代：卤素、氰基、羟基、羧基、硝基、甲酰基、磺酸基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；(R 4 ) p4 represents that the hydrogen on the imidazo[1,5-c]pyrimidine ring is replaced by p4 R 4 , p4 is 0, 1 or 2, each R 4 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -COC 1-8 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -COOC 1-8 alkyl (preferably -COOC 1-6 alkyl, more preferably -COOC 1-3 alkyl), -CONH 2 , -CONHC 1-8 alkyl (preferably -CONHC 1-6 alkyl, more preferably -CONHC 1-3 alkyl), -CON(C 1-8 alkyl) 2 (preferably -CON(C 1-6 alkyl) 2 , more preferably -CON(C 1-3 alkyl) 2 ), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NH 2 , -SO 2 NHC 1-8 alkyl (preferably -SO 2 NHC 1-6 alkyl, more preferably -SO 2 NHC 1-3 alkyl), -SO 2 N(C 1-8 alkyl) 2 (preferably -SO 2 N(C 1-6 alkyl) 2 , more preferably -SO 2 N(C 1-6 alkyl) 2 C 1-8 alkyl) 2 ), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 12 membered heterocycloalkyl (preferably 4 to 8 membered heterocycloalkyl, more preferably 4 to 6 membered heterocycloalkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl) and C 6-14 aryl (preferably C 6-12 aryl); the C 1-8 alkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, -COC 1-8 alkyl, -COOC 1-8 alkyl, -CONH 2 , -CONHC 1-8 alkyl, -CON(C 1-8 alkyl) 2 , -SOC 1-8 alkyl, -SO 2 C 1-8 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-8 alkyl, -SO 2 N ( C 1-8 alkyl) 2 , C The C 3-8 cycloalkyl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, and C 6-14 aryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3-12 membered heterocycloalkyl (preferably 4-8 membered heterocycloalkyl, more preferably 4-6 membered heterocycloalkyl), 5-10 membered heteroaryl (preferably 5-6 membered heteroaryl) and C 6-14 aryl (preferably C 6-12 aryl);

其中，X1为POI与L或ULM的连接位点，且R1和R2中至少一个为X1。Wherein, X 1 is the connection site between POI and L or ULM, and at least one of R 1 and R 2 is X 1 .

在一些实施方案中，W1、W2、W3各自独立地选自键、-CH2-、-C(O)NH-和-NHC(O)-。In some embodiments, W 1 , W 2 , W 3 are each independently selected from a bond, -CH 2 -, -C(O)NH-, and -NHC(O)-.

在一些实施方案中，W4、W5各自独立地选自-CH-和-C-。In some embodiments, W 4 , W 5 are each independently selected from -CH- and -C-.

在一些实施方案中，式(A-1)所示的结构为式(A-2)所示的结构或其异构体，
In some embodiments, the structure represented by formula (A-1) is the structure represented by formula (A-2) or an isomer thereof,

在一些实施方案中，p1为0。In some embodiments, p1 is zero.

在一些实施方案中，p1为1。In some embodiments, p1 is 1.

在一些实施方案中，R1选自X1、氢、氰基、羧基、硝基、甲酰基、磺酸基、甲基、乙基、丙基、异丙基、叔丁基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、羟甲基、羟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、环己烯基、环戊烯基、四氢吡咯基、四氢呋喃基、哌啶基、哌嗪基、吡啶基、吡嗪基、哒嗪基、三嗪基、苯基、-CH2-环丙基、-CH2-四氢吡咯基、-CH2-吡咯基、-CH2-苯基、-CH2-吡啶基、-CH2-喹啉基和-CH2-环己烯基。In some embodiments, R 1 is selected from Xi 1 , hydrogen, cyano, carboxyl, nitro, formyl, sulfonic acid, methyl, ethyl, propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, phenyl, -CH 2 -cyclopropyl, -CH 2 -tetrahydropyrrolyl, -CH 2 -pyrrolyl, -CH 2 -phenyl, -CH 2 -pyridinyl, -CH 2 -quinolinyl, and -CH 2 -cyclohexenyl.

在一些实施方案中，R1选自X1、氢、-CN、-COOH、-NO2、-CHO、-SO3H、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2OH、-CH2CH2OH、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-OC(CH3)3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-COCH3、-COOCH3、-CONH2、-CONHCH3、-CON(CH3)2、-SOCH3、-SO2CH3、-SO2NH2、-SO2NHCH3和-SO2N(CH3)2。 In some embodiments , R 1 is selected from the group consisting of ​ ​ ​ ​ ​ ​ F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 OH, -CH 2 CH 2 OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -SOCH 3 , -SO 2 CH 3 , -SO 2 NH 2 , -SO 2 NHCH 3 and -SO 2 N(CH 3 ) 2 .

在一些实施方案中，R1选自X1、氢、-CH3、-CHF2、-CF3、-CH2OH、-OCH3、-OCH2CH3、-COCH3、-COOCH3、-CONH2、-CONHCH3、-CON(CH3)2、-SOCH3、-SO2CH3、-SO2NH2、-SO2NHCH3和-SO2N(CH3)2。In some embodiments, R1 is selected from Xi , hydrogen, -CH3, -CHF2 , -CF3 , -CH2OH, -OCH3 , -OCH2CH3 , -COCH3 , -COOCH3 , -CONH2 , -CONHCH3 , -CON ( CH3 ) 2 , -SOCH3 , -SO2CH3 , -SO2NH2 , -SO2NHCH3 , and -SO2N ( CH3 ) 2 .

在一些实施方案中，R1选自X1、-CH3和-CF3。In some embodiments, R 1 is selected from the group consisting of X 1 , —CH 3 , and —CF 3 .

在一些实施方案中，R1选自X1和-CF3。In some embodiments, R 1 is selected from X 1 and —CF 3 .

在一些实施方案中，p1为1，R1为X1或-CF3。In some embodiments, p1 is 1, and R 1 is X 1 or -CF 3 .

在一些实施方案中，p1为1，R1为X1。In some embodiments, p1 is 1 and R 1 is X 1 .

在一些实施方案中，p1为1，R1为-CF3。In some embodiments, p1 is 1 and R1 is -CF3 .

在一些实施方案中，p2为0。In some embodiments, p2 is 0.

在一些实施方案中，p2为1。In some embodiments, p2 is 1.

在一些实施方案中，R2选自X1、氢、氘、C1-3烷基(优选为甲基、乙基、异丙基)、卤代C1-3烷基(优选为三氟甲基、二氟乙基、三氟乙基、二氟丙基)、C3-6环烷基(优选为环丙基、环丁基)和4至6元杂环烷基；所述的C1-3烷基、卤代C1-3烷基、C3-6环烷基、4至6元杂环烷基为未取代或被1、2、3或4个选自下组的取代基取代：氟、氯、溴、羟基、羧基、硝基、甲酰基、磺酸基、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、环丙基、环丁基、环戊基、环己基、环己烯基、吡咯基、吡唑基、吡啶基、苯基、嘧啶基、喹啉基、萘基、-CH2-环丙基、-CH2-四氢吡咯基、-CH2-吡咯基、-CH2-苯基、-CH2-吡啶基、-CH2-喹啉基、-CH2-环己烯基、-CH2-氮杂环丁烷、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)。In some embodiments, R 2 is selected from X 1 , hydrogen, deuterium, C 1-3 alkyl (preferably methyl, ethyl, isopropyl), halogenated C 1-3 alkyl (preferably trifluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl), C 3-6 cycloalkyl (preferably cyclopropyl, cyclobutyl) and 4 to 6 membered heterocycloalkyl; the C 1-3 alkyl, halogenated C 1-3 alkyl, C The 3-6- membered cycloalkyl and 4- to 6-membered heterocycloalkyl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, carboxyl, nitro, formyl, sulfonic acid, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl, quinolyl, naphthyl, -CH2-cyclopropyl, -CH2 - tetrahydropyrrolyl, -CH2 -pyrrolyl, -CH2 -phenyl, -CH2 -pyridinyl, -CH2 -quinolyl, -CH2 - cyclohexenyl, -CH2-azetidine, -CH2 -piperidine, -CH2 -piperazine, tetrahydro-2H-pyran and -CH 2 -(tetrahydro-2H-pyran).

在一些实施方案中，R2选自X1、氢、氘、甲基、乙基、丙基、异丙基、叔丁基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、二氟丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁烷基、四氢吡咯基、哌啶基、哌嗪基、-CH2-环丙基、-CH2-氮杂环丁烷、-CH2-四氢吡咯、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)。In some embodiments, R2 is selected from Xi , hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, -CH2 -cyclopropyl, -CH2-azetidine, -CH2 -tetrahydropyrrole, -CH2 -piperidine, -CH2 -piperazine, tetrahydro-2H-pyran, and -CH2- (tetrahydro-2H-pyran ) .

在一些实施方案中，R2选自X1、氢、氘、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CF2CH3、环丙基、环丁基、环戊基、环己基、氮杂环丁烷基、四氢吡咯基、哌啶基、哌嗪基、-CH2-环丙基、-CH2-氮杂环丁烷、-CH2-四氢吡咯、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)。In some embodiments, R2 is selected from Xi , hydrogen, deuterium, -CH3, -CH2CH3 , -CH2CH2CH3 , -CH( CH3 ) 2 , -C( CH3 ) 3 , -CH2F , -CHF2 , -CF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -CH2CF2CH3 , cyclopropyl , cyclobutyl , cyclopentyl, cyclohexyl , azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl , -CH2 - cyclopropyl , -CH2-azetidine, -CH2 -tetrahydropyrrole, -CH2-piperidine, -CH2 -piperazine, tetrahydro - 2H -pyran, and -CH2- (tetrahydro- 2H -pyran).

在一些实施方案中，R2选自X1、-CH3、-CH2CHF2、-CH2CF2CH3和-CH(CH3)2。In some embodiments, R 2 is selected from the group consisting of X 1 , -CH 3 , -CH 2 CHF 2 , -CH 2 CF 2 CH 3 , and -CH(CH 3 ) 2 .

在一些实施方案中，R2选自X1和-CH(CH3)2。In some embodiments, R 2 is selected from X 1 and -CH(CH 3 ) 2 .

在一些实施方案中，R2为X1。In some embodiments, R 2 is X 1 .

在一些实施方案中，R2为-CH(CH3)2。In some embodiments, R 2 is -CH(CH 3 ) 2 .

在一些实施方案中，p2为1，R2为X1或-CH(CH3)2。In some embodiments, p2 is 1 and R 2 is X 1 or -CH(CH 3 ) 2 .

在一些实施方案中，p2为1，R2为X1。In some embodiments, p2 is 1 and R 2 is X 1 .

在一些实施方案中，p2为1，R2为-CH(CH3)2。In some embodiments, p2 is 1 and R 2 is -CH(CH 3 ) 2 .

在一些实施方案中，p3为0。In some embodiments, p3 is 0.

在一些实施方案中，p3为1。In some embodiments, p3 is 1.

在一些实施方案中，p3为3。In some embodiments, p3 is 3.

在一些实施方案中，R3选自氢、氘、氟、氯、溴、碘、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、环己烯基、吡咯基、吡唑基、吡啶基、苯基、嘧啶基、喹啉基、萘基、-CH2-环丙基、-CH2-四氢吡咯基、-CH2-吡咯基、-CH2-苯基、-CH2-吡啶基、-CH2-喹啉基、-CH2-环己烯基、-CH2-氮杂环丁烷、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)。In some embodiments, R 3 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl, quinolyl, naphthyl, -CH 2 -cyclopropyl, -CH 2 -tetrahydropyrrolyl, -CH 2 -pyrrolyl, -CH 2 -phenyl, -CH 2 -pyridinyl, -CH 2 -quinolyl, -CH 2 -cyclohexenyl, -CH 2 -azetidine, -CH 2 -piperidine, -CH 2 -piperazine, tetrahydro-2H-pyran and -CH 2 -(tetrahydro-2H-pyran).

在一些实施方案中，R3选自氢、氘、氟、氯、溴、碘、-CH3、-CH2CH3、-CH(CH3)2、-CH2CH2CH3、-CH2F、-CHF2、-CF3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-OCH2F、-OCHF2、-OCF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-OCH2CH2F、-OCH2CHF2和-OCH2CF3。In some embodiments, R3 is selected from hydrogen, deuterium, fluorine, chlorine , bromine, iodine , -CH3 , -CH2CH3, -CH( CH3 ) 2 , -CH2CH2CH3 , -CH2F , -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH ( CH3 ) 2 , -OCH2F , -OCHF2 , -OCF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -OCH2CH2F , -OCH2CHF2 , and -OCH2CF3 .

在一些实施方案中，p3为1，R3为氟。In some embodiments, p3 is 1 and R3 is fluoro.

在一些实施方案中，结构为 In some embodiments, the structure for

在一些实施方案中，相邻的两个R3以及与其相连的碳原子形成C3-6环烷基环、3至6元杂环烷基环或5至6元杂芳基环。In some embodiments, two adjacent R 3 and the carbon atom to which they are attached form a C 3-6 cycloalkyl ring, a 3- to 6-membered heterocycloalkyl ring, or a 5- to 6-membered heteroaryl ring.

在一些实施方案中，相邻的两个R3以及与其相连的碳原子形成环丙烷环、环丁烷环、环戊烷环、环己烷环、环己烯环、环戊烯环、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、吡咯环、呋喃环、噻吩环、恶唑环、噻唑环、吡唑环、咪唑环、三唑环、吡啶环、嘧啶环、哒嗪环、吡嗪环或三嗪环。In some embodiments, two adjacent R3 and the carbon atom to which they are attached form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cyclohexene ring, a cyclopentene ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, a thiazole ring, a pyrazole ring, an imidazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring or a triazine ring.

在一些实施方案中，相邻的两个R3以及与其相连的碳原子形成环丙烷环。In some embodiments, two adjacent R 3 and the carbon atom to which they are attached form a cyclopropane ring.

在一些实施方案中，p3为3，其中一个R3为氟，另两个R3以及与其相连的碳原子形成环丙烷环。In some embodiments, p3 is 3, wherein one R 3 is fluorine, and the other two R 3 and the carbon atom to which they are attached form a cyclopropane ring.

在一些实施方案中，结构为 In some embodiments, the structure for

在一些实施方案中，结构为 In some embodiments, the structure for

在一些实施方案中，A1环中所述的C3-15环烷基环选自环丙烷环、环丁烷环、环戊烷环、双环戊烷环、环己烷环、螺[3.3]庚烷环、螺环[3.4]辛烷环、螺[3.5]壬烷环、萘烷环、十四氢蒽环、八氢-1'H-螺[环戊烷-1,2'-萘]环、环己烯环和螺[4.5]癸-6-烯环。In some embodiments, the C 3-15 cycloalkyl ring in the A1 ring is selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a bicyclopentane ring, a cyclohexane ring, a spiro[3.3]heptane ring, a spiro[3.4]octane ring, a spiro[3.5]nonane ring, a decalin ring, a tetradecahydroanthracene ring, an octahydro-1'H-spiro[cyclopentane-1,2'-naphthalene] ring, a cyclohexene ring and a spiro[4.5]dec-6-ene ring.

在一些实施方案中，A1环中所述的3至15元杂环烷基环选自氮杂环丁烷环、四氢吡咯环、四氢呋喃环、四氢噻吩环、哌啶环、哌嗪环、2,5-二氢-1H-吡咯环、2,3-二氢-1H-吡咯环、1,2,3,6-四氢吡啶环、1,2,3,4-四氢吡啶环、3,4-二氢-2H-1,4-恶嗪环、1,3-二氧杂环戊烯环、2,3,6,7-四氢-1H-氮平环、2,3,4,7-四氢-1H-氮平环、2,3,4,5-四氢-1H-氮平环、2-氮杂螺[3.3]庚烷环、6-氮杂螺[3.4]辛烷环、7-氮杂螺[3.5]壬烷环、2,6-二氮杂螺[3.3]庚烷环、2,6-二氮杂螺[3.4]辛烷环、2,7-二氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环和2-氮杂螺[4.5]癸-6-烯环。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in the A1 ring is selected from an azetidine ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a piperazine ring, a 2,5-dihydro-1H-pyrrole ring, a 2,3-dihydro-1H-pyrrole ring, a 1,2,3,6-tetrahydropyridine ring, a 1,2,3,4-tetrahydropyridine ring, a 3,4-dihydro-2H-1,4-oxazine ring, a 1,3-dioxole ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ...azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-azacyclopentane ring, a 2,3,6,7-tetrahydro-1H-aza 2,3,4,7-tetrahydro-1H-azapine ring, 2,3,4,5-tetrahydro-1H-azapine ring, 2-azaspiro[3.3]heptane ring, 6-azaspiro[3.4]octane ring, 7-azaspiro[3.5]nonane ring, 2,6-diazaspiro[3.3]heptane ring, 2,6-diazaspiro[3.4]octane ring, 2,7-diazaspiro[3.5]nonane ring, 2-azaspiro[3.5]nonane ring and 2-azaspiro[4.5]dec-6-ene ring.

在一些实施方案中，A1环中所述的5至15元杂芳基环选自吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、三唑环、四唑环、噁唑环、噻唑环、恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环、苯并吡咯环、苯并呋喃环、苯并噻吩环、苯并吡唑环、苯并咪唑环、苯并噻唑环、苯并噁唑环、吡啶并吡咯环、吡啶并呋喃环、吡啶并噻吩环、吡啶并吡唑环、吡啶并咪唑环、吡啶并噻唑环、吡啶并噁唑环、嘧啶并吡咯环、哒嗪并吡咯环、吡嗪并吡咯环、嘧啶并吡唑环、哒嗪并吡唑环、吡嗪并吡唑环、嘧啶并咪唑环、哒嗪并咪唑环、吡嗪并咪唑环、喹啉环、异喹啉环和9H-吡啶并[2,3-b]吲哚环。In some embodiments, the 5- to 15-membered heteroaryl ring in the A1 ring is selected from a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a benzopyrrole ring, a benzofuran ring, a benzothiophene ring, a benzopyrazole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a benzofuran ring, a benzothiophene ring, a benzopyrazole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a pyridine ... a pyridopyrrole ring, a pyridofuran ring, a pyridothiophene ring, a pyridopyrazole ring, a pyridoimidazole ring, a pyridothiazole ring, a pyridooxazole ring, a pyrimidopyrrole ring, a pyridazinopyrrole ring, a pyrazinopyrrole ring, a pyrimidopyrazole ring, a pyridazinopyrazole ring, a pyrazinopyrazole ring, a pyrimidoimidazole ring, a pyridazinoimidazole ring, a pyrazinoimidazole ring, a quinoline ring, an isoquinoline ring and a 9H-pyrido[2,3-b]indole ring.

在一些实施方案中，A1环中所述的C6-14芳环选自苯环和萘环。In some embodiments, the C 6-14 aromatic ring in the A1 ring is selected from a benzene ring and a naphthalene ring.

在一些实施方案中，A1环选自苯环、吡啶环、嘧啶环、哒嗪环、吡嗪环、三嗪环、吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、噁唑环和噻唑环。In some embodiments, the A1 ring is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, and a thiazole ring.

在一些实施方案中，A1环选自苯环、吡啶环和吡唑环。In some embodiments, the A1 ring is selected from a benzene ring, a pyridine ring, and a pyrazole ring.

在一些实施方案中，A1环选自苯环和吡啶环。In some embodiments, the A1 ring is selected from a benzene ring and a pyridine ring.

在一些实施方案中，结构选自 其中，R1、R2、p1如说明书中所定义，且R1和R2中至少一个为X1。In some embodiments, the structure Selected from Wherein, R 1 , R 2 , and p1 are as defined in the specification, and at least one of R 1 and R 2 is X 1 .

在一些实施方案中，结构选自：其中，R1、R2、p1如说明书中所定义，且R1和R2中至少一个为X1。In some embodiments, the structure Selected from: Wherein, R 1 , R 2 , and p1 are as defined in the specification, and at least one of R 1 and R 2 is X 1 .

在一些实施方案中，结构选自 In some embodiments, the structure Selected from

在一些实施方案中，结构选自： In some embodiments, the structure Selected from:

在一些实施方案中，结构选自其中Y1、Y2、Y3各自独立地为CH或N，(R1)p1、R2、A1如说明书所述，X1为POI与L或ULM的连接位点。In some embodiments, the structure Selected from Wherein Y 1 , Y 2 , and Y 3 are each independently CH or N, (R 1 ) p1 , R 2 , and A1 are as described in the specification, and X 1 is the connection site between POI and L or ULM.

在一些实施方案中，Y1、Y2、Y3各自独立地为CH。In some embodiments, Y 1 , Y 2 , and Y 3 are each independently CH.

在一些实施方案中，Y2、Y3各自独立地为CH，Y1为N。In some embodiments, Y 2 and Y 3 are each independently CH, and Y 1 is N.

在一些实施方案中，Y1、Y3各自独立地为CH，Y2为N。In some embodiments, Y 1 and Y 3 are each independently CH, and Y 2 is N.

在一些实施方案中，Y1、Y2各自独立地为CH，Y3为N。In some embodiments, Y 1 and Y 2 are each independently CH, and Y 3 is N.

在一些实施方案中，Y1、Y2各自独立地为N，Y3为CH。In some embodiments, Y 1 and Y 2 are each independently N, and Y 3 is CH.

在一些实施方案中，Y2、Y3各自独立地为N，Y1为CH。In some embodiments, Y 2 and Y 3 are each independently N, and Y 1 is CH.

在一些实施方案中，Y1、Y2、Y3各自独立地为N。In some embodiments, Y 1 , Y 2 , and Y 3 are each independently N.

在一些实施方案中，结构选自 其中X1为POI与L或ULM的连接位点。In some embodiments, the structure Selected from Where X1 is the connection site between POI and L or ULM.

在一些实施方案中，结构选自、 其中X1为POI与L或ULM的连接位点。In some embodiments, the structure Selected from Where X1 is the connection site between POI and L or ULM.

在一些实施方案中，结构选自： 其中X1为POI与L或ULM的连接位点。In some embodiments, the structure Selected from: Where X1 is the connection site between POI and L or ULM.

在一些实施方案中，结构选自： 其中X1为POI与L或ULM的连接位点。In some embodiments, the structure Selected from: Where X1 is the connection site between POI and L or ULM.

在一些实施方案中，POI选自以下结构： 其中X1为POI与L或ULM的连接位点。In some embodiments, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.

在一些实施方案中，POI选自以下结构： 其中X1为POI与L或ULM的连接位点。In some embodiments, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.

在一些实施方案中，POI选自以下结构： 其中X1为POI与L或ULM的连接位点。In some embodiments, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.

在一些实施方案中，式(I)所示化合物为式(I-C)所示结构，
In some embodiments, the compound represented by formula (I) is represented by formula (IC),

其中W1、W2、W3、W4、W5、A1环、R1、R2、R3、R4、L、ULM、p1、p2、p3、p4、n0如说明书中所定义，且R1、R2不为X1。in W 1 , W 2 , W 3 , W 4 , W 5 , A1 ring, R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p2, p3, p4 and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .

在一些实施方案中，式(I)所示化合物为式(I-D)所示结构，
In some embodiments, the compound represented by formula (I) is represented by formula (ID),

其中W1、W2、W3、W4、W5、A1环、R1、R2、R3、R4、L、ULM、p1、p2、p3、p4、n0如说明书中所定义，且R1、R2不为X1。in W 1 , W 2 , W 3 , W 4 , W 5 , A1 ring, R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p2, p3, p4 and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .

在一些实施方案中，式(I)所示化合物为式(I-E)所示结构，
In some embodiments, the compound represented by formula (I) is represented by formula (IE),

其中W1、W2、W3、W4、W5、A1环、R1、R3、R4、L、ULM、p1、p3、p4、n0如说明书中所定义，且R1不为X1。in W 1 , W 2 , W 3 , W 4 , W 5 , A1 ring, R 1 , R 3 , R 4 , L, ULM, p1, p3, p4 and n0 are as defined in the specification, and R 1 is not X 1 .

在一些实施方案中，式(I)所示化合物为式(I-F)所示结构，
In some embodiments, the compound represented by formula (I) is represented by formula (IF),

其中W1、W2、W3、W4、W5、A1环、R2、R3、R4、L、ULM、p2、p3、p4、n0如说明书中所定义，且R2不为X1。in W 1 , W 2 , W 3 , W 4 , W 5 , A1 ring, R 2 , R 3 , R 4 , L, ULM, p2, p3, p4 and n0 are as defined in the specification, and R 2 is not X 1 .

在一些实施方案中，式(I)所示化合物为式(I-A)所示结构，
In some embodiments, the compound represented by formula (I) is represented by formula (IA),

其中A1环、R1、R3、R4、L、ULM、p1、p3、p4、n0如说明书中所定义，且R1不为X1。in Ring A1, R 1 , R 3 , R 4 , L, ULM, p1, p3, p4 and n0 are as defined in the specification, and R 1 is not X 1 .

在一些实施方案中，式(I)所示化合物为式(I-B)所示结构，
In some embodiments, the compound represented by formula (I) is represented by formula (IB),

其中A1环、R1、R2、R3、R4、L、ULM、p1、p3、p4、n0如说明书中所定义，且R1、R2不为X1。in Ring A1, R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p3, p4 and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .

在一些实施方案中，式(I)所示化合物为式(I-B-1)所示结构，
In some embodiments, the compound represented by formula (I) is represented by formula (IB-1),

其中R1、R2、R3、R4、L、ULM、p1、p3、p4、n0、Y1、Y2、Y3如说明书中所定义，且R1、R2不为X1。in R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p3, p4, n0, Y 1 , Y 2 , and Y 3 are as defined in the specification, and R 1 and R 2 are not X 1 .

在一些实施方案中，式(I)所示化合物选自以下结构：
其中R1、R2、R3、L、ULM、p1、p3、n0如说明书中所定义，且R1、R2不为X1。In some embodiments, the compound represented by formula (I) is selected from the following structures:
wherein R 1 , R 2 , R 3 , L, ULM, p1, p3, and n0 are as defined in the specification, and R 1 and R 2 are not X 1 .

在一些实施方案中，式(I)所示化合物选自以下结构： 其中L、ULM、n0如说明书中所定义。In some embodiments, the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, and n0 are as defined in the specification.

在一些实施方案中，式(I)所示化合物选自以下结构：
其中L、ULM、n0如说明书中所定义。In some embodiments, the compound represented by formula (I) is selected from the following structures:
Wherein L, ULM, and n0 are as defined in the specification.

在一些实施方案中，式(I)所示化合物选自以下结构：
其中L、ULM、n0如说明书中所定义。In some embodiments, the compound represented by formula (I) is selected from the following structures:
Wherein L, ULM, and n0 are as defined in the specification.

在一些实施方案中，L为式(L-1)所示的结构或其异构体，
-(La)m1-
(L-1)，In some embodiments, L is a structure represented by formula (L-1) or an isomer thereof,
-(L a ) m1 -
(L-1),

其中，m1独立的为0、1、2、3、4、5、6、7、8、9或10；wherein m1 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

La每次出现，各自独立地选自键、-C(O)-、-C(O)NRL1-、-NRL1-、-O-、-S-、C1-10亚烷基(优选为C1-8亚烷基，更优选为C1-6亚烷基，进一步优选为C1-3亚烷基)、C1-10亚烷氧基(优选为C1-8亚烷氧基、更优选为C1-6亚烷氧基、进一步优选为C1-3亚烷氧基)、C2-10亚烯基(优选为C2-8亚烯基，更优选为C2-6亚烯基，进一步优选为C2-4亚烯基)、C2-10亚炔基(优选为C2-8亚炔基，更优选为C2-6亚炔基，进一步优选为C2-4亚炔基)、C3-15环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环、进一步优选为4至6元杂环烷基环)、5至15元杂芳基环(优选为5至14元杂芳基环，更优选为5至12元杂芳基环，进一步优选为5至10元杂芳基环，进一步优选为5至6元杂芳基环)和C6-14芳环(优选为苯环或萘环)；所述的C1-10亚烷基、C1-10亚烷氧基、C2-10亚烯基、C2-10亚炔基、C3-15环烷基环、3至15元杂环烷基环、5至15元杂芳基环、C6-14芳环为未取代或被1、2、3或4个RL2取代，所述的RL2各自独立地选自氘、卤素(优选为氟、氯或溴)、羟基、氰基、氨基、羧基、甲酰基、氧代基、磺酸基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基C1-6烷基、C3-6环烷基、C3-6环烷基C1-6烷基、3至6元杂环烷基、3至6元杂环烷基C1-6烷基、5至6元杂芳基、5至6元杂芳基C1-6烷基、苯基、苯基C1-6烷基、-COC1-6烷基、-COOC1-6烷基、-OCOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基和-SO2N(C1-6烷基)2；Each occurrence of L a is independently selected from a bond, -C(O)-, -C(O)NR L1 -, -NR L1 -, -O-, -S-, C 1-10 alkylene (preferably C 1-8 alkylene, more preferably C 1-6 alkylene, and further preferably C 1-3 alkylene), C 1-10 alkyleneoxy (preferably C 1-8 alkyleneoxy, more preferably C 1-6 alkyleneoxy, and further preferably C 1-3 alkyleneoxy), C 2-10 alkenylene (preferably C 2-8 alkenylene, more preferably C 2-6 alkenylene, and further preferably C 2-4 alkenylene), C 2-10 alkynylene (preferably C 2-8 alkynylene, more preferably C 2-6 alkynylene, and further preferably C 2-4 alkynylene), C 3-15 cycloalkyl ring (preferably C 3-10 cycloalkyl ring, more preferably C 3-8 cycloalkyl ring, and further preferably C wherein the C 1-10 alkylene group, C 1-10 alkylene group, C 2-10 alkenylene group, C 2-10 alkynylene group, C 3-15 cycloalkyl ring, 3-15 membered heterocycloalkyl ring, 5-15 membered heteroaryl ring and C 6-14 aromatic ring are unsubstituted or substituted with 1 , 2 , 3 or 4 R L2 , wherein R L2 is each independently selected from deuterium, halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, amino, carboxyl, formyl, oxo, sulfonic acid, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, hydroxy-substituted C1-6 alkyl, cyano-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, 3- to 6 -membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl C1-6 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl C1-6 alkyl, phenyl, phenyl C1-6 alkyl, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl, -CONH2 , -CONHC1-6 alkyl, -CON(C3-6) 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl and -SO 2 N(C 1-6 alkyl) 2 ;

RL1每次出现，各自独立地选自氢、氘、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)和卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)。Each occurrence of RL1 is independently selected from hydrogen, deuterium, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), halo-substituted C1-8 alkoxy (preferably halo-substituted C1-6 alkoxy, more preferably halo-substituted C1-3 alkoxy) and halo-substituted C1-8 alkyl (preferably halo-substituted C1-6 alkyl, more preferably halo-substituted C1-3 alkyl).

在一些实施方案中，RL1每次出现，各自独立地选自氢、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、三氟乙基、二氟乙基、一氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、三氟乙氧基、二氟乙氧基和一氟乙氧基。In some embodiments, each occurrence of R is independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoroethoxy, difluoroethoxy, and monofluoroethoxy.

在一些实施方案中，RL1每次出现，各自独立地选自氢、甲基、乙基、二氟甲基和一氟甲基。In some embodiments, each occurrence of R L1 is independently selected from hydrogen, methyl, ethyl, difluoromethyl, and monofluoromethyl.

在一些实施方案中，RL1为氢。In some embodiments, R L1 is hydrogen.

在一些实施方案中，RL2各自独立地选自氘、卤素(优选为氟、氯或溴)、羟基、氰基、氨基、羧基、羟甲基、羟乙基、甲基、乙基、二氟甲基、一氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、环丙基、环丁基、环戊基、环己基、环己烯基、环戊烯基、四氢吡咯基、四氢呋喃基、苯基、吡咯基、呋喃基、噻吩基、噻唑基、噁唑基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-环己烯基、-CH2-环戊烯基、-CH2-四氢吡咯基、-CH2-四氢呋喃基、-CH2-苯基、-CH2-吡咯基、-CH2-三唑基、-CH2-四唑基、-CH2-吡啶基、-CH2-吡嗪基、-CH2-三嗪基、甲氧基、乙氧基、二氟甲氧基、一氟甲氧基、三氟甲氧基、乙酰基、乙酰氨基和磺酰胺基。In some embodiments, each RL is independently selected from deuterium, halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, amino, carboxyl, hydroxymethyl, hydroxyethyl, methyl, ethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-cyclohexenyl, -CH2-cyclopentenyl, -CH2-tetrahydropyrrolyl, -CH2-tetrahydrofuran ...cyclohexenyl, -CH2-cyclopentenyl, -CH2-tetrahydropyrrolyl, -CH2 -tetrahydrofuranyl, -CH2 -cyclohexenyl, -CH2-cyclohexenyl, -CH2 -cyclopentenyl, -CH2 -cyclohexenyl, -CH2-cyclohexenyl, -CH2 -cyclohexenyl, -CH2-cyclohexenyl, -CH2 -cyclohexenyl, -CH2-cyclohexenyl, -CH2 -cyclohexenyl, -CH2 -cyclohexenyl, -CH2-tetrahydropyrrolyl, 2 -phenyl, -CH2 -pyrrolyl, -CH2-triazolyl, -CH2 -tetrazolyl, -CH2 -pyridinyl, -CH2 -pyrazinyl, -CH2 -triazinyl, methoxy, ethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethoxy , acetyl, acetylamino and sulfonamido.

在一些实施方案中，RL2各自独立地选自氘、-F、-Cl、-Br、-OH、-CN、-CHO、-COOH、-NH2、-CH2OH、-CH2CH2OH、-CH3、-CH2CH3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-OCH3、-OCH2CH3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-COCH3、-CH2-环丙基、环丙基、-CONH2、-COOCH3、-OCOCH3、-CONHCH3、-CON(CH3)2、-SOCH3、-SO2CH3、-SO2NH2、-SO2NHCH3和-SO2N(CH3)2。In some embodiments, each RL2 is independently selected from deuterium, -F, -Cl , -Br , -OH , -CN , -CHO, -COOH, -NH2 , -CH2OH , -CH2CH2OH , -CH3 , -CH2CH3 , -CH2F, -CHF2 , -CF3 , -CH2CH2F, -CH2CHF2 , -CH2CF3 , -OCH3 , -OCH2CH3, -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2, -OCH2CF3 , -COCH3 , -CH2 - cyclopropyl , cyclopropyl , -CONH2 , -COOCH3 , -OCOCH3, -CONHCH3 , -CON(CH 3 ) 2 , -SOCH 3 , -SO 2 CH 3 , -SO 2 NH 2 , -SO 2 NHCH 3 and -SO 2 N(CH 3 ) 2 .

在一些实施方案中，RL2各自独立地选自氘、-F、-Cl、-Br、-OH、-CN、-COOH、-NH2、-CH2OH、-CH2CH2OH、-CH3、-CH2CH3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-OCH3、-OCH2CH3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-COCH3、-CH2-环丙基、环丙基和-CONH2。In some embodiments, each RL2 is independently selected from deuterium, -F, -Cl , -Br , -OH , -CN , -COOH , -NH2, -CH2OH , -CH2CH2OH, -CH3 , -CH2CH3 , -CH2F , -CHF2 , -CF3, -CH2CH2F, -CH2CHF2 , -CH2CF3 , -OCH3 , -OCH2CH3 , -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2 , -OCH2CF3 , -COCH3 , -CH2 - cyclopropyl, cyclopropyl , and -CONH2 .

在一些实施方案中，RL2各自独立地选自氟、氯、溴、甲基、羟基和羟甲基。In some embodiments, R L2 are each independently selected from fluoro, chloro, bromo, methyl, hydroxy, and hydroxymethyl.

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-C(O)-、-C(O)NH-、-O-、-S-、-NH-、C1-10亚烷基、C1-10亚烷氧基、C3-12环烷基环、4至12元杂环烷基环、5至6元杂芳基环和苯环；所述的C3-12环烷基环、4至12元杂环烷基环、5至6元杂芳基环、苯环为未取代或被1、2、3或4个RL2取代，所述的RL2选自氟、甲基、羟基和羟甲基。In some embodiments, the La is each independently selected from the following structures or isomers thereof: -C(O)-, -C(O)NH-, -O-, -S-, -NH-, C1-10 alkylene, C1-10 alkyleneoxy, C3-12 cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring; the C3-12 cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring are unsubstituted or substituted with 1, 2, 3 or 4 RL2 , and the RL2 is selected from fluorine, methyl, hydroxyl and hydroxymethyl.

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-(CH2)m2-、-O(CH2)m2-、-(CH2)m2O-、环丙烷环、环丁烷环、双环戊烷环、环戊烷环、环己烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、羟基取代的哌啶环、羟基取代的哌嗪环、羟甲基取代的哌啶环、羟甲基取代的哌嗪环、2-氮杂螺[3.3]庚烷环、6-氮杂螺[3.4]辛烷环、7-氮杂螺[3.5]壬烷环、2,6-二氮杂螺[3.3]庚烷环、2,6-二氮杂螺[3.4]辛烷环、2,7-二氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环、螺[3.3]庚烷环、螺[3.4]辛烷环、螺[3.5]壬烷环、苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、三嗪环、噻吩环、呋喃环、吡咯环、噻唑环、噁唑环、吡唑环、咪唑环、三唑环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷；其中，m2每次出现，各自独立地为1、2、3、4、5、6、7、8、9或10。In some embodiments, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH 2 ) m2 -, -O(CH 2 ) m2 -, -(CH 2 ) m2 O-, cyclopropane ring, cyclobutane ring, bicyclopentane ring, cyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, 2-azaspiro[3.3]heptane ring, 6-azaspiro[3.4]octane ring, 7-azaspiro[3.5]nonane ring, 2,6-diazaspiro[3.3]heptane ring, 2,6-diazaspiro[3.4]octane ring, 2,7-diazaspiro[3.5]nonane ring, 2-azaspiro[3.5]nonane ring, spiro[3.3]heptane ring, spiro[3.4]octane ring, spiro[3.5]nonane ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, triazine ring, thiophene ring, furan ring, pyrrole ring, thiazole ring, oxazole ring, pyrazole ring, imidazole ring, triazole ring, (2S,6R)-2,6-dimethylpiperazine, 3-azabicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane and 3,9-diazaspiro[5.5]undecane; wherein, each occurrence of m2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-(CH2)m2-、-O(CH2)m2-、-(CH2)m2O-、环丙烷环、环丁烷环、环戊烷环、双环戊烷环、环己烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、羟基取代的哌啶环、羟基取代的哌嗪环、羟甲基取代的哌啶环、羟甲基取代的哌嗪环、2-氮杂螺[3.3]庚烷环、7-氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环、苯环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷；其中，m2每次出现，各自独立地为1、2、3、4、5、6、7、8、9或10。In some embodiments, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH 2 ) m2 -, -O(CH 2 ) m2 -, -(CH 2 ) m2 O-, cyclopropane ring, cyclobutane ring, cyclopentane ring, bicyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, 2-azaspiro[3.3]heptane ring, 7-azaspiro[3.5]nonane ring, 2-azaspiro[3.5]nonane ring, benzene ring, (2S,6R)-2,6-dimethylpiperazine, 3-nitrogen heterobicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane and 3,9-diazaspiro[5.5]undecane; wherein m2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 at each occurrence.

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)7-、-(CH2)8-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、羟基取代的哌啶环、羟基取代的哌嗪环、羟甲基取代的哌啶环、羟甲基取代的哌嗪环、环丁烷环、环戊烷环、环己烷环、苯环、双环戊烷环、2-氮杂螺[3.3]庚烷环、2-氮杂螺[3.4]辛烷环、2-氮杂螺[3.5]壬烷环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷。In some embodiments, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH2-, -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4- , - ( CH2 ) 5- , - ( CH2 ) 7- , -( CH2 ) 8- , -OCH2- , -OCH2CH2-, -CH2O- , -CH2CH2 O-, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, benzene ring, bicyclopentane ring, 2-azaspiro[3.3]heptane ring, 2-azaspiro[3.4]octane ring, 2-azaspiro[3.5]nonane ring, (2S,6 R)-2,6-dimethylpiperazine, 3-azabicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane, and 3,9-diazaspiro[5.5]undecane.

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)7-、-(CH2)8-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、 In some embodiments, the La is each independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-,

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)7-、-(CH2)8-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、 In some embodiments, the La is each independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-,

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-CONH-、-CO-、-NH-、-CH2-、 In some embodiments, the La is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -NH-, -CH 2 -,

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-CONH-、-CO-、-CH2-、-NH-、 In some embodiments, the La is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -CH 2 -, -NH-,

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-CONH-、-CH2-、-NH-、-CO-、 In some embodiments, the La is independently selected from the following structures or isomers thereof: -CONH-, -CH2- , -NH-, -CO-,

在一些实施方案中，所述的La各自独立地选自以下结构或其异构体：-CH2-、-NH-、-CONH-、-CO-、 In some embodiments, the La is independently selected from the following structures or isomers thereof: -CH2- , -NH-, -CONH-, -CO-,

在一些实施方案中，所述的L选自以下结构或其异构体：-(CH2)m3-、-C(O)-(CH2)m3-、-C(O)NH-(CH2)m3-、-C(O)NH-(CH2)m3-O-、-Cy0-NH-(CH2)m3-、-C(O)NH-Cy0-、-C(O)-Cy0-、-(CH2)m3-C(O)-Cy0-、-(CH2)m3-Cy0-、-(CH2)m3-C(O)NH-(CH2)m3O-Cy0-O(CH2)m3-、-Cy0-Cy0-、-Cy0-CH2-Cy0-、-C(O)-Cy0-CH2-Cy0-、-C(O)NH-Cy0-CH2-Cy0-、-Cy0-C(O)-Cy0-、-C(O)-Cy0-C(O)-Cy0-、-C(O)NH-Cy0-C(O)-Cy0-、-Cy0-O-Cy0-、-Cy0-C(O)NH-Cy0-、-NH(CH2)m3-、-(CH2)m3O(CH2)m3-、-Cy0-C(O)-(CH2)m3-、-NH-Cy0-(CH2)m3-Cy0-和-(CH2)m3-Cy0-O-Cy0-O(CH2)m3-；其中，m3每次出现，独立地为0,1,2,3,4,5,6,7,8,9或10；Cy0每次出现，独立地选自C3-12环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至12元杂环烷基环(优选为的3至10元杂环烷基环，更优选为3至8元杂环烷基环，进一步优选为3至6元杂环烷基环)、5至6元杂芳基环和苯环；所述C3-12环烷基环、3至12元杂环烷基环、5至6元杂芳基环、苯环为未取代或被1、2、3或4个RL2取代，RL2每次出现，各自独立地选自氘、卤素、羟基、氰基、氨基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、羟基取代的C1-3烷基、氰基取代的C1-3烷基、氨基取代的C1-3烷基、C1-3烷氧基C1-3烷基、C3-6环烷基、C3-6环烷基C1-3烷基、-COC1-3烷基、-COOC1-3烷基、-OCOC1-3烷基、-CONH2、-CONHC1-3烷基和-CON(C1-3烷基)2。In some embodiments, L is selected from the following structures or isomers thereof: -( CH2 ) m3- , -C(O)-( CH2 ) m3- , -C(O)NH-( CH2 ) m3- , -C(O)NH-( CH2 ) m3 -O-, -Cy0 -NH-( CH2 ) m3- , -C(O)NH- Cy0- , -C(O)-Cy0-, -(CH2) m3 -C(O)-Cy0-, -( CH2 ) m3 - C (O)-Cy0-, -( CH2 ) m3 - Cy0- , -( CH2 ) m3 -C(O)NH-( CH2 ) m3 O-Cy0-O( CH2 ) m3- , -Cy0 - Cy0-, -Cy0 - CH2- Cy0- , -C(O) -Cy0 - CH2 - Cy0. -, -C(O)NH-Cy 0 -CH 2 -Cy 0 -, -Cy 0 -C(O)-Cy 0 -, -C(O)-Cy 0 -C(O)-Cy 0 -, -C(O)NH-Cy 0 -C(O)-Cy 0 -, -Cy 0 -O-Cy 0 -, -Cy 0 -C(O)NH-Cy 0 -, -NH(CH 2 ) m3 -, -(CH 2 ) m3 O(CH 2 ) m3 -, -Cy 0 -C(O)-(CH 2 ) m3 -, -NH-Cy 0 -(CH 2 ) m3 -Cy 0 -and -(CH 2 ) m3 -Cy 0 -O-Cy 0 -O(CH 2 ) m3 -; wherein m3 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it appears; Cy 0 is independently selected from a C 3-12 cycloalkyl ring (preferably a C 3-10 cycloalkyl ring, more preferably a C 3-8 cycloalkyl ring, and further preferably a C 3-6 cycloalkyl ring), a 3- to 12-membered heterocycloalkyl ring (preferably a 3- to 10-membered heterocycloalkyl ring, more preferably a 3- to 8-membered heterocycloalkyl ring, and further preferably a 3- to 6-membered heterocycloalkyl ring), a 5- to 6-membered heteroaryl ring and a benzene ring; the C 3-12 cycloalkyl ring, the 3- to 12-membered heterocycloalkyl ring, the 5- to 6-membered heteroaryl ring, and the benzene ring are unsubstituted or substituted with 1, 2, 3 or 4 RL2 , and RL2 is independently selected from deuterium, halogen, hydroxyl, cyano, amino, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, halogenated C C 1-3 alkyl, -C 1-3 alkyl, -C 1-3 alkyl, -C 3-6 cycloalkyl, -C 3-6 cycloalkylC 1-3 alkyl, -COC 1-3 alkyl, -COOC 1-3 alkyl , -OCOC 1-3 alkyl, -CONH 2 , -CONHC 1-3 alkyl and -CON(C 1-3 alkyl ) 2 .

在一些实施方案中，所述Cy0各自独立地自环丙烷环、环丁烷环、环戊烷环、双环戊烷环、环己烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、羟基取代的哌啶环、羟甲基取代的哌啶环、哌嗪环、2-氮杂螺[3.3]庚烷环、6-氮杂螺[3.4]辛烷环、7-氮杂螺[3.5]壬烷环、2,6-二氮杂螺[3.3]庚烷环、2,6-二氮杂螺[3.4]辛烷环、2,7-二氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环、螺[3.3]庚烷环、螺环[3.4]辛烷环、螺[3.5]壬烷环、苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、三嗪环、噻吩环、呋喃环、吡咯环、噻唑环、噁唑环、吡唑环、咪唑环、三唑环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷、1,1,3,3-四甲基环丁烷、3-氟哌啶、(S)-3-氟哌啶、(R)-3-氟哌啶、3,3-二氟哌啶。In some embodiments, the Cy O is each independently selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a bicyclopentane ring, a cyclohexane ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a hydroxy-substituted piperidine ring, a hydroxymethyl-substituted piperidine ring, a piperazine ring, a 2-azaspiro[3.3]heptane ring, a 6-azaspiro[3.4]octane ring, a 7-azaspiro[3.5]nonane ring, a 2,6-diazaspiro[3.3]heptane ring, a 2,6-diazaspiro[3.4]octane ring, a 2,7-diazaspiro[3.5]nonane ring, a 2-azaspiro[3.5]nonane ring, a spiro[3.3]heptane ring, a spiro[3.4]octane ring, a spiro[3.5]nonane ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridinium ... azine ring, a triazine ring, a thiophene ring, a furan ring, a pyrrole ring, a thiazole ring, an oxazole ring, a pyrazole ring, an imidazole ring, a triazole ring, (2S,6R)-2,6-dimethylpiperazine, 3-azabicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane and 3,9-diazaspiro[5.5]undecane, 1,1,3,3-tetramethylcyclobutane, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,3-difluoropiperidine.

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、哌嗪环、3,3,5,5-四甲基哌啶、环己烷环、环丁烷环、1,1,3,3-四甲基环丁烷、氮杂环丁烷环、3,3-二氟哌啶、3-氟哌啶、(S)-3-氟哌啶、(R)-3-氟哌啶、3,5-二甲基哌啶、2,6-二甲基哌嗪、3,9-二氮杂螺[5.5]十一烷、2-氮杂螺[3.5]壬烷、2-氮杂螺[3.3]庚烷、7-氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、3-氮杂双环[3.2.1]辛烷。In some embodiments, the Cy O is each independently selected from the following structures or isomers thereof: piperidine ring, piperazine ring, 3,3,5,5-tetramethylpiperidine, cyclohexane ring, cyclobutane ring, 1,1,3,3-tetramethylcyclobutane, azetidine ring, 3,3-difluoropiperidine, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,5-dimethylpiperidine, 2,6-dimethylpiperazine, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 3-azabicyclo[3.2.1]octane.

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、哌嗪环、3,3,5,5-四甲基哌啶、3,3-二氟哌啶、3-氟哌啶、(S)-3-氟哌啶、(R)-3-氟哌啶、3,3-二甲基哌啶、2,6-二甲基哌嗪、氮杂环丁烷环、1,1,3,3-四甲基环丁烷、环己烷环、3,9-二氮杂螺[5.5]十一烷、2-氮杂螺[3.5]壬烷、2-氮杂螺[3.3]庚烷、7-氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,7-二氮杂螺[3.5]壬烷、3-氮杂双环[3.2.1]辛烷。In some embodiments, the Cy O is each independently selected from the following structures or isomers thereof: piperidine ring, piperazine ring, 3,3,5,5-tetramethylpiperidine, 3,3-difluoropiperidine, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,3-dimethylpiperidine, 2,6-dimethylpiperazine, azetidine ring, 1,1,3,3-tetramethylcyclobutane, cyclohexane ring, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.2.1]octane.

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、3,3-二氟哌啶、3,9-二氮杂螺[5.5]十一烷、7-氮杂螺[3.5]壬烷、3-氮杂双环[3.2.1]辛烷。In some embodiments, the Cy O is independently selected from the following structures or isomers thereof: piperidine ring, 3,3-difluoropiperidine, 3,9-diazaspiro[5.5]undecane, 7-azaspiro[3.5]nonane, 3-azabicyclo[3.2.1]octane.

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、3,3-二氟哌啶、3,9-二氮杂螺[5.5]十一烷、7-氮杂螺[3.5]壬烷。In some embodiments, the Cy 0 is each independently selected from the following structures or isomers thereof: piperidine ring, 3,3-difluoropiperidine, 3,9-diazaspiro[5.5]undecane, 7-azaspiro[3.5]nonane.

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体： In some embodiments, the Cy O is each independently selected from the following structures or isomers thereof:

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体： In some embodiments, the Cy O is each independently selected from the following structures or isomers thereof:

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体： In some embodiments, the Cy O is each independently selected from the following structures or isomers thereof:

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体： In some embodiments, the Cy O is each independently selected from the following structures or isomers thereof:

在一些实施方案中，所述Cy0各自独立地选自以下结构或其异构体： In some embodiments, the Cy O is each independently selected from the following structures or isomers thereof:

在一些实施方案中，所述L选自以下结构或其异构体：
其中，X00为L与ULM或POI的连接位点。In some embodiments, L is selected from the following structures or isomers thereof:
Wherein, X 00 is the connection site between L and ULM or POI.

在一些实施方案中，所述的L选自以下结构或其异构体：
其中，X00为L与ULM或POI的连接位点。In some embodiments, L is selected from the following structures or isomers thereof:
Wherein, X 00 is the connection site between L and ULM or POI.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点。In some embodiments, L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点。In some embodiments, L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点。In some embodiments, L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点。In some embodiments, L is selected from the following structures or isomers thereof: Wherein, X 00 is the connection site between L and ULM or POI.

在一些实施方案中，所述L选自以下结构或其异构体：
其中，X10为L与POI的连接位点，X20为L与ULM连接的位点。In some embodiments, L is selected from the following structures or isomers thereof:
Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点。In some embodiments, L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点。In some embodiments, L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点。In some embodiments, L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.

在一些实施方案中，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点。In some embodiments, L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM.

在一些实施方案中，ULM为式(U-1)所示化合物或其异构体：
In some embodiments, ULM is a compound represented by formula (U-1) or an isomer thereof:

其中，in,

表示(双键)或(单键)； express (double bond) or (single bond);

U0为键、-N(RU0)-、-CON(RU0)-、-CH2-或-(CH2)2-； U0 is a bond, -N(R U0 )-, -CON(R U0 )-, -CH 2 - or -(CH 2 ) 2 -;

RU0每次出现，各自独立地为氢或C1-3烷基；Each occurrence of R U0 is independently hydrogen or C 1-3 alkyl;

B环不存在、或选自5至15元杂芳基环(优选为6至12元杂芳基环，更优选为6至10元杂芳基环)、3至15元杂环烷基环(优选为5至12元杂环烷基环，更优选为5至10元杂环烷基环)、C3-15环烷基环和C6-10芳环(优选为苯环)；Ring B is absent or is selected from a 5- to 15-membered heteroaryl ring (preferably a 6- to 12-membered heteroaryl ring, more preferably a 6- to 10-membered heteroaryl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 5- to 12-membered heterocycloalkyl ring, more preferably a 5- to 10-membered heterocycloalkyl ring), a C 3-15 cycloalkyl ring, and a C 6-10 aromatic ring (preferably a benzene ring);

S1、S3、S5各自独立地选自键、-O-、-NH-、-N-、-CH2-、-CH-、-C(O)-、-C(O)O-、-C(O)S-、-CH2C(O)-、-CH2C(S)-、-C(S)-、-CONH-、-CH＝N-、-N＝N-、-CH＝CH-、-SO-和-SO2-；S 1 , S 3 , and S 5 are each independently selected from a bond, -O-, -NH-, -N-, -CH 2 -, -CH-, -C(O)-, -C(O)O-, -C(O)S-, -CH 2 C(O)-, -CH 2 C(S)-, -C(S)-, -CONH-, -CH=N-, -N=N-, -CH=CH-, -SO-, and -SO 2 -;

S2、S4各自独立地选自-N-、-NH-、-CH-和-CH2-；S 2 and S 4 are each independently selected from -N-, -NH-, -CH- and -CH 2 -;

S6选自C、-CH-和N；S 6 is selected from C, -CH- and N;

(RB1)b1表示B环上的氢被b1个RB1取代，b1为0、1、2或3，每个RB1相同或不同，各自独立地选自X2、氘、卤素(优选为氟、氯或溴)、氰基、羧基、羟基、硝基、-NRa1Rb1、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、-SC1-8烷基(优选为-SC1-6烷基，更优选为-SC1-3烷基)、-SOC1-8烷基(优选为-SOC1-6烷基，更优选为-SOC1-3烷基)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、氨基取代的C1-8烷基(优选为氨基取代的C1-6烷基，更优选为氨基取代的C1-3烷基)、氰基取代的C1-8烷基(优选为氰基取代的C1-6烷基，更优选为氰基取代的C1-3烷基)、羟基取代的C1-8烷基(优选为羟基取代的C1-6烷基，更优选为羟基取代的C1-3烷基)、羧基取代的C1-8烷基(优选为羧基取代的C1-6烷基，更优选为羧基取代的C1-3烷基)、-COC1-8烷基(优选为-COC1-6烷基，更优选为-COC1-3烷基)、-COOC1-8烷基-CONRa2Rb2(优选为-COOC1-6烷基-CONRa2Rb2，更优选为-COOC1-3烷基-CONRa2Rb2)、-SO2NRa2Rb2、C3-15环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环、进一步优选为4至6元杂环烷基环)、5至10元杂芳基环(优选为5至6元杂芳基环)和C6-10芳环(优选为苯环或萘环)；或相邻的两个RB1与其相连的碳原子形成C3-15环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环、进一步优选为4至6元杂环烷基环)、5至6元杂芳基环或苯环；所述的C3-15环烷基环、3至15元杂环烷基环、5至6元杂芳基环或苯环为未取代或被1、2、3或4个选自下组的取代基取代：X2、氘、卤素(优选为氟、氯或溴)、氰基、羧基、羟基、硝基、-NRa1Rb1、C1-6烷基、C1-6烷氧基、-SC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONRa2Rb2和-SO2NRa2Rb2；(R B1 ) b1 represents that the hydrogen on the B ring is replaced by b1 R B1s , b1 is 0, 1, 2 or 3, each R B1 is the same or different and is independently selected from X 2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, -NR a1 R b1 , C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-8 alkyl), C 1-8 alkyl-CONR a2 R b2 (preferably -COC 1-6 alkyl , more preferably -COC 1-3 alkyl) ; C 1-8 alkyl - CONR a2 R b2 ( preferably -COC 1-6 alkyl , more preferably -COC 1-3 alkyl ) ; R 1-6 alkyl-CONR a2 R b2 , more preferably -COOC 1-3 alkyl-CONR a2 R b2 ), -SO 2 NR a2 R b2 , a C 3-15 cycloalkyl ring (preferably a C 3-10 cycloalkyl ring, more preferably a C 3-8 cycloalkyl ring, and further preferably a C 3-6 cycloalkyl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 4- to 12-membered heterocycloalkyl ring, more preferably a 4- to 10-membered heterocycloalkyl ring, further preferably a 4- to 8-membered heterocycloalkyl ring, and further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 10-membered heteroaryl ring (preferably a 5- to 6-membered heteroaryl ring) and a C 6-10 aromatic ring (preferably a benzene ring or a naphthalene ring); or two adjacent R B1s and the carbon atom to which they are attached form a C 3-15 cycloalkyl ring (preferably a C 3-10 cycloalkyl ring, more preferably a C 3-8 cycloalkyl ring, and further preferably a C wherein the C 3-15 cycloalkyl ring, the 3-15 membered heterocycloalkyl ring, the 5-6 membered heteroaryl ring or the benzene ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of X 2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, -NR a1 R b1 , C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -SOC 1-6 alkyl , -SO 2 C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONR a2 R b2 and -SO 2 NR a2 R b2 ;

(RB2)b2表示C环上的氢被b2个RB2取代，b2为0、1、2、3或4，每个RB2相同或不同，各自独立地选自X2、氘、卤素(优选为氟、氯或溴)、氰基、羧基、羟基、-NRa1Rb1、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-OCOC1-6烷基、-CONRa2Rb2、-OC(O)C1-6烷基取代的C1-6烷基和-COOC1-6烷基取代的C1-6烷基；( RB2 ) b2 represents that the hydrogen on the C ring is replaced by b2 RB2 , b2 is 0, 1, 2, 3 or 4, each RB2 is the same or different and is independently selected from X2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, -NRa1Rb1 , C1-6 alkyl , C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl , -CONRa2Rb2, C1-6 alkyl substituted with -OC (O) C1-6 alkyl and C1-6 alkyl substituted with -COOC1-6 alkyl;

Ra1、Rb1、Ra2、Rb2各自独立地选自氢、C1-6烷基、卤代C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、羧基取代的C1-6烷基、氨基取代的C1-6烷基、-COC1-6烷基和-COOC1-6烷基； Ra1 , Rb1 , Ra2 , and Rb2 are each independently selected from hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, cyano-substituted C1-6 alkyl, carboxyl-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, -COC1-6 alkyl, and -COOC1-6 alkyl;

其中，X2为ULM与L或POI的连接位点，且RB1和RB2中至少一个为X2。Wherein, X2 is the connection site between ULM and L or POI, and at least one of RB1 and RB2 is X2 .

在一些实施方案中，RB1和RB2不同时为X2。In some embodiments, RB1 and RB2 are not both X2 .

在一些实施方案中，B环不存在。In some embodiments, the B ring is absent.

在一些实施方案中，B环中所述的5至15元杂芳基环选自吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、三唑环、四唑环、噁唑环、噻唑环、恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环、苯并吡咯环、苯并呋喃环、苯并噻吩环、苯并吡唑环、苯并咪唑环、苯并噻唑环、苯并噁唑环、吡啶并吡咯环、吡啶并呋喃环、吡啶并噻吩环、吡啶并吡唑环、吡啶并咪唑环、吡啶并噻唑环、吡啶并噁唑环、嘧啶并吡咯环、哒嗪并吡咯环、吡嗪并吡咯环、嘧啶并吡唑环、哒嗪并吡唑环、吡嗪并吡唑环、嘧啶并咪唑环、哒嗪并咪唑环、吡嗪并咪唑环、喹啉环、异喹啉环和9H-吡啶并[2,3-b]吲哚环。In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a benzopyrrole ring, a benzofuran ring, a benzothiophene ring, a benzopyrazole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a pyridine ring, a The rings include a pyrrole ring, a pyridofuran ring, a pyridothiophene ring, a pyridopyrazole ring, a pyridoimidazole ring, a pyridothiazole ring, a pyridooxazole ring, a pyrimidopyrrole ring, a pyridazinepyrrole ring, a pyrazinepyrrole ring, a pyrimidopyrazole ring, a pyridazinepyrazole ring, a pyrazinepyrazole ring, a pyrimidoimidazole ring, a pyridazineimidazole ring, a quinoline ring, an isoquinoline ring and a 9H-pyrido[2,3-b]indole ring.

在一些实施方案中，B环中所述的5至15元杂芳基环选自吡啶环和苯并吡唑环。In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from a pyridine ring and a benzopyrazole ring.

在一些实施方案中，B环中所述的5至15元杂芳基环选自： 其中表示与U0的共价连接。In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的5至15元杂芳基环选自：其中表示与U0的共价连接。In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的C6-10芳环选自苯环和萘环。In some embodiments, the C 6-10 aromatic ring in Ring B is selected from a benzene ring and a naphthalene ring.

在一些实施方案中，B环中所述的C6-10芳环为苯环。In some embodiments, the C 6-10 aromatic ring in Ring B is a benzene ring.

在一些实施方案中，B环中所述的3至15元杂环烷基环选自：其中表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from: in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的3至15元杂环烷基环为其中，Q1、Q2、Q3、Q4各自独立地选自-CH-、N和N-O；S7、S8各自独立地选自键、-O-、-NH-、-CH2-、-C(O)-、-C(O)O-、-C(O)S-、-CH2C(O)-、-CH2C(S)-、-C(S)-、-CONH-、-CH＝N-、-N＝N-、-CH＝CH-、-SO-和-SO2-；表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from —CH—, N, and NO; S 7 and S 8 are each independently selected from a bond, —O—, —NH—, —CH 2 —, —C(O)—, —C(O)O—, —C(O)S—, —CH 2 C(O)—, —CH 2 C(S)—, —C(S)—, —CONH—, —CH═N—, —N═N—, —CH═CH—, —SO—, and —SO 2 —; Indicates covalent attachment to U 0 .

在一些实施方案中，Q1、Q2、Q3、Q4各自独立地为-CH-。In some embodiments, Q 1 , Q 2 , Q 3 , and Q 4 are each independently -CH-.

在一些实施方案中，S8选自-CH＝N-、-N＝N-、-CH2C(O)-、-C(O)O-、-CONH-和-CH＝CH-。In some embodiments, S8 is selected from -CH=N-, -N=N-, -CH2C (O)-, -C(O)O-, -CONH-, and -CH=CH-.

在一些实施方案中，S7、S8各自独立地选自-CH2-和-C(O)-。In some embodiments, S 7 and S 8 are each independently selected from -CH 2 - and -C(O)-.

在一些实施方案中，S7为-CH2-，S8为-C(O)-。In some embodiments, S7 is -CH2- and S8 is -C(O)-.

在一些实施方案中，S7为-C(O)-，S8为-C(O)-。In some embodiments, S7 is -C(O)- and S8 is -C(O)-.

在一些实施方案中，S7为-CH2-，S8为-C(S)-。In some embodiments, S7 is -CH2- and S8 is -C(S)-.

在一些实施方案中，S7为-C(O)-，S8为-C(S)-。In some embodiments, S7 is -C(O)- and S8 is -C(S)-.

在一些实施方案中，S7为键，S8为-CONH-。In some embodiments, S7 is a bond and S8 is -CONH-.

在一些实施方案中，结构选自下组所示结构或其异构体： 其中表示与U0的共价连接。In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的3至15元杂环烷基环为其中，环B1、环B2各自独立地选自C4-8环烷基环、4至8元杂环烷基环、5至6元杂芳基环和苯环；S9、S10各自独立地选自键、-CH2-和-C(O)-；表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B1 and Ring B2 are each independently selected from a C 4-8 cycloalkyl ring, a 4- to 8-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring and a benzene ring; S 9 and S 10 are each independently selected from a bond, -CH 2 - and -C(O)-; Indicates covalent attachment to U 0 .

在一些实施方案中，结构选自其中表示与U0的共价连接。In some embodiments, the structure Selected from in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的3至15元杂环烷基环选自 其中环B3、环B4、环B5各自独立地选自C5-7环烷基环和5至7元杂环烷基环，Q1、Q2、Q3、Q4、S7、S8如说明书中所述，表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from wherein Ring B3, Ring B4 and Ring B5 are each independently selected from a C 5-7 cycloalkyl ring and a 5- to 7-membered heterocycloalkyl ring, Q 1 , Q 2 , Q 3 , Q 4 , S 7 and S 8 are as described in the specification, Indicates covalent attachment to U 0 .

在一些实施方案中，环B3、环B4、环B5各自独立地选自部分不饱和的C5-7环烷基环和部分不饱和的5至7元杂环烷基环。In some embodiments, Ring B3, Ring B4, and Ring B5 are each independently selected from a partially unsaturated C 5-7 cycloalkyl ring and a partially unsaturated 5- to 7-membered heterocycloalkyl ring.

在一些实施方案中，环B3、环B4、环B5各自独立地选自2,5-二氢-1H-吡咯、2,3-二氢-1H-吡咯、1,2,3,6-四氢吡啶、1,2,3,4-四氢吡啶、3,4-二氢-2H-1,4-恶嗪、1,3-二氧杂环戊烯、2,3,6,7-四氢-1H-氮平、2,3,4,7-四氢-1H-氮平和2,3,4,5-四氢-1H-氮平。In some embodiments, Ring B3, Ring B4, Ring B5 are each independently selected from 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-1,4-oxazine, 1,3-dioxole, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine and 2,3,4,5-tetrahydro-1H-azepine.

在一些实施方案中，B环中所述的3至15元杂环烷基环选自 其中表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的3至15元杂环烷基环为其中表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is in Indicates covalent attachment to U 0 .

在一些实施方案中，环B3为5至7元含氮杂环烷基环。In some embodiments, Ring B3 is a 5- to 7-membered nitrogen-containing heterocycloalkyl ring.

在一些实施方案中，环B3为部分不饱和的5至7元含氮杂环烷基环。In some embodiments, Ring B3 is a partially unsaturated 5- to 7-membered nitrogen-containing heterocycloalkyl ring.

在一些实施方案中，环B3选自2,5-二氢-1H-吡咯、2,3-二氢-1H-吡咯、1,2,3,6-四氢吡啶、1,2,3,4-四氢吡啶、2,3,6,7-四氢-1H-氮平、2,3,4,7-四氢-1H-氮平和2,3,4,5-四氢-1H-氮平。In some embodiments, Ring B3 is selected from 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine, and 2,3,4,5-tetrahydro-1H-azepine.

在一些实施方案中，结构选自 其中表示与U0的共价连接。In some embodiments, the structure Selected from in Indicates covalent attachment to U 0 .

在一些实施方案中，结构选自其中表示与U0的共价连接。In some embodiments, the structure Selected from in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的3至15元杂环烷基环为其中环B7为5至10元杂环烷基环，Q5、Q6、Q7、Q8、Q9各自独立地选自C、-CH-和N，表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B7 is a 5- to 10-membered heterocycloalkyl ring, Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently selected from C, -CH-, and N, Indicates covalent attachment to U 0 .

在一些实施方案中，环B7为1，3-二氧杂环戊烯。In some embodiments, Ring B7 is 1,3-dioxole.

在一些实施方案中，结构选自其中表示与U0的共价连接。In some embodiments, the structure Selected from in Indicates covalent attachment to U 0 .

在一些实施方案中，B环中所述的3至15元杂环烷基环为其中环B6选自5至6元杂芳基环和苯环；Q11、Q12、Q13各自独立地选自-C-、-N-、-S-、-O-、-NH-；S7、S8如说明书中所述，表示与U0的共价连接。In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B6 is selected from a 5- to 6-membered heteroaryl ring and a benzene ring; Q 11 , Q 12 , Q 13 are each independently selected from -C-, -N-, -S-, -O-, -NH-; S 7 and S 8 are as described in the specification, Indicates covalent attachment to U 0 .

在一些实施方案中，环B6为苯环。In some embodiments, Ring B6 is a benzene ring.

在一些实施方案中，Q11选自-S-、-O-、-NH-，Q12、Q13各自独立地选自-C-。In some embodiments, Q 11 is selected from -S-, -O-, and -NH-, and Q 12 and Q 13 are each independently selected from -C-.

在一些实施方案中，结构选自：其中表示与U0的共价连接。In some embodiments, the structure Selected from: in Indicates covalent attachment to U 0 .

在一些实施方案中，B环选自： 其中表示与U0的共价连接。In some embodiments, Ring B is selected from: in Indicates covalent attachment to U 0 .

在一些实施方案中，B环选自以下结构或其异构体： 其中表示与U0的共价连接。In some embodiments, Ring B is selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 .

在一些实施方案中，B环选自以下结构或其异构体：其中表示与U0的共价连接。In some embodiments, Ring B is selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 .

在一些实施方案中，RB1各自独立地为X2、氘、氟、氯、溴、氰基、羧基、羟基、硝基、-NH2、-N(CH3)2、-NHCH3、-NHCOCH3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、三氟甲基、二氟甲基、一氟甲基、三氟甲氧基、二氟甲氧基、一氟甲氧基、-SCH3、-SOCH3、-SO2CH3、-CH2NH2、-(CH2)2NH2、-(CH2)3NH2、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH2COOH、-(CH2)2COOH、-(CH2)3COOH、-COCH3、-COCH2CH3、-COOCH3、-COOCH2CH3、-CONH2或-SO2NH2；或相邻的两个RB1与其相连的碳原子形成环丁烷基环、环戊烷基环、环己烷基环、环庚烷基环、环戊烯环、环己烯环、环庚烯环、四氢吡咯环、四氢呋喃环、四氢噻吩环、哌啶环、吡嗪环、1,2,3,4-四氢吡啶环、1,2,3,4-四氢吡喃环、3,4-二氢-2H-1,4-恶嗪环、2,3,4,5-四氢-1H-氮平环、吡咯环、吡唑环、噁唑环、噻唑环、吡喃环、吡啶环、哒嗪环、嘧啶环或苯环；所述的环丁烷基环、环戊烷基环、环己烷基环、环庚烷基环、环戊烯环、环己烯环、环庚烯环、四氢吡咯环、四氢呋喃环、四氢噻吩环、哌啶环、吡嗪环、1,2,3,4-四氢吡啶环、1,2,3,4-四氢吡喃环、3,4-二氢-2H-1,4-恶嗪环、2,3,4,5-四氢-1H-氮平环、吡咯环、吡唑环、噁唑环、噻唑环、吡喃环、吡啶环、哒嗪环、嘧啶环或苯环为未取代或被1、2、3或4个选自下组的取代基取代：X2、氘、氟、氯、溴、氰基、羧基、羟基、硝基、氨基、甲基、三氟甲基、甲氧基、三氟甲氧基、-SCH3、-SOCH3、-SO2CH3、-COCH3、-COOCH3、-CONH2和-SO2NH2。In some embodiments, each R B1 is independently X 2 , deuterium, fluorine, chlorine, bromine, cyano, carboxyl, hydroxyl, nitro, -NH 2 , -N(CH 3 ) 2 , -NHCH 3 , -NHCOCH 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, -SCH 3 , -SOCH 3 , -SO 2 CH 3 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -CH 2 CN , -(CH 2 ) 2 CN , -(CH 2 ) 3 CN , -CH 2 OH , -(CH 2 ) 2 OH , -(CH 2 ) 3 OH , -CH 2 COOH, -(CH 2 ) 2 COOH, -(CH 2 ) 3 COOH, -COCH 3 , -COCH 2 CH 3 , -COOCH 3 , -COOCH 2 CH 3 , -CONH 2 or -SO 2 NH 2 ; or two adjacent R B1 and the carbon atom to which it is connected form a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a pyrazine ring, a 1,2,3,4-tetrahydropyridine ring, a 1,2,3,4-tetrahydropyran ring, a 3,4-dihydro-2H-1,4-oxazine ring, a 2,3,4,5-tetrahydro-1H-azepine ring, a pyrrole ring, a pyrazole ring, an oxazole ring, a thiazole ring, a pyran ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a benzene ring; the cyclobutane ring , cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, cyclopentene ring, cyclohexene ring, cycloheptene ring, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, pyrazine ring, 1,2,3,4-tetrahydropyridine ring, 1,2,3,4-tetrahydropyran ring, 3,4-dihydro-2H-1,4-oxazine ring, 2,3,4,5-tetrahydro-1H-azepine ring, pyrrole ring, pyrazole ring, oxazole ring, thiazole ring, pyran ring, pyridine ring, pyridazine ring, pyrimidine ring or benzene ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: X 2 , deuterium, fluorine, chlorine, bromine, cyano, carboxyl, hydroxyl, nitro, amino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -SCH 3 , -SOCH 3 , -SO 2 CH 3 , -COCH 3 , -COOCH 3 , -CONH 2 , and -SO 2 NH 2 .

在一些实施方案中，RB1选自氟、氯、羟基、甲基、三氟甲基和甲氧基。In some embodiments, R B1 is selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and methoxy.

在一些实施方案中，b1为1，RB1为氟。In some embodiments, b1 is 1 and R B1 is fluoro.

在一些实施方案中，b1为1，RB1为X2。In some embodiments, b1 is 1 and RB1 is X2 .

在一些实施方案中，选自： 其中X2为ULM与L或POI的连接位点，表示与U0的共价连接。In some embodiments, Selected from: Where X2 is the connection site between ULM and L or POI, Indicates covalent attachment to U 0 .

在一些实施方案中，选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点，表示与U0的共价连接。In some embodiments, Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI, Indicates covalent attachment to U 0 .

在一些实施方案中，选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点，表示与U0的共价连接。In some embodiments, Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI, Indicates covalent attachment to U 0 .

在一些实施方案中，U0为键、-NH-、-CONH-或-CH2-。In some embodiments, U 0 is a bond, -NH-, -CONH-, or -CH 2 -.

在一些实施方案中，U0为键。In some embodiments, U 0 is a bond.

在一些实施方案中，U0为-NH-。In some embodiments, U 0 is -NH-.

在一些实施方案中，U0为-CONH-。In some embodiments, U 0 is -CONH-.

在一些实施方案中，U0为-CH2-。In some embodiments, U 0 is -CH 2 -.

在一些实施方案中，S1、S3为-C(O)-，S2为-NH-，S4、S5为-CH2-。In some embodiments, S 1 and S 3 are -C(O)-, S 2 is -NH-, and S 4 and S 5 are -CH 2 -.

在一些实施方案中，S6为CH。In some embodiments, S6 is CH.

在一些实施方案中，S6为N。In some embodiments, S6 is N.

在一些实施方案中，b2为0。In some embodiments, b2 is 0.

在一些实施方案中，结构选自下组所示结构或其异构体： 其中表示与U0的共价连接。In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 .

在一些实施方案中，结构选自下组所示结构或其异构体： 其中表示与U0的共价连接。In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 .

在一些实施方案中，ULM选自以下结构或其异构体：
其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof:
Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM选自以下结构或其异构体：
其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof:
Wherein X2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof: Wherein X2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM为式(U-2)所示结构或其异构体：
In some embodiments, ULM is a structure represented by formula (U-2) or an isomer thereof:

其中，in,

(RU7)r1表示四氢吡咯环上的氢被r1个RU7取代，r1为0、1、2或3，每个RU7相同或不同，各自独立地选自卤素(优选为氟、氯或溴)、羟基、氨基、C1-3烷氧基、卤代C1-3烷氧基和-OCOC1-3烷基；(R U7 ) r1 represents that the hydrogen on the tetrahydropyrrole ring is replaced by r1 R U7 , r1 is 0, 1, 2 or 3, each R U7 is the same or different, and each is independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, amino, C 1-3 alkoxy, halogenated C 1-3 alkoxy and -OCOC 1-3 alkyl;

RU1为-C(RU3RU4)-U1； RU1 is -C ( RU3RU4 ) -U1 ;

U1选自以下结构或其异构体：X2、-NHCO-X2、-NHCOCH3、5至6元杂芳基环、 所述的5至6元杂芳基环、为未取代或被1、2或3个选自下组的取代基取代：X2、卤素、羟基、氰基、氨基、羧基、C1-6烷基(优选为甲基、乙基、异丙基)、C1-6烷氧基(优选为甲氧基、乙氧基、异丙氧基)、卤代C1-6烷基(优选为三氟甲基)、卤代C1-6烷氧基(优选为三氟甲氧基)、-COC1-6烷基(优选为-COCH3)、-COOC1-6烷基(优选为-COOCH3)、-CONH2、-CONHC1-6烷基(优选为-CONHCH3)、-CON(C1-6烷基)2(优选为-CON(CH3)2)和羟基取代的C1-6烷基(优选为-CH2OH)；U 1 is selected from the following structures or isomers thereof: X 2 , -NHCO-X 2 , -NHCOCH 3 , 5- to 6-membered heteroaryl ring, The 5- to 6-membered heteroaryl ring, is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X 2 , halogen, hydroxy, cyano, amino, carboxyl, C 1-6 alkyl (preferably methyl, ethyl, isopropyl), C 1-6 alkoxy (preferably methoxy, ethoxy, isopropoxy), halogenated C 1-6 alkyl (preferably trifluoromethyl), halogenated C 1-6 alkoxy (preferably trifluoromethoxy), -COC 1-6 alkyl (preferably -COCH 3 ), -COOC 1-6 alkyl (preferably -COOCH 3 ), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHCH 3 ), -CON(C 1-6 alkyl) 2 (preferably -CON(CH 3 ) 2 ) and hydroxy-substituted C 1-6 alkyl (preferably -CH 2 OH);

RUa选自氢、卤素(优选为氟、氯或溴)、氰基、羟基、羧基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-COC1-6烷基、-NHCOC1-6烷基、-N(C1-6烷基)COC1-6烷基、-NHC1-6烷基和-N(C1-6烷基)2；R Ua is selected from hydrogen, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxyl, carboxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 ;

RU3、RU4各自独立地选自氢、氘、卤素、氰基、羧基、羟基、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、卤代C1-6烷基(优选为C1-3烷氧基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)和-SC1-6烷基(优选为-SC1-3烷基)；或RU3、RU4与所连接的碳原子共同形成C3-7环烷基(优选为的C3-6环烷基)和3至7元杂环烷基(优选为4至6元杂环烷基)；所述的C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-SC1-6烷基、C3-7环烷基、3至7元杂环烷基为未取代或被1、2或3个选自下组的取代基取代：X2、卤素(优选为氟、氯或溴)、氰基、羧基和羟基；R U3 and R U4 are each independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably C 1-3 alkoxy), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy) and -SC 1-6 alkyl (preferably -SC 1-3 alkyl); or R U3 and R U4 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl (preferably C 3-6 cycloalkyl) and a 3 to 7 membered heterocycloalkyl (preferably 4 to 6 membered heterocycloalkyl); the C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -SC 1-6 alkyl, C 3-7 -membered cycloalkyl, 3- to 7-membered heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X 2 , halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl and hydroxyl;

RU5、RU6各自独立地选自X2、氢、氘、卤素、氨基、氰基、羧基、羟基、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(卤代C1-3烷氧基)、-SC1-6烷基(优选为-SC1-3烷基)、CONHC1-6烷基取代的C1-6烷基、CON(C1-6烷基)2取代的C1-6烷基、羧基取代的C1-6烷基和COOC1-6烷基取代的C1-6烷基；R U5 and R U6 are each independently selected from X 2 , hydrogen, deuterium, halogen, amino, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (halogenated C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), C 1-6 alkyl substituted by CONHC 1-6 alkyl, C 1-6 alkyl substituted by CON(C 1-6 alkyl) 2 , C 1-6 alkyl substituted by carboxyl, and C 1-6 alkyl substituted by COOC 1-6 alkyl;

(RU2)r2表示D环上的氢被r2个RU2取代，r2为0、1、2或3，每个RU2相同或不同，各自独立地选自X2、氢、氘、卤素(优选为氟、氯)、硝基、氰基、羧基、羟基、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷基、羟基取代的C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、-NRa3Rb3、-COC1-6烷基、-COOC1-6烷基、-OCOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SC1-6烷基、5至6元杂芳基和苯基；所述的5至6元杂芳基、苯基为未取代或被1、2或3个选自下组的取代基取代：氢、氘、卤素、氰基、羧基、羟基、C1-6烷基(优选为C1-3烷基)、羟基取代的C1-6烷基(优选为羟基取代的C1-3烷基)、C1-6烷氧基C1-6烷基(优选为C1-3烷氧基C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)、-NH2、-NHCOC1-6烷基(优选为-NHCOC1-3烷基)、-COC1-6烷基(优选为-COC1-3烷基)、-COOC1-6烷基(优选为-COOC1-3烷基)、-OCOC1-6烷基(优选为-OCOC1-3烷基)、-CONH2、-NHCONH2、-CONHC1-6烷基、-NHCONHC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基和-SC1-6烷基；(R U2 ) r2 represents that the hydrogen on the D ring is replaced by r2 R U2 , r2 is 0, 1, 2 or 3, each R U2 is the same or different and is independently selected from X 2 , hydrogen, deuterium, halogen (preferably fluorine, chlorine), nitro, cyano, carboxyl, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkyl substituted with hydroxyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NR a3 R b3 , -COC 1-6 alkyl, -COOC 1-6 alkyl, -OCOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SC The 5- to 6-membered heteroaryl and phenyl groups are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), hydroxy-substituted C 1-6 alkyl (preferably C 1-3 alkoxy C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl ), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy) , -NH 2 , -NHCOC 1-6 alkyl (preferably -NHCOC 1-3 alkyl), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -COOC 1-6 alkyl (preferably -COOC 1-3 alkyl), -OCOC 1-6 alkyl (preferably -OCOC 1-3 alkyl), -CONH 2 , -NHCONH 2 , -CONHC 1-6 alkyl, -NHCONHC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl and -SC 1-6 alkyl;

D环选自苯环、5至6元杂芳基环、C3-10环烷基环(优选为C3-8环烷基环，更优选为C3-6环烷基环)和3至10元杂环烷基环(优选为3至8元杂环烷基环，更优选为3至6元杂环烷基环)；The D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-10 cycloalkyl ring (preferably a C 3-8 cycloalkyl ring, more preferably a C 3-6 cycloalkyl ring) and a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring);

Ra3、Rb3各自独立地选自氢、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、-SC1-6烷基(优选为-SC1-3烷基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)、-COC1-6烷基(优选为-COC1-3烷基)、-CONH2、-CONHC1-6烷基(优选为-CONHC1-3烷基)、-CON(C1-6烷基)2(优选为-CON(C1-3烷基)2)、5至6元杂芳基和苯基；其中，所述5至6元杂芳基、苯基各自独立地为未被取代或被1、2或3个选自下组的取代基取代：氢、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、-SC1-6烷基(优选为-SC1-3烷基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)、-COC1-6烷基(优选为-COC1-3烷基)、-CONH2、-CONHC1-6烷基(优选为-CONHC1-3烷基)和-CON(C1-6烷基)2(优选为-CON(C1-3烷基)2)；R a3 and R b3 are each independently selected from hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHC 1-3 alkyl), -CON(C 1-6 alkyl) 2 (preferably -CON(C 1-3 alkyl) 2 ), 5- to 6-membered heteroaryl and phenyl; wherein the 5- to 6-membered heteroaryl and phenyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), C -SC 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHC 1-3 alkyl) and -CON(C 1-6 alkyl) 2 (preferably -CON(C 1-3 alkyl) 2 );

其中，X2为ULM与L或POI的连接位点，且U1、RU5、RU6和RU2中至少一个为X2，或RU1至少含一个X2。Wherein, X 2 is the connection site between ULM and L or POI, and at least one of U 1 , RU5 , RU6 and RU2 is X 2 , or RU1 contains at least one X 2 .

在一些实施方案中，U1、RU5、RU6和RU2中的一个为X2。In some embodiments, one of U 1 , RU5 , RU6 , and RU2 is X 2 .

在一些实施方案中，RU1含一个X2。In some embodiments, R U1 contains one X 2 .

在一些实施方案中，r1为2，RU7选自氟和羟基。In some embodiments, R1 is 2, and R U7 is selected from fluoro and hydroxy.

在一些实施方案中，式(U-2)所示结构为式(U-2-1)所示结构或其异构体：
In some embodiments, the structure represented by formula (U-2) is the structure represented by formula (U-2-1) or an isomer thereof:

在一些实施方案中，RU7选自羟基、氨基、-OCH3、-OCF3和-OCOCH3。In some embodiments, R U7 is selected from hydroxy, amino, -OCH 3 , -OCF 3 , and -OCOCH 3 .

在一些实施方案中，RU7为羟基。In some embodiments, R U7 is hydroxy.

在一些实施方案中，RUa选自氟、氰基、甲基、乙基、三氟甲基和三氟甲氧基。In some embodiments, R Ua is selected from fluoro, cyano, methyl, ethyl, trifluoromethyl, and trifluoromethoxy.

在一些实施方案中，RUa选自氟和氰基。In some embodiments, R Ua is selected from fluoro and cyano.

在一些实施方案中，U1选自X2、-NHCO-X2、-NHCOCH3、 其中X2为ULM与L或POI的连接位点。In some embodiments, U 1 is selected from X 2 , -NHCO-X 2 , -NHCOCH 3 , Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，U1选自-NHCO-X2和其中X2为ULM与L或POI的连接位点。In some embodiments, U is selected from -NHCO-X and Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，RU3、RU4各自独立地为氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基；或RU3、RU4与其所连接的碳原子形成C3-6环烷基环。In some embodiments, R U3 and R U4 are each independently hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy; or R U3 and R U4 and the carbon atom to which they are attached form a C 3-6 cycloalkyl ring.

在一些实施方案中，RU3、RU4各自独立的为氢、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3、-CF3、-CHF2、-CH2F、-OCH3、-OCH(CH3)2、-OC(CH3)3、-OCF3、-OCHF2、-OCH2F、氟代异丙基或氟代叔丁基；或RU3、RU4与其所连接的碳原子形成环丙基环、环丁基环、环戊基环或环己基环。In some embodiments, R U3 and R U4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, fluoroisopropyl or fluorotert-butyl; or R U3 and R U4 and the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.

在一些实施方案中，RU3、RU4各自独立的为氢、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2或-C(CH3)3；或RU3、RU4与其所连接的碳原子形成环丙基环。In some embodiments, R U3 and R U4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 ; or R U3 and R U4 and the carbon atom to which they are attached form a cyclopropyl ring.

在一些实施方案中，RU3、RU4各自独立地为氢、-CH(CH3)2或-C(CH3)3。In some embodiments, R U3 , R U4 are each independently hydrogen, -CH(CH 3 ) 2 , or -C(CH 3 ) 3 .

在一些实施方案中，RU1选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点。In some embodiments, R U1 is selected from the following structures or isomers thereof: Wherein X2 is the connection site between ULM and L or POI.

在一些实施方案中，RU1选自以下结构： 其中X2为ULM与L或POI的连接位点。In some embodiments, R U1 is selected from the following structures: Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，RU1选自以下结构：其中X2为ULM与L或POI的连接位点。In some embodiments, R U1 is selected from the following structures: Wherein X2 is the connection site between ULM and L or POI.

在一些实施方案中，RU5、RU6各自独立地为X2、氢、氘、卤素、羟基、羧基、氰基、氨基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基或卤代C1-3烷氧基。In some embodiments, R U5 and R U6 are each independently X 2 , hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl or halogenated C 1-3 alkoxy.

在一些实施方案中，RU5、RU6各自独立地为氢、C1-3烷基或卤代C1-3烷基。In some embodiments, R U5 and R U6 are each independently hydrogen, C 1-3 alkyl, or halogenated C 1-3 alkyl.

在一些实施方案中，RU5、RU6各自独立地为氢、-CH3、-OCH3、-CF3、-OCF3、-CHF2、-CH2F、-OCHF2或-OCH2F。In some embodiments, R U5 , R U6 are each independently hydrogen, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 , -CHF 2 , -CH 2 F, -OCHF 2 , or -OCH 2 F.

在一些实施方案中，RU5、RU6各自独立地为氢或-CH3。In some embodiments, R U5 , R U6 are each independently hydrogen or -CH 3 .

在一些实施方案中，r2为0。In some embodiments, r2 is 0.

在一些实施方案中，r2为1。In some embodiments, r2 is 1.

在一些实施方案中，r2为2。In some embodiments, r2 is 2.

在一些实施方案中，RU2为5至6元杂芳基或苯基，所述的5至6元杂芳基或苯基为未取代或被1、2或3个选自下组的取代基取代：氘、卤素(优选为氟、氯)、氰基、羧基、羟基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、-NH2、-NHCOC1-3烷基、-COC1-3烷基、-COOC1-3烷基、-OCOC1-3烷基、-CONH2、-NHCONH2、-CONHC1-3烷基、-NHCONHC1-3烷基、-SOC1-3烷基、-SO2C1-3烷基和-SC1-3烷基。In some embodiments, R U2 is a 5- to 6-membered heteroaryl or phenyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -NH 2 , -NHCOC 1-3 alkyl, -COC 1-3 alkyl, -COOC 1-3 alkyl, -OCOC 1-3 alkyl, -CONH 2 , -NHCONH 2 , -CONHC 1-3 alkyl, -NHCONHC 1-3 alkyl, -SOC 1-3 alkyl, -SO 2 C 1-3 alkyl and -SC 1-3 alkyl.

在一些实施方案中，所述的5至6元杂芳基选自噻唑基、噁唑基、吡唑基、咪唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、四氮唑基和三氮唑基。In some embodiments, the 5- to 6-membered heteroaryl is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazolyl.

在一些实施方案中，所述的5至6元杂芳基选自 In some embodiments, the 5- to 6-membered heteroaryl is selected from

在一些实施方案中，所述的5至6元杂芳基为 In some embodiments, the 5- to 6-membered heteroaryl is

在一些实施方案中，所述的5至6元杂芳基环选自噻唑环、噁唑环、吡唑环、咪唑环、吡咯环、吡啶环、嘧啶环、哒嗪环、吡嗪环、四氮唑环和三氮唑环。In some embodiments, the 5- to 6-membered heteroaryl ring is selected from a thiazole ring, an oxazole ring, a pyrazole ring, an imidazole ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a tetrazole ring, and a triazole ring.

在一些实施方案中，RU2为氰基。In some embodiments, R U2 is cyano.

在一些实施方案中，Ra3、Rb3各自独立地选自氢、5至6元杂芳基和苯基；所述的5至6元杂芳基为噻唑基、噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、三唑基和四唑基；所述的5至6元杂芳基和苯基为未取代或被1或2个选自下组的取代基取代：氢、甲基、乙基、异丙基、三氟甲基、三氟甲氧基、-COCH3和-CONH2。In some embodiments, R a3 and R b3 are each independently selected from hydrogen, 5- to 6-membered heteroaryl and phenyl; the 5- to 6-membered heteroaryl is thiazolyl, oxazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, pyrrolyl, triazolyl and tetrazolyl; the 5- to 6-membered heteroaryl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, -COCH 3 and -CONH 2 .

在一些实施方案中，RU2为-NHRa3，其中Ra3为5至6元杂芳基或苯基，所述的5至6元杂芳基选自噻唑基、咪唑基、吡唑基、噁唑基、吡啶基和嘧啶基；所述的5至6元杂芳基或苯基为未被取代或被1、2或3个选自下组的取代基取代：C1-3烷氧基、卤代C1-3烷氧基、C1-3烷基、卤代C1-3烷基、-SC1-3烷基和-OCOC1-3烷基。In some embodiments, R U2 is -NHR a3 , wherein R a3 is a 5- to 6-membered heteroaryl or phenyl group, wherein the 5- to 6-membered heteroaryl group is selected from thiazolyl, imidazolyl, pyrazolyl, oxazolyl, pyridinyl and pyrimidinyl; and the 5- to 6-membered heteroaryl or phenyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkyl, halo C 1-3 alkyl, -SC 1-3 alkyl and -OCOC 1-3 alkyl.

在一些实施方案中，RU2为-NHRa3，其中Ra3为噻唑基；所述的噻唑基被1、2或3个选自下组的取代基取代：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、一氟乙氧基、二氟乙氧基和三氟乙氧基。In some embodiments, R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl is substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy and trifluoroethoxy.

在一些实施方案中，RU2为-NHRa3，其中Ra3为噻唑基；所述的噻唑基被1、2或3个选自下组的取代基取代：甲基、乙基、丙基和异丙基。In some embodiments, R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl being substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl and isopropyl.

在一些实施方案中，RU2选自以下结构：氰基、 In some embodiments, R U2 is selected from the following structures: cyano,

在一些实施方案中，r2为1，RU2选自氰基、 In some embodiments, R2 is 1, R U2 is selected from cyano,

在一些实施方案中，r2为1，RU2为 In some embodiments, r2 is 1, R U2 is

在一些实施方案中，r2为2，RU2分别为X2和其中X2为ULM与L或POI的连接位点。In some embodiments, r2 is 2, R and U2 are X2 and Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，D环选自苯环、5至6元杂芳基环、C3-6环烷基环和3至6元杂环烷基环。In some embodiments, the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-6 cycloalkyl ring, and a 3- to 6-membered heterocycloalkyl ring.

在一些实施方案中，D环选自苯环和5至6元杂芳基环。In some embodiments, the D ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring.

在一些实施方案中，D环选自苯环、吡咯环、噻吩环、呋喃环、吡唑环、咪唑环、三唑环、噻唑环、噁唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、环丙烷基环、环丁烷基环、环戊烷基环、环己烷基环、哌啶环、哌嗪环和四氢吡咯环。In some embodiments, the D ring is selected from a benzene ring, a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a triazole ring, a thiazole ring, an oxazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a piperidine ring, a piperazine ring and a tetrahydropyrrole ring.

在一些实施方案中，D环选自苯环和吡啶环。In some embodiments, the D ring is selected from a benzene ring and a pyridine ring.

在一些实施方案中，选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点。In some embodiments, Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，选自以下结构或其异构体： In some embodiments, Selected from the following structures or isomers thereof:

在一些实施方案中，ULM选自以下结构或其异构体：



；其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof:



; wherein X 2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM选自以下结构或其异构体：其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM选自以下结构或其异构体：其中X2为ULM与L或POI的连接位点。In some embodiments, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

在一些实施方案中，ULM为式(U-3)所示结构或其异构体：
In some embodiments, ULM is a structure represented by formula (U-3) or an isomer thereof:

其中，Rn1选自C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-SC1-6烷基、C3-12环烷基、C3-12杂环烷基、C6-14芳基、5至10元杂芳基；所述C1-6烷基、C3-12环烷基、C3-12杂环烷基、C6-14芳基、5至10元杂芳基为未取代或被1,2,3或4个选自下组的取代基取代：卤素、硝基、氰基、羟基、羧基、氧代基、-CHO、氨基、C1-6烷基、-SC1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NHCOC1-6烷基、-COC1-6烷基、-COOC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、C3-12环烷基、C3-12杂环烷基；wherein R n1 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -SC 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5 to 10 membered heteroaryl; the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5 to 10 membered heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, C 1-6 alkyl, -SC 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NHCOC C 1-6 alkyl, -COC 1-6 alkyl, -COOC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl;

Rn2、Rn3与相连的N共同形成4至12元杂环烷基环；所述的杂环烷基为未取代或被1,2,3或4个选自下组的取代基取代：X2、卤素、硝基、氰基、羟基、羧基、氧代基、-CHO、氨基、C1-6烷基、-SC1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NHCOC1-6烷基、-COC1-6烷基、-COOC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、C3-12环烷基、C3-12杂环烷基、C6-14芳基、5至10元杂芳基。R n2 , R n3 and the connected N together form a 4- to 12-membered heterocycloalkyl ring; the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the following group: X 2 , halogen, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, C 1-6 alkyl, -SC 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -COC 1-6 alkyl, -COOC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5- to 10-membered heteroaryl.

在一些实施方案中，Rn1选自叔丁基、吗啉基取代的叔丁基、噻唑、吡唑、恶唑、异恶唑、苯环、吡啶、苯并噻唑、环丁烷；所述的噻唑、吡唑、恶唑、异恶唑、苯环、吡啶、苯并噻唑、环丁烷为未取代或被1,2,3或4个选自下组的取代基取代：卤素、氰基、羟基、硝基、三氟甲基、二氟甲基、一氟甲基、甲基、乙基、丙基、异丙基、甲氧基、-SCH3、-SOCH3、-SO2CH3、-NHCH3、-N(CH3)2、-COCH3。In some embodiments, R n1 is selected from tert-butyl, tert-butyl substituted with morpholinyl, thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane; the thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the following group: halogen, cyano, hydroxyl, nitro, trifluoromethyl, difluoromethyl, monofluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, -SCH 3 , -SOCH 3 , -SO 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -COCH 3 .

在一些实施方案中，Rn1选自叔丁基、吡啶基，所述的吡啶基被溴取代。In some embodiments, R n1 is selected from tert-butyl, pyridinyl, and the pyridinyl is substituted with bromine.

在一些实施方案中，Rn2、Rn3与相连的N共同形成4至12元杂环烷基环，所述的4至12元杂环烷基环选自四氢吡咯环、哌啶环、吗啉环、哌嗪环、3,6-二氮杂双环[3.1.1]庚烷、2,5-二氮杂双环[2.2.1]庚烷、(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷、1,4-二氮杂卓、3,9-二氮杂螺[5.5]十一烷、4,7-二氮杂螺[2.5]辛烷；所述的4至12元杂环烷基环未取代或被1,2,3或4个选自下组的取代基取代：X2、氟、氯、溴、硝基、氰基、羟基、羧基、氧代基、-CHO、氨基、甲基、叔丁基、甲氧基、叔丁氧基、三氟甲基、三氟甲氧基、-NH(CH3)、-N(CH3)2、-NHCOCH3、-COCH3、-COOCH3、-SOCH3、-SO2CH3、环丙基。In some embodiments, R n2 , R n3 and the attached N together form a 4- to 12-membered heterocycloalkyl ring, wherein the 4- to 12-membered heterocycloalkyl ring is selected from a tetrahydropyrrole ring, a piperidine ring, a morpholine ring, a piperazine ring, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, (1R,5S)-3,8-diazabicyclo[3.2.1]octane, 1,4-diazapine, 3,9-diazaspiro[5.5]undecane, 4,7-diazaspiro[2.5]octane; the 4- to 12-membered heterocycloalkyl ring is unsubstituted or substituted with 1,2,3 or 4 substituents selected from the group consisting of: X 2 , fluorine, chlorine, bromine, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, methyl, tert-butyl, methoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, -NH(CH 3 ), -N(CH 3 ) 2 , -NHCOCH 3 , -COCH 3 , -COOCH 3 , -SOCH 3 , -SO 2 CH 3 , cyclopropyl.

在一些实施方案中，Rn2、Rn3与相连的N共同形成哌啶环。In some embodiments, R n2 , R n3 and the attached N together form a piperidine ring.

在一些实施方案中，ULM选自以下结构： In some embodiments, the ULM is selected from the following structures:

在一些实施方案中，式(I)化合物为选自实施例中的具体化合物。In some embodiments, the compound of formula (I) is a specific compound selected from the Examples.

在一些实施方案中，式(I)化合物为选自下列的化合物或其立体异构体：








In some embodiments, the compound of formula (I) is a compound selected from the following or a stereoisomer thereof:








在一些实施方案中，式(I)化合物为选自下列的化合物或其立体异构体：



In some embodiments, the compound of formula (I) is a compound selected from the following or a stereoisomer thereof:



本申请第二方面提供了一种药物组合物，包括本申请第一方面所述式(I)所示化合物、或其药学上可接受的盐、或其立体异构体；以及药学上可接受的载体。The second aspect of the present application provides a pharmaceutical composition, comprising the compound represented by formula (I) described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

本申请第三方面提供了本申请第一方面所述的(I)所示化合物、或其药学上可接受的盐、或其立体异构体，或本申请第二方面提供的药物组合物在制备治疗EED介导的疾病的药物中的用途。The third aspect of the present application provides the use of the compound shown in (I) described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition provided in the second aspect of the present application in the preparation of a drug for treating EED-mediated diseases.

在一些实施方案中，所述EED介导的疾病为肿瘤或自身免疫疾病。In some embodiments, the EED-mediated disease is a tumor or an autoimmune disease.

在一些实施方案中，所述EED介导的疾病为癌症。In some embodiments, the EED-mediated disease is cancer.

在一些实施方案中，所述癌症选自多发性骨髓瘤、白血病、非小细胞肺癌、结肠癌、中枢神经系统癌症、黑素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌。In some embodiments, the cancer is selected from multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.

本申请第四方面提供了一种预防和/或治疗EED介导的疾病的方法，包括给予受试者治疗有效量的本申请第一方面所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，或者本申请第二方面所述的药物组合物。The fourth aspect of the present application provides a method for preventing and/or treating EED-mediated diseases, comprising administering to a subject a therapeutically effective amount of a compound represented by formula (I) as described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition as described in the second aspect of the present application.

在一些实施方案中，所述EED介导的疾病为肿瘤或自身免疫疾病。In some embodiments, the EED-mediated disease is a tumor or an autoimmune disease.

在一些实施方案中，所述EED介导的疾病为癌症。In some embodiments, the EED-mediated disease is cancer.

在一些实施方案中，所述癌症选自多发性骨髓瘤、白血病、非小细胞肺癌、结肠癌、中枢神经系统癌症、黑素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌。In some embodiments, the cancer is selected from multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.

本申请第五方面提供了一种用作药物或用于治疗的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体。The fifth aspect of the present application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof for use as a medicine or for treatment.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

此处所说明的附图用来提供对本申请的进一步理解，构成本申请的一部分，本申请的示意性实施例及其说明用于解释本申请，并不构成对本申请的不当限定。The drawings described herein are used to provide further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

图1为化合物H39对Karpas-422细胞内的EED蛋白降解的蛋白印迹图；FIG1 is a Western blot showing the degradation of EED protein by compound H39 in Karpas-422 cells;

图2为化合物H39对Karpas-422细胞内的EED蛋白的剂量-降解活性图；FIG2 is a graph showing the dose-degradation activity of compound H39 on EED protein in Karpas-422 cells;

图3为化合物D1和化合物H39在体内的抗肿瘤活性结果图；FIG3 is a graph showing the in vivo anti-tumor activity results of compound D1 and compound H39;

图4为化合物D1和化合物H39对小鼠体重的影响结果图；FIG4 is a graph showing the effects of compound D1 and compound H39 on mouse body weight;

图5为化合物D1和化合物H80在体内的抗肿瘤活性结果图；FIG5 is a graph showing the in vivo anti-tumor activity results of compound D1 and compound H80;

图6为化合物D1和化合物H80对小鼠体重的影响结果图。FIG6 is a graph showing the effects of compound D1 and compound H80 on the body weight of mice.

具体实施方式DETAILED DESCRIPTION

本发明人经过广泛而深入的研究，意外地发现了一种靶向降解和/或抑制EED蛋白的双功能化合物，该化合物具有优异的EED蛋白降解作用、优异的肿瘤细胞(如wsuDLCL-2细胞、Pfeiffer细胞等)增殖抑制作用、优异的药代动力学特征，较好的CYP450作用，安全性好，更适于治疗EED蛋白活性异常的疾病或病症(如癌症等增殖性疾病)。在此基础上，发明人完成了本申请。After extensive and in-depth research, the inventor unexpectedly discovered a bifunctional compound that targets degradation and/or inhibits EED protein, which has excellent EED protein degradation, excellent tumor cell (such as wsuDLCL-2 cells, Pfeiffer cells, etc.) proliferation inhibition, excellent pharmacokinetic characteristics, good CYP450 effect, good safety, and is more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer). On this basis, the inventor completed this application.

术语定义Definition of terms

为了能够更清楚地理解本发明的技术内容，下面对本申请的术语作进一步说明。In order to more clearly understand the technical content of the present invention, the terms of the present application are further explained below.

本申请提供了一种双功能化合物或PROTAC化合物，其具有POI—ULM的结构或POI—L—ULM的结构，其中POI是EED蛋白靶向的配体(或与EED蛋白结合的配体)，ULM是E3连接酶连接基团(或结合的基团)，L是连接POI和ULM的连接链。该PROTAC化合物可以通过POI部分与EED蛋白结合，从而将EED蛋白拉向E3连接酶，从而诱导降解(和/或抑制)EED蛋白的作用。常用的E3连接酶配体包括VHL(Von Hippel-Lindau)E3泛素连接酶连接基团(简称为VLM)、CRBN(cereblon)E3泛素连接酶连接基团(简称为CLM)、MDM2(mouse double minute 2 homologue)E3泛素连接酶连接基团(简称为MLM)、cIAP(cellular inhibitor of apoptosis)E3泛素连接酶连接基团(简称为ILM)等。POI是EED蛋白靶向的配体，可以与EED蛋白结合。The present application provides a bifunctional compound or PROTAC compound having a POI-ULM structure or a POI-L-ULM structure, wherein POI is a ligand targeted by the EED protein (or a ligand bound to the EED protein), ULM is an E3 ligase linker (or a binding group), and L is a linker chain connecting POI and ULM. The PROTAC compound can bind to the EED protein through the POI portion, thereby pulling the EED protein toward the E3 ligase, thereby inducing the degradation (and/or inhibition) of the EED protein. Commonly used E3 ligase ligands include VHL (Von Hippel-Lindau) E3 ubiquitin ligase linker (abbreviated as VLM), CRBN (cereblon) E3 ubiquitin ligase linker (abbreviated as CLM), MDM2 (mouse double minute 2 homologue) E3 ubiquitin ligase linker (abbreviated as MLM), cIAP (cellular inhibitor of apoptosis) E3 ubiquitin ligase linker (abbreviated as ILM), etc. POI is a ligand targeting EED protein and can bind to EED protein.

“烷基”指直链和支链的饱和的脂族烃基。“C1-10烷基”是指具有1至10个碳原子的烷基，优选为C1-8烷基；更优选为C1-6烷基；进一步优选为C1-3烷基；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体。"Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. "C 1-10 alkyl" refers to an alkyl group having 1 to 10 carbon atoms, preferably a C 1-8 alkyl group; more preferably a C 1-6 alkyl group; and further preferably a C 1-3 alkyl; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methyl pentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.

“烯基”指直链或支链的具有一个或多个碳碳双键(C＝C)的不饱和脂族烃基，“C2-10烯基”指具有2至10个碳原子的烯基，优选为C2-8烯基，更优选为C2-6烯基，进一步优选为C2-4烯基，定义类似；烯基的非限制性实施例包括乙烯基、丙烯基、异丙烯基、正丁烯基、异丁烯基、戊烯基、己烯基等。"Alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C); " C2-10 alkenyl" refers to an alkenyl group having 2 to 10 carbon atoms, preferably a C2-8 alkenyl group, more preferably a C2-6 alkenyl group, further preferably a C2-4 alkenyl group, and the definition is similar; non-limiting examples of alkenyl include ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl and the like.

“炔基”指直链和支链的具有一个或多个碳碳三键的不饱和脂族烃基，“C2-10炔基”指具有2至10个碳原子的炔基，优选为C2-8炔基，更优选为C2-6炔基，进一步优选为C2-4炔基，定义类似；炔基的非限制性实施例包括乙炔基、丙炔基、正丁炔基、异丁炔基、戊炔基、己炔基等。"Alkynyl" refers to a straight chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon triple bonds; " C2-10 alkynyl" refers to an alkynyl group having 2 to 10 carbon atoms, preferably a C2-8 alkynyl group, more preferably a C2-6 alkynyl group, further preferably a C2-4 alkynyl group, and the definition is similar; non-limiting examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl and the like.

“亚烷基”是二价的，需要两个结合配偶体。在形式上，第二价通过从烷基上除去氢原子产生，如-CH3和-CH2-、-CH2CH3和-CH2CH2-或-CH(CH3)-等。在某些实施例中，优选为C1-10亚烷基、更优选为C1-8亚烷基、进一步优选为C1-6亚烷基、最优选为C1-3亚烷基。例如C1-3亚烷基包括-CH2-、-(CH2)2-、-CH(CH3)-、-(CH2)3-、-CH(CH2CH3)-、-CH2CH(CH3)-和-C(CH3)2-。在某些实施例中，亚烷基可以为亚甲基、亚乙基、亚丙基、1-甲基亚乙基、亚丁基、1-甲基亚丙基、1,1-二甲基亚乙基、1,2-二甲基亚乙基、亚戊基、1,1-二甲基亚丙基、2,2-二甲基亚丙基、1,2-二甲基亚丙基、1,3-二甲基亚丙基等。在没有任何进一步定义的情况下，通用术语亚丙基、亚丁基、亚戊基、亚己基等意指具有相应数量的碳原子的所有可想到的异构形式，即亚丙基包括1-甲基亚乙基，并且亚丁基包括1-甲基亚丙基、2-甲基亚丙基、1,1-二甲基亚乙基和1,2-二甲基亚乙基。"Alkylene" is divalent and requires two binding partners. Formally, the second valence is generated by removing a hydrogen atom from an alkyl group, such as -CH3 and -CH2- , -CH2CH3 and -CH2CH2- or -CH ( CH3 )-, etc. In certain embodiments, C1-10 alkylene is preferred, C1-8 alkylene is more preferred, C1-6 alkylene is further preferred, and C1-3 alkylene is most preferred. For example, C1-3 alkylene includes -CH2-, - ( CH2 ) 2- , -CH( CH3 )-, -( CH2 ) 3- , -CH( CH2CH3 ) - , -CH2CH ( CH3 )- and -C( CH3 ) 2- . In certain embodiments, the alkylene group may be methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, etc. In the absence of any further definition, the generic terms propylene, butylene, pentylene, hexylene, etc. are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e., propylene includes 1-methylethylene, and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

“亚烯基”由至少两个碳原子组成，其中至少两个相邻的碳原子通过C-C双键连接在一起，并且碳原子只能是一个C-C双键的一部分。在形式上，上文定义的亚烷基中，相邻碳原子上的两个氢原子在形式上被除去并且自由价饱和形成第二键，则形成相应的亚烯基。在某些实施例中，优选为C2-10亚烯基、更优选为C2-8亚烯基、进一步优选为C2-6亚烯基、最优选为C2-4亚烯基。在某些实施例中，亚烯基可以为亚乙烯基、亚丙烯基、1-甲基亚乙烯基、亚丁烯基、1-甲基亚丙烯基、1,1-二甲基亚乙烯基、1,2-二甲基亚乙烯基、亚戊烯基、1,1-二甲基亚丙烯基、2,2-二甲基亚丙烯基、1,2-二甲基亚丙烯基、1,3-二甲基亚丙烯基，亚己烯基等。在没有任何进一步定义的情况下，通用术语亚丙烯基、亚丁烯基、亚戊烯基、亚己烯基等意指具有相应数量的碳原子的所有可想到的异构体形式，即亚丙烯基包括1-甲基亚丙烯基，并且亚丁烯基包括1-甲基亚丙烯基、2-甲基亚丙烯基、1,1-二甲基亚乙烯基和1,2-二甲基亚乙烯基。对于一个或多个双键，亚烯基可任选地以顺式或反式或者E或Z形式存在。"Alkenylene" consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond, and the carbon atom can only be part of one C-C double bond. Formally, in the alkylene defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, forming the corresponding alkenylene. In certain embodiments, it is preferably C 2-10 alkenylene, more preferably C 2-8 alkenylene, further preferably C 2-6 alkenylene, and most preferably C 2-4 alkenylene. In certain embodiments, the alkenylene can be vinylene, propenylene, 1-methylvinylene, butenylene, 1-methylpropenylene, 1,1-dimethylvinylene, 1,2-dimethylvinylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene, etc. In the absence of any further definition, the generic terms propenylene, butenylene, pentenylene, hexenylene and the like are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propenylene includes 1-methylpropenylene, and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylvinylene and 1,2-dimethylvinylene. Alkenylene may optionally be present in cis or trans or in E or Z form for one or more double bonds.

“亚炔基”指由至少两个碳原子组成，其中至少两个相邻的碳原子通过C-C三键连接在一起。在形式上，在上文所定义的亚烷基中，相邻的两个碳原子上分别除去两个氢并且自由价饱和形成另外两个键，则形成相应的亚炔基。在某些实施例中，优选为C2-10亚炔基，更优选为C2-8亚炔基，进一步优选为C2-6亚炔基，最优选为C2-4亚炔基。在某些实施例中，亚炔基可以为亚乙炔基、亚丙炔基、1-甲基亚乙炔基、亚丁炔基、1-甲基亚丙炔基、1,1-二甲基亚乙炔基、1,2-二甲基亚乙炔基、亚戊炔基、1,1-二甲基亚丙炔基、2,2-二甲基亚丙炔基、1,2-二甲基亚丙炔基、1,3-二甲基亚丙炔基、亚己炔基等。在没有任何进一步定义的情况下，通用术语亚丙炔基、亚丁炔基、亚戊炔基、亚己炔基等意指具有相应数量的碳原子的所有可想到的异构形式，即亚丙炔基包括1-甲基亚乙炔基，并且亚丁炔基包括1-甲基亚丙炔基、2-甲基亚丙炔基、1,1-二甲基亚乙炔基和1,2-二甲基亚乙炔基。"Alkynylidene" refers to a group consisting of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C triple bond. Formally, in the alkylene group defined above, two hydrogen atoms are removed from two adjacent carbon atoms and the free valence is saturated to form two additional bonds, thereby forming the corresponding alkynylene group. In certain embodiments, it is preferably a C 2-10 alkynylene group, more preferably a C 2-8 alkynylene group, further preferably a C 2-6 alkynylene group, and most preferably a C 2-4 alkynylene group. In certain embodiments, the alkynylene group can be ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, etc. Without any further definition, the generic terms propynylene, butynylene, pentynylene, hexynylene and the like are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

“亚烷氧基”指二价的烷氧基。在某些实施例中，优选为C1-10亚烷氧基，更优选为C1-8亚烷氧基，进一步优选为C1-6亚烷氧基，最优选为C1-3亚烷氧基。在某些实施例中，亚烷氧基可以为-OCH2-、-OCH(CH3)CH2-、-OCH2CH2O-、-CH2CH2O-等。在没有任何进一步定义的情况下，通用术语亚丙氧基、亚丁氧基、亚戊氧基、亚己氧基等意指具有相应数量的碳原子的所有可想到的异构形式，即亚丙氧基包括-O(CH2)3O-、-O(CH2)3-、-OCH2CH(CH3)-、-OC(CH3)2-、-OCH(CH3)CH2-、-OCH2CH(CH3)O-、-OC(CH3)2O-和-OCH(CH3)CH2O-。"Alkyleneoxy" refers to a divalent alkoxy group. In certain embodiments, it is preferably a C 1-10 alkyleneoxy group, more preferably a C 1-8 alkyleneoxy group, further preferably a C 1-6 alkyleneoxy group, and most preferably a C 1-3 alkyleneoxy group. In certain embodiments, the alkyleneoxy group may be -OCH 2 -, -OCH(CH 3 )CH 2 -, -OCH 2 CH 2 O-, -CH 2 CH 2 O-, and the like. Without any further definition, the generic terms propyleneoxy, butyleneoxy, pentyleneoxy, hexyleneoxy and the like are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propyleneoxy includes -O( CH2 ) 3O- , -O(CH2) 3- , -OCH2CH( CH3 )-, -OC(CH3) 2- , -OCH( CH3 ) CH2- , -OCH2CH( CH3 ) O- , -OC( CH3 ) 2O- and -OCH( CH3 ) CH2O- .

“环烷基”和“环烷基环”可互换使用，均指单环或多环环状烃基，该基团可以与芳基或杂芳基稠合。环烷基环可以任选地被取代。在某些实施方案中，环烷基环为螺环、桥环。在某些实施方案中，环烷基环含有一个或多个羰基，例如氧代的基团。“C3-15环烷基”是指具有3至15个碳原子的单环或多环环烷基，如螺[4.5]癸烷、螺[3.3]庚烷、螺[5.5]十一烷、二螺[5.2.59.26]十六烷、十氢薁、1，2-二乙基环戊-1-烯、双环[3.3.2]癸烷。优选为C3-8环烷基如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丁酮、环戊酮、环戊烷-1,3-二酮等。优选为C3-7环烷基，如环庚烷、螺[3.3]庚烷等，更优选为C3-6环烷基，包括环丙基、环丁基、环戊基和环己基。可以为饱和环烷基，如环己基、环丙基等。可以为部分不饱和环烷基，如环己烯、1，2-二乙基环戊-1-烯等。"Cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to monocyclic or polycyclic cyclic hydrocarbon groups, which may be fused to aryl or heteroaryl groups. The cycloalkyl ring may be optionally substituted. In certain embodiments, the cycloalkyl ring is a spiro ring or a bridged ring. In certain embodiments, the cycloalkyl ring contains one or more carbonyl groups, such as an oxo group. "C 3-15 cycloalkyl" refers to a monocyclic or polycyclic cycloalkyl group having 3 to 15 carbon atoms, such as spiro[4.5]decane, spiro[3.3]heptane, spiro[5.5]undecane, dispiro[5.2.59.26]hexadecane, decahydroazulene, 1,2-diethylcyclopent-1-ene, bicyclo[3.3.2]decane. Preferably, C 3-8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. It is preferably a C 3-7 cycloalkyl group, such as cycloheptane, spiro[3.3]heptane, etc., and more preferably a C 3-6 cycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It may be a saturated cycloalkyl group, such as cyclohexyl, cyclopropyl, etc. It may be a partially unsaturated cycloalkyl group, such as cyclohexene, 1,2-diethylcyclopent-1-ene, etc.

“螺环”是指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为4元/5元、5元/5元或5元/6元双螺环。例如：
"Spiro" refers to a polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Spirocycles are divided into bispirocycles or polyspirocycles according to the number of rings, preferably bispirocycles. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispirocycle. For example:

“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个环原子选自氮、氧或S(O)n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例如：
"Spiro heterocycle" refers to a polycyclic hydrocarbon in which one atom (called spiro atom) is shared between the monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Spiro heterocycles are divided into bispiro heterocycles or polyspiro heterocycles according to the number of rings, preferably bispiro heterocycles. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocycle. For example:

“桥环”是指共用两个或两个以上碳原子的多环基团，共用的碳原子称为桥头碳，两个桥头碳之间可以是碳链，也可以是一个键，称为桥。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥环。例如：
"Bridged ring" refers to a polycyclic group that shares two or more carbon atoms. The shared carbon atoms are called bridgehead carbons. The two bridgehead carbons can be a carbon chain or a bond, called a bridge. These can contain one or more double bonds, but no ring has a completely conjugated π electron system. Bicyclic or tricyclic bridged rings are preferred. For example:

“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O)n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥杂环。例如：
"Bridged heterocycle" refers to a polycyclic group that shares two or more atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. Preferably, the bridged heterocycle is bicyclic or tricyclic. For example:

“杂环烷基”和“杂环烷基环”可互换使用，均指包含至少一个选自氮、氧和硫的杂原子的环烷基，该基团可以与芳基或杂芳基稠合。杂环烷基环可以为饱和杂环烷基环或部分不饱和杂环烷基环。杂环烷基环可以任选地被取代。在某些实施方案中，杂环烷基环为螺杂环、桥杂环。在某些实施方案中，杂环烷基环含有一个或多个羰基或硫代羰基，例如包含氧代和硫代的基团。“3至15元杂环烷基”是指具有3至15个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子。优选为3至10元杂环烷基，更优选为3至7元杂环烷基，进一步更优选为3至7元杂环烷基，进一步优选为3至6元杂环烷基。杂环烷基的非限制性实施例包括氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物、四氢吡喃基、氮杂环丁烷-2-酮基、氧杂环丁烷-2-酮基、二氢呋喃-2(3H)-酮基、吡咯烷-2-酮基、吡咯烷-2,5-二酮基、二氢呋喃-2,5-二酮基、哌啶-2-酮基、四氢-2H-吡喃-2-酮基、哌嗪-2-酮基、吗啉-3-酮基、2,3-二氢呋喃、2,5-二氢呋喃、2,5-二氢-1H-吡咯、1,2,3,4-四氢吡啶、1,2,3,6-四氢吡啶等。"Heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably and refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which group may be fused with an aryl or heteroaryl group. The heterocycloalkyl ring may be a saturated heterocycloalkyl ring or a partially unsaturated heterocycloalkyl ring. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, the heterocycloalkyl ring is a spiro heterocycle or a bridged heterocycle. In certain embodiments, the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thio. "3 to 15-membered heterocycloalkyl" refers to a group having 3 to 15 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Preferably, it is a 3 to 10-membered heterocycloalkyl, more preferably a 3 to 7-membered heterocycloalkyl, further more preferably a 3 to 7-membered heterocycloalkyl, further preferably a 3 to 6-membered heterocycloalkyl. Non-limiting examples of heterocycloalkyl include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-onyl, oxetan-2-onyl, dihydrofuran- 2(3H)-one, pyrrolidine-2-one, pyrrolidine-2,5-dione, dihydrofuran-2,5-dione, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazine-2-one, morpholin-3-one, 2,3-dihydrofuran, 2,5-dihydrofuran, 2,5-dihydro-1H-pyrrole, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, and the like.

“芳基”和“芳环”可互换使用，均指具有环碳原子的单环、双环或多环的4n+2芳族环体系(例如，具有以环状排列共享的6或10或14个π电子)的基团。本发明中，芳环可以任选地被取代。“C6-14芳基”是指具有6至14个环碳原子的芳基。“C6-10芳基”是指具有6至10个环碳原子的芳基。非限制性实施例包括苯基、萘基、蒽基。"Aryl" and "aromatic ring" are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms. In the present invention, the aromatic ring may be optionally substituted. "C 6-14 aryl" refers to an aryl group having 6 to 14 ring carbon atoms. "C 6-10 aryl" refers to an aryl group having 6 to 10 ring carbon atoms. Non-limiting examples include phenyl, naphthyl, anthracenyl.

“杂芳基”和“杂芳基环”可互换使用，均指具有环碳原子和环杂原子的单环、双环或多环的4n+2芳族环体系(例如，具有以环状排列共享的6或10或14个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。本发明中，杂芳基还包括其中上述杂芳基环与一个或多个环烷基环、杂环烷基环、环烯基环、杂环烯基环或芳环稠合的环系统。杂芳基环可以任选地被取代。“5至15元杂芳基”是指具有5至15个环原子，其中1、2、3或4个环原子为杂原子的单环杂芳基。“5至6元杂芳基”是指具有5至6个环原子，其中1、2、3或4个环原子为杂原子的单环杂芳基。非限制性实施例包括噻吩基、呋喃基、噻唑基、异噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-恶二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基、喹啉基、异喹啉基、苯并吡咯基、苯并呋喃基、苯并噻吩基、苯并吡唑基、苯并咪唑基、苯并三唑基、苯并四唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并噻二唑基、吡啶并吡咯基、吡啶并呋喃基、吡啶并噻吩基、吡啶并吡唑基、吡啶并咪唑基、吡啶并三唑基、吡啶并四唑基、吡啶并噁唑基、吡啶并异噁唑基、吡啶并噁二唑基、吡啶并噻唑基、吡啶并噻二唑基、嘧啶并吡咯基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并三唑基、嘧啶并四唑基、嘧啶并噁唑基、嘧啶并异噁唑基、嘧啶并噁二唑基、嘧啶并噻唑基、嘧啶并噻二唑基、哒嗪并吡咯基、哒嗪并呋喃基、哒嗪并噻吩基、哒嗪并吡唑基、哒嗪并咪唑基、哒嗪并三唑基、哒嗪并四唑基、哒嗪并噁唑基、哒嗪并异噁唑基、哒嗪并噁二唑基、哒嗪并噻唑基、哒嗪并噻二唑基、吡嗪并吡咯基、吡嗪并呋喃基、吡嗪并噻吩基、吡嗪并吡唑基、吡嗪并咪唑基、吡嗪并三唑基、吡嗪并四唑基、吡嗪并噁唑基、吡嗪并异噁唑基、吡嗪并噁二唑基、吡嗪并噻唑基、吡嗪并噻二唑基、三嗪并吡咯基、三嗪并呋喃基、三嗪并噻吩基、三嗪并吡唑基、三嗪并咪唑基、三嗪并三唑基、三嗪并四唑基、三嗪并噁唑基、三嗪并异噁唑基、三嗪并噁二唑基、三嗪并噻唑基、三嗪并噻二唑基、苯并喹啉基、苯并异喹啉基、咔唑。“杂原子”是指氮、氧或硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。"Heteroaryl" and "heteroaryl ring" are used interchangeably and refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the present invention, heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. The heteroaryl ring may be optionally substituted. "5 to 15-membered heteroaryl" refers to a monocyclic heteroaryl having 5 to 15 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms. "5 to 6-membered heteroaryl" refers to a monocyclic heteroaryl having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms. Non-limiting examples include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinolyl, benzopyrrolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzotriazolyl, benzotetrazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, pyridopyrrolyl, pyridofuranyl, pyridothiphenyl, pyridopyrazolyl, pyridoimidazolyl, pyridotriazolyl, pyridotetrazolyl, pyridooxazolyl, pyridoisoxazolyl, pyridooxadiazolyl, pyridothiazolyl, pyridothiadiazolyl, pyridothiadiazolyl, pyrimidopyrrolyl, pyrimido furanyl, pyrimidothiphenyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidotriazolyl, pyrimidotetrazolyl, pyrimidooxazolyl, pyrimidooisoxazolyl, pyrimidooxadiazolyl, pyrimidothiazolyl, pyrimidothiadiazolyl, pyrimidothiazolyl, pyrimidothiadiazolyl, pyrimidothiazolyl, pyrimidothiadiazolyl, pyridazinopyrrolyl, pyridazinofuranyl, pyridazinothienyl, pyridazinopyrazolyl, pyridazinoimidazolyl, pyridazinotriazolyl, pyridazinotetrazolyl, pyridazinooxazolyl, pyridazinoisoxazolyl, pyridazinooxadiazolyl, pyridazinothiazolyl, pyridazinothiadiazolyl, pyrazinopyrrolyl, pyrazinofuranyl , pyrazinothiphenyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyrazinotriazolyl, pyrazinetetrazolyl, pyrazinoxazolyl, pyrazinoisoxazolyl, pyrazinooxadiazolyl, pyrazinothiazolyl, pyrazinothiadiazolyl, triazinopyrrolyl, triazinofuranyl, triazinothiphenyl, triazinopyrazolyl, triazinoimidazolyl, triazinotriazolyl, triazinotetrazolyl, triazinooxazolyl, triazinothiazolyl, triazinothiadiazolyl, benzoquinolyl, benzisoquinolyl, carbazole. "Heteroatom" refers to nitrogen, oxygen or sulfur. In heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings.

“卤素”指氟(F)、氯(Cl)、溴(Br)或碘(I)。"Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

“卤代”指基团中一个或多个(如1、2、3个或全部)氢被卤素所取代。"Halo" means that one or more (eg, 1, 2, 3 or all) hydrogen atoms in a group are replaced by halogen.

“卤代烷基”指烷基被一个或多个(如1、2、3个或全部)卤素取代，其中烷基的定义如上所述。优选为卤代C1-8烷基，更选为卤代C1-6烷基，更优选为卤代C1-3烷基。卤代烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。"Haloalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3 or all) halogens, wherein the definition of alkyl is as described above. Preferably, it is a halogenated C 1-8 alkyl group, more preferably a halogenated C 1-6 alkyl group, and more preferably a halogenated C 1-3 alkyl group. Examples of haloalkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

“烷氧基”指-O-烷基，其中烷基的定义如上所述。优选C1-8烷氧基，更优选C1-6烷氧基，最优选C1-3烷氧基。烷氧基的非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。"Alkoxy" refers to -O-alkyl, wherein alkyl is as defined above. Preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, most preferably C 1-3 alkoxy. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.

“烷氧基烷基”指烷基被一个或多个烷氧基取代，其中烷基、烷氧基的定义如上所述。优选为C1-6烷氧基C1-6烷基，更优选为C1-3烷氧基C1-3烷基。烷氧基烷基的非限制性实施例包含-CH2OCH3、-CH2OCH2CH3、-CH2CH2OCH3等。"Alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above . Preferably , it is C1-6alkoxyC1-6alkyl , more preferably C1-3alkoxyC1-3alkyl . Non - limiting examples of alkoxyalkyl include -CH2OCH3 , -CH2OCH2CH3 , -CH2CH2OCH3 , etc.

“环烷基烷基”指烷基被一个或多个环烷基取代，其中烷基、环烷基的定义如上所述。优选为C3-6环烷基C1-6烷基，更优选为C3-6环烷基C1-3烷基。环烷基烷基的非限制性实施例包含-CH2-环丙基、-CH2-环丁基、-CH2-环丁基等。"Cycloalkylalkyl" refers to an alkyl group substituted by one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group are as defined above. Preferably, it is C 3-6 cycloalkylC 1-6 alkyl, and more preferably, it is C 3-6 cycloalkylC 1-3 alkyl. Non-limiting examples of cycloalkylalkyl include -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclobutyl, and the like.

“烯基烷基”指烷基被一个或多个烯基取代，其中烷基、烯基的定义如上所述。优选为C2-8烯基C1-10烷基，更优选为C2-8烯基C1-8烷基，进一步优选为C2-8烯基C1-6烷基，进一步优选为C2-8烯基C1-3烷基。环烷基烷基的非限制性实施例包含等。"Alkenylalkyl" refers to an alkyl group substituted with one or more alkenyl groups, wherein the definitions of alkyl and alkenyl are as described above. Preferably, it is C2-8 alkenyl C1-10 alkyl, more preferably C2-8 alkenyl C1-8 alkyl, further preferably C2-8 alkenyl C1-6 alkyl, further preferably C2-8 alkenyl C1-3 alkyl. Non-limiting examples of cycloalkylalkyl include wait.

“炔基烷基”指烷基被一个或多个炔基取代，其中烷基、炔基的定义如上所述。优选为C2-8炔基C1-10烷基，更优选为C2-8炔基C1-8烷基，进一步优选为C2-8炔基C1-6烷基，进一步优选为C2-8炔基C1-3烷基。环烷基烷基的非限制性实施例包含等。"Alkynylalkyl" refers to an alkyl group substituted with one or more alkynyl groups, wherein the definitions of alkyl and alkynyl are as described above. Preferably, it is C2-8alkynylC1-10alkyl , more preferably C2-8alkynylC1-8alkyl , further preferably C2-8alkynylC1-6alkyl , further preferably C2-8alkynylC1-3alkyl . Non - limiting examples of cycloalkylalkyl include wait.

“杂环烷基烷基”指烷基被一个或多个杂环烷基取代，其中烷基、杂环烷基的定义如上所述。优选为4至10元杂环烷基C1-6烷基，更优选为4至8元杂环烷基C1-3烷基，进一步优选为3至6元杂环烷基C1-3烷基，进一步优选为4至6元杂环烷基C1-3烷基。杂环烷基烷基的非限制性实施例包含-CH2-四氢吡咯基、-CH2-氮杂环丁烷基、-CH2-哌啶基、-CH2-哌嗪基等。"Heterocycloalkylalkyl" refers to an alkyl group substituted by one or more heterocycloalkyl groups, wherein alkyl and heterocycloalkyl are as defined above. Preferably, it is a 4- to 10-membered heterocycloalkylC 1-6 alkyl group, more preferably a 4- to 8-membered heterocycloalkylC 1-3 alkyl group, further preferably a 3- to 6-membered heterocycloalkylC 1-3 alkyl group, further preferably a 4- to 6 - membered heterocycloalkylC 1-3 alkyl group. Non-limiting examples of heterocycloalkylalkyl groups include -CH 2 -tetrahydropyrrolyl, -CH 2 -azetidinyl, -CH 2 -piperidinyl, -CH 2 -piperazinyl, and the like.

“羟基取代的烷基”至烷基被一个或多个羟基取代，其中烷基的定义如上所述。优选为羟基取代的C1-10烷基，更优选为羟基取代的C1-8烷基，进一步优选为羟基取代的C1-6烷基，更优选为羟基取代的C1-3烷基。“羟基取代的烷基”的非限制性实施例包含-CH2OH、-CH2CH2OH、-CH(OH)CH3等。"Hydroxy-substituted alkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein the definition of alkyl is as described above. Preferably, it is a C 1-10 alkyl group substituted with hydroxy groups, more preferably a C 1-8 alkyl group substituted with hydroxy groups, further preferably a C 1-6 alkyl group substituted with hydroxy groups, and more preferably a C 1-3 alkyl group substituted with hydroxy groups. Non-limiting examples of "hydroxy-substituted alkyl group" include -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , and the like.

“氰基取代的烷基”至烷基被一个或多个氰基取代，其中烷基的定义如上所述。优选为氰基取代的C1-10烷基，更优选为氰基取代的C1-8烷基，进一步优选为氰基取代的C1-6烷基，进一步优选为氰基取代的C1-3烷基。“氰基取代的烷基”的非限制性实施例包含-CH2CN、-CH2CH2CN、-CH(CN)CH3等。"Cyano-substituted alkyl" refers to an alkyl group substituted with one or more cyano groups, wherein the definition of alkyl is as described above. Preferably, it is a cyano-substituted C 1-10 alkyl group, more preferably a cyano-substituted C 1-8 alkyl group, further preferably a cyano-substituted C 1-6 alkyl group, further preferably a cyano-substituted C 1-3 alkyl group. Non-limiting examples of "cyano-substituted alkyl" include -CH 2 CN, -CH 2 CH 2 CN, -CH(CN)CH 3 , and the like.

“羧基取代的烷基”至烷基被一个或多个羧基取代，其中烷基的定义如上所述。优选为羧基取代的C1-10烷基，更优选为羧基取代的C1-8烷基，进一步优选为羧基取代的C1-6烷基，进一步优选为羧基取代的C1-3烷基。“羧基取代的烷基”的非限制性实施例包含-CH2COOH、-CH2CH2 COOH、-CH(COOH)CH3等。"Carboxyl-substituted alkyl" refers to an alkyl group substituted with one or more carboxyl groups, wherein the alkyl group is as defined above. Preferably, it is a carboxyl-substituted C 1-10 alkyl group, more preferably a carboxyl-substituted C 1-8 alkyl group, further preferably a carboxyl-substituted C 1-6 alkyl group, further preferably a carboxyl-substituted C 1-3 alkyl group. Non-limiting examples of "carboxyl-substituted alkyl" include -CH 2 COOH, -CH 2 CH 2 COOH, -CH(COOH)CH 3 , and the like.

“氨基取代的烷基”至烷基被一个或多个氨基取代，其中烷基的定义如上所述。优选为氨基取代的C1-10烷基，更优选为氨基取代的C1-8烷基，进一步优选为氨基取代的C1-6烷基，进一步优选为氨基取代的C1-3烷基。“氨基取代的烷基”的非限制性实施例包含-CH2NH2、-CH2CH2NH2、-CH(NH2)CH3等。"Amino-substituted alkyl" refers to an alkyl group substituted by one or more amino groups, wherein the definition of alkyl is as described above. Preferably, it is an amino-substituted C 1-10 alkyl group, more preferably an amino-substituted C 1-8 alkyl group, further preferably an amino-substituted C 1-6 alkyl group, further preferably an amino-substituted C 1-3 alkyl group. Non-limiting examples of "amino-substituted alkyl" include -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH(NH 2 )CH 3 , and the like.

“卤代烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C1-10烷氧基，更优选为卤代C1-8烷氧基，进一步优选为卤代C1-6烷氧基，进一步优选为卤代C1-3烷氧基。卤代烷氧基包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。"Haloalkoxy" refers to an alkoxy group substituted by one or more (e.g., 1, 2, 3, 4 or 5) halogens, wherein the definition of alkoxy is as described above. Preferably, it is a halogenated C 1-10 alkoxy group, more preferably a halogenated C 1-8 alkoxy group, further preferably a halogenated C 1-6 alkoxy group, further preferably a halogenated C 1-3 alkoxy group. Halogenated alkoxy groups include (but are not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

“氨基”指-NH2，“氰基”指-CN，“硝基”指-NO2，“苯甲基”指-CH2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH3，“乙酰氨基”指-C(O)NH2，“羟甲基”指-CH2OH，“羟乙基”指-CH2CH2OH或-CHOHCH3，“羟基”指-OH，“硫醇”指-SH；“甲酰基”指-CHO；“磺酸基”指-SO3H。“Amino” refers to -NH 2 , “cyano” refers to -CN, “nitro” refers to -NO 2 , “benzyl” refers to -CH 2 -phenyl, “oxo” refers to =O, “carboxy” refers to -C(O)OH, “acetyl” refers to -C(O)CH 3 , “acetamido” refers to -C(O)NH 2 , “hydroxymethyl” refers to -CH 2 OH, “hydroxyethyl” refers to -CH 2 CH 2 OH or -CHOHCH 3 , “hydroxy” refers to -OH, “thiol” refers to -SH; “formyl” refers to -CHO; and “sulfonate” refers to -SO 3 H.

本文所述连接位点，指一个基团通过一根共价键与另一个基团连接的连接点。如本申请定义中“R2为X1时，X1为POI与L或ULM的连接位点”是指POI通过一根共价键与L或ULM连接，X1为与L或ULM的连接点，该定义与“结构为时；其中X1为POI与L或ULM的连接位点”所表示的意思相同。The attachment site as used herein refers to the point at which one group is connected to another group through a covalent bond. For example, in the definition of this application, "when R 2 is X 1 , X 1 is the attachment site of POI and L or ULM" means that POI is connected to L or ULM through a covalent bond, and X 1 is the attachment point to L or ULM. This definition is similar to "a structure having "wherein X1 is the connection site between POI and L or ULM" has the same meaning as that expressed.

如对于式(I)化合物，当POI为结构X1表示与L或ULM的连接点时，其含义与结构n0为0或1时，所表示的意思相同。For example, for the compound of formula (I), when POI is a structure When X1 represents a connection point with L or ULM, its meaning is the same as that of the structure When n 0 is 0 or 1, the meaning is the same.

再如对于式(I)化合物，ULM结构X2表示与L或POI的连接点时，其含义与结构n0为0或1时，所表示的意思相同。For example, for the compound of formula (I), the ULM structure When X2 represents a connection point with L or POI, its meaning is the same as the structure When n 0 is 0 or 1, the meaning is the same.

再如对于式(I)化合物，连接链结构X10表示与POI的连接点时，X20表示与ULM的连接点，其含义与结构所表示的意思相同。For example, for the compound of formula (I), the connecting chain structure X 10 indicates the connection point with POI, and X 20 indicates the connection point with ULM. Its meaning is the same as the structure. The meaning expressed is the same.

“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms, preferably 1 to 5 hydrogen atoms, are independently replaced by a corresponding number of substituents in a group, and more preferably 1 to 3 hydrogen atoms are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (such as olefinic) bonds.

本发明中未指出取代基数目时表示任选可取代数目的取代基进行取代。When the number of substituents is not indicated in the present invention, it means that the substituents may be substituted with the number of substituents that can be substituted.

除非另有定义，本发明所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。Unless otherwise defined, the "substituents independently selected from..." mentioned in the present invention means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different, and the substituents selected are independently of each other.

除非另有定义，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基优选为1至5个以下基团，独立地选自氘、卤素(优选为氟、氯)、氰基、羟基、羧基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、C2-4烯基、C2-4炔基、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、氰基取代C1-8烷基(优选为氰基取代C1-6烷基，更优选为氰基取代C1-3烷基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、NRA0RB0、-SO2C1-3烷基、-S(O)C1-3烷基、-C(O)NRA10RB10、-C(O)C1-8烷基(优选为-C(O)C1-6烷基，更优选为-C(O)C1-3烷基)、-C(O)OC1-8烷基(优选为-C(O)OC1-6烷基，更优选为-C(O)OC1-3烷基)、-OC(O)C1-8烷基(优选为-OC(O)C1-6烷基，更优选为-OC(O)C1-3烷基)、C3-6环烷基、C3-6环烷基氧基、3至6元杂环烷基、苯基、5至6元杂芳基；其中取代基中的所述3至6元杂环烷基、苯基、5至6元杂芳基为未取代的或被1、2或3个各自独立地选自卤素、氰基、羟基、羧基、C1-3烷基、C1-3烷氧基、C2-4烯基、C2-4炔基、卤代C1-3烷基、卤代C1-3烷氧基、NRA0RB0、-SO2C1-3烷基、-S(O)C1-3烷基、-C(O)NRA10RB10、-C(O)OC1-3烷基、-OC(O)C1-3烷基、C3-6环烷基、C3-6环烷基氧基、3至6元杂环烷基、苯基、5至6元杂芳基；Unless otherwise defined, any group herein may be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 groups or less, independently selected from deuterium, halogen (preferably fluorine, chlorine), cyano, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), cyano-substituted C 1-8 alkyl (preferably cyano-substituted C 1-6 alkyl, more preferably cyano-substituted C 1-3 alkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), NR A0 R B0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR A10 R B10 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl; wherein the 3 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl in the substituent is unsubstituted or replaced by 1, 2 or 3 groups independently selected from halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C C 1-3 alkyl, halogenated C 1-3 alkoxy, NR A0 R B0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR A10 R B10 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl;

RA10、RB10各自独立地为氢或C1-3烷基；或者RA10、RB10与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未被取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C1-3烷基、C1-3烷氧基、C2-4烯基、C2-4炔基、卤代C1-3烷基、卤代C1-3烷氧基、-SO2C1-3烷基、-S(O)C1-3烷基、-C(O)NH2、-C(O)NH(C1-3烷基)、-C(O)N(C1-3烷基)2、-C(O)OC1-3烷基、-OC(O)C1-3烷基、C3-6环烷基、C3-6环烷基氧基、3至6元杂环烷基；R A10 and R B10 are each independently hydrogen or C 1-3 alkyl; or R A10 , R B10 and the nitrogen atom to which they are connected together form a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 -membered cycloalkyloxy, 3- to 6-membered heterocycloalkyl;

RA0、RB0各自独立地为氢、C1-3烷基或乙酰基；或者RA0、RB0与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未被取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C1-3烷基、C1-3烷氧基、C2-4烯基、C2-4炔基、卤代C1-3烷基、卤代C1-3烷氧基、-SO2C1-3烷基、-S(O)C1-3烷基、-C(O)NH2、-C(O)NH(C1-3烷基)、-C(O)N(C1-3烷基)2、-C(O)OC1-3烷基、-OC(O)C1-3烷基、C3-6环烷基、C3-6环烷基氧基、3至6元杂环烷基。R A0 and R B0 are each independently hydrogen, C 1-3 alkyl or acetyl; or R A0 , R B0 and the nitrogen atom to which they are connected together form a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 -membered cycloalkyloxy, 3- to 6-membered heterocycloalkyl.

本发明中，一个方案中出现两个或更多个“优选”时，任意的两个“优选”可以是彼此独立的。In the present invention, when two or more “preferably” appear in one embodiment, any two “preferably” may be independent of each other.

本发明中，当取代基的数量大于1时，任意的两个取代基可以相同或不同。如，可以为两个相同或不同的卤素取代，可以为一个卤素和一个羟基取代。In the present invention, when the number of substituents is greater than 1, any two substituents may be the same or different. For example, they may be substituted by two halogens that are the same or different, or by one halogen and one hydroxyl.

本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。Each type of substituent group described above may itself be substituted by the groups described herein.

药物组合物Pharmaceutical composition

通常本发明化合物或其药学上可接受的盐、或其立体异构体可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。Usually the compounds of the present invention or their pharmaceutically acceptable salts, or their stereoisomers can be used in suitable dosage forms with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules and syrups.

“药学上可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。"Pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient that is compatible with a patient, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to a target site without terminating the activity of the agent.

本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。The compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。"Therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

“患者”是指一种动物，优选为哺乳动物，更优选为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。"Patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。"Treatment" means to lessen, slow the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

所述“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的与无机酸或有机酸所形成的盐。"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other adverse effects.

“药学上可接受的碱加成盐”，包括但不限于无机碱的盐和有机碱的盐。"Pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases and salts with organic bases.

本发明的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。当化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括这两种立体异构体以及这两种立体异构体的混合物，如外消旋体、非对映异构体混合物等。除非另有说明，用楔形键表示一个立体中心的绝对构型。当本文所述的化合物含有烯属双键或其他几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构体形式均包括在本申请的范围内。The compounds of the present invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound comprises enantiomers. When a compound contains more than one chiral center, diastereomers may exist. The present invention includes both stereoisomers and mixtures of both stereoisomers, such as racemates, diastereomeric mixtures, etc. Unless otherwise indicated, the compounds are represented by wedge-shaped bonds. Represents the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of this application.

本发明化合物的对映异构体、非对映异构体以及这些异构体的混合物均在本发明的保护范围内。对映异构体、非对映异构体可以通过本领域已知的方法进行拆分，例如结晶以及手性色谱等方法。The enantiomers, diastereomers and mixtures of these isomers of the compounds of the present invention are all within the protection scope of the present invention. Enantiomers and diastereomers can be separated by methods known in the art, such as crystallization and chiral chromatography.

制备方法Preparation method

本发明提供了式(I)化合物的制备方法，使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本发明描述的方法组合可以合成式(I)化合物。本发明给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。所述反应可以按顺序使用，以提供本发明的化合物，或者它们可以用于合成片段，所述片段通过本发明所描述的方法和/或本领域已知的方法随后加入。The present invention provides methods for preparing compounds of formula (I), which can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. The solvents, temperatures and other reaction conditions provided herein can be varied according to the art. The reactions can be used in sequence to provide compounds of the present invention, or they can be used to synthesize fragments, which are subsequently added by the methods described herein and/or methods known in the art.

上述方案中的反应，本领域技术人员可参照本发明中记载的具体实施例或者根据现有文献，根据参与反应的化合物的性质进行适应性调整，而不会给本领域技术人员造成困难。The reactions in the above schemes can be adaptively adjusted by those skilled in the art with reference to the specific embodiments described in the present invention or according to existing literature according to the properties of the compounds involved in the reactions without causing difficulties to those skilled in the art.

本发明描述的化合物可以使用与下述类似的方法或实施例中所述的示例性方法，或本领域技术人员所用的相关公开文献，通过使用适当的可选择的起始原料合成化合物。用于合成本发明所描述的化合物的起始原料或中间体可以被合成或可以从商业来源获得，如现有文献未报道或无法从商业途径获得，则可以采用类似物的类似现有制备方法或本发明中记载的类似制备方法制备得到。如本发明描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本发明公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本发明提供的分子中的各种部分。The compounds described in the present invention can be synthesized using appropriate optional starting materials using methods similar to the following or the exemplary methods described in the examples, or related open literature used by those skilled in the art. The starting materials or intermediates used to synthesize the compounds described in the present invention can be synthesized or can be obtained from commercial sources. If the existing literature is not reported or cannot be obtained from commercial sources, similar existing preparation methods of analogs or similar preparation methods recorded in the present invention can be used to prepare. Compounds such as described in the present invention and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art. The general method for preparing the compounds disclosed in the present invention can be from reactions known in the art, and the reaction can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various parts into the molecules provided by the present invention.

与现有技术相比，本发明的主要优点在于：本申请的化合物具有优异的EED蛋白降解作用和肿瘤细胞增殖抑制作用，且具有优异的药代动力学特征，对细胞色素酶P450(CYP450)具有较好的作用，安全性好，更适于治疗EED蛋白活性异常的疾病或病症(如癌症等增殖性疾病)。Compared with the prior art, the main advantages of the present invention are that the compounds of the present invention have excellent EED protein degradation effect and tumor cell proliferation inhibition effect, and have excellent pharmacokinetic characteristics, have a good effect on cytochrome P450 (CYP450), have good safety, and are more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).

下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention.

试剂与仪器Reagents and instruments

1H NMR：Bruker AVANCE-400核磁仪，内标为四甲基硅烷(TMS)。 1 H NMR: Bruker AVANCE-400 nuclear magnetic spectrometer, internal standard is tetramethylsilane (TMS).

LC-MS：Agilent 1290HPLC System/6130/6150MS液质联用质谱仪(生产商：安捷伦)，柱子Waters BEH/CHS，50×2.1mm，1.7μm。LC-MS: Agilent 1290 HPLC System/6130/6150MS liquid chromatography-mass spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50×2.1 mm, 1.7 μm.

制备高效液相色谱(pre-HPLC)：GX-281(生产商：吉尔森)。Preparative high performance liquid chromatography (pre-HPLC): GX-281 (Manufacturer: Gilson).

采用ISCO Combiflash-Rf75或Rf200型自动过柱仪，Agela 4g、12g、20g、40g、80g、120g一次性硅胶柱。Use ISCO Combiflash-Rf75 or Rf200 automatic column analyzer and Agela 4g, 12g, 20g, 40g, 80g, and 120g disposable silica gel columns.

已知的起始原料可以采用或按照本领域已知的方法来合成，或可以购自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)和达瑞化学品等公司。Known starting materials can be used or synthesized according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc and Darui Chemicals.

实施例中，反应进程的监测可采用薄层色谱法(TLC)，化合物纯化可采用柱层析。柱层析或TLC所用的展开剂体系可选自：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、石油醚和乙酸乙酯体系和丙酮体系等，溶剂的体积比根据化合物的极性不同而进行调节。In the embodiment, the reaction progress can be monitored by thin layer chromatography (TLC), and the compound purification can be performed by column chromatography. The developing solvent system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc. The volume ratio of the solvent is adjusted according to the different polarities of the compound.

如本文所用，PE：石油醚，EA：乙酸乙酯，THF：四氢呋喃，H2O：水，DMF：N,N-二甲基甲酰胺，DME：二甲醚，DCM：二氯甲烷，MeOH：甲醇，EtOH：乙醇，DMSO：二甲亚砜，ACN：乙腈，DIPEA：N,N-二异丙基乙胺，TEA/Et3N：三乙胺，TFA：三氟乙酸，FA：甲酸，SOCl2：氯化亚砜，CCl4：四氯化碳，AcOH/CH3COOH：乙酸，p-TsOH：对甲苯磺酸，NMI：N-甲基咪唑，NMP：N-甲基吡咯烷酮，LiOH：氢氧化锂，TCFH：N,N,N',N'-四甲基氯甲脒六氟磷酸盐，HATU：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，Na(CN)BH3或NaBH3CN：氰基硼氢化钠，NaBH(OAc)3：三乙酰氧基硼氢化钠，NaBH：硼氢化钠，(Boc)2O：二碳酸二叔丁酯，PdOH/C：氢氧化钯/碳，Pd/C：钯碳，Pd(dppf)Cl2：1,1'-双二苯基膦二茂铁二氯化钯；Pd(OAc)2：醋酸钯，Ruphos-Pd-G3：甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)，Pd2(dba)3：三(二亚苄基丙酮)二钯，CataCXium A：正丁基二(1-金刚烷基)膦，Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽，XPhos：2-二环己基膦-2',4',6'-三异丙基联苯，Ruphos：2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯，K2CO3：碳酸钾，Cs2CO3：碳酸铯，NaHCO3：碳酸氢钠，t-BuOK：叔丁醇钾，t-BuONa：叔丁醇钠，(Pin)2B2：双(频哪醇)二硼，NBS：N-溴代琥珀酰亚胺，AIBN：偶氮二异丁腈，LiHMDS：二(三甲基硅基)氨基锂，NH4HCO3：碳酸氢铵，NH4Cl：氯化铵，NaH：氢化钠，NaOH：氢氧化钠，KOAc：醋酸钾，CuBr：溴化亚铜，BnBr：溴化苄，PTSA：对甲苯磺酰胺。As used herein, PE: petroleum ether, EA: ethyl acetate, THF: tetrahydrofuran, H 2 O: water, DMF: N,N-dimethylformamide, DME: dimethyl ether, DCM: dichloromethane, MeOH: methanol, EtOH: ethanol, DMSO: dimethyl sulfoxide, ACN: acetonitrile, DIPEA: N,N-diisopropylethylamine, TEA/Et 3 N: triethylamine, TFA: trifluoroacetic acid, FA: formic acid, SOCl 2 : thionyl chloride, CCl 4 : carbon tetrachloride, AcOH/CH 3 COOH: acetic acid, p-TsOH: p-toluenesulfonic acid, NMI: N-methylimidazole, NMP: N-methylpyrrolidone, LiOH: lithium hydroxide, TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Na(CN)BH 3 or NaBH 3 CN: sodium cyanoborohydride, NaBH(OAc) 3 : sodium triacetoxyborohydride, NaBH: sodium borohydride, (Boc) 2 O: di-tert-butyl dicarbonate, PdOH/C: palladium hydroxide/carbon, Pd/C: palladium on carbon, Pd(dppf)Cl 2 : 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride; Pd(OAc) 2 : palladium acetate, Ruphos-Pd-G3: (2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium, CataCXium A: n-butyldi(1-adamantyl)phosphine, Xantphos: 4,5-bis(diphenylphosphino-9,9-dimethylxanthene, XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl, K 2 CO 3 : potassium carbonate, Cs 2 CO 3 : cesium carbonate, NaHCO 3 : sodium bicarbonate, t-BuOK: potassium tert-butoxide, t-BuONa: sodium tert-butoxide, (Pin) 2 B 2 : bis(pinacol)diboron, NBS: N-bromosuccinimide, AIBN: azobisisobutyronitrile, LiHMDS: lithium bis(trimethylsilyl)amide, NH 4 HCO 3 : ammonium bicarbonate, NH 4 Cl: ammonium chloride, NaH: sodium hydride, NaOH: sodium hydroxide, KOAc: potassium acetate, CuBr: cuprous bromide, BnBr: benzyl bromide, PTSA: p-toluenesulfonamide.

如本文中涉及的百分比含量，如无特别说明，对于固液混合和固相-固相混合均指质量百分比，对于液相-液相混合指体积百分比。如无特别说明，溶剂均为水。As for the percentage content involved in this article, unless otherwise specified, for solid-liquid mixing and solid-solid mixing, it refers to mass percentage, and for liquid-liquid mixing, it refers to volume percentage. Unless otherwise specified, the solvent is water.

如本文所用，室温是指约20-30℃。As used herein, room temperature refers to about 20-30°C.

如本文所用，“过夜”是指约进行10h～16h。As used herein, "overnight" means about 10 to 16 hours.

中间体Z1的制备
Preparation of intermediate Z1

步骤1:将4-溴-3-甲酰基苯甲酸甲酯(5g,20.57mmol)和丙-2-胺(2.43g,41.14mmol)溶于乙醇(60mL)中，然后加入乙酸(3.09g,51.43mmol,2.94mL)。该反应在20℃下搅拌18h,然后降低温度到0℃，加入Na(CN)BH3(2.59g,41.14mmol)，并在0℃搅拌3h。反应完成后，用碳酸氢钠水溶液淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash(80g，0-100％EA/PE)纯化，得到产物Z1-a(5.4g,淡黄色固体),收率91.73％。MS m/z(ESI):286.1[M+H]+。Step 1: Dissolve methyl 4-bromo-3-formylbenzoate (5 g, 20.57 mmol) and propan-2-amine (2.43 g, 41.14 mmol) in ethanol (60 mL), then add acetic acid (3.09 g, 51.43 mmol, 2.94 mL). The reaction was stirred at 20 ° C for 18 h, then the temperature was lowered to 0 ° C, Na (CN) BH 3 (2.59 g, 41.14 mmol) was added, and stirred at 0 ° C for 3 h. After the reaction was completed, it was quenched with sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (80 g, 0-100% EA/PE) to obtain product Z1-a (5.4 g, light yellow solid), with a yield of 91.73%. MS m/z (ESI): 286.1 [M + H] + .

步骤2:将Z1-a(5.4g,18.87mmol)溶于DCM(60mL)中，然后将Et3N(7.64g,75.48mmol)加入其中，降低温度到0℃，再将(Boc)2O(6.18g,28.31mmol)滴加到反应液中。该反应在0℃下升到室温并搅拌18小时。反应完成后，将反应液浓缩后经CombiFlash(40g，0-35％EA/PE)纯化，得到产物Z1-b(4.7g,无色油状),收率：64.48％。MS m/z(ESI):286.1[M-100+H]+。Step 2: Z1-a (5.4 g, 18.87 mmol) was dissolved in DCM (60 mL), and then Et 3 N (7.64 g, 75.48 mmol) was added thereto, the temperature was lowered to 0°C, and (Boc) 2 O (6.18 g, 28.31 mmol) was added dropwise to the reaction solution. The reaction was heated to room temperature at 0°C and stirred for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (40 g, 0-35% EA/PE) to obtain the product Z1-b (4.7 g, colorless oil), yield: 64.48%. MS m/z (ESI): 286.1 [M-100+H] + .

步骤3:将8-溴-5-(((5-氟-2，3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1，5-c]嘧啶-1-羧酸乙酯(1g,2.30mmol)和Z1-b(1.77g,4.60mmol)溶于DME(20mL)和水(2mL)中，然后加入Pd(OAc)2(51.58mg,229.75μmol)，CataCXium A(164.75mg,459.51μmol)，K2CO3(1.27g,9.19mmol)和(Pin)2B2(1.17g,4.60mmol)。该反应在70℃下搅拌18h。反应完成后，将反应液过滤，滤液浓缩后经CombiFlash(24g，0-80％EA/PE)纯化，得到Z1-c(950mg,淡黄色固体),收率：62.49％。MS m/z(ESI):562.2[M-100+H]+。Step 3: Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1 g, 2.30 mmol) and Z1-b (1.77 g, 4.60 mmol) were dissolved in DME (20 mL) and water (2 mL), then Pd(OAc) 2 (51.58 mg, 229.75 μmol), CataCXium A (164.75 mg, 459.51 μmol), K 2 CO 3 (1.27 g, 9.19 mmol) and (Pin) 2 B 2 (1.17 g, 4.60 mmol) were added. The reaction was stirred at 70° C. for 18 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and purified by CombiFlash (24 g, 0-80% EA/PE) to obtain Z1-c (950 mg, light yellow solid), yield: 62.49%. MS m/z (ESI): 562.2 [M-100+H] + .

步骤4:将Z1-c(950mg,1.44mmol)溶于DCM(15mL)中，然后加入TFA(163.70mg,1.44mmol,2.5mL)。该反应在20℃下搅拌3h。反应完成后，将反应液浓缩得到Z1-d(806mg,油状物,粗品)，收率：99.97％。MS m/z(ESI):562.2[M+H]+。Step 4: Z1-c (950 mg, 1.44 mmol) was dissolved in DCM (15 mL), and then TFA (163.70 mg, 1.44 mmol, 2.5 mL) was added. The reaction was stirred at 20°C for 3 h. After the reaction was completed, the reaction solution was concentrated to obtain Z1-d (806 mg, oil, crude product), yield: 99.97%. MS m/z (ESI): 562.2 [M+H] + .

步骤5:将Z1-d(806mg,1.44mmol)溶于THF(20mL)和水(5mL)中，然后加入LiOH(1.03g,43.06mmol)。该反应在75℃下搅拌18h。反应完成后，冷却至室温，过滤，滤液用稀盐酸(3mol/L)调pH至2-3,浓缩得到中间体Z1(2.1g,棕色固体，粗品)。MS m/z(ESI):520.2[M+H]+。Step 5: Dissolve Z1-d (806 mg, 1.44 mmol) in THF (20 mL) and water (5 mL), then add LiOH (1.03 g, 43.06 mmol). The reaction was stirred at 75 °C for 18 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was adjusted to pH 2-3 with dilute hydrochloric acid (3 mol/L), and concentrated to obtain intermediate Z1 (2.1 g, brown solid, crude product). MS m/z (ESI): 520.2 [M+H] + .

中间体Z2的制备
Preparation of intermediate Z2

步骤1:将5-溴-4-甲基吡啶甲酸(12.5g,57.86mmol)溶于MeOH(250mL)中，然后加入SOCl2(17.15g,144.14mmol,10.47mL)，在84℃下搅拌2h。反应完成后，冷却至室温，用饱和碳酸氢钠水溶液淬灭，用乙酸乙酯(3×500mL)萃取，合并有机相用饱和食盐水洗涤，经无水硫酸钠干燥，浓缩后得到Z2-a(13g,白色固体,粗品),收率：97.66％。MS m/z(ESI):230.0[M+H]+。Step 1: Dissolve 5-bromo-4-methylpicolinic acid (12.5 g, 57.86 mmol) in MeOH (250 mL), then add SOCl 2 (17.15 g, 144.14 mmol, 10.47 mL) and stir at 84°C for 2 h. After the reaction is completed, cool to room temperature, quench with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate (3×500 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain Z2-a (13 g, white solid, crude product), yield: 97.66%. MS m/z (ESI): 230.0 [M+H] + .

步骤2:将Z2-a(5g,21.73mmol)溶于CCl4(70mL)中，然后加入NBS(11.60g,65.20mmol)和AIBN(356.88mg,2.17mmol)，在80℃下搅拌18h。反应完成后，冷却至室温，过滤，滤液浓缩得到Z2-b(8.43g,淡黄色油状，粗品)，收率：100.00％。MS m/z(ESI):385.8[M+H]+。Step 2: Z2-a (5 g, 21.73 mmol) was dissolved in CCl 4 (70 mL), and then NBS (11.60 g, 65.20 mmol) and AIBN (356.88 mg, 2.17 mmol) were added, and stirred at 80° C. for 18 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated to obtain Z2-b (8.43 g, light yellow oil, crude product), yield: 100.00%. MS m/z (ESI): 385.8 [M+H] + .

步骤3:将Z2-b(8g,20.63mmol)溶于THF(100mL)，降温到0-5℃，滴加亚磷酸二乙酯(3.11g,22.69mmol)和DIPEA(4g,30.94mmol,5.39mL)，然后25℃反应1h。反应结束后将反应液浓缩后经CombiFlash(120g，0-50％PE/EA)纯化，得到Z2-c(4.2g,白色固体),收率：65.91％。MS m/z(ESI):307.9[M+H]+。Step 3: Dissolve Z2-b (8 g, 20.63 mmol) in THF (100 mL), cool to 0-5°C, add diethyl phosphite (3.11 g, 22.69 mmol) and DIPEA (4 g, 30.94 mmol, 5.39 mL) dropwise, and react at 25°C for 1 h. After the reaction, concentrate the reaction solution and purify it with CombiFlash (120 g, 0-50% PE/EA) to obtain Z2-c (4.2 g, white solid), yield: 65.91%. MS m/z (ESI): 307.9 [M+H] + .

步骤4:将Z2-c(2g,6.47mmol)溶于EtOH(1mL)，将反应降温到0℃，加入异丙胺(1.91g,32.37mmol)，自然升到室温继续搅拌2h。将反应液浓缩后得到Z2-d(1.86g,无色油状物,粗品),收率：100.00％。MS m/z(ESI):287.0[M+H]+。Step 4: Dissolve Z2-c (2 g, 6.47 mmol) in EtOH (1 mL), cool the reaction mixture to 0°C, add isopropylamine (1.91 g, 32.37 mmol), warm to room temperature and continue stirring for 2 h. Concentrate the reaction mixture to obtain Z2-d (1.86 g, colorless oil, crude product), yield: 100.00%. MS m/z (ESI): 287.0 [M+H] + .

步骤5:将Z2-d(1.86g,6.48mmol)溶于DCM(20mL)，冰水下加入Et3N(3.28g,32.39mmol)，然后加入(Boc)2O(3.53g,9.72mmol,纯度60％)，自然升到室温继续搅拌18h。反应结束后，将反应液浓缩后经CombiFlash(24g，0-50％EA/PE)纯化，得到Z2-e(2.4g,无色油状物),收率：95.68％。MS m/z(ESI):387.1[M+H]+。Step 5: Z2-d (1.86 g, 6.48 mmol) was dissolved in DCM (20 mL), and Et 3 N (3.28 g, 32.39 mmol) was added under ice water, and then (Boc) 2 O (3.53 g, 9.72 mmol, purity 60%) was added, and the mixture was naturally warmed to room temperature and stirred for 18 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-50% EA/PE) to obtain Z2-e (2.4 g, colorless oil), yield: 95.68%. MS m/z (ESI): 387.1 [M+H] + .

步骤6:将Z2-e(500mg,1.15mmol)和8-溴-5-(((5-氟-2，3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1，5-c]嘧啶-1-羧酸乙酯(667.33mg,1.72mmol)溶于DME(10mL)和水(1mL)中，然后加入Pd(OAc)2(77.37mg,344.63μmol)，CataCXium A(205.94mg,574.39μmol)，K2CO3(793.86mg,5.74mmol)和(Pin)2B2(875.15mg,3.45mmol)，在70℃条件下搅拌18h。反应结束后，将反应液过滤，滤液浓缩后经CombiFlash(12g，0-80％EA/PE)纯化，得到Z2-f(212mg,淡黄色固体),收率：2.78e-2％。MS m/z(ESI):663.3[M+H]+。Step 6: Z2-e (500 mg, 1.15 mmol) and ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (667.33 mg, 1.72 mmol) were dissolved in DME (10 mL) and water (1 mL), and then Pd(OAc) 2 (77.37 mg, 344.63 μmol), CataCXium A (205.94 mg, 574.39 μmol), K 2 CO 3 (793.86 mg, 5.74 mmol) and (Pin) 2 B 2 (875.15 mg, 3.45 mmol) were added and stirred at 70° C. for 18 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and purified by CombiFlash (12 g, 0-80% EA/PE) to obtain Z2-f (212 mg, light yellow solid), yield: 2.78e-2%. MS m/z (ESI): 663.3 [M+H] + .

步骤7:将Z2-f(300mg,452.69μmol)溶于DCM(15mL)，然后加入TFA(4mL)，在室温下搅拌18h。反应完成后，用碳酸氢钠水溶液中和，再用二氯甲烷和甲醇(10:1；3×70mL)混合溶液萃取，合并有机相用无水硫酸钠干燥，浓缩后得到Z2-g(248mg,淡黄色固体,粗品)，收率：99.87％。MS m/z(ESI):563.3[M+H]+。Step 7: Z2-f (300 mg, 452.69 μmol) was dissolved in DCM (15 mL), and then TFA (4 mL) was added and stirred at room temperature for 18 h. After the reaction was completed, it was neutralized with sodium bicarbonate aqueous solution, and then extracted with a mixed solution of dichloromethane and methanol (10:1; 3×70 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain Z2-g (248 mg, light yellow solid, crude product), yield: 99.87%. MS m/z (ESI): 563.3 [M+H] + .

步骤8:将Z2-g(248.44mg,441.59μmol)溶于THF(20mL)和水(5mL)中，然后加入LiOH(317.26mg,13.25mmol)，在75℃条件下搅拌18h。反应完成后，冷却至室温，过滤，滤液用稀盐酸(3mol/L)调pH至2-3,浓缩后冻干，得到中间体Z2(763mg,土黄色固体，30％内容物),收率：99.63％。MS m/z(ESI):521.2[M+H]+。Step 8: Z2-g (248.44 mg, 441.59 μmol) was dissolved in THF (20 mL) and water (5 mL), and then LiOH (317.26 mg, 13.25 mmol) was added and stirred at 75°C for 18 h. After the reaction was completed, it was cooled to room temperature and filtered. The filtrate was adjusted to pH 2-3 with dilute hydrochloric acid (3 mol/L), concentrated and freeze-dried to obtain intermediate Z2 (763 mg, khaki solid, 30% content), yield: 99.63%. MS m/z (ESI): 521.2 [M+H] + .

中间体Z3的制备
Preparation of intermediate Z3

步骤1:在室温下，将2-溴-5-硝基苯甲醛(5.0g,21.74mmol)和丙-2-胺(1.67g,28.26mmol)溶在DCM(40mL)和甲醇(4mL)中，随后加入醋酸(1.69g,28.69mmol)，在25℃下搅拌16小时。然后加入NaBH4(1.64g,43.47mmol)，在25℃下继续搅拌2小时。在反应完全后，将反应液倒入饱和碳酸氢钠水溶液(50mL)中，二氯甲烷(30mL×3)萃取水相，合并有机相用无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(EA/PE＝50～60％)，得到Z3-a(3.70g，黄色油状物)。收率:62.32％。MS m/z(ESI):273.0[M+H]+。Step 1: 2-Bromo-5-nitrobenzaldehyde (5.0 g, 21.74 mmol) and propan-2-amine (1.67 g, 28.26 mmol) were dissolved in DCM (40 mL) and methanol (4 mL) at room temperature, followed by the addition of acetic acid (1.69 g, 28.69 mmol) and stirring at 25°C for 16 hours. Then NaBH 4 (1.64 g, 43.47 mmol) was added and stirring continued at 25°C for 2 hours. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution (50 mL), the aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (EA/PE=50-60%) to obtain Z3-a (3.70 g, yellow oil). Yield: 62.32%. MS m/z(ESI):273.0[M+H] + .

步骤2:将Z3-a(2.90g,10.62mmol)溶在DCM(10mL)中，加入三乙胺(3.22g,31.85mmol)和(Boc)2O(4.63g,21.24mmol)，升温至40℃搅拌4小时。在反应完全后，将反应液浓缩后经硅胶柱层析纯化(EA/PE＝10～20％)，得Z3-b(3.60g，白色固体)，收率:90.84％。MS m/z(ESI):373.2[M+H]+。Step 2: Dissolve Z3-a (2.90 g, 10.62 mmol) in DCM (10 mL), add triethylamine (3.22 g, 31.85 mmol) and (Boc) 2 O (4.63 g, 21.24 mmol), heat to 40°C and stir for 4 hours. After the reaction is complete, concentrate the reaction solution and purify it by silica gel column chromatography (EA/PE=10-20%) to obtain Z3-b (3.60 g, white solid), yield: 90.84%. MS m/z (ESI): 373.2 [M+H] + .

步骤3:将8-溴-5-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1,5-c]嘧啶-1-羧酸乙酯(350mg,4.60mmol)和Z3-b(600mg,1.61mmol)溶于乙二醇二甲醚(5mL)和水(0.5mL)中，加入Pd(OAc)2(36mg,0.20mmol)、CataCXium A(115mg,0.40mmol)、碳酸钾(556mg,5.00mmol)和(Pin)2B2(613mg,2.41mmol)，在70℃氮气氛围下搅拌18小时。反应完成后，冷却至室温，将反应液浓缩后经硅胶柱层析纯化(MeOH/DCM＝3～5％)，得到Z3-c(200mg，黄色固体)，收率:38.34％。MS m/z(ESI):649.3[M+H]+。Step 3: Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (350 mg, 4.60 mmol) and Z3-b (600 mg, 1.61 mmol) were dissolved in ethylene glycol dimethyl ether (5 mL) and water (0.5 mL), and Pd(OAc) 2 (36 mg, 0.20 mmol), CataCXium A (115 mg, 0.40 mmol), potassium carbonate (556 mg, 5.00 mmol) and (Pin) 2 B 2 (613 mg, 2.41 mmol) were added, and the mixture was stirred at 70° C. under nitrogen atmosphere for 18 hours. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH/DCM=3-5%) to obtain Z3-c (200 mg, yellow solid), yield: 38.34%. MS m/z (ESI): 649.3 [M+H] + .

步骤4:将Z3-c(200mg,0.31mmol)溶于DCM(5mL)中，加入TFA(2.5mL)，在25℃下搅拌2小时。反应完成后，将反应液浓缩后得到Z3-d(165mg，黄色油)，收率:97.56％。MS m/z(ESI):549.4[M+H]+。Step 4: Dissolve Z3-c (200 mg, 0.31 mmol) in DCM (5 mL), add TFA (2.5 mL), and stir at 25° C. for 2 hours. After the reaction is completed, the reaction solution is concentrated to obtain Z3-d (165 mg, yellow oil), yield: 97.56%. MS m/z (ESI): 549.4 [M+H] + .

步骤5:将Z3-d(165mg,0.30mmol)溶于THF(6mL)、甲醇(2mL)和水(2mL)中，加入氢氧化锂一水合物(126mg,3.01mmol)，在70℃下搅拌12小时。反应完成后，将反应液浓缩后经过柱机反相(C18，MeCN/0.1％FA in H2O＝40％～60％)纯化，得到Z3-e(60mg，黄色固体)，收率:38.32％。MS m/z(ESI):521.2[M+H]+。Step 5: Dissolve Z3-d (165 mg, 0.30 mmol) in THF (6 mL), methanol (2 mL) and water (2 mL), add lithium hydroxide monohydrate (126 mg, 3.01 mmol), and stir at 70°C for 12 hours. After the reaction is completed, the reaction solution is concentrated and purified by column reverse phase (C18, MeCN/0.1% FA in H 2 O=40% to 60%) to obtain Z3-e (60 mg, yellow solid), yield: 38.32%. MS m/z (ESI): 521.2 [M+H] + .

步骤6:将Z3-e(60mg,0.12mmol)溶于DMF(3mL)中，依次加入HATU(88mg,0.23mmol)和DIPEA(74mg,0.58mmol)，在25℃下搅拌2小时。反应完成后，向反应液加水(10mL)淬灭，用乙酸乙酯(20mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩得到Z3-f(50mg，黄色固体，粗品)，收率:86.33％。MS m/z(ESI):503.2[M+H]+。Step 6: Z3-e (60 mg, 0.12 mmol) was dissolved in DMF (3 mL), HATU (88 mg, 0.23 mmol) and DIPEA (74 mg, 0.58 mmol) were added in sequence, and stirred at 25°C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give Z3-f (50 mg, yellow solid, crude product), yield: 86.33%. MS m/z (ESI): 503.2 [M+H] + .

步骤7:将Z3-f(50mg,0.10mmol)溶于THF(6mL)、甲醇(2mL)和醋酸(2mL)中，加入锌粉(65mg,1.00mmol)，在45℃下搅拌1小时。反应完成后，将反应液通过硅藻土过滤，滤饼用甲醇(6mL×2)洗涤，滤液加水(20mL)稀释，用乙酸乙酯(20mL×2)萃取，合并有机相用无水硫酸钠干燥，浓缩后得到中间体Z3(40mg，黄色固体，粗品)，收率:85.08％。MS m/z(ESI):473.0[M+H]+。Step 7: Dissolve Z3-f (50 mg, 0.10 mmol) in THF (6 mL), methanol (2 mL) and acetic acid (2 mL), add zinc powder (65 mg, 1.00 mmol), and stir at 45 ° C for 1 hour. After the reaction is completed, the reaction solution is filtered through diatomaceous earth, the filter cake is washed with methanol (6 mL × 2), the filtrate is diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases are combined and dried over anhydrous sodium sulfate, and concentrated to obtain intermediate Z3 (40 mg, yellow solid, crude product), yield: 85.08%. MS m/z (ESI): 473.0 [M + H] + .

实施例1化合物H1的制备
Example 1 Preparation of Compound H1

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(1g,2.32mmol)和4-(叔丁氧基羰基氨基)丁酸(542.83mg,2.67mmol)溶于DMF(10mL)中，然后将NMI(1.01g,12.31mmol)加入其中。该反应在20℃下搅拌10分钟,然后加入TCHF(781.99mg,2.79mmol)，室温搅拌3h。反应完成后，将反应液浓缩后经CombiFlash(24g，0-10％，MeOH/DCM)纯化，得到产物H1-a(1.3g,白色固体),收率：90.90％。MS m/z(ESI):616.4[M+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1 g, 2.32 mmol) and 4-(tert-butoxycarbonylamino)butyric acid (542.83 mg, 2.67 mmol) were dissolved in DMF (10 mL), and NMI (1.01 g, 12.31 mmol) was added. The reaction was stirred at 20 ° C for 10 minutes, and then TCHF (781.99 mg, 2.79 mmol) was added and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10%, MeOH/DCM) to obtain the product H1-a (1.3 g, white solid), yield: 90.90%. MS m/z(ESI):616.4[M+H] + .

步骤2:将H1-a(1.3g,2.11mmol)溶于DCM(12mL)中，然后加入TFA(2.41g,21.11mmol)。该反应在20℃下搅拌18h。反应完成后，用饱和碳酸氢钠水溶液淬灭，用二氯甲烷和甲醇(10:1；3×150mL)萃取，合并有机相经无水硫酸钠干燥，浓缩后得到H1-b(1g,粘稠的淡黄色,粗品)，收率：91.86％。MS m/z(ESI):516.3[M+H]+。Step 2: H1-a (1.3 g, 2.11 mmol) was dissolved in DCM (12 mL), and then TFA (2.41 g, 21.11 mmol) was added. The reaction was stirred at 20 °C for 18 h. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane and methanol (10:1; 3×150 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give H1-b (1 g, viscous light yellow, crude product), yield: 91.86%. MS m/z (ESI): 516.3 [M+H] + .

步骤3:将中间体Z1(300mg)溶于THF(20mL)中，然后加入DIPEA(1.04g,8.08mmol,1.41mL)和HATU(980.35mg,2.60mmol)。该反应在20℃下搅拌18h，再加入H1-b(387.11mg,750.70μmol)，继续搅拌3h。应完成后，将反应液浓缩后经CombiFlash(12g，0-15％MeOH/DCM)纯化，再经过制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：35％-68％乙腈变化)纯化，得到H1(123.78mg),收率：21.45％。MS m/z(ESI):500.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.74(s,1H),8.60-8.47(m,2H),7.91(dd,J＝22.7,10.2Hz,3H),7.57(d,J＝8.1Hz,1H),7.38(q,J＝8.2Hz,4H),6.97-6.88(m,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.15(d,J＝15.1Hz,2H),4.73(s,2H),4.60-4.47(m,3H),4.42(dd,J＝14.3,7.1Hz,2H),4.34(s,1H),4.27-4.11(m,3H),3.72-3.58(m,2H),3.33-3.15(m,6H),2.41(d,J＝6.5Hz,3H),2.32(dd,J＝14.5,7.0Hz,1H),2.27-2.16(m,1H),2.01(d,J＝8.4Hz,1H),1.89(ddd,J＝12.8,8.5,4.5Hz,1H),1.75(s,2H),1.24(d,J＝6.7Hz,3H),1.15(d,J＝6.8Hz,3H),0.92(d,J＝7.7Hz,9H)。Step 3: Dissolve intermediate Z1 (300 mg) in THF (20 mL), then add DIPEA (1.04 g, 8.08 mmol, 1.41 mL) and HATU (980.35 mg, 2.60 mmol). The reaction was stirred at 20°C for 18 h, then H1-b (387.11 mg, 750.70 μmol) was added and stirred for 3 h. After completion, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 35%-68% acetonitrile change) to obtain H1 (123.78 mg), yield: 21.45%. MS m/z(ESI):500.3[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.95(s,1H),8.74(s,1H),8.60-8.47(m,2H),7.91(dd,J＝22.7,10.2Hz,3H),7.57(d,J＝8.1Hz,1H),7.38(q,J＝8.2Hz,4H),6.97-6.88 (m,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.15(d,J＝15.1Hz,2H),4.73(s,2H),4.60-4.47(m,3H),4.42(dd,J＝14.3,7.1Hz,2H),4.34(s,1H) ,4.27-4.11(m,3H),3.72-3.58(m,2H),3.33-3.15(m,6H),2.41(d,J＝6.5Hz,3H),2.32(dd,J＝14.5,7.0Hz,1H),2.27-2.16(m,1H),2.01 (d,J＝8.4Hz,1H),1.89(ddd,J＝12.8,8.5,4.5Hz,1H),1.75(s,2H),1.24(d,J＝6.7Hz,3H),1.15(d,J＝6.8Hz,3H),0.92(d,J＝7.7Hz,9H).

实施例2化合物H2的制备
Example 2 Preparation of Compound H2

步骤1:将5-溴-2-(三氟甲基)异烟醛(5g,19.68mmol)和4-氨基哌啶-1-甲酸叔丁酯(9.07g,45.27mmol)溶于EtOH(80mL)，加入TFA(5.91g,98.42mmol)，室温搅拌18h，然后降温到-10℃，加入Na(CN)BH3(2.72g,43.31mmol)，在0℃下搅拌2h。反应完成后，反应液中加入饱和碳酸氢钠水溶液中和，浓缩去除有机溶剂，水相用二氯甲烷萃取，有机相经无水硫酸钠干燥后浓缩，得到H2-a(6.6g,淡黄色油状),收率：76.50％。MS m/z(ESI):382.0[M-56+H]+。Step 1: Dissolve 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (5 g, 19.68 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (9.07 g, 45.27 mmol) in EtOH (80 mL), add TFA (5.91 g, 98.42 mmol), stir at room temperature for 18 h, then cool to -10°C, add Na(CN)BH 3 (2.72 g, 43.31 mmol), and stir at 0°C for 2 h. After the reaction is completed, add saturated sodium bicarbonate aqueous solution to the reaction solution for neutralization, concentrate to remove the organic solvent, extract the aqueous phase with dichloromethane, and dry the organic phase over anhydrous sodium sulfate and concentrate to obtain H2-a (6.6 g, light yellow oil), yield: 76.50%. MS m/z (ESI): 382.0 [M-56+H] + .

步骤2:将H2-a(6.6g,15.06mmol)和(Boc)2O(4.93g,22.59mmol)溶于DCM(100mL)中，加入Et3N(6.10g,60.24mmol)，在室温下搅拌1h。反应完成后，将反应液浓缩后经CombiFlash(80g，0-70％EA/PE)纯化，得到H2-b(4.7g,无色固体),收率：57.97％。MS m/z(ESI):560.2[M+Na]+。Step 2: H2-a (6.6 g, 15.06 mmol) and (Boc) 2 O (4.93 g, 22.59 mmol) were dissolved in DCM (100 mL), Et 3 N (6.10 g, 60.24 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (80 g, 0-70% EA/PE) to obtain H2-b (4.7 g, colorless solid), yield: 57.97%. MS m/z (ESI): 560.2 [M+Na] + .

步骤3:将8-溴-5-(((5-氟-2，3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1，5-c]嘧啶-1-羧酸乙酯(2g,4.60mmol)和H2-b(4.7g,8.73mmol)溶于DME(40mL)和水(4mL)，加入Pd(OAc)2(103.16mg,459.51μmol)、CataCXium A(329.50mg,919.02μmol)、K2CO3(2.54g,18.38mmol)和(Pin)2B2(2.33g,9.19mmol)，在70℃下搅拌18h。反应完成后，冷却至室温，将反应液浓缩后经CombiFlash(80g，0～100％EA/PE)纯化，得到H2-c(2g,淡黄色固体),收率：53.48％。MS m/z(ESI):814.4[M+H]+。Step 3: Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (2 g, 4.60 mmol) and H2-b (4.7 g, 8.73 mmol) were dissolved in DME (40 mL) and water (4 mL), and Pd(OAc) 2 (103.16 mg, 459.51 μmol), CataCXium A (329.50 mg, 919.02 μmol), K 2 CO 3 (2.54 g, 18.38 mmol) and (Pin) 2 B 2 (2.33 g, 9.19 mmol) were added and stirred at 70° C. for 18 h. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was concentrated and purified by CombiFlash (80 g, 0-100% EA/PE) to obtain H2-c (2 g, light yellow solid), yield: 53.48%. MS m/z (ESI): 814.4 [M+H] + .

步骤4:将H2-c(2g,2.46mmol)溶于DCM(25mL)中，加入TFA(2.80g,24.57mmol)，在室温下搅拌36h。反应完成后，加入碳酸氢钠水溶液中和，用二氯甲烷和甲醇混合溶剂(10：1)萃取，有机相用无水硫酸钠干燥，浓缩后得到H2-d(1.2g,淡黄色固体,粗品)，收率：79.58％。MS m/z(ESI):614.3[M+H]+。Step 4: H2-c (2 g, 2.46 mmol) was dissolved in DCM (25 mL), TFA (2.80 g, 24.57 mmol) was added, and the mixture was stirred at room temperature for 36 h. After the reaction was completed, sodium bicarbonate aqueous solution was added for neutralization, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (10:1). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain H2-d (1.2 g, light yellow solid, crude product), with a yield of 79.58%. MS m/z (ESI): 614.3 [M+H] + .

步骤5:将H2-d(1.2g,1.96mmol)溶于THF(20mL)和水(5mL)，加入LiOH(1.41g,58.67mmol)，在75℃下搅拌18h。反应完成后，反应液冷却至室温，过滤，滤液用稀盐酸(3mol/L)调pH至2-3,浓缩得到H2-e(3.3g)。MS m/z(ESI):586.2[M+H]+。Step 5: H2-d (1.2 g, 1.96 mmol) was dissolved in THF (20 mL) and water (5 mL), LiOH (1.41 g, 58.67 mmol) was added, and the mixture was stirred at 75°C for 18 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was adjusted to pH 2-3 with dilute hydrochloric acid (3 mol/L), and concentrated to obtain H2-e (3.3 g). MS m/z (ESI): 586.2 [M+H] + .

步骤6:将H2-e(3.3g)溶于THF(20mL)和DMF(5mL)中，加入DIPEA(4.11g,31.76mmol,5.53mL)和HATU(1.20g,3.18mmol)，在室温下搅拌3h。反应完成后，用水溶液淬灭反应，再用二氯甲烷和甲醇(10：1)萃取三次，合并有机相用无水硫酸钠干燥，浓缩后经CombiFlash(24g，0-23％，MeOH/DCM+1％Et3N)纯化，得到H2-f(270mg,淡黄色固体),收率：29.95％。MS m/z(ESI):568.2[M+H]+。Step 6: H2-e (3.3 g) was dissolved in THF (20 mL) and DMF (5 mL), and DIPEA (4.11 g, 31.76 mmol, 5.53 mL) and HATU (1.20 g, 3.18 mmol) were added, and stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with aqueous solution, and then extracted three times with dichloromethane and methanol (10:1), and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (24 g, 0-23%, MeOH/DCM+1% Et 3 N) to obtain H2-f (270 mg, light yellow solid), yield: 29.95%. MS m/z (ESI): 568.2 [M+H] + .

步骤7:将H2-f(70mg,123.34μmol)和1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)哌啶-4-甲醛(91.12mg,246.68μmol)溶于DMSO(3mL)和EtOH(1mL)，加入NaBH3CN(62.01mg,986.72μmol)和乙酸(37.03mg,616.70μmol)，在90℃下微波搅拌0.5h。反应完成后，冷却至室温，浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：56％-86％乙腈变化)纯化，得到H2(54.01mg),收率：45.26％。MS m/z(ESI):921.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.85(s,1H),8.78(s,1H),8.74(s,1H),8.09(s,1H),7.63(d,J＝8.5Hz,1H),7.58(s,1H),7.29(s,1H),7.22(d,J＝8.8Hz,1H),6.98-6.89(m,1H),6.69(dd,J＝8.7,3.9Hz,1H),5.27(d,J＝15.0Hz,1H),5.05(dd,J＝12.9,5.3Hz,1H),4.74(d,J＝4.8Hz,2H),4.54(t,J＝8.8Hz,2H),4.40(d,J＝15.0Hz,1H),4.02(d,J＝12.4Hz,2H),3.82(s,1H),3.32(d,J＝8.9Hz,2H),3.08-2.73(m,5H),2.62-2.50(m,2H),2.33(d,J＝11.6Hz,1H),2.13(s,2H),2.05-1.84(m,3H),1.78(d,J＝10.7Hz,3H),1.59(s,1H),1.30-0.94(m,4H)。Step 7: H2-f (70 mg, 123.34 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (91.12 mg, 246.68 μmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), and NaBH 3 CN (62.01 mg, 986.72 μmol) and acetic acid (37.03 mg, 616.70 μmol) were added, and stirred in microwave at 90° C. for 0.5 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 56%-86% acetonitrile change) to obtain H2 (54.01mg), yield: 45.26%. MS m/z (ESI): 921.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),8.85(s,1H),8.78(s,1H),8.74(s,1H),8.09(s,1H),7.63(d,J＝8.5Hz,1H),7.58(s,1H),7.29(s,1H),7.22(d,J＝8 .8Hz,1H),6.98-6.89(m,1H),6.69(dd,J＝8.7,3.9Hz,1H),5.27(d,J＝15.0Hz,1H),5.05(dd,J＝12.9,5.3Hz,1H),4.74(d,J＝4.8Hz, 2H),4.54(t,J＝8.8Hz,2H),4.40(d,J＝15.0Hz,1H),4.02(d,J＝12.4Hz,2H),3.82(s,1H),3.32(d,J＝8.9Hz,2H),3.08-2.73(m,5H), 2.62-2.50(m,2H),2.33(d,J＝11.6Hz,1H),2.13(s,2H),2.05-1.84(m,3H),1.78(d,J＝10.7Hz,3H),1.59(s,1H),1.30-0.94(m,4H).

实施例3化合物H3的制备
Example 3 Preparation of Compound H3

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(540mg,1.21mmol)和顺式-3-(叔丁氧羰基氨基)环丁烷羧酸(522.88mg,2.43mmol)溶于DMF(7mL)中，然后加入DIPEA(313.96mg,2.43mmol,423.12μL)和HATU(641.53mg,1.70mmol)。该反应在室温下搅拌2h。反应完成后，将反应液浓缩后经CombiFlash(24g，0-10％MeOH/DCM)纯化，得到H3-a(430mg,白色固体),收率：55.16％。MS m/z(ESI):542.3[M-100+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (540 mg, 1.21 mmol) and cis-3-(tert-butyloxycarbonylamino)cyclobutanecarboxylic acid (522.88 mg, 2.43 mmol) were dissolved in DMF (7 mL), and then DIPEA (313.96 mg, 2.43 mmol, 423.12 μL) and HATU (641.53 mg, 1.70 mmol) were added. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to give H3-a (430 mg, white solid), yield: 55.16%. MS m/z(ESI):542.3[M-100+H] + .

步骤2:将H3-a(430mg,669.97μmol)溶于EtOH(5mL)中，然后加入稀盐酸(4mol/L,2mL)。该反应在室温下搅拌18h。反应完成后，将反应液浓缩后得到H3-b(320mg,黄色固体，粗品),收率：88.17％。MS m/z(ESI):542.3[M+H]+。Step 2: H3-a (430 mg, 669.97 μmol) was dissolved in EtOH (5 mL), and then diluted hydrochloric acid (4 mol/L, 2 mL) was added. The reaction was stirred at room temperature for 18 h. After the reaction was completed, the reaction solution was concentrated to obtain H3-b (320 mg, yellow solid, crude product), yield: 88.17%. MS m/z (ESI): 542.3 [M+H] + .

步骤3:将中间体Z1(100mg,192.48μmol)溶于DMF(5mL)中，然后加入DIPEA(348.28mg,2.69mmol,469.38μL)和HATU(326.78mg,866.18μmol)，该反应在室温下搅拌18h。然后加入H3-b(312.80mg,577.44μmol)，该反应在室温下继续搅拌2h。反应完成后，将反应液浓缩后经CombiFlash(12g，0-15％MeOH/DCM)纯化，再经过制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：35％-68％乙腈变化)纯化，得到H3(14.19mg,纯度：100％)，收率：7.19％。MS m/z(ESI):513.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.74(s,1H),8.71(d,J＝7.6Hz,1H),8.57(s,1H),8.37(d,J＝8.1Hz,1H),7.99(s,1H),7.93(d,J＝8.4Hz,1H),7.75(d,J＝8.8Hz,1H),7.57(d,J＝8.1Hz,1H),7.46-7.33(m,4H),6.98-6.87(m,1H),6.68(dd,J＝8.6,3.9Hz,1H),5.16(d,J＝15.0Hz,1H),5.09(s,1H),4.96-4.84(m,1H),4.73(s,2H),4.60-4.48(m,3H),4.42(t,J＝8.0Hz,1H),4.35(dd,J＝16.2,8.0Hz,1H),4.28(s,1H),4.23-4.09(m,2H),3.59(d,J＝11.4Hz,2H),3.32(s,3H),2.97-2.87(m,1H),2.44(s,2H),2.42(d,J＝2.3Hz,1H),2.31(s,1H),2.29-2.13(m,2H),2.05-1.95(m,1H),1.79(s,1H),1.37(d,J＝7.0Hz,3H),1.25(d,J＝6.7Hz,3H),1.15(d,J＝6.8Hz,3H),0.93(s,9H)。Step 3: Intermediate Z1 (100 mg, 192.48 μmol) was dissolved in DMF (5 mL), and then DIPEA (348.28 mg, 2.69 mmol, 469.38 μL) and HATU (326.78 mg, 866.18 μmol) were added, and the reaction was stirred at room temperature for 18 h. H3-b (312.80 mg, 577.44 μmol) was then added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 35%-68% acetonitrile change) to obtain H3 (14.19 mg, purity: 100%), yield: 7.19%. MS m/z (ESI): 513.3 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.97(s,1H),8.74(s,1H),8.71(d,J＝7.6Hz,1H),8.57(s,1H),8.37(d,J＝8.1H z,1H),7.99(s,1H),7.93(d,J＝8.4Hz,1H),7.75(d,J＝8.8Hz,1H),7.57(d,J＝8.1H z,1H),7.46-7.33(m,4H),6.98-6.87(m,1H),6.68(dd,J＝8.6,3.9Hz,1H),5.16( d,J＝15.0Hz,1H),5.09(s,1H),4.96-4.84(m,1H),4.73(s,2H),4.60-4.48(m,3H) ,4.42(t,J＝8.0Hz,1H),4.35(dd,J＝16.2,8.0Hz,1H),4.28(s,1H),4.23-4.09(m ,2H),3.59(d,J＝11.4Hz,2H),3.32(s,3H),2.97-2.87(m,1H),2.44(s,2H),2.42( d,J＝2.3Hz,1H),2.31(s,1H),2.29-2.13(m,2H),2.05-1.95(m,1H),1.79(s,1H), 1.37(d,J＝7.0Hz,3H), 1.25(d,J＝6.7Hz,3H), 1.15(d,J＝6.8Hz,3H), 0.93(s,9H).

实施例4化合物H4的制备
Example 4 Preparation of Compound H4

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(900mg,2.02mmol)和6-(叔丁氧基羰基氨基)己酸(515.03mg,2.23mmol)溶于DMF(10mL)中，然后加入DIPEA(784.90mg,6.07mmol,1.06mL)和HATU(1.15g,3.04mmol)。该反应在室温下搅拌1h。反应完成后，将反应液浓缩后经CombiFlash(24g，0-10％MeOH/DCM)纯化，得到H4-a(0.89g,淡黄色固体),收率：66.83％。MS m/z(ESI):558.3[M-100+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (900 mg, 2.02 mmol) and 6-(tert-butoxycarbonylamino)hexanoic acid (515.03 mg, 2.23 mmol) were dissolved in DMF (10 mL), and then DIPEA (784.90 mg, 6.07 mmol, 1.06 mL) and HATU (1.15 g, 3.04 mmol) were added. The reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to give H4-a (0.89 g, light yellow solid), yield: 66.83%. MS m/z(ESI):558.3[M-100+H] + .

步骤2:将H4-a(0.89g,1.35mmol)溶于DCM(10mL)中，然后加入稀盐酸(4mol/L,3mL)。该反应在室温下搅拌30分钟。反应完成后,将反应液浓缩后得到H4-b(800mg,淡黄色固体，盐酸盐)，收率：99.52％。MS m/z(ESI):558.3[M+H]+。Step 2: H4-a (0.89 g, 1.35 mmol) was dissolved in DCM (10 mL), and then diluted hydrochloric acid (4 mol/L, 3 mL) was added. The reaction was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated to obtain H4-b (800 mg, light yellow solid, hydrochloride), yield: 99.52%. MS m/z (ESI): 558.3 [M+H] + .

步骤3:将中间体Z1(100mg,192.48μmol)溶于DMF(10mL)中，然后加入DIPEA(995.09mg,7.70mmol,1.34mL)和HATU(290.47mg,769.94μmol)。该反应在室温下搅拌18h,然后加入H4-b(343.13mg,577.45μmol,盐酸盐并继续搅拌1h。反应完成后，将反应液浓缩后经CombiFlash(12g，0-13％MeOH/DCM)纯化，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：40％-48％乙腈变化)纯化，得到H4(7.9mg,纯度100％),收率：3.94％。MS m/z(ESI):521.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.74(s,1H),8.56(s,1H),8.47(d,J＝5.5Hz,1H),8.34(d,J＝7.8Hz,1H),7.95(s,1H),7.87(d,J＝8.2Hz,1H),7.77(d,J＝9.2Hz,1H),7.57(d,J＝8.2Hz,1H),7.38(dq,J＝17.3,8.6Hz,4H),6.97-6.89(m,1H),6.68(dd,J＝8.7,3.9Hz,1H),5.15(d,J＝15.3Hz,1H),5.07(d,J＝3.6Hz,1H),4.94-4.86(m,1H),4.73(d,J＝3.8Hz,2H),4.52(dd,J＝16.6,7.9Hz,3H),4.41(t,J＝8.0Hz,1H),4.26(s,1H),4.19(dd,J＝13.7,6.5Hz,2H),3.59(s,2H),3.29-3.17(m,4H),2.43(s,3H),2.24(dd,J＝14.5,6.8Hz,1H),2.17-2.08(m,1H),2.00(d,J＝8.0Hz,1H),1.82-1.74(m,1H),1.64-1.40(m,5H),1.35(d,J＝7.0Hz,3H),1.32-1.18(m,5H),1.15(d,J＝6.9Hz,3H),0.91(s,9H)。Step 3: Intermediate Z1 (100 mg, 192.48 μmol) was dissolved in DMF (10 mL), and then DIPEA (995.09 mg, 7.70 mmol, 1.34 mL) and HATU (290.47 mg, 769.94 μmol) were added. The reaction was stirred at room temperature for 18 h, then H4-b (343.13 mg, 577.45 μmol, hydrochloride) was added and stirred for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-13% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 40%-48% acetonitrile change) to obtain H4 (7.9 mg, purity 100%), yield: 3.94%. MS m/z (ESI): 521.3 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.96(s,1H),8.74(s,1H),8.56(s,1H),8.47(d,J＝5.5Hz,1H),8.34(d,J＝7.8Hz, 1H),7.95(s,1H),7.87(d,J＝8.2Hz,1H),7.77(d,J＝9.2Hz,1H),7.57(d,J＝8.2Hz,1 H),7.38(dq,J＝17.3,8.6Hz,4H),6.97-6.89(m,1H),6.68(dd,J＝8.7,3.9Hz,1H),5 .15(d,J＝15.3Hz,1H),5.07(d,J＝3.6Hz,1H),4.94-4.86(m,1H),4.73(d,J＝3.8Hz,2 H),4.52(dd,J＝16.6,7.9Hz,3H),4.41(t,J＝8.0Hz,1H),4.26(s,1H),4.19(dd,J＝1 3.7,6.5Hz,2H),3.59(s,2H),3.29-3.17(m,4H),2.43(s,3H),2.24(dd,J＝14.5,6.8 Hz,1H),2.17-2.08(m,1H),2.00(d,J＝8.0Hz,1H),1.82-1.74(m,1H),1.64-1.40(m ,5H),1.35(d,J＝7.0Hz,3H),1.32-1.18(m,5H),1.15(d,J＝6.9Hz,3H),0.91(s,9H).

实施例5化合物H5的制备
Example 5 Preparation of Compound H5

步骤1:将化合物4-((叔丁氧基羰基)氨基)环己烷甲酸(1.35g,5.57mmol)和化合物(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基))乙基)吡咯烷-2-甲酰胺(2g,4.6mmol)加入到DMF(2mL)，然后加入HATU(2.12g,5.57mmol)和DIPEA(2mL)，室温搅拌10分钟，经硅胶柱层析(DCM/MeOH 0-10％)纯化，得到H5-a(2.27g)，收率:75.4％。MS m/z(ESI):670[M+H]+。Step 1: Compound 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.35 g, 5.57 mmol) and compound (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide (2 g, 4.6 mmol) were added to DMF (2 mL), and then HATU (2.12 g, 5.57 mmol) and DIPEA (2 mL) were added, stirred at room temperature for 10 minutes, and purified by silica gel column chromatography (DCM/MeOH 0-10%) to obtain H5-a (2.27 g), yield: 75.4%. MS m/z (ESI): 670 [M+H] + .

步骤2:将H5-a(2.27g,3.4mmol)溶解于乙酸乙酯中，然后滴加盐酸乙酸乙酯溶液(20mL，4mol/L)，室温搅拌1h，浓缩后得到H5-b(1.76g)，收率:95.6％。MS m/z(ESI):570[M+H]+。Step 2: H5-a (2.27 g, 3.4 mmol) was dissolved in ethyl acetate, and then a hydrochloric acid ethyl acetate solution (20 mL, 4 mol/L) was added dropwise, stirred at room temperature for 1 h, and concentrated to obtain H5-b (1.76 g), yield: 95.6%. MS m/z (ESI): 570 [M+H] + .

步骤3:将Z1(100mg,0.192mmol)溶解于DMF(3mL)，然后加入DIPEA(2mL)，再加入HATU(218mg,0.576mmol)，室温下搅拌10分钟，然后加入H5-b(109mg,0.192mmol)继续搅拌20分钟，浓缩后经高压液相纯化(waters-sunfire-10um-19*150mm柱(流动相:28％-38％(v/v)乙腈和甲酸水溶液)，得到H5(3.76mg)，收率:2.9％。MS m/z(ESI):527.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.74(s,1H),8.55(d,J＝5.1Hz,1H),8.35(d,J＝7.8Hz,1H),8.28-8.13(m,1H),7.95(d,J＝1.7Hz,1H),7.89(d,J＝8.0Hz,1H),7.75-7.60(m,1H),7.56(d,J＝8.1Hz,1H),7.39(ddd,J＝12.5,8.7,7.0Hz,5H),6.93(dd,J＝10.3,8.6Hz,1H),6.68(dd,J＝8.6,3.9Hz,1H),5.20-5.05(m,2H),4.95-4.84(m,1H),4.73(d,J＝4.9Hz,2H),4.52(q,J＝9.0Hz,3H),4.41(t,J＝8.1Hz,1H),4.32-4.12(m,3H),3.75(s,1H),3.66-3.52(m,2H),2.88(s,1H),2.44(d,J＝1.2Hz,3H),2.40-2.31(m,1H),1.98(d,J＝9.6Hz,2H),1.90-1.75(m,4H),1.36(d,J＝6.8Hz,5H),1.29-1.18(m,5H),1.15(d,J＝6.8Hz,4H),0.94(d,J＝1.9Hz,9H)。Step 3: Z1 (100 mg, 0.192 mmol) was dissolved in DMF (3 mL), and then DIPEA (2 mL) was added, followed by HATU (218 mg, 0.576 mmol), and the mixture was stirred at room temperature for 10 minutes. H5-b (109 mg, 0.192 mmol) was then added and stirred for 20 minutes. After concentration, the mixture was purified by high pressure liquid chromatography (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid aqueous solution) to obtain H5 (3.76 mg), yield: 2.9%. MS m/z (ESI): 527.3 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.97(s,1H),8.74(s,1H),8.55(d,J＝5.1Hz,1H),8.35(d,J＝7.8Hz,1H),8. 28-8.13(m,1H),7.95(d,J＝1.7Hz,1H),7.89(d,J＝8.0Hz,1H),7.75-7.60(m,1 H),7.56(d,J＝8.1Hz,1H),7.39(ddd,J＝12.5,8.7,7.0Hz,5H),6.93(dd,J＝10 .3,8.6Hz,1H),6.68(dd,J＝8.6,3.9Hz,1H),5.20-5.05(m,2H),4.95-4.84(m, 1H),4.73(d,J＝4.9Hz,2H),4.52(q,J＝9.0Hz,3H),4.41(t,J＝8.1Hz,1H),4.3 2-4.12(m,3H),3.75(s,1H),3.66-3.52(m,2H),2.88(s,1H),2.44(d,J＝1.2Hz ,3H),2.40-2.31(m,1H),1.98(d,J＝9.6Hz,2H),1.90-1.75(m,4H),1.36(d,J =6.8Hz, 5H), 1.29-1.18 (m, 5H), 1.15 (d, J = 6.8Hz, 4H), 0.94 (d, J = 1.9Hz, 9H).

实施例6化合物H6的制备
Example 6 Preparation of Compound H6

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(500mg,1.12mmol)和2-(叔丁氧基羰基氨基)乙酸(256.12mg,1.46mmol)溶解在DMF(5mL)中，室温搅拌加入HATU(636.43mg,1.69mmol)，DIPEA(363.38mg,2.81mmol,489.73μL)，室温搅拌5h。反应结束后，将反应液倒入水中，二氯甲烷(30mL×2)萃取，合并有机相用无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到H6-a(510mg,黄色固体)，收率：75.36％。MS m/z(ESI):602[M+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 1.12 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (256.12 mg, 1.46 mmol) were dissolved in DMF (5 mL), HATU (636.43 mg, 1.69 mmol) and DIPEA (363.38 mg, 2.81 mmol, 489.73 μL) were added with stirring at room temperature, and the mixture was stirred at room temperature for 5 h. After the reaction, the reaction solution was poured into water, extracted with dichloromethane (30 mL×2), and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH:DCM=0-10%) to obtain H6-a (510 mg, yellow solid), yield: 75.36%. MS m/z (ESI): 602 [M+H] + .

步骤2:将H6-a(600mg,997.08μmol)溶解在DCM(10mL)中，室温搅拌加入稀盐酸(4mol/L,5mL)，室温搅拌2h。反应结束后，将反应液浓缩，得到H6-b(500.18mg,黄色固体),收率：100.00％。MS m/z(ESI):502[M+H]+。Step 2: H6-a (600 mg, 997.08 μmol) was dissolved in DCM (10 mL), diluted hydrochloric acid (4 mol/L, 5 mL) was added with stirring at room temperature, and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to obtain H6-b (500.18 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 502 [M+H] + .

步骤3:将H10-a(100mg,192.48μmol)溶解在DMF(5mL)中，室温搅拌加入HATU(290.47mg,769.94μmol)和DIPEA(746.32mg,5.77mmol,1.01mL)，室温搅拌过夜，加入H6-b(193.12mg,384.97μmol)，室温搅拌5小时。反应结束后，将反应液倒入水中，二氯甲烷(30mL×2)萃取，合并有机相用无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-70％乙腈变化)纯化，得到H6(9.86mg,纯度：98.32％),收率：5.11％。MS m/z(ESI):493.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.93-8.81(m,1H),8.75(s,1H),8.59(s,1H),8.38(d,J＝7.7Hz,1H),8.00(s,1H),7.91(d,J＝7.8Hz,1H),7.76(dd,J＝27.2,9.5Hz,1H),7.61(d,J＝6.8Hz,1H),7.54-7.39(m,3H),7.36(dd,J＝8.4,2.8Hz,2H),6.99-6.87(m,1H),6.68(dd,J＝8.7,3.9Hz,1H),5.26-3.32(m,21H),2.43(d,J＝8.8Hz,2H),2.08-1.97(m,1H),1.77(s,1H),1.52-0.67(m,16H)。Step 3: H10-a (100 mg, 192.48 μmol) was dissolved in DMF (5 mL), HATU (290.47 mg, 769.94 μmol) and DIPEA (746.32 mg, 5.77 mmol, 1.01 mL) were added with stirring at room temperature, and the mixture was stirred at room temperature overnight. H6-b (193.12 mg, 384.97 μmol) was added and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction solution was poured into water, extracted with dichloromethane (30 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography (MeOH:DCM=0-10%), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-70% acetonitrile) to obtain H6 (9.86 mg, purity: 98.32%), yield: 5.11%. MS m/z (ESI): 493.3 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.96(s,1H),8.93-8.81(m,1H),8.75(s,1H),8.59(s,1H),8.38(d,J＝7.7Hz,1H),8.00(s ,1H),7.91(d,J＝7.8Hz,1H),7.76(dd,J＝27.2,9.5Hz,1H),7.61(d,J＝6.8Hz,1H),7.54-7.3 9(m,3H),7.36(dd,J＝8.4,2.8Hz,2H),6.99-6.87(m,1H),6.68(dd,J＝8.7,3.9Hz,1H),5.26 -3.32(m,21H),2.43(d,J=8.8Hz,2H),2.08-1.97(m,1H),1.77(s,1H),1.52-0.67(m,16H).

实施例7化合物H7的制备
Example 7 Preparation of Compound H7

步骤1:将2-(2,6-二氧哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(2.76g,9.99mmol)和氮杂环丁烷-3-醇(1.46g,13.33mmol,HCl)溶于DMF(10mL)，加入K2CO3(4.14g,29.98mmol)，在80℃下搅拌18h。反应完成后，过滤，滤液浓缩后经CombiFlash(40g，0-10％DCM/ACN)纯化，得到H7-a(1.1g,黄色的粘稠物)，收率：33.43％。MS m/z(ESI):330.1[M+H]+。Step 1: Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 9.99 mmol) and azetidine-3-ol (1.46 g, 13.33 mmol, HCl) in DMF (10 mL), add K 2 CO 3 (4.14 g, 29.98 mmol), and stir at 80° C. for 18 h. After the reaction is completed, filter, concentrate the filtrate, and purify it with CombiFlash (40 g, 0-10% DCM/ACN) to obtain H7-a (1.1 g, yellow viscous material), yield: 33.43%. MS m/z (ESI): 330.1 [M+H] + .

步骤2:将H7-a(0.9g,2.73mmol)溶于DCM(30mL)中，加入戴斯-马丁氧化剂(2.32g,5.47mmol)，在室温下搅拌4h。反应完成后，过滤，滤液浓缩后经CombiFlash(20g，0-10％DCM/THF)纯化，得到H7-b(250mg,黄色固体),收率：27.95％。MS m/z(ESI):328.0[M+H]+。Step 2: H7-a (0.9 g, 2.73 mmol) was dissolved in DCM (30 mL), and Dess-Martin periodinane (2.32 g, 5.47 mmol) was added and stirred at room temperature for 4 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated and purified by CombiFlash (20 g, 0-10% DCM/THF) to obtain H7-b (250 mg, yellow solid), yield: 27.95%. MS m/z (ESI): 328.0 [M+H] + .

步骤3:将H2-f(66mg,116.29μmol)和H7-b(133.21mg,407.02μmol)溶于DMSO(3mL)和EtOH(1mL)中，加入乙酸(20.95mg,348.88μmol)，搅拌1小时，再加入Na(CN)BH3(58.46mg,930.34μmol)，继续在室温下搅拌18h。反应完成后，反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：0.04％FA H2O-乙腈；波长：254/214nm；梯度：35％-68％乙腈变化)纯化，得到H7(47.40mg)，收率：44.96％。MS m/z(ESI):879.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.85(s,1H),8.78(s,1H),8.74(s,1H),8.11(d,J＝2.7Hz,1H),7.64(d,J＝8.1Hz,1H),7.58(s,1H),6.98-6.89(m,1H),6.78(s,1H),6.74-6.60(m,2H),5.28(d,J＝15.1Hz,1H),5.04(dd,J＝12.6,5.4Hz,1H),4.91(s,1H),4.74(d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.38(d,J＝14.7Hz,1H),4.09(s,2H),3.83(s,3H),3.33(s,2H),2.97-2.78(m,3H),2.62-2.52(m,2H),2.33(d,J＝12.1Hz,2H),2.07-1.81(m,3H),1.63(dd,J＝25.7,4.5Hz,1H),1.02(d,J＝11.9Hz,1H)。Step 3: H2-f (66 mg, 116.29 μmol) and H7-b (133.21 mg, 407.02 μmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), acetic acid (20.95 mg, 348.88 μmol) was added, and the mixture was stirred for 1 hour, and then Na(CN)BH 3 (58.46 mg, 930.34 μmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 35%-68% acetonitrile change) to obtain H7 (47.40 mg), yield: 44.96%. MS m/z (ESI): 879.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.04(s,1H),8.85(s,1H),8.78(s,1H),8.74(s,1H),8.11(d,J＝2.7Hz,1H),7.64(d,J＝8.1Hz,1H),7.58(s,1H),6.9 8-6.89(m,1H),6.78(s,1H),6.74-6.60(m,2H),5.28(d,J＝15.1Hz,1H),5.04(dd,J＝12.6,5.4Hz,1H),4.91(s,1H),4.74 (d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.38(d,J＝14.7Hz,1H),4.09(s,2H),3.83(s,3H),3.33(s,2H),2.97-2.78(m,3 H), 2.62-2.52 (m, 2H), 2.33 (d, J = 12.1Hz, 2H), 2.07-1.81 (m, 3H), 1.63 (dd, J = 25.7, 4.5Hz, 1H), 1.02 (d, J = 11.9Hz, 1H).

实施例8化合物H8的制备
Example 8 Preparation of Compound H8

步骤1:将2-(2,6-二氧哌啶-3-基)-5-氟异吲哚啉-1，3-二酮(2.76g,9.99mmol)和吖丁啶-3-基甲醇(2.47g,19.98mmol,盐酸盐)溶于DMF(10mL)中，加入K2CO3(5.52g,39.97mmol)，在70℃下搅拌18h。反应完成后，过滤，滤液浓缩后经CombiFlash(40g，0-50％DCM/ACN)纯化，得到H8-a(230mg,黄色固体),收率：6.70％。MS m/z(ESI):344.1[M+H]+。Step 1: Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 9.99 mmol) and azetidine-3-ylmethanol (2.47 g, 19.98 mmol, hydrochloride) in DMF (10 mL), add K 2 CO 3 (5.52 g, 39.97 mmol), and stir at 70° C. for 18 h. After the reaction is completed, filter, concentrate the filtrate, and purify it with CombiFlash (40 g, 0-50% DCM/ACN) to obtain H8-a (230 mg, yellow solid), yield: 6.70%. MS m/z (ESI): 344.1 [M+H] + .

步骤2:将H8-a(0.23g,669.90μmol)溶于DCM(30mL)中，加入戴斯-马丁氧化剂(852.40mg,2.01mmol)，在室温下搅拌18h，过滤，滤液浓缩后经CombiFlash(12g，0-10％MeOH/DCM)纯化，得到H8-b(130mg,黄色固体),收率：56.86％。MS m/z(ESI):342.1[M+H]+。Step 2: H8-a (0.23 g, 669.90 μmol) was dissolved in DCM (30 mL), Dess-Martin periodinane (852.40 mg, 2.01 mmol) was added, stirred at room temperature for 18 h, filtered, and the filtrate was concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H8-b (130 mg, yellow solid), yield: 56.86%. MS m/z (ESI): 342.1 [M+H] + .

步骤3:将H2-f(65mg,114.53μmol)和H8-b(78.18mg,229.06μmol)溶于DMSO(3mL)和EtOH(1mL)中，加入乙酸(20.63mg,343.59μmol),搅拌1小时，再加入Na(CN)BH3(57.58mg,916.24μmol)，继续在室温下搅拌18h。反应完成后，反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：0.04％FA H2O-乙腈；波长：254/214nm；梯度：26％-56％乙腈变化)纯化，得到H8(48.90mg),收率：46.62％。MS m/z(ESI):893.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.86(s,1H),8.79(s,1H),8.75(s,1H),8.11(d,J＝9.2Hz,1H),7.62(d,J＝8.3Hz,1H),7.59(s,1H),6.98-6.89(m,1H),6.76(d,J＝1.9Hz,1H),6.69(dd,J＝8.7,3.8Hz,1H),6.63(dd,J＝8.4,1.9Hz,1H),5.29(d,J＝14.9Hz,1H),5.03(dd,J＝12.9,5.3Hz,1H),4.74(d,J＝5.0Hz,2H),4.53(t,J＝8.8Hz,2H),4.37(d,J＝14.9Hz,1H),4.13(t,J＝8.0Hz,2H),3.82(s,1H),3.71(d,J＝5.4Hz,2H),3.32(d,J＝8.9Hz,4H),3.03(s,3H),2.93-2.68(m,3H),2.62-2.51(m,2H),2.40-2.11(m,2H),2.05-1.93(m,1H),1.68(s,1H),1.02(d,J＝11.6Hz,1H)。Step 3: H2-f (65 mg, 114.53 μmol) and H8-b (78.18 mg, 229.06 μmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), acetic acid (20.63 mg, 343.59 μmol) was added, and the mixture was stirred for 1 hour, and then Na(CN)BH 3 (57.58 mg, 916.24 μmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 26%-56% acetonitrile change) to obtain H8 (48.90 mg), yield: 46.62%. MS m/z (ESI): 893.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.04(s,1H),8.86(s,1H),8.79(s,1H),8.75(s,1H),8.11(d,J＝9.2Hz,1H),7.62(d,J＝8.3Hz,1H),7.59(s,1H),6.98-6.89(m,1H),6. 76(d,J＝1.9Hz,1H),6.69(dd,J＝8.7,3.8Hz,1H),6.63(dd,J＝8.4,1.9Hz,1H),5.29(d,J＝14.9Hz,1H),5.03(dd,J＝12.9,5.3Hz,1H),4.74 (d,J＝5.0Hz,2H),4.53(t,J＝8.8Hz,2H),4.37(d,J＝14.9Hz,1H),4.13(t,J＝8.0Hz,2H),3.82(s,1H),3.71(d,J＝5.4Hz,2H),3.32(d,J＝8. 9Hz,4H),3.03(s,3H),2.93-2.68(m,3H),2.62-2.51(m,2H),2.40-2.11(m,2H),2.05-1.93(m,1H),1.68(s,1H),1.02(d,J＝11.6Hz,1H).

实施例9化合物H9的制备
Example 9 Preparation of Compound H9

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(500mg,1.12mmol)和4-(叔丁氧基羰基氨基)丁酸(251.42mg,1.24mmol)溶于DMF(5mL)，然后加入DIPEA(436.05mg,3.37mmol,587.67μL)和HATU(636.43mg,1.69mmol)，在室温条件下搅拌1h。反应完成后，将反应液浓缩后经CombiFlash(24g，0-10％MeOH/DCM)纯化，得到H9-a(430mg,淡黄色固体),收率：60.71％。MS m/z(ESI):530.3[M-100+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 1.12 mmol) and 4-(tert-butoxycarbonylamino)butyric acid (251.42 mg, 1.24 mmol) were dissolved in DMF (5 mL), and then DIPEA (436.05 mg, 3.37 mmol, 587.67 μL) and HATU (636.43 mg, 1.69 mmol) were added and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H9-a (430 mg, light yellow solid), yield: 60.71%. MS m/z(ESI):530.3[M-100+H] + .

步骤2:将H9-a(430mg,682.75μmol)溶于DCM(10mL)，然后加入稀盐酸(4mol/L,3mL),在室温下搅拌30分钟。反应结束后，将反应液浓缩，得到H9-b(386mg,黄色固体,盐酸盐)，收率：99.86％。MS m/z(ESI):530.3[M+H]+。Step 2: H9-a (430 mg, 682.75 μmol) was dissolved in DCM (10 mL), and then diluted hydrochloric acid (4 mol/L, 3 mL) was added and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated to obtain H9-b (386 mg, yellow solid, hydrochloride), yield: 99.86%. MS m/z (ESI): 530.3 [M+H] + .

步骤3:将中间体Z2(210mg,30％内容物,134.48μmol)溶于DMF(5mL)中，加入DIPEA(1.48g,11.48mmol,2mL)和(202.95mg,537.93mmol)，在室温条件下搅拌0.5h,然后加入H9-b(110mg,194.29μmol,盐酸盐)，室温继续搅拌1h。反应完成后，将反应液浓缩后经CombiFlash(12g，0-15％MeOH/DCM)纯化，再通制备HPLC(制备柱：21.2X250mm C18柱；体系：10mmNH4HCO3H2O-乙腈；波长：254/214nm；梯度：46％-57％乙腈变化)纯化，得到H9(4.26mg)，收率：3.06％。MS m/z(ESI):507.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.86(s,1H),8.77(s,1H),8.73-8.60(m,2H),8.35(d,J＝7.9Hz,1H),8.13(s,1H),7.90(d,J＝9.1Hz,1H),7.52(d,J＝7.0Hz,1H),7.37(dt,J＝23.6,11.8Hz,4H),6.97-6.89(m,1H),6.68(dd,J＝8.7,3.8Hz,1H),5.16(d,J＝14.8Hz,1H),5.08(d,J＝3.5Hz,1H),4.90(dd,J＝14.3,7.0Hz,1H),4.74(s,2H),4.60-4.45(m,3H),4.40(dd,J＝15.6,7.7Hz,2H),4.30-4.15(m,2H),3.59(s,2H),2.43(s,3H),2.29(d,J＝12.5Hz,2H),2.22-2.08(m,2H),2.07-1.92(m,2H),1.78(dd,J＝12.8,4.7Hz,3H),1.44(d,J＝6.5Hz,1H),1.35(d,J＝7.0Hz,3H),1.24(d,J＝6.7Hz,3H),1.15(d,J＝6.8Hz,3H),0.92(s,9H)。Step 3: Dissolve the intermediate Z2 (210 mg, 30% content, 134.48 μmol) in DMF (5 mL), add DIPEA (1.48 g, 11.48 mmol, 2 mL) and (202.95 mg, 537.93 mmol), stir at room temperature for 0.5 h, then add H9-b (110 mg, 194.29 μmol, hydrochloride), and continue stirring at room temperature for 1 h. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mm NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 46%-57% acetonitrile change) to obtain H9 (4.26 mg), yield: 3.06%. MS m/z(ESI):507.8[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.96(s,1H),8.86(s,1H),8.77(s,1H),8.73-8.60(m,2H),8.35(d,J=7. 9Hz,1H),8.13(s,1H),7.90(d,J＝9.1Hz,1H),7.52(d,J＝7.0Hz,1H),7.37(d t,J＝23.6,11.8Hz,4H),6.97-6.89(m,1H),6.68(dd,J＝8.7,3.8Hz,1H),5.1 6(d,J＝14.8Hz,1H),5.08(d,J＝3.5Hz,1H),4.90(dd,J＝14.3,7.0Hz,1H),4. 74(s,2H),4.60-4.45(m,3H),4.40(dd,J＝15.6,7.7Hz,2H),4.30-4.15(m,2 H),3.59(s,2H),2.43(s,3H),2.29(d,J＝12.5Hz,2H),2.22-2.08(m,2H),2. 07-1.92(m,2H),1.78(dd,J＝12.8,4.7Hz,3H),1.44(d,J＝6.5Hz,1H),1.35( d, J＝7.0Hz, 3H), 1.24 (d, J＝6.7Hz, 3H), 1.15 (d, J＝6.8Hz, 3H), 0.92 (s, 9H).

实施例10化合物H10的制备
Example 10 Preparation of Compound H10

步骤1：将中间体Z1(300mg,0.58mmol)溶于DMF(10mL)中，加入DIPEA(448mg,3.46mmol)和HATU(654mg,1.73mmol),室温搅拌过夜。反应结束后，将反应液倒入水中，用乙酸乙酯萃取(30mL×2)，合并有机相经无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～30％)，得到H10-a(154mg,黄色固体)，收率：53.18％。MS m/z(ESI):502.2[M+H]+。Step 1: Dissolve the intermediate Z1 (300 mg, 0.58 mmol) in DMF (10 mL), add DIPEA (448 mg, 3.46 mmol) and HATU (654 mg, 1.73 mmol), and stir at room temperature overnight. After the reaction is completed, pour the reaction solution into water, extract with ethyl acetate (30 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (MeOH:DCM=0-30%) to obtain H10-a (154 mg, yellow solid), yield: 53.18%. MS m/z (ESI): 502.2 [M+H] + .

步骤2：将H10-a(570mg,1.14mmol)和1-甲基咪唑(280mg,3.41mmol)溶于乙腈(10mL)中，加入TCFH(383mg,1.36mmol)，搅拌10分钟后，加入4-氨基苯甲酸甲酯(344mg,2.27mmol)，室温继续搅拌20小时。反应结束后，将反应液倒入水中，用乙酸乙酯萃取(30mL×2)，合并有机相经无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到H10-b(150mg,黄色固体)，收率：20.79％。MS m/z(ESI):635.3[M+H]+。Step 2: H10-a (570 mg, 1.14 mmol) and 1-methylimidazole (280 mg, 3.41 mmol) were dissolved in acetonitrile (10 mL), TCFH (383 mg, 1.36 mmol) was added, and after stirring for 10 minutes, methyl 4-aminobenzoate (344 mg, 2.27 mmol) was added, and stirring was continued at room temperature for 20 hours. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (30 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH: DCM = 0-10%) to obtain H10-b (150 mg, yellow solid), yield: 20.79%. MS m/z (ESI): 635.3 [M + H] + .

步骤3：将H10-b(120mg,0.19mmol)溶于MeOH(15mL)和水(3mL)中，加入LiOH(80mg,1.89mmol)，室温搅拌过夜。反应结束后，将反应液浓缩后用稀盐酸(1mol/L)调至pH＝5，二氯甲烷萃取(30mL×2)，合并有机相经无水硫酸钠干燥，浓缩得到H10-c(25mg),收率：21.30％。直接用于下一步反应。MS m/z(ESI):621.2[M+H]+。Step 3: H10-b (120 mg, 0.19 mmol) was dissolved in MeOH (15 mL) and water (3 mL), and LiOH (80 mg, 1.89 mmol) was added, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and adjusted to pH = 5 with dilute hydrochloric acid (1 mol/L), extracted with dichloromethane (30 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H10-c (25 mg), yield: 21.30%. It was directly used for the next step reaction. MS m/z (ESI): 621.2 [M + H] + .

步骤4：将H10-c(23mg,0.037mmol)和(2S，4R)-1-((S)-2-氨基-3，3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(33mg,0.074mmol)溶于DMF(5mL)中，加入DIPEA(15mg,0.11mmol)和HATU(21mg,0.056mmol),室温搅拌4小时。反应结束后，将反应液倒入水中，用乙酸乙酯萃取(30mL×2)，合并有机相用无水硫酸钠干燥，浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)纯化，得到H10(4.95mg),收率：12.45％。MS m/z(ESI):524.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.96(d,J＝7.4Hz,1H),8.75(s,1H),8.61(s,1H),8.40(d,J＝7.8Hz,1H),8.10-8.01(m,2H),7.94-7.86(m,4H),7.79(d,J＝9.0Hz,1H),7.67(d,J＝8.1Hz,1H),7.45-7.32(m,5H),6.97-6.89(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.20(d,J＝15.1Hz,1H),5.12(d,J＝3.5Hz,1H),4.91(dd,J＝14.4,7.1Hz,1H),4.75(d,J＝11.5Hz,3H),4.53(t,J＝8.8Hz,2H),4.45(t,J＝8.1Hz,1H),4.31-4.16(m,3H),3.67(s,2H),3.33(s,1H),3.29(s,1H),2.44(s,3H),2.06-1.99(m,1H),1.83-1.75(m,1H),1.37(d,J＝7.0Hz,3H),1.26(d,J＝6.7Hz,3H),1.17(d,J＝6.9Hz,3H),1.09-0.96(m,9H)。Step 4: H10-c (23 mg, 0.037 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (33 mg, 0.074 mmol) were dissolved in DMF (5 mL), and DIPEA (15 mg, 0.11 mmol) and HATU (21 mg, 0.056 mmol) were added and stirred at room temperature for 4 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (30 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile) to obtain H10 (4.95 mg), yield: 12.45%. MS m/z (ESI): 524.3 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.47(s,1H),8.96(d,J＝7.4Hz,1H),8.75(s,1H),8.61(s,1H),8.40( d,J＝7.8Hz,1H),8.10-8.01(m,2H),7.94-7.86(m,4H),7.79(d,J＝9.0Hz, 1H),7.67(d,J＝8.1Hz,1H),7.45-7.32(m,5H),6.97-6.89(m,1H),6.69(d d,J＝8.6,3.9Hz,1H),5.20(d,J＝15.1Hz,1H),5.12(d,J＝3.5Hz,1H),4.91 (dd,J＝14.4,7.1Hz,1H),4.75(d,J＝11.5Hz,3H),4.53(t,J＝8.8Hz,2H),4 .45(t,J＝8.1Hz,1H),4.31-4.16(m,3H),3.67(s,2H),3.33(s,1H),3.29( s,1H),2.44(s,3H),2.06-1.99(m,1H),1.83-1.75(m,1H),1.37(d,J＝7.0 Hz, 3H), 1.26 (d, J = 6.7Hz, 3H), 1.17 (d, J = 6.9Hz, 3H), 1.09-0.96 (m, 9H).

实施例11化合物H11的制备
Example 11 Preparation of Compound H11

步骤1:将中间体Z1(100mg,192.48μmol)溶于DMF(5mL)中，将DIPEA(1.48g,11.48mmol,2mL)加入，使其完全溶解后，再加入HATU(217.86mg,577.45μmol)。该反应在室温条件下搅拌半小时,原料反应完全，再加入4-氨基哌啶-1-甲酸叔丁酯(192.75mg,962.42μmol)，室温再反应1小时，将反应液浓缩后经CombiFlash(12g，0-10％MeOH/DCM)纯化，得到H11-a(100mg,淡黄色固体),收率：75.98％。MS m/z(ESI):683.8[M+H]+。Step 1: Dissolve the intermediate Z1 (100 mg, 192.48 μmol) in DMF (5 mL), add DIPEA (1.48 g, 11.48 mmol, 2 mL) to completely dissolve it, and then add HATU (217.86 mg, 577.45 μmol). The reaction was stirred at room temperature for half an hour. After the raw materials reacted completely, tert-butyl 4-aminopiperidine-1-carboxylate (192.75 mg, 962.42 μmol) was added and reacted at room temperature for another hour. The reaction solution was concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H11-a (100 mg, light yellow solid), yield: 75.98%. MS m/z (ESI): 683.8 [M+H] + .

步骤2:将H11-a(100mg,146.25μmol)溶于DCM(5mL)中，加入TFA(146.25μmol,0.8mL)，在室温下搅拌18h，反应完成后，用饱和NaHCO3中和，用二氯甲烷和甲醇(10:1；3×50mL)的混合溶剂萃取，合并有机相，经无水硫酸钠干燥，浓缩后得到H11-b(85mg,淡黄色油状物,粗品)，收率：99.58％。MS m/z(ESI):584.3[M+H]+。Step 2: H11-a (100 mg, 146.25 μmol) was dissolved in DCM (5 mL), TFA (146.25 μmol, 0.8 mL) was added, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, it was neutralized with saturated NaHCO 3 , extracted with a mixed solvent of dichloromethane and methanol (10:1; 3×50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain H11-b (85 mg, light yellow oil, crude product), yield: 99.58%. MS m/z (ESI): 584.3 [M+H] + .

步骤3:将H11-b(60mg,102.80μmol)和H8-b(105.26mg,308.40μmol)溶于DMSO(3mL)和EtOH(1mL)中，微波80℃搅拌30分钟，冷却至室温后加入NaBH3CN(58.14mg,925.20μmol)，在室温下搅拌0.5h。反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：38％-40％乙腈变化)纯化，得到H11(4.83mg,纯度99.04％),收率：5.12％。MS m/z(ESI):455.2[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.73(s,1H),8.56(s,1H),8.27(s,1H),7.61(d,J＝8.3Hz,1H),7.54(d,J＝8.0Hz,1H),7.49(s,1H),7.38(s,1H),7.36(dd,J＝7.9,1.6Hz,1H),6.97-6.88(m,1H),6.73(d,J＝1.9Hz,1H),6.68(dd,J＝8.7,3.9Hz,1H),6.60(dd,J＝8.4,2.0Hz,1H),5.12(d,J＝14.9Hz,1H),5.03(dd,J＝12.9,5.4Hz,1H),4.71(d,J＝4.7Hz,2H),4.53(t,J＝8.8Hz,2H),4.34-4.00(m,5H),3.70(d,J＝5.0Hz,2H),3.58(s,1H),3.07(s,2H),2.99-2.75(m,5H),2.75-2.62(m,2H),2.61-2.49(m,2H),1.93(dd,J＝46.0,41.0Hz,4H),1.27(d,J＝6.7Hz,4H),1.13(d,J＝6.8Hz,3H)。Step 3: H11-b (60 mg, 102.80 μmol) and H8-b (105.26 mg, 308.40 μmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), stirred at 80°C for 30 minutes, cooled to room temperature, and then NaBH 3 CN (58.14 mg, 925.20 μmol) was added, and stirred at room temperature for 0.5 h. The reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 38%-40% acetonitrile change) to obtain H11 (4.83 mg, purity 99.04%), yield: 5.12%. MS m/z (ESI): 455.2 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.04(s,1H),8.73(s,1H),8.56(s,1H),8.27(s,1H),7.61(d,J＝8.3Hz,1H),7.54(d,J＝8.0Hz,1H),7.49(s,1H),7.38(s,1H),7.36(dd,J ＝7.9,1.6Hz,1H),6.97-6.88(m,1H),6.73(d,J＝1.9Hz,1H),6.68(dd,J＝8.7,3.9Hz,1H),6.60(dd,J＝8.4,2.0Hz,1H),5.12(d,J＝14.9Hz,1H) ,5.03(dd,J＝12.9,5.4Hz,1H),4.71(d,J＝4.7Hz,2H),4.53(t,J＝8.8Hz,2H),4.34-4.00(m,5H),3.70(d,J＝5.0Hz,2H),3.58(s,1H),3.07(s ,2H),2.99-2.75(m,5H),2.75-2.62(m,2H),2.61-2.49(m,2H),1.93(dd,J＝46.0,41.0Hz,4H),1.27(d,J＝6.7Hz,4H),1.13(d,J＝6.8Hz,3H).

实施例12化合物H12的制备
Example 12 Preparation of Compound H12

步骤1:将中间体Z1(100mg,192.48μmol)溶于DMF(5mL)中，加入DIPEA(1.48g,11.48mmol,2mL)，使其完全溶解后，然后加入HATU(217.86mg,577.45μmol)，在室温下搅拌0.5h。原料反应完全，再加入哌嗪-1-羧酸叔丁酯(107.55mg,577.45μmol)，室温下继续反应1h。反应结束后，将反应液浓缩后经CombiFlash(12g，0～10％MeOH/DCM)纯化，得到H12-a(70mg,淡黄色固体),收率：54.30％。MS m/z(ESI):670.3[M+H]+。Step 1: Dissolve intermediate Z1 (100 mg, 192.48 μmol) in DMF (5 mL), add DIPEA (1.48 g, 11.48 mmol, 2 mL) to completely dissolve it, then add HATU (217.86 mg, 577.45 μmol) and stir at room temperature for 0.5 h. After the reaction of the raw materials is complete, add tert-butyl piperazine-1-carboxylate (107.55 mg, 577.45 μmol) and continue to react at room temperature for 1 h. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H12-a (70 mg, light yellow solid), yield: 54.30%. MS m/z (ESI): 670.3 [M+H] + .

步骤2:将H12-a(70mg,104.52μmol)溶于DCM(5.80mL)中，加入TFA(3mL)，在室温下搅拌18h。反应完成后，将反应液浓缩，用碳酸氢钠中和，用二氯甲烷和甲醇(10:1；3×50mL)混合溶剂萃取，合并有机相经无水硫酸钠干燥，浓缩后得到H12-b(57mg,淡黄色油状物，粗品),收率：95.74％。MS m/z(ESI):570.2[M+H]+。Step 2: H12-a (70 mg, 104.52 μmol) was dissolved in DCM (5.80 mL), TFA (3 mL) was added, and the mixture was stirred at room temperature for 18 h. After the reaction was completed, the reaction solution was concentrated, neutralized with sodium bicarbonate, extracted with a mixed solvent of dichloromethane and methanol (10:1; 3×50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H12-b (57 mg, light yellow oil, crude product), yield: 95.74%. MS m/z (ESI): 570.2 [M+H] + .

步骤3:将H12-b(57.00mg,100.07μmol)和H8-b(60mg,175.79μmol)溶于DMSO(3mL)和EtOH(1mL)中，微波80℃搅拌30分钟，冷却至室温后加入NaBH3CN(60mg,954.78μmol)，在室温下搅拌0.5小时。反应完全后，将反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：40％-48％乙腈变化)纯化，得到H12(14.06mg),收率：15.06％。MS m/z(ESI):895.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.74(s,1H),8.54(s,1H),7.61(d,J＝8.3Hz,1H),7.55(d,J＝8.0Hz,1H),7.51(s,1H),7.42-7.34(m,2H),6.96-6.88(m,1H),6.75(d,J＝2.0Hz,1H),6.68(dd,J＝8.6,3.9Hz,1H),6.62(dd,J＝8.4,2.0Hz,1H),5.12(d,J＝15.0Hz,1H),5.03(dd,J＝12.8,5.3Hz,1H),4.72(d,J＝4.7Hz,2H),4.53(t,J＝8.8Hz,2H),4.25-4.16(m,1H),4.12(dd,J＝13.7,7.3Hz,3H),3.75-3.64(m,2H),3.62-3.32(m,3H),3.29-3.07(m,3H),3.06-2.78(m,3H),2.67-2.51(m,3H),2.42(s,4H),2.03-1.94(m,1H),1.28(d,J＝6.7Hz,3H),1.14(d,J＝6.8Hz,3H)。Step 3: H12-b (57.00 mg, 100.07 μmol) and H8-b (60 mg, 175.79 μmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), stirred at 80°C for 30 minutes, cooled to room temperature, and then NaBH 3 CN (60 mg, 954.78 μmol) was added and stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 40%-48% acetonitrile change) to obtain H12 (14.06 mg), yield: 15.06%. MS m/z (ESI): 895.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.04(s,1H),8.74(s,1H),8.54(s,1H),7.61(d,J＝8.3Hz,1H),7.55(d,J＝8.0Hz,1H),7.51(s,1H),7.42-7.34(m,2H),6.96-6.88(m, 1H),6.75(d,J＝2.0Hz,1H),6.68(dd,J＝8.6,3.9Hz,1H),6.62(dd,J＝8.4,2.0Hz,1H),5.12(d,J＝15.0Hz,1H),5.03(dd,J＝12.8,5.3Hz,1 H),4.72(d,J＝4.7Hz,2H),4.53(t,J＝8.8Hz,2H),4.25-4.16(m,1H),4.12(dd,J＝13.7,7.3Hz,3H),3.75-3.64(m,2H),3.62-3.32(m,3H) ,3.29-3.07(m,3H),3.06-2.78(m,3H),2.67-2.51(m,3H),2.42(s,4H),2.03-1.94(m,1H),1.28(d,J＝6.7Hz,3H),1.14(d,J＝6.8Hz,3H).

实施例13化合物H13的制备
Example 13 Preparation of Compound H13

步骤:将H11-b(50mg,85.67μmol)和1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)氮杂环丁烷-3-羧酸(45.92mg,128.50μmol)溶于DMF(5mL)中，加入DIPEA(55.36mg,428.34μmol,74.61μL)和HATU(64.64mg,171.33μmol)，在室温下搅拌1h。反应完成后，将反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：0.04％FA H2O-乙腈；波长：254/214nm；梯度：38％-48％乙腈变化)纯化，得到H13(2.43mg,纯度：94.41％),收率：2.90％。MS m/z(ESI):923.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.74(s,1H),8.58(s,1H),8.32(d,J＝7.3Hz,1H),7.96(s,1H),7.89(d,J＝7.9Hz,1H),7.64(d,J＝8.3Hz,1H),7.58(d,J＝7.9Hz,1H),7.39(s,1H),6.98-6.87(m,1H),6.83(s,1H),6.68(d,J＝8.5Hz,2H),5.15(d,J＝15.0Hz,1H),5.04(dd,J＝13.0,5.0Hz,1H),4.73(s,2H),4.52(t,J＝8.6Hz,2H),4.35(d,J＝10.2Hz,1H),4.31-4.15(m,3H),4.11(d,J＝6.8Hz,3H),4.00-3.87(m,1H),3.80(s,1H),3.67(d,J＝13.3Hz,1H),3.14(t,J＝13.8Hz,1H),2.93-2.70(m,2H),2.55(dd,J＝15.3,11.3Hz,2H),2.05-1.94(m,1H),1.94-1.77(m,2H),1.46(dt,J＝21.1,10.3Hz,3H),1.34-1.16(m,4H),1.15(d,J＝6.8Hz,3H)。Procedure: H11-b (50 mg, 85.67 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylic acid (45.92 mg, 128.50 μmol) were dissolved in DMF (5 mL), and DIPEA (55.36 mg, 428.34 μmol, 74.61 μL) and HATU (64.64 mg, 171.33 μmol) were added and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 0.04% FA H 2 O-acetonitrile; wavelength: 254/214nm; gradient: 38%-48% acetonitrile change) to obtain H13 (2.43mg, purity: 94.41%), yield: 2.90%. MS m/z (ESI): 923.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),8.74(s,1H),8.58(s,1H),8.32(d,J＝7.3Hz,1H),7.96(s,1H ),7.89(d,J＝7.9Hz,1H),7.64(d,J＝8.3Hz,1H),7.58(d,J＝7.9Hz,1H),7.39( s,1H),6.98-6.87(m,1H),6.83(s,1H),6.68(d,J＝8.5Hz,2H),5.15(d,J＝15. 0Hz,1H),5.04(dd,J＝13.0,5.0Hz,1H),4.73(s,2H),4.52(t,J＝8.6Hz,2H),4 .35(d,J＝10.2Hz,1H),4.31-4.15(m,3H),4.11(d,J＝6.8Hz,3H),4.00-3.87( m,1H),3.80(s,1H),3.67(d,J＝13.3Hz,1H),3.14(t,J＝13.8Hz,1H),2.93-2. 70(m,2H),2.55(dd,J＝15.3,11.3Hz,2H),2.05-1.94(m,1H),1.94-1.77(m,2 H), 1.46 (dt, J = 21.1, 10.3Hz, 3H), 1.34-1.16 (m, 4H), 1.15 (d, J = 6.8Hz, 3H).

实施例14化合物H14的制备
Example 14 Preparation of Compound H14

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(300mg,674.78μmol)和5-(叔丁氧基羰基氨基)戊酸(175.93mg,809.74μmol)溶解在DMF(5mL)中，室温搅拌依次加入HATU(381.86mg,1.01mmol)，DIPEA(436.05mg,3.37mmol,587.67μL)，室温搅拌4小时。反应结束后，将反应液浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到H14-a(380mg,黄色固体)，收率：87.47％。Step 1: (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300 mg, 674.78 μmol) and 5-(tert-butoxycarbonylamino)pentanoic acid (175.93 mg, 809.74 μmol) were dissolved in DMF (5 mL), and HATU (381.86 mg, 1.01 mmol) and DIPEA (436.05 mg, 3.37 mmol, 587.67 μL) were added in sequence with stirring at room temperature, and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM=0-10%) to obtain H14-a (380 mg, yellow solid), yield: 87.47%.

MS m/z(ESI):644[M+H]+。MS m/z(ESI):644[M+H] + .

步骤2:将H14-a(350mg,543.62μmol)溶解在DCM(5mL)中，室温搅拌加入稀盐酸(4mol/L,3mL)，室温搅拌2h。反应结束后，将反应液浓缩，得到H14-b(295.58mg,黄色固体),收率：100.00％。MS m/z(ESI):544[M+H]+。Step 2: H14-a (350 mg, 543.62 μmol) was dissolved in DCM (5 mL), and diluted hydrochloric acid (4 mol/L, 3 mL) was added with stirring at room temperature, and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to obtain H14-b (295.58 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 544 [M+H] + .

步骤3:将H10-a(100mg,192.48μmol)溶解在DMF(5mL)中，室温搅拌加入HATU(363.09mg,962.42μmol)，DIPEA(746.32mg,5.77mmol,1.01mL)，室温搅拌2小时，再加入H14-b(209.31mg,384.97μmol)，室温搅拌过夜。反应结束后，将反应液浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：0％-75％乙腈变化)纯化，得到H14(2.1mg,纯度：97.26％),收率：1.03％。MS m/z(ESI):514.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.75(s,1H),8.51(t,J＝5.6Hz,1H),8.35(d,J＝7.9Hz,1H),7.96(s,1H),7.87(d,J＝8.1Hz,1H),7.79(d,J＝9.4Hz,1H),7.56(d,J＝8.2Hz,1H),7.47-7.29(m,4H),6.98-6.87(m,1H),6.68(dd,J＝8.7,3.8Hz,1H),5.21-4.07(m,14H),3.58(s,2H),2.47-0.80(m,33H)。Step 3: H10-a (100 mg, 192.48 μmol) was dissolved in DMF (5 mL), and HATU (363.09 mg, 962.42 μmol) and DIPEA (746.32 mg, 5.77 mmol, 1.01 mL) were added under stirring at room temperature, and the mixture was stirred at room temperature for 2 hours, and H14-b (209.31 mg, 384.97 μmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH: DCM = 0-10%), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-75% acetonitrile change) to obtain H14 (2.1 mg, purity: 97.26%), yield: 1.03%. MS m/z(ESI):514.3[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.96(s,1H),8.75(s,1H),8.51(t,J＝5.6Hz,1H),8.35(d,J＝7.9Hz,1H),7.96(s,1H),7.87(d,J＝8.1Hz,1H),7.79(d,J＝9.4Hz,1H),7.56 (d,J＝8.2Hz,1H),7.47-7.29(m,4H),6.98-6.87(m,1H),6.68(dd,J＝8.7,3.8Hz,1H),5.21-4.07(m,14H),3.58(s,2H),2.47-0.80(m,33H).

实施例15化合物H15的制备
Example 15 Preparation of Compound H15

步骤:将H12-b(68mg,119.38μmol)和1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)氮杂环丁烷-3-羧酸(63.98mg,179.06μmol)溶于DMF(5mL)中，加入DIPEA(154.29mg,1.19mmol,207.93μL)和HATU(67.56mg,179.06μmol)，在室温下搅拌1h。反应完成后，将反应液浓缩后经CombiFlash(12g，0～10％MeOH/DCM)纯化，得到H15(13.57mg),收率：12.46％。MS m/z(ESI):909.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.75(s,1H),8.58(s,1H),7.64(d,J＝8.3Hz,1H),7.61-7.50(m,2H),7.48-7.41(m,1H),7.40(s,1H),6.97-6.88(m,1H),6.81(s,1H),6.68(dd,J＝8.6,4.0Hz,2H),5.14(d,J＝15.0Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.72(d,J＝3.2Hz,2H),4.53(t,J＝8.8Hz,2H),4.34-4.04(m,6H),3.93(s,2H),3.56(s,8H),2.95-2.74(m,2H),2.65-2.50(m,2H),2.04-1.95(m,1H),1.28(d,J＝6.6Hz,3H),1.15(d,J＝6.7Hz,3H)。Procedure: H12-b (68 mg, 119.38 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)azetidine-3-carboxylic acid (63.98 mg, 179.06 μmol) were dissolved in DMF (5 mL), and DIPEA (154.29 mg, 1.19 mmol, 207.93 μL) and HATU (67.56 mg, 179.06 μmol) were added, and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H15 (13.57 mg), yield: 12.46%. MS m/z (ESI): 909.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),8.75(s,1H),8.58(s,1H),7.64(d,J＝8.3Hz,1H),7.61-7.50(m,2H),7.48-7.41(m,1H),7. 40(s,1H),6.97-6.88(m,1H),6.81(s,1H),6.68(dd,J＝8.6,4.0Hz,2H),5.14(d,J＝15.0Hz,1H),5.04(dd,J ＝12.9,5.4Hz,1H),4.72(d,J＝3.2Hz,2H),4.53(t,J＝8.8Hz,2H),4.34-4.04(m,6H),3.93(s,2H),3.56(s,8 H),2.95-2.74(m,2H),2.65-2.50(m,2H),2.04-1.95(m,1H),1.28(d,J＝6.6Hz,3H),1.15(d,J＝6.7Hz,3H).

实施例16化合物H16的制备
Example 16 Preparation of Compound H16

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(500mg,1.12mmol)和1-叔丁氧羰基哌啶-4-羧酸(515.70mg,2.25mmol)溶于DMF(10mL)中，加入DIPEA(726.76mg,5.62mmol,979.45μL)和HATU(848.58mg,2.25mmol)，在室温下搅拌1h。反应完成后，将反应液浓缩后经CombiFlash(24g，0-10％MeOH/DCM)纯化，得到H16-a(354mg),收率：47.99％。MS m/z(ESI):556.3[M-100+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (500 mg, 1.12 mmol) and 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid (515.70 mg, 2.25 mmol) were dissolved in DMF (10 mL), and DIPEA (726.76 mg, 5.62 mmol, 979.45 μL) and HATU (848.58 mg, 2.25 mmol) were added and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H16-a (354 mg), yield: 47.99%. MS m/z(ESI):556.3[M-100+H] + .

步骤2:将H16-a(354mg,539.76μmol)溶于DCM(10mL)，加入稀盐酸(4mol/L,2mL),在20℃下搅拌1h。反应完成后，将反应液浓缩得到H16-b(299.96mg,黄色固体),收率：100.00％。MS m/z(ESI):556.3[M+H]+。Step 2: H16-a (354 mg, 539.76 μmol) was dissolved in DCM (10 mL), diluted hydrochloric acid (4 mol/L, 2 mL) was added, and stirred at 20°C for 1 h. After the reaction was completed, the reaction solution was concentrated to obtain H16-b (299.96 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 556.3 [M+H] + .

步骤3:将中间体Z1(100mg,192.48μmol)和DIPEA(1.48g,11.48mmol,2mL)溶于DMF(5mL)中，加入HATU(254.16mg,673.69μmol)，在室温下搅拌0.5h,然后加入H16-b(213.94mg,384.97μmol)，室温下继续搅拌0.5h。反应完成后，将反应液浓缩后经CombiFlash(12g，0-10％MeOH/DCM)纯化，得到H16(18.29mg),收率：9.14％。MS m/z(ESI):520.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.74(s,1H),8.54(s,1H),8.36(d,J＝7.7Hz,1H),7.84(d,J＝9.1Hz,1H),7.58-7.47(m,2H),7.45-7.32(m,5H),6.96-6.89(m,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.11(d,J＝15.3Hz,2H),4.95-4.85(m,1H),4.72(s,2H),4.51(dd,J＝17.5,8.8Hz,3H),4.41(t,J＝8.0Hz,1H),4.26(s,1H),4.21(d,J＝15.2Hz,1H),4.15-4.08(m,1H),3.78-3.43(m,4H),3.33(s,1H),3.29(s,1H),3.05(s,1H),2.82(s,1H),2.67(s,1H),2.43(s,3H),2.05-1.94(m,1H),1.88-1.63(m,3H),1.49(dd,J＝31.1,8.6Hz,3H),1.35(d,J＝6.9Hz,3H),1.30-1.23(m,3H),1.17-1.03(m,3H),0.92(s,9H)。Step 3: Dissolve intermediate Z1 (100 mg, 192.48 μmol) and DIPEA (1.48 g, 11.48 mmol, 2 mL) in DMF (5 mL), add HATU (254.16 mg, 673.69 μmol), stir at room temperature for 0.5 h, then add H16-b (213.94 mg, 384.97 μmol), and continue stirring at room temperature for 0.5 h. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H16 (18.29 mg), yield: 9.14%. MS m/z (ESI): 520.3 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.96(s,1H),8.74(s,1H),8.54(s,1H),8.36(d,J＝7.7Hz,1H),7.84(d ,J＝9.1Hz,1H),7.58-7.47(m,2H),7.45-7.32(m,5H),6.96-6.89(m,1H), 6.68(dd,J＝8.6,3.8Hz,1H),5.11(d,J＝15.3Hz,2H),4.95-4.85(m,1H),4.72(s,2H),4.51(dd,J＝17.5,8.8Hz,3H),4.41(t,J＝8.0Hz,1H),4.26(s ,1H),4.21(d,J＝15.2Hz,1H),4.15-4.08(m,1H),3.78-3.43(m,4H),3.3 3(s,1H),3.29(s,1H),3.05(s,1H),2.82(s,1H),2.67(s,1H),2.43(s,3H ),2.05-1.94(m,1H),1.88-1.63(m,3H),1.49(dd,J＝31.1,8.6Hz,3H),1 .35(d,J=6.9Hz,3H),1.30-1.23(m,3H),1.17-1.03(m,3H),0.92(s,9H).

实施例17化合物H17的制备
Example 17 Preparation of Compound H17

步骤1:将(2S，4R)-1-((S)-2-氨基-3，3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(0.85g,1.97mmol)和5-叔丁氧基-5-氧代-戊酸(427.31mg,2.27mmol)溶于DCM(10mL)中，加入DIPEA(1g,7.29mmol)和HATU(1.33g,3.5mmol)，在室温下搅拌30分钟。反应完成后，将反应液浓缩后经过CombiFlash(24g，0-10％MeOH/DCM)纯化，得到H17-a(1.1g,1.83mmol),收率：92.75％。MS m/z(ESI):601.4[M+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.85 g, 1.97 mmol) and 5-tert-butoxy-5-oxo-pentanoic acid (427.31 mg, 2.27 mmol) were dissolved in DCM (10 mL), and DIPEA (1 g, 7.29 mmol) and HATU (1.33 g, 3.5 mmol) were added and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H17-a (1.1 g, 1.83 mmol), yield: 92.75%. MS m/z (ESI): 601.4 [M+H] + .

步骤2:将H17-a(1.1g,1.83mmol)溶于THF(10mL)中，加入稀盐酸(4mol/L,12mL),在室温下搅拌30分钟,反应完成后，用饱和碳酸氢钠水溶液中和，二氯甲烷和甲醇混合溶剂(10：1，30mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后得到H17-b(412mg,无色粘稠物，粗品),收率：41.31％。MS m/z(ESI):545.3[M+H]+。Step 2: H17-a (1.1 g, 1.83 mmol) was dissolved in THF (10 mL), diluted hydrochloric acid (4 mol/L, 12 mL) was added, and stirred at room temperature for 30 minutes. After the reaction was completed, it was neutralized with a saturated sodium bicarbonate aqueous solution, extracted with a mixed solvent of dichloromethane and methanol (10:1, 30 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H17-b (412 mg, colorless viscous substance, crude product), yield: 41.31%. MS m/z (ESI): 545.3 [M+H] + .

步骤3:将H2-f(70mg,123.34μmol)和H17-b(80.61mg,148.01μmol)溶于DMF(4mL)中，加入DIPEA(71.73mg,555.03μmol)和HATU(69.80mg,185.01μmol)，在室温下搅拌1h。反应完成后，将反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：44％-74％乙腈变化)纯化，得到H17(33.57mg),收率：24.87％。MS m/z(ESI):547.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.85(s,1H),8.78(s,1H),8.75(s,1H),8.59-8.46(m,1H),8.11(d,J＝6.3Hz,1H),7.84(d,J＝9.6Hz,1H),7.59(s,1H),7.39(dd,J＝13.6,6.0Hz,4H),6.98-6.88(m,1H),6.69(dd,J＝8.6,3.8Hz,1H),5.28(d,J＝14.8Hz,1H),5.09(s,1H),4.74(s,2H),4.53(t,J＝8.8Hz,3H),4.39(dd,J＝23.7,10.3Hz,4H),4.20(d,J＝15.3Hz,1H),4.04(s,1H),3.86(s,1H),3.64(d,J＝6.2Hz,2H),3.33(s,2H),3.11-2.79(m,2H),2.42(s,3H),2.35-1.95(m,7H),1.89(s,1H),1.70(d,J＝6.4Hz,3H),1.22(s,1H),1.07(d,J＝9.5Hz,1H),0.92(d,J＝9.1Hz,9H)。Step 3: H2-f (70 mg, 123.34 μmol) and H17-b (80.61 mg, 148.01 μmol) were dissolved in DMF (4 mL), and DIPEA (71.73 mg, 555.03 μmol) and HATU (69.80 mg, 185.01 μmol) were added, and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 44%-74% acetonitrile change) to obtain H17 (33.57 mg), yield: 24.87%. MS m/z (ESI): 547.8 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.96(s,1H),8.85(s,1H),8.78(s,1H),8.75(s,1H),8.59-8.46(m,1H),8.11(d,J＝6.3Hz,1H),7.84(d,J＝9.6Hz,1H),7.59(s,1H),7.3 9(dd,J＝13.6,6.0Hz,4H),6.98-6.88(m,1H),6.69(dd,J＝8.6,3.8Hz,1H),5.28(d,J＝14.8Hz,1H),5.09(s,1H),4.74(s,2H),4.53(t,J＝8 .8Hz,3H),4.39(dd,J＝23.7,10.3Hz,4H),4.20(d,J＝15.3Hz,1H),4.04(s,1H),3.86(s,1H),3.64(d,J＝6.2Hz,2H),3.33(s,2H),3.11-2. 79(m,2H),2.42(s,3H),2.35-1.95(m,7H),1.89(s,1H),1.70(d,J＝6.4Hz,3H),1.22(s,1H),1.07(d,J＝9.5Hz,1H),0.92(d,J＝9.1Hz,9H).

实施例18化合物H18的制备
Example 18 Preparation of Compound H18

步骤1:将2-(2，6-二氧哌啶-3-基)-4-羟基异吲哚啉-1，3-二酮(1g,3.65mmol)和N-(8-溴辛基)氨基甲酸叔丁酯(1g,3.24mmol)溶于DMF(10mL)中，加入K2CO3(2.02g,14.59mmol)，在50℃下搅拌18h。反应完成后，将反应液冷却至室温，过滤，滤液浓缩后经CombiFlash(12g，0-100％EA/PE)纯化，得到H18-a(335mg,无色油状物),收率：18.32％。MS m/z(ESI):402.2[M-100+H]+。Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1 g, 3.65 mmol) and tert-butyl N-(8-bromooctyl)carbamate (1 g, 3.24 mmol) were dissolved in DMF (10 mL), K 2 CO 3 (2.02 g, 14.59 mmol) was added, and stirred at 50° C. for 18 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by CombiFlash (12 g, 0-100% EA/PE) to obtain H18-a (335 mg, colorless oil), yield: 18.32%. MS m/z (ESI): 402.2 [M-100+H] + .

步骤2:将H18-a(335mg,667.90μmol)溶于DCM(20mL)中，加入HCl(4mol/L的乙酸乙酯溶液,3mL)，在室温下搅拌18h。反应结束后，将反应液浓缩，得到H18-b(268mg,白色固体),收率：99.95％。MS m/z(ESI):402.2[M+H]+。Step 2: H18-a (335 mg, 667.90 μmol) was dissolved in DCM (20 mL), HCl (4 mol/L ethyl acetate solution, 3 mL) was added, and stirred at room temperature for 18 h. After the reaction was completed, the reaction solution was concentrated to obtain H18-b (268 mg, white solid), yield: 99.95%. MS m/z (ESI): 402.2 [M+H] + .

步骤3:将中间体Z1(100mg,192.48μmol)溶于DMF(1.02mL)中，加入DIPEA(199.02mg,1.54mmol,268.22μL)和HATU(363.09mg,962.42μmol)，在室温下搅拌18小时,然后再加入H18-b(149.18mg,371.61μmol)，在室温下继续搅拌2小时。反应完成后，将反应液浓缩后经CombiFlash(12g，0～15％ACN/DCM)纯化，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：47％-78％乙腈变化)纯化，得到H18(34.59mg),收率：19.12％。MS m/z(ESI):885.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.74(s,1H),8.56(t,J＝5.1Hz,1H),8.47(t,J＝5.6Hz,1H),7.95(s,1H),7.87(dd,J＝8.1,1.5Hz,1H),7.80-7.73(m,1H),7.56(d,J＝8.2Hz,1H),7.48(d,J＝8.6Hz,1H),7.40(d,J＝7.7Hz,2H),6.98-6.88(m,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.14(d,J＝15.0Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.72(d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.24-4.13(m,3H),3.27(dd,J＝15.5,7.8Hz,4H),2.92-2.79(m,1H),2.54(dd,J＝21.0,10.9Hz,2H),2.05-1.96(m,1H),1.90(d,J＝12.6Hz,1H),1.78-1.70(m,2H),1.67(s,1H),1.52(d,J＝6.8Hz,2H),1.44(s,2H),1.33(d,J＝7.4Hz,5H),1.23(d,J＝6.7Hz,3H),1.16(t,J＝8.1Hz,3H)。Step 3: Dissolve intermediate Z1 (100 mg, 192.48 μmol) in DMF (1.02 mL), add DIPEA (199.02 mg, 1.54 mmol, 268.22 μL) and HATU (363.09 mg, 962.42 μmol), stir at room temperature for 18 hours, then add H18-b (149.18 mg, 371.61 μmol), and continue stirring at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% ACN/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 47%-78% acetonitrile change) to obtain H18 (34.59 mg), yield: 19.12%. MS m/z (ESI): 885.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),8.74(s,1H),8.56(t,J＝5.1Hz,1H),8.47(t,J＝5.6Hz,1H),7. 95(s,1H),7.87(dd,J＝8.1,1.5Hz,1H),7.80-7.73(m,1H),7.56(d,J＝8.2Hz,1H ),7.48(d,J＝8.6Hz,1H),7.40(d,J＝7.7Hz,2H),6.98-6.88(m,1H),6.68(dd,J＝ 8.6,3.8Hz,1H),5.14(d,J＝15.0Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.72(d, J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.24-4.13(m,3H),3.27(dd,J＝15.5,7.8H z,4H),2.92-2.79(m,1H),2.54(dd,J＝21.0,10.9Hz,2H),2.05-1.96(m,1H),1. 90(d,J＝12.6Hz,1H),1.78-1.70(m,2H),1.67(s,1H),1.52(d,J＝6.8Hz,2H),1. 44 (s, 2H), 1.33 (d, J = 7.4Hz, 5H), 1.23 (d, J = 6.7Hz, 3H), 1.16 (t, J = 8.1Hz, 3H).

实施例19化合物H19的制备
Example 19 Preparation of Compound H19

步骤：将H10-a(100mg,192.48μmol)溶解在DMF(5mL)中，室温搅拌加入HATU(363.09mg,962.42μmol)，DIPEA(746.32mg,5.77mmol,1.01mL)室温搅拌过夜，再加入(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(171.15mg,384.97μmol)，室温搅拌5小时。反应液倒入水中，二氯甲烷(30mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：0％-65％乙腈变化)纯化，得到H19(6.14mg,纯度：99.41％),收率：3.42％。MS m/z(ESI):929[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.74(s,1H),8.57(s,1H),8.40(d,J＝7.4Hz,1H),8.12-7.88(m,3H),7.57(d,J＝8.2Hz,1H),7.47-7.33(m,4H),6.98-6.88(m,1H),6.69(dd,J＝8.6,3.8Hz,1H),5.19-5.06(m,2H),5.01-4.69(m,5H),4.49(dt,J＝16.0,8.5Hz,3H),4.36-4.13(m,3H),3.68(s,2H),3.33(s,2H),2.46-2.40(m,2H),2.04(d,J＝11.3Hz,1H),1.80(s,1H),1.52(s,1H),1.37(d,J＝6.6Hz,3H),1.30-1.11(m,6H),1.02(d,J＝7.5Hz,9H)。Steps: H10-a (100 mg, 192.48 μmol) was dissolved in DMF (5 mL), HATU (363.09 mg, 962.42 μmol) and DIPEA (746.32 mg, 5.77 mmol, 1.01 mL) were added with stirring at room temperature and stirred overnight at room temperature, and then (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (171.15 mg, 384.97 μmol) was added and stirred at room temperature for 5 hours. The reaction solution was poured into water and extracted with dichloromethane (30 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH:DCM=0-10%), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-65% acetonitrile) to obtain H19 (6.14 mg, purity: 99.41%), yield: 3.42%. MS m/z (ESI): 929 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.97(s,1H),8.74(s,1H),8.57(s,1H),8.40(d,J＝7.4Hz,1H),8.12-7.88(m,3H),7.57(d,J＝8.2Hz,1H) ,7.47-7.33(m,4H),6.98-6.88(m,1H),6.69(dd,J＝8.6,3.8Hz,1H),5.19-5.06(m,2H),5.01-4.69(m,5H) ,4.49(dt,J＝16.0,8.5Hz,3H),4.36-4.13(m,3H),3.68(s,2H),3.33(s,2H),2.46-2.40(m,2H),2.04(d,J ＝11.3Hz,1H),1.80(s,1H),1.52(s,1H),1.37(d,J＝6.6Hz,3H),1.30-1.11(m,6H),1.02(d,J＝7.5Hz,9H).

实施例20化合物H20的制备
Example 20 Preparation of Compound H20

步骤1:将(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(600mg,1.35mmol)和N-叔丁氧羰基-8-氨基辛酸(385.00mg,1.48mmol)溶解于DMF(15mL)，室温下加入HATU(1.02g,2.70mmol)和DIPEA(523.26mg,4.05mmol)，在室温下搅拌2小时。反应结束后，向反应液中加入水(100mL)，用乙酸乙酯(50mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩后经combilfahs(MeOH：DCM＝0-10％)纯化，得到H20-a(565mg,黄色固体),收率：61.04％。MS m/z(ESI):586.4[M-100+H]+。Step 1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (600 mg, 1.35 mmol) and N-tert-butoxycarbonyl-8-aminooctanoic acid (385.00 mg, 1.48 mmol) were dissolved in DMF (15 mL), HATU (1.02 g, 2.70 mmol) and DIPEA (523.26 mg, 4.05 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by combilfahs (MeOH:DCM=0-10%) to obtain H20-a (565 mg, yellow solid), yield: 61.04%. MS m/z (ESI): 586.4 [M-100+H] + .

步骤2:将H20-a(565mg,823.72μmol)溶解于THF(5mL)中，冰浴下(0℃)加入盐酸二氧六环溶液(4mol/L,5.01mL)，在室温下搅拌4小时。反应结束后，将反应液浓缩得到H20-b(482mg,黄色固体，粗品)，粗品直接用于下一步。MS m/z(ESI):586.3[M+H]+。Step 2: H20-a (565 mg, 823.72 μmol) was dissolved in THF (5 mL), and dioxane hydrochloride solution (4 mol/L, 5.01 mL) was added under ice bath (0°C), and stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated to obtain H20-b (482 mg, yellow solid, crude product), which was directly used in the next step. MS m/z (ESI): 586.3 [M+H] + .

步骤3:将H10-a(96.53mg,192.48μmol)和H20-b(172.33mg,251.24μmol)溶解于DMF(5mL)中，室温下加入HATU(157.98mg,418.74μmol)和DIPEA(27.06mg,209.37μmol,36.47μL)，在室温下搅拌3小时。反应结束后，将反应液浓缩后经combiflash(MeOH：DCM＝0～14％)纯化，再经过碱法制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：48％-53％乙腈变化)纯化，然后经过酸法制备HPLC(制备柱：21.2X250mm C18柱；体系：0.04％TFA/H2O-乙腈；波长：254/214nm；梯度：41％-71％乙腈变化)，得到H20(2.17mg,纯度100％),收率：0.94％。MS m/z(ESI):535.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.74(s,1H),8.57(s,1H),8.48(t,J＝5.6Hz,1H),8.34(d,J＝7.8Hz,1H),7.95(d,J＝1.9Hz,1H),7.87(dd,J＝8.1,1.8Hz,1H),7.76(d,J＝9.2Hz,1H),7.56(d,J＝8.2Hz,1H),7.45-7.33(m,5H),6.92(dd,J＝10.3,8.6Hz,1H),6.68(dd,J＝8.7,3.9Hz,1H),5.22-5.01(m,2H),4.89(t,J＝7.2Hz,1H),4.72(d,J＝4.2Hz,2H),4.59-4.46(m,3H),4.40(t,J＝8.0Hz,1H),4.30-4.12(m,3H),3.59(d,J＝3.8Hz,2H),2.43(s,3H),2.29-2.17(m,1H),2.10(q,J＝7.0Hz,1H),2.03-1.93(m,1H),1.77(ddd,J＝12.9,8.4,4.7Hz,1H),1.57-1.41(m,4H),1.35(d,J＝7.0Hz,3H),1.32-1.19(m,11H),1.15(d,J＝6.8Hz,3H),0.91(s,9H)。Step 3: H10-a (96.53 mg, 192.48 μmol) and H20-b (172.33 mg, 251.24 μmol) were dissolved in DMF (5 mL), HATU (157.98 mg, 418.74 μmol) and DIPEA (27.06 mg, 209.37 μmol, 36.47 μL) were added at room temperature, and stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated and purified by combiflash (MeOH: DCM = 0-14%), and then purified by alkaline preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O -acetonitrile; wavelength: 254/214nm; gradient: 48%-53% acetonitrile), and then purified by acid preparative HPLC (preparative column: 21.2X250mm C18 column; system: 0.04% TFA/ H2O -acetonitrile; wavelength: 254/214nm; gradient: 41%-71% acetonitrile) to obtain H20 (2.17mg, purity 100%), yield: 0.94%. MS m/z (ESI): 535.3 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.96(s,1H),8.74(s,1H),8.57(s,1H),8.48(t,J＝5.6Hz,1H),8.34(d,J＝7 .8Hz,1H),7.95(d,J＝1.9Hz,1H),7.87(dd,J＝8.1,1.8Hz,1H),7.76(d,J＝9.2H z,1H),7.56(d,J＝8.2Hz,1H),7.45-7.33(m,5H),6.92(dd,J＝10.3,8.6Hz,1H ),6.68(dd,J＝8.7,3.9Hz,1H),5.22-5.01(m,2H),4.89(t,J＝7.2Hz,1H),4.72 (d,J＝4.2Hz,2H),4.59-4.46(m,3H),4.40(t,J＝8.0Hz,1H),4.30-4.12(m,3H ),3.59(d,J＝3.8Hz,2H),2.43(s,3H),2.29-2.17(m,1H),2.10(q,J＝7.0Hz,1H ),2.03-1.93(m,1H),1.77(ddd,J＝12.9,8.4,4.7Hz,1H),1.57-1.41(m,4H),1 .35(d,J＝7.0Hz,3H),1.32-1.19(m,11H),1.15(d,J＝6.8Hz,3H),0.91(s,9H).

实施例21化合物H21的制备
Example 21 Preparation of Compound H21

步骤1:将H10-a(190mg,378.86μmol)和4-氨基哌啶-1-甲酸叔丁酯(151.75mg,757.71μmol)溶解于DMF(10mL)，加入HATU(285.86mg,757.71μmol)和DIPEA(146.89mg,1.14mmol,197.97μL)，在室温下搅拌16小时。反应结束后，将反应液浓缩后经combination falsh(MeOH：DCM＝0～8％)纯化，得到H11-a(215mg,棕色固体，粗品)，粗品直接用于下一步反应。MS m/z(ESI):683.8[M+H]+。Step 1: H10-a (190 mg, 378.86 μmol) and tert-butyl 4-aminopiperidine-1-carboxylate (151.75 mg, 757.71 μmol) were dissolved in DMF (10 mL), HATU (285.86 mg, 757.71 μmol) and DIPEA (146.89 mg, 1.14 mmol, 197.97 μL) were added, and stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated and purified by combination falsh (MeOH: DCM = 0-8%) to obtain H11-a (215 mg, brown solid, crude product), which was directly used in the next step. MS m/z (ESI): 683.8 [M+H] + .

步骤2:将H11-a(195mg,285.18μmol)溶解于1,4二氧六环(4.00mL)中，在室温下加入盐酸乙酸乙酯溶液(2mol/L,2mL)，在室温下搅拌16小时。反应结束后，向反应液中加入DCM(20mL)，再加入饱和碳酸氢钠水溶液(50mL)，搅拌5分钟，有固体析出，过滤，滤饼浓缩，得到H11-b(95mg,黄色固体，粗品)未作进一步纯化，直接用于下一步反应。MS m/z(ESI):583.8[M+H]+。Step 2: H11-a (195 mg, 285.18 μmol) was dissolved in 1,4-dioxane (4.00 mL), and a hydrochloric acid ethyl acetate solution (2 mol/L, 2 mL) was added at room temperature, and stirred at room temperature for 16 hours. After the reaction was completed, DCM (20 mL) was added to the reaction solution, and then a saturated sodium bicarbonate aqueous solution (50 mL) was added, and stirred for 5 minutes. Solids precipitated, filtered, and the filter cake was concentrated to obtain H11-b (95 mg, yellow solid, crude product) without further purification, and directly used in the next step. MS m/z (ESI): 583.8 [M+H] + .

步骤3:将H11-b(40mg,68.53μmol)和1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)哌啶-4-甲醛(37.97mg,102.80μmol)溶解于DMSO(3mL)和EtOH(1mL)的混合溶液中，在微波反应器中80℃下搅拌0.5小时，自然降温至室温，室温下加入NaBH3CN(43.07mg,685.34μmol)，室温下继续搅拌2小时。反应结束后，将反应液浓缩后，粗品经过碱法制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：47％-52％乙腈变化)纯化，得到H21(16.28mg,纯度：97.01％),收率：23.85％。MS m/z(ESI):469.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.73(s,1H),8.57(d,J＝5.0Hz,1H),8.26(d,J＝7.7Hz,1H),7.99-7.85(m,2H),7.63(d,J＝8.6Hz,1H),7.56(d,J＝8.1Hz,1H),7.39(s,1H),7.29(d,J＝2.2Hz,1H),7.21(d,J＝8.7Hz,1H),6.93(dd,J＝10.3,8.7Hz,1H),6.68(dd,J＝8.7,3.9Hz,1H),5.14(d,J＝15.0Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.72(d,J＝4.9Hz,2H),4.52(t,J＝8.8Hz,2H),4.26-4.13(m,2H),4.03(d,J＝12.8Hz,2H),3.77(s,1H),3.29(s,1H),2.95(t,J＝12.5Hz,2H),2.84(d,J＝11.3Hz,3H),2.60-2.50(m,2H),2.14(d,J＝6.6Hz,2H),2.04-1.89(m,3H),1.78(d,J＝12.4Hz,5H),1.58(d,J＝11.5Hz,2H),1.28-1.20(m,5H),1.15(d,J＝6.7Hz,4H)。Step 3: H11-b (40 mg, 68.53 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (37.97 mg, 102.80 μmol) were dissolved in a mixed solution of DMSO (3 mL) and EtOH (1 mL), stirred at 80 °C for 0.5 h in a microwave reactor, cooled naturally to room temperature, NaBH 3 CN (43.07 mg, 685.34 μmol) was added at room temperature, and stirring was continued at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated and the crude product was purified by alkaline preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 47%-52% acetonitrile change) to obtain H21 (16.28mg, purity: 97.01%), yield: 23.85%. MS m/z (ESI): 469.3 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),8.73(s,1H),8.57(d,J＝5.0Hz,1H),8.26(d,J＝7.7Hz,1H),7. 99-7.85(m,2H),7.63(d,J＝8.6Hz,1H),7.56(d,J＝8.1Hz,1H),7.39(s,1H),7. 29(d,J＝2.2Hz,1H),7.21(d,J＝8.7Hz,1H),6.93(dd,J＝10.3,8.7Hz,1H),6.68 (dd,J＝8.7,3.9Hz,1H),5.14(d,J＝15.0Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4 .72(d,J＝4.9Hz,2H),4.52(t,J＝8.8Hz,2H),4.26-4.13(m,2H),4.03(d,J＝12. 8Hz,2H),3.77(s,1H),3.29(s,1H),2.95(t,J＝12.5Hz,2H),2.84(d,J＝11.3Hz ,3H),2.60-2.50(m,2H),2.14(d,J＝6.6Hz,2H),2.04-1.89(m,3H),1.78(d,J＝ 12.4Hz, 5H), 1.58 (d, J = 11.5Hz, 2H), 1.28-1.20 (m, 5H), 1.15 (d, J = 6.7Hz, 4H).

实施例22化合物H22的制备
Example 22 Preparation of Compound H22

步骤1:(2S，4R)-1-((S)-2-氨基-3，3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(300mg,674.78μmol)和3-(叔丁氧基羰基氨基)丙酸(153.21mg,809.74μmol)溶解在DMF(5mL)中，室温搅拌下依次加入HATU(381.86mg,1.01mmol)，DIPEA(436.05mg,3.37mmol,587.67μL)，室温搅拌4小时。反应结束后，将反应液浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到H22-a(260mg,黄色固体),收率：62.57％。MS m/z(ESI):616[M+H]+。Step 1: (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300 mg, 674.78 μmol) and 3-(tert-butoxycarbonylamino)propionic acid (153.21 mg, 809.74 μmol) were dissolved in DMF (5 mL), and HATU (381.86 mg, 1.01 mmol) and DIPEA (436.05 mg, 3.37 mmol, 587.67 μL) were added successively under stirring at room temperature, and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM=0-10%) to obtain H22-a (260 mg, yellow solid), yield: 62.57%. MS m/z(ESI):616[M+H] + .

步骤2:将H22-a(260mg,422.23μmol)溶解在DCM(5mL)中，室温搅拌下加入HCl的乙酸乙酯溶液(4.0mol/L,3mL)，室温搅拌2小时。反应结束后，将反应液浓缩，得到H22-b(217.73mg,黄色固体),收率：100.00％。MS m/z(ESI):516[M+H]+。Step 2: H22-a (260 mg, 422.23 μmol) was dissolved in DCM (5 mL), and HCl in ethyl acetate (4.0 mol/L, 3 mL) was added under stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H22-b (217.73 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 516 [M+H] + .

步骤3:将H10-a(100mg,192.48μmol)和H22-b(198.52mg,384.97μmol)溶解在DMF(5mL)中，室温搅拌依次加入HATU(363.09mg,962.42μmol)，DIPEA(746.32mg,5.77mmol,1.01mL)，室温搅拌过夜。反应结束后，将反应液浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，再经HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：0％-85％乙腈变化)纯化，得到H22(1.84mg,纯度100％),收率：0.96％。MS m/z(ESI):500.3[M/2+H]+.1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.75(s,1H),8.50(s,1H),8.36(d,J＝7.9Hz,1H),7.95(d,J＝8.5Hz,2H),7.86(d,J＝8.1Hz,1H),7.56(d,J＝8.1Hz,1H),7.39(dt,J＝18.0,8.3Hz,4H),6.95-6.88(m,1H),6.67(dd,J＝8.6,3.8Hz,1H),5.15(d,J＝15.3Hz,2H),4.94-4.85(m,1H),4.72(s,2H),4.52(t,J＝8.7Hz,3H),4.41(t,J＝8.1Hz,1H),4.20(dd,J＝29.8,17.4Hz,3H),3.60(s,2H),3.46(d,J＝5.5Hz,2H),2.55(d,J＝7.8Hz,2H),2.43(s,3H),1.98(d,J＝7.3Hz,2H),1.77(s,1H),1.35(d,J＝7.0Hz,3H),1.23(t,J＝6.9Hz,4H),1.15(d,J＝6.8Hz,3H),0.89(d,J＝9.7Hz,9H)。Step 3: H10-a (100 mg, 192.48 μmol) and H22-b (198.52 mg, 384.97 μmol) were dissolved in DMF (5 mL), and HATU (363.09 mg, 962.42 μmol) and DIPEA (746.32 mg, 5.77 mmol, 1.01 mL) were added in sequence under stirring at room temperature, and stirred overnight at room temperature. After the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH: DCM = 0-10%), and then purified by HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-85% acetonitrile change) to obtain H22 (1.84 mg, purity 100%), yield: 0.96%. MS m/z(ESI):500.3[M/2+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.96(s,1H),8.75(s,1H),8.50(s,1H),8.36(d,J＝7.9Hz,1H),7.95(d,J＝8.5Hz,2H),7.86(d,J＝8.1Hz,1H),7.56(d,J＝8.1Hz,1H),7. 39(dt,J＝18.0,8.3Hz,4H),6.95-6.88(m,1H),6.67(dd,J＝8.6,3.8Hz,1H),5.15(d,J＝15.3Hz,2H),4.94-4.85(m,1H),4.72(s,2H),4.5 2(t,J＝8.7Hz,3H),4.41(t,J＝8.1Hz,1H),4.20(dd,J＝29.8,17.4Hz,3H),3.60(s,2H),3.46(d,J＝5.5Hz,2H),2.55(d,J＝7.8Hz,2H),2.4 3(s,3H),1.98(d,J＝7.3Hz,2H),1.77(s,1H),1.35(d,J＝7.0Hz,3H),1.23(t,J＝6.9Hz,4H),1.15(d,J＝6.8Hz,3H),0.89(d,J＝9.7Hz,9H).

实施例23化合物H23的制备
Example 23 Preparation of Compound H23

步骤1:将(2S，4R)-1-((S)-2-氨基-3，3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(0.5g,1.12mmol)和1-叔丁氧基羰基氮杂环丁烷-3-羧酸(452.60mg,2.25mmol)溶于DMF(10mL)中，加入DIPEA(581.40mg,4.50mmol,783.56μL)和HATU(848.58mg,2.25mmol)，在室温下搅拌1小时。反应完成后，将反应液浓缩后经CombiFlash(24g，0～10％MeOH/DCM)纯化，得到H23-a(180mg,白色固体),收率：26.08％。MS m/z(ESI):628.3[M+H]+。Step 1: (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.5 g, 1.12 mmol) and 1-tert-butoxycarbonylazetidine-3-carboxylic acid (452.60 mg, 2.25 mmol) were dissolved in DMF (10 mL), and DIPEA (581.40 mg, 4.50 mmol, 783.56 μL) and HATU (848.58 mg, 2.25 mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H23-a (180 mg, white solid), yield: 26.08%. MS m/z(ESI):628.3[M+H] + .

步骤2:将H23-a(170mg,270.79μmol)溶于DCM(10mL)中，加入HCl的乙酸乙酯溶液(4M,2mL)，在室温下搅拌1小时。反应结束后，将反应液浓缩后得到H23-b(142mg,黄色固体,HCl),收率：92.95％。MS m/z(ESI):528.3[M+H]+。Step 2: H23-a (170 mg, 270.79 μmol) was dissolved in DCM (10 mL), and HCl in ethyl acetate (4 M, 2 mL) was added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain H23-b (142 mg, yellow solid, HCl), yield: 92.95%. MS m/z (ESI): 528.3 [M+H] + .

步骤3:将中间体Z1(100mg,192.48μmol)和DIPEA(1.48g,11.48mmol,2mL)溶于DMF(5mL)中，加入HATU(290.47mg,769.94μmol)，在室温下搅拌0.5小时,然后加入H23-b(142mg,251.71μmol,HCl)，室温下继续搅拌0.5小时。反应完成后，将反应液浓缩后经CombiFlash(12g，0～10％MeOH/DCM)纯化，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：40％-45％乙腈变化)纯化，得到H23(1.93mg),收率：0.99％。MS m/z(ESI):506.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.74(s,1H),8.57(s,1H),8.41-8.32(m,1H),8.15(d,J＝9.2Hz,1H),7.72(s,1H),7.64(d,J＝8.0Hz,1H),7.56(d,J＝8.1Hz,1H),7.44-7.33(m,4H),6.97-6.88(m,1H),6.68(dd,J＝8.7,3.8Hz,1H),5.11(t,J＝15.7Hz,2H),5.02-4.82(m,2H),4.72(s,2H),4.52(t,J＝8.8Hz,3H),4.40(dd,J＝26.8,19.2Hz,2H),4.29-4.16(m,3H),4.10(s,2H),3.99(s,1H),3.60(s,3H),2.43(s,3H),2.09-1.88(m,2H),1.77(s,1H),1.35(d,J＝3.7Hz,3H),1.28(d,J＝6.5Hz,3H),1.21(s,1H),1.12(d,J＝6.7Hz,3H),1.03-0.81(m,9H)。Step 3: Dissolve intermediate Z1 (100 mg, 192.48 μmol) and DIPEA (1.48 g, 11.48 mmol, 2 mL) in DMF (5 mL), add HATU (290.47 mg, 769.94 μmol), stir at room temperature for 0.5 hours, then add H23-b (142 mg, 251.71 μmol, HCl), and continue stirring at room temperature for 0.5 hours. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (12 g, 0-10% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 40%-45% acetonitrile change) to obtain H23 (1.93 mg), yield: 0.99%. MS m/z(ESI):506.3[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.96(s,1H),8.74(s,1H),8.57(s,1H),8.41-8.32(m,1H),8.15(d,J＝9.2Hz,1H),7.72(s,1H),7.64(d,J＝8.0Hz,1H),7.56(d,J＝ 8.1Hz,1H),7.44-7.33(m,4H),6.97-6.88(m,1H),6.68(dd,J＝8.7,3.8Hz,1H),5.11(t,J＝15.7Hz,2H),5.02-4.82(m,2H),4.72(s,2 H),4.52(t,J＝8.8Hz,3H),4.40(dd,J＝26.8,19.2Hz,2H),4.29-4.16(m,3H),4.10(s,2H),3.99(s,1H),3.60(s,3H),2.43(s,3H),2 .09-1.88(m,2H),1.77(s,1H),1.35(d,J＝3.7Hz,3H),1.28(d,J＝6.5Hz,3H),1.21(s,1H),1.12(d,J＝6.7Hz,3H),1.03-0.81(m,9H).

实施例24化合物H24的制备
Example 24 Preparation of Compound H24

步骤1:将(2S，4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S，-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(400mg,0.90mmol)溶于DCM(3mL)中，在0℃下加入三乙胺(273mg,2.70mmol)和二氢-2H-吡喃-2,6(3H)-二酮(103mg,0.90mmol)，反应液在25℃下搅拌1小时。在反应完全后，将反应液浓缩后经硅胶柱层析纯化(MeOH/DCM＝10～15％)纯化，得到H24-a(220mg，白色固体),收率:43.77％。MS m/z(ESI):559.4[M+H]+。Step 1: (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S,-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (400 mg, 0.90 mmol) was dissolved in DCM (3 mL), triethylamine (273 mg, 2.70 mmol) and dihydro-2H-pyran-2,6(3H)-dione (103 mg, 0.90 mmol) were added at 0°C, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH/DCM=10-15%) to obtain H24-a (220 mg, white solid), yield: 43.77%. MS m/z (ESI): 559.4 [M+H] + .

步骤2:将中间体Z3(18mg,0.04mmol)和H24-a(26mg,0.05mmol)溶于DMF(1.5mL)中，加入HATU(22mg,0.06mmol)和DIPEA(15mg,0.11mmol)，在25℃下搅拌12小时。反应完全后，将反应液过滤，滤液通过制备HPLC(Waters-Xbridge-C18-10μm-19*250mm柱(流动相:38％-68％(v/v)乙腈和水(含0.1％甲酸))纯化，得到H24(6mg)，产率:15.54％。MS m/z(ESI):1014.6[M+H]+。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.99(s,1H),8.77(s,1H),8.49-8.42(m,1H),8.40-8.34(m,1H),7.90-7.84(m,1H),7.80(s,1H),7.64-7.58(m,1H),7.45-7.41(m,3H),7.39-7.37(m,2H),7.33(s,1H),6.98-6.91(m,1H),6.72-6.67(m,1H),5.09-4.99(m,1H),4.94-4.89(m,1H),4.76-4.69(m,2H),4.57-4.51(m,3H),4.45-4.40(m,1H),4.31-4.23(m,1H),4.18-4.10(m,1H),3.63-3.60(m,2H),3.33-3.29(m,3H),2.45(s,3H),2.36-2.32(m,2H),2.27-2.17(m,2H),2.05-1.96(m,2H),1.84-1.73(m,3H),1.37(d,J＝6.8Hz,3H),1.24(t,J＝5.6Hz,6H),0.95(s,9H)。Step 2: The intermediate Z3 (18 mg, 0.04 mmol) and H24-a (26 mg, 0.05 mmol) were dissolved in DMF (1.5 mL), HATU (22 mg, 0.06 mmol) and DIPEA (15 mg, 0.11 mmol) were added, and the mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm column (mobile phase: 38%-68% (v/v) acetonitrile and water (containing 0.1% formic acid)) to obtain H24 (6 mg), yield: 15.54%. MS m/z (ESI): 1014.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.04(s,1H),8.99(s,1H),8.77(s,1H),8.49-8.42(m,1H),8.40-8.34(m,1H),7.90-7.84(m,1H),7.80(s,1H),7.64-7.58(m,1H),7. 45-7.41(m,3H),7.39-7.37(m,2H),7.33(s,1H),6.98-6.91(m,1H),6.72-6.67(m,1H),5.09-4.99(m,1H),4.94-4.89(m,1H),4.76-4.69 (m,2H),4.57-4.51(m,3H),4.45-4.40(m,1H),4.31-4.23(m,1H),4.18-4.10(m,1H),3.63-3.60(m,2H),3.33-3.29(m,3H),2.45(s,3H) ,2.36-2.32(m,2H),2.27-2.17(m,2H),2.05-1.96(m,2H),1.84-1.73(m,3H),1.37(d,J＝6.8Hz,3H),1.24(t,J＝5.6Hz,6H),0.95(s,9H).

实施例25化合物H25的制备
Example 25 Preparation of Compound H25

步骤：将H12-b(34mg,0.06mmol)和1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代异吲哚-5-基]哌啶-4-甲醛(33mg,0.09mmol)溶于DMSO(0.5mL)和EtOH(1.5mL)中，加入乙酸(8mg,0.12mmol),在80℃微波加热0.5小时，然后降至室温，加入NaBH3CN(8mg,0.12mmol)，室温下继续搅拌20小时。反应结束后，将反应液浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：0％-70％乙腈变化)纯化，得到H25(14.64mg)，收率：25.3％。MS m/z(ESI):462.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.73(s,1H),8.54(d,J＝4.9Hz,1H),7.63(d,J＝8.5Hz,1H),7.58-7.47(m,2H),7.38(d,J＝5.5Hz,2H),7.28(s,1H),7.21(d,J＝8.7Hz,1H),6.99-6.88(m,1H),6.68(dd,J＝8.7,3.9Hz,1H),5.16-4.98(m,2H),4.71(d,J＝4.6Hz,2H),4.53(t,J＝8.8Hz,2H),4.25-4.08(m,2H),4.02(d,J＝12.4Hz,2H),3.57(s,2H),3.35(d,J＝16.3Hz,1H),3.30-3.26(m，2H)，2.89(dt,J＝17.8,9.1Hz,3H),2.55(dd,J＝1.6,5.3Hz,1H),2.35(d J＝25.4,12.8Hz,4H),2.17(d,J＝6.5Hz,2H),2.03-1.90(m,2H),1.79(d,J＝11.6Hz,3H),1.35-0.93(m,9H)。Procedure: H12-b (34 mg, 0.06 mmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde (33 mg, 0.09 mmol) were dissolved in DMSO (0.5 mL) and EtOH (1.5 mL), acetic acid (8 mg, 0.12 mmol) was added, and microwave heating was performed at 80°C for 0.5 h, then the temperature was lowered to room temperature, NaBH 3 CN (8 mg, 0.12 mmol) was added, and stirring was continued at room temperature for 20 h. After the reaction, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3H2O - acetonitrile; wavelength: 254/214nm; gradient: 0%-70% acetonitrile change) to obtain H25 (14.64mg), yield: 25.3%. MS m/z (ESI): 462.3 [M/2+H] + . 1H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),8.73(s,1H),8.54(d,J＝4.9Hz,1H),7.63(d,J＝8.5Hz,1H),7.58-7.47(m,2H),7.38(d,J＝5. 5Hz,2H),7.28(s,1H),7.21(d,J＝8.7Hz,1H),6.99-6.88(m,1H),6.68(dd,J＝8.7,3.9Hz,1H),5.16-4.98(m, 2H),4.71(d,J＝4.6Hz,2H),4.53(t,J＝8.8Hz,2H),4.25-4.08(m,2H),4.02(d,J＝12.4Hz,2H),3.57(s,2H),3 .35(d,J＝16.3Hz,1H),3.30-3.26(m,2H),2.89(dt,J＝17.8,9.1Hz,3H),2.55(dd,J＝1.6,5.3Hz,1H),2.35(d J＝25.4,12.8Hz,4H),2.17(d,J＝6.5Hz,2H),2.03-1.90(m,2H),1.79(d,J＝11.6Hz,3H),1.35-0.93(m,9H).

实施例26化合物H26的制备
Example 26 Preparation of Compound H26

步骤:将H27-e(100mg,185.36μmol)和H8-b(253.07mg,741.45μmol)溶解于DCM(6mL)中，室温搅拌2小时，然后加入NaBH(OAc)3(196.43mg,926.81μmol)，室温再搅拌2小时。反应完成后，将反应液浓缩后经CombiFlash(12g，0～15％MeOH/DCM)纯化，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：48％-55％乙腈变化)纯化，得到H26(20.43mg)，收率：11.81％。MS m/z(ESI):865.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.85(s,1H),8.78(s,2H),7.77(s,1H),7.62(d,J＝8.5Hz,2H),6.98-6.90(m,1H),6.76(d,J＝1.9Hz,1H),6.69(dd,J＝8.7,3.9Hz,1H),6.62(dd,J＝8.5,2.0Hz,1H),5.25(d,J＝15.3Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.74(s,2H),4.54(t,J＝8.9Hz,2H),4.20(d,J＝15.4Hz,1H),4.10(t,J＝8.0Hz,3H),3.78(s,1H),3.75-3.61(m,3H),3.35(s,1H),3.31-3.28(m,1H),3.19-3.06(m,2H),2.93-2.74(m,2H),2.71(d,J＝7.6Hz,2H),2.61-2.50(m,2H),2.04-1.92(m,1H)。Steps: H27-e (100 mg, 185.36 μmol) and H8-b (253.07 mg, 741.45 μmol) were dissolved in DCM (6 mL), stirred at room temperature for 2 hours, then NaBH(OAc) 3 (196.43 mg, 926.81 μmol) was added, and stirred at room temperature for another 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 48%-55% acetonitrile change) to obtain H26 (20.43 mg), yield: 11.81%. MS m/z (ESI): 865.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.06(s,1H),8.85(s,1H),8.78(s,2H),7.77(s,1H),7.62(d,J＝8.5Hz,2H),6.98-6.90(m,1H),6.76(d,J＝1.9Hz,1H) ,6.69(dd,J＝8.7,3.9Hz,1H),6.62(dd,J＝8.5,2.0Hz,1H),5.25(d,J＝15.3Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.74(s ,2H),4.54(t,J＝8.9Hz,2H),4.20(d,J＝15.4Hz,1H),4.10(t,J＝8.0Hz,3H),3.78(s,1H),3.75-3.61(m,3H),3.35(s,1H) ,3.31-3.28(m,1H),3.19-3.06(m,2H),2.93-2.74(m,2H),2.71(d,J＝7.6Hz,2H),2.61-2.50(m,2H),2.04-1.92(m,1H).

实施例27化合物H27的制备
Example 27 Preparation of Compound H27

步骤1:将5-溴-2-(三氟甲基)异烟醛(2.8g,11.02mmol)和3-氨基氮杂环丁烷-1-羧酸叔丁酯(2.85g,16.54mmol)溶于EtOH(30mL)中，加入AcOH(132.40mg,2.20mmol,0.4mL)，在室温条件下搅拌18小时,然后加入NaBH3CN(3.46g,55.12mmol)，室温继续搅拌3小时。反应完成后，向反应液中加入饱和氯化按水溶液淬灭反应，用二氯甲烷(100mL×3)萃取，合并有机相，经无水硫酸钠干燥，浓缩得到H27-a(4.5g,淡黄色油状物,粗品)，收率：99.51％。MS m/z(ESI):354.0[M-56+H]+。Step 1: Dissolve 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (2.8 g, 11.02 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (2.85 g, 16.54 mmol) in EtOH (30 mL), add AcOH (132.40 mg, 2.20 mmol, 0.4 mL), stir at room temperature for 18 hours, then add NaBH 3 CN (3.46 g, 55.12 mmol), and continue stirring at room temperature for 3 hours. After the reaction is completed, add saturated ammonium chloride aqueous solution to the reaction solution to quench the reaction, extract with dichloromethane (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain H27-a (4.5 g, light yellow oil, crude product), yield: 99.51%. MS m/z (ESI): 354.0 [M-56+H] + .

步骤2:将H27-a(4.5g,10.97mmol)和Et3N(7.77g,76.79mmol,11.10mL)溶于DCM(88.90mL)中，加入(Boc)2O(7.18g,32.91mmol)，在室温条件下搅拌18小时。反应完成后，将反应液浓缩后经CombiFlash(40g，0～15％EA/PE)纯化，得到H27-b(3g,无色油状物),收率：53.59％。MS m/z(ESI):398.0[M-112+H]+。Step 2: H27-a (4.5 g, 10.97 mmol) and Et 3 N (7.77 g, 76.79 mmol, 11.10 mL) were dissolved in DCM (88.90 mL), (Boc) 2 O (7.18 g, 32.91 mmol) was added, and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (40 g, 0-15% EA/PE) to obtain H27-b (3 g, colorless oil), yield: 53.59%. MS m/z (ESI): 398.0 [M-112+H] + .

步骤3:将8-溴-5-(((5-氟-2，3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1，5-c]嘧啶-1-羧酸乙酯(1.5g,3.45mmol)和H27-b(3g,5.88mmol)溶于DME(30mL)和水(3mL)中，加入Pd(OAc)2(77.37mg,344.63μmol)、CataCXium A(247.13mg,689.26μmol)、K2CO3(1.91g,13.79mmol)和(Pin)2B2(1.75g,6.89mmol)，在70℃条件下搅拌18小时。反应完成后，将反应液冷却至室温，过滤，滤液浓缩后经CombiFlash(80g，0～100％EA/PE)纯化，得到H27-c(1.87g,淡黄色固体),收率：69.05％。MS m/z(ESI):674.2[M-112+H]+。Step 3: Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (1.5 g, 3.45 mmol) and H27-b (3 g, 5.88 mmol) were dissolved in DME (30 mL) and water (3 mL), and Pd(OAc) 2 (77.37 mg, 344.63 μmol), CataCXium A (247.13 mg, 689.26 μmol), K 2 CO 3 (1.91 g, 13.79 mmol) and (Pin) 2 B 2 (1.75 g, 6.89 mmol) were added, and the mixture was stirred at 70° C. for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by CombiFlash (80 g, 0-100% EA/PE) to obtain H27-c (1.87 g, light yellow solid), yield: 69.05%. MS m/z (ESI): 674.2 [M-112+H] + .

步骤4:将H27-c(1.87g,2.38mmol)溶于DCM(5mL)中，加入HCl的乙酸乙酯溶液(4mol/L,5mL),在室温下搅拌18小时，反应完成后，用碳酸氢钠水溶液淬灭，再用DCM和MeOH混合溶液(DCM:MeOH＝10:1，100mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash(24g，5～20％DCM+1％Et3N/MeOH)纯化，得到H27-d(486mg,白色固体),收率：34.88％。MS m/z(ESI):586.2[M+H]+。Step 4: H27-c (1.87 g, 2.38 mmol) was dissolved in DCM (5 mL), and HCl in ethyl acetate (4 mol/L, 5 mL) was added, and stirred at room temperature for 18 hours. After the reaction was completed, it was quenched with sodium bicarbonate aqueous solution, and then extracted with a mixed solution of DCM and MeOH (DCM: MeOH = 10: 1, 100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (24 g, 5-20% DCM + 1% Et 3 N / MeOH) to obtain H27-d (486 mg, white solid), yield: 34.88%. MS m/z (ESI): 586.2 [M + H] + .

步骤5:将H27-d(460mg,785.58μmol)溶于EtOH(3mL)中，加入CH3ONa(424.40mg,7.86mmol)，在80℃下搅拌2小时。反应完成后，将反应液倒入饱和氯化铵水溶液中，过滤，滤饼经干燥，得到产物H27-e(360mg,白色固体),收率：84.94％。MS m/z(ESI):540.2[M+H]+。Step 5: H27-d (460 mg, 785.58 μmol) was dissolved in EtOH (3 mL), CH 3 ONa (424.40 mg, 7.86 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution, filtered, and the filter cake was dried to obtain the product H27-e (360 mg, white solid), yield: 84.94%. MS m/z (ESI): 540.2 [M+H] + .

步骤6:将H27-e(100mg,185.36μmol)和1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代异吲哚-5-基]哌啶-4-甲醛(273.87mg,741.45μmol)溶解于DMSO(1mL)和EtOH(3mL)中，微波90℃搅拌0.5小时，然后降到室温，然后加入NaBH3CN(69.89mg,1.11mmol)，室温下继续搅拌0.5小时。反应完成后，将反应液冷却室温，水溶液淬灭，用DCM和MeOH混合溶液(DCM:MeOH＝10:1，100mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash(12g，0～15％MeOH/DCM)纯化，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：55％-60％乙腈变化)纯化，得到H27(2.01mg),收率：1.13％。MS m/z(ESI):893.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.01(s,1H),8.83(s,1H),8.41(s,1H),8.05(s,1H),7.78(s,1H),7.62(d,J＝8.7Hz,1H),7.35-7.11(m,2H),6.96-6.84(m,1H),6.66(dd,J＝8.7,3.8Hz,1H),5.32(t,J＝9.7Hz,1H),5.04(dd,J＝14.8,7.4Hz,1H),4.71(d,J＝9.1Hz,2H),4.60(d,J＝12.1Hz,1H),4.57-4.41(m,2H),4.36(s,1H),4.20(t,J＝13.1Hz,1H),4.16-4.04(m,2H),3.98(d,J＝17.7Hz,1H),3.91(d,J＝10.2Hz,2H),3.76-3.65(m,2H),3.61(d,J＝13.8Hz,2H),2.89(ddd,J＝25.3,22.1,8.0Hz,3H),2.68-2.51(m,2H),2.11(s,1H),1.98(d,J＝6.6Hz,1H),1.72(d,J＝11.0Hz,1H),1.62(d,J＝14.5Hz,1H),1.39(dd,J＝27.7,12.1Hz,1H),1.04(dd,J＝24.4,13.3Hz,1H)。Step 6: H27-e (100 mg, 185.36 μmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde (273.87 mg, 741.45 μmol) were dissolved in DMSO (1 mL) and EtOH (3 mL), stirred at 90 °C in a microwave for 0.5 h, then cooled to room temperature, and then NaBH 3 CN (69.89 mg, 1.11 mmol) was added and stirring was continued at room temperature for 0.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, the aqueous solution was quenched, and extracted with a mixed solution of DCM and MeOH (DCM:MeOH=10:1, 100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 55%-60% acetonitrile change) to obtain H27 (2.01 mg), yield: 1.13%. MS m/z (ESI): 893.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),9.01(s,1H),8.83(s,1H),8.41(s,1H),8.05(s,1H),7.78(s,1 H),7.62(d,J＝8.7Hz,1H),7.35-7.11(m,2H),6.96-6.84(m,1H),6.66(dd,J＝8.7 ,3.8Hz,1H),5.32(t,J＝9.7Hz,1H),5.04(dd,J＝14.8,7.4Hz,1H),4.71(d,J＝9.1 Hz,2H),4.60(d,J＝12.1Hz,1H),4.57-4.41(m,2H),4.36(s,1H),4.20(t,J＝13.1 Hz,1H),4.16-4.04(m,2H),3.98(d,J＝17.7Hz,1H),3.91(d,J＝10.2Hz,2H),3.76 -3.65(m,2H),3.61(d,J＝13.8Hz,2H),2.89(ddd,J＝25.3,22.1,8.0Hz,3H),2.68 -2.51(m,2H),2.11(s,1H),1.98(d,J＝6.6Hz,1H),1.72(d,J＝11.0Hz,1H),1.62( d, J＝14.5Hz, 1H), 1.39 (dd, J＝27.7, 12.1Hz, 1H), 1.04 (dd, J＝24.4, 13.3Hz, 1H).

实施例28化合物H28的制备
Example 28 Preparation of Compound H28

步骤:将H27-e(100mg,185.36μmol)和1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)氮杂环丁烷-3-羧酸(99.35mg,278.04μmol)溶于DMF(5mL)中，加入DIPEA(167.70mg,1.30mmol,226.01μL)和HATU(209.79mg,556.09μmol)，在室温下搅拌1小时。反应完成后，将反应液浓缩后经CombiFlash(12g，0～15％MeOH/DCM)纯化，再经制备HPLC(制备柱：21.2X250mm C18柱；体系：0.04％FA/H2O-乙腈；波长：254/214nm；梯度：42％-62％乙腈变化)纯化，得到H28(21.30mg),收率：12.61％。MS m/z(ESI):879.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.85(s,1H),8.81(s,2H),7.92(d,J＝11.2Hz,1H),7.69-7.57(m,2H),6.97-6.89(m,1H),6.80(d,J＝11.6Hz,1H),6.73-6.60(m,2H),5.35(d,J＝14.8Hz,1H),5.04(d,J＝12.9Hz,1H),4.74(s,2H),4.64(s,2H),4.54(t,J＝8.7Hz,2H),4.39(d,J＝21.5Hz,1H),4.32(d,J＝15.0Hz,1H),4.16(dd,J＝18.5,8.9Hz,4H),4.00(dd,J＝30.5,20.5Hz,3H),3.63(s,1H),2.84(d,J＝13.2Hz,1H),2.66-2.49(m,3H),2.00(s,1H)。Procedure: H27-e (100 mg, 185.36 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylic acid (99.35 mg, 278.04 μmol) were dissolved in DMF (5 mL), DIPEA (167.70 mg, 1.30 mmol, 226.01 μL) and HATU (209.79 mg, 556.09 μmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA/H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 42%-62% acetonitrile change) to obtain H28 (21.30 mg), yield: 12.61%. MS m/z (ESI): 879.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),8.85(s,1H),8.81(s,2H),7.92(d,J＝11.2Hz,1H),7.69-7.57(m,2H),6.97-6.89(m,1H), 6.80(d,J＝11.6Hz,1H),6.73-6.60(m,2H),5.35(d,J＝14.8Hz,1H),5.04(d,J＝12.9Hz,1H),4.74(s,2H),4. 64(s,2H),4.54(t,J＝8.7Hz,2H),4.39(d,J＝21.5Hz,1H),4.32(d,J＝15.0Hz,1H),4.16(dd,J＝18.5,8.9Hz ,4H),4.00(dd,J＝30.5,20.5Hz,3H),3.63(s,1H),2.84(d,J＝13.2Hz,1H),2.66-2.49(m,3H),2.00(s,1H).

实施例29化合物H29的制备
Example 29 Preparation of Compound H29

步骤1:化合物5-溴-2-(三氟甲基)吡啶-4-甲醛(1.0g,3.94mmol)和3-氨基吡咯烷-1-甲酸叔丁酯(1.47g,7.87mmol)溶解在DCM(20mL)中，室温搅拌加入NaBH(OAc)3(2.50g,11.81mmol)，室温搅拌1小时，加入NaBH3CN(1.24g,19.68mmol)，室温继续搅拌1小时。反应结束后，将反应液倒入水中，乙酸乙酯(30mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩后得到H29-a(1.65g,黄色油状物),收率：98.79％。MS m/z(ESI):424[M+H]+.Step 1: Compound 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (1.0 g, 3.94 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (1.47 g, 7.87 mmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (2.50 g, 11.81 mmol) was added under stirring at room temperature, and stirred at room temperature for 1 hour. NaBH 3 CN (1.24 g, 19.68 mmol) was added, and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (30 mL×2), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H29-a (1.65 g, yellow oil), with a yield of 98.79%. MS m/z (ESI): 424 [M+H] + .

步骤2:将H29-a(1.5g,3.54mmol)和叔丁氧基羰基碳酸叔丁酯(2.31g,10.61mmol)溶解在DCM(20mL)中，室温搅拌加入三乙胺(2.14g,21.21mmol)，升温至45℃搅拌4小时。将反应液浓缩后经硅胶柱层析纯化(EA:PE＝0～53)，得到H29-b(700mg,黄色油状物),收率：37.76％。MS m/z(ESI):468,470[M+H-56]+.Step 2: H29-a (1.5 g, 3.54 mmol) and tert-butyl tert-butoxycarbonyl carbonate (2.31 g, 10.61 mmol) were dissolved in DCM (20 mL), triethylamine (2.14 g, 21.21 mmol) was added under stirring at room temperature, and the mixture was heated to 45°C and stirred for 4 hours. The reaction solution was concentrated and purified by silica gel column chromatography (EA:PE=0-53) to obtain H29-b (700 mg, yellow oil), yield: 37.76%. MS m/z (ESI): 468,470 [M+H-56] + .

步骤3:将8-溴-5-[(5-氟-2,3-二氢苯并呋喃-4-基)甲基氨基]咪唑并[1,5-c]嘧啶-1-甲酸乙酯(0.5g,1.15mmol)和H29-b(903.58mg,1.72mmol)溶于DME(10mL)和H2O(1mL)中，加入Pd(OAc)2(25.79mg,114.88μmol)，CataCXium A(82.38mg,229.75μmol)，碳酸钾(635.09mg,4.60mmol)，(Pin)2B2,(583.43mg,2.30mmol)，在70℃下搅拌18小时。反应完成后，将反应液冷却至室温，浓缩后经CombiFlash纯化(80g，0～100％EA/PE)，得到H29-c(250mg,淡黄色固体),收率：27.21％。Step 3: Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (0.5 g, 1.15 mmol) and H29-b (903.58 mg, 1.72 mmol) were dissolved in DME (10 mL) and H 2 O (1 mL), and Pd(OAc) 2 (25.79 mg, 114.88 μmol), CataCXium A (82.38 mg, 229.75 μmol), potassium carbonate (635.09 mg, 4.60 mmol), (Pin) 2 B 2 , (583.43 mg, 2.30 mmol) were added, and the mixture was stirred at 70° C. for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated and purified by CombiFlash (80 g, 0-100% EA/PE) to obtain H29-c (250 mg, light yellow solid) with a yield of 27.21%.

步骤4:将H29-c(250mg,312.57μmol)溶解在DCM(10mL)中，室温搅拌加入2,2,2-三氟乙酸(35.64mg,312.57μmol,3mL)，室温搅拌2小时。反应结束后，将反应液浓缩，得到H29-d(187.41mg,黄色固体),收率：100.00％。MS m/z(ESI):600[M+H]+。Step 4: H29-c (250 mg, 312.57 μmol) was dissolved in DCM (10 mL), and 2,2,2-trifluoroacetic acid (35.64 mg, 312.57 μmol, 3 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H29-d (187.41 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 600 [M+H] + .

步骤5:将H29-d(540.62mg,10.01mmol)溶解在甲醇(20mL)中，加入甲醇钠(540.62mg,10.01mmol)，升温至70℃搅拌过夜。将反应液倒入饱和碳酸钠中，EA(30mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H29-e(184.63mg,黄色固体，粗品)，收率：100.00％，直接用于下一步。MS m/z(ESI):554[M+H]+。Step 5: H29-d (540.62 mg, 10.01 mmol) was dissolved in methanol (20 mL), sodium methoxide (540.62 mg, 10.01 mmol) was added, and the temperature was raised to 70°C and stirred overnight. The reaction solution was poured into saturated sodium carbonate, extracted with EA (30 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give H29-e (184.63 mg, yellow solid, crude product), yield: 100.00%, which was used directly in the next step. MS m/z (ESI): 554 [M+H] + .

步骤6:将H29-e(200mg,361.33μmol)和H8-b(246.66mg,722.66μmol)溶解在DCM(20mL)中，室温搅拌加入NaBH(OAc)3(382.90mg,1.81mmol)，室温搅拌过夜。将反应液倒入水中，DCM(30mL×2)萃取。合并滤液和萃取时分液漏斗上面的固体，经硅胶柱层析(MeOH:DCM0～10％)纯化、再经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：0％-70％乙腈变化)纯化，得到H29(8.49mg,纯度：100％),收率：1.79％。MS m/z(ESI):879[M+H]+.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.94-8.67(m,3H),8.38(s,1H),8.21(s,1H),7.61(t,J＝7.9Hz,2H),6.94(t,J＝9.3Hz,1H),6.68(ddd,J＝34.2,21.1,9.5Hz,3H),5.30-3.44(m,13H),3.25-2.54(m,8H),2.07(dd,J＝100.6,63.6Hz,4H),1.48(s,1H)。Step 6: H29-e (200 mg, 361.33 μmol) and H8-b (246.66 mg, 722.66 μmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (382.90 mg, 1.81 mmol) was added with stirring at room temperature, and stirred at room temperature overnight. The reaction solution was poured into water and extracted with DCM (30 mL×2). The filtrate and the solid on the separatory funnel during extraction were combined, purified by silica gel column chromatography (MeOH: DCM 0-10%), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-70% acetonitrile change) to obtain H29 (8.49 mg, purity: 100%), yield: 1.79%. MS m/z(ESI):879[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.06(s,1H),8.94-8.67(m,3H),8.38(s,1H),8.21(s,1H),7.61(t,J＝7.9Hz,2H),6.94(t,J＝9.3Hz,1H),6.68(d dd,J＝34.2,21.1,9.5Hz,3H),5.30-3.44(m,13H),3.25-2.54(m,8H),2.07(dd,J＝100.6,63.6Hz,4H),1.48(s,1H).

实施例30化合物H30的制备
Example 30 Preparation of Compound H30

步骤1:化合物5-溴-2-(三氟甲基)吡啶-4-甲醛(1.0g,3.94mmol)和6-氨基-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯(1.00g,4.72mmol)溶解在DCM(15mL)中，室温搅拌加入NaBH(OAc)3(2.50g,11.81mmol)，室温搅拌过夜。将反应液倒入水中，EA(30mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(EA:PE＝0～30％)，得到H30-a(1.77g,无色油状物),收率：100.00％。MS m/z(ESI):450,452[M+H]+。Step 1: Compound 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (1.0 g, 3.94 mmol) and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (1.00 g, 4.72 mmol) were dissolved in DCM (15 mL), and NaBH(OAc) 3 (2.50 g, 11.81 mmol) was added with stirring at room temperature, and stirred at room temperature overnight. The reaction solution was poured into water, extracted with EA (30 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE=0-30%) to obtain H30-a (1.77 g, colorless oil), yield: 100.00%. MS m/z (ESI): 450,452 [M+H] + .

步骤2:将H30-a(1.7g,3.78mmol)溶解在DCM(20mL)中，室温搅拌加入三乙胺(1.14g,11.33mmol)和(Boc)2O(1.03g，4.73mmol)，室温搅拌过夜。将反应液浓缩后经硅胶柱层析纯化(EA:PE＝0～30％)，得到H30-b(1.8g,黄色油状物),收率：86.62％。MS m/z(ESI):450[M+H-100]+。Step 2: H30-a (1.7 g, 3.78 mmol) was dissolved in DCM (20 mL), triethylamine (1.14 g, 11.33 mmol) and (Boc) 2 O (1.03 g, 4.73 mmol) were added under stirring at room temperature, and stirred overnight at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography (EA:PE = 0-30%) to obtain H30-b (1.8 g, yellow oil), yield: 86.62%. MS m/z (ESI): 450 [M+H-100] + .

步骤3:将8-溴-5-[(5-氟-2,3-二氢苯并呋喃-4-基)甲基氨基]咪唑并[1,5-c]嘧啶-1-甲酸乙酯(0.7g,1.61mmol)和H30-b(1.77g,3.22mmol)溶于DME(20mL)和水(2mL)中，加入Pd(OAc)2(36.11mg,160.83μmol)，CataCXium A(115.33mg,321.66μmol)，碳酸钾(889.12mg,6.43mmol)，(Pin)2B2(816.81mg,3.22mmol)，在70℃下搅拌18小时。将反应液经CombiFlash纯化(80g，0～100％EA/PE)，得到H30-c(700mg,淡黄色固体),收率：52.70％。MS m/z(ESI):770[M+H-56]+。Step 3: Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (0.7 g, 1.61 mmol) and H30-b (1.77 g, 3.22 mmol) were dissolved in DME (20 mL) and water (2 mL), and Pd(OAc) 2 (36.11 mg, 160.83 μmol), CataCXium A (115.33 mg, 321.66 μmol), potassium carbonate (889.12 mg, 6.43 mmol), (Pin) 2 B 2 (816.81 mg, 3.22 mmol) were added, and the mixture was stirred at 70° C. for 18 hours. The reaction solution was purified by CombiFlash (80 g, 0-100% EA/PE) to obtain H30-c (700 mg, light yellow solid), yield: 52.70%. MS m/z (ESI): 770 [M+H-56] + .

步骤4:将H30-c(700mg,847.62μmol,1mL)溶解在DCM(10mL)中，室温搅拌加入三氟乙酸(96.65mg,847.62μmol,3mL)，室温搅拌2小时。反应结束后，将反应液浓缩，得到H30-d(530.28mg,黄色固体)，收率：100.00％。MS m/z(ESI):626[M+H]+。Step 4: H30-c (700 mg, 847.62 μmol, 1 mL) was dissolved in DCM (10 mL), trifluoroacetic acid (96.65 mg, 847.62 μmol, 3 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H30-d (530.28 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 626 [M+H] + .

步骤5:将H30-d(600mg,959.06μmol)溶解在甲醇(25mL)中，加入甲醇钠(1.55g,28.77mmol)，升温至70℃搅拌过夜。反应结束后，将反应液倒入饱和碳酸钠中，EA(30mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩后得到H30-e(555.82mg,粗品，黄色固体),收率：100.00％，直接用于下一步。MS m/z(ESI):580[M+H]+。Step 5: H30-d (600 mg, 959.06 μmol) was dissolved in methanol (25 mL), sodium methoxide (1.55 g, 28.77 mmol) was added, and the mixture was heated to 70°C and stirred overnight. After the reaction was completed, the reaction solution was poured into saturated sodium carbonate, extracted with EA (30 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H30-e (555.82 mg, crude product, yellow solid), yield: 100.00%, which was used directly in the next step. MS m/z (ESI): 580 [M+H] + .

步骤6:将H30-e(300mg,517.65μmol)和1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]哌啶-4-甲醛(382.41mg,1.04mmol)溶解在DCM(20mL)中，室温搅拌下加入醋酸硼氢化钠(548.55mg,2.59mmol)，室温搅拌过夜。反应结束后，将反应液倒入水中，DCM(30mL×2)萃取。合并滤液和萃取时分液漏斗上面的固体，依次经碱法制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-70％乙腈变化)、酸法制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM甲酸/H2O-乙腈；波长：254/214nm；梯度：0％-75％乙腈变化)纯化，得到H30(32.32mg,纯度：94.9％),收率：6.35％。MS m/z(ESI):467[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.17-10.88(m,1H),8.81(d,J＝19.0Hz,2H),8.27(s,1H),7.84(s,1H),7.70-7.55(m,2H),7.28(s,1H),7.20(d,J＝8.7Hz,1H),7.00-6.89(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.20(d,J＝14.7Hz,1H),5.05(dd,J＝13.0,5.5Hz,1H),4.74(s,2H),4.53(t,J＝8.9Hz,2H),4.35(d,J＝15.4Hz,1H),4.21-4.09(m,1H),4.00(d,J＝12.7Hz,2H),3.38-3.06(m,6H),2.98-2.51(m,5H),2.31(dt,J＝29.2,16.8Hz,5H),2.00(s,2H),1.72(d,J＝12.1Hz,2H),1.55(s,1H),1.12(d,J＝12.2Hz,2H)。Step 6: H30-e (300 mg, 517.65 μmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carboxaldehyde (382.41 mg, 1.04 mmol) were dissolved in DCM (20 mL), and sodium acetate borohydride (548.55 mg, 2.59 mmol) was added under stirring at room temperature, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into water and extracted with DCM (30 mL×2). The filtrate and the solid on the separatory funnel during extraction were combined and purified by alkaline preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 0%-70% acetonitrile) and acid preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM formic acid/ H2O -acetonitrile; wavelength: 254/214nm; gradient: 0%-75% acetonitrile) to obtain H30 (32.32mg, purity: 94.9%), yield: 6.35%. MS m/z (ESI): 467 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.17-10.88(m,1H),8.81(d,J＝19.0Hz,2H),8.27(s,1H),7.84(s,1H),7.70-7.55(m,2H),7.28(s,1H),7.20(d,J＝8 .7Hz,1H),7.00-6.89(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.20(d,J＝14.7Hz,1H),5.05(dd,J＝13.0,5.5Hz,1H),4.74(s ,2H),4.53(t,J＝8.9Hz,2H),4.35(d,J＝15.4Hz,1H),4.21-4.09(m,1H),4.00(d,J＝12.7Hz,2H),3.38-3.06(m,6H),2.98 -2.51(m,5H),2.31(dt,J＝29.2,16.8Hz,5H),2.00(s,2H),1.72(d,J＝12.1Hz,2H),1.55(s,1H),1.12(d,J＝12.2Hz,2H).

实施例31化合物H31的制备
Example 31 Preparation of Compound H31

步骤1:化合物5-溴-2-(三氟甲基)吡啶-4-甲醛(1.0g,3.94mmol)和2-氨基-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(1.00g,4.17mmol)溶解在DCM(15mL)中，室温搅拌加入NaBH(OAc)3(2.50g,11.81mmol)，室温搅拌1小时。再加入NaBH3CN(1.24g,19.68mmol)，室温搅拌2小时。将反应液倒入水中，EA(30mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(EA:PE＝0～30％)，得到H31-a(1.88g,无色油状物),收率：100.00％。MS m/z(ESI):478,480[M+H]+。Step 1: Compound 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (1.0 g, 3.94 mmol) and tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (1.00 g, 4.17 mmol) were dissolved in DCM (15 mL), and NaBH(OAc) 3 (2.50 g, 11.81 mmol) was added with stirring at room temperature, and stirred at room temperature for 1 hour. NaBH 3 CN (1.24 g, 19.68 mmol) was added, and stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with EA (30 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE=0-30%) to obtain H31-a (1.88 g, colorless oil), yield: 100.00%. MS m/z (ESI): 478,480 [M+H] + .

步骤2:将H31-a(1.8g,3.76mmol)和叔丁氧基羰基碳酸叔丁酯(1.48g,6.77mmol)溶解在DCM(20mL)中，室温搅拌加入三乙胺(1.14g,11.29mmol)，室温搅拌过夜。将反应液浓缩后经硅胶柱层析纯化(EA:PE＝0～30％)，得到H31-b(1.85g,黄色油状物),收率：84.99％。MS m/z(ESI):478[M+H-100]+。Step 2: H31-a (1.8 g, 3.76 mmol) and tert-butyl tert-butoxycarbonyl carbonate (1.48 g, 6.77 mmol) were dissolved in DCM (20 mL), triethylamine (1.14 g, 11.29 mmol) was added with stirring at room temperature, and stirred at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (EA:PE = 0-30%) to obtain H31-b (1.85 g, yellow oil), yield: 84.99%. MS m/z (ESI): 478 [M+H-100] + .

步骤3:将8-溴-5-[(5-氟-2,3-二氢苯并呋喃-4-基)甲基氨基]咪唑并[1,5-c]嘧啶-1-甲酸乙酯(0.7g,1.61mmol)和H31-b(1.86g,3.22mmol)溶于DME(20mL)，Water(2mL)中，加入Pd(OAc)2(36.11mg,160.83μmol)，CataCXium A(115.33mg,321.66μmol)，K2CO3(889.12mg,6.43mmol)，(Pin)2B2(816.81mg,3.22mmol)，在70℃条件下搅拌18小时。反应完成后，将反应液冷却至室温，浓缩后经CombiFlash纯化(80g，0～100％EA/PE)，得到H31-c(750mg,淡黄色固体),收率：54.61％。MS m/z(ESI):854[M+H]+。Step 3: Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (0.7 g, 1.61 mmol) and H31-b (1.86 g, 3.22 mmol) were dissolved in DME (20 mL) and Water (2 mL), and Pd(OAc) 2 (36.11 mg, 160.83 μmol), CataCXium A (115.33 mg, 321.66 μmol), K 2 CO 3 (889.12 mg, 6.43 mmol) and (Pin) 2 B 2 (816.81 mg, 3.22 mmol) were added, and the mixture was stirred at 70° C. for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated and purified by CombiFlash (80 g, 0-100% EA/PE) to obtain H31-c (750 mg, light yellow solid), yield: 54.61%. MS m/z (ESI): 854 [M+H] + .

步骤4:将H31-c(700mg,819.77μmol)溶解在DCM(10mL)中，室温搅拌加入2,2,2-三氟乙酸(93.47mg,819.77μmol,3.0mL)，室温搅拌2小时。反应结束后，将反应液浓缩，得到H31-d(512.86mg,黄色固体)，收率：100.00％。MS m/z(ESI):654[M+H]+。Step 4: H31-c (700 mg, 819.77 μmol) was dissolved in DCM (10 mL), and 2,2,2-trifluoroacetic acid (93.47 mg, 819.77 μmol, 3.0 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H31-d (512.86 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 654 [M+H] + .

步骤5:将H31-d(600mg,917.90μmol)溶解在甲醇(25mL)中，加入甲醇钠(1.49g,27.54mmol)，升温至70℃搅拌过夜。反应结束后，将反应液倒入饱和碳酸钠中，EA(30mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H31-e(557.71mg,粗品，黄色固体),收率：100.00％，直接用于下一步。MS m/z(ESI):608[M+H]+。Step 5: H31-d (600 mg, 917.90 μmol) was dissolved in methanol (25 mL), sodium methoxide (1.49 g, 27.54 mmol) was added, and the mixture was heated to 70°C and stirred overnight. After the reaction was completed, the reaction solution was poured into saturated sodium carbonate, extracted with EA (30 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H31-e (557.71 mg, crude product, yellow solid), yield: 100.00%, which was used directly in the next step. MS m/z (ESI): 608 [M+H] + .

步骤6:将H31-e(300mg,493.75μmol)和1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代-异吲哚啉-5-基]哌啶-4-甲醛(364.75mg,987.49μmol)溶解在DCM(20mL)中，室温搅拌加入NaBH(OAc)3(523.22mg,2.47mmol)，室温搅拌过夜。反应结束后，将反应液倒入水中，DCM(30mL×2)萃取。合并DCM和萃取时分液漏斗上黏着的固体，先后经过碱法制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：0％-70％乙腈变化)、酸法制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM甲酸H2O-乙腈；波长：254/214nm；梯度：0％-75％乙腈变化)纯化，得到H31(8.49mg,纯度：100％),收率：1.79％。MS m/z(ESI):481[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.80(d,J＝23.5Hz,2H),8.29(s,1H),7.87(s,1H),7.69-7.55(m,2H),7.28(s,1H),7.21(d,J＝8.4Hz,1H),6.99-6.88(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.22(d,J＝15.1Hz,1H),5.05(dd,J＝12.7,5.5Hz,1H),4.74(s,2H),4.54(t,J＝8.9Hz,2H),4.37(d,J＝15.4Hz,1H),4.26(d,J＝9.4Hz,1H),4.02(d,J＝12.3Hz,2H),3.32(t,J＝8.7Hz,4H),2.99-2.80(m,3H),2.73-2.50(m,3H),2.40-1.90(m,9H),1.67(dd,J＝72.5,13.6Hz,6H),1.10(d,J＝10.8Hz,2H)。Step 6: H31-e (300 mg, 493.75 μmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carboxaldehyde (364.75 mg, 987.49 μmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (523.22 mg, 2.47 mmol) was added with stirring at room temperature, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was poured into water and extracted with DCM (30 mL×2). DCM and the solid adhering to the separatory funnel during extraction were combined and purified by alkaline preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3H2O - acetonitrile ; wavelength: 254/214nm; gradient: 0%-70% acetonitrile) and acid preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM formic acid H2O -acetonitrile; wavelength: 254/214nm; gradient: 0%-75% acetonitrile) to obtain H31 (8.49mg, purity: 100%), yield: 1.79%. MS m/z (ESI): 481 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.07(s,1H),8.80(d,J＝23.5Hz,2H),8.29(s,1H),7.87(s,1H),7.69-7.55(m,2H),7.28(s,1H),7.21(d,J＝8.4Hz ,1H),6.99-6.88(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.22(d,J＝15.1Hz,1H),5.05(dd,J＝12.7,5.5Hz,1H),4.74(s, 2H),4.54(t,J＝8.9Hz,2H),4.37(d,J＝15.4Hz,1H),4.26(d,J＝9.4Hz,1H),4.02(d,J＝12.3Hz,2H),3.32(t,J＝8.7Hz, 4H), 2.99-2.80 (m, 3H), 2.73-2.50 (m, 3H), 2.40-1.90 (m, 9H), 1.67 (dd, J = 72.5, 13.6Hz, 6H), 1.10 (d, J = 10.8Hz, 2H).

实施例32化合物H32的制备
Example 32 Preparation of Compound H32

步骤1：将2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚-1,3-二酮(300mg,1.09mmol)和4-叔丁氧羰基氨基哌啶(326mg,1.63mmol)溶于DMF(3mL)中，加入DIPEA(702mg,5.43mmol)。反应液加热到80℃，搅拌过夜。反应结束后，将反应液倒入水中，EA萃取(30mL×2)，合并有机相经无水硫酸钠干燥，浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到H32-a(240mg,黄色固体)，收率：48.41％。MS m/z(ESI):457.2[M+H]+。Step 1: Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (300 mg, 1.09 mmol) and 4-tert-butyloxycarbonylaminopiperidine (326 mg, 1.63 mmol) in DMF (3 mL), and add DIPEA (702 mg, 5.43 mmol). Heat the reaction solution to 80°C and stir overnight. After the reaction, pour the reaction solution into water, extract with EA (30 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (MeOH: DCM = 0-10%) to obtain H32-a (240 mg, yellow solid), yield: 48.41%. MS m/z (ESI): 457.2 [M+H] + .

步骤2：将H32-a(240mg,0.53mmol)溶于DCM(10mL)中，加入HCl的乙酸乙酯溶液(4mol/L,5.26mmol),在室温搅拌4小时。反应结束后，将反应液浓缩后得到H32-b(185mg，粗品),收率：98.74％，直接用于下一步反应。MS m/z(ESI):357.1[M+H]+。Step 2: H32-a (240 mg, 0.53 mmol) was dissolved in DCM (10 mL), and HCl in ethyl acetate (4 mol/L, 5.26 mmol) was added, and stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated to obtain H32-b (185 mg, crude product), yield: 98.74%, which was directly used for the next step. MS m/z (ESI): 357.1 [M+H] + .

步骤3：将中间体Z1(30mg,0.058mmol)溶于DMF(5mL)中，加入DIPEA(223mg,1.72mmol)和HATU(100mg,0.27mmol),室温搅拌0.5小时，然后加入H32-b(31mg,0.087mmol)，反应液继续室温下搅拌20小时。反应结束后，将反应液浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)纯化，得到H32(4.99mg),收率：9.86％。MS m/z(ESI):840.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.76(s,1H),8.60(s,1H),8.33(d,J＝7.7Hz,1H),7.98(d,J＝1.6Hz,1H),7.90(dd,J＝8.2,1.6Hz,1H),7.69(d,J＝8.6Hz,1H),7.58(d,J＝8.2Hz,1H),7.44-7.36(m,2H),7.30(dd,J＝8.7,2.1Hz,1H),6.98-6.91(m,1H),6.70(dd,J＝8.6,3.9Hz,1H),5.16(d,J＝15.1Hz,1H),5.08(dd,J＝12.8,5.4Hz,1H),4.74(s,2H),4.54(t,J＝8.8Hz,2H),4.28-4.07(m,5H),3.30(d,J＝8.8Hz,2H),3.16(t,J＝12.2Hz,2H),2.94-2.84(m,1H),2.64-2.52(m,2H),2.03(dd,J＝10.8,5.3Hz,1H),1.96-1.86(m,2H),1.69-1.56(m,2H),1.25(d,J＝6.7Hz,3H),1.16(d,J＝6.9Hz,3H)。Step 3: Dissolve the intermediate Z1 (30 mg, 0.058 mmol) in DMF (5 mL), add DIPEA (223 mg, 1.72 mmol) and HATU (100 mg, 0.27 mmol), stir at room temperature for 0.5 hours, then add H32-b (31 mg, 0.087 mmol), and continue to stir the reaction solution at room temperature for 20 hours. After the reaction is completed, the reaction solution is concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H32 (4.99 mg), yield: 9.86%. MS m/z (ESI): 840.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),8.76(s,1H),8.60(s,1H),8.33(d,J＝7.7Hz,1H),7.98(d,J＝1.6Hz,1H),7.90(dd,J＝8.2,1.6Hz,1H),7.69(d,J＝8.6Hz,1H),7 .58(d,J＝8.2Hz,1H),7.44-7.36(m,2H),7.30(dd,J＝8.7,2.1Hz,1H),6.98-6.91(m,1H),6.70(dd,J＝8.6,3.9Hz,1H),5.16(d,J＝15.1Hz,1H), 5.08(dd,J＝12.8,5.4Hz,1H),4.74(s,2H),4.54(t,J＝8.8Hz,2H),4.28-4.07(m,5H),3.30(d,J＝8.8Hz,2H),3.16(t,J＝12.2Hz,2H),2.94-2.8 4(m,1H),2.64-2.52(m,2H),2.03(dd,J＝10.8,5.3Hz,1H),1.96-1.86(m,2H),1.69-1.56(m,2H),1.25(d,J＝6.7Hz,3H),1.16(d,J＝6.9Hz,3H).

实施例33化合物H33的制备
Example 33 Preparation of Compound H33

步骤1:将中间体Z1(200mg,384.97μmol)和哌啶-4-羧酸乙酯(302.60mg,1.92mmol)溶于DMF(8mL)中，加入DIPEA(298.53mg,2.31mmol,402.33μL)和HATU(290.47mg,769.94μmol)，在室温下搅拌2小时。反应完成后，将反应液浓缩后经CombiFlash(24g，0～10％MeOH/DCM)纯化，得到H33-a(220mg,淡黄色固体),收率：89.20％。MS m/z(ESI):641.3[M+H]+。Step 1: Dissolve intermediate Z1 (200 mg, 384.97 μmol) and ethyl piperidine-4-carboxylate (302.60 mg, 1.92 mmol) in DMF (8 mL), add DIPEA (298.53 mg, 2.31 mmol, 402.33 μL) and HATU (290.47 mg, 769.94 μmol), and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H33-a (220 mg, light yellow solid), yield: 89.20%. MS m/z (ESI): 641.3 [M+H] + .

步骤2:将H33-a(220mg,343.37μmol)溶于THF(4mL)和水(1mL)中，加入LiOH(65.79mg,2.75mmol)，在75℃下搅拌18小时。反应完成后，将反应液冷却至室温，浓缩，用稀盐酸(2mol/L)调节pH＝3-4,用二氯甲烷(60mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后得到H33-b(145mg,淡黄色固体,粗品)，收率：68.93％。MS m/z(ESI):613.3[M+H]+。Step 2: H33-a (220 mg, 343.37 μmol) was dissolved in THF (4 mL) and water (1 mL), LiOH (65.79 mg, 2.75 mmol) was added, and the mixture was stirred at 75°C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and the pH was adjusted to 3-4 with dilute hydrochloric acid (2 mol/L), extracted with dichloromethane (60 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, H33-b (145 mg, light yellow solid, crude product) was obtained, with a yield of 68.93%. MS m/z (ESI): 613.3 [M+H] + .

步骤3:将H33-b(60mg,97.94μmol)和2-(2,6-二氧代哌啶-3-基)-6,7-二氢吡咯并[3,4-f]异吲哚-1,3(2H,5H)-二酮(27.74mg,82.62μmol)溶于DMF(5mL)中，加入DIPEA(101.26mg,783.48μmol,136.47μL)，室温搅拌0.5小时，然后加入HATU(110.84mg,293.81μmol)，室温下继续搅拌1小时。待原料反应完全，将反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：0.04％FA/H2O-乙腈；波长：254/214nm；梯度：40％-60％乙腈变化)纯化，得到H33(2.02mg),收率：2.16％。MS m/z(ESI):447.4[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.79(s,1H),8.56(s,1H),7.89(d,J＝18.6Hz,2H),7.56(d,J＝8.0Hz,2H),7.41(d,J＝7.6Hz,2H),6.97-6.88(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.14(dd,J＝16.6,11.5Hz,3H),4.82-4.68(m,3H),4.53(t,J＝8.8Hz,3H),4.24(d,J＝14.7Hz,1H),4.18-4.09(m,1H),3.80(s,1H),3.32(t,J＝8.7Hz,2H),3.21-3.10(m,1H),2.88(s,3H),2.60(dd,J＝29.5,12.9Hz,2H),2.07(s,1H),2.00-1.67(m,3H),1.60(s,2H),1.29(d,J＝6.6Hz,3H),1.22(d,J＝2.3Hz,1H),1.15(d,J＝6.9Hz,3H)。Step 3: H33-b (60 mg, 97.94 μmol) and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (27.74 mg, 82.62 μmol) were dissolved in DMF (5 mL), and DIPEA (101.26 mg, 783.48 μmol, 136.47 μL) was added. The mixture was stirred at room temperature for 0.5 h, and then HATU (110.84 mg, 293.81 μmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction of the raw materials was complete, the reaction solution was purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 0.04% FA/H 2 O-acetonitrile; wavelength: 254/214nm; gradient: 40%-60% acetonitrile change) to obtain H33 (2.02mg), yield: 2.16%. MS m/z (ESI): 447.4 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.12(s,1H),8.79(s,1H),8.56(s,1H),7.89(d,J＝18.6Hz,2H),7.56(d,J＝8.0Hz,2H),7.41(d,J＝7.6Hz,2H),6.97-6.8 8(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.14(dd,J＝16.6,11.5Hz,3H),4.82-4.68(m,3H),4.53(t,J＝8.8Hz,3H),4.24(d,J＝ 14.7Hz,1H),4.18-4.09(m,1H),3.80(s,1H),3.32(t,J＝8.7Hz,2H),3.21-3.10(m,1H),2.88(s,3H),2.60(dd,J＝29.5,12. 9Hz, 2H), 2.07 (s, 1H), 2.00-1.67 (m, 3H), 1.60 (s, 2H), 1.29 (d, J = 6.6Hz, 3H), 1.22 (d, J = 2.3Hz, 1H), 1.15 (d, J = 6.9Hz, 3H).

实施例34化合物H34的制备
Example 34 Preparation of Compound H34

步骤:将中间体Z1(100mg,0.192mmol)溶解于DMF(3mL)中，然后加入DIPEA(2mL)和HATU(218mg,0.576mmol)，室温下搅拌10分钟，TLC检测发现中间产物生成，然后加入H3-b(104mg,0.192mmol)，继续搅拌20分钟。反应完成后，将反应液浓缩后经制备HPLC纯化(waters-sunfire-10um-19*150mm柱(流动相:28％-38％(v/v)乙腈和甲酸水)，得到H34(20mg)，产率:6.6％。MS m/z(ESI):513.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.83-8.67(m,2H),8.57(s,1H),8.36(s,1H),7.98(s,1H),7.92(d,J＝8.1Hz,1H),7.76(d,J＝9.2Hz,1H),7.56(d,J＝8.2Hz,1H),7.46-7.31(m,5H),6.93(t,J＝9.5Hz,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.15(d,J＝14.9Hz,1H),4.90(t,J＝7.2Hz,1H),4.72(d,J＝4.9Hz,2H),4.60-4.46(m,3H),4.47-4.06(m,5H),3.30(t,J＝8.8Hz,3H),3.01-2.85(m,1H),2.43(s,3H),2.37-2.09(m,4H),1.99(s,1H),1.78(s,1H),1.36(d,J＝7.0Hz,3H),1.32-1.20(m,4H),1.14(d,J＝6.7Hz,3H),0.92(s,9H)。Steps: Dissolve the intermediate Z1 (100 mg, 0.192 mmol) in DMF (3 mL), then add DIPEA (2 mL) and HATU (218 mg, 0.576 mmol), stir at room temperature for 10 minutes, TLC detection shows that the intermediate product is generated, then add H3-b (104 mg, 0.192 mmol), and continue stirring for 20 minutes. After the reaction is completed, the reaction solution is concentrated and purified by preparative HPLC (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid water) to obtain H34 (20 mg), yield: 6.6%. MS m/z (ESI): 513.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.97(s,1H),8.83-8.67(m,2H),8.57(s,1H),8.36(s,1H),7.98(s,1H),7.92(d,J＝8.1Hz,1H),7.76(d,J＝9.2Hz,1H),7.56 (d,J＝8.2Hz,1H),7.46-7.31(m,5H),6.93(t,J＝9.5Hz,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.15(d,J＝14.9Hz,1H),4.90(t,J＝7 .2Hz,1H),4.72(d,J＝4.9Hz,2H),4.60-4.46(m,3H),4.47-4.06(m,5H),3.30(t,J＝8.8Hz,3H),3.01-2.85(m,1H),2.43(s,3H ),2.37-2.09(m,4H),1.99(s,1H),1.78(s,1H),1.36(d,J＝7.0Hz,3H),1.32-1.20(m,4H),1.14(d,J＝6.7Hz,3H),0.92(s,9H).

实施例35化合物H35的制备
Example 35 Preparation of Compound H35

步骤1:将中间体Z1(200mg,384.97μmol)和4-(二甲氧基甲基)哌啶(306.48mg，1.92mmol)溶于DMF(8mL)中，加入DIPEA(298.53mg,2.31mmol,402.33μL)和HATU(290.47mg,769.94μmol)，在室温下搅拌2小时。反应完成后，将反应液浓缩后经CombiFlash纯化(24g，0～10％MeOH/DCM)，得到H35-a(220mg,淡黄色固体),收率：89.20％。MS m/z(ESI):643.3[M+H]+。Step 1: Dissolve intermediate Z1 (200 mg, 384.97 μmol) and 4-(dimethoxymethyl)piperidine (306.48 mg, 1.92 mmol) in DMF (8 mL), add DIPEA (298.53 mg, 2.31 mmol, 402.33 μL) and HATU (290.47 mg, 769.94 μmol), and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H35-a (220 mg, light yellow solid), yield: 89.20%. MS m/z (ESI): 643.3 [M+H] + .

步骤2:将H35-a(220mg,342.30μmol)溶于EtOH(4mL)和H2O(2mL)中，加入p-TsOH(176.83mg,1.03mmol)，在90℃下搅拌6小时。反应完成后，冷却到室温，将反应液浓缩后加入水稀释至30mL，加入碳酸氢钠饱和水溶液调至pH＝8，再用二氯甲烷(60mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(10g，0～10％MeOH/DCM)，得到H35-b(187mg,黑色粘稠固体),收率：91.56％。MS m/z(ESI):597.3[M+H]+。Step 2: H35-a (220 mg, 342.30 μmol) was dissolved in EtOH (4 mL) and H 2 O (2 mL), p-TsOH (176.83 mg, 1.03 mmol) was added, and the mixture was stirred at 90°C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was concentrated, and water was added to dilute the mixture to 30 mL. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 8, and the mixture was extracted with dichloromethane (60 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (10 g, 0-10% MeOH/DCM) to obtain H35-b (187 mg, black viscous solid), yield: 91.56%. MS m/z (ESI): 597.3 [M+H] + .

步骤3:将H35-b(100mg,167.60μmol)和2-(2,6-二氧代哌啶-3-基)-6,7-二氢吡咯并[3,4-f]异吲哚-1,3(2H,5H)-二酮(50.16mg,167.60μmol)溶于EtOH(10mL)中，加入DIPEA(32.49mg,251.40μmol,43.79μL)在微波90℃下搅拌0.5小时,然后加入CH3COOH(20.13mg,335.20μmol)，继续在微波90℃条件下搅拌0.5小时，降到室温后加入NaBH3CN(52.66mg,838.01μmol)，室温搅拌3小时。反应完成后，向反应液中加入饱和氯化铵水溶液，用二氯甲烷(60mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash(4g，0～15％MeOH/DCM)纯化，得到H35-c(107mg,淡黄色固体),收率：72.64％。MS m/z(ESI):879.3[M+H]+。Step 3: H35-b (100 mg, 167.60 μmol) and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (50.16 mg, 167.60 μmol) were dissolved in EtOH (10 mL), and DIPEA (32.49 mg, 251.40 μmol, 43.79 μL) was added, and the mixture was stirred at 90°C in a microwave for 0.5 hour, and then CH 3 COOH (20.13 mg, 335.20 μmol) was added, and the mixture was stirred at 90°C in a microwave for 0.5 hour. After cooling to room temperature, NaBH 3 CN (52.66 mg, 838.01 μmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (60 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (4 g, 0-15% MeOH/DCM) to obtain H35-c (107 mg, light yellow solid), yield: 72.64%. MS m/z (ESI): 879.3 [M+H] + .

步骤4:将H35-c(107mg,121.74μmol)溶于EtOH(10mL)中，加入NaBH3CN(76.50mg,1.22mmol)，在20℃下搅拌4小时。反应完成后，将反应液经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)纯化，得到H35(1.03mg,白色固体),收率：0.84％。MS m/z(ESI):880.3[M+H]+。Step 4: H35-c (107 mg, 121.74 μmol) was dissolved in EtOH (10 mL), and NaBH 3 CN (76.50 mg, 1.22 mmol) was added, and the mixture was stirred at 20° C. for 4 hours. After the reaction was completed, the reaction solution was purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H35 (1.03 mg, white solid), yield: 0.84%. MS m/z (ESI): 880.3 [M+H] + .

实施例36化合物H36的制备
Example 36 Preparation of Compound H36

步骤1:将7-氧代-2-氮杂螺[3.5]壬烷-2-羧酸叔丁酯(717mg，3mmol)加入到二氧六环(1mL)中，然后加入盐酸二氧六环溶液(4mol/L，10mL)，室温搅拌5小时。反应完成后，将反应液过滤，二氯甲烷(5mL)洗涤滤饼，滤饼自然干燥，得到H36-a(525mg)，产率:100％。MS m/z(ESI):176[M+H]+。Step 1: tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (717 mg, 3 mmol) was added to dioxane (1 mL), and then dioxane hydrochloride solution (4 mol/L, 10 mL) was added and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with dichloromethane (5 mL), and the filter cake was dried naturally to obtain H36-a (525 mg), yield: 100%. MS m/z (ESI): 176 [M + H] + .

步骤2:将H36-a(525mg,3mmol)和化合物2-(2,6-二氧哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(828mg，3mmol)加入到DMF(2mL)中，加入DIPEA(1mL)，加热至125℃并在125℃下搅拌2小时。反应完成后，将反应液倒入水(100mL)中，用乙酸乙酯萃取(30mL×3)，合并有机相浓缩后经硅胶柱层析(PE/EA 0-60％)纯化，得到H36-b(790mg)，产率:66.7％。MS m/z(ESI):396[M+H]+。Step 2: Add H36-a (525 mg, 3 mmol) and compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (828 mg, 3 mmol) to DMF (2 mL), add DIPEA (1 mL), heat to 125°C and stir at 125°C for 2 hours. After the reaction is completed, pour the reaction solution into water (100 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, concentrate and purify by silica gel column chromatography (PE/EA 0-60%) to obtain H36-b (790 mg), yield: 66.7%. MS m/z (ESI): 396 [M+H] + .

步骤3:将H36-b(790mg，2mmol)溶于氨气二氧六环溶液(10mL，1.6mol/L)中，加入钛酸四异丙酯(1136mg，4mmol)，室温搅拌2小时，然后加入NaBH(150mg)，继续搅拌30分钟。反应完成后，将反应液经硅胶柱层析纯化(0-5％DCM/MeOH)，得到H36-c(475mg)，产率:75％。MS m/z(ESI):397.2[M+H]+。Step 3: H36-b (790 mg, 2 mmol) was dissolved in ammonia dioxane solution (10 mL, 1.6 mol/L), tetraisopropyl titanate (1136 mg, 4 mmol) was added, and the mixture was stirred at room temperature for 2 hours, and then NaBH (150 mg) was added and stirred for 30 minutes. After the reaction was completed, the reaction solution was purified by silica gel column chromatography (0-5% DCM/MeOH) to obtain H36-c (475 mg), yield: 75%. MS m/z (ESI): 397.2 [M+H] + .

步骤4:将H36-c(100mg,250umol)和H10-a(126mg,250umol))溶于DMF(2mL)中，加入TCFH(16mg，55ummol)、N-甲基咪唑(1mL)室温搅拌。将所得混合物油泵拉干送制备，滤液通过高压液相纯化(waters-sunfire-10um-19*150mm柱(流动相:28％-38％(v/v)乙腈和甲酸水)，得到H36(14mg)，产率:6％。MS m/z(ESI):880.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.74(s,1H),8.59(s,1H),8.29(d,J＝7.9Hz,1H),7.97(d,J＝1.8Hz,1H),7.90(d,J＝8.2Hz,1H),7.60(dd,J＝23.1,8.2Hz,2H),7.40(s,1H),6.94(dd,J＝10.2,8.7Hz,1H),6.79(d,J＝2.0Hz,1H),6.67(ddd,J＝10.4,8.5,3.0Hz,2H),5.15(d,J＝15.1Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.73(d,J＝4.9Hz,2H),4.53(t,J＝8.7Hz,2H),4.28-4.12(m,2H),3.81(s,3H),3.72(s,2H),1.97(d,J＝12.8Hz,3H),1.80(d,J＝11.9Hz,2H),1.74-1.57(m,3H),1.43(d,J＝12.0Hz,3H),1.32-1.20(m,5H),1.15(d,J＝6.8Hz,4H)。Step 4: H36-c (100 mg, 250 umol) and H10-a (126 mg, 250 umol) were dissolved in DMF (2 mL), TCFH (16 mg, 55 ummol) and N-methylimidazole (1 mL) were added and stirred at room temperature. The resulting mixture was pumped dry and sent to the preparation, and the filtrate was purified by high pressure liquid phase (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid water) to obtain H36 (14 mg), yield: 6%. MS m/z (ESI): 880.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.06(s,1H),8.74(s,1H),8.59(s,1H),8.29(d,J＝7.9Hz,1H),7.97(d,J＝1.8Hz,1H),7.90(d,J＝8.2Hz,1H),7.60(dd,J＝23.1, 8.2Hz,2H),7.40(s,1H),6.94(dd,J＝10.2,8.7Hz,1H),6.79(d,J＝2.0Hz,1H),6.67(ddd,J＝10.4,8.5,3.0Hz,2H),5.15(d,J＝15.1H z,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.73(d,J＝4.9Hz,2H),4.53(t,J＝8.7Hz,2H),4.28-4.12(m,2H),3.81(s,3H),3.72(s,2H),1. 97(d,J＝12.8Hz,3H),1.80(d,J＝11.9Hz,2H),1.74-1.57(m,3H),1.43(d,J＝12.0Hz,3H),1.32-1.20(m,5H),1.15(d,J＝6.8Hz,4H).

实施例37化合物H37的制备
Example 37 Preparation of Compound H37

步骤1:在室温下，将中间体Z3(50mg,0.11mmol)和N-叔丁氧羰基-4-哌啶酮(42mg,0.21mmol)溶在DCM(2mL)中，加入醋酸(20mg,0.33mmol)和NaBH(OAc)3(67mg,0.32mmol)，在25℃下搅拌16小时。在反应完成后，将反应液浓缩后经硅胶柱层析纯化(DCM/MeOH＝0～10％)，得到H37-a(30mg，黄色油)。收率:43.23％。MS m/z(ESI):656.2[M+H]+。Step 1: At room temperature, intermediate Z3 (50 mg, 0.11 mmol) and N-tert-butyloxycarbonyl-4-piperidone (42 mg, 0.21 mmol) were dissolved in DCM (2 mL), acetic acid (20 mg, 0.33 mmol) and NaBH(OAc) 3 (67 mg, 0.32 mmol) were added, and stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (DCM/MeOH=0-10%) to obtain H37-a (30 mg, yellow oil). Yield: 43.23%. MS m/z (ESI): 656.2 [M+H] + .

步骤2:将H37-a(30mg,0.05mmol)溶于甲醇(1mL)中，加入盐酸/甲醇溶液(1mL,4mol/L)，室温搅拌反应3小时。在反应完成后，将反应液浓缩后得到H37-b(25mg，黄色油)，收率:98.35％。MS m/z(ESI):556.2[M+H]+。Step 2: H37-a (30 mg, 0.05 mmol) was dissolved in methanol (1 mL), and hydrochloric acid/methanol solution (1 mL, 4 mol/L) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain H37-b (25 mg, yellow oil), with a yield of 98.35%. MS m/z (ESI): 556.2 [M+H] + .

步骤3:将H37-b(20mg,0.04mmol)和1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)哌啶-4-甲醛(26mg,0.07mmol)溶于DCM(5mL)中，加入醋酸(2mg,0.04mmol)和NaBH(OAc)3(23mg,0.11mmol)，在25℃下搅拌82小时。在反应完成后，将反应液浓缩后经制备硅胶板(DCM：MeOH＝8：1)纯化，得到H37(3mg，淡黄色固体)，产率:6.11％。MS m/z(ESI):909.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),11.09(s,1H),8.71(s,1H),8.39-8.30(m,1H),7.66(d,J＝8.6Hz,1H),7.32(s,1H),7.22(dd,J＝17.2,9.0Hz,4H),6.99-6.90(m,1H),6.76-6.67(m,2H),6.63(d,J＝8.0Hz,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.94(d,J＝14.8Hz,1H),4.70(d,J＝4.7Hz,2H),4.54(t,J＝8.8Hz,2H),4.24-4.17(m,1H),4.10-3.97(m,3H),3.30(d,J＝9.0Hz,2H),3.02-2.93(m,2H),2.92-2.83(m,2H),2.63-2.55(m,1H),2.04-1.98(m,3H),1.91(s,2H),1.85-1.79(m,2H),1.51-1.42(m,2H),1.30-1.27(m,4H),1.25(d,J＝3.7Hz,2H),1.24-1.22(m,6H),0.88-0.82(m,1H)。Step 3: H37-b (20 mg, 0.04 mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde (26 mg, 0.07 mmol) were dissolved in DCM (5 mL), acetic acid (2 mg, 0.04 mmol) and NaBH(OAc) 3 (23 mg, 0.11 mmol) were added, and the mixture was stirred at 25° C. for 82 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative silica gel plate (DCM: MeOH = 8: 1) to obtain H37 (3 mg, light yellow solid), yield: 6.11%. MS m/z (ESI): 909.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.09(s,1H),11.09(s,1H),8.71(s,1H),8.39-8.30(m,1H),7.66(d,J＝8.6Hz,1H),7.32(s,1H),7.22(dd,J＝17.2,9.0Hz,4H),6.99-6.9 0(m,1H),6.76-6.67(m,2H),6.63(d,J＝8.0Hz,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.94(d,J＝14.8Hz,1H),4.70(d,J＝4.7Hz,2H),4.54(t,J＝8 .8Hz,2H),4.24-4.17(m,1H),4.10-3.97(m,3H),3.30(d,J＝9.0Hz,2H),3.02-2.93(m,2H),2.92-2.83(m,2H),2.63-2.55(m,1H),2.04-1.98 (m,3H),1.91(s,2H),1.85-1.79(m,2H),1.51-1.42(m,2H),1.30-1.27(m,4H),1.25(d,J＝3.7Hz,2H),1.24-1.22(m,6H),0.88-0.82(m,1H).

实施例38化合物H38的制备
Example 38 Preparation of Compound H38

步骤1:在0℃下，向4-氨基哌啶-1-羧酸叔丁酯(6g，29.9mmol)的DCM(100mL)溶液中加入5-溴-2-(三氟甲基)吡啶-4-甲醛(8g，31.5mmol)和乙酸(0.1mL，1.75mmol)，在氮气氛围下，25℃搅拌反应1.5小时。然后在氮气氛围下加入NaBH(OAc)3(12.7g，59.9mmol)，在氮气氛围下，25℃搅拌2小时。反应完成后，将混合物倒入饱和NaHCO3水溶液(50mL)中，并用乙酸乙酯(50mL×3)萃取，合并的有机相经无水硫酸钠干燥，浓缩后经硅胶柱层析(PE：EA＝10∶1-1∶1)纯化，得到H2-a(13.4g，黄色液体)，收率：81.6％。MS m/z(ESI):382.0[M-56+H]+。Step 1: At 0°C, 5-bromo-2-(trifluoromethyl)pyridine-4-carboxaldehyde (8 g, 31.5 mmol) and acetic acid (0.1 mL, 1.75 mmol) were added to a solution of tert-butyl 4-aminopiperidine-1-carboxylate (6 g, 29.9 mmol) in DCM (100 mL), and the mixture was stirred at 25°C for 1.5 hours under a nitrogen atmosphere. Then NaBH(OAc) 3 (12.7 g, 59.9 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 25°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was poured into a saturated aqueous NaHCO 3 solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA=10:1-1:1) to obtain H2-a (13.4 g, yellow liquid), with a yield of 81.6%. MS m/z(ESI):382.0[M-56+H] + .

步骤2:在0℃下，向H2-a(13.4g，24.5mmol)的DCM(150mL)溶液中加入(Boc)2O(8.01g，36.7mmol)和三乙胺(10.2mL，73.4mmol)，在氮气氛围下，60℃搅拌反应18小时。反应完成后，将混合物浓缩后经硅胶柱层析色纯化(PE：EA＝10∶1-3∶1)纯化，得到H2-b(12.4g，白色固体)，收率：94.2％。MS m/z(ESI):438.0[M-100+H]+。Step 2: At 0°C, (Boc) 2 O (8.01 g, 36.7 mmol) and triethylamine (10.2 mL, 73.4 mmol) were added to a solution of H2-a (13.4 g, 24.5 mmol) in DCM (150 mL), and the mixture was stirred at 60°C for 18 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (PE: EA = 10: 1-3: 1) to obtain H2-b (12.4 g, white solid), yield: 94.2%. MS m/z (ESI): 438.0 [M-100+H] + .

步骤3:将H2-b(4.45g，8.27mmol)溶于DME(40mL)和水(4mL)中，加入8-溴-5-(((5-氟-2，3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1,5-c]嘧啶-1-羧酸乙酯(2g，4.60mmol)，双(Pin)2B2(2.33g，9.19mmol)、CataCXium A(329mg，0.92mmol)、Pd(OAc)2(103mg，0.46mmol)和K2CO3(2.54g，18.4mmol)，在氮气氛围下，70℃下搅拌18小时。将混合物浓缩后经硅胶柱层析(DCM:MeOH＝100∶1-30∶1)纯化，得到H2-c(2g，白色固体)，收率：53.5％。MS m/z(ESI):714.3[M-100+H]+。Step 3: H2-b (4.45 g, 8.27 mmol) was dissolved in DME (40 mL) and water (4 mL), and 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (2 g, 4.60 mmol), bis(Pin) 2 B 2 (2.33 g, 9.19 mmol), CataCXium A (329 mg, 0.92 mmol), Pd(OAc) 2 (103 mg, 0.46 mmol) and K 2 CO 3 (2.54 g, 18.4 mmol) were added, and the mixture was stirred at 70° C. for 18 hours under nitrogen atmosphere. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=100:1-30:1) to obtain H2-c (2 g, white solid), yield: 53.5%. MS m/z (ESI): 714.3 [M-100+H] + .

步骤4:向H2-c(2g，2.46mmol)的EA(15mL)溶液中加入盐酸乙酸乙酯溶液(4mol/L，15mL)，在25℃下搅拌2小时。反应完成后，将混合物浓缩，得到H2-d(1.8g，黄色固体)，收率：95.9％。MS m/z(ESI):614.2[M+H]+。Step 4: To a solution of H2-c (2 g, 2.46 mmol) in EA (15 mL) was added a hydrochloric acid ethyl acetate solution (4 mol/L, 15 mL), and stirred at 25° C. for 2 hours. After the reaction was completed, the mixture was concentrated to give H2-d (1.8 g, yellow solid), yield: 95.9%. MS m/z (ESI): 614.2 [M+H] + .

步骤5:向H2-d(500mg，0.66mmol)的MeOH(10mL)和水(2mL)中加入氢氧化锂水合物(412mg，9.84mmol)，在氮气氛围下，70℃下搅拌3小时。反应完成后，将混合物浓缩后用水(5mL)稀释，并用盐酸水溶液(2mol/L)调节至pH＝7，浓缩后经制备HPLC(洗脱液：10％-30％(v/v)乙腈和水，添加0.025％甲酸)纯化，得到H2-e(260mg，白色固体)，收率：67.7％。MS m/z(ESI):586.2[M+H]+。Step 5: Lithium hydroxide hydrate (412 mg, 9.84 mmol) was added to MeOH (10 mL) and water (2 mL) of H2-d (500 mg, 0.66 mmol), and stirred at 70°C for 3 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated and diluted with water (5 mL), and adjusted to pH = 7 with aqueous hydrochloric acid (2 mol/L). After concentration, it was purified by preparative HPLC (eluent: 10%-30% (v/v) acetonitrile and water, with 0.025% formic acid added) to obtain H2-e (260 mg, white solid), yield: 67.7%. MS m/z (ESI): 586.2 [M+H] + .

步骤6:向H2-e(250mg，0.43mmol)的DMF(4mL)和THF(20mL)溶液中加入HATU(194mg，0.51mmol)和DIPEA(276mg，2.13mmol)，在氮气氛围下，25℃下搅拌30分钟。反应完成后，将混合物浓缩后加入水(10mL)稀释，过滤并干燥滤饼，得到H2-f(150mg，红色固体)，收率：30.9％。MS m/z(ESI):568.2[M+H]+。Step 6: HATU (194 mg, 0.51 mmol) and DIPEA (276 mg, 2.13 mmol) were added to a solution of H2-e (250 mg, 0.43 mmol) in DMF (4 mL) and THF (20 mL), and stirred at 25° C. for 30 minutes under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated and diluted with water (10 mL), filtered and the filter cake was dried to obtain H2-f (150 mg, red solid), yield: 30.9%. MS m/z (ESI): 568.2 [M+H] + .

步骤7:向H2-f(50mg，0.04mmol)的DMF(2mL)溶液中加入1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)氮杂环丁烷-3-羧酸(16mg，0.04mmol)、HATU(25mg，0.07mmol)和DIPEA(17mg，0.13mmol)，在氮气氛围下，25℃搅拌30分钟。反应完成后，将混合物过滤，滤饼用制备HPLC(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈43％-95％，流速：25mL/min)纯化，得到H38(12mg，黄色固体)，收率：30％。MS m/z(ESI):907.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.88(s,1H),8.83-8.71(m,2H),8.17(d,J＝4.0Hz,1H),7.69-7.57(m,2H),6.95(t,J＝9.2Hz,1H),6.87-6.79(m,1H),6.74-6.59(m,2H),5.36-5.23(m,1H),5.12-5.01(m,1H),4.76(d,J＝3.6Hz,2H),4.60-4.34(m,4H),4.32-4.01(m,5H),3.99-3.86(m,1H),3.69(t,J＝13.6Hz,1H),3.31(s,1H),3.15-2.96(m,1H),2.93-2.80(m,1H),2.71-2.53(m,2H),2.26-1.96(m,3H),1.77-1.63(m,1H),1.53-0.98(m,3H)。Step 7: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylic acid (16 mg, 0.04 mmol), HATU (25 mg, 0.07 mmol) and DIPEA (17 mg, 0.13 mmol) were added to a solution of H2-f (50 mg, 0.04 mmol) in DMF (2 mL), and stirred at 25 ° C for 30 minutes under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and the filter cake was purified by preparative HPLC (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 μm-19*250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 43%-95%, flow rate: 25 mL/min) to obtain H38 (12 mg, yellow solid), yield: 30%. MS m/z(ESI):907.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.08(s,1H),8.88(s,1H),8.83-8.71(m,2H),8.17(d,J＝4.0Hz,1H),7.69-7.57(m,2H),6.95(t,J＝9.2 Hz,1H),6.87-6.79(m,1H),6.74-6.59(m,2H),5.36-5.23(m,1H),5.12-5.01(m,1H),4.76(d,J＝3.6Hz,2H ),4.60-4.34(m,4H),4.32-4.01(m,5H),3.99-3.86(m,1H),3.69(t,J＝13.6Hz,1H),3.31(s,1H),3.15-2. 96(m,1H),2.93-2.80(m,1H),2.71-2.53(m,2H),2.26-1.96(m,3H),1.77-1.63(m,1H),1.53-0.98(m,3H).

实施例39化合物H39的制备
Example 39 Preparation of Compound H39

步骤1:室温下向单口瓶中加入3-(5-溴-3-甲基-2-氧代-2,3-二氢1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮(278mg,0.820mmol)、XPhos(76.7mg,0.160mmol)、Ruphos-Pd-G3(138mg,0.160mmol)、4-(二甲氧基甲基)-哌啶(170mg,1.07mmol)和甲苯(6mL)，氮气氛围下室温搅拌下加入LiHMDS(1mol/L,4.11mL,4.11mmol)，80℃下反应2小时。反应完成后，向反应液中加入水(20mL)，用乙酸乙酯萃取(20mL×3)，合并有机相经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，浓缩后经硅胶柱层析色谱(MeOH/DCM＝0％-10％)纯化，得到H39-a(218mg，棕色固体)，收率:63.67％。MS m/z(ESI):417.2[M+H]+。Step 1: 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (278 mg, 0.820 mmol), XPhos (76.7 mg, 0.160 mmol), Ruphos-Pd-G3 (138 mg, 0.160 mmol), 4-(dimethoxymethyl)-piperidine (170 mg, 1.07 mmol) and toluene (6 mL) were added to a single-necked bottle at room temperature, and LiHMDS (1 mol/L, 4.11 mL, 4.11 mmol) was added with stirring at room temperature under nitrogen atmosphere, and the mixture was reacted at 80 °C for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH/DCM=0%-10%) to obtain H39-a (218 mg, brown solid), yield: 63.67%. MS m/z (ESI): 417.2 [M+H] + .

步骤2:室温下向单口瓶中加入H39-a(218mg,0.520mmol)和THF(1.5mL)，室温搅拌下加入稀盐酸(2mol/L,1.50mL,3.00mmol)，70℃下反应1小时。在反应完成后，向反应体系中加入水(20mL)，用饱和NaHCO3水溶液调节pH至7，用乙酸乙酯萃取(30mL×3)，合并有机相经饱和食盐水(10mL)洗涤，无水硫酸钠干燥，浓缩后得到H39-b(140mg，黄色固体)，收率:72.69％。MS m/z(ESI):371.0[M+H]+。Step 2: Add H39-a (218 mg, 0.520 mmol) and THF (1.5 mL) to a single-mouth bottle at room temperature, add dilute hydrochloric acid (2 mol/L, 1.50 mL, 3.00 mmol) under stirring at room temperature, and react at 70°C for 1 hour. After the reaction is completed, add water (20 mL) to the reaction system, adjust the pH to 7 with saturated NaHCO 3 aqueous solution, extract with ethyl acetate (30 mL×3), wash the combined organic phases with saturated brine (10 mL), dry over anhydrous sodium sulfate, and concentrate to obtain H39-b (140 mg, yellow solid), yield: 72.69%. MS m/z (ESI): 371.0 [M+H] + .

步骤3:室温下向单口瓶中加入H39-b(70.0mg,0.190mmol)、H2-f(91.0mg,0.160mmol)、DMSO(3mL)和乙醇(1mL)，室温搅拌下加入NaBH3CN(76.7mg,1.28mmol)和醋酸(45.9μL,0.800mmol)，90℃微波条件下反应1小时。在反应完成后，将反应液过滤，滤液通过制备型HPLC(Waters-SunFire-C18-10μm-19*250mm(流动相:2％-95％(v/v)乙腈和水(0.1％甲酸))纯化，得到H39(12.52mg)，产率:8.47％。MS m/z(ESI):922.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.88(s,1H),8.83-8.74(m,2H),8.11(s,1H),7.62(s,1H),7.01-6.89(m,2H),6.83(d,J＝2.2Hz,1H),6.71(dd,J＝8.6,3.8Hz,1H),6.63(dd,J＝8.7,2.2Hz,1H),5.38-5.23(m,2H),4.76(d,J＝5.0Hz,2H),4.55(t,J＝8.8Hz,2H),4.38(d,J＝15.0Hz,1H),3.94-3.80(m,1H),3.60(d,J＝11.5Hz,2H),3.38-3.32(m,9H),3.22-3.00(m,2H),2.94-2.83(m,1H),2.74-2.56(m,5H),2.54(s,1H),2.02-1.95(m,1H),1.86-1.68(m,4H),1.34-1.23(m,2H),1.06(d,J＝12.2Hz,1H)。Step 3: H39-b (70.0 mg, 0.190 mmol), H2-f (91.0 mg, 0.160 mmol), DMSO (3 mL) and ethanol (1 mL) were added to a single-mouth bottle at room temperature, and NaBH 3 CN (76.7 mg, 1.28 mmol) and acetic acid (45.9 μL, 0.800 mmol) were added under stirring at room temperature, and the mixture was reacted under microwave conditions at 90° C. for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19*250 mm (mobile phase: 2%-95% (v/v) acetonitrile and water (0.1% formic acid)) to obtain H39 (12.52 mg), with a yield of 8.47%. MS m/z (ESI): 922.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.08(s,1H),8.88(s,1H),8.83-8.74(m,2H),8.11(s,1H),7.62(s,1H),7.01-6.89(m,2H),6.83(d,J＝2.2Hz,1H),6 .71(dd,J＝8.6,3.8Hz,1H),6.63(dd,J＝8.7,2.2Hz,1H),5.38-5.23(m,2H),4.76(d,J＝5.0Hz,2H),4.55(t,J＝8.8Hz,2H) ,4.38(d,J＝15.0Hz,1H),3.94-3.80(m,1H),3.60(d,J＝11.5Hz,2H),3.38-3.32(m,9H),3.22-3.00(m,2H),2.94-2.83(m ,1H),2.74-2.56(m,5H),2.54(s,1H),2.02-1.95(m,1H),1.86-1.68(m,4H),1.34-1.23(m,2H),1.06(d,J=12.2Hz,1H).

实施例40化合物H40的制备
Example 40 Preparation of Compound H40

步骤1:在室温下，将2-(2,6-二氧哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(500mg,1.81mmol)和4-(二甲氧基甲基)哌啶(432mg,2.72mmol)溶在DMSO(10mL)中，加入DIPEA(702mg,5.43mmol)，在120℃下搅拌2小时。在反应完全后，将反应液倒入水(30mL)中，乙酸乙酯(30mL×3)萃取水相，合并有机相经无水硫酸钠干燥，浓缩得到H40-a(690mg，黄色固体)，收率:91.75％。MS m/z(ESI):416.2[M+H]+。Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol) and 4-(dimethoxymethyl)piperidine (432 mg, 2.72 mmol) were dissolved in DMSO (10 mL) at room temperature, and DIPEA (702 mg, 5.43 mmol) was added and stirred at 120°C for 2 hours. After the reaction was complete, the reaction solution was poured into water (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain H40-a (690 mg, yellow solid), yield: 91.75%. MS m/z (ESI): 416.2 [M+H] + .

步骤2:将H40-a(690mg,1.66mmol)溶在THF(4mL)中，加入盐酸水溶液(2mol/L,4mL)，升温至70℃搅拌反应1小时。在反应完成后，向反应液中加水(20mL)，用饱和碳酸氢钠水溶液调节pH～7，用乙酸乙酯(30mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H40-b(450mg，黄色固体，纯度80％)，收率:73.35％。MS m/z(ESI):370.2[M+H]+。Step 2: H40-a (690 mg, 1.66 mmol) was dissolved in THF (4 mL), and aqueous hydrochloric acid solution (2 mol/L, 4 mL) was added, and the temperature was raised to 70°C and stirred for reaction for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (30 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain H40-b (450 mg, yellow solid, purity 80%), with a yield of 73.35%. MS m/z (ESI): 370.2 [M+H] + .

步骤3:将H40-b(34mg,0.07mmol，纯度80％)和H2-f(30mg,0.04mmol)溶于DMSO(3mL)和EtOH(1mL)中，加入NaBH3CN(18mg,0.30mmol)和乙酸(11mg,0.19mmol)，在95℃微波反应1小时。反应完成后，将反应液过滤，滤液通过制备型HPLC(Waters-Xbridge-C18-10μm-19*250mm柱(流动相:49％to 95％(v/v)乙腈和水(含0.1％甲酸))纯化，得到H40(10mg，黄色固体)，产率:29.34％。MS m/z(ESI):921.6[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.88(s,1H),8.82-8.70(m,2H),8.20(s,1H,FA),8.10(s,1H),7.73-7.64(m,1H),7.58(s,1H),7.38-7.27(m,2H),7.01-6.91(m,1H),6.73-6.67(m,1H),5.32-5.26(m,1H),5.13-5.05(m,1H),4.79-4.71(m,2H),4.60-4.51(m,2H),4.46-4.38(m,1H),3.89-3.80(m,1H),3.72-3.64(m,2H),2.94-2.83(m,5H),2.65-2.58(m,3H),2.36-2.31(m,1H),2.25-2.15(m,3H),2.06-1.91(m,4H),1.86-1.77(m,2H),1.73-1.56(m,2H),1.34-1.28(m,2H),1.12-1.02(m,1H)。Step 3: H40-b (34 mg, 0.07 mmol, purity 80%) and H2-f (30 mg, 0.04 mmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), and NaBH 3 CN (18 mg, 0.30 mmol) and acetic acid (11 mg, 0.19 mmol) were added, and microwave reaction was performed at 95° C. for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm column (mobile phase: 49% to 95% (v/v) acetonitrile and water (containing 0.1% formic acid)) to obtain H40 (10 mg, yellow solid), yield: 29.34%. MS m/z (ESI): 921.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.10(s,1H),8.88(s,1H),8.82-8.70(m,2H),8.20(s,1H,FA),8.10(s,1H),7.73-7.64(m,1H),7.58(s,1H),7.38-7 .27(m,2H),7.01-6.91(m,1H),6.73-6.67(m,1H),5.32-5.26(m,1H),5.13-5.05(m,1H),4.79-4.71(m,2H),4.60-4.51 (m,2H),4.46-4.38(m,1H),3.89-3.80(m,1H),3.72-3.64(m,2H),2.94-2.83(m,5H),2.65-2.58(m,3H),2.36-2.31(m, 1H),2.25-2.15(m,3H),2.06-1.91(m,4H),1.86-1.77(m,2H),1.73-1.56(m,2H),1.34-1.28(m,2H),1.12-1.02(m,1H).

实施例43化合物H43的制备
Example 43 Preparation of Compound H43

参照实施例39的制备方法，按照上述合成路线，制备得到H43，其制备HPLC的纯化条件为制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)，得H43(14.68mg,纯度98.93％)，收率：30.29％。MS m/z(ESI):454.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.85(s,1H),8.77(d,J＝7.6Hz,2H),8.10(s,1H),7.58(s,1H),7.41(d,J＝9.2Hz,1H),6.98-6.86(m,2H),6.79(s,1H),6.69(dd,J＝8.8,4.0Hz,1H),5.27(d,J＝14.8Hz,1H),4.74(s,2H),4.53(t,J＝8.8Hz,2H),4.40(d,J＝14.8Hz,1H),3.90-3.83(m,5H),3.82-3.73(m,3H),3.29(s,2H),2.87(s,2H),2.75-2.64(m,4H),2.38-2.25(m,1H),2.20-2.10(m,3H),1.96-1.85(m,2H),1.83-1.74(m,2H),1.73-1.54(m,2H),1.28-1.15(m,2H),1.07-0.99(m,1H)。Referring to the preparation method of Example 39, H43 was prepared according to the above synthetic route. The purification conditions of the preparative HPLC were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change), H43 (14.68mg, purity 98.93%), yield: 30.29%. MS m/z (ESI): 454.3 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ10.50(s,1H),8.85(s,1H),8.77(d,J＝7.6Hz,2H),8.10(s,1H),7.58(s,1H),7.41(d,J＝9.2Hz,1H),6.98-6.86(m, 2H),6.79(s,1H),6.69(dd,J＝8.8,4.0Hz,1H),5.27(d,J＝14.8Hz,1H),4.74(s,2H),4.53(t,J＝8.8Hz,2H),4.40(d,J ＝14.8Hz,1H),3.90-3.83(m,5H),3.82-3.73(m,3H),3.29(s,2H),2.87(s,2H),2.75-2.64(m,4H),2.38-2.25(m,1H) ,2.20-2.10(m,3H),1.96-1.85(m,2H),1.83-1.74(m,2H),1.73-1.54(m,2H),1.28-1.15(m,2H),1.07-0.99(m,1H).

实施例45化合物H45的制备
Example 45 Preparation of Compound H45

步骤1:将双(三氯甲基)碳酸酯(8.69mg,29.29μmol)溶解于DCM(5mL)中，冰浴下(0℃)加入哌嗪-1-羧酸叔丁酯(21.82mg,117.18μmol)，混合溶液慢慢升温至室温并在室温下搅拌反应1小时，继续在0℃下加入2-(2,6-二氧哌啶-3-基)-5-(哌啶-4-基)异吲哚啉-1,3-二酮(20mg,58.59μmol)，继续在室温下搅拌反应16小时。反应完成后，将反应液浓缩得到H45-a(105mg,189.67μmol)。MS m/z(ESI):453.9[M-100+H]+。Step 1: Dissolve bis(trichloromethyl) carbonate (8.69 mg, 29.29 μmol) in DCM (5 mL), add tert-butyl piperazine-1-carboxylate (21.82 mg, 117.18 μmol) under ice bath (0°C), slowly warm the mixed solution to room temperature and stir at room temperature for 1 hour, continue to add 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindoline-1,3-dione (20 mg, 58.59 μmol) at 0°C, continue to stir at room temperature for 16 hours. After the reaction is completed, the reaction solution is concentrated to obtain H45-a (105 mg, 189.67 μmol). MS m/z (ESI): 453.9 [M-100+H] + .

步骤2:将H45-a(105mg,189.67μmol)溶解于DCM(5mL)中，室温下加入TFA(6.92mg,60.65μmol,1mL)，混合溶液在室温下搅拌反应2小时。反应完成后，将反应液浓缩得到H45-b(86mg,白色固体，粗品)，未作进一步纯化，直接用于下一步反应。MS m/z(ESI):453.9[M-100+H]+。Step 2: H45-a (105 mg, 189.67 μmol) was dissolved in DCM (5 mL), TFA (6.92 mg, 60.65 μmol, 1 mL) was added at room temperature, and the mixed solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H45-b (86 mg, white solid, crude product), which was directly used in the next step without further purification. MS m/z (ESI): 453.9 [M-100+H] + .

步骤3:将H10-a(50mg,99.70μmol)和H45-b(90.43mg,199.40μmol)溶解于DMF(5mL)中，室温下加入HATU(75.23mg,199.40μmol)和DIPEA(64.43mg,498.50μmol,86.83μL)，室温下搅拌反应16小时。反应完成后，将反应液过滤，滤液浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：62％-67％乙腈变化)，得到H45(1.62mg,纯度96.56％)，收率：1.62％。MS m/z(ESI):936.6[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.88-7.70(m,3H),7.60-7.49(m,2H),7.45-7.36(m,2H),6.92(t,J＝9.5Hz,1H),6.67(dd,J＝8.7,3.8Hz,1H),5.17-5.05(m,2H),4.71(s,2H),4.52(t,J＝8.8Hz,2H),4.25-4.09(m,3H),3.72(s,7H),3.03-2.52(m,8H),2.03(s,3H),1.82-1.60(m,4H),1.32-1.06(m,8H)。Step 3: H10-a (50 mg, 99.70 μmol) and H45-b (90.43 mg, 199.40 μmol) were dissolved in DMF (5 mL), HATU (75.23 mg, 199.40 μmol) and DIPEA (64.43 mg, 498.50 μmol, 86.83 μL) were added at room temperature, and the mixture was stirred for 16 hours at room temperature. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 62%-67% acetonitrile change) to obtain H45 (1.62 mg, purity 96.56%), yield: 1.62%. MS m/z(ESI):936.6[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.72(s,1H),7.88-7.70(m,3H),7.60-7.49(m,2H),7.45-7.36(m,2H),6.92(t,J＝9.5Hz,1H),6.67(dd,J＝8.7,3.8Hz,1H),5.17-5.05(m,2H ),4.71(s,2H),4.52(t,J＝8.8Hz,2H),4.25-4.09(m,3H),3.72(s,7H), 3.03-2.52(m,8H),2.03(s,3H),1.82-1.60(m,4H),1.32-1.06(m,8H).

实施例46化合物H46的制备
Example 46 Preparation of Compound H46

步骤1:将3-(2,6-双(苄氧基)吡啶-3-基)-6-溴-1-甲基-1H-吲唑(1g,2.00mmol)和4-(二甲氧基甲基)哌啶(636.41mg,4.00mmol)溶于1,4-二氧六环(15mL)中，氩气保护下加入Pd2(dba)3(183.00mg,199.85μmol)和XPhos(190.54mg,399.69μmol)和Cs2CO3(1.30g,4.00mmol)，升温至100℃搅拌过夜。反应完成后，将反应液浓缩后加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(12g，0～40％EA/PE)，得到H46-a(0.9g,棕色油状物),收率：77.82％。MS m/z(ESI):579.3[M+H]+。Step 1: 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (1 g, 2.00 mmol) and 4-(dimethoxymethyl)piperidine (636.41 mg, 4.00 mmol) were dissolved in 1,4-dioxane (15 mL), Pd 2 (dba) 3 (183.00 mg, 199.85 μmol) and XPhos (190.54 mg, 399.69 μmol) and Cs 2 CO 3 (1.30 g, 4.00 mmol) were added under argon protection, and the temperature was raised to 100° C. and stirred overnight. After the reaction was completed, the reaction solution was concentrated and water and ethyl acetate were added, and the ethyl acetate was extracted three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (12 g, 0-40% EA/PE) to obtain H46-a (0.9 g, brown oil), yield: 77.82%. MS m/z (ESI): 579.3 [M+H] + .

步骤2:将H46-a(0.9g,1.56mmol)溶于CF3CH2OH(20mL)中，加入TFA(212.80mg,1.87mmol)和Pd/C(165.51mg,155.52μmol,10％纯度)，氢气氛围下室温搅拌过夜。反应完成后，将反应液过滤，滤液浓缩后溶于THF中，再用三乙胺调pH值至弱碱性，浓缩后经CombiFlash纯化(12g，0～10％MeOH/DCM)，得到H46-b(0.35g,棕色油状物),收率：56.20％。MS m/z(ESI):401.3[M+H]+。Step 2: H46-a (0.9 g, 1.56 mmol) was dissolved in CF 3 CH 2 OH (20 mL), TFA (212.80 mg, 1.87 mmol) and Pd/C (165.51 mg, 155.52 μmol, 10% purity) were added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated and dissolved in THF, and the pH value was adjusted to weak alkalinity with triethylamine. After concentration, it was purified by CombiFlash (12 g, 0-10% MeOH/DCM) to obtain H46-b (0.35 g, brown oil), yield: 56.20%. MS m/z (ESI): 401.3 [M+H] + .

步骤3:将H46-b(300mg,749.12μmol)溶于DCM(5mL)中，加入氯化氢的1,4-二氧六环溶液(4mol/L，5mL)，室温搅拌20分钟。反应完成后，将反应与浓缩后用二氯甲烷溶解，加入少量的三乙胺，经CombiFlash纯化(4g，0～10％MeOH/DCM)，得到H46-c(0.2g,浅黄色固体),收率：75.33％。MS m/z(ESI):355.2[M+H]+。Step 3: H46-b (300 mg, 749.12 μmol) was dissolved in DCM (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 5 mL) was added, and stirred at room temperature for 20 minutes. After the reaction was completed, the reaction mixture was concentrated and dissolved in dichloromethane, and a small amount of triethylamine was added. Purification by CombiFlash (4 g, 0-10% MeOH/DCM) gave H46-c (0.2 g, light yellow solid), yield: 75.33%. MS m/z (ESI): 355.2 [M+H] + .

步骤4:将H2-f(50mg,88.10μmol)和H46-c(46.83mg,132.15μmol)溶于DMSO(1mL)和EtOH(0.5mL)中，加入NaBH3CN(27.68mg,440.50μmol)和乙酸(10.58mg,176.20μmol)，微波中升温至90℃搅拌45分钟。反应完成后，将反应液浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)纯化，得H46(29.12mg,纯度93.72％),收率：34.19％。MS m/z(ESI):453.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.84(s,1H),8.76(s,2H),8.09(s,1H),7.57(s,1H),7.45(d,J＝8.8Hz,1H),6.98-6.86(m,2H),6.81(s,1H),6.69(dd,J＝8.8,4.0Hz,1H),5.27(d,J＝14.8Hz,1H),4.73(s,2H),4.53(t,J＝8.8Hz,2H),4.39(d,J＝15.2Hz,1H),4.23(dd,J＝9.2,5.2Hz,1H),3.87(s,3H),3.83-3.71(m,3H),3.32-3.28(m,2H),2.92-2.83(m,2H),2.75-2.65(m,2H),2.62-2.53(m,2H),2.40-2.24(m,2H),2.21-2.08(m,4H),1.97-1.84(m,2H),1.83-1.74(m,2H),1.72-1.52(m,2H),1.30-1.15(m,2H),1.08-0.99(m,1H)。Step 4: H2-f (50 mg, 88.10 μmol) and H46-c (46.83 mg, 132.15 μmol) were dissolved in DMSO (1 mL) and EtOH (0.5 mL), and NaBH 3 CN (27.68 mg, 440.50 μmol) and acetic acid (10.58 mg, 176.20 μmol) were added, and the mixture was heated to 90° C. and stirred for 45 minutes in a microwave. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H46 (29.12 mg, purity 93.72%), yield: 34.19%. MS m/z(ESI):453.8[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ10.86(s,1H),8.84(s,1H),8.76(s,2H),8.09(s,1H),7.57(s,1H),7.45(d,J＝8.8Hz,1H),6.98-6.86(m,2H),6.81(s,1H),6. 69(dd,J＝8.8,4.0Hz,1H),5.27(d,J＝14.8Hz,1H),4.73(s,2H),4.53(t,J＝8.8Hz,2H),4.39(d,J＝15.2Hz,1H),4.23(dd,J＝9.2, 5.2Hz,1H),3.87(s,3H),3.83-3.71(m,3H),3.32-3.28(m,2H),2.92-2.83(m,2H),2.75-2.65(m,2H),2.62-2.53(m,2H),2.40- 2.24(m,2H),2.21-2.08(m,4H),1.97-1.84(m,2H),1.83-1.74(m,2H),1.72-1.52(m,2H),1.30-1.15(m,2H),1.08-0.99(m,1H).

实施例47和实施例48化合物H47和化合物H48的制备
Example 47 and Example 48 Preparation of Compound H47 and Compound H48

步骤1:将5-溴-2-(三氟甲基)异烟醛(1.1g,4.33mmol)和4-氨基-3-氟哌啶-1-羧酸叔丁酯(1g,4.58mmol)溶于EtOH(10mL)中，加入CH3COOH(312.08mg,5.20mmol)，室温搅拌18小时，然后降温到0℃，加入NaBH3CN(598.72mg,9.53mmol)，在0℃条件下搅拌2小时。反应完成后，向反应液中加入饱和碳酸氢钠水溶液，浓缩去除有机溶剂，水相用二氯甲烷(80mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H47-a(1.98g,淡黄色油状物,粗品),收率：100.00％。MS m/z(ESI):400.0[M-56+H]+。Step 1: Dissolve 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (1.1 g, 4.33 mmol) and tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (1 g, 4.58 mmol) in EtOH (10 mL), add CH 3 COOH (312.08 mg, 5.20 mmol), stir at room temperature for 18 hours, then cool to 0°C, add NaBH 3 CN (598.72 mg, 9.53 mmol), and stir at 0°C for 2 hours. After the reaction is completed, add saturated sodium bicarbonate aqueous solution to the reaction solution, concentrate to remove the organic solvent, extract the aqueous phase with dichloromethane (80 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain H47-a (1.98 g, light yellow oil, crude product), yield: 100.00%. MS m/z (ESI): 400.0[M-56+H] + .

步骤2:将H47-a(1.98g,4.34mmol)溶于DCM(30mL)中，加入Et3N(1.76g,17.36mmol)和(Boc)2O(1.89g,8.68mmol)，在室温下搅拌18小时。反应完成后，将反应液浓缩后经CombiFlash纯化(12g，0～10％EA/PE)，得到H47-b(2.1g,无色的油状物),收率：86.98％。MS m/z(ESI):444.0[M-56-56+H]+。Step 2: H47-a (1.98 g, 4.34 mmol) was dissolved in DCM (30 mL), Et 3 N (1.76 g, 17.36 mmol) and (Boc) 2 O (1.89 g, 8.68 mmol) were added, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-10% EA/PE) to obtain H47-b (2.1 g, colorless oil), yield: 86.98%. MS m/z (ESI): 444.0 [M-56-56+H] + .

步骤3:将8-溴-5-[(5-氟-2,3-二氢苯并呋喃-4-基)甲基氨基]咪唑并[1,5-c]嘧啶-1-甲酸乙酯(2.2g,5.05mmol)和H47-b(1.65g,2.97mmol)溶于水(10mL)和DME(100mL)中，然后加入Pd(OAc)2(453.92mg,2.02mmol)，CataCXium A(724.91mg,2.02mmol)，K2CO3(3.49g,25.27mmol)和(Pin)2B2(3.21g,12.64mmol)，在70℃条件下搅拌18小时。反应完成后，将反应液过滤，滤饼用二氯甲烷洗涤，滤液浓缩后经CombiFlash纯化(40g，0～50％EA/PE)，得到H47-c(1.4g,淡黄色固体),收率：33.30％。MS m/z(ESI):732.0[M-100+H]+。Step 3: Ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylate (2.2 g, 5.05 mmol) and H47-b (1.65 g, 2.97 mmol) were dissolved in water (10 mL) and DME (100 mL), and then Pd(OAc) 2 (453.92 mg, 2.02 mmol), CataCXium A (724.91 mg, 2.02 mmol), K 2 CO 3 (3.49 g, 25.27 mmol) and (Pin) 2 B 2 (3.21 g, 12.64 mmol) were added and stirred at 70° C. for 18 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with dichloromethane, the filtrate was concentrated and purified by CombiFlash (40 g, 0-50% EA/PE) to obtain H47-c (1.4 g, light yellow solid), yield: 33.30%. MS m/z (ESI): 732.0 [M-100+H] + .

步骤4:将H47-c(2.8g,3.37mmol)溶于DCM(20mL)中，加入HCl/1,4-二氧六环(4mol/L,10.10mL)，在室温下搅拌3小时。反应完成后，将反应与浓缩后得到H47-d(2.13g,淡黄色固体),收率：100.00％。MS m/z(ESI):632.3[M+H]+。Step 4: H47-c (2.8 g, 3.37 mmol) was dissolved in DCM (20 mL), HCl/1,4-dioxane (4 mol/L, 10.10 mL) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated to obtain H47-d (2.13 g, light yellow solid), yield: 100.00%. MS m/z (ESI): 632.3 [M+H] + .

步骤5:将H47-d(2.1g,3.32mmol)溶于DCM(25mL)中，加入(Boc)2O(870.78mg,3.99mmol)和Et3N(336.45mg,3.32mmol)，在室温下搅拌2小时。反应完成后，将反应液浓缩后经CombiFlash纯化(24g，0～40％DCM/EA)，得到H47-e(2.2g,淡黄色固体),收率：90.43％。MS m/z(ESI):733.3[M+H]+。Step 5: H47-d (2.1 g, 3.32 mmol) was dissolved in DCM (25 mL), (Boc) 2 O (870.78 mg, 3.99 mmol) and Et 3 N (336.45 mg, 3.32 mmol) were added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-40% DCM/EA) to obtain H47-e (2.2 g, light yellow solid), yield: 90.43%. MS m/z (ESI): 733.3 [M+H] + .

步骤6:将H47-e(2.4g,3.28mmol)溶于THF(30mL)和水(10mL)中，加入LiOH(500mg,20.88mmol)，在80℃下搅拌18小时。反应完成后，将反应液浓缩后用稀盐酸(1mol/L)调pH＝5-6，过滤，滤饼经过真空干燥得到H47-f(1.7g,黄色固体),收率：73.66％。MS m/z(ESI):704.3[M+H]+。Step 6: H47-e (2.4 g, 3.28 mmol) was dissolved in THF (30 mL) and water (10 mL), LiOH (500 mg, 20.88 mmol) was added, and the mixture was stirred at 80°C for 18 hours. After the reaction was completed, the reaction solution was concentrated and adjusted to pH 5-6 with dilute hydrochloric acid (1 mol/L), filtered, and the filter cake was vacuum dried to obtain H47-f (1.7 g, yellow solid), yield: 73.66%. MS m/z (ESI): 704.3 [M+H] + .

步骤7:将H47-f(1.7g,2.42mmol)溶于DMF(10mL)中，加入Et3N(2.44g,24.16mmol)和HATU(1.82g,4.83mmol)，在室温下搅拌1小时。反应完成后，将反应液浓缩后经CombiFlash纯化(24g，0～10％MeOH/DCM)，得到H47-g(320mg,淡黄色固体),收率：19.32％。MS m/z(ESI):630.2[M-56+H]+。Step 7: H47-f (1.7 g, 2.42 mmol) was dissolved in DMF (10 mL), Et 3 N (2.44 g, 24.16 mmol) and HATU (1.82 g, 4.83 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H47-g (320 mg, light yellow solid), yield: 19.32%. MS m/z (ESI): 630.2 [M-56+H] + .

步骤8:将H47-g(320mg,466.72μmol)溶于MeOH(1mL)和DCM(12mL)中，加入HCl/1,4-二氧六环(4mol/L,2mL)，在室温下搅拌4小时。反应完成后，反应液用饱和碳酸氢钠水溶液中和，二氯甲烷(80mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H47-h(270mg,淡黄色固体),收率：98.80％。MS m/z(ESI):586.2[M+H]+。Step 8: H47-g (320 mg, 466.72 μmol) was dissolved in MeOH (1 mL) and DCM (12 mL), HCl/1,4-dioxane (4 mol/L, 2 mL) was added, and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was neutralized with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (80 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain H47-h (270 mg, light yellow solid), yield: 98.80%. MS m/z (ESI): 586.2 [M+H] + .

步骤9:将H47-h(450mg,768.54μmol)和H39-b(413.33mg,1.12mmol)溶于DCM(20mL)中，加入NaBH(OAc)3(488.65mg,2.31mmol)，在室温下搅拌3小时。反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2×250mm C18柱；体系：水+0.04％FA，乙腈；波长：254/214nm；梯度：40％-70％乙腈变化)，得到H47(50.26mg)，MS m/z(ESI):470.7[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.79(d,J＝18.2Hz,3H),7.86(s,1H),7.58(d,J＝10.3Hz,1H),6.98-6.86(m,2H),6.82(s,1H),6.69(d,J＝5.3Hz,1H),6.63(d,J＝8.7Hz,1H),5.32-5.19(m,2H),4.75(s,3H),4.68-4.33(m,5H),3.57(s,2H),3.30(s,3H),3.07(s,2H),2.96-2.78(m,2H),2.63(dd,J＝23.2,12.8Hz,4H),2.23(s,5H),1.98(d,J＝7.1Hz,1H),1.81(s,2H),1.62(s,2H),1.26(s,2H)；和H48(49.09mg)，MS m/z(ESI):470.7[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.81(dd,J＝12.4,8.2Hz,3H),8.00(s,1H),7.58(d,J＝10.3Hz,1H),6.98-6.87(m,2H),6.82(s,1H),6.69(dd,J＝8.5,3.9Hz,1H),6.63(d,J＝9.0Hz,1H),5.26(dd,J＝18.2,10.4Hz,2H),4.76(d,J＝14.2Hz,3H),4.66-4.38(m,4H),3.58(d,J＝11.5Hz,2H),3.29(s,3H),3.20(d,J＝16.8Hz,1H),3.09-2.81(m,3H),2.78-2.51(m,5H),2.15(dd,J＝33.8,19.6Hz,4H),1.98(d,J＝6.1Hz,1H),1.81(s,2H),1.59(d,J＝20.8Hz,3H),1.26(s,2H)。Step 9: H47-h (450 mg, 768.54 μmol) and H39-b (413.33 mg, 1.12 mmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (488.65 mg, 2.31 mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: water + 0.04% FA, acetonitrile; wavelength: 254/214 nm; gradient: 40%-70% acetonitrile change) to obtain H47 (50.26 mg), MS m/z (ESI): 470.7 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),8.79(d,J＝18.2Hz,3H),7.86(s,1H),7.58(d,J＝10.3Hz,1H),6.98-6.86(m,2H), 6.82(s,1H),6.69(d,J＝5.3Hz,1H),6.63(d,J＝8.7Hz,1H),5.32-5.19(m,2H),4.75(s,3H),4.68-4 .33(m,5H),3.57(s,2H),3.30(s,3H),3.07(s,2H),2.96-2.78(m,2H),2.63(dd,J＝23.2,12.8Hz,4 H), 2.23 (s, 5H), 1.98 (d, J = 7.1Hz, 1H), 1.81 (s, 2H), 1.62 (s, 2H), 1.26 (s, 2H); and H48 (49.09mg), MS m/z(ESI):470.7[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),8.81(dd,J＝12.4,8.2Hz,3H),8.00(s,1H),7.58(d,J＝10.3Hz,1H),6.98-6.87(m,2H),6.82(s, 1H),6.69(dd,J＝8.5,3.9Hz,1H),6.63(d,J＝9.0Hz,1H),5.26(dd,J＝18.2,10.4Hz,2H),4.76(d,J＝14.2Hz,3H), 4.66-4.38(m,4H),3.58(d,J＝11.5Hz,2H),3.29(s,3H),3.20(d,J＝16.8Hz,1H),3.09-2.81(m,3H),2.78-2.51( m, 5H), 2.15 (dd, J = 33.8, 19.6Hz, 4H), 1.98 (d, J = 6.1Hz, 1H), 1.81 (s, 2H), 1.59 (d, J = 20.8Hz, 3H), 1.26 (s, 2H).

实施例49化合物H49的制备
Example 49 Preparation of Compound H49

步骤1:将3-氟异烟醛(12g,95.92mmol)溶于甲苯(200mL)中，加入PTSA(1.65g,9.59mmol)和MeOH(19.98g,575.54mmol,25.22mL)，在120℃下回流搅拌18小时。反应完成后，反应液冷却至室温，用饱和碳酸氢钠水溶液淬灭，二氯甲烷(300mL×2)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(120g，0～50％EA/PE)，得到H49-a(11.3g,无色的油状物),收率：68.82％。MS m/z(ESI):172.1[M+H]+。Step 1: 3-Fluoroisonicotinaldehyde (12 g, 95.92 mmol) was dissolved in toluene (200 mL), PTSA (1.65 g, 9.59 mmol) and MeOH (19.98 g, 575.54 mmol, 25.22 mL) were added, and the mixture was refluxed and stirred at 120°C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (300 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-50% EA/PE) to obtain H49-a (11.3 g, colorless oil), yield: 68.82%. MS m/z (ESI): 172.1 [M+H] + .

步骤2:将H49-a(11.3g,66.02mmol)溶于丙酮(100mL)中，加入BnBr(12.98g,75.92mmol)，在70℃下搅拌18小时。反应完成后，将反应液浓缩后加入乙酸乙酯(70ml)打浆，过滤，滤饼经真空干燥得到H49-b(16g,白色固体,HBr),收率：70.62％。MS m/z(ESI):262.1[M-Br]+。Step 2: H49-a (11.3 g, 66.02 mmol) was dissolved in acetone (100 mL), BnBr (12.98 g, 75.92 mmol) was added, and the mixture was stirred at 70°C for 18 hours. After the reaction was completed, the reaction solution was concentrated and ethyl acetate (70 ml) was added for slurrying, filtered, and the filter cake was vacuum dried to obtain H49-b (16 g, white solid, HBr), yield: 70.62%. MS m/z (ESI): 262.1 [M-Br] + .

步骤3:将H49-b(15g,57.19mmol,HBr)溶于MeOH(120mL)中，降低温度到0℃，分批加入NaBH4(4.33g,114.37mmol)，在0℃条件下搅拌4小时。反应完成后，将反应液浓缩后加入水(100mL)，用乙酸乙酯(300mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(60g，0～100％PE/DCM+1％Et3N)，得到H49-c(11.7g,无色的油状物),收率：77.11％。MS m/z(ESI):266.2[M+H]+。Step 3: H49-b (15 g, 57.19 mmol, HBr) was dissolved in MeOH (120 mL), the temperature was lowered to 0°C, NaBH 4 (4.33 g, 114.37 mmol) was added in batches, and the mixture was stirred at 0°C for 4 hours. After the reaction was completed, the reaction solution was concentrated and water (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (60 g, 0-100% PE/DCM+1% Et 3 N) to obtain H49-c (11.7 g, colorless oil), yield: 77.11%. MS m/z (ESI): 266.2 [M+H] + .

步骤4:将H49-c(11.7g,44.10mmol)溶于EtOH(120mL)中，加入PdOH/C(10.89g,20％纯度)和甲酸铵(55.61g,881.95mmol)，在90℃下搅拌18小时。反应完成后，将反应液通过硅藻土过滤，滤液浓缩后得到H49-d(5.5g,粘稠油状物),收率：70.38％。MS m/z(ESI):178.1[M+H]+。Step 4: H49-c (11.7 g, 44.10 mmol) was dissolved in EtOH (120 mL), PdOH/C (10.89 g, 20% purity) and ammonium formate (55.61 g, 881.95 mmol) were added, and stirred at 90°C for 18 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain H49-d (5.5 g, viscous oil), yield: 70.38%. MS m/z (ESI): 178.1 [M+H] + .

步骤5:将H49-d(1g,2.96mmol)，3-(5-溴-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮(890.91mg,5.03mmol)，Ruphos(275.99mg,591.44μmol)和Ruphos-Pd-G3(495.26mg,591.44μmol)溶于甲苯(40mL)中，然后在氮气保护下加入LiHMDS(1mol/L，THF溶液,14.79mmol,14.79mL)，在80℃下搅拌2小时。反应完成后，将反应液倒入水(50mL)中，用乙酸乙酯(100mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(24g，0～10％MeOH/DCM)，得到H49-e(380mg,淡黄色固体),收率：29.58％。MS m/z(ESI):435.2[M+H]+。Step 5: H49-d (1 g, 2.96 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (890.91 mg, 5.03 mmol), Ruphos (275.99 mg, 591.44 μmol) and Ruphos-Pd-G3 (495.26 mg, 591.44 μmol) were dissolved in toluene (40 mL), and LiHMDS (1 mol/L, THF solution, 14.79 mmol, 14.79 mL) was added under nitrogen protection, and the mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (24 g, 0-10% MeOH/DCM) to obtain H49-e (380 mg, light yellow solid), yield: 29.58%. MS m/z (ESI): 435.2 [M+H] + .

步骤6:将H49-e(146.05mg,336.16μmol)溶于甲酸(8.54g,185.55mmol,7.00mL)中，在50℃条件下搅拌2小时。反应完成后，将反应液浓缩后得到H49-f(130mg,红色粘稠产物),收率：99.57％。MS m/z(ESI):389.2[M+H]+。Step 6: H49-e (146.05 mg, 336.16 μmol) was dissolved in formic acid (8.54 g, 185.55 mmol, 7.00 mL) and stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H49-f (130 mg, red viscous product), yield: 99.57%. MS m/z (ESI): 389.2 [M+H] + .

步骤7:将H2-f(100mg,176.20μmol)和H49-f(130mg,334.71μmol)溶于DCM(20mL)中，加入NaBH(OAc)3(224.06mg,1.06mmol)，在室温下搅拌18小时。反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2×250mm C18柱；体系：水+0.04％FA，乙腈；波长：254/214nm；梯度：40％-70％乙腈变化)，得到H49(3.94mg),收率：2.24％。MS m/z(ESI):470.7[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.85(s,1H),8.78(s,2H),8.26(s,1H),8.11(s,1H),7.59(s,1H),6.99-6.88(m,2H),6.82(s,1H),6.69(dd,J＝8.6,3.7Hz,1H),6.61(d,J＝8.3Hz,1H),5.28(d,J＝15.6Hz,2H),4.79(dd,J＝37.6,26.6Hz,3H),4.53(t,J＝8.8Hz,2H),4.40(d,J＝14.7Hz,1H),3.81(d,J＝11.0Hz,2H),3.62(d,J＝10.6Hz,1H),3.29(s,3H),2.97-2.80(m,4H),2.79-2.54(m,5H),2.43-2.28(m,2H),2.24-2.11(m,2H),2.04-1.86(m,3H),1.61(s,3H),1.05(s,1H)。Step 7: H2-f (100 mg, 176.20 μmol) and H49-f (130 mg, 334.71 μmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (224.06 mg, 1.06 mmol) was added, and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: water + 0.04% FA, acetonitrile; wavelength: 254/214 nm; gradient: 40%-70% acetonitrile change) to obtain H49 (3.94 mg), yield: 2.24%. MS m/z (ESI): 470.7 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),8.85(s,1H),8.78(s,2H),8.26(s,1H),8.11(s,1H),7.59(s,1H),6.99-6.88(m,2H),6.82(s,1H ),6.69(dd,J＝8.6,3.7Hz,1H),6.61(d,J＝8.3Hz,1H),5.28(d,J＝15.6Hz,2H),4.79(dd,J＝37.6,26.6Hz,3H),4.5 3(t,J＝8.8Hz,2H),4.40(d,J＝14.7Hz,1H),3.81(d,J＝11.0Hz,2H),3.62(d,J＝10.6Hz,1H),3.29(s,3H),2.97-2. 80(m,4H),2.79-2.54(m,5H),2.43-2.28(m,2H),2.24-2.11(m,2H),2.04-1.86(m,3H),1.61(s,3H),1.05(s,1H).

实施例51化合物H51的制备
Example 51 Preparation of Compound H51

步骤1:化合物3,3-二氟-4-(羟甲基)哌啶-1-甲酸叔丁酯(1.0g,3.98mmol)溶解在DCM(20mL)中，室温搅拌下加入氯化氢乙酸乙酯溶液(4.0mol/L,10mL)，室温搅拌2小时。反应完成后，将反应液浓缩得到H51-a(601.56mg,黄色固体),收率：100.00％。MS m/z(ESI):152[M+H]+。Step 1: Compound 3,3-difluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.98 mmol) was dissolved in DCM (20 mL), and hydrogen chloride ethyl acetate solution (4.0 mol/L, 10 mL) was added under stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H51-a (601.56 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 152 [M+H] + .

步骤2:将H51-a(601.56mg,3.98mmol)溶解在DCM(20mL)中，室温搅拌加入TEA(1.21g,11.94mmol)，室温搅拌30分钟，降温至0℃，加入氯甲酸苄酯(678.92mg,3.98mmol)，0℃下搅拌2小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(EA:PE＝0～50％)，得到H51-b(1.0g,黄色固体),收率：88.08％。MS m/z(ESI):286[M+H]+。Step 2: H51-a (601.56 mg, 3.98 mmol) was dissolved in DCM (20 mL), TEA (1.21 g, 11.94 mmol) was added with stirring at room temperature, stirred at room temperature for 30 minutes, cooled to 0°C, benzyl chloroformate (678.92 mg, 3.98 mmol) was added, and stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (EA:PE = 0-50%) to obtain H51-b (1.0 g, yellow solid), yield: 88.08%. MS m/z (ESI): 286 [M+H] + .

步骤3:将H51-b(1.0g,3.51mmol)溶解在DCM(20mL)中，室温搅拌加入(1,1-二乙酰氧基-3-氧代-1,2-苯并氧醇-1-基)乙酸酯(1.78g,4.21mmol)，室温搅拌2小时。反应完成后，将反应液过滤，滤液浓缩后经硅胶柱层析纯化(EA:PE＝0～50％)，得到H51-c(850mg,黄色固体),收率：85.60％。MS m/z(ESI):284[M+H]+。Step 3: H51-b (1.0 g, 3.51 mmol) was dissolved in DCM (20 mL), and (1,1-diacetoxy-3-oxo-1,2-benzoxylan-1-yl) acetate (1.78 g, 4.21 mmol) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (EA:PE=0-50%) to obtain H51-c (850 mg, yellow solid), yield: 85.60%. MS m/z (ESI): 284 [M+H] + .

步骤4:将H51-c(850mg,3.00mmol)溶解在MeOH(20mL)中，室温搅拌下加入三甲氧基甲烷(1.59g,15.00mmol)，p-TSOH(25.84mg,0.15mmol)，室温搅拌过夜。反应完车后，将反应液浓缩后经硅胶柱层析纯化(EA:PE＝0～50％)，得到H51-d(800mg,黄色油状物),收率：81％。MS m/z(ESI):330[M+H]+。Step 4: H51-c (850 mg, 3.00 mmol) was dissolved in MeOH (20 mL), and trimethoxymethane (1.59 g, 15.00 mmol) and p-TSOH (25.84 mg, 0.15 mmol) were added under stirring at room temperature, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (EA: PE = 0-50%) to obtain H51-d (800 mg, yellow oil), yield: 81%. MS m/z (ESI): 330 [M+H] + .

步骤5:将H51-d(830mg,2.52mmol)溶解在MeOH(20mL)中，加入Pd/C(576.39mg,541.62μmol,10％纯度)，氢气氛围下室温搅拌2小时。反应完成后，将反应液过滤，滤液浓缩得到H51-e(300mg,无色油状物),收率：60.98％。MS m/z(ESI):196[M+H]+.Step 5: H51-d (830 mg, 2.52 mmol) was dissolved in MeOH (20 mL), Pd/C (576.39 mg, 541.62 μmol, 10% purity) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain H51-e (300 mg, colorless oil), yield: 60.98%. MS m/z (ESI): 196 [M+H] + .

步骤6-步骤8参照实施例39的制备方法，按照上述合成路线制备得到H51，MS m/z(ESI):958[M+H]+。Step 6-Step 8: Referring to the preparation method of Example 39, H51 was prepared according to the above synthetic route, MS m/z (ESI): 958 [M+H] + .

实施例56化合物H56的制备
Example 56 Preparation of Compound H56

步骤1-步骤5参照实施例88的制备方法，按照上述合成路线制备得到H56-e。MS m/z(ESI):545.3[M+H]+。Step 1 to Step 5 refer to the preparation method of Example 88, and prepare H56-e according to the above synthetic route. MS m/z (ESI): 545.3 [M+H] + .

步骤6:将H56-e(300mg,550.84μmol)溶于MeOH(3mL)中加入甲醇钠的甲醇溶液(30wt％，3mL)，85℃反应16h。反应完成后，向反应液中加水，DCM:MeOH＝10:1萃取2次，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash(4g，0～50％MeOH/DCM)纯化，得到H56-f(80mg,黄色固体，收率：29.13％)。MS m/z(ESI):499.2[M+H]+。Step 6: H56-e (300 mg, 550.84 μmol) was dissolved in MeOH (3 mL) and a methanol solution of sodium methoxide (30 wt%, 3 mL) was added, and the mixture was reacted at 85°C for 16 h. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted twice with DCM:MeOH=10:1. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (4 g, 0-50% MeOH/DCM) to obtain H56-f (80 mg, yellow solid, yield: 29.13%). MS m/z (ESI): 499.2 [M+H] + .

步骤7:将H56-f(25mg,50.15μmol)和H39-b(27.86mg,75.22μmol)溶于EtOH(0.5mL)和DMSO(1mL)中，微波下升温至85℃搅拌30min，然后加入NaBH(OAc)3(31.88mg,150.44μmol)，最后微波下升温至85℃搅拌30min。反应完成后，将反应液浓缩后经CombiFlash(4g，0～12％MeOH/DCM)初步纯化，再经制备HPLC纯化(制备柱：21.2×250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95乙腈变化)，得到H56(1.9mg,纯度95.3％),收率：4.23％。MS m/z(ESI):427.3[M/2+H]+。1HNMR(400MHz,DMSO-d6)δ11.05(s,1H),8.73(s,1H),8.51(t,J＝5.1Hz,1H),7.54-7.45(m,2H),7.45-7.32(m,3H),6.97-6.88(m,2H),6.80(d,J＝2.1Hz,1H),6.68(dd,J＝8.7,3.8Hz,1H),6.61(dd,J＝8.6,2.2Hz,1H),5.26(dd,J＝13.0,5.4Hz,1H),5.11(d,J＝15.0Hz,1H),4.71(d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.21(d,J＝15.1Hz,1H),3.76(s,1H),3.57(d,J＝11.8Hz,2H),3.28(s,3H),2.85(d,J＝13.9Hz,3H),2.73-2.53(m,4H),2.32(d,J＝10.9Hz,1H),2.15(s,3H),2.02-1.86(m,3H),1.78(d,J＝12.4Hz,2H),1.60(s,2H),1.23(d,J＝8.8Hz,4H),1.12(d,J＝11.3Hz,1H)。Step 7: H56-f (25 mg, 50.15 μmol) and H39-b (27.86 mg, 75.22 μmol) were dissolved in EtOH (0.5 mL) and DMSO (1 mL), heated to 85°C and stirred for 30 min under microwave, then NaBH(OAc) 3 (31.88 mg, 150.44 μmol) was added, and finally heated to 85°C and stirred for 30 min under microwave. After the reaction was completed, the reaction solution was concentrated and initially purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H56 (1.9 mg, purity 95.3%), yield: 4.23%. MS m/z (ESI): 427.3 [M/2+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),8.73(s,1H),8.51(t,J＝5.1Hz,1H),7.54-7.45(m,2H),7.45-7.32(m,3H),6.97-6.88(m,2H),6.80(d,J＝2.1Hz,1H),6.6 8(dd,J＝8.7,3.8Hz,1H),6.61(dd,J＝8.6,2.2Hz,1H),5.26(dd,J＝13.0,5.4Hz,1H),5.11(d,J＝15.0Hz,1H),4.71(d,J＝4.9Hz,2H),4.53( t,J＝8.8Hz,2H),4.21(d,J＝15.1Hz,1H),3.76(s,1H),3.57(d,J＝11.8Hz,2H),3.28(s,3H),2.85(d,J＝13.9Hz,3H),2.73-2.53(m,4H),2. 32(d,J＝10.9Hz,1H),2.15(s,3H),2.02-1.86(m,3H),1.78(d,J＝12.4Hz,2H),1.60(s,2H),1.23(d,J＝8.8Hz,4H),1.12(d,J＝11.3Hz,1H).

实施例61化合物H61的制备
Example 61 Preparation of Compound H61

参照实施例39的制备方法，按照上述合成路线，制备得到化合物H61，其制备HPLC纯化条件为：waters-sunfire-10um-19×150mm柱(流动相:28％-38％(v/v)乙腈和甲酸/水。MS m/z(ESI):962[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.83(s,1H),8.76(d,J＝8.3Hz,2H),7.87(s,1H),7.60(s,1H),7.03-6.86(m,2H),6.80(s,1H),6.69(dd,J＝8.7,3.8Hz,1H),6.61(d,J＝8.3Hz,1H),5.35-5.16(m,2H),4.74(d,J＝4.8Hz,2H),4.55(d,J＝8.8Hz,2H),4.37(d,J＝14.9Hz,1H),4.25(t,J＝8.7Hz,1H),3.55(d,J＝11.7Hz,2H),3.28(s,3H),2.87(s,1H),2.73-2.53(m,4H),2.38-1.89(m,11H),1.76(d,J＝12.6Hz,2H),1.60(s,5H),1.20(d,J＝10.5Hz,4H)。Referring to the preparation method of Example 39, compound H61 was prepared according to the above synthetic route. The preparative HPLC purification conditions were: waters-sunfire-10um-19×150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid/water). MS m/z (ESI): 962 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),8.83(s,1H),8.76(d,J＝8.3Hz,2H),7.87(s,1H),7.60(s,1H),7.03-6.86(m,2H),6.80(s ,1H),6.69(dd,J＝8.7,3.8Hz,1H),6.61(d,J＝8.3Hz,1H),5.35-5.16(m,2H),4.74(d,J＝4.8Hz,2H),4.55(d ,J＝8.8Hz,2H),4.37(d,J＝14.9Hz,1H),4.25(t,J＝8.7Hz,1H),3.55(d,J＝11.7Hz,2H),3.28(s,3H),2.87(s ,1H),2.73-2.53(m,4H),2.38-1.89(m,11H),1.76(d,J＝12.6Hz,2H),1.60(s,5H),1.20(d,J＝10.5Hz,4H).

实施例62化合物H62的制备
Example 62 Preparation of Compound H62

步骤1：将H31-e(50mg,82.29μmol)和H46-c(46.66mg,131.67μmol)溶于DMSO(1.5mL)和EtOH(0.6mL)中，加入AcOH(9.88mg,164.58μmol)，微波下升温至90℃搅拌30分钟。然后加入NaBH3CN(51.71mg,822.91μmol)，最后微波下升温至90℃搅拌20分钟。反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)，得H62(28.14mg,纯度100％),收率：36.15％。MS m/z(ESI):473.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.83(s,1H),8.76(d,J＝8.0Hz,2H),7.86(s,1H),7.60(s,1H),7.45(d,J＝8.8Hz,1H),6.93(dd,J＝10.4,8.4Hz,1H),6.90-6.85(m,1H),6.80(s,1H),6.69(dd,J＝8.8,4.0Hz,1H),5.22(d,J＝15.2Hz,1H),4.73(d,J＝4.8Hz,2H),4.53(t,J＝8.8Hz,2H),4.36(d,J＝15.2Hz,1H),4.32-4.19(m,2H),3.86(s,3H),3.75(d,J＝12.0Hz,2H),3.34(s,1H),2.69(t,J＝12.0Hz,2H),2.59(q,J＝6.8,6.0Hz,2H),2.33-1.97(m,12H),1.77(d,J＝12.4Hz,2H),1.66-1.51(m,5H),1.20(d,J＝10.4Hz,2H)。Step 1: H31-e (50 mg, 82.29 μmol) and H46-c (46.66 mg, 131.67 μmol) were dissolved in DMSO (1.5 mL) and EtOH (0.6 mL), AcOH (9.88 mg, 164.58 μmol) was added, and the mixture was heated to 90°C and stirred for 30 minutes under microwave. Then NaBH 3 CN (51.71 mg, 822.91 μmol) was added, and the mixture was heated to 90°C and stirred for 20 minutes under microwave. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O -acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change) to obtain H62 (28.14mg, purity 100%), yield: 36.15%. MS m/z (ESI): 473.8 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ10.84(s,1H),8.83(s,1H),8.76(d,J＝8.0Hz,2H),7.86(s,1H),7.60(s,1H),7.45(d,J＝8.8Hz,1H),6.93(dd,J＝10.4,8.4 Hz,1H),6.90-6.85(m,1H),6.80(s,1H),6.69(dd,J＝8.8,4.0Hz,1H),5.22(d,J＝15.2Hz,1H),4.73(d,J＝4.8Hz,2H),4.53(t ,J＝8.8Hz,2H),4.36(d,J＝15.2Hz,1H),4.32-4.19(m,2H),3.86(s,3H),3.75(d,J＝12.0Hz,2H),3.34(s,1H),2.69(t,J＝12. 0Hz, 2H), 2.59 (q, J = 6.8, 6.0Hz, 2H), 2.33-1.97 (m, 12H), 1.77 (d, J = 12.4Hz, 2H), 1.66-1.51 (m, 5H), 1.20 (d, J = 10.4Hz, 2H).

实施例65化合物H65的制备
Example 65 Preparation of Compound H65

步骤1:将化合物6-溴-5-氟-3-碘-1-甲基-1H-吲唑(1239mg，3.5mmol)，2,6-双(苄氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂硼烷-2-基)吡啶(1460mg，3.5mmol)，Pd(dppf)Cl2(120mg，0.16mmol)，Cs2CO3(3.41g，10.47mmol)依次加入到1,4-二氧六环(10mL)中，然后加入水(2mL)，置换氮气三次，加热到110℃搅拌反应15小时。反应完成后倒入水中，乙酸乙酯萃取(30mL×3)，合并有机相经饱和氯化钠洗涤(50mL×1)，浓缩后经硅胶柱层析纯化(PE/EA＝0-50％)得H65-a(1036mg),收率:57％。MS m/z(ESI):518[M+H]+。Step 1: Compound 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1239 mg, 3.5 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (1460 mg, 3.5 mmol), Pd(dppf)Cl 2 (120 mg, 0.16 mmol), and Cs 2 CO 3 (3.41 g, 10.47 mmol) were added to 1,4-dioxane (10 mL) in sequence, and then water (2 mL) was added, nitrogen was replaced three times, and the mixture was heated to 110° C. and stirred for 15 hours. After the reaction was completed, the mixture was poured into water and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride (50 mL×1), concentrated, and purified by silica gel column chromatography (PE/EA=0-50%) to obtain H65-a (1036 mg), yield: 57%. MS m/z (ESI): 518 [M+H] + .

步骤2:将H65-a(1036mg，2mmol)加入到MeOH(5mL)中，然后加入Pd/C(200mg，10wt％)，氢气氛围下室温搅拌反应3小时。反应完成后，过滤，滤液浓缩得到H65-b(680mg)，收率:100％。MS m/z(ESI):340[M+H]+。Step 2: H65-a (1036 mg, 2 mmol) was added to MeOH (5 mL), and then Pd/C (200 mg, 10 wt%) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain H65-b (680 mg), with a yield of 100%. MS m/z (ESI): 340 [M+H] + .

步骤3:将H65-b(680mg，2mmol)、4-(二甲氧基甲基)哌啶(477mg，3mmol)、Ruphos-Pd-G3(340mg，0.41mmol)和Cs2CO3(1952mg，6mmol)依次加入到1,4-二氧六环(10mL)中，置换氮气三次后加热120℃搅拌反应15小时。反应完成后倒入水中，然后用乙酸乙酯萃取(30mL×3)，合并有机相并用饱和食盐水洗涤(50mL×1)，浓缩后经硅胶柱层析纯化(PE/EA＝0-100％)，得H65-c(84mg)，收率:10％。MS m/z(ESI):419[M+H]+。Step 3: H65-b (680 mg, 2 mmol), 4-(dimethoxymethyl)piperidine (477 mg, 3 mmol), Ruphos-Pd-G3 (340 mg, 0.41 mmol) and Cs 2 CO 3 (1952 mg, 6 mmol) were added to 1,4-dioxane (10 mL) in sequence, and the nitrogen was replaced three times, and then heated at 120°C and stirred for 15 hours. After the reaction was completed, it was poured into water, and then extracted with ethyl acetate (30 mL×3), the organic phases were combined and washed with saturated brine (50 mL×1), concentrated, and purified by silica gel column chromatography (PE/EA=0-100%) to obtain H65-c (84 mg), yield: 10%. MS m/z (ESI): 419 [M+H] + .

步骤4:将H65-c(84mg，0.2mmol)加入到DCM(5mL)中，然后加入TFA(2mL)，室温搅拌反应1小时。反应完成后，浓缩得到H65-d(74.5mg)，收率:100％。MS m/z(ESI):373[M+H]+。Step 4: H65-c (84 mg, 0.2 mmol) was added to DCM (5 mL), and then TFA (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, H65-d (74.5 mg) was obtained by concentration, with a yield of 100%. MS m/z (ESI): 373 [M+H] + .

步骤5:将H2-f(113mg，0.2mmol)加入到DMSO(5mL)中，加入3滴乙酸和H65-d(74.5mg，0.2mmol)，微波加热90℃反应1小时，然后加入NaBH(OAc)3(100mg)，继续微波加热90℃反应1小时。反应完成后，经制备HPLC纯化(waters-sunfire-10um-19*150mm柱(流动相:28％-38％(v/v)乙腈和甲酸/水)，H65(2mg)，产率:10.5％。MS m/z(ESI):924[M+H]+。1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.85(s,1H),8.78(d,J＝4.4Hz,2H),8.10(s,1H),7.58(s,1H),7.42(d,J＝12.5Hz,1H),7.08(d,J＝7.1Hz,1H),6.94(dd,J＝10.3,8.7Hz,1H),6.69(dd,J＝8.6,3.8Hz,1H),5.27(d,J＝14.9Hz,1H),4.74(d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.41(d,J＝15.0Hz,1H),4.25(dd,J＝9.7,5.1Hz,1H),3.92(s,3H),3.82(d,J＝12.4Hz,1H),2.89(s,2H),2.74-2.56(m,4H),2.41-2.26(m,2H),2.25-2.06(m,4H),2.04-1.75(m,5H),1.61(t,J＝15.6Hz,2H),1.39-1.14(m,4H),1.12-0.75(m,2H)。Step 5: H2-f (113 mg, 0.2 mmol) was added to DMSO (5 mL), 3 drops of acetic acid and H65-d (74.5 mg, 0.2 mmol) were added, microwave heating was carried out at 90°C for 1 hour, and then NaBH(OAc) 3 (100 mg) was added, and microwave heating was continued at 90°C for 1 hour. After the reaction was completed, it was purified by preparative HPLC (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid/water), H65 (2 mg), yield: 10.5%. MS m/z (ESI): 924 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),8.85(s,1H),8.78(d,J＝4.4Hz,2H),8.10(s,1H),7.58(s,1H),7.42(d,J＝12.5Hz,1H),7.08(d,J＝7.1Hz,1H ),6.94(dd,J＝10.3,8.7Hz,1H),6.69(dd,J＝8.6,3.8Hz,1H),5.27(d,J＝14.9Hz,1H),4.74(d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz ,2H),4.41(d,J＝15.0Hz,1H),4.25(dd,J＝9.7,5.1Hz,1H),3.92(s,3H),3.82(d,J＝12.4Hz,1H),2.89(s,2H),2.74-2.56(m, 4H),2.41-2.26(m,2H),2.25-2.06(m,4H),2.04-1.75(m,5H),1.61(t,J＝15.6Hz,2H),1.39-1.14(m,4H),1.12-0.75(m,2H).

实施例66化合物H66的制备
Example 66 Preparation of Compound H66

步骤1:将化合物3-(5-溴-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮(1011mg，3mmol)、3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯(1524mg，6mmol)、Ruphos-Pd-G3(450mg，0.54mmol)和Cs2CO3(2928mg，1.5mmol)依次加入到1,4-二氧六环(15mL)中，置换氮气三次后加热至120℃搅拌反应15小时。反应完成后，将反应液倒入水中，用乙酸乙酯萃取(30mL×3)，合并有机相经饱和食盐水洗涤(50mL×1)，经硅胶柱层析纯化(PE/EA＝0-100％)，得到H66-a(100mg)。产率:6.7％。MS m/z(ESI):512[M+H]+。Step 1: Compound 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1011 mg, 3 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1524 mg, 6 mmol), Ruphos-Pd-G3 (450 mg, 0.54 mmol) and Cs 2 CO 3 (2928 mg, 1.5 mmol) were added to 1,4-dioxane (15 mL) in sequence, and the nitrogen was replaced three times and then heated to 120° C. and stirred for 15 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (30 mL×3), the combined organic phases were washed with saturated brine (50 mL×1), and purified by silica gel column chromatography (PE/EA=0-100%) to obtain H66-a (100 mg). Yield: 6.7%. MS m/z (ESI): 512 [M+H] + .

步骤2:将H66-a(100mg，0.2mmol)加入到DCM(5mL)中，加入TFA(2mL)，室温搅拌反应1小时。反应完成后，浓缩得到H66-b(82mg)。产率:100％。MS m/z(ESI):412[M+H]+。Step 2: Add H66-a (100 mg, 0.2 mmol) to DCM (5 mL), add TFA (2 mL), and stir at room temperature for 1 hour. After the reaction is completed, concentrate to obtain H66-b (82 mg). Yield: 100%. MS m/z (ESI): 412 [M+H] + .

步骤3:将H66-b(100mg，0.2mmol)加入到DMF(5mL)中，加入DIPEA(1mL)和HATU(76mg，0.2mmol)，室温搅拌反应10分钟后加入H10-a(82mg，0.2mmol)继续反应1小时。反应完成后，将反应液经制备HPLC纯化(waters-sunfire-10um-19*150mm柱(流动相:28％-38％(v/v)乙腈和甲酸/水)，得到H66(2mg)。产率:1％。MS m/z(ESI):895[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.58(s,1H),8.40(s,1H),7.61-7.48(m,2H),7.45-7.34(m,2H),7.01-6.88(m,2H),6.82(d,J＝2.2Hz,1H),6.66(ddd,J＝20.9,8.7,3.0Hz,2H),5.27(dd,J＝12.9,5.4Hz,1H),5.13(d,J＝15.0Hz,1H),4.72(d,J＝4.5Hz,2H),4.53(t,J＝8.8Hz,2H),4.27-4.01(m,2H),3.64(d,J＝52.6Hz,4H),3.09(s,4H),2.87(t,J＝14.0Hz,2H),2.74-2.51(m,3H),2.04-1.84(m,1H),1.55(d,J＝75.1Hz,9H),1.35-0.93(m,8H)。Step 3: H66-b (100 mg, 0.2 mmol) was added to DMF (5 mL), and DIPEA (1 mL) and HATU (76 mg, 0.2 mmol) were added. After stirring at room temperature for 10 minutes, H10-a (82 mg, 0.2 mmol) was added and the reaction was continued for 1 hour. After the reaction was completed, the reaction solution was purified by preparative HPLC (waters-sunfire-10um-19*150mm column (mobile phase: 28%-38% (v/v) acetonitrile and formic acid/water) to obtain H66 (2 mg). Yield: 1%. MS m/z (ESI): 895 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.74(s,1H),8.58(s,1H),8.40(s,1H),7.61-7.48(m,2H),7.45-7.34(m,2H),7.01-6.88(m,2H),6.82 (d,J＝2.2Hz,1H),6.66(ddd,J＝20.9,8.7,3.0Hz,2H),5.27(dd,J＝12.9,5.4Hz,1H),5.13(d,J＝15.0Hz,1H ),4.72(d,J＝4.5Hz,2H),4.53(t,J＝8.8Hz,2H),4.27-4.01(m,2H),3.64(d,J＝52.6Hz,4H),3.09(s,4H), 2.87(t,J＝14.0Hz,2H),2.74-2.51(m,3H),2.04-1.84(m,1H),1.55(d,J＝75.1Hz,9H),1.35-0.93(m,8H).

实施例67化合物H67的制备
Example 67 Preparation of Compound H67

步骤1:将3-(2,6-双(苄氧基)吡啶-3-基)-6-溴-1-甲基-1H-吲唑(1.5g,3.00mmol)和3,9-二氮杂螺[5.5]十一烷-3-甲酸叔丁酯(1.53g,6.00mmol)溶于二氧六环(20mL)中，氩气保护下加入Pd2(dba)3(274.50mg,299.77μmol)和X-Phos(285.81mg,599.54μmol)和Cs2CO3(1.95g,6.00mmol)，升温至100℃搅拌过夜。反应完成后，将反应液浓缩后然后加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(20g，0～40％EA/PE)，得到H67-a(2g,棕色油状物),收率：99.01％。Step 1: Dissolve 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (1.5 g, 3.00 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.53 g, 6.00 mmol) in dioxane (20 mL), add Pd 2 (dba) 3 (274.50 mg, 299.77 μmol) and X-Phos (285.81 mg, 599.54 μmol) and Cs 2 CO 3 (1.95 g, 6.00 mmol) under argon protection, and heat to 100° C. and stir overnight. After the reaction was completed, the reaction solution was concentrated and then water and ethyl acetate were added. The ethyl acetate was extracted three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by CombiFlash (20 g, 0-40% EA/PE) to obtain H67-a (2 g, brown oil). The yield was 99.01%.

步骤2:将H67-a(2g,2.97mmol)溶于EtOH(30mL)和THF(20mL)中，加入Pd/C(315.86mg,296.81μmol,10％纯度)，氢气氛围下40℃搅拌过夜。反应完成后，将反应液过滤掉催化剂，浓缩得到H67-b(1g,灰色固体，粗品),收率：67.98％，不纯化直接下一步反应。MS m/z(ESI):496.3[M+H]+。Step 2: H67-a (2 g, 2.97 mmol) was dissolved in EtOH (30 mL) and THF (20 mL), and Pd/C (315.86 mg, 296.81 μmol, 10% purity) was added, and stirred at 40°C overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered to remove the catalyst and concentrated to obtain H67-b (1 g, gray solid, crude product), yield: 67.98%, and was directly used for the next step without purification. MS m/z (ESI): 496.3 [M+H] + .

步骤3:将H67-b(1g,2.02mmol)溶于氯化氢的1,4-二氧六环(4mol/L，15mL)中，室温搅拌2小时。反应完成后，将反应液浓缩得到H67-c(0.7g,灰色固体,粗品,HCl)，收率：80.32％。不纯化直接下一步反应。MS m/z(ESI):396.2[M+H]+。Step 3: H67-b (1 g, 2.02 mmol) was dissolved in 1,4-dioxane (4 mol/L, 15 mL) of hydrogen chloride and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H67-c (0.7 g, gray solid, crude product, HCl), yield: 80.32%. It was directly reacted in the next step without purification. MS m/z (ESI): 396.2 [M+H] + .

步骤4:将中间体Z1(833.33mg,481.21μmol)溶于DMF(5mL)中，加入HATU(907.73mg,2.41mmol)和DIPEA(1.24g,9.62mmol,1.68mL)，室温搅拌20min，加入H67-c(285.48mg,721.82μmol)，室温继续搅拌2小时。反应完成后，向反应液中加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相，浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)，再经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM FA/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)纯化，得到H67(5.56mg,纯度99.45％),收率：1.31％。MS m/z(ESI):440.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.73(s,1H),8.60-8.53(m,1H),7.54(d,J＝8.0Hz,1H),7.51(d,J＝1.6Hz,1H),7.45(d,J＝9.2Hz,1H),7.41-7.36(m,2H),6.96-6.88(m,2H),6.83(d,J＝2.0Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.12(d,J＝15.2Hz,1H),4.71(d,J＝4.8Hz,2H),4.52(t,J＝8.8Hz,2H),4.27-4.16(m,2H),4.11(p,J＝6.8Hz,1H),3.76-3.54(m,2H),3.32-3.27(m,7H),3.23(s,4H),2.66-2.53(m,2H),2.33-2.20(m,1H),2.17-2.08(m,1H),1.70-1.40(m,8H),1.27(d,J＝6.8Hz,3H),1.13(d,J＝6.8Hz,3H)。Step 4: Dissolve intermediate Z1 (833.33 mg, 481.21 μmol) in DMF (5 mL), add HATU (907.73 mg, 2.41 mmol) and DIPEA (1.24 g, 9.62 mmol, 1.68 mL), stir at room temperature for 20 min, add H67-c (285.48 mg, 721.82 μmol), and continue stirring at room temperature for 2 hours. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and ethyl acetate was used for extraction three times. The organic phases were combined, concentrated, and purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O -acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change), and then purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM FA/ H2O -acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change) to obtain H67 (5.56mg, purity 99.45%), yield: 1.31%. MS m/z (ESI): 440.3 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ10.85(s,1H),8.73(s,1H),8.60-8.53(m,1H),7.54(d,J＝8.0Hz,1H),7.51(d,J＝1.6Hz,1H),7.45(d,J＝9.2Hz,1H),7.41 -7.36(m,2H),6.96-6.88(m,2H),6.83(d,J＝2.0Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.12(d,J＝15.2Hz,1H),4.71(d,J＝4.8 Hz,2H),4.52(t,J＝8.8Hz,2H),4.27-4.16(m,2H),4.11(p,J＝6.8Hz,1H),3.76-3.54(m,2H),3.32-3.27(m,7H),3.23(s,4H) ,2.66-2.53(m,2H),2.33-2.20(m,1H),2.17-2.08(m,1H),1.70-1.40(m,8H),1.27(d,J＝6.8Hz,3H),1.13(d,J＝6.8Hz,3H).

实施例68化合物H68的制备
Example 68 Preparation of Compound H68

参照实施例66的制备方法，按照上述合成路线，制备得到化合物H68，其制备HPLC的纯化条件为(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)。MS m/z(ESI):440.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.73(s,1H),8.55(t,J＝5.2Hz,1H),7.55(d,J＝8.0Hz,1H),7.51(d,J＝0.8Hz,1H),7.44-7.36(m,3H),6.96-0.89(m,2H),6.81(d,J＝0.8Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.13(d,J＝14.8Hz,1H),4.72(d,J＝4.8Hz,2H),4.53(t,J＝8.8Hz,2H),4.20(d,J＝14.8Hz,1H),4.16-4.09(m,1H),3.89-3.84(m,4H),3.71(s,2H),3.59(s,2H),3.41-3.36(m,1H),3.31-3.20(m,6H),2.71(t,J＝6.4Hz,2H),1.68-1.43(m,8H),1.28(d,J＝6.8Hz,3H),1.14(d,J＝6.8Hz,3H)。Referring to the preparation method of Example 66, compound H68 was prepared according to the above synthetic route. The purification conditions of its preparative HPLC were (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change). MS m/z (ESI): 440.8 [M/2+H] + . 1H NMR (400MHz, DMSO- d6 )δ10.49(s,1H),8.73(s,1H),8.55(t,J＝5.2Hz,1H),7.55(d,J＝8.0Hz,1H),7.51(d,J＝0.8Hz,1H),7.44-7.36(m,3H), 6.96-0.89(m,2H),6.81(d,J＝0.8Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.13(d,J＝14.8Hz,1H),4.72(d,J＝4.8Hz,2H),4 .53(t,J＝8.8Hz,2H),4.20(d,J＝14.8Hz,1H),4.16-4.09(m,1H),3.89-3.84(m,4H),3.71(s,2H),3.59(s,2H),3.41-3 .36(m,1H),3.31-3.20(m,6H),2.71(t,J＝6.4Hz,2H),1.68-1.43(m,8H),1.28(d,J＝6.8Hz,3H),1.14(d,J＝6.8Hz,3H).

实施例69化合物H69的制备
Example 69 Preparation of Compound H69

参照实施例66的制备方法，按照上述合成路线，制备得到化合物H69，制备HPLC的纯化条件为：制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化。MS m/z(ESI):440.7[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.73(s,1H),8.55(t,J＝4.6Hz,1H),7.54(d,J＝8.0Hz,1H),7.51(d,J＝1.2Hz,1H),7.48(d,J＝9.2Hz,1H),7.40-7.37(m,2H),7.05-7.03(m,2H),6.93(dd,J＝9.6,9.0Hz,1H),6.69(dd,J＝8.6,4.0Hz,1H),5.13(d,J＝14.8Hz,1H),5.02(dd,J＝13.2,5.2Hz,1H),4.72(d,J＝4.2Hz,2H),4.53(t,J＝8.8Hz,2H),4.30(d,J＝16.8Hz,1H),4.22-4.08(m,3H),3.70(s,2H),3.59(s,2H),3.40-3.32(m,5H),3.29(s,1H),2.93-2.83(m,1H),2.60-2.53(m,1H),2.40-2.29(m,1H),1.97-1.90(m,1H),1.64-1.41(m,8H),1.28(d,J＝6.8Hz,3H),1.14(d,J＝6.8Hz,3H)。Referring to the preparation method of Example 66, compound H69 was prepared according to the above synthetic route. The purification conditions of preparative HPLC were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change. MS m/z (ESI): 440.7 [M/2+H] + . 1H NMR (400MHz, DMSO- d6 )δ10.93(s,1H),8.73(s,1H),8.55(t,J＝4.6Hz,1H),7.54(d,J＝8.0Hz,1H),7.51(d,J＝1.2Hz,1H),7.48(d,J＝9.2Hz,1H),7.40-7.37(m,2H) ,7.05-7.03(m,2H),6.93(dd,J＝9.6,9.0Hz,1H),6.69(dd,J＝8.6,4.0Hz,1H),5.13(d,J＝14.8Hz,1H),5.02(dd,J＝13.2,5.2Hz,1H),4.72(d, J＝4.2Hz,2H),4.53(t,J＝8.8Hz,2H),4.30(d,J＝16.8Hz,1H),4.22-4.08(m,3H),3.70(s,2H),3.59(s,2H),3.40-3.32(m,5H),3.29(s,1H),2 .93-2.83(m,1H),2.60-2.53(m,1H),2.40-2.29(m,1H),1.97-1.90(m,1H),1.64-1.41(m,8H),1.28(d,J＝6.8Hz,3H),1.14(d,J＝6.8Hz,3H).

实施例70化合物H70的制备
Example 70 Preparation of Compound H70

步骤1:将2-溴-5-碘代苯甲醛(10g,32.16mmol)和丙-2-胺(2.28g,38.60mmol,3.35mL)溶解在DCM(150mL)中，室温搅拌加入NaBH(OAc)3(13.63g,64.33mmol)，室温搅拌16小时。反应完成后，将反应液倒入水中，DCM(100ml×2)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H70-a(11g,浅黄色油状物),收率：96.61％。不纯化直接下一步反应。MS m/z(ESI):354.0[M+H]+。Step 1: Dissolve 2-bromo-5-iodobenzaldehyde (10 g, 32.16 mmol) and propan-2-amine (2.28 g, 38.60 mmol, 3.35 mL) in DCM (150 mL), add NaBH(OAc) 3 (13.63 g, 64.33 mmol) with stirring at room temperature, and stir at room temperature for 16 hours. After the reaction is completed, pour the reaction solution into water, extract with DCM (100 ml × 2), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain H70-a (11 g, light yellow oil), yield: 96.61%. Directly react in the next step without purification. MS m/z (ESI): 354.0 [M+H] + .

步骤2:将H70-a(11g,31.07mmol)和(Boc)2O(13.56g,62.14mmol,15.07mL)溶解在DCM(150mL)中，室温搅拌加入TEA(9.43g,93.21mmol,13.00mL)，室温搅拌3小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(EA:PE＝0～10％)，得到H70-b(12g,26.42mmol),收率：85.04％。MS m/z(ESI):397.9[M-56+H]+。Step 2: H70-a (11 g, 31.07 mmol) and (Boc) 2 O (13.56 g, 62.14 mmol, 15.07 mL) were dissolved in DCM (150 mL), TEA (9.43 g, 93.21 mmol, 13.00 mL) was added with stirring at room temperature, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (EA: PE = 0-10%) to obtain H70-b (12 g, 26.42 mmol), yield: 85.04%. MS m/z (ESI): 397.9 [M-56 + H] + .

步骤3:将H70-b和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.29g,4.18mmol)溶于1,4-二氧六环(30mL)、水(6mL)和DMSO(3mL)混合溶液中，氩气保护下加入Pd(dppf)Cl2(322.24mg,440.39μmol)和K2CO3(1.22g,8.81mmol)，升温至80℃搅拌16小时。反应完成后，向反应液中加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(20g，0～20％EA/PE)，得到H70-c(1.6g,浅黄色油状物),收率：71.31％。MS m/z(ESI):353.0[M-156+H]+。Step 3: H70-b and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.29 g, 4.18 mmol) were dissolved in a mixed solution of 1,4-dioxane (30 mL), water (6 mL) and DMSO (3 mL), and Pd(dppf)Cl 2 (322.24 mg, 440.39 μmol) and K 2 CO 3 (1.22 g, 8.81 mmol) were added under argon protection, and the temperature was raised to 80°C and stirred for 16 hours. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (20 g, 0-20% EA/PE) to obtain H70-c (1.6 g, light yellow oil), yield: 71.31%. MS m/z (ESI): 353.0 [M-156+H] + .

步骤4:将H70-c和(Pin)2B2(1.20g,4.71mmol)溶于1,4-二氧六环(30mL)中，加入KOAc(924.64mg,9.42mmol)和Pd(dppf)Cl2(229.79mg,314.05μmol)，氩气氛围下升温至95℃搅拌过夜。反应完成后，过滤掉固体，滤液浓缩后经CombiFlash纯化(20g，0～20％EA/PE)，得到H70-d(1.5g,浅棕色固体),收率：85.82％。MS m/z(ESI):401.3[M-156+H]+。Step 4: H70-c and (Pin) 2 B 2 (1.20 g, 4.71 mmol) were dissolved in 1,4-dioxane (30 mL), KOAc (924.64 mg, 9.42 mmol) and Pd(dppf)Cl 2 (229.79 mg, 314.05 μmol) were added, and the mixture was heated to 95°C and stirred overnight under an argon atmosphere. After the reaction was completed, the solid was filtered off, and the filtrate was concentrated and purified by CombiFlash (20 g, 0-20% EA/PE) to obtain H70-d (1.5 g, light brown solid), yield: 85.82%. MS m/z (ESI): 401.3 [M-156+H] + .

步骤5:将H70-d(1.45g,2.61mmol)溶于MeOH(20mL)中，加入Pd/C(277.27mg,260.54μmol,10％纯度)，氢气氛围下室温搅拌1小时。反应完成后，过滤掉催化剂，滤液浓缩后得到H70-e(1.3g,浅黄色固体),收率：89.33％。不纯化直接下一步反应。MS m/z(ESI):403.3[M-156+H]+。Step 5: H70-d (1.45 g, 2.61 mmol) was dissolved in MeOH (20 mL), Pd/C (277.27 mg, 260.54 μmol, 10% purity) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the catalyst was filtered off, and the filtrate was concentrated to obtain H70-e (1.3 g, light yellow solid), yield: 89.33%. The mixture was directly reacted in the next step without purification. MS m/z (ESI): 403.3 [M-156+H] + .

步骤6:将H70-e(1.3g,2.33mmol)和8-溴-5-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1,5-c]嘧啶-1-羧酸乙酯(810.41mg,1.86mmol)溶于DMSO(2mL)、水(3mL)和1,4-二氧六环(20mL)混合溶液中，氩气保护下加入Pd(dppf)Cl2(170.30mg,232.74μmol)和K2CO3(643.35mg,4.65mmol)，升温至95℃搅拌3小时。反应完成后，向反应液中加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(20g，0～70％EA/PE)，得到H70-f(1.4g,浅黄色固体),收率：76.44％。MS m/z(ESI):687.4[M-100+H]+。Step 6: H70-e (1.3 g, 2.33 mmol) and ethyl 8-bromo-5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (810.41 mg, 1.86 mmol) were dissolved in a mixed solution of DMSO (2 mL), water (3 mL) and 1,4-dioxane (20 mL), and Pd(dppf)Cl 2 (170.30 mg, 232.74 μmol) and K 2 CO 3 (643.35 mg, 4.65 mmol) were added under argon protection, and the temperature was raised to 95° C. and stirred for 3 hours. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (20 g, 0-70% EA/PE) to obtain H70-f (1.4 g, light yellow solid), yield: 76.44%. MS m/z (ESI): 687.4 [M-100+H] + .

步骤7:将H70-f(1.4g,1.78mmol)溶于DCM(5mL)，缓慢加入氯化氢的1,4-二氧六环溶液(4mol/L，10mL)，室温搅拌1小时。反应完成后，将反应液浓缩后用PE和EA打浆，得到H70-g(1g,淡黄色固体，粗品),收率：95.81％，不纯化直接下一步反应。MS m/z(ESI):587.3[M+H]+。Step 7: H70-f (1.4 g, 1.78 mmol) was dissolved in DCM (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL) was slowly added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and slurried with PE and EA to obtain H70-g (1 g, light yellow solid, crude product), yield: 95.81%, and was directly used for the next step without purification. MS m/z (ESI): 587.3 [M+H] + .

步骤8:将H70-g(0.4g,641.89μmol,HCl)溶于MeOH(5mL)中，加入甲醇钠(2.31g,12.84mmol,纯度30％)，升温至80℃搅拌16小时。反应完成后，将反应液浓缩后加入水和二氯甲烷，二氯甲烷萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到H70-h(0.2g,浅黄色固体,粗品)，收率：57.63％，不纯化直接下一步反应。MS m/z(ESI):541.3[M+H]+。Step 8: H70-g (0.4 g, 641.89 μmol, HCl) was dissolved in MeOH (5 mL), sodium methoxide (2.31 g, 12.84 mmol, purity 30%) was added, and the temperature was raised to 80°C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated and water and dichloromethane were added. The dichloromethane was extracted three times, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain H70-h (0.2 g, light yellow solid, crude product), yield: 57.63%, and the product was directly used for the next step without purification. MS m/z (ESI): 541.3 [M+H] + .

步骤9:将H70-h(60mg,110.98μmol)和2-(2,6-二氧代-哌啶-3-基)-5-氟-异吲哚-1,3-二酮(91.97mg,332.95μmol)溶于DMSO(2mL)中，加入DIPEA(71.72mg,554.91μmol,96.65μL)，升温至100℃搅拌2小时。反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)，得H70(13.02mg,纯度98.43％),收率：14.49％。MS m/z(ESI):797.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.71(s,1H),8.44(d,J＝5.6Hz,1H),7.67(d,J＝8.4Hz,1H),7.44-7.36(m,3H),7.33-7.26(m,3H),6.93(dd,J＝10.0,8.8Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.11-5.00(m,2H),4.71(d,J＝4.4Hz,2H),4.53(t,J＝8.8Hz,2H),4.28-4.10(m,4H),3.31-3.25(m,2H),3.13-3.01(m,2H),2.93-2.82(m,2H),2.63-2.51(m,2H),2.01(d,J＝6.0Hz,1H),1.93-1.87(m,2H),1.82-1.67(m,2H),1.26(d,J＝6.8Hz,3H),1.13(d,J＝6.8Hz,3H)。Step 9: H70-h (60 mg, 110.98 μmol) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (91.97 mg, 332.95 μmol) were dissolved in DMSO (2 mL), and DIPEA (71.72 mg, 554.91 μmol, 96.65 μL) was added, and the mixture was heated to 100° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H70 (13.02 mg, purity 98.43%), yield: 14.49%. MS m/z(ESI):797.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.12(s,1H),8.71(s,1H),8.44(d,J＝5.6Hz,1H),7.67(d,J＝8.4Hz,1H),7.44-7.36(m,3H),7.33-7.26(m, 3H),6.93(dd,J＝10.0,8.8Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.11-5.00(m,2H),4.71(d,J＝4.4Hz,2H),4.53 (t,J＝8.8Hz,2H),4.28-4.10(m,4H),3.31-3.25(m,2H),3.13-3.01(m,2H),2.93-2.82(m,2H),2.63-2.51(m,2 H), 2.01 (d, J = 6.0Hz, 1H), 1.93-1.87 (m, 2H), 1.82-1.67 (m, 2H), 1.26 (d, J = 6.8Hz, 3H), 1.13 (d, J = 6.8Hz, 3H).

实施例71化合物H71的制备
Example 71 Preparation of Compound H71

步骤1:将中间体Z3(2g,4.23mmol)溶解在乙腈(100mL)中，室温搅拌加入CuBr(1.82g,12.70mmol)，亚硝酸异戊酯(991.68mg,8.47mmol)，室温搅拌过夜。反应完成后，将反应液浓缩后经硅胶柱层析纯化(先EA:PE＝0～50％，后MeOH:DCM＝0～10％)，得到H71-a(2.0g,黄色固体),收率：88.09％。MS m/z(ESI):536[M+H]+。Step 1: Dissolve the intermediate Z3 (2 g, 4.23 mmol) in acetonitrile (100 mL), add CuBr (1.82 g, 12.70 mmol) and isoamyl nitrite (991.68 mg, 8.47 mmol) with stirring at room temperature, and stir at room temperature overnight. After the reaction is completed, the reaction solution is concentrated and purified by silica gel column chromatography (EA:PE = 0-50%, then MeOH:DCM = 0-10%) to obtain H71-a (2.0 g, yellow solid), yield: 88.09%. MS m/z (ESI): 536 [M+H] + .

步骤2:将H71-a(250mg,466.07μmol)和哌嗪-1-羧酸叔丁酯(434.03mg,2.33mmol)溶解在1,4-二氧六环(10mL)和DMSO(2mL)中，氩气保护下依次加入Pd2(dba)3(85.36mg,93.21μmol)，Xantphos(53.94mg,93.21μmol)，t-BuONa(223.96mg,2.33mmol)，微波升温至120℃搅拌2小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到H71-b(150mg,黄色固体),收率：50.15％。MS m/z(ESI):642[M+H]+。Step 2: H71-a (250 mg, 466.07 μmol) and tert-butyl piperazine-1-carboxylate (434.03 mg, 2.33 mmol) were dissolved in 1,4-dioxane (10 mL) and DMSO (2 mL), and Pd 2 (dba) 3 (85.36 mg, 93.21 μmol), Xantphos (53.94 mg, 93.21 μmol), t-BuONa (223.96 mg, 2.33 mmol) were added in sequence under argon protection, and the mixture was heated to 120° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM=0-10%) to obtain H71-b (150 mg, yellow solid), yield: 50.15%. MS m/z (ESI): 642 [M+H] + .

步骤3:将H71-b(130mg,202.58μmol)溶解在DCM(9.96mL)和MeOH(2.99mL)中，室温搅拌加入氯化氢的乙酸乙酯溶液(4.0mol/L,5mL)，室温搅拌3小时。反应完成后，将反应液浓缩，得到H71-c(109.72mg,黄色固体),收率：100.00％。MS m/z(ESI):542[M+H]+。Step 3: H71-b (130 mg, 202.58 μmol) was dissolved in DCM (9.96 mL) and MeOH (2.99 mL), and a solution of hydrogen chloride in ethyl acetate (4.0 mol/L, 5 mL) was added with stirring at room temperature, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain H71-c (109.72 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 542 [M+H] + .

步骤4:将H71-c(100mg,184.63μmol)和2-(2,6-二氧-3-哌啶基)-5-氟异吲哚-1,3-二酮(102.00mg,369.26μmol)溶解在NMP(5mL)中，加入DIPEA(477.25mg,3.69mmol,643.19μL)，升温至120℃搅拌2小时。反应完成后，将反应液浓缩后经制备HPLC纯化，得到H71(4.54mg,纯度100％),收率：3.08％。MS m/z(ESI):798[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.71(s,1H),8.38(s,1H),7.71(d,J＝8.5Hz,1H),7.41(s,1H),7.34(dd,J＝13.6,8.6Hz,2H),7.27(s,1H),7.16(s,1H),7.02(d,J＝8.5Hz,1H),6.97-6.89(m,1H),6.68(dd,J＝8.5,3.8Hz,1H),5.13-4.98(m,2H),4.70(d,J＝4.7Hz,2H),4.53(t,J＝8.7Hz,2H),4.26-4.15(m,1H),4.10(d,J＝15.2Hz,1H),3.64(s,4H),3.42(d,J＝12.5Hz,3H),3.29(d,J＝8.8Hz,3H),2.86(d,J＝11.9Hz,1H),2.65-2.51(m,2H),2.01(s,1H),1.30(d,J＝6.7Hz,3H),1.18(d,J＝6.8Hz,3H)。Step 4: H71-c (100 mg, 184.63 μmol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoroisoindole-1,3-dione (102.00 mg, 369.26 μmol) were dissolved in NMP (5 mL), and DIPEA (477.25 mg, 3.69 mmol, 643.19 μL) was added, and the mixture was heated to 120° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC to obtain H71 (4.54 mg, purity 100%), with a yield of 3.08%. MS m/z (ESI): 798 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.09(s,1H),8.71(s,1H),8.38(s,1H),7.71(d,J＝8.5Hz,1H),7.41(s,1H),7.34(dd,J＝13.6,8.6Hz,2H),7.27(s,1 H),7.16(s,1H),7.02(d,J＝8.5Hz,1H),6.97-6.89(m,1H),6.68(dd,J＝8.5,3.8Hz,1H),5.13-4.98(m,2H),4.70(d,J＝4 .7Hz,2H),4.53(t,J＝8.7Hz,2H),4.26-4.15(m,1H),4.10(d,J＝15.2Hz,1H),3.64(s,4H),3.42(d,J＝12.5Hz,3H),3.29 (d,J＝8.8Hz,3H),2.86(d,J＝11.9Hz,1H),2.65-2.51(m,2H),2.01(s,1H),1.30(d,J＝6.7Hz,3H),1.18(d,J＝6.8Hz,3H).

实施例74化合物H74的制备
Example 74 Preparation of Compound H74

步骤1:将H71-a(200mg,372.86μmol)和4-(二甲氧基甲基)哌啶(296.84mg,1.86mmol)溶解在1,4-二氧六环(20mL)和DMSO(4mL)中，氩气保护下加入Pd2(dba)3(68.29mg,74.57μmol)，Xantphos(43.15mg,74.57μmol)，t-BuONa(215.00mg,2.24mmol)，微波升温至120℃搅拌3小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(先EA:PE＝0～50％，再MeOH:DCM＝0～10％)，得到H74-a(100mg,黄色固体),收率：43.63％。MS m/z(ESI):615[M+H]+。Step 1: H71-a (200 mg, 372.86 μmol) and 4-(dimethoxymethyl)piperidine (296.84 mg, 1.86 mmol) were dissolved in 1,4-dioxane (20 mL) and DMSO (4 mL), and Pd 2 (dba) 3 (68.29 mg, 74.57 μmol), Xantphos (43.15 mg, 74.57 μmol), t-BuONa (215.00 mg, 2.24 mmol) were added under argon protection, and the mixture was heated to 120° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (EA:PE=0-50%, then MeOH:DCM=0-10%) to obtain H74-a (100 mg, yellow solid), yield: 43.63%. MS m/z (ESI): 615 [M+H] + .

步骤2:将H74-a(20mg,32.54μmol)溶解在DCM(5mL)中，室温搅拌加入TFA(3.71mg,32.54μmol,2mL)，室温搅拌3小时。反应完成后，将反应液浓缩得到H74-b(18.50mg,黄色固体),收率：100.00％。MS m/z(ESI):569[M+H]+。Step 2: H74-a (20 mg, 32.54 μmol) was dissolved in DCM (5 mL), TFA (3.71 mg, 32.54 μmol, 2 mL) was added with stirring at room temperature, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain H74-b (18.50 mg, yellow solid), yield: 100.00%. MS m/z (ESI): 569 [M+H] + .

步骤3:将H74-b(20mg,35.17μmol)和H99-b(24.08mg,70.34μmol)溶解在DCM(5mL)中，室温搅拌加入NaBH(OAc)3(7.45mg,35.17μmol)，室温搅拌过夜。反应完成后，将反应液浓缩后经制备HPLC纯化，得到H74(1.67mg,纯度94.53％),收率：5.02％。MS m/z(ESI):895[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.69(s,1H),8.35(s,2H),7.67(d,J＝8.6Hz,1H),7.37-7.17(m,3H),7.06(s,1H),6.99-6.88(m,2H),6.68(dd,J＝8.7,3.7Hz,1H),5.31(s,1H),5.08-4.93(m,2H),4.70(d,J＝4.4Hz,2H),4.53(t,J＝8.9Hz,2H),4.19(s,1H),4.06(d,J＝14.6Hz,1H),3.78(d,J＝28.4Hz,2H),3.42(s,3H),3.07-2.52(m,9H),2.20(s,2H),1.98(d,J＝6.7Hz,2H),1.79(s,3H),1.48-1.36(m,1H),1.34-1.10(m,7H),0.84(s,1H)。Step 3: H74-b (20 mg, 35.17 μmol) and H99-b (24.08 mg, 70.34 μmol) were dissolved in DCM (5 mL), and NaBH(OAc) 3 (7.45 mg, 35.17 μmol) was added with stirring at room temperature, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC to obtain H74 (1.67 mg, purity 94.53%), yield: 5.02%. MS m/z (ESI): 895 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.08(s,1H),8.69(s,1H),8.35(s,2H),7.67(d,J＝8.6Hz,1H),7.37-7.17(m,3H),7.06(s,1H),6.99- 6.88(m,2H),6.68(dd,J＝8.7,3.7Hz,1H),5.31(s,1H),5.08-4.93(m,2H),4.70(d,J＝4.4Hz,2H),4.53(t ,J＝8.9Hz,2H),4.19(s,1H),4.06(d,J＝14.6Hz,1H),3.78(d,J＝28.4Hz,2H),3.42(s,3H),3.07-2.52(m, 9H), 2.20 (s, 2H), 1.98 (d, J = 6.7Hz, 2H), 1.79 (s, 3H), 1.48-1.36 (m, 1H), 1.34-1.10 (m, 7H), 0.84 (s, 1H).

实施例76化合物H76的制备
Example 76 Preparation of Compound H76

步骤1：将H10-a(337mg,0.67mmol)溶于DMF(10mL)中，加入DIPEA(522.42mg,4.04mmol)和HA TU(508mg,1.35mmol)，在室温搅拌1小时。反应完成后，将反应液浓缩后经CombiFlash纯化(0～10％Me OH/DCM)，得到H76-a(300mg,黄色固体)，收率：81.77％。MS m/z(ESI):545.3[M+H]+。Step 1: H10-a (337 mg, 0.67 mmol) was dissolved in DMF (10 mL), and DIPEA (522.42 mg, 4.04 mmol) and HA TU (508 mg, 1.35 mmol) were added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (0-10% MeOH/DCM) to obtain H76-a (300 mg, yellow solid), yield: 81.77%. MS m/z (ESI): 545.3 [M+H] + .

步骤2：将H76-a(300mg,0.55mmol)溶于THF(30mL)，在-78℃加入LAH(2.5mol/L,0.88mL)，在氩气保护下搅拌2小时。反应完成后，向反应液中加入十水硫酸钠淬灭，过滤，滤液浓缩，得到H76-b(225mg),收率：84.12％，直接用于下一步反应。MS m/z(ESI):486.2[M+H]+。Step 2: H76-a (300 mg, 0.55 mmol) was dissolved in THF (30 mL), LAH (2.5 mol/L, 0.88 mL) was added at -78 °C, and stirred for 2 hours under argon protection. After the reaction was completed, sodium sulfate decahydrate was added to the reaction solution for quenching, filtration was performed, and the filtrate was concentrated to obtain H76-b (225 mg), yield: 84.12%, which was directly used for the next step reaction. MS m/z (ESI): 486.2 [M+H] + .

步骤3：将H76-b(80mg,0.16mmol)和H67-b(65mg,0.16mmol)溶于DCM(15mL)中，加入乙酸(10mg,0.16mmol)，室温下搅拌1小时，然后加入NaBH(OAc)3(70mg,0.33mmol)，继续搅拌过夜。反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)，得到H76(3.2mg),收率：2.25％。MS m/z(ESI):433.2[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.74(s,1H),8.51(t,J＝4.7Hz,1H),7.46(dd,J＝11.6,8.3Hz,3H),7.37-7.28(m,2H),6.93(dd,J＝20.7,10.2Hz,2H),6.83(s,1H),6.70(dd,J＝8.7,3.9Hz,1H),5.09(d,J＝15.3Hz,1H),4.73(d,J＝4.8Hz,2H),4.55(t,J＝8.7Hz,2H),4.27-4.13(m,3H),3.88(s,3H),3.61-3.45(m,4H),3.21(s,4H),2.68-2.58(m,2H),2.40(s,3H),2.36-2.22(m,2H),2.19-2.11(m,1H),1.54(d,J＝29.8Hz,8H),1.28(d,J＝6.7Hz,3H),1.18(d,J＝6.8Hz,3H)。Step 3: H76-b (80 mg, 0.16 mmol) and H67-b (65 mg, 0.16 mmol) were dissolved in DCM (15 mL), acetic acid (10 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then NaBH(OAc) 3 (70 mg, 0.33 mmol) was added, and stirring was continued overnight. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H76 (3.2 mg), yield: 2.25%. MS m/z (ESI): 433.2 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),8.74(s,1H),8.51(t,J＝4.7Hz,1H),7.46(dd,J＝11.6,8.3Hz,3H),7.37-7.28(m,2H),6.93(dd, J＝20.7,10.2Hz,2H),6.83(s,1H),6.70(dd,J＝8.7,3.9Hz,1H),5.09(d,J＝15.3Hz,1H),4.73(d,J＝4.8Hz,2H),4. 55(t,J＝8.7Hz,2H),4.27-4.13(m,3H),3.88(s,3H),3.61-3.45(m,4H),3.21(s,4H),2.68-2.58(m,2H),2.40(s, 3H), 2.36-2.22 (m, 2H), 2.19-2.11 (m, 1H), 1.54 (d, J = 29.8Hz, 8H), 1.28 (d, J = 6.7Hz, 3H), 1.18 (d, J = 6.8Hz, 3H).

实施例78化合物H78的制备
Example 78 Preparation of Compound H78

步骤1:将3,3,5,5-四甲基哌啶-4-酮(3.7g,19.30mmol,HCl)和K2CO3(8.00g,57.90mmol)溶于DMF(40.00mL)中，加入BnBr(4.95g,28.95mmol,3.44mL)，升温至60℃搅拌过夜。反应完成后，将反应液冷却至室温，加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(40g，0～5％DCM/PE)，得到H78-a(4.7g,无色油状物),收率：99.25％。MS m/z(ESI):246.2[M+H]+。Step 1: 3,3,5,5-tetramethylpiperidin-4-one (3.7 g, 19.30 mmol, HCl) and K 2 CO 3 (8.00 g, 57.90 mmol) were dissolved in DMF (40.00 mL), BnBr (4.95 g, 28.95 mmol, 3.44 mL) was added, and the temperature was raised to 60°C and stirred overnight. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, and ethyl acetate was extracted three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (40 g, 0-5% DCM/PE) to obtain H78-a (4.7 g, colorless oil), yield: 99.25%. MS m/z (ESI): 246.2 [M+H] + .

步骤2:将H78-a(4.7g,19.16mmol)和羟胺(3.99g,57.47mmol,HCl)溶于MeOH(80mL)中，加入NaOAc(7.86g,95.78mmol)，升温至70℃搅拌72小时。反应完成后，将反应液浓缩后加入水和二氯甲烷，用二氯甲烷萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到H78-b(4.99g,白色固体,粗品)，收率：100.00％，不纯化直接下一步反应。MS m/z(ESI):261.2[M+H]+。Step 2: H78-a (4.7 g, 19.16 mmol) and hydroxylamine (3.99 g, 57.47 mmol, HCl) were dissolved in MeOH (80 mL), NaOAc (7.86 g, 95.78 mmol) was added, and the temperature was raised to 70°C and stirred for 72 hours. After the reaction was completed, the reaction solution was concentrated and water and dichloromethane were added, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain H78-b (4.99 g, white solid, crude product), yield: 100.00%, and the mixture was directly used for the next step without purification. MS m/z (ESI): 261.2 [M+H] + .

步骤3:将H78-b(4.5g,17.28mmol)溶于THF(80mL)中，加入LiAlH4(3.94g,103.70mmol)，升温至70℃搅拌3小时。反应完成后，将反应液冷却至室温，加入大量THF,冰浴下缓慢滴加水(4mL),15％NaOH(4mL),水(12mL)，再搅拌半小时，加入无水硫酸钠搅拌十分钟，过滤掉固体，滤液浓缩得到H78-c(4.2g,浅黄色油状物,粗品)，收率：98.63％。不纯化直接下一步反应。MS m/z(ESI):247.2[M+H]+。Step 3: H78-b (4.5 g, 17.28 mmol) was dissolved in THF (80 mL), LiAlH 4 (3.94 g, 103.70 mmol) was added, and the temperature was raised to 70°C and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, a large amount of THF was added, and water (4 mL), 15% NaOH (4 mL), and water (12 mL) were slowly added dropwise under an ice bath, and stirred for another half an hour, anhydrous sodium sulfate was added and stirred for ten minutes, the solid was filtered off, and the filtrate was concentrated to obtain H78-c (4.2 g, light yellow oil, crude product), yield: 98.63%. The reaction was directly carried out in the next step without purification. MS m/z (ESI): 247.2 [M+H] + .

步骤4:将H78-c(4.2g,17.05mmol)溶于DCM(60mL)中，加入(Boc)2O(7.44g,34.09mmol,7.83mL)和TEA(5.17g,51.14mmol,7.13mL)，室温搅拌过夜。反应完成后，将反应液浓缩后经经CombiFlash纯化(40g，0～100％DCM/PE)，得到H78-d(5g,浅黄色固体),收率：84.65％。MS m/z(ESI):347.3[M+H]+。Step 4: H78-c (4.2 g, 17.05 mmol) was dissolved in DCM (60 mL), (Boc) 2 O (7.44 g, 34.09 mmol, 7.83 mL) and TEA (5.17 g, 51.14 mmol, 7.13 mL) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (40 g, 0-100% DCM/PE) to obtain H78-d (5 g, light yellow solid), yield: 84.65%. MS m/z (ESI): 347.3 [M+H] + .

步骤5:将H78-d(1g,2.89mmol)溶于THF(20mL)中，加入Pd/C(305.91mg,288.60μmol,10％纯度)，氢气置换三次，在氢气球下室温搅拌16小时。反应完成后，将反应液过滤，滤液浓缩得到H78-e(0.6g,浅白色固体,粗品)，收率：81.09％，不纯化直接下一步反应。MS m/z(ESI):257.2[M+H]+。Step 5: H78-d (1 g, 2.89 mmol) was dissolved in THF (20 mL), Pd/C (305.91 mg, 288.60 μmol, 10% purity) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 16 hours under a hydrogen balloon. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain H78-e (0.6 g, light white solid, crude product), yield: 81.09%, which was directly used for the next step without purification. MS m/z (ESI): 257.2 [M+H] + .

步骤6:将3-(2,6-双(苄氧基)吡啶-3-基)-6-溴-1-甲基-1H-吲唑(0.5g,999.23μmol)和H78-e(256.19mg,999.23μmol)溶于1,4-二氧六环(15mL)中，氩气保护下加入Pd2(dba)3(91.50mg,99.92μmol)、X-Phos(95.27mg,199.85μmol)和Cs2CO3(651.14mg,2.00mmol)，升温至100℃搅拌过夜。反应完成后，将反应液浓缩后加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(12g，0～30％EA/PE)，得到H78-f(250mg,浅棕色油状物),收率：37.02％。MS m/z(ESI):676.3[M+H]+。Step 6: 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (0.5 g, 999.23 μmol) and H78-e (256.19 mg, 999.23 μmol) were dissolved in 1,4-dioxane (15 mL), Pd 2 (dba) 3 (91.50 mg, 99.92 μmol), X-Phos (95.27 mg, 199.85 μmol) and Cs 2 CO 3 (651.14 mg, 2.00 mmol) were added under argon protection, and the temperature was raised to 100° C. and stirred overnight. After the reaction was completed, the reaction solution was concentrated and water and ethyl acetate were added, and the ethyl acetate was extracted three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (12 g, 0-30% EA/PE) to obtain H78-f (250 mg, light brown oil), yield: 37.02%. MS m/z (ESI): 676.3 [M+H] + .

步骤7:将H78-f(250mg,369.90μmol)和Pd/C(393.65mg,369.90μmol,10％纯度)溶于EtOH(5mL)和THF(5mL)中，氢气氛围下升温至40℃搅拌4小时。反应完成后，将反应液过滤，滤液浓缩得到H78-g(180mg,浅黄色固体),收率：97.79％。不纯化直接下一步反应。MS m/z(ESI):498.3[M+H]+。Step 7: H78-f (250 mg, 369.90 μmol) and Pd/C (393.65 mg, 369.90 μmol, 10% purity) were dissolved in EtOH (5 mL) and THF (5 mL), and the mixture was heated to 40°C and stirred for 4 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain H78-g (180 mg, light yellow solid), with a yield of 97.79%. The mixture was directly used for the next step without purification. MS m/z (ESI): 498.3 [M+H] + .

步骤8:将H78-g(180mg,361.72μmol)溶于DCM(3mL)中,加入TFA(1mL)，室温搅拌1小时。反应完成后，将反应液过滤，滤液浓缩得到H78-h(0.1g,浅黄色固体,粗品)，收率：69.55％。不纯化直接下一步反应。MS m/z(ESI):398.3[M+H]+。Step 8: H78-g (180 mg, 361.72 μmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain H78-h (0.1 g, light yellow solid, crude product), yield: 69.55%. It was directly used for the next step without purification. MS m/z (ESI): 398.3 [M+H] + .

步骤9:将H10-a(50mg,99.70μmol)和H78-h(47.56mg,119.64μmol)溶于DMF(3mL)中，加入HATU(75.23mg,199.40μmol)和DIPEA(38.66mg,299.10μmol,52.10μL)，室温搅拌1小时。反应完成后，向反应液中加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(4g，0～10％MeOH/DCM)，再经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)，得H78(15.27mg,纯度96.71％),收率：16.81％。MS m/z(ESI):441.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.75(s,1H),8.57(s,1H),8.03-7.99(m,1H),7.92(d,J＝8.0Hz,1H),7.63(d,J＝10.4Hz,1H),7.59(d,J＝8.0Hz,1H),7.48(d,J＝8.8Hz,1H),7.42(s,1H),6.94(t,J＝9.6Hz,1H),6.88(d,J＝9.2Hz,2H),6.69(dd,J＝8.8,3.6Hz,1H),5.15(d,J＝15.2Hz,1H),4.74(d,J＝4.8Hz,2H),4.54(t,J＝8.8Hz,2H),4.38-4.21(m,3H),3.89(s,4H),3.57(d,J＝12.0Hz,2H),3.33(s,1H),3.29(s,1H),2.69-2.57(m,4H),2.33-2.23(m,1H),2.19-2.09(m,1H),1.24(d,J＝6.8Hz,3H),1.20(d,J＝6.8Hz,3H),1.15(d,J＝10.0Hz,6H),0.88(d,J＝7.2Hz,6H)。Step 9: H10-a (50 mg, 99.70 μmol) and H78-h (47.56 mg, 119.64 μmol) were dissolved in DMF (3 mL), HATU (75.23 mg, 199.40 μmol) and DIPEA (38.66 mg, 299.10 μmol, 52.10 μL) were added, and stirred at room temperature for 1 hour. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by CombiFlash ( 4 g, 0-10% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 /H2O-acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change) to obtain H78 (15.27mg, purity 96.71%), yield: 16.81%. MS m/z (ESI): 441.3 [M/2+H] + . 1H NMR (400MHz, DMSO- d6 )δ10.85(s,1H),8.75(s,1H),8.57(s,1H),8.03-7.99(m,1H),7.92(d,J＝8.0Hz,1H),7.63(d,J＝10.4Hz,1H),7.59(d,J＝8.0Hz,1H),7.4 8(d,J＝8.8Hz,1H),7.42(s,1H),6.94(t,J＝9.6Hz,1H),6.88(d,J＝9.2Hz,2H),6.69(dd,J＝8.8,3.6Hz,1H),5.15(d,J＝15.2Hz,1H),4.74( d,J＝4.8Hz,2H),4.54(t,J＝8.8Hz,2H),4.38-4.21(m,3H),3.89(s,4H),3.57(d,J＝12.0Hz,2H),3.33(s,1H),3.29(s,1H),2.69-2.57(m ,4H),2.33-2.23(m,1H),2.19-2.09(m,1H),1.24(d,J＝6.8Hz,3H),1.20(d,J＝6.8Hz,3H),1.15(d,J＝10.0Hz,6H),0.88(d,J＝7.2Hz,6H).

实施例80化合物H80的制备
Example 80 Preparation of Compound H80

步骤1:将H70-h(1.3g,2.40mmol)和H39-b(1.07g,2.89mmol)溶于DCM(30mL)和DMSO(10mL)中，室温搅拌0.5小时，然后加入NaBH(OAc)3(1.53g,7.21mmol)，室温搅拌1小时。减压浓缩除去溶剂，加入乙酸乙酯和碳酸氢钠水溶液，过滤出固体，母液乙酸乙酯萃取三次，合并有机相，减压浓缩得到粗产品。粗产物和滤饼混合，经CombiFlash过柱分离(12g，0～10％MeOH/DCM)得到粗品，然后粗品经制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)纯化得H80(1.1g,1.23mmol,51.11％收率)，白色固体。LCMS m/z(ESI):895.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.71(s,1H),8.45(t,J＝5.2Hz,1H),7.39(d,J＝10.0Hz,2H),7.32(s,1H),7.27(d,J＝8.0Hz,1H),6.99-6.88(m,2H),6.81(d,J＝2.0Hz,1H),6.73-6.66(m,1H),6.66-6.60(m,1H),5.27(dd,J＝12.8,5.2Hz,1H),5.05(d,J＝15.2Hz,1H),4.70(d,J＝4.8Hz,2H),4.53(t,J＝8.8Hz,2H),4.25-4.10(m,2H),3.58(d,J＝11.6Hz,2H),3.30(d,J＝8.8Hz,4H),3.03-2.82(m,3H),2.70-2.54(m,5H),2.24-2.15(m,2H),2.03-1.92(m,3H),1.86-1.60(m,7H),1.26(t,J＝8.0Hz,6H),1.15(d,J＝6.8Hz,3H).Step 1: H70-h (1.3 g, 2.40 mmol) and H39-b (1.07 g, 2.89 mmol) were dissolved in DCM (30 mL) and DMSO (10 mL), stirred at room temperature for 0.5 hours, then NaBH(OAc) 3 (1.53 g, 7.21 mmol) was added, and stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure, ethyl acetate and sodium bicarbonate aqueous solution were added, the solid was filtered out, the mother liquor was extracted with ethyl acetate three times, the organic phases were combined, and the crude product was obtained by concentration under reduced pressure. The crude product and the filter cake were mixed and separated by CombiFlash column (12 g, 0-10% MeOH/DCM) to obtain a crude product, which was then purified by preparative liquid chromatography (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H80 (1.1 g, 1.23 mmol, 51.11% yield), a white solid. LCMS m/z (ESI): 895.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.06(s,1H),8.71(s,1H),8.45(t,J＝5.2Hz,1H),7.39(d,J＝10.0Hz,2H),7.32(s,1H),7.27(d,J＝8.0Hz,1H),6.99-6.88( m,2H),6.81(d,J＝2.0Hz,1H),6.73-6.66(m,1H),6.66-6.60(m,1H),5.27(dd,J＝12.8,5.2Hz,1H),5.05(d,J＝15.2Hz,1H),4. 70(d,J＝4.8Hz,2H),4.53(t,J＝8.8Hz,2H),4.25-4.10(m,2H),3.58(d,J＝11.6Hz,2H),3.30(d,J＝8.8Hz,4H),3.03-2.82(m,3 H),2.70-2.54(m,5H),2.24-2.15(m,2H),2.03-1.92(m,3H),1.86-1.60(m,7H),1.26(t,J＝8.0Hz,6H),1.15(d,J＝6.8Hz,3H).

步骤2:将H80(1.1g,1.23mmol)溶于DCM(100mL)中，0℃缓慢滴加HCl/二氧六环(4M,6.15mL)。室温搅拌1小时。减压浓缩除去溶剂得到淡黄色固体，然后把固体用纯净水超声溶解冻干得到淡黄色固体产物H80-a(1.14g,1.20mmol,97.52％收率,97.52％纯度,盐酸盐)，淡黄色产物。LCMS m/z(ESI):895.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),11.12(s,1H),10.60(s,1H),9.03(d,J＝6.4Hz,1H),8.73(s,1H),7.78(s,1H),7.58(s,1H),7.47(d,J＝8.0Hz,1H),7.43-7.38(m,2H),7.33-7.24(m,2H),6.93(dd,J＝10.4,8.8Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.43(dd,J＝12.8,5.2Hz,1H),5.09(d,J＝15.2Hz,1H),4.72(d,J＝4.4Hz,2H),4.53(t,J＝8.8Hz,2H),4.24(dd,J＝13.2,6.4Hz,2H),3.70-3.56(m,4H),3.37(s,3H),3.32(t,J＝8.8Hz,3H),3.15-3.02(m,3H),2.96-2.85(m,2H),2.76-2.58(m,2H),2.42-2.14(m,5H),2.10-1.89(m,5H),1.27(d,J＝6.8Hz,3H),1.19(d,J＝6.8Hz,3H).Step 2: H80 (1.1 g, 1.23 mmol) was dissolved in DCM (100 mL), and HCl/dioxane (4 M, 6.15 mL) was slowly added dropwise at 0°C. Stir at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to obtain a light yellow solid, which was then ultrasonically dissolved in purified water and freeze-dried to obtain a light yellow solid product H80-a (1.14 g, 1.20 mmol, 97.52% yield, 97.52% purity, hydrochloride), a light yellow product. LCMS m/z (ESI): 895.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.92(s,1H),11.12(s,1H),10.60(s,1H),9.03(d,J＝6.4Hz,1H),8.73(s,1H),7.78(s,1H),7.58(s,1H),7.47(d,J＝8.0Hz,1H),7.43-7 .38(m,2H),7.33-7.24(m,2H),6.93(dd,J＝10.4,8.8Hz,1H),6.68(dd,J＝8.8,4.0Hz,1H),5.43(dd,J＝12.8,5.2Hz,1H),5.09(d,J＝15.2Hz, 1H),4.72(d,J＝4.4Hz,2H),4.53(t,J＝8.8Hz,2H),4.24(dd,J＝13.2,6.4Hz,2H),3.70-3.56(m,4H),3.37(s,3H),3.32(t,J＝8.8Hz,3H),3. 15-3.02(m,3H),2.96-2.85(m,2H),2.76-2.58(m,2H),2.42-2.14(m,5H),2.10-1.89(m,5H),1.27(d,J＝6.8Hz,3H),1.19(d,J＝6.8Hz,3H).

实施例88化合物H88的制备
Example 88 Preparation of Compound H88

步骤1:将H78-e(1.39g,5.43mmol)和2-(2,6-二氧-3-哌啶基)-5-氟异吲哚-1,3-二酮(1g,3.62mmol)溶于DMF(15mL)中，加入DIPEA(1.87g,14.48mmol,2.52mL)，升温至100℃搅拌18小时。反应完成后，将反应与浓缩后加入水和乙酸乙酯(80mL)，分离出有机相，水相用乙酸乙酯萃取(80mL×2)，合并有机相经饱和食盐水(80mL)洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(20g，0～30％EA/PE)，得到H88-a(480mg),收率：25.87％。MS m/z(ESI):513.3[M+H]+。Step 1: H78-e (1.39 g, 5.43 mmol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoroisoindole-1,3-dione (1 g, 3.62 mmol) were dissolved in DMF (15 mL), and DIPEA (1.87 g, 14.48 mmol, 2.52 mL) was added, and the temperature was raised to 100°C and stirred for 18 hours. After the reaction was completed, the reaction was concentrated and water and ethyl acetate (80 mL) were added to separate the organic phase, and the aqueous phase was extracted with ethyl acetate (80 mL×2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (20 g, 0-30% EA/PE) to obtain H88-a (480 mg), yield: 25.87%. MS m/z (ESI): 513.3 [M+H] + .

步骤2:将H88-a(0.48g,936.41μmol)溶于DCM(12mL)中，加如氯化氢的1,4-二氧六环溶液(4mol/L,6mL)，在室温下搅拌2小时。反应完成后，将反应液浓缩，得到H88-b(420mg,黄色固体,HCl),收率：99.91％。MS m/z(ESI):413.3[M-HCl+H]+。Step 2: H88-a (0.48 g, 936.41 μmol) was dissolved in DCM (12 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 6 mL) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H88-b (420 mg, yellow solid, HCl), yield: 99.91%. MS m/z (ESI): 413.3 [M-HCl+H] + .

步骤3:将4-溴-3-甲酰基苯甲酸甲酯(7.2g,29.62mmol)和2,2-二氟乙-1-胺(2.64g,32.59mmol)溶于DCM(40mL)中，室温搅拌18小时，加入NaBH(OAc)3(12.56g,59.25mmol)，在室温下继续搅拌4小时。反应完成后，反应液用饱和碳酸氢钠水溶液淬灭，二氯甲烷萃取(80mL×3)，无水硫酸钠干燥，浓缩得到H88-c(9g,淡黄色油状物),收率：98.60％。MS m/z(ESI):308.0[M+H]+。Step 3: Dissolve methyl 4-bromo-3-formylbenzoate (7.2 g, 29.62 mmol) and 2,2-difluoroethane-1-amine (2.64 g, 32.59 mmol) in DCM (40 mL), stir at room temperature for 18 hours, add NaBH(OAc) 3 (12.56 g, 59.25 mmol), and continue stirring at room temperature for 4 hours. After the reaction is completed, the reaction solution is quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (80 mL×3), dried over anhydrous sodium sulfate, and concentrated to obtain H88-c (9 g, light yellow oil), yield: 98.60%. MS m/z (ESI): 308.0 [M+H] + .

步骤4:将H88-c(9g,29.21mmol)和Et3N(19.12g,87.63mmol)溶解在DCM(50mL)中，室温搅拌并加入(Boc)2O(19.12g,87.63mmol)，升温至45℃搅拌过夜。反应完成后，将反应液浓缩后经CombiFlash纯化(120g，0～40％DCM/PE)，得到H88-d(7.2g,黄色油状物),收率：60.38％。MS m/z(ESI):352.0[M-56+H]+。Step 4: H88-c (9 g, 29.21 mmol) and Et 3 N (19.12 g, 87.63 mmol) were dissolved in DCM (50 mL), stirred at room temperature, and (Boc) 2 O (19.12 g, 87.63 mmol) was added, and the temperature was raised to 45°C and stirred overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (120 g, 0-40% DCM/PE) to obtain H88-d (7.2 g, yellow oil), yield: 60.38%. MS m/z (ESI): 352.0 [M-56+H] + .

步骤5:将H88-d(7.2g,17.64mmol),KOAc(6.06g,61.73mmol),B2(pin)2(8.96g,35.27mmol)和Pd(dppf)2Cl2(1.29g,1.76mmol)溶于1,4-二氧六环(100mL)中，在95℃下搅拌6小时。反应完成后，将反应液冷却至室温，用水淬灭，乙酸乙酯(300mL×3)萃取，合并有机相经饱和食盐水洗涤(150mL)，无水硫酸钠干燥，浓缩后经CombiFlash纯化(120g，0～20％DCM/PE)，得到H88-e(6.2g,无色油状物),收率：77.21％。MS m/z(ESI):356.2[M-100+H]+。Step 5: H88-d (7.2 g, 17.64 mmol), KOAc (6.06 g, 61.73 mmol), B 2 (pin) 2 (8.96 g, 35.27 mmol) and Pd(dppf) 2 Cl 2 (1.29 g, 1.76 mmol) were dissolved in 1,4-dioxane (100 mL) and stirred at 95°C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (300 mL×3), and the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-20% DCM/PE) to obtain H88-e (6.2 g, colorless oil), yield: 77.21%. MS m/z (ESI): 356.2 [M-100+H] + .

步骤6:将8-溴-5-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(3g,6.89mmol)和H88-e(4.71g,10.34mmol)溶于水(8mL)，DMSO(5mL)和1,4-二氧六环(40mL)混合溶液中，加入Pd(dppf)2Cl2(504.34mg,689.26μmol)和K2CO3(1.91g,13.79mmol)，在100℃氮气氛围下搅拌4小时。反应完成后，将反应液冷却至室温，加水淬灭，乙酸乙酯(300mL×3)萃取，无水硫酸钠干燥，浓缩后经CombiFlash纯化(40g，0～100％EA/PE)，得到H88-f(4.2g,黄色固体),收率：89.13％。MS m/z(ESI):628.2[M-56+H]+。Step 6: Ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (3 g, 6.89 mmol) and H88-e (4.71 g, 10.34 mmol) were dissolved in a mixed solution of water (8 mL), DMSO (5 mL) and 1,4-dioxane (40 mL), Pd(dppf) 2 Cl 2 (504.34 mg, 689.26 μmol) and K 2 CO 3 (1.91 g, 13.79 mmol) were added, and the mixture was stirred at 100 °C under nitrogen atmosphere for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (300 mL×3), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (40 g, 0-100% EA/PE) to obtain H88-f (4.2 g, yellow solid), yield: 89.13%. MS m/z (ESI): 628.2 [M-56+H] + .

步骤7:将H88-f(4.2g,6.14mmol)溶于DCM(30mL)中，加入氯化氢的1,4-二氧六环溶液(4mol/L,10mL)，在室温下搅拌2小时。反应完成后，将反应液浓缩得到H88-g(3.8g,黄色固体,HCl),收率：99.76％。MS m/z(ESI):584.2[M-HCl+H]+。Step 7: H88-f (4.2 g, 6.14 mmol) was dissolved in DCM (30 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H88-g (3.8 g, yellow solid, HCl), yield: 99.76%. MS m/z (ESI): 584.2 [M-HCl+H] + .

步骤8:将H88-g(3.8g,6.51mmol)溶于THF(40mL)和水(10mL)的混合溶液中，加入LiOH(3.12g,130.24mmol)，在80℃下搅拌18小时。反应完成后，将反应液冷却至室温，用稀盐酸(2mol/L)调节pH＝2-3，然后过滤，用水洗涤滤饼，滤饼经过真空干燥，得到H88-h(3.1g,黄色固体),收率：87.92％。MS m/z(ESI):542.2[M+H]+。Step 8: H88-g (3.8 g, 6.51 mmol) was dissolved in a mixed solution of THF (40 mL) and water (10 mL), LiOH (3.12 g, 130.24 mmol) was added, and the mixture was stirred at 80°C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, pH was adjusted to 2-3 with dilute hydrochloric acid (2 mol/L), and then filtered, the filter cake was washed with water, and the filter cake was vacuum dried to obtain H88-h (3.1 g, yellow solid), yield: 87.92%. MS m/z (ESI): 542.2 [M+H] + .

步骤9:将H88-h(100mg,184.68μmol)和DIPEA(716.06mg,5.54mmol,965.04μL)溶于DMF(6mL)中，加入HATU(140.35mg,369.36μmol)，室温下搅拌10分钟，加入H88-b(99.49mg,221.62μmol,HCl)，室温搅拌过夜。反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2×250mm C18柱；体系：水+0.04％FA，乙腈；波长：254/214nm；梯度：40％-70％乙腈变化)，得到H88(40.09mg),收率：23.65％。MS m/z(ESI):459.7[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.63(s,1H),7.99(s,1H),7.92(d,J＝8.2Hz,1H),7.69(d,J＝10.6Hz,1H),7.59(t,J＝8.5Hz,2H),7.47(s,1H),7.35(s,1H),7.28(d,J＝8.8Hz,1H),6.99-6.89(m,1H),6.69(dd,J＝8.6,3.8Hz,1H),6.27(t,J＝56.5Hz,2H),5.30(d,J＝15.1Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.74(s,2H),4.53(t,J＝8.8Hz,2H),4.30(d,J＝14.9Hz,1H),4.23-4.08(m,1H),4.03(d,J＝10.4Hz,3H),3.52(dd,J＝30.6,13.7Hz,1H),3.33(s,4H),2.94(d,J＝13.0Hz,2H),2.85(d,J＝13.0Hz,1H),2.56(d,J＝21.4Hz,2H),2.05-1.94(m,1H),1.03(d,J＝5.4Hz,5H),0.91(d,J＝4.9Hz,5H)。Step 9: H88-h (100 mg, 184.68 μmol) and DIPEA (716.06 mg, 5.54 mmol, 965.04 μL) were dissolved in DMF (6 mL), HATU (140.35 mg, 369.36 μmol) was added, and the mixture was stirred at room temperature for 10 minutes. H88-b (99.49 mg, 221.62 μmol, HCl) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: water + 0.04% FA, acetonitrile; wavelength: 254/214 nm; gradient: 40%-70% acetonitrile change) to obtain H88 (40.09 mg), yield: 23.65%. MS m/z (ESI): 459.7 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.80(s,1H),8.63(s,1H),7.99(s,1H),7.92(d,J＝8.2Hz,1H),7.69(d,J＝10.6Hz,1H),7.59(t,J＝8.5Hz,2H),7.47(s,1H),7.35(s,1H),7.28 (d,J＝8.8Hz,1H),6.99-6.89(m,1H),6.69(dd,J＝8.6,3.8Hz,1H),6.27(t,J＝56.5Hz,2H),5.30(d,J＝15.1Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H) ,4.74(s,2H),4.53(t,J＝8.8Hz,2H),4.30(d,J＝14.9Hz,1H),4.23-4.08(m,1H),4.03(d,J＝10.4Hz,3H),3.52(dd,J＝30.6,13.7Hz,1H),3.33(s ,4H),2.94(d,J＝13.0Hz,2H),2.85(d,J＝13.0Hz,1H),2.56(d,J＝21.4Hz,2H),2.05-1.94(m,1H),1.03(d,J＝5.4Hz,5H),0.91(d,J＝4.9Hz,5H).

实施例91化合物H91的制备
Example 91 Preparation of Compound H91

步骤1:将6-溴-3-碘-2-甲基-2H-吲(1.3g,3.86mmol)和2,6-二(苄氧基)-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(1.45g,3.47mmol)溶于THF(30mL)和水(5mL)中，氩气保护下加入Pd(dppf)Cl2(282.30mg,385.81μmol)和Cs2CO3(2.51g,7.72mmol)，升温至80℃搅拌过夜。反应完成后，将反应液冷却至室温，然后加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(12g，0～20％EA/PE)，得到H91-a(1.6g,浅白色固体),收率：82.88％。MS m/z(ESI):500.1[M+H]+。Step 1: Dissolve 6-bromo-3-iodo-2-methyl-2H-indole (1.3 g, 3.86 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.45 g, 3.47 mmol) in THF (30 mL) and water (5 mL), add Pd(dppf)Cl 2 (282.30 mg, 385.81 μmol) and Cs 2 CO 3 (2.51 g, 7.72 mmol) under argon protection, heat to 80°C and stir overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and then water and ethyl acetate were added, and the ethyl acetate was extracted three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (12 g, 0-20% EA/PE) to obtain H91-a (1.6 g, light white solid), yield: 82.88%. MS m/z (ESI): 500.1 [M+H] + .

步骤2-步骤5：参照实施例46的制备方法，按照上述合成路线，制备得到化合物H91，其制备HPLC纯化条件为制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化。MS m/z(ESI):453.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.85(s,1H),8.77(s,2H),8.10(s,1H),7.58(s,1H),7.38(d,J＝9.2Hz,1H),6.98-6.90(m,1H),6.83(dd,J＝9.2,2.0Hz,1H),6.72-6.66(m,2H),5.27(d,J＝14.8Hz,1H),4.74(s,2H),4.59(dd,J＝12.8,4.8Hz,1H),4.53(t,J＝8.8Hz,2H),4.40(d,J＝15.2Hz,1H),3.94(s,3H),3.87-3.76(m,1H),3.60(d,J＝11.6Hz,2H),3.32-3.27(m,2H),2.87(s,2H),2.76(s,1H),2.65-2.52(m,3H),2.31(s,1H),2.22-2.05(m,4H),1.97-1.75(m,4H),1.68-1.52(m,2H),1.31-1.13(m,3H),1.07-0.98(m,1H)。Step 2-Step 5: Referring to the preparation method of Example 46, compound H91 was prepared according to the above synthetic route. The preparative HPLC purification conditions were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O -acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change. MS m/z (ESI): 453.8 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.04(s,1H),8.85(s,1H),8.77(s,2H),8.10(s,1H),7.58(s,1H),7.38(d,J＝9.2Hz,1H),6.98-6.90(m,1H),6.83(dd,J＝9. 2,2.0Hz,1H),6.72-6.66(m,2H),5.27(d,J＝14.8Hz,1H),4.74(s,2H),4.59(dd,J＝12.8,4.8Hz,1H),4.53(t,J＝8.8Hz,2H),4. 40(d,J＝15.2Hz,1H),3.94(s,3H),3.87-3.76(m,1H),3.60(d,J＝11.6Hz,2H),3.32-3.27(m,2H),2.87(s,2H),2.76(s,1H),2. 65-2.52(m,3H),2.31(s,1H),2.22-2.05(m,4H),1.97-1.75(m,4H),1.68-1.52(m,2H),1.31-1.13(m,3H),1.07-0.98(m,1H).

实施例92化合物H92的制备
Example 92 Preparation of Compound H92

步骤1-步骤2：参照实施例46的制备方法，按照上述合成路线，制备得到H92-b，MS m/z(ESI):311.1[M+H]+。Step 1-Step 2: Referring to the preparation method of Example 46, H92-b was prepared according to the above synthetic route, MS m/z (ESI): 311.1 [M+H] + .

步骤3:将H92-b(150mg,483.41μmol)溶于EA(5mL)中，加入IBX(270.73mg,966.82μmol)，升温至70℃搅拌2小时。反应完成后，将反应液过滤，滤液浓缩后经CombiFlash纯化(4g，0～10％MeOH/DCM)，得到H92-c(90mg,浅黄色固体),收率：60.39％。MS m/z(ESI):309.1[M+H]+。Step 3: H92-b (150 mg, 483.41 μmol) was dissolved in EA (5 mL), and IBX (270.73 mg, 966.82 μmol) was added, and the mixture was heated to 70°C and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and purified by CombiFlash (4 g, 0-10% MeOH/DCM) to obtain H92-c (90 mg, light yellow solid), yield: 60.39%. MS m/z (ESI): 309.1 [M+H] + .

步骤4:参照实施例46的制备方法，按照上述合成路线，制备得到H92，其制备HPLC的纯化条件为制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化。MS m/z(ESI):860.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.84(s,1H),8.77(s,2H),8.10(s,1H),7.58(s,1H),6.93(t,J＝9.6Hz,1H),6.69(dd,J＝8.8,4.0Hz,1H),6.08(d,J＝11.2Hz,2H),5.26(d,J＝14.8Hz,1H),4.73(s,2H),4.53(t,J＝8.8Hz,2H),4.38(d,J＝14.8Hz,1H),4.00(dd,J＝12.4,5.2Hz,1H),3.90(t,J＝7.6Hz,2H),3.78(s,1H),3.45(t,J＝6.8Hz,2H),3.28(s,1H),2.95-2.63(m,5H),2.53(d,J＝7.6Hz,2H),2.35-2.19(m,2H),2.10-1.85(m,5H),1.57(d,J＝11.2Hz,1H),0.98(d,J＝12.0Hz,1H)。Step 4: Referring to the preparation method of Example 46, H92 was prepared according to the above synthetic route. The purification conditions of the preparative HPLC were as follows: preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile. MS m/z (ESI): 860.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ10.84(s,1H),8.84(s,1H),8.77(s,2H),8.10(s,1H),7.58(s,1H),6.93(t,J＝9.6Hz,1H),6.69(dd,J＝8.8,4.0H z,1H),6.08(d,J＝11.2Hz,2H),5.26(d,J＝14.8Hz,1H),4.73(s,2H),4.53(t,J＝8.8Hz,2H),4.38(d,J＝14.8Hz,1H), 4.00(dd,J＝12.4,5.2Hz,1H),3.90(t,J＝7.6Hz,2H),3.78(s,1H),3.45(t,J＝6.8Hz,2H),3.28(s,1H),2.95-2.63(m ,5H),2.53(d,J＝7.6Hz,2H),2.35-2.19(m,2H),2.10-1.85(m,5H),1.57(d,J＝11.2Hz,1H),0.98(d,J＝12.0Hz,1H).

实施例93化合物H93的制备
Example 93 Preparation of Compound H93

步骤1-步骤2：参照实施例78的制备方法，按照上述合成路线，制备得到H93-b,MS m/z(ESI):229[M+H]+。Step 1-Step 2: Referring to the preparation method of Example 78, according to the above synthetic route, H93-b was prepared, MS m/z (ESI): 229 [M+H] + .

步骤3-步骤5：参照实施例67的制备方法，按照上述合成路线，制备得到H93，MS m/z(ESI):868[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.75(s,1H),8.59(s,1H),8.29(s,1H),8.00(s,1H),7.92(d,J＝8.4Hz,1H),7.61(dd,J＝16.8,8.2Hz,2H),7.41(s,1H),7.35(s,1H),7.25(d,J＝9.8Hz,1H),6.98-6.88(m,1H),6.69(d,J＝4.8Hz,1H),5.15(d,J＝15.4Hz,1H),5.06(d,J＝13.1Hz,1H),4.72(s,2H),4.53(t,J＝8.5Hz,2H),4.23(d,J＝14.7Hz,2H),4.04(s,2H),3.89(s,1H),3.29-2.53(m,7H),2.32-1.90(m,4H),1.20(d,J＝29.7Hz,6H),0.92(dd,J＝30.8,6.1Hz,5H)。Step 3-Step 5: Referring to the preparation method of Example 67, H93 was prepared according to the above synthetic route. MS m/z (ESI): 868 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.61 (dd, J=16.8, 8.2 Hz, 2H), 7.41 (s, 1H), 7.35 (s, 1H), 7.25 (d, J=9.8 Hz, 1H), 6.98-6.88 (m, 1H), 6.69 (d, J=4.8 Hz, 1H), 5.15 ( d,J＝15.4Hz,1H),5.06(d,J＝13.1Hz,1H),4.72(s,2H),4.53(t,J＝8.5Hz,2H),4.23(d,J＝14.7Hz,2H),4.04(s, 2H), 3.89 (s, 1H), 3.29-2.53 (m, 7H), 2.32-1.90 (m, 4H), 1.20 (d, J = 29.7Hz, 6H), 0.92 (dd, J = 30.8, 6.1Hz, 5H).

实施例94化合物H94的制备
Example 94 Preparation of Compound H94

步骤1:将2-(2,6-二氧代-3-哌啶基)-5-氟-异吲哚啉-1,3-二酮(300mg,1.09mmol)和N-(3-氮杂双环[3.2.1]辛-8-基)氨基甲酸苄酯(311.02mg,1.19mmol)溶解在NMP(951.94mL)中，升温至120℃搅拌1.5小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到H94-a(100mg,黄色固体),收率：17.82％。MS m/z(ESI):517[M+H]+。Step 1: Dissolve 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (300 mg, 1.09 mmol) and N-(3-azabicyclo[3.2.1]octan-8-yl)benzylcarbamate (311.02 mg, 1.19 mmol) in NMP (951.94 mL), heat to 120°C and stir for 1.5 hours. After the reaction is completed, the reaction solution is concentrated and purified by silica gel column chromatography (MeOH:DCM=0-10%) to obtain H94-a (100 mg, yellow solid), yield: 17.82%. MS m/z (ESI): 517 [M+H] + .

步骤2:将H94-a(90mg,174.23μmol)溶解在MeOH(5mL)中，加入钯炭(185.42mg,174.23μmol,10％纯度)，氢气保护下室温搅拌6小时。反应完成后，将反应液过滤，滤液浓缩得到H94-b(50mg,黄色固体),收率：75.04％。MS m/z(ESI):383[M+H]+。Step 2: H94-a (90 mg, 174.23 μmol) was dissolved in MeOH (5 mL), palladium carbon (185.42 mg, 174.23 μmol, 10% purity) was added, and stirred at room temperature for 6 hours under hydrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain H94-b (50 mg, yellow solid), yield: 75.04%. MS m/z (ESI): 383 [M+H] + .

步骤3:将中间体Z1(100mg,192.48μmol)溶解在DMF(3mL)中，室温搅拌加入HATU(290.47mg,769.94μmol)，DIPEA(248.77mg,1.92mmol,335.27μL)，室温搅拌20分钟，加入H94-b(73.61mg,192.48μmol)，室温搅拌1小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(MeOH:DCM＝0～10％)，得到，在经过HPLC分离纯化得到H94(5.51mg,纯度98.8％),收率：3.27％。MS m/z(ESI):866[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.75(s,1H),8.60(s,1H),8.10(s,1H),7.95(s,1H),7.88(d,J＝8.7Hz,1H),7.66(d,J＝8.5Hz,1H),7.59(d,J＝8.1Hz,1H),7.38(d,J＝18.6Hz,1H),7.26(s,1H),7.16(s,1H),7.00-6.87(m,1H),6.69(d,J＝5.0Hz,1H),5.15(d,J＝14.8Hz,1H),5.06(d,J＝7.4Hz,2H),4.73(s,2H),4.53(t,J＝8.5Hz,2H),4.25(d,J＝14.8Hz,2H),3.97(s,1H),3.85(d,J＝10.1Hz,2H),3.28(s,1H),3.12(d,J＝10.9Hz,2H),2.87(s,1H),2.57(s,3H),1.99(s,3H),1.54(d,J＝8.0Hz,2H),1.20(dd,J＝28.5,6.8Hz,7H)。Step 3: The intermediate Z1 (100 mg, 192.48 μmol) was dissolved in DMF (3 mL), and HATU (290.47 mg, 769.94 μmol) and DIPEA (248.77 mg, 1.92 mmol, 335.27 μL) were added with stirring at room temperature, and the mixture was stirred at room temperature for 20 minutes. H94-b (73.61 mg, 192.48 μmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH: DCM = 0-10%) to obtain H94 (5.51 mg, purity 98.8%), and the yield was 3.27%. MS m/z (ESI): 866 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),8.75(s,1H),8.60(s,1H),8.10(s,1H),7.95(s,1H),7.88(d,J＝8.7Hz,1H),7.66(d,J＝8.5Hz,1H),7.59(d,J＝ 8.1Hz,1H),7.38(d,J＝18.6Hz,1H),7.26(s,1H),7.16(s,1H),7.00-6.87(m,1H),6.69(d,J＝5.0Hz,1H),5.15(d,J＝14.8Hz,1H ),5.06(d,J＝7.4Hz,2H),4.73(s,2H),4.53(t,J＝8.5Hz,2H),4.25(d,J＝14.8Hz,2H),3.97(s,1H),3.85(d,J＝10.1Hz,2H),3.2 8(s,1H),3.12(d,J＝10.9Hz,2H),2.87(s,1H),2.57(s,3H),1.99(s,3H),1.54(d,J＝8.0Hz,2H),1.20(dd,J＝28.5,6.8Hz,7H).

实施例96化合物H96的制备
Example 96 Preparation of Compound H96

步骤1：将中间体Z1(120mg,0.23mmol)溶于DMF(2.82mL)中，加入DIPEA(180mg,1.39mmol)和HA TU(261.43mg,692.94μmol)，室温搅拌0.5小时，然后加入(3S,5R)-3,5-二甲基哌嗪-1-甲酸叔丁酯(74mg,0.35mmol)，室温继续搅拌过夜。反应完成后，将反应液倒入水中，二氯甲烷(20mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(0～10％MeOH/DCM)，得到H96-a(69mg，黄色固体),收率：42.81％。MS m/z(ESI):698.3[M+H]+。Step 1: Dissolve the intermediate Z1 (120 mg, 0.23 mmol) in DMF (2.82 mL), add DIPEA (180 mg, 1.39 mmol) and HA TU (261.43 mg, 692.94 μmol), stir at room temperature for 0.5 hours, then add (3S, 5R)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (74 mg, 0.35 mmol), and continue stirring at room temperature overnight. After the reaction is completed, pour the reaction solution into water, extract with dichloromethane (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by CombiFlash (0-10% MeOH/DCM) to obtain H96-a (69 mg, yellow solid), yield: 42.81%. MS m/z (ESI): 698.3 [M+H] + .

步骤2：将H96-a(30mg，0.043mmol)溶于DCM(5mL)中，加入HCl/EA(4mol/L,0.5mL)，室温搅拌2小时。反应完成后，将反应液浓缩得到H96-b(25mg，粗品),收率：97.3％。直接用于下一步反应。MS m/z(ESI):598.3[M+H]+。Step 2: H96-a (30 mg, 0.043 mmol) was dissolved in DCM (5 mL), HCl/EA (4 mol/L, 0.5 mL) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain H96-b (25 mg, crude product), yield: 97.3%. It was directly used for the next step reaction. MS m/z (ESI): 598.3 [M+H] + .

步骤3：将H96-b(23.54mg,39.39μmol)溶于DCM(8mL)中，加入乙酸(6.76mg,112.55μmol)，在室温搅拌1小时，然后加入NaBH(OAc)3(23.85mg,112.55μmol)，继续搅拌过夜。反应完成后，将反应液浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)纯化，得到H96(1.39mg),收率：2.55％。MS m/z(ESI):476.3[M/2+H]+。1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.74(s,1H),8.61-8.56(m,1H),7.64(d,J＝8.5Hz,1H),7.55(d,J＝8.0Hz,1H),7.48(s,1H),7.41-7.32(m,2H),7.30(s,1H),7.23(d,J＝8.8Hz,1H),6.96-6.91(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.73(s,1H),5.33-5.29(m,1H),5.12(d,J＝14.8Hz,1H),5.04(dd,J＝12.7,5.6Hz,1H),4.71(dd,J＝10.8,7.9Hz,1H),4.58-4.48(m,2H),4.20(d,J＝14.9Hz,1H),4.05(d,J＝13.3Hz,2H),3.37-3.28(m,2H),3.08-2.82(m,5H),2.82-2.52(m,6H),2.13(d,J＝15.4Hz,3H),2.04-1.79(m,6H),1.42-1.08(m,9H),0.89-0.79(m,2H)。Step 3: H96-b (23.54 mg, 39.39 μmol) was dissolved in DCM (8 mL), acetic acid (6.76 mg, 112.55 μmol) was added, and the mixture was stirred at room temperature for 1 hour, and then NaBH(OAc) 3 (23.85 mg, 112.55 μmol) was added, and stirring was continued overnight. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H96 (1.39 mg), yield: 2.55%. MS m/z (ESI): 476.3 [M/2+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ11.10(s,1H),8.74(s,1H),8.61-8.56(m,1H),7.64(d,J＝8.5Hz,1H),7.55(d,J＝8.0Hz,1H),7.48(s,1H),7.41-7.32(m,2H),7.30( s,1H),7.23(d,J＝8.8Hz,1H),6.96-6.91(m,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.73(s,1H),5.33-5.29(m,1H),5.12(d,J＝14.8Hz,1H) ,5.04(dd,J＝12.7,5.6Hz,1H),4.71(dd,J＝10.8,7.9Hz,1H),4.58-4.48(m,2H),4.20(d,J＝14.9Hz,1H),4.05(d,J＝13.3Hz,2H),3.37 -3.28(m,2H),3.08-2.82(m,5H),2.82-2.52(m,6H),2.13(d,J＝15.4Hz,3H),2.04-1.79(m,6H),1.42-1.08(m,9H),0.89-0.79(m,2H).

实施例98化合物H98的制备
Example 98 Preparation of Compound H98

步骤1:将中间体Z1(150mg,288.73μmol)溶解在DMF(4.50mL)中，室温搅拌加入HATU(326.78mg,866.18μmol)，DIPEA(373.16mg,2.89mmol,502.91μL)，室温搅拌5分钟，加入4-氨基-3,3-二氟-哌啶-1-甲酸叔丁酯(272.86mg,1.15mmol)，室温搅拌2小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(先EA:PE＝0～50％，后MeOH:DCM＝0～10％)，得到H98-a(180mg,黄色固体),收率：86.62％。MS m/z(ESI):720[M+H]+。Step 1: Dissolve the intermediate Z1 (150 mg, 288.73 μmol) in DMF (4.50 mL), add HATU (326.78 mg, 866.18 μmol) and DIPEA (373.16 mg, 2.89 mmol, 502.91 μL) at room temperature, stir at room temperature for 5 minutes, add 4-amino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (272.86 mg, 1.15 mmol), and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and purified by silica gel column chromatography (EA:PE=0-50%, then MeOH:DCM=0-10%) to obtain H98-a (180 mg, yellow solid), yield: 86.62%. MS m/z (ESI): 720 [M+H] + .

步骤2:将H98-a(180mg,250.09μmol)溶解在MeOH(5mL)和DCM(10mL)中，室温搅拌加入氯化氢乙酸乙酯溶液(4.0mol/L,7.50mL)，室温搅拌2小时。反应完成后，将反应液浓缩后加入少量甲醇溶解，加入饱和碳酸钠水溶液，DCM萃取，合并有机相经无水硫酸钠干燥，浓缩得到H98-b(100mg,黄色固体),收率：64.53％。MS m/z(ESI):620[M+H]+。Step 2: H98-a (180 mg, 250.09 μmol) was dissolved in MeOH (5 mL) and DCM (10 mL), and hydrogen chloride ethyl acetate solution (4.0 mol/L, 7.50 mL) was added with stirring at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and dissolved with a small amount of methanol, and saturated sodium carbonate aqueous solution was added, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain H98-b (100 mg, yellow solid), yield: 64.53%. MS m/z (ESI): 620 [M+H] + .

步骤3:将H98-b(120mg,193.66μmol)和2-(2,6-二氧-3-哌啶基)-5-氟异吲哚-1,3-二酮(267.47mg,968.31μmol)溶解在NMP(5mL)中，加入DIPEA(500.59mg,3.87mmol,674.65μL)，升温至120℃搅拌24小时。反应完成后，将反应液浓缩后经硅胶柱层析纯化(先EA:PE＝0～50％，后MeOH:DCM＝0～10％)，然后经制备HPLC纯化，得到H98(9.81mg,纯度95.44％),收率：5.52％。MS m/z(ESI):876[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.74(s,1H),8.57(d,J＝24.5Hz,2H),7.97(dd,J＝41.2,24.2Hz,3H),7.68(t,J＝7.9Hz,1H),7.59(d,J＝7.7Hz,1H),7.49(s,1H),7.40(d,J＝8.9Hz,2H),7.01-6.90(m,1H),6.73-6.63(m,1H),5.20-5.02(m,2H),4.73(s,2H),4.53(t,J＝8.9Hz,2H),4.19(s,4H),3.27(s,3H),3.14(s,1H),2.87(s,1H),2.57(d,J＝19.8Hz,2H),2.01(s,3H),1.60(s,1H),1.23(d,J＝4.2Hz,3H),1.15(d,J＝6.3Hz,3H)。Step 3: H98-b (120 mg, 193.66 μmol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoroisoindole-1,3-dione (267.47 mg, 968.31 μmol) were dissolved in NMP (5 mL), and DIPEA (500.59 mg, 3.87 mmol, 674.65 μL) was added, and the mixture was heated to 120° C. and stirred for 24 hours. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (EA:PE=0-50% first, then MeOH:DCM=0-10%), and then purified by preparative HPLC to obtain H98 (9.81 mg, purity 95.44%), yield: 5.52%. MS m/z (ESI): 876 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),8.74(s,1H),8.57(d,J＝24.5Hz,2H),7.97(dd,J＝41.2,24.2Hz,3H),7.68(t,J＝7.9Hz ,1H),7.59(d,J＝7.7Hz,1H),7.49(s,1H),7.40(d,J＝8.9Hz,2H),7.01-6.90(m,1H),6.73-6.63(m,1H) ,5.20-5.02(m,2H),4.73(s,2H),4.53(t,J＝8.9Hz,2H),4.19(s,4H),3.27(s,3H),3.14(s,1H),2.87( s, 1H), 2.57 (d, J = 19.8Hz, 2H), 2.01 (s, 3H), 1.60 (s, 1H), 1.23 (d, J = 4.2Hz, 3H), 1.15 (d, J = 6.3Hz, 3H).

实施例99化合物H99的制备
Example 99 Preparation of Compound H99

参照实施例66的制备方法，按照上述合成路线，制备得到H99，其制备HPLC的纯化条件为制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化。MS m/z(ESI):812.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.72(s,1H),8.47(s,1H),7.66(d,J＝8.4Hz,1H),7.51-7.43(m,2H),7.34(d,J＝4.8Hz,3H),7.25(d,J＝8.8Hz,1H),6.93(t,J＝9.6Hz,1H),6.69(dd,J＝8.8,3.6Hz,1H),5.15-5.02(m,2H),4.71(s,2H),4.53(t,J＝8.8Hz,2H),4.18(d,J＝14.0Hz,2H),3.63(d,J＝13.2Hz,1H),3.53-3.41(m,4H),2.87(s,2H),2.68-2.58(m,1H),2.53(s,4H),1.99(t,J＝8.0Hz,2H),1.27(d,J＝6.8Hz,3H),1.22(s,2H),1.16(d,J＝6.8Hz,3H)。Referring to the preparation method of Example 66, H99 was prepared according to the above synthetic route. The purification conditions of its preparation HPLC were as follows: preparation column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O - acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change. MS m/z(ESI):812.3[M+H] + . 1H NMR(400MHz,DMSO- d6 )δ11.15(s,1H),8.72(s,1H),8.47(s,1H),7.66(d,J＝8.4Hz,1H),7.51-7.43(m,2H),7.34(d,J＝4.8Hz,3H), 7.25(d,J＝8.8Hz,1H),6.93(t,J＝9.6Hz,1H),6.69(dd,J＝8.8,3.6Hz,1H),5.15-5.02(m,2H),4.71(s,2H),4 .53(t,J＝8.8Hz,2H),4.18(d,J＝14.0Hz,2H),3.63(d,J＝13.2Hz,1H),3.53-3.41(m,4H),2.87(s,2H),2.68- 2.58(m,1H),2.53(s,4H),1.99(t,J＝8.0Hz,2H),1.27(d,J＝6.8Hz,3H),1.22(s,2H),1.16(d,J＝6.8Hz,3H).

实施例101化合物H101的制备
Example 101 Preparation of Compound H101

步骤1:将N-(2-溴-5-碘苄基)丙-2-胺(11g,31.07mmol)溶于DCM(100mL)中加入(Boc)2O(40.69g,186.43mmol)，三乙胺(22.01g,217.50mmol,30.34mL)，室温反应过夜。反应完成后，向反应液中加水，乙酸乙酯萃取2次，合并有机相用饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(120g，0～10％＝EA/PE)纯化，得到H101-a(10g,黄色油状产物)，收率：70.87％。MS m/z(ESI):397.9[M-56+H]+。Step 1: Dissolve N-(2-bromo-5-iodobenzyl)propan-2-amine (11 g, 31.07 mmol) in DCM (100 mL), add (Boc) 2 O (40.69 g, 186.43 mmol), triethylamine (22.01 g, 217.50 mmol, 30.34 mL), and react at room temperature overnight. After the reaction is completed, water is added to the reaction solution, and ethyl acetate is extracted twice. The combined organic phases are washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-10% = EA/PE) to obtain H101-a (10 g, yellow oily product), yield: 70.87%. MS m/z (ESI): 397.9 [M-56+H] + .

步骤2：将H101-a(5.5g,12.11mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)环己-3-烯-1-羧酸乙酯(3.39g,12.11mmol)溶于1,4-二氧六环(50mL)，水(10mL)和DMSO(5mL)的混合溶液中，氩气保护下加入Pd(dppf)Cl2(1.33g,1.82mmol)和K2CO3(3.35g,24.22mmol)。升温至80℃搅拌16小时。反应完成后，向反应液中加水，乙酸乙酯萃取2次，合并有机相用饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(80g，0～80％EA/PE)纯化，得到H101-b(4g,黄色固体)，收率：68.75％。MS m/z(ESI):481.1[M+H]+。Step 2: H101-a (5.5 g, 12.11 mmol) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (3.39 g, 12.11 mmol) were dissolved in a mixed solution of 1,4-dioxane (50 mL), water (10 mL) and DMSO (5 mL), and Pd(dppf)Cl 2 (1.33 g, 1.82 mmol) and K 2 CO 3 (3.35 g, 24.22 mmol) were added under argon protection. The temperature was raised to 80°C and stirred for 16 hours. After the reaction was completed, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (80 g, 0-80% EA/PE) to obtain H101-b (4 g, yellow solid), yield: 68.75%. MS m/z (ESI): 481.1 [M+H] + .

步骤3:将H101-b(1g,2.08mmol)溶于1,4-二氧六环(10mL)加入Pd(dppf)Cl2(228.23mg,312.22μmol)，(Pin)2B2(687.13mg,2.71mmol)，KOAc(407.96mg,4.16mmol)，氩气氛围下100℃反应16h。反应完成后，向反应液中加水，乙酸乙酯萃取2次，合并有机相用饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(20g，0～40％EA/PE)纯化，得到H101-c(1g,黄色固体)，收率：91.08％。MS m/z(ESI):428.3[M-100+H]+。Step 3: H101-b (1 g, 2.08 mmol) was dissolved in 1,4-dioxane (10 mL), and Pd(dppf)Cl 2 (228.23 mg, 312.22 μmol), (Pin) 2 B 2 (687.13 mg, 2.71 mmol), and KOAc (407.96 mg, 4.16 mmol) were added. The mixture was reacted at 100°C for 16 h under an argon atmosphere. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate twice. The combined organic phases were washed with saturated brine twice, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (20 g, 0-40% EA/PE) to obtain H101-c (1 g, yellow solid). The yield was 91.08%. MS m/z (ESI): 428.3 [M-100+H] + .

步骤4:将H101-c(1g,1.90mmol)溶于EtOH(10mL)中加入钯/碳(100mg,189.57μmol)，室温反应2h。反应完成后，将反应液过滤，滤液浓缩后得到H101-d(1g,黄色固体)，收率：99.62％。MS m/z(ESI):430.3[M+H]+。Step 4: H101-c (1 g, 1.90 mmol) was dissolved in EtOH (10 mL), palladium/carbon (100 mg, 189.57 μmol) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain H101-d (1 g, yellow solid), with a yield of 99.62%. MS m/z (ESI): 430.3 [M+H] + .

步骤5:将H101-d(1g,1.89mmol)溶解于THF(15mL)中，加入硼烷二甲硫醚(130.64mg,9.44mmol)，在室温下搅拌反应16小时。反应完成后，向反应液中缓慢滴加甲醇，直至没有气泡产生，60℃搅拌1h，浓缩后经CombiFlash(12g，0～100％EA/PE)纯化，得到H101-e(800mg,白色固体)，收率：86.90％。MS m/z(ESI):388.3[M-100+H]+。Step 5: H101-d (1 g, 1.89 mmol) was dissolved in THF (15 mL), and borane dimethyl sulfide (130.64 mg, 9.44 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, methanol was slowly added dropwise to the reaction solution until no bubbles were generated, and the mixture was stirred at 60°C for 1 hour. After concentration, it was purified by CombiFlash (12 g, 0-100% EA/PE) to obtain H101-e (800 mg, white solid), with a yield of 86.90%. MS m/z (ESI): 388.3 [M-100+H] + .

步骤6：将H101-e(940mg 1.93mmol)，8-溴-5-[(5-氟-2,3-二氢苯并呋喃-4-基)甲基氨基]咪唑并[1,5-c]嘧啶-1-甲酸乙酯(700mg,1.61mmol)溶于水(3mL)和1，4-二氧六环(15mL)的混合溶液中，加入Pd(dppf)Cl2(176.35mg,241.24μmol)，K2CO3(444.56mg,3.22mmol)，置换氩气3次，90℃反应3h。反应完成后，将反应液过滤，滤液浓缩后经CombiFlash(12g，0～60％EA/PE)纯化，得到H101-f(410mg,黄色固体)，收率：35.61％。MS m/z(ESI):616.4[M-100+H]+。Step 6: H101-e (940 mg 1.93 mmol), 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (700 mg, 1.61 mmol) were dissolved in a mixed solution of water (3 mL) and 1,4-dioxane (15 mL), Pd(dppf)Cl 2 (176.35 mg, 241.24 μmol), K 2 CO 3 (444.56 mg, 3.22 mmol) were added, argon was replaced 3 times, and the reaction was carried out at 90° C. for 3 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated and purified by CombiFlash (12 g, 0-60% EA/PE) to obtain H101-f (410 mg, yellow solid), yield: 35.61%. MS m/z(ESI):616.4[M-100+H] + .

步骤7:将H101-f(400mg,558.78μmol)溶于DCM(10mL)中，加入氯化氢的1,4-二氧六环溶液(4mol/L,3mL)，室温反应2h。反应完成后，将反应液浓缩后用饱和碳酸氢钠水溶液调pH＝8，DCM萃取2次，合并有机相用饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(12g，0～40％MeOH/DCM)纯化，得到H101-g(340mg,黄色固体)，收率：98.82％。MS m/z(ESI):616.4[M+H]+。Step 7: H101-f (400 mg, 558.78 μmol) was dissolved in DCM (10 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 3 mL) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated and adjusted to pH = 8 with a saturated sodium bicarbonate aqueous solution, extracted with DCM twice, and the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (12 g, 0-40% MeOH/DCM) to obtain H101-g (340 mg, yellow solid), yield: 98.82%. MS m/z (ESI): 616.4 [M+H] + .

步骤8:将H101-g(340mg,552.18μmol)溶于甲MeOH(5mL)中加入NaOH(110.43mg,2.76mmol)的水(2mL)溶液。室温反应过夜。反应完成后，将反应液浓缩后得到H101-h(320mg,淡黄色固体)，收率：98.61％。MS m/z(ESI):588.3[M+H]+。Step 8: H101-g (340 mg, 552.18 μmol) was dissolved in MeOH (5 mL) and NaOH (110.43 mg, 2.76 mmol) in water (2 mL) was added. The reaction was allowed to react overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain H101-h (320 mg, light yellow solid), yield: 98.61%. MS m/z (ESI): 588.3 [M+H] + .

步骤9:将H101-h(320mg,544.51μmol)溶于DMF(5mL)中，加入HATU(267.06mg,707.86μmol)和DIPEA(175.94mg,1.36mmol)，室温反应2h。反应完成后，向反应液中加水，乙酸乙酯萃取2次，合并有机相用饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(12g，0～40％MeOH/DCM)纯化，得到H101-i(240mg,黄色固体)，收率：77.37％。MS m/z(ESI):570.3[M+H]+。Step 9: H101-h (320 mg, 544.51 μmol) was dissolved in DMF (5 mL), HATU (267.06 mg, 707.86 μmol) and DIPEA (175.94 mg, 1.36 mmol) were added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (12 g, 0-40% MeOH/DCM) to obtain H101-i (240 mg, yellow solid), with a yield of 77.37%. MS m/z (ESI): 570.3 [M+H] + .

步骤10:将H101-i(230mg,403.74μmol)溶于DCM(10mL)中加入戴斯-马丁氧化剂(171.24mg,403.74μmol)，室温反应2h。反应完成后，将反应液浓缩后经CombiFlash(4g，0～10％MeOH/DCM)纯化，得到H101-j(130mg,黄色固体)，收率：56.72％。MS m/z(ESI):568.3[M+H]+。Step 10: H101-i (230 mg, 403.74 μmol) was dissolved in DCM (10 mL) and Dess-Martin periodinane (171.24 mg, 403.74 μmol) was added and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (4 g, 0-10% MeOH/DCM) to obtain H101-j (130 mg, yellow solid), yield: 56.72%. MS m/z (ESI): 568.3 [M+H] + .

步骤11:将H101-j(50mg,88.08μmol)和2-(2,6-二氧-3-哌啶基)-5-(4-哌啶基)异吲哚-1,3-二酮(39.09mg,114.51μmol)溶解于EtOH(0.5mL)和DMSO(2mL)混合溶剂中，微波下升温至85℃搅拌30min，然后加入NaBH(OAc)3(74.67mg,352.33μmol)，最后微波下升温至85°搅拌30min。反应完成后，将反应液浓缩后经CombiFlash(4g，0～12％MeOH/DCM)初步纯化，再经过制备HPLC纯化(制备柱：21.2×250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95乙腈变化)，得到H101(1.23mg,纯度93％),收率：1.45％。MS m/z(ESI):447.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.72(s,1H),8.44(s,1H),7.89-7.73(m,3H),7.43-7.34(m,2H),7.35-7.21(m,2H),6.93(dd,J＝10.3,8.6Hz,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.16-4.99(m,2H),4.70(d,J＝4.5Hz,2H),4.52(t,J＝8.8Hz,2H),4.30-4.07(m,2H),3.07-2.69(m,5H),2.68-2.50(m,4H),2.40-2.33(m,1H),2.16(d,J＝7.0Hz,1H),2.06-1.89(m,5H),1.84-1.72(m,4H),1.64(d,J＝20.7Hz,4H),1.45(q,J＝15.0,14.1Hz,2H),1.26-1.20(m,4H),1.15(d,J＝6.8Hz,3H)。Step 11: H101-j (50 mg, 88.08 μmol) and 2-(2,6-dioxo-3-piperidinyl)-5-(4-piperidinyl)isoindole-1,3-dione (39.09 mg, 114.51 μmol) were dissolved in a mixed solvent of EtOH (0.5 mL) and DMSO (2 mL), heated to 85°C under microwave and stirred for 30 min, then NaBH(OAc) 3 (74.67 mg, 352.33 μmol) was added, and finally heated to 85° under microwave and stirred for 30 min. After the reaction was completed, the reaction solution was concentrated and initially purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H101 (1.23 mg, purity 93%), yield: 1.45%. MS m/z (ESI): 447.3 [M/2+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),8.72(s,1H),8.44(s,1H),7.89-7.73(m,3H),7.43-7.34(m,2H),7.35-7.21(m,2H),6.93(dd,J＝1 0.3,8.6Hz,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.16-4.99(m,2H),4.70(d,J＝4.5Hz,2H),4.52(t,J＝8.8Hz,2H),4.30 -4.07(m,2H),3.07-2.69(m,5H),2.68-2.50(m,4H),2.40-2.33(m,1H),2.16(d,J＝7.0Hz,1H),2.06-1.89(m,5H), 1.84-1.72(m,4H),1.64(d,J＝20.7Hz,4H),1.45(q,J＝15.0,14.1Hz,2H),1.26-1.20(m,4H),1.15(d,J＝6.8Hz,3H).

实施例102化合物H102的制备
Example 102 Preparation of Compound H102

步骤1:将3-羟基-2,2,4,4-(四甲氧基)环丁基氨基甲酸叔丁脂(3.43g,14.11mmol)溶于DMF(30mL)中，0℃加入NaH(1.41g,35.26mmol,60％纯度)，低温搅拌0.5小时，然后加入5-氟-N-甲基-2-硝基苯胺(2g,11.75mmol)和DMF(5mL)，恢复到室温搅拌2小时。反应完成后，在冰浴条件下缓慢滴加水淬灭反应，然后加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(40g，0～30％EA/PE)得到H102-a(4g,黄色固体),收率：86.48％。MS m/z(ESI):394.2[M+H]+。Step 1: Dissolve tert-butyl 3-hydroxy-2,2,4,4-(tetramethoxy)cyclobutylcarbamate (3.43 g, 14.11 mmol) in DMF (30 mL), add NaH (1.41 g, 35.26 mmol, 60% purity) at 0°C, stir at low temperature for 0.5 hours, then add 5-fluoro-N-methyl-2-nitroaniline (2 g, 11.75 mmol) and DMF (5 mL), return to room temperature and stir for 2 hours. After the reaction is completed, slowly add water dropwise under ice bath conditions to quench the reaction, then add water and ethyl acetate, extract with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate and purify with CombiFlash (40 g, 0-30% EA/PE) to obtain H102-a (4 g, yellow solid), yield: 86.48%. MS m/z (ESI): 394.2 [M+H] + .

步骤2:将H102-a(2g,5.08mmol)溶于MeOH(20mL)和THF(20mL)和饱和NH4Cl水溶液(10mL)中，加入铁粉(2.84g,50.83mmol)，升温至70℃搅拌过夜。反应完成后，将反应液过滤，滤液浓缩后加入乙酸乙酯和水，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到H102-b(1.7g,黄色固体)，收率：92.01％，不纯化直接下一步反应。MS m/z(ESI):364.3[M+H]+。Step 2: H102-a (2 g, 5.08 mmol) was dissolved in MeOH (20 mL), THF (20 mL) and saturated NH 4 Cl aqueous solution (10 mL), iron powder (2.84 g, 50.83 mmol) was added, and the temperature was raised to 70°C and stirred overnight. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, ethyl acetate and water were added, and ethyl acetate was extracted three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain H102-b (1.7 g, yellow solid), yield: 92.01%, and the next step reaction was carried out directly without purification. MS m/z (ESI): 364.3 [M+H] + .

步骤3:将H102-b(1.7g,4.68mmol)和CDI(834.18mg,5.14mmol)和DIPEA(906.67mg,7.02mmol,1.22mL)溶于THF(30mL)中，升温至75℃搅拌3小时。反应完成后，将反应液冷却至室温，加入水和乙酸乙酯，乙酸乙酯萃取3次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(12g，0～80％EA/PE)，再经石油醚打浆，过滤，滤饼烘干得到H102-c(1.4g,白色固体),收率：76.86％。MS m/z(ESI):390.2[M+H]+。Step 3: H102-b (1.7 g, 4.68 mmol), CDI (834.18 mg, 5.14 mmol) and DIPEA (906.67 mg, 7.02 mmol, 1.22 mL) were dissolved in THF (30 mL), heated to 75 ° C and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water and ethyl acetate were added, and ethyl acetate was extracted 3 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by CombiFlash (12 g, 0-80% EA/PE), and then slurried with petroleum ether, filtered, and the filter cake was dried to obtain H102-c (1.4 g, white solid), yield: 76.86%. MS m/z (ESI): 390.2 [M+H] + .

步骤4:氩气氛围0℃下将t-BuOK(216.08mg,1.93mmol)加入到H102-c(0.5g,1.28mmol)的THF(10mL)溶液中，加完0℃反应0.5小时，再于0℃下加入1-(4-甲氧基苄基)-2,6-二氧代哌啶-3-基三氟甲磺酸酯(734.28mg,1.93mmol)的THF(5mL)溶液，0℃继续反应0.5小时。将反应液倒入冰水中，加入乙酸乙酯萃取(20mL×2)，合并有机相经饱和食盐水洗涤，浓缩后经硅胶柱层析纯化(PE：EA＝50％：50％～0％：80％)，得H102-d(0.5g,灰色固体)，收率：62.75％。MS m/z(ESI):621.4[M+H]+。Step 4: t-BuOK (216.08 mg, 1.93 mmol) was added to a solution of H102-c (0.5 g, 1.28 mmol) in THF (10 mL) at 0°C under an argon atmosphere, and the mixture was reacted at 0°C for 0.5 hours. Then, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (734.28 mg, 1.93 mmol) in THF (5 mL) was added at 0°C, and the reaction was continued at 0°C for 0.5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, concentrated, and purified by silica gel column chromatography (PE: EA = 50%: 50% to 0%: 80%) to obtain H102-d (0.5 g, gray solid), yield: 62.75%. MS m/z (ESI): 621.4 [M+H] + .

步骤5:将H102-d(0.5g,805.50μmol)溶于甲苯(10mL)中，加入甲磺酸(774.13mg,8.05mmol,552.95μL)，升温至110℃搅拌10小时。反应完成后，将反应液浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM FA/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)纯化，得H102-e(40mg),收率：12.40％。MS m/z(ESI):401.2[M+H]+。Step 5: H102-d (0.5 g, 805.50 μmol) was dissolved in toluene (10 mL), and methanesulfonic acid (774.13 mg, 8.05 mmol, 552.95 μL) was added, and the temperature was raised to 110° C. and stirred for 10 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM FA/H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H102-e (40 mg), yield: 12.40%. MS m/z (ESI): 401.2 [M+H] + .

步骤6:将H102-e(38.33mg,95.71μmol)和H10-a(40mg,79.76μmol)溶于DMF(3mL)中，加入HATU(45.14mg,119.64μmol)和DIPEA(30.92mg,239.28μmol,41.68μL)，室温搅拌1小时。反应完成后，加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)纯化，得H102(23.55mg,100％纯度)，收率：33.40％。MS m/z(ESI):442.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.75(s,1H),8.58(s,1H),7.96(d,J＝2.0Hz,1H),7.89(dd,J＝8.0,1.6Hz,1H),7.84(d,J＝9.2Hz,1H),7.60(d,J＝8.0Hz,1H),7.41(s,1H),7.00(d,J＝8.4Hz,1H),6.94(t,J＝9.6Hz,1H),6.73(d,J＝2.4Hz,1H),6.69(dd,J＝8.8,4.0Hz,1H),6.52(dd,J＝8.8,2.4Hz,1H),5.30(dd,J＝13.2,5.6Hz,1H),5.15(d,J＝15.2Hz,1H),4.73(s,2H),4.53(t,J＝8.8Hz,2H),4.31-4.21(m,2H),4.14(s,1H),4.06(d,J＝9.2Hz,1H),3.28(s,2H),2.94-2.82(m,1H),2.73-2.49(m,5H),2.03-1.94(m,1H),1.25-1.16(m,18H)。Step 6: H102-e (38.33 mg, 95.71 μmol) and H10-a (40 mg, 79.76 μmol) were dissolved in DMF (3 mL), HATU (45.14 mg, 119.64 μmol) and DIPEA (30.92 mg, 239.28 μmol, 41.68 μL) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H102 (23.55 mg, 100% purity), yield: 33.40%. MS m/z(ESI):442.8[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.04(s,1H),8.75(s,1H),8.58(s,1H),7.96(d,J＝2.0Hz,1H),7.89(dd,J＝8.0,1.6Hz,1H),7.84(d,J＝9.2Hz,1H),7.60(d,J＝ 8.0Hz,1H),7.41(s,1H),7.00(d,J＝8.4Hz,1H),6.94(t,J＝9.6Hz,1H),6.73(d,J＝2.4Hz,1H),6.69(dd,J＝8.8,4.0Hz,1H),6.52(d d,J＝8.8,2.4Hz,1H),5.30(dd,J＝13.2,5.6Hz,1H),5.15(d,J＝15.2Hz,1H),4.73(s,2H),4.53(t,J＝8.8Hz,2H),4.31-4.21(m,2H ), 4.14 (s, 1H), 4.06 (d, J = 9.2Hz, 1H), 3.28 (s, 2H), 2.94-2.82 (m, 1H), 2.73-2.49 (m, 5H), 2.03-1.94 (m, 1H), 1.25-1.16 (m, 18H).

实施例103和实施例104化合物H103和H104的制备
Example 103 and Example 104 Preparation of Compounds H103 and H104

步骤1:将H101-j(30mg,52.85μmol)和H99-b(36.19mg,105.70μmol)溶解于DCM(5mL)和DMSO(1mL)混合溶剂中，在室温下搅拌反应0.5小时，加入NaBH(OAc)3(33.60mg,158.55μmol)，室温下继续搅拌反应3小时。原料反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：67％-72％乙腈变化)，得到H103(2.07mg,纯度99.54％),收率：4.36％。MS m/z(ESI):447.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.71(s,1H),8.43(t,J＝5.2Hz,1H),7.67(d,J＝8.5Hz,1H),7.41-7.35(m,2H),7.32(d,J＝4.2Hz,2H),7.25(d,J＝8.3Hz,2H),6.97-6.88(m,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.12-4.99(m,2H),4.70(d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.25-4.08(m,2H),3.43(d,J＝5.8Hz,5H),3.27(d,J＝7.3Hz,2H),2.85(d,J＝12.6Hz,1H),2.68-2.50(m,6H),2.18(d,J＝7.0Hz,2H),2.05-1.78(m,5H),1.68-1.42(m,3H),1.26(d,J＝6.7Hz,3H),1.15(d,J＝6.9Hz,3H),1.04(d,J＝12.9Hz,2H)。和H104(2.67mg,纯度100％),收率：5.65％。MS m/z(ESI):447.8[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.71(s,1H),8.44(t,J＝5.1Hz,1H),7.66(d,J＝8.5Hz,1H),7.42-7.35(m,2H),7.35-7.20(m,4H),6.93(dd,J＝10.3,8.7Hz,1H),6.68(dd,J＝8.6,3.9Hz,1H),5.15-4.96(m,2H),4.71(d,J＝4.9Hz,2H),4.53(t,J＝8.8Hz,2H),4.28-4.08(m,2H),3.53-3.39(m,5H),3.28(s,2H),2.86(ddd,J＝17.3,13.8,5.4Hz,1H),2.68-2.51(m,6H),2.38(d,J＝7.6Hz,2H),2.08-1.89(m,2H),1.78-1.51(m,8H),1.27(d,J＝6.7Hz,3H),1.15(d,J＝6.9Hz,3H)。Step 1: H101-j (30 mg, 52.85 μmol) and H99-b (36.19 mg, 105.70 μmol) were dissolved in a mixed solvent of DCM (5 mL) and DMSO (1 mL), stirred at room temperature for 0.5 hours, and NaBH(OAc) 3 (33.60 mg, 158.55 μmol) was added, and the reaction was continued at room temperature for 3 hours. After the reaction of the raw materials was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 67%-72% acetonitrile change) to obtain H103 (2.07 mg, purity 99.54%), yield: 4.36%. MS m/z (ESI): 447.8 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.06(s,1H),8.71(s,1H),8.43(t,J＝5.2Hz,1H),7.67(d,J＝8.5Hz,1H),7.41-7.35(m,2H),7.32(d,J＝4.2Hz,2H),7.25 (d,J＝8.3Hz,2H),6.97-6.88(m,1H),6.68(dd,J＝8.6,3.8Hz,1H),5.12-4.99(m,2H),4.70(d,J＝4.9Hz,2H),4.53(t,J＝8.8H z, 2H), 4.25-4.08 (m, 2H), 3.43 (d, J = 5.8 Hz, 5H), 3.27 (d, J = 7.3 Hz, 2H), 2.85 (d, J = 12.6 Hz, 1H), 2.68-2.50 (m, 6H), 2.18 (d, J = 7.0 Hz, 2H), 2.05-1.78 (m, 5H), 1.68-1.42 (m, 3H), 1.26 (d, J = 6.7 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 12.9 Hz, 2H). And H104 (2.67 mg, purity 100%), yield: 5.65%. MS m/z (ESI): 447.8 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.06(s,1H),8.71(s,1H),8.44(t,J＝5.1Hz,1H),7.66(d,J＝8.5Hz,1H),7.42-7.35(m,2H),7.35-7.20(m,4H) ,6.93(dd,J＝10.3,8.7Hz,1H),6.68(dd,J＝8.6,3.9Hz,1H),5.15-4.96(m,2H),4.71(d,J＝4.9Hz,2H),4.53(t,J＝ 8.8Hz,2H),4.28-4.08(m,2H),3.53-3.39(m,5H),3.28(s,2H),2.86(ddd,J＝17.3,13.8,5.4Hz,1H),2.68-2.51( m, 6H), 2.38 (d, J = 7.6Hz, 2H), 2.08-1.89 (m, 2H), 1.78-1.51 (m, 8H), 1.27 (d, J = 6.7Hz, 3H), 1.15 (d, J = 6.9Hz, 3H).

实施例105化合物H105的制备
Example 105 Preparation of Compound H105

步骤1:将H70-h(10mg,18.50μmol)和H51-g(16.39mg,55.49μmol)溶于DCM(3mL)中，室温搅拌2h，然后加入NaBH(OAc)3(15.68mg,73.99μmol)，室温搅拌过夜。反应完成后，将反应液浓缩后经CombiFlash(4g，0～12％MeOH/DCM)初步纯化，再经制备HPLC纯化(制备柱：21.2×250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95乙腈变化)，得到H105(1.14mg,纯度93.6％),收率：6.20％。MS m/z(ESI):466.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.71(s,1H),8.44(s,1H),7.39(d,J＝8.6Hz,2H),7.34-7.24(m,2H),6.92(dd,J＝18.8,8.4Hz,3H),6.68(dt,J＝9.3,4.9Hz,2H),5.28(dd,J＝13.0,5.2Hz,1H),5.05(d,J＝15.0Hz,1H),4.73-4.68(m,2H),4.53(t,J＝8.7Hz,2H),4.22-4.11(m,2H),3.75(s,1H),3.05(d,J＝12.2Hz,2H),2.91(s,1H),2.82-2.63(m,3H),2.43-2.17(m,4H),2.06(s,1H),1.98(d,J＝7.9Hz,2H),1.91(s,2H),1.89(d,J＝4.3Hz,5H),1.76(s,3H),1.67(s,5H),1.55(d,J＝10.2Hz,2H),1.48-1.34(m,2H)。Step 1: H70-h (10 mg, 18.50 μmol) and H51-g (16.39 mg, 55.49 μmol) were dissolved in DCM (3 mL), stirred at room temperature for 2 h, then NaBH(OAc) 3 (15.68 mg, 73.99 μmol) was added, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and preliminarily purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95 acetonitrile change) to obtain H105 (1.14 mg, purity 93.6%), yield: 6.20%. MS m/z (ESI): 466.3 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),8.71(s,1H),8.44(s,1H),7.39(d,J＝8.6Hz,2H),7.34-7.24(m,2H),6.92(dd,J＝18.8,8.4Hz,3H),6.68(d t,J＝9.3,4.9Hz,2H),5.28(dd,J＝13.0,5.2Hz,1H),5.05(d,J＝15.0Hz,1H),4.73-4.68(m,2H),4.53(t,J＝8.7Hz,2H),4.22 -4.11(m,2H),3.75(s,1H),3.05(d,J＝12.2Hz,2H),2.91(s,1H),2.82-2.63(m,3H),2.43-2.17(m,4H),2.06(s,1H),1.98( d,J＝7.9Hz,2H),1.91(s,2H),1.89(d,J＝4.3Hz,5H),1.76(s,3H),1.67(s,5H),1.55(d,J＝10.2Hz,2H),1.48-1.34(m,2H).

实施例106化合物H106的制备
Example 106 Preparation of Compound H106

步骤1:将4-溴-2-甲基吡唑-3-甲醛(5g,26.45mmol)和4-氨基哌啶-1-甲酸叔丁酯(5.83g,29.10mmol)溶于TFA(1mL)中加入MeOH(60mL)，室温搅拌30min，加入NaBH3CN(3.49g,55.55mmol)，室温反应1.5h。反应完成后，向反应液中加水，乙酸乙酯萃取2次，合并有机相经饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(80g，0～40％EA/PE)纯化，得到H106-a(8.8g,黄色油状物),收率：89.12％。MS m/z(ESI):317.1[M-56+H]+。Step 1: Dissolve 4-bromo-2-methylpyrazole-3-carboxaldehyde (5 g, 26.45 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (5.83 g, 29.10 mmol) in TFA (1 mL), add MeOH (60 mL), stir at room temperature for 30 min, add NaBH 3 CN (3.49 g, 55.55 mmol), and react at room temperature for 1.5 h. After the reaction is completed, add water to the reaction solution, extract twice with ethyl acetate, wash the combined organic phases with saturated brine twice, dry with anhydrous sodium sulfate, concentrate, and purify with CombiFlash (80 g, 0-40% EA/PE) to obtain H106-a (8.8 g, yellow oil), yield: 89.12%. MS m/z (ESI): 317.1 [M-56+H] + .

步骤2:将H106-a(9g,24.11mmol)溶于DCM(100mL)中，加入(Boc)2O(10.52g,48.22mmol)，TEA(7.32g,72.33mmol,10.09mL)和DMAP(294.55mg,2.41mmol)，室温反应过夜。反应完成后，向反应液中加水，乙酸乙酯萃取2次，合并有机相经饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(80g，0～40％EA/PE)纯化，得到H106-b(6g,黄色油状物)，收率：52.57％。MS m/z(ESI):317.1[M-156+H]+。Step 2: H106-a (9 g, 24.11 mmol) was dissolved in DCM (100 mL), (Boc) 2 O (10.52 g, 48.22 mmol), TEA (7.32 g, 72.33 mmol, 10.09 mL) and DMAP (294.55 mg, 2.41 mmol) were added, and the mixture was reacted at room temperature overnight. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate twice. The combined organic phases were washed with saturated brine twice, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (80 g, 0-40% EA/PE) to obtain H106-b (6 g, yellow oil), with a yield of 52.57%. MS m/z (ESI): 317.1 [M-156+H] + .

步骤3:将H106-b(2.18g,4.6mmol)和8-溴-5-[(5-氟-2,3-二氢苯并呋喃-4-基)甲基氨基]咪唑并[1,5-c]嘧啶-1-甲酸乙酯(1g,2.30mmol)溶于水(2mL)和乙二醇二甲醚(15mL)中，加入Pd(OAc)2(103.16mg,459.51μmol)，正丁基二(1-金刚烷基)膦(164.96mg,459.51μmol)，K2CO3(1.27g,9.19mmol)和(Pin)2B2(1.22g,4.82mmol)，75℃反应16h。反应完成后，向反应液中加水，乙酸乙酯萃取2次，合并有机相经饱和食盐水洗2次，无水硫酸钠干燥，浓缩后经CombiFlash(20g，0～80％EA/PE)纯化，得到H106-c(800mg,黄色固体)，收率：46.50％。MS m/z(ESI):649.4[M-100+H]+。Step 3: H106-b (2.18 g, 4.6 mmol) and 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (1 g, 2.30 mmol) were dissolved in water (2 mL) and ethylene glycol dimethyl ether (15 mL), and Pd(OAc) 2 (103.16 mg, 459.51 μmol), n-butyldi(1-adamantyl)phosphine (164.96 mg, 459.51 μmol), K 2 CO 3 (1.27 g, 9.19 mmol) and (Pin) 2 B 2 (1.22 g, 4.82 mmol) were added, and the reaction was carried out at 75° C. for 16 h. After the reaction was completed, water was added to the reaction solution, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (20 g, 0-80% EA/PE) to obtain H106-c (800 mg, yellow solid), yield: 46.50%. MS m/z (ESI): 649.4 [M-100+H] + .

步骤4:将H106-c(800mg,1.07mmol)溶于DCM(10mL)中，加入TFA(5mL)，室温反应16h。反应完成后，将反应液浓缩后加入TEA和DCM溶清，经CombiFlash(12g，0～50％MeOH/DCM)纯化，得到H106-d(400mg,黄色固体)，收率：68.25％。MS m/z(ESI):549.3[M+H]+。Step 4: H106-c (800 mg, 1.07 mmol) was dissolved in DCM (10 mL), TFA (5 mL) was added, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated, TEA and DCM were added to dissolve the solution, and the mixture was purified by CombiFlash (12 g, 0-50% MeOH/DCM) to obtain H106-d (400 mg, yellow solid), yield: 68.25%. MS m/z (ESI): 549.3 [M+H] + .

步骤5:将H106-d(250mg,455.7μmol)溶于MeOH(3mL)中，加入甲醇钠的甲醇溶液(30wt％，3mL)，85℃反应16h。反应完成后，向反应液中加水，用DCM:MeOH＝10:1的混合溶液萃取2次，合并有机相经无水硫酸钠干燥，浓缩得到H106-e(30mg,黄色固体)，收率：13.1％。MS m/z(ESI):503.5[M+H]+。Step 5: H106-d (250 mg, 455.7 μmol) was dissolved in MeOH (3 mL), and a methanol solution of sodium methoxide (30 wt%, 3 mL) was added, and the mixture was reacted at 85°C for 16 h. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted twice with a mixed solution of DCM:MeOH=10:1. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain H106-e (30 mg, yellow solid), with a yield of 13.1%. MS m/z (ESI): 503.5 [M+H] + .

步骤6:将H106-e(30mg,59.70μmol)和H51-g(24.26mg,59.70μmol)溶于DCM(4mL)中，室温搅拌2h，然后加入NaBH(OAc)3(37.96mg,179.09μmol)，室温搅拌过夜。反应完成后，将反应液浓缩后经CombiFlash(4g，0～12％MeOH/DCM)初步纯化，再经过制备HPLC纯化(制备柱：21.2×250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95乙腈变化)，得到H106(7.82mg,纯度99.4％)，收率：14.58％。MS m/z(ESI):447.2[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.70(s,1H),8.33(t,J＝5.2Hz,1H),7.76(s,1H),7.44(s,1H),6.98-6.89(m,2H),6.89-6.87(m,1H),6.66(dt,J＝9.7,3.5Hz,2H),5.28(dd,J＝12.8,5.4Hz,1H),5.11(d,J＝16.5Hz,1H),4.75-4.62(m,2H),4.56-4.42(m,3H),3.97(d,J＝1.9Hz,3H),3.75(s,2H),3.59(d,J＝11.8Hz,1H),3.28(d,J＝13.7Hz,5H),2.99(q,J＝13.0Hz,2H),2.93-2.74(m,3H),2.70-2.53(m,3H),2.35(q,J＝10.4,9.9Hz,2H),2.07(ddd,J＝60.2,18.8,9.5Hz,5H),1.90-1.73(m,1H),1.57(dd,J＝34.6,11.8Hz,2H),1.22(s,1H)。Step 6: H106-e (30 mg, 59.70 μmol) and H51-g (24.26 mg, 59.70 μmol) were dissolved in DCM (4 mL), stirred at room temperature for 2 h, then NaBH(OAc) 3 (37.96 mg, 179.09 μmol) was added, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and preliminarily purified by CombiFlash (4 g, 0-12% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95 acetonitrile change) to obtain H106 (7.82 mg, purity 99.4%), yield: 14.58%. MS m/z(ESI):447.2[M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),8.70(s,1H),8.33(t,J＝5.2Hz,1H),7.76(s,1H),7.44(s,1H),6.98-6.89(m,2H),6.89-6.87(m,1H),6.66(dt,J ＝9.7,3.5Hz,2H),5.28(dd,J＝12.8,5.4Hz,1H),5.11(d,J＝16.5Hz,1H),4.75-4.62(m,2H),4.56-4.42(m,3H),3.97(d,J＝1.9Hz, 3H),3.75(s,2H),3.59(d,J＝11.8Hz,1H),3.28(d,J＝13.7Hz,5H),2.99(q,J＝13.0Hz,2H),2.93-2.74(m,3H),2.70-2.53(m,3H), 2.35(q,J＝10.4,9.9Hz,2H),2.07(ddd,J＝60.2,18.8,9.5Hz,5H),1.90-1.73(m,1H),1.57(dd,J＝34.6,11.8Hz,2H),1.22(s,1H).

实施例107化合物H107的制备
Example 107 Preparation of Compound H107

步骤1:将3,3-二氟-4-氧代哌啶-1-羧酸叔丁酯(12g,51.01mmol)和苄胺(5.47g,51.01mmol)溶于DCM(100mL)中，然后加入NaBH(OAc)3(21.62g,102.03mmol)，在室温下搅拌18小时。反应完成后，用饱和NaHCO3水溶液淬灭，再二氯甲烷(200mL×3)萃取，合并有机相经饱和食盐水(60mL×1)洗涤，无水硫酸钠干燥，浓缩得到H107-a(16.65g,油状物),收率：100.00％。MS m/z(ESI):327.2[M+H]+。Step 1: tert-Butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (12 g, 51.01 mmol) and benzylamine (5.47 g, 51.01 mmol) were dissolved in DCM (100 mL), and then NaBH(OAc) 3 (21.62 g, 102.03 mmol) was added and stirred at room temperature for 18 hours. After the reaction was completed, it was quenched with saturated NaHCO 3 aqueous solution, extracted with dichloromethane (200 mL×3), and the combined organic phases were washed with saturated brine (60 mL×1), dried over anhydrous sodium sulfate, and concentrated to give H107-a (16.65 g, oily substance), yield: 100.00%. MS m/z(ESI):327.2[M+H] + .

步骤2:将H107-a(16.65g,51.01mmol)和苯甲醛(8.12g,76.52mmol)溶于DCM(100mL)中，然后加入NaBH(OAc)3(21.62g,102.03mmol)，在室温下搅拌18小时。反应完成后，用饱和碳酸氢钠水溶液淬灭，用二氯甲烷(200mL×3)萃取，合并有机相经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(120g，0～45％PE/DCM)，得到H107-b(6.4g,白色固体),收率：30.12％。MS m/z(ESI):417.3[M+H]+。Step 2: H107-a (16.65 g, 51.01 mmol) and benzaldehyde (8.12 g, 76.52 mmol) were dissolved in DCM (100 mL), and then NaBH(OAc) 3 (21.62 g, 102.03 mmol) was added and stirred at room temperature for 18 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (200 mL×3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-45% PE/DCM) to obtain H107-b (6.4 g, white solid), yield: 30.12%. MS m/z (ESI): 417.3 [M+H] + .

步骤3:将H107-b(6.4g,15.37mmol)溶于DCM(35mL)中，然后加入HCl/1,4-二氧六环(4mol/L,25mL)，在室温下搅拌18小时。反应完成后，将反应液浓缩，然后再用饱和NaHCO3水溶液中和，用乙酸乙酯(150mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H107-c(4.6g,白色固体),收率：94.62％。MS m/z(ESI):317.2[M+H]+。Step 3: H107-b (6.4 g, 15.37 mmol) was dissolved in DCM (35 mL), and then HCl/1,4-dioxane (4 mol/L, 25 mL) was added and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated, then neutralized with saturated NaHCO 3 aqueous solution, extracted with ethyl acetate (150 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H107-c (4.6 g, white solid), yield: 94.62%. MS m/z (ESI): 317.2 [M+H] + .

步骤4:将3-(5-溴-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮(1g,2.96mmol)和H107-c(1.50g,4.73mmol)溶于甲苯(60mL)中，然后加入Ruphos(275.99mg,591.44μmol)和Ruphos-Pd-G3(495.26mg,591.44μmol)，在氮气下加入LiHMDS(1mol/L的THF溶液,14.79mL),在90℃条件下搅拌2小时。反应完成后，冷却至室温，将反应液倒入水(60mL)中，用乙酸乙酯(100mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(24g，0～100％EA/PE)，得到H107-d(1.1g,黄色固体),收率：64.85％。MS m/z(ESI):574.2[M+H]+。Step 4: 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol) and H107-c (1.50 g, 4.73 mmol) were dissolved in toluene (60 mL), and then Ruphos (275.99 mg, 591.44 μmol) and Ruphos-Pd-G3 (495.26 mg, 591.44 μmol) were added, and LiHMDS (1 mol/L THF solution, 14.79 mL) was added under nitrogen, and stirred at 90 ° C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, poured into water (60 mL), extracted with ethyl acetate (100 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (24 g, 0-100% EA/PE) to obtain H107-d (1.1 g, yellow solid), yield: 64.85%. MS m/z (ESI): 574.2 [M+H] + .

步骤5:将H107-d(1.1g,1.92mmol)和Pd/C(300mg,10％纯度和50％水)溶于THF(30mL)中，在50℃和氢气氛围下搅拌6小时。反应完成后，将反应液通过硅藻土过滤，用少量甲醇洗涤滤饼，滤液浓缩得到H107-e(690mg,淡黄色固体),收率：91.47％。MS m/z(ESI):394.1[M+H]+。Step 5: H107-d (1.1 g, 1.92 mmol) and Pd/C (300 mg, 10% purity and 50% water) were dissolved in THF (30 mL) and stirred at 50° C. under a hydrogen atmosphere for 6 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with a small amount of methanol, and the filtrate was concentrated to obtain H107-e (690 mg, light yellow solid), yield: 91.47%. MS m/z (ESI): 394.1 [M+H] + .

步骤6:将H10-a(30mg,59.82μmol)和H107-e(35.30mg,89.73μmol)溶于DMF(2mL)，加入HATU(45.14mg,119.64μmol)和DIPEA(23.19mg,179.46μmol,31.26μL)，室温搅拌1小时。反应完成后，向反应液中加入水和乙酸乙酯，乙酸乙酯萃取三次，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(4g，0～15％MeOH/DCM)，再经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：5％-95％乙腈变化)，得H107(12.32mg,纯度100％)，收率：23.49％。MS m/z(ESI):877.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.74(s,1H),8.58(d,J＝8.8Hz,2H),8.04(d,J＝12.4Hz,1H),7.98(d,J＝8.4Hz,1H),7.61(d,J＝8.0Hz,1H),7.42(d,J＝6.2Hz,1H),7.01-6.90(m,3H),6.75-6.66(m,2H),5.29(dd,J＝12.8,5.2Hz,1H),5.16(d,J＝15.2Hz,1H),4.73(s,2H),4.53(t,J＝8.8Hz,3H),4.29-4.14(m,2H),3.94(s,1H),3.71(d,J＝12.0Hz,1H),3.32(s,4H),3.29-3.14(m,2H),3.03-2.83(m,2H),2.75-2.56(m,2H),2.16-1.86(m,3H),1.25(t,J＝6.8Hz,3H),1.16(dd,J＝7.2,2.0Hz,3H)。Step 6: H10-a (30 mg, 59.82 μmol) and H107-e (35.30 mg, 89.73 μmol) were dissolved in DMF (2 mL), HATU (45.14 mg, 119.64 μmol) and DIPEA (23.19 mg, 179.46 μmol, 31.26 μL) were added, and stirred at room temperature for 1 hour. After the reaction was completed, water and ethyl acetate were added to the reaction solution, and ethyl acetate was used for extraction three times. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (4 g, 0-15% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250mm C18 column; system: 10mM NH4HCO3 / H2O -acetonitrile; wavelength: 254/214nm; gradient: 5%-95% acetonitrile change) to obtain H107 (12.32 mg, purity 100%), yield: 23.49%. MS m/z (ESI): 877.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.04(s,1H),8.74(s,1H),8.58(d,J＝8.8Hz,2H),8.04(d,J＝12.4Hz,1H),7.98(d,J＝8.4Hz,1H),7.61(d,J＝8.0Hz, 1H),7.42(d,J＝6.2Hz,1H),7.01-6.90(m,3H),6.75-6.66(m,2H),5.29(dd,J＝12.8,5.2Hz,1H),5.16(d,J＝15.2Hz,1H ),4.73(s,2H),4.53(t,J＝8.8Hz,3H),4.29-4.14(m,2H),3.94(s,1H),3.71(d,J＝12.0Hz,1H),3.32(s,4H),3.29-3.1 4(m,2H),3.03-2.83(m,2H),2.75-2.56(m,2H),2.16-1.86(m,3H),1.25(t,J＝6.8Hz,3H),1.16(dd,J＝7.2,2.0Hz,3H).

实施例108化合物H108的制备
Example 108 Preparation of Compound H108

步骤1:将2-溴-5-碘代苯甲醛(10g,32.1mmol)和2,2-二氟乙胺(3.52g,43.42mmol)溶于DCM(80mL)中，室温搅拌18小时，加入NaBH(OAc)3(13.63g,64.33mmol)，在室温下搅拌24小时。反应完成后，用饱和NaHCO3水溶液淬灭，再二氯甲烷(150mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H108-a(12g,淡黄色油状物),收率：99.23％。MS m/z(ESI):375.9[M+H]+。Step 1: 2-bromo-5-iodobenzaldehyde (10 g, 32.1 mmol) and 2,2-difluoroethylamine (3.52 g, 43.42 mmol) were dissolved in DCM (80 mL), stirred at room temperature for 18 hours, and NaBH(OAc) 3 (13.63 g, 64.33 mmol) was added, and stirred at room temperature for 24 hours. After the reaction was completed, it was quenched with saturated aqueous NaHCO 3 solution, and then extracted with dichloromethane (150 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to give H108-a (12 g, light yellow oil), yield: 99.23%. MS m/z (ESI): 375.9 [M+H] + .

步骤2:将H108-a(12g,31.92mmol)和Et3N(16.12g,159.58mmol)溶解在DCM(50mL)中，室温搅拌下加入Boc2O(20.90g,95.75mmol)，将反应液升温至45℃搅拌过夜。反应完成后，将反应液浓缩后经CombiFlash纯化(120g，0～40％EA/PE)，得到H108-b(15g,黄色油状物),收率：98.71％。MS m/z(ESI):419.9[M-56+H]+。Step 2: H108-a (12 g, 31.92 mmol) and Et 3 N (16.12 g, 159.58 mmol) were dissolved in DCM (50 mL), and Boc 2 O (20.90 g, 95.75 mmol) was added under stirring at room temperature, and the reaction solution was heated to 45°C and stirred overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (120 g, 0-40% EA/PE) to obtain H108-b (15 g, yellow oil), yield: 98.71%. MS m/z (ESI): 419.9 [M-56+H] + .

步骤3:将H108-b(15g,31.51mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(9.74g,31.51mmol)溶于1,4-二氧六环(90mL)，H2O(16mL)和DMSO(9mL)中，加入Pd(dppf)Cl2(2.31g,3.15mmol)和K2CO3(8.71g,63.01mmol)，在80℃条件下搅拌16小时。反应完成后，将反应液倒入水(150mL)中淬灭，用乙酸乙酯(250mL×3)萃取，合并有机相经饱和食盐水(150mL)洗涤，无水硫酸钠干燥，浓缩后经CombiFlash纯化(120g，0～40％EA/PE)，得到H108-c(10g,无色粘稠油状物),收率：59.73％。MS m/z(ESI):375.0[M-156+H]+。Step 3: H108-b (15 g, 31.51 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9.74 g, 31.51 mmol) were dissolved in 1,4-dioxane (90 mL), H 2 O (16 mL) and DMSO (9 mL), Pd(dppf)Cl 2 (2.31 g, 3.15 mmol) and K 2 CO 3 (8.71 g, 63.01 mmol) were added, and the mixture was stirred at 80° C. for 16 hours. After the reaction was completed, the reaction solution was poured into water (150 mL) for quenching, extracted with ethyl acetate (250 mL×3), the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-40% EA/PE) to obtain H108-c (10 g, colorless viscous oil), yield: 59.73%. MS m/z (ESI): 375.0 [M-156+H] + .

步骤4:将H108-c(10g,18.82mmol)和Pd(dppf)Cl2(1.38g,1.88mmol)溶于1,4-二氧六环(120mL)中，加入B2(pin)2(7.17g,28.23mmol)和KOAc(4.62g,47.04mmol)，在氮气氛围下升温至95℃并搅拌6小时。反应完成后，将反应液冷却到室温，过滤，滤液浓缩后经CombiFlash纯化(80g，0～20％EA/PE)，得到H108-d(8g,淡黄色油状物),收率：73.49％。MS m/z(ESI):423.2[M-156+H]+。Step 4: H108-c (10 g, 18.82 mmol) and Pd(dppf)Cl 2 (1.38 g, 1.88 mmol) were dissolved in 1,4-dioxane (120 mL), and B 2 (pin) 2 (7.17 g, 28.23 mmol) and KOAc (4.62 g, 47.04 mmol) were added. The mixture was heated to 95°C and stirred for 6 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by CombiFlash (80 g, 0-20% EA/PE) to obtain H108-d (8 g, light yellow oil), yield: 73.49%. MS m/z (ESI): 423.2 [M-156+H] + .

步骤5:将H108-d(8g,13.83mmol)和Pd/C(2.2g,10％纯度和50％水)溶于MeOH(100mL)中，在氢气氛围下室温条件下搅拌1小时。反应完成后，将反应液过滤，滤饼用少量甲醇洗涤，滤液浓缩得到H108-e(6g,淡黄色固体),收率：74.74％。MS m/z(ESI):425.2[M-156+H]+。Step 5: H108-d (8 g, 13.83 mmol) and Pd/C (2.2 g, 10% purity and 50% water) were dissolved in MeOH (100 mL) and stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with a small amount of methanol, and the filtrate was concentrated to obtain H108-e (6 g, light yellow solid), yield: 74.74%. MS m/z (ESI): 425.2 [M-156+H] + .

步骤6:将H108-e(3.52g,6.07mmol)和8-溴-5-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(2.2g,5.05mmol)溶于1,4-二氧六环(33mL)和H2O(6mL)，DMSO(3.3mL)中，在氩气保护下加入Pd(dppf)Cl2(369.85mg,505.46μmol)和K2CO3(1.40g,10.11mmol)，反应液升温至95℃并搅拌3小时。反应完成后，将反应液浓缩后加入水(60mL)和乙酸乙酯(100mL)，过滤掉絮状物，滤液用乙酸乙酯(150mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(40g，0～70％EA/PE)，得到H108-f(3g),收率：73.37％。MS m/z(ESI):653.4[M-156+H]+。Step 6: H108-e (3.52 g, 6.07 mmol) and ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylate (2.2 g, 5.05 mmol) were dissolved in 1,4-dioxane (33 mL), H 2 O (6 mL) and DMSO (3.3 mL). Pd(dppf)Cl 2 (369.85 mg, 505.46 μmol) and K 2 CO 3 (1.40 g, 10.11 mmol) were added under argon protection. The reaction solution was heated to 95° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was concentrated, and water (60 mL) and ethyl acetate (100 mL) were added to filter out the floccules. The filtrate was extracted with ethyl acetate (150 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (40 g, 0-70% EA/PE) to obtain H108-f (3 g), with a yield of 73.37%. MS m/z (ESI): 653.4 [M-156+H] + .

步骤7:将H108-f(3g,3.71mmol)溶于DCM(30mL)中，加入HCl/1,4-二氧六环(4mol/L,15mL)，在室温下搅拌3小时。反应完成后，将反应液浓缩后用饱和碳酸氢钠水溶液淬灭，用二氯甲烷洗涤有机相，水相过滤，滤饼干燥得到H108-g(2.31g,黄色固体,HCl),收率：96.55％。MS m/z(ESI):609.3[M+H]+。Step 7: H108-f (3 g, 3.71 mmol) was dissolved in DCM (30 mL), HCl/1,4-dioxane (4 mol/L, 15 mL) was added, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and quenched with saturated sodium bicarbonate aqueous solution, the organic phase was washed with dichloromethane, the aqueous phase was filtered, and the filter cake was dried to obtain H108-g (2.31 g, yellow solid, HCl), yield: 96.55%. MS m/z (ESI): 609.3 [M+H] + .

步骤8:将H108-g(2.31g,3.58mmol,HCl)溶于THF(40mL)和H2O(8mL)中，加入LiOH(1.61g,67.06mmol)，在80℃条件下搅拌18小时。反应完成后，将反应液冷却至室温，用二氯甲烷(250mL×3)萃取，合并有机相经无水硫酸钠干燥，浓缩得到H108-h(1.4g),收率：69.50％。MS m/z(ESI):563.2[M+H]+。Step 8: H108-g (2.31 g, 3.58 mmol, HCl) was dissolved in THF (40 mL) and H 2 O (8 mL), LiOH (1.61 g, 67.06 mmol) was added, and the mixture was stirred at 80° C. for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with dichloromethane (250 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H108-h (1.4 g), with a yield of 69.50%. MS m/z (ESI): 563.2 [M+H] + .

步骤9:将H108-h(150mg,266.63μmol)和H39-b(197.52mg,533.25μmol)溶于DCM(10mL)中，然后加入NaBH(OAc)3(226.04mg,1.07mmol)，在室温下搅拌3小时。反应完成后，将反应液浓缩后经CombiFlash(4g，0～14％MeOH/DCM)初步纯化，再经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)，得到H108(39.69mg),收率：16.09％。MS m/z(ESI):917.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.77(s,1H),8.51(s,1H),7.52(s,1H),7.40(s,1H),7.38(s,1H),7.30(d,J＝7.9Hz,1H),6.93(dd,J＝12.5,9.2Hz,2H),6.81(s,1H),6.69(dd,J＝8.6,3.8Hz,1H),6.62(d,J＝7.0Hz,1H),6.24(t,J＝56.1Hz,1H),5.27(dd,J＝12.8,5.3Hz,1H),5.20(d,J＝14.8Hz,1H),4.71(d,J＝4.8Hz,2H),4.53(t,J＝8.7Hz,2H),4.15(d,J＝14.9Hz,1H),4.08(d,J＝11.3Hz,1H),3.58(d,J＝10.6Hz,3H),3.34(s,4H),2.98(d,J＝10.2Hz,2H),2.87(t,J＝14.6Hz,1H),2.74-2.51(m,5H),2.20(d,J＝6.9Hz,2H),1.98(d,J＝7.1Hz,3H),1.88-1.55(m,7H),1.37-1.14(m,3H)。Step 9: H108-h (150 mg, 266.63 μmol) and H39-b (197.52 mg, 533.25 μmol) were dissolved in DCM (10 mL), and then NaBH(OAc) 3 (226.04 mg, 1.07 mmol) was added and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and preliminarily purified by CombiFlash (4 g, 0-14% MeOH/DCM), and then purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H108 (39.69 mg), yield: 16.09%. MS m/z (ESI): 917.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.04(s,1H),8.77(s,1H),8.51(s,1H),7.52(s,1H),7.40(s,1H),7.38(s,1H),7.30(d,J＝7.9Hz,1H),6.93(dd,J＝12.5,9.2Hz,2H),6.8 1(s,1H),6.69(dd,J＝8.6,3.8Hz,1H),6.62(d,J＝7.0Hz,1H),6.24(t,J＝56.1Hz,1H),5.27(dd,J＝12.8,5.3Hz,1H),5.20(d,J＝14.8Hz,1H),4 .71(d,J＝4.8Hz,2H),4.53(t,J＝8.7Hz,2H),4.15(d,J＝14.9Hz,1H),4.08(d,J＝11.3Hz,1H),3.58(d,J＝10.6Hz,3H),3.34(s,4H),2.98(d,J＝ 10.2Hz,2H),2.87(t,J＝14.6Hz,1H),2.74-2.51(m,5H),2.20(d,J＝6.9Hz,2H),1.98(d,J＝7.1Hz,3H),1.88-1.55(m,7H),1.37-1.14(m,3H).

实施例109化合物H109的制备
Example 109 Preparation of Compound H109

步骤1-步骤7:参照实施例70的制备方法，按照上述合成路线，制备得到H109-g，MS m/z(ESI):623.3[M+H]+。Step 1-Step 7: Referring to the preparation method of Example 70, according to the above synthetic route, H109-g was prepared, MS m/z (ESI): 623.3 [M+H] + .

步骤8:将H109-g(2.45g,3.93mmol)溶解于THF(40mL)和水(20mL)中，加入LiOH(1.41g,59.02mmol)，在80℃下搅拌反应20小时。反应完成后，将反应液用稀盐酸(1mol/L)调pH至3～4，浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：0.04％FA，乙腈；波长：254/214nm；梯度：48％-58％乙腈变化)，得到H109-h(300mg,白色固体)，收率：12.82％。MS m/z(ESI):595.3[M+H]+。Step 8: H109-g (2.45 g, 3.93 mmol) was dissolved in THF (40 mL) and water (20 mL), LiOH (1.41 g, 59.02 mmol) was added, and the mixture was stirred at 80°C for 20 hours. After the reaction was completed, the reaction solution was adjusted to pH 3-4 with dilute hydrochloric acid (1 mol/L), concentrated, and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 0.04% FA, acetonitrile; wavelength: 254/214 nm; gradient: 48%-58% acetonitrile change) to obtain H109-h (300 mg, white solid), yield: 12.82%. MS m/z (ESI): 595.3 [M+H] + .

步骤9:将H109-h(250mg,420.43μmol)和DIPEA(163.01mg,1.26mmol,219.69μL)溶解于DMF(5mL)中，加入HATU(111.03mg,294.30μmol)，在室温下(25℃)搅拌反应1小时。反应完成后，将反应液浓缩后经combiflash(MeOH：DCM＝0～20％)纯化，得到H109-i(100mg,黄色固体)，收率：41.25％。MS m/z(ESI):577.2[M+H]+。Step 9: H109-h (250 mg, 420.43 μmol) and DIPEA (163.01 mg, 1.26 mmol, 219.69 μL) were dissolved in DMF (5 mL), HATU (111.03 mg, 294.30 μmol) was added, and the mixture was stirred at room temperature (25°C) for 1 hour. After the reaction was completed, the reaction solution was concentrated and purified by combiflash (MeOH: DCM = 0-20%) to obtain H109-i (100 mg, yellow solid), yield: 41.25%. MS m/z (ESI): 577.2 [M+H] + .

步骤10:将H109-i(90mg,156.08μmol)和H39-b(115.63mg,312.17μmol)溶解于DCM(20mL)中，加入NaBH(OAc)3(99.24mg,468.25μmol)，在室温下(25℃)搅拌反应2小时。反应完成后，将反应液浓缩后经制备HPLC纯化(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：60％-63％乙腈变化)，得到H109(15.87mg,纯度：95.74％),收率：10.46％。MS m/z(ESI):466.3[M/2+H]+。1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.78(s,1H),8.51(s,1H),7.47-7.35(m,3H),7.31(dd,J＝8.1,1.7Hz,1H),6.97-6.87(m,2H),6.81(d,J＝2.2Hz,1H),6.69(dd,J＝8.7,3.8Hz,1H),6.62(dd,J＝8.7,2.2Hz,1H),5.35-5.13(m,2H),4.71(d,J＝3.9Hz,2H),4.53(t,J＝8.7Hz,2H),4.31(d,J＝15.7Hz,1H),4.13(d,J＝15.1Hz,1H),3.57(d,J＝11.5Hz,2H),3.53-3.39(m,2H),3.29(s,4H),2.92(dd,J＝38.3,6.3Hz,3H),2.62(tt,J＝16.7,4.8Hz,5H),2.19(d,J＝7.1Hz,2H),1.97(d,J＝11.7Hz,3H),1.85-1.59(m,10H),1.25(q,J＝9.3,7.9Hz,2H)。Step 10: H109-i (90 mg, 156.08 μmol) and H39-b (115.63 mg, 312.17 μmol) were dissolved in DCM (20 mL), and NaBH(OAc) 3 (99.24 mg, 468.25 μmol) was added, and the mixture was stirred at room temperature (25° C.) for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 60%-63% acetonitrile change) to obtain H109 (15.87 mg, purity: 95.74%), yield: 10.46%. MS m/z (ESI): 466.3 [M/2+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.03(s,1H),8.78(s,1H),8.51(s,1H),7.47-7.35(m,3H),7.31(dd,J＝8.1,1.7Hz,1H),6.97-6.87(m,2H),6.81(d,J＝2.2Hz, 1H),6.69(dd,J＝8.7,3.8Hz,1H),6.62(dd,J＝8.7,2.2Hz,1H),5.35-5.13(m,2H),4.71(d,J＝3.9Hz,2H),4.53(t,J＝8.7Hz,2H),4 .31(d,J＝15.7Hz,1H),4.13(d,J＝15.1Hz,1H),3.57(d,J＝11.5Hz,2H),3.53-3.39(m,2H),3.29(s,4H),2.92(dd,J＝38.3,6.3Hz, 3H), 2.62 (tt, J＝16.7, 4.8Hz, 5H), 2.19 (d, J＝7.1Hz, 2H), 1.97 (d, J＝11.7Hz, 3H), 1.85-1.59 (m, 10H), 1.25 (q, J＝9.3, 7.9Hz, 2H).

实施例163化合物H163的制备
Example 163 Preparation of Compound H163

步骤1：NaH(5.0g，125.5mmol)加入无水DMSO(70mL)中，降温至0℃。将溶有2-(二苯基亚甲基氨基)乙酸乙酯(18.4g，69mmol)的DMSO(50mL)溶液滴加到上述混合物。10分钟后，滴加5-溴-4-氯-2-(甲硫基)嘧啶(15g，62.7mmol)的DMSO(50mL)溶液。混合物在室温下搅拌2小时。反应液用饱和NH4Cl水溶液淬灭，乙酸乙酯萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash过柱(0～30％EA/PE)纯化，得到H163-a(28g),收率：95％。MS m/z(ESI):470.0[M+H]+。Step 1: NaH (5.0 g, 125.5 mmol) was added to anhydrous DMSO (70 mL) and the temperature was lowered to 0°C. A solution of ethyl 2-(diphenylmethyleneamino)acetate (18.4 g, 69 mmol) in DMSO (50 mL) was added dropwise to the above mixture. After 10 minutes, a solution of 5-bromo-4-chloro-2-(methylthio)pyrimidine (15 g, 62.7 mmol) in DMSO (50 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated NH 4 Cl aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash column (0-30% EA/PE) to obtain H163-a (28 g), yield: 95%. MS m/z (ESI): 470.0 [M+H] + .

步骤2：将H163-a(19.6g,41.67mmol)溶于THF(200mL)和水(120mL)中，在0℃加入浓盐酸(40mL)。反应液用饱和Na2CO3水溶液中和至pH＝9，二氯甲烷萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash纯化(0～50％EA/PE)，得到H163-b(11.86g,黄色固体)，收率：92.96％。MS m/z(ESI):306.0[M+H]+。Step 2: H163-a (19.6 g, 41.67 mmol) was dissolved in THF (200 mL) and water (120 mL), and concentrated hydrochloric acid (40 mL) was added at 0°C. The reaction solution was neutralized with saturated Na 2 CO 3 aqueous solution to pH = 9, extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (0-50% EA/PE) to obtain H163-b (11.86 g, yellow solid), yield: 92.96%. MS m/z (ESI): 306.0 [M+H] + .

步骤3：将H163-b(11.3g,36.91mmol)和1-(叔丁氧基羰基)哌啶-4-羧酸(8.46g,36.91mmol)溶于DMF(60mL)中，加入DIPEA(14.31g,110.72mmol)和HATU(18.10g,47.98mmol)，反应液在室温下搅拌20小时。反应完成后，将反应液倒入水中，用乙酸乙酯萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash分离纯化(0～50％EA/PE)，得到H163-c(17.91g,黄色固体)，收率：34.61％。MS m/z(ESI):461.0[M+H-56]+。Step 3: H163-b (11.3 g, 36.91 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (8.46 g, 36.91 mmol) were dissolved in DMF (60 mL), and DIPEA (14.31 g, 110.72 mmol) and HATU (18.10 g, 47.98 mmol) were added. The reaction solution was stirred at room temperature for 20 hours. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash separation (0-50% EA/PE) to obtain H163-c (17.91 g, yellow solid), yield: 34.61%. MS m/z (ESI): 461.0 [M+H-56] + .

步骤4：将H163-c(8.8g,17.01mmol)溶于DCM(80mL)中，降温至0℃，加入间氯过氧苯甲酸(8.29g,85％纯度)，反应液在0℃搅拌2小时。反应完成后，得到含H163-d的反应液，将反应液过滤，洗涤滤饼，滤液直接用于下一步反应。MS m/z(ESI):433.0[M+H-100]+。Step 4: H163-c (8.8 g, 17.01 mmol) was dissolved in DCM (80 mL), cooled to 0°C, and m-chloroperbenzoic acid (8.29 g, 85% purity) was added. The reaction solution was stirred at 0°C for 2 hours. After the reaction was completed, a reaction solution containing H163-d was obtained. The reaction solution was filtered, the filter cake was washed, and the filtrate was directly used for the next reaction. MS m/z (ESI): 433.0 [M+H-100] + .

步骤5：将H163-d(9g,16.87mmol)和(5-氟-2,3-二氢苯并呋喃-4-基)甲胺(3.67g,21.93mmol)溶于DCM(60mL)中，加入DIPEA(21.81g,168.72mmol,29.39mL)，反应液在室温搅拌过夜。反应完成后，将反应液浓缩后经CombiFlash分离纯化(0～100％EA/PE)，得到H163-e(10.46g,黄色固体)，收率：97.40％。MS m/z(ESI):580.1[M+H-56]+。Step 5: H163-d (9 g, 16.87 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (3.67 g, 21.93 mmol) were dissolved in DCM (60 mL), and DIPEA (21.81 g, 168.72 mmol, 29.39 mL) was added. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash separation (0-100% EA/PE) to obtain H163-e (10.46 g, yellow solid), yield: 97.40%. MS m/z (ESI): 580.1 [M+H-56] + .

步骤6：将H163-e(4g,6.28mmol)溶于DCE(100mL)中，加入吡啶(25.53g,322.75mmol)和三氯氧膦(21.39g,139.47mmol)，反应液加热到100℃搅拌2小时。反应完成后，将反应液倒入水中，加入饱和NaHCO3水溶液中和，过滤，洗涤滤饼，滤液用乙酸乙酯萃取，合并有机相经无水硫酸钠干燥，浓缩得到H163-f(2.5g,粗品)，收率：76.74％，直接用于下一步反应。MS m/z(ESI):518.2[M+H]+。Step 6: H163-e (4 g, 6.28 mmol) was dissolved in DCE (100 mL), pyridine (25.53 g, 322.75 mmol) and trichlorophosphine (21.39 g, 139.47 mmol) were added, and the reaction solution was heated to 100 ° C and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into water, saturated NaHCO 3 aqueous solution was added for neutralization, filtered, the filter cake was washed, and the filtrate was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to obtain H163-f (2.5 g, crude product), yield: 76.74%, which was directly used for the next step reaction. MS m/z (ESI): 518.2 [M+H] + .

步骤7：将H163-f(5g,9.65mmol)溶于DCM(30mL)中，加入DIPEA(3.90g,5.38mL)和二碳酸二叔丁酯(4.21g,19.29mmol)，反应液在室温搅拌过夜。反应完成后，将反应液浓缩后经CombiFlash分离纯化(0～100％EA/PE)，得到H163-g(2.55g,黄色固体)，收率：42.74％。MS m/z(ESI):618.2[M+H]+。Step 7: H163-f (5 g, 9.65 mmol) was dissolved in DCM (30 mL), and DIPEA (3.90 g, 5.38 mL) and di-tert-butyl dicarbonate (4.21 g, 19.29 mmol) were added. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash separation (0-100% EA/PE) to obtain H163-g (2.55 g, yellow solid), yield: 42.74%. MS m/z (ESI): 618.2 [M+H] + .

步骤8：将H163-g(2g,3.23mmol)和N-[[5-溴-2-(三氟甲基)-4-吡啶基]甲基]-N-异丙基氨基甲酸叔丁酯(1.28g,3.23mmol)溶于DME(50mL)和水(5mL)中，加入Pd(OAc)2(145.20mg,0.65mmol)、CataCXium A(464mg,1.29mmol)、K2CO3(1.34g,9.70mmol)和联硼酸频那醇酯(2.46g,9.70mmol)，反应液在75℃氩气保护下反应20小时。反应完成后，将反应液倒入水中，用乙酸乙酯萃取，合并有机相经无水硫酸钠干燥，浓缩后经CombiFlash分离纯化(0～100％EA/PE)，得到H163-h(1.1g,黄色固体)，收率：39.74％。Step 8: H163-g (2 g, 3.23 mmol) and tert-butyl N-[[5-bromo-2-(trifluoromethyl)-4-pyridinyl]methyl]-N-isopropylcarbamate (1.28 g, 3.23 mmol) were dissolved in DME (50 mL) and water (5 mL), and Pd(OAc) 2 (145.20 mg, 0.65 mmol), CataCXium A (464 mg, 1.29 mmol), K 2 CO 3 (1.34 g, 9.70 mmol) and biboric acid pinacol ester (2.46 g, 9.70 mmol) were added, and the reaction solution was reacted at 75 °C under argon protection for 20 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash separation (0-100% EA/PE) to obtain H163-h (1.1 g, yellow solid) with a yield of 39.74%.

步骤9：将H163-h(1g,1.17mmol)溶于DCM(30mL)中，加入TFA(8.93g,78.35mmol)。反应液在室温下搅拌4小时。反应完成后，将反应液减压浓缩后用饱和NaHCO3水溶液中和至碱性，二氯甲烷萃取，合并有机相经无水硫酸钠干燥，浓缩后经制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)纯化，得到H163-i(550mg),收率：71.80％。MS m/z(ESI):656.3[M+H]+。Step 9: H163-h (1 g, 1.17 mmol) was dissolved in DCM (30 mL), and TFA (8.93 g, 78.35 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and neutralized with a saturated NaHCO 3 aqueous solution to alkalinity, extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H163-i (550 mg), yield: 71.80%. MS m/z (ESI): 656.3 [M+H] + .

步骤10：将H163-i(148mg,0.23mmol)溶于甲苯(15mL)和四氢呋喃(1mL)中，加入三甲基铝(2mol/L,1.35mL,30％纯度)，反应液在60℃搅拌1小时。反应完成后，将反应液在0℃用甲醇淬灭，浓缩后经CombiFlash分离纯化(0～20％MeOH/DCM)，得到H163-j(33mg,黄色固体)，收率：23.98％。MS m/z(ESI):610.3[M+H]+。Step 10: H163-i (148 mg, 0.23 mmol) was dissolved in toluene (15 mL) and tetrahydrofuran (1 mL), trimethylaluminum (2 mol/L, 1.35 mL, 30% purity) was added, and the reaction solution was stirred at 60°C for 1 hour. After the reaction was completed, the reaction solution was quenched with methanol at 0°C, concentrated and purified by CombiFlash (0-20% MeOH/DCM) to obtain H163-j (33 mg, yellow solid), yield: 23.98%. MS m/z (ESI): 610.3 [M+H] + .

步骤11：将H163-j(15mg,24.61μmol)和1-[2-(2,6-二氧代-3-哌啶基)-1,3-二氧代异吲哚啉-5-基]哌啶-4-甲醛(18mg,49.21μmol)溶于DCM(10mL)中，加入NaBH(OAc)3(8mg,36.91μmol)，反应液在室温下搅拌过夜。反应完成后，将反应液浓缩后经制备HPLC(制备柱：21.2X250mm C18柱；体系：10mM NH4HCO3/H2O-乙腈；波长：254/214nm；梯度：0％-60％乙腈变化)纯化，得到H163(7.68mg),收率：32.06％。MS m/z(ESI):963.4[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.84(s,1H),8.07(s,1H),7.74-7.60(m,2H),7.43(s,1H),7.30(s,1H),7.23(d,J＝8.7Hz,1H),6.97-6.88(m,1H),6.69(dd,J＝8.7,3.8Hz,1H),5.21(d,J＝14.7Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.65(s,1H),4.58(t,J＝9.4Hz,2H),4.34(d,J＝14.8Hz,1H),4.21(t,J＝10.2Hz,1H),4.04(d,J＝11.6Hz,2H),3.59-3.40(m,3H),3.04-2.81(m,5H),2.69-2.51(m,5H),2.19-1.90(m,6H),1.88-1.65(m,5H),1.26(d,J＝6.7Hz,3H),1.13(d,J＝6.8Hz,4H).Step 11: H163-j (15 mg, 24.61 μmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carboxaldehyde (18 mg, 49.21 μmol) were dissolved in DCM (10 mL), and NaBH(OAc) 3 (8 mg, 36.91 μmol) was added. The reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2X250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 0%-60% acetonitrile change) to obtain H163 (7.68 mg), yield: 32.06%. MS m/z (ESI): 963.4 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.06(s,1H),8.84(s,1H),8.07(s,1H),7.74-7.60(m,2H),7.43(s,1H),7.30(s,1H),7.23(d,J＝8.7Hz,1H),6.9 7-6.88(m,1H),6.69(dd,J＝8.7,3.8Hz,1H),5.21(d,J＝14.7Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.65(s,1H),4.58 (t,J＝9.4Hz,2H),4.34(d,J＝14.8Hz,1H),4.21(t,J＝10.2Hz,1H),4.04(d,J＝11.6Hz,2H),3.59-3.40(m,3H),3.04- 2.81(m,5H),2.69-2.51(m,5H),2.19-1.90(m,6H),1.88-1.65(m,5H),1.26(d,J＝6.7Hz,3H),1.13(d,J＝6.8Hz,4H).

表1所列化合物可参照上述的制备方法制备得到：The compounds listed in Table 1 can be prepared by referring to the above preparation method:

表1








Table 1








表2所列化合物也可参照上述的制备方法制备得到：The compounds listed in Table 2 can also be prepared by referring to the above preparation method:

表2








Table 2








生物测试Biological Testing

测试例1.化合物对EED蛋白降解测试Test Example 1. Test on the degradation of EED protein by compounds

1.1化合物对wsuDLCL-2细胞内的EED蛋白降解测试1.1 Test of compound degradation of EED protein in wsuDLCL-2 cells

材料与试剂如表3所示：Materials and reagents are shown in Table 3:

表3材料与试剂
Table 3 Materials and reagents

本实验采用In-cell western(ICW)的方法，对wsuDLCL-2细胞中的EED蛋白表达量进行定量分析，以检测化合物对靶蛋白的降解活性。In this experiment, the In-cell western (ICW) method was used to quantitatively analyze the expression of EED protein in wsuDLCL-2 cells to detect the degradation activity of the compound on the target protein.

1、wsuDLCL-2细胞购自南京科佰(货号CBP60073)，以RPMI-1640完全培养基(含10％v/v胎牛血清)按照供应商的推荐条件传代培养并维持对数生长状态，测试中使用的细胞其传代次数不超过20次；1. wsuDLCL-2 cells were purchased from Nanjing Kebai (Cat. No. CBP60073) and subcultured in RPMI-1640 complete medium (containing 10% v/v fetal bovine serum) according to the supplier's recommended conditions and maintained in a logarithmic growth state. The cells used in the test were subcultured no more than 20 times;

2、细胞种植前一天，以100μL包被缓冲液(含20μg/mL多聚赖氨酸的磷酸盐缓冲液)于室温下包被96孔板2小时，弃去包被液后以300μL磷酸盐缓冲液冲洗1次并弃去液体，置于超净工作台中自然晾干后以Parafilm包裹板边防止受潮，保存于4℃冰箱中待用；2. One day before cell seeding, coat the 96-well plate with 100 μL coating buffer (phosphate buffer containing 20 μg/mL poly-lysine) at room temperature for 2 hours. After discarding the coating solution, rinse once with 300 μL phosphate buffer and discard the liquid. Place it in a clean bench to dry naturally, wrap the edge of the plate with Parafilm to prevent moisture, and store it in a refrigerator at 4°C for use;

3、细胞种板前收集于离心管中，于250rcf离心3分钟并弃去培养基，以新鲜的完全培养基重悬后，吸取20μL细胞液并在Countstar细胞计数仪上计算细胞浓度，调整密度后以20,000个细胞/90μL的方式种植于准备好的包被板中，置于37℃，5％CO2培养箱中预孵育4小时；3. Before seeding the cells, collect them in a centrifuge tube, centrifuge at 250 rcf for 3 minutes and discard the culture medium. Resuspend them in fresh complete culture medium, aspirate 20 μL of cell solution and calculate the cell concentration on a Countstar cell counter. After adjusting the density, seed them in the prepared coated plate at 20,000 cells/90 μL and pre-incubate them in a 37°C, 5% CO 2 incubator for 4 hours.

4、以10μL对照液(含2.5％v/v DMSO的非完全培养基，RPMI-1640培养基，在其中加入2.5％v/v的DMSO配置而成)处理阴性和阳性对照组，使用非完全培养基配置化合物梯度稀释液后，以10μL稀释液加入对应的培养孔中，测试中DMSO的终浓度为0.25％v/v，随后置于37℃，5％CO2培养箱中孵育48小时(EED检测)；4. Treat the negative and positive control groups with 10 μL of control solution (incomplete medium containing 2.5% v/v DMSO, RPMI-1640 medium, prepared by adding 2.5% v/v DMSO), prepare the compound gradient dilution solution using incomplete medium, add 10 μL of dilution solution to the corresponding culture wells, the final concentration of DMSO in the test is 0.25% v/v, and then incubate in a 37°C, 5% CO2 incubator for 48 hours (EED detection);

5、以10μL固定液(含5％v/v戊二醛的磷酸盐缓冲液)直接加入细胞中并于室温下固定细胞30分钟，弃去固定液，随后以100μL透化液(含0.1％v/v Triton X-100的磷酸盐缓冲液)于室温下透化细胞30分钟，弃去透化液；5. Add 10 μL of fixative solution (phosphate buffer containing 5% v/v glutaraldehyde) directly to the cells and fix the cells at room temperature for 30 minutes, discard the fixative solution, and then permeabilize the cells with 100 μL of permeabilization solution (phosphate buffer containing 0.1% v/v Triton X-100) at room temperature for 30 minutes, and discard the permeabilization solution;

6、配置足量的抗体稀释液(含1％w/v牛血清白蛋白的Tris缓冲盐-吐温溶液)，保存于4℃冰箱中待用；6. Prepare sufficient antibody diluent (Tris buffered saline-Tween solution containing 1% w/v bovine serum albumin) and store in a 4°C refrigerator for later use;

7、配置一抗稀释液(以抗体稀释液按1:500比例稀释EED抗体)，在阴性对照组中加入100μL不含抗体的抗体稀释液，其余组以100μL一抗稀释液加入细胞中，置于4℃下过夜孵育；7. Prepare the primary antibody diluent (dilute the EED antibody with the antibody diluent at a ratio of 1:500), add 100 μL of the antibody diluent without antibody to the negative control group, and add 100 μL of the primary antibody diluent to the cells in the other groups, and incubate overnight at 4°C;

8、弃去一抗稀释液，以300μL Tris缓冲盐-吐温溶液清洗3次培养板后弃去清洗液，配置二抗稀释液(以抗体稀释液按1:500比例稀释HRP偶联抗体)，以100μL加入细胞中，置于室温下孵育2小时；8. Discard the primary antibody diluent, wash the culture plate three times with 300 μL Tris buffered saline-Tween solution, then discard the washing solution, prepare the secondary antibody diluent (dilute the HRP-coupled antibody with the antibody diluent at a ratio of 1:500), add 100 μL to the cells, and incubate at room temperature for 2 hours;

9、弃去二抗稀释液，以300μL Tris缓冲盐-吐温溶液清洗3次培养板后弃去清洗液，加入100μL TMB底物溶液，于室温下避光孵育15分钟，随后加入停止液(2M硫酸)终止反应，随后于读板仪上读取OD450nm数值，结果用于分析靶蛋白降解比例和化合物活性；9. Discard the secondary antibody diluent, wash the culture plate three times with 300 μL Tris buffered saline-Tween solution, then discard the washing solution, add 100 μL TMB substrate solution, incubate at room temperature in the dark for 15 minutes, then add stop solution (2M sulfuric acid) to terminate the reaction, and then read the OD 450nm value on the plate reader. The results are used to analyze the degradation ratio of the target protein and the activity of the compound;

10、设置阴性对照组的信号值为Bottom，阳性对照组的信号值为Top，化合物的浓度值(对数)为X轴，对应浓度的OD450nm值为Y轴，HillSlope为斜率因子，采用四参数对数曲线(4PL logistic model)进行拟合，计算方式见下：10. Set the signal value of the negative control group to Bottom, the signal value of the positive control group to Top, the concentration value (logarithm) of the compound as the X-axis, the OD 450nm value of the corresponding concentration as the Y-axis, HillSlope as the slope factor, and use the four-parameter logarithmic curve (4PL logistic model) for fitting. The calculation method is as follows:

Y＝Bottom+(Top-Bottom)/(1+10^((LogDC50-X)*HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogDC50-X)*HillSlope))

拟合后计算求得化合物的DC50值，并根据DC50比较化合物的靶蛋白降解活性。After fitting, the DC50 values of the compounds were calculated and the target protein degradation activities of the compounds were compared based on DC50 .

测试结果显示，本申请实施例化合物对EED蛋白具有优异的降解作用，其半数最大降解浓度DC50值小于1μM，部分实施例化合物的DC50值小于500nM，部分实施例化合物的DC50值小于100nM。本发明实施例化合物对EED蛋白的最大降解率Dmax大于50％。部分实施例化合物的降解活性如表4所示。The test results show that the compounds of the present invention have excellent degradation effects on EED protein, and their half maximum degradation concentration DC 50 value is less than 1 μM, the DC 50 value of some of the compounds of the present invention is less than 500 nM, and the DC 50 value of some of the compounds of the present invention is less than 100 nM. The maximum degradation rate Dmax of the compounds of the present invention on EED protein is greater than 50%. The degradation activity of some of the compounds of the present invention is shown in Table 4.

表4化合物对wsuDLCL-2细胞内EED蛋白的降解活性
Table 4 Degradation activity of compounds on EED protein in wsuDLCL-2 cells

1.2化合物对Karpas-422细胞内的EED蛋白降解测试(ICW法)1.2 Compounds Degradation of EED Protein in Karpas-422 Cells (ICW Method)

试剂与材料如表5所示：Reagents and materials are shown in Table 5:

表5试剂与材料

Table 5 Reagents and materials

本实验采用In-cell western(ICW)的方法，对Karpas-422细胞中的EED蛋白表达量进行定量分析，以检测化合物对靶蛋白的降解活性。In this experiment, the In-cell western (ICW) method was used to quantitatively analyze the expression of EED protein in Karpas-422 cells to detect the degradation activity of the compound on the target protein.

1.Karpas-422细胞购自南京科佰(货号CBP60629)，以RPMI-1640完全培养基(含10％v/v胎牛血清)按照供应商的推荐条件传代培养并维持对数生长状态，测试中使用的细胞其传代次数不超过20次；1. Karpas-422 cells were purchased from Nanjing Kebai (Cat. No. CBP60629) and subcultured in RPMI-1640 complete medium (containing 10% v/v fetal bovine serum) according to the supplier's recommended conditions and maintained in a logarithmic growth state. The cells used in the test were subcultured no more than 20 times;

2.细胞种植前一天，以30μL包被缓冲液(含30μg/mL多聚赖氨酸的磷酸盐缓冲液)于室温下包被384孔板2小时；随后弃去包被液，以90μL磷酸盐缓冲液冲洗1次并弃去液体，置于超净工作台中自然晾干后以Parafilm包裹板边防止受潮，保存于4℃冰箱中待用；2. One day before cell seeding, coat the 384-well plate with 30 μL coating buffer (phosphate buffer containing 30 μg/mL poly-lysine) at room temperature for 2 hours; then discard the coating solution, rinse once with 90 μL phosphate buffer and discard the liquid, place it in a clean bench to dry naturally, wrap the edge of the plate with Parafilm to prevent moisture, and store it in a 4°C refrigerator for use;

3.细胞种植前收集于离心管中，于250rcf离心3分钟并弃去培养基，以新鲜的完全培养基重悬后，吸取20μL细胞液并在Countstar细胞计数仪上计算细胞浓度，调整密度后以15,000个细胞/45μL的方式种植于准备好的包被板中，置于37℃，5％CO2培养箱中预孵育4小时；3. Before cell planting, collect the cells in a centrifuge tube, centrifuge at 250rcf for 3 minutes and discard the culture medium. After resuspending with fresh complete culture medium, take 20μL of cell solution and calculate the cell concentration on the Countstar cell counter. After adjusting the density, plant 15,000 cells/45μL in the prepared coated plate and place it in a 37℃, 5% CO2 incubator for 4 hours;

4.以5μL对照液(含1％v/v DMSO的无血清培养基)处理阴性和阳性对照组，使用对照液配置化合物梯度稀释液后，以5μL稀释液加入对应的培养孔中，测试中DMSO的终浓度为0.1％，随后置于37℃，5％CO2培养箱中孵育18小时；4. Treat the negative and positive control groups with 5 μL of control solution (serum-free medium containing 1% v/v DMSO), use the control solution to prepare the compound gradient dilution solution, add 5 μL of the dilution solution to the corresponding culture wells, the final concentration of DMSO in the test is 0.1%, and then incubate in a 37°C, 5% CO2 incubator for 18 hours;

5.取出培养板，以10μL固定液(含3％v/v戊二醛的磷酸盐缓冲液)直接加入细胞中并于室温下固定细胞30分钟，弃去液体，随后以30μL透化染色液(含0.1％v/v Triton X-100和20μg/mL Hoechst 33342的磷酸盐缓冲液)于室温下处理细胞30分钟，弃去透化液，并在酶标仪上读取360nm激发/460nm发射的荧光值；5. Take out the culture plate, add 10 μL of fixative solution (phosphate buffer containing 3% v/v glutaraldehyde) directly to the cells and fix the cells at room temperature for 30 minutes, discard the liquid, then treat the cells with 30 μL of permeabilization staining solution (phosphate buffer containing 0.1% v/v Triton X-100 and 20 μg/mL Hoechst 33342) at room temperature for 30 minutes, discard the permeabilization solution, and read the fluorescence value of 360nm excitation/460nm emission on the microplate reader;

6.以50μL修复液(50mM柠檬酸缓冲液)加入所有孔中，于恒温孵育震荡仪上70℃下孵育2小时，随后取出微孔板并平衡至室温后，弃去液体；6. Add 50 μL of repair solution (50 mM citrate buffer) to all wells and incubate at 70°C on a constant temperature incubator shaker for 2 hours. Then remove the microplate and equilibrate to room temperature, then discard the liquid;

7.配置足量的抗体稀释液(含1％w/v牛血清白蛋白的Tris缓冲盐-吐温溶液)，保存于4℃冰箱中待用；7. Prepare sufficient antibody diluent (Tris buffered saline-Tween solution containing 1% w/v bovine serum albumin) and store in a 4°C refrigerator for later use;

8.配置一抗稀释液(以抗体稀释液按1:1000比例稀释EED抗体)，在阴性对照组中加入30μL不含抗体的抗体稀释液，其余组以30μL一抗稀释液加入细胞中，置于4℃下过夜孵育；8. Prepare the primary antibody diluent (dilute the EED antibody with the antibody diluent at a ratio of 1:1000), add 30 μL of the antibody diluent without antibody to the negative control group, and add 30 μL of the primary antibody diluent to the cells in the other groups, and incubate overnight at 4°C;

9.弃去一抗稀释液，以90μL Tris缓冲盐-吐温溶液清洗3次培养板后弃去清洗液，配置二抗稀释液(以抗体稀释液按1:500比例稀释HRP偶联抗体)，以30μL加入细胞中，置于室温下孵育2小时；9. Discard the primary antibody diluent, wash the culture plate three times with 90 μL Tris buffered saline-Tween solution, then discard the washing solution, prepare the secondary antibody diluent (dilute the HRP-conjugated antibody with the antibody diluent at a ratio of 1:500), add 30 μL to the cells, and incubate at room temperature for 2 hours;

10.弃去二抗稀释液，以90μL Tris缓冲盐-吐温溶液清洗3次培养板后弃去清洗液，加入30μL TMB底物溶液，于室温下避光孵育15分钟，随后加入30μL停止液(2M硫酸)终止反应，随后于读板仪上读取OD450nm数值，结果用于分析靶蛋白降解比例和化合物活性；10. Discard the secondary antibody diluent, wash the culture plate three times with 90 μL Tris buffered saline-Tween solution, then discard the washing solution, add 30 μL TMB substrate solution, incubate at room temperature in the dark for 15 minutes, then add 30 μL stop solution (2M sulfuric acid) to terminate the reaction, and then read the OD450nm value on the plate reader. The results are used to analyze the degradation ratio of the target protein and the activity of the compound;

11.设置阴性对照组的信号值为Bottom，阳性对照组的信号值为Top，化合物的浓度值(对数)为X轴，对应浓度的OD450nm值为Y轴，采用四参数对数曲线(4PL logistic model)进行拟合，计算方式见下：Y＝Bottom+(Top-Bottom)/(1+10^((LogDC50-X)*HillSlope))，拟合后计算求得化合物的DC50值，并根据DC50比较化合物的靶蛋白降解活性。11. Set the signal value of the negative control group to Bottom, the signal value of the positive control group to Top, the concentration value (logarithm) of the compound as the X-axis, the OD450nm value of the corresponding concentration as the Y-axis, and use the four-parameter logistic curve (4PL logistic model) for fitting. The calculation method is as follows: Y = Bottom + (Top-Bottom) / (1 + 10^((LogDC50-X)*HillSlope)). After fitting, calculate the DC50 value of the compound and compare the target protein degradation activity of the compound based on DC50.

测试结果显示本申请的化合物具有优异的EED蛋白降解活性，尤其是具有相较于化合物D2更好的EED蛋白降解活性，具体结果如表6所示。The test results show that the compounds of the present application have excellent EED protein degradation activity, especially better EED protein degradation activity than compound D2. The specific results are shown in Table 6.

表6化合物对Karpas-422细胞内EED蛋白的降解活性

注：负值是由于数据处理时，低浓度组化合物与对照组存在少量系统误差。Table 6 Degradation activity of compounds on EED protein in Karpas-422 cells

Note: Negative values are due to a small amount of systematic error between the low-concentration group and the control group during data processing.

其中，化合物D2为(CAS：2639882-72-5)，可通过参照现有技术制备得到或者通过市售获得。Wherein, compound D2 is (CAS: 2639882-72-5), which can be prepared by referring to the prior art or obtained from the market.

1.3化合物对Karpas-422细胞内的EED蛋白降解测试(WB法)1.3 Compounds Degradation of EED Protein in Karpas-422 Cells (WB Method)

材料与试剂如表7所示：Materials and reagents are shown in Table 7:

表7材料与试剂
Table 7 Materials and reagents

本实验采用Western blotting(WB)的方法，对Karpas-422细胞中的EED蛋白表达量进行定量分析，以检测化合物对靶蛋白的降解活性。In this experiment, Western blotting (WB) was used to quantitatively analyze the expression of EED protein in Karpas-422 cells to detect the degradation activity of the compound on the target protein.

1.Karpas-422细胞购自南京科佰(货号CBP60629)，以RPMI-1640完全培养基(含10％v/v FBS)按照供应商的推荐条件传代培养并维持对数生长状态，测试中使用的细胞其传代次数不超过20次；1. Karpas-422 cells were purchased from Nanjing Kebai (Cat. No. CBP60629) and subcultured in RPMI-1640 complete medium (containing 10% v/v FBS) according to the supplier's recommended conditions and maintained in logarithmic growth state. The cells used in the test were subcultured no more than 20 times;

2.细胞种植前收集于离心管中，于250rcf离心3分钟并弃去培养基，以新鲜的完全培养基重悬后，吸取20μL细胞液并在Countstar细胞计数仪上计算细胞浓度，调整密度后以1×106细胞/900μL的方式种植于12孔培养板中，置于37℃，5％CO2培养箱中预孵育4小时；2. Before cell planting, collect the cells in a centrifuge tube, centrifuge at 250rcf for 3 minutes and discard the culture medium. After resuspending with fresh complete culture medium, take 20μL of cell solution and calculate the cell concentration on the Countstar cell counter. After adjusting the density, plant it in a 12-well culture plate at 1×10 6 cells/900μL and place it in a 37°C, 5% CO 2 incubator for pre-incubation for 4 hours;

3.以100μL对照液(含1％v/v DMSO的无血清培养基)处理阴性和阳性对照组，使用对照液配置化合物梯度稀释液后，以100μL稀释液加入对应的培养孔中，测试中DMSO的终浓度为0.1％，随后置于37℃，5％CO2培养箱中孵育24小时；3. Treat the negative and positive control groups with 100 μL of control solution (serum-free medium containing 1% v/v DMSO), use the control solution to prepare the compound gradient dilution solution, add 100 μL of the dilution solution to the corresponding culture wells, the final concentration of DMSO in the test is 0.1%, and then incubate in a 37°C, 5% CO2 incubator for 24 hours;

4.处理结束后，收集细胞至1.5mL离心管中，于500rcf离心3分钟并弃去培养基，以1mL PBS重悬后，再次于500rcf离心3分钟并吸去溶液，配置RIPA裂解液(50mM Tris，100mM NaCl，1mM EDTA，1％Triton X-100，1×Halt抑制剂混合物)，以100μL裂解液重悬后，置于4℃下裂解15分钟，随后于低温离心机中以10,000rcf在4℃下离心10分钟，小心吸取90μL上清液至96孔PCR板中，并加入30μL样品缓冲液混合均匀，保存于-20℃冰箱中待用；4. After the treatment, collect the cells into a 1.5mL centrifuge tube, centrifuge at 500rcf for 3 minutes and discard the culture medium, resuspend with 1mL PBS, centrifuge again at 500rcf for 3 minutes and aspirate the solution, prepare RIPA lysis buffer (50mM Tris, 100mM NaCl, 1mM EDTA, 1% Triton X-100, 1×Halt inhibitor mixture), resuspend with 100μL lysis buffer, place at 4℃ for 15 minutes, then centrifuge at 10,000rcf at 4℃ for 10 minutes in a low-temperature centrifuge, carefully pipette 90μL supernatant into a 96-well PCR plate, add 30μL sample buffer and mix well, and store in a -20℃ refrigerator for use;

5.电泳前取出样品于室温下融化后，放入热循环仪中于70℃下变性10分钟，随后于室温下冷却，与此同时装配电泳系统，倒入足量SDS-MOPS电泳缓冲液没过凝胶，轻轻移除胶梳并静置数分钟，样品冷却后进行上样，每个孔中加入10μL样品，在边缘孔中加入1μL蛋白标记物，随后于70v下电泳180分钟；5. Before electrophoresis, take out the sample and melt it at room temperature, then put it into a thermal cycler and denature it at 70°C for 10 minutes, then cool it at room temperature. At the same time, assemble the electrophoresis system, pour enough SDS-MOPS electrophoresis buffer to cover the gel, gently remove the gel comb and let it stand for a few minutes. After the sample cools down, add 10μL of sample to each well, add 1μL of protein marker to the edge well, and then electrophoresed at 70V for 180 minutes;

6.电泳结束后，小心拆卸凝胶后放入超纯水中待用，取出转印膜，依照产品说明书准备转印复合物并放入凝胶，配置完毕后放入转印仪中于20v下转印6分钟，结束后取出膜，根据蛋白标记物的位置进行裁剪，将裁剪后的膜转移到孵育盒中，并加入10mL TBST溶液，于摇床上60rpm下漂洗3分钟，随后弃去溶液；6. After the electrophoresis is finished, carefully disassemble the gel and put it in ultrapure water for later use. Take out the transfer membrane, prepare the transfer complex according to the product instructions and put it into the gel. After the configuration is completed, put it into the transfer instrument and transfer it at 20V for 6 minutes. After the end, take out the membrane, cut it according to the position of the protein marker, transfer the cut membrane to the incubation box, add 10mL TBST solution, rinse it on a shaker at 60rpm for 3 minutes, and then discard the solution;

7.配置含4％BSA的TBST溶液作为封闭液，每张膜加入15mL封闭液，于摇床上60rpm，室温下漂洗3分钟，随后弃去溶液，重新加入15mL封闭液，并加入10μL的EED抗体，置于4℃下摇床上60rpm孵育过夜；7. Prepare TBST solution containing 4% BSA as blocking solution, add 15 mL of blocking solution to each membrane, rinse at room temperature for 3 minutes on a shaker at 60 rpm, then discard the solution, add 15 mL of blocking solution again, add 10 μL of EED antibody, and incubate overnight on a shaker at 4°C at 60 rpm;

8.第二天，弃去抗体孵育液，每张膜加入15mL TBST溶液，于摇床上60rpm，室温下漂洗10分钟，随后弃去溶液，每张膜以此方式共计漂洗3次，随后重新加入15mL封闭液，并加入10μL的兔IgG抗体，置于室温下摇床上60rpm孵育2小时；8. On the second day, discard the antibody incubation solution, add 15 mL TBST solution to each membrane, rinse on a shaker at 60 rpm at room temperature for 10 minutes, then discard the solution, rinse each membrane in this way for a total of 3 times, then add 15 mL blocking solution again, add 10 μL rabbit IgG antibody, and incubate on a shaker at room temperature at 60 rpm for 2 hours;

9.孵育结束后弃去抗体孵育液，每张膜加入15mL TBST溶液，于摇床上60rpm，室温下漂洗10分钟，随后弃去溶液，每张膜以此方式共计漂洗3次，随后置于超纯水中准备成像；9. After the incubation, discard the antibody incubation solution, add 15mL TBST solution to each membrane, rinse on a shaker at 60rpm at room temperature for 10 minutes, then discard the solution. Rinse each membrane in this way for a total of 3 times, and then place it in ultrapure water for imaging;

10.配置足量ECL底物，将膜置于成像板上，加入500μL底物，轻晃成像板使得溶液可以均匀覆盖整张膜，随后用吸水纸小心吸去大部分溶液后，置入成像仪中开始成像；10. Prepare enough ECL substrate, place the membrane on the imaging plate, add 500 μL of substrate, shake the imaging plate gently so that the solution can evenly cover the entire membrane, then carefully absorb most of the solution with absorbent paper, and place it in the imager to start imaging;

11.成像完毕后，导出图片文件，使用Image J软件进行像素分析，得到每个条带的灰度值，设置DMSO组的灰度值为最大信号，各处理组与DMSO组相比减少的灰度比例，即降解率为Y轴，化合物的浓度值(对数)为X轴，DMSO组降解率％为Bottom，100％降解率为Top，采用四参数对数曲线(4PL logistic model)进行拟合，计算方式见下：11. After imaging, export the image file and use Image J software for pixel analysis to obtain the gray value of each band. Set the gray value of the DMSO group as the maximum signal. The gray ratio of each treatment group compared with the DMSO group, that is, the degradation rate, is on the Y axis, the concentration value (logarithm) of the compound is on the X axis, the DMSO group degradation rate% is Bottom, and the 100% degradation rate is Top. Use the four-parameter logistic curve (4PL logistic model) for fitting. The calculation method is as follows:

Y＝Bottom+(Top-Bottom)/(1+10^((LogDC50-X)*HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogDC50-X)*HillSlope))

拟合后计算求得化合物的DC50值。The DC50 value of the compound was calculated after fitting.

测得H39的DC50为0.09nM，Dmax:82.1％，具体如图1和图2所示，图1为不同浓度化合物H39对Karpas-422细胞内的EED蛋白降解的蛋白印迹图，图2为化合物H39对Karpas-422细胞内的EED蛋白的剂量-降解活性图，横坐标为化合物H39浓度(nM)，纵坐标为降解率D(％)。The DC 50 of H39 was measured to be 0.09 nM, and Dmax: 82.1%, as shown in Figures 1 and 2. Figure 1 is a protein blot of the degradation of EED protein in Karpas-422 cells by compound H39 at different concentrations, and Figure 2 is a dose-degradation activity diagram of EED protein in Karpas-422 cells by compound H39, with the abscissa representing the concentration of compound H39 (nM) and the ordinate representing the degradation rate D (%).

测试例2.化合物对肿瘤细胞的增殖抑制测试Test Example 2. Test on the inhibition of tumor cell proliferation by compounds

2.1化合物对wsuDLCL-2细胞的增殖抑制作用2.1 Inhibitory effect of compounds on the proliferation of wsuDLCL-2 cells

材料与试剂如表8所示：Materials and reagents are shown in Table 8:

表8材料与试剂
Table 8 Materials and reagents

本实验采用Cell Titer-Glo试剂，对wsuDLCL-2细胞的增殖活性进行定量分析，以检测化合物对肿瘤细胞增殖的抑制能力；In this experiment, Cell Titer-Glo reagent was used to quantitatively analyze the proliferation activity of wsuDLCL-2 cells to detect the inhibitory ability of the compounds on tumor cell proliferation;

1、wsuDLCL-2细胞购自南京科佰(货号CBP60073及CBP60629)，以RPMI-1640完全培养基(含10％v/v胎牛血清)按照供应商的推荐条件传代培养并维持对数生长状态，测试中使用的细胞其传代次数不超过20次；1. wsuDLCL-2 cells were purchased from Nanjing Kebai (Cat. No. CBP60073 and CBP60629) and subcultured in RPMI-1640 complete medium (containing 10% v/v fetal bovine serum) according to the supplier's recommended conditions and maintained in a logarithmic growth state. The cells used in the test were subcultured no more than 20 times;

2、细胞种板前收集于离心管中，于250rcf离心3分钟并弃去培养基，以新鲜的完全培养基重悬后，吸取20μL细胞液并在Countstar细胞计数仪上计算细胞浓度，调整密度后以3,000个细胞/180μL的方式种植于96孔板中，置于37℃，5％CO2培养箱中预孵育4小时；2. Before seeding the cells, collect them in a centrifuge tube, centrifuge at 250 rcf for 3 minutes and discard the culture medium. Resuspend them in fresh complete culture medium, aspirate 20 μL of cell solution and calculate the cell concentration on a Countstar cell counter. After adjusting the density, seed them in a 96-well plate at 3,000 cells/180 μL and pre-incubate them in a 37°C, 5% CO 2 incubator for 4 hours.

3、以20μL对照液(含2.5％v/v DMSO的非完全培养基)处理阴性和阳性对照组，使用非完全培养基配置化合物梯度稀释液后，以20μL稀释液加入对应的培养孔中，测试中DMSO的终浓度为0.25％v/v，随后置于37℃，5％CO2培养箱中孵育144小时；3. Treat the negative and positive control groups with 20 μL of control solution (incomplete medium containing 2.5% v/v DMSO). After preparing the compound gradient dilution solution using incomplete medium, add 20 μL of dilution solution to the corresponding culture wells. The final concentration of DMSO in the test is 0.25% v/v. Then incubate in a 37°C, 5% CO2 incubator for 144 hours.

4、直接在细胞培养物中加入150μL的Cell Titer-Glo(CTG)试剂，于室温下避光孵育30分钟，随后于读板仪上读取辉光数值，结果用于分析细胞增殖比例和化合物活性；4. Add 150 μL of Cell Titer-Glo (CTG) reagent directly to the cell culture, incubate at room temperature in the dark for 30 minutes, and then read the glow value on the plate reader. The results are used to analyze the cell proliferation ratio and compound activity.

5、设置阴性对照组的信号值为Bottom，阳性对照组的信号值为Top，化合物的浓度值(对数)为X轴，对应浓度的辉光读值为Y轴，HillSlope为斜率因子，采用四参数对数曲线(4PL logistic model)进行拟合，计算方式见下：5. Set the signal value of the negative control group to Bottom, the signal value of the positive control group to Top, the concentration value (logarithm) of the compound as the X-axis, the glow reading value of the corresponding concentration as the Y-axis, HillSlope as the slope factor, and use the four-parameter logistic curve (4PL logistic model) for fitting. The calculation method is as follows:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

拟合后计算求得化合物的IC50值，并根据IC50比较化合物的增殖抑制活性。After fitting, the IC50 values of the compounds were calculated and the proliferation inhibition activities of the compounds were compared based on the IC50 values .

测试结果显示，本申请的实施例化合物对肿瘤细胞，如wsuDLCL-2细胞具有优异的增殖抑制活性，其IC50值小于500nM，部分化合物的IC50值小于100nM。部分实施例化合物的增殖抑制活性如表9所示。The test results show that the example compounds of the present application have excellent proliferation inhibition activity on tumor cells, such as wsuDLCL-2 cells, with IC 50 values less than 500 nM, and IC 50 values of some compounds less than 100 nM. The proliferation inhibition activity of some example compounds is shown in Table 9.

表9实施例化合物对wsuDLCL-2细胞的增殖抑制活性
Table 9 Proliferation inhibition activity of the compounds in the examples on wsuDLCL-2 cells

2.2.化合物对Pfeiffer细胞的增殖抑制作用2.2. Inhibitory effect of compounds on the proliferation of Pfeiffer cells

材料与试剂如表10所示：Materials and reagents are shown in Table 10:

表10材料与试剂
Table 10 Materials and reagents

本实验采用Cell Titer-Glo试剂，对Pfeiffer细胞的增殖活性进行定量分析，以检测化合物对肿瘤细胞增殖的抑制能力；This experiment uses Cell Titer-Glo reagent to quantitatively analyze the proliferation activity of Pfeiffer cells to detect the inhibitory ability of compounds on tumor cell proliferation;

Pfeiffer细胞购自南京科佰(购自ATCC，货号#CRL2632)，以RPMI-1640完全培养基(含10％v/v胎牛血清)按照供应商的推荐条件传代培养并维持对数生长状态，测试中使用的细胞自复苏后其传代次数不超过20次；Pfeiffer cells were purchased from Nanjing Kebai (purchased from ATCC, catalog number #CRL2632) and subcultured and maintained in logarithmic growth state in RPMI-1640 complete medium (containing 10% v/v fetal bovine serum) according to the supplier's recommended conditions. The cells used in the test had been passaged no more than 20 times since recovery;

细胞种板前收集于离心管中，于250rcf离心3分钟并弃去培养基，以新鲜的完全培养基重悬后，吸取20μL细胞液并在Countstar细胞计数仪上计算细胞浓度，调整密度后以2,000个细胞/45μL的方式种植于384孔板中，置于37℃，5％CO2培养箱中预孵育4小时；Before seeding the cells, collect them in a centrifuge tube, centrifuge at 250 rcf for 3 minutes and discard the culture medium. After resuspending with fresh complete culture medium, take 20 μL of cell solution and calculate the cell concentration on a Countstar cell counter. After adjusting the density, seed them in a 384-well plate at 2,000 cells/45 μL and pre-incubate them in a 37°C, 5% CO2 incubator for 4 hours.

以5μL对照液(含1％v/v DMSO的非完全培养基)处理阴性和阳性对照组，使用非完全培养基配置化合物梯度稀释液后，以5μL稀释液加入对应的培养孔中，测试中DMSO的终浓度为0.1％v/v，随后置于37℃，5％CO2培养箱中孵育144小时；The negative and positive control groups were treated with 5 μL of control solution (incomplete medium containing 1% v/v DMSO). After preparing the compound gradient dilution solution using incomplete medium, 5 μL of the dilution solution was added to the corresponding culture wells. The final concentration of DMSO in the test was 0.1% v/v, and then placed in a 37°C, 5% CO2 incubator for 144 hours;

直接在细胞培养物中加入40μL的Cell Titer-Glo试剂，于室温下避光孵育30分钟，随后于读板仪上读取辉光数值，结果用于分析细胞增殖比例和化合物活性；Directly add 40 μL of Cell Titer-Glo reagent to the cell culture, incubate at room temperature in the dark for 30 minutes, and then read the glow value on the plate reader. The results are used to analyze the cell proliferation ratio and compound activity.

设置阴性对照组的信号值为Bottom，阳性对照组的信号值为Top，化合物的浓度值(对数)为X轴，对应浓度的辉光读值为Y轴，HillSlope为斜率因子，采用四参数对数曲线(4PL logistic model)进行拟合，计算方式见下：Set the signal value of the negative control group to Bottom, the signal value of the positive control group to Top, the concentration value (logarithm) of the compound as the X-axis, the glow reading value of the corresponding concentration as the Y-axis, HillSlope as the slope factor, and use the four-parameter logistic curve (4PL logistic model) for fitting. The calculation method is as follows:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

拟合后计算求得化合物的IC50值，并根据IC50比较化合物的增殖抑制活性。After fitting, the IC50 values of the compounds were calculated and the proliferation inhibition activities of the compounds were compared based on the IC50 values .

测试结果显示，本申请的实施例化合物对肿瘤细胞，如Pfeiffer细胞具有优异的增殖抑制活性，其IC50值小于500nM，部分化合物的IC50值小于100nM，部分化合物的IC50值小于10nM，部分化合物的IC50值小于1nM，部分化合物的IC50值小于0.1nM。测试结果如表11所示：The test results show that the example compounds of the present application have excellent proliferation inhibition activity on tumor cells, such as Pfeiffer cells, with an IC 50 value of less than 500 nM, an IC 50 value of less than 100 nM for some compounds, an IC 50 value of less than 10 nM for some compounds, an IC 50 value of less than 1 nM for some compounds, and an IC 50 value of less than 0.1 nM for some compounds. The test results are shown in Table 11:

表11实施例化合物对Pfeiffer细胞的增殖抑制活性

Table 11 Proliferation inhibition activity of the compounds in the examples on Pfeiffer cells

其中，化合物D2为(CAS：2639882-72-5)，可通过参照现有技术制备得到或者通过市售获得。Wherein, compound D2 is (CAS: 2639882-72-5), which can be prepared by referring to the prior art or obtained from the market.

测试例3化合物对人B细胞非霍奇金淋巴瘤Karpas-422细胞系BALB/c nude小鼠皮下移植瘤模型生长作用测试Test Example 3: Effect of Compounds on Growth of Human B Cell Non-Hodgkin Lymphoma Karpas-422 Cell Line BALB/c nude Mouse Subcutaneous Transplant Tumor Model

材料与试剂见表12Materials and reagents are shown in Table 12

表12材料与试剂
Table 12 Materials and reagents

仪器设备见表13Instruments and equipment see Table 13

表13仪器设备
Table 13 Instruments and Equipment

1.动物1. Animals

动物种属及品系：BALB/c nude小鼠Animal species and strain: BALB/c nude mice

给药记录：无给药史Medication record: No medication history

性别、年龄、体重：雌性，6-8周，体重18-25克Gender, age, weight: female, 6-8 weeks, weight 18-25 grams

养殖方/供应商：上海南方模式生物科技股份有限公司Farmer/Supplier: Shanghai Model Organisms Technology Co., Ltd.

适应期：不少于3-7天Adaptation period: no less than 3-7 days

房间：SPF区房间Room: SPF area room

室内温度：20-26℃Indoor temperature: 20-26℃

室内相对湿度：40-70％Indoor relative humidity: 40-70%

灯光：日光灯照明，12小时照明(08:00-20:00)及12小时无照明Lighting: Fluorescent lighting, 12 hours of lighting (08:00-20:00) and 12 hours of no lighting

动物饲养：每笼2-6只(同一给药组)Animal feeding: 2-6 animals per cage (same dosing group)

食物：无限量获取饲料(经辐照消毒，陕西秦乐药业化工有限公司，中国)Food: unlimited access to feed (irradiated and sterilized, Shaanxi Qinle Pharmaceutical Chemical Co., Ltd., China)

水：无限量获取饮用水(经超纯水过滤系统净化的自来水)Water: Unlimited access to drinking water (tap water purified by ultrapure water filtration system)

从供应商购入雌性BALB/c nude小鼠，用于挑选合适体重范围和肿瘤大小的动物入组。动物均无携带特定病原，到达实验室时约为6-8周。Female BALB/c nude mice were purchased from a supplier to select animals of appropriate weight range and tumor size for inclusion in the study. All animals were specific pathogen-free and were approximately 6-8 weeks old when they arrived at the laboratory.

2.实验过程2. Experimental Procedure

2.1细胞培养2.1 Cell culture

用于本实验的人B细胞非霍奇金淋巴瘤Karpas-422细胞系，以RPMI-1640培养基添加10％FBS培养于含5％CO2的37℃培养箱。细胞连续培养十代之前，将含1×107Karpas-422细胞的PBS100μL和等体积Matrigel混匀后，通过皮下注射分别接种于小鼠背部右边靠近腋下，接种体积为200μL左右。接种前用3-4％异氟烷将小鼠麻醉。The human B-cell non-Hodgkin's lymphoma Karpas-422 cell line used in this experiment was cultured in RPMI-1640 medium supplemented with 10% FBS in a 37°C incubator containing 5% CO 2. Before the cells were cultured for ten consecutive generations, 100 μL of PBS containing 1×10 7 Karpas-422 cells and an equal volume of Matrigel were mixed and inoculated subcutaneously into the right side of the back of the mouse near the armpit, with an inoculation volume of about 200 μL. The mice were anesthetized with 3-4% isoflurane before inoculation.

2.2动物分组和给药方案2.2 Animal grouping and dosing regimen

当肿瘤生长到平均约70-150mm3左右时，荷瘤小鼠根据肿瘤体积和体重被随机分组，每组8只。分组给药当天定义为第0天。测试一和测试二的分组情况和给药方案分别如表14和表15所示，对照组分别腹腔注射10％DMSO+40％PEG 400+50％含10％HP-β-CD的50mM Citrate(pH＝4.0)溶液(测试一)和70％含5％的葡萄糖水溶液+30％含15％HP-β-CD的水溶液(测试二)：When the tumor grew to an average of about 70-150 mm 3 , the tumor-bearing mice were randomly divided into groups according to the tumor volume and body weight, with 8 mice in each group. The day of group administration was defined as day 0. The grouping and administration scheme of test one and test two are shown in Table 14 and Table 15, respectively. The control group was intraperitoneally injected with 10% DMSO + 40% PEG 400 + 50% 50mM Citrate (pH = 4.0) solution containing 10% HP-β-CD (test one) and 70% aqueous solution containing 5% glucose + 30% aqueous solution containing 15% HP-β-CD (test two):

表14测试一的分组和给药方案

注：N：每组动物只数。给药体积：动物的给药体积按照10μL/g体重进行调整。NA为未给药。Table 14 Grouping and dosing regimen for test 1

Note: N: number of animals in each group. Dosing volume: the dosing volume of animals was adjusted to 10 μL/g body weight. NA means no dosing.

表15测试二的分组和给药方案

注：N：每组动物只数。给药体积：动物的给药体积按照10μL/g体重进行调整。NA为未给药。Table 15 Grouping and dosing regimen for test 2

Note: N: number of animals in each group. Dosing volume: the dosing volume of animals was adjusted to 10 μL/g body weight. NA means no dosing.

2.3受试物的配制2.3 Preparation of test substances

测试一和测试二的受试物的配制和储存分别如表16和表17所示：The preparation and storage of the test substances for Test 1 and Test 2 are shown in Table 16 and Table 17, respectively:

表16测试一受试物的配制和储存方案
Table 16 Preparation and storage plan for test substance

表17测试二受试物的配制和储存方案
Table 17 Preparation and storage plan of test substance in test 2

2.4评价方法2.4 Evaluation Method

笼边观察：每天观察每只小鼠的外观及行为，自给药开始连续观察至实验结束。所有非正常的外观形态和行为活动都记录在实验室临床观察表内。Cage observation: Observe the appearance and behavior of each mouse every day, from the start of drug administration to the end of the experiment. All abnormal appearance and behavior activities are recorded in the laboratory clinical observation form.

肿瘤体积：对于皮下移植瘤模型，分组后每周两次测量肿瘤体积。肿瘤体积(V)的计算方法如下：V＝(长×宽2)/2。每只裸鼠相对肿瘤体积(RTV)的计算方法是：RTV＝Vt/V0，其中Vt为每次的测量体积，V0为治疗开始时的体积。Tumor volume: For the subcutaneous transplant tumor model, the tumor volume was measured twice a week after grouping. The calculation method of tumor volume (V) is as follows: V = (length × width 2 ) / 2. The calculation method of relative tumor volume (RTV) of each nude mouse is: RTV = V t /V 0 , where V t is the volume measured each time and V 0 is the volume at the beginning of treatment.

动物体重：分组后每周两次测量并记录老鼠体重。Animal body weight: After grouping, the body weight of mice was measured and recorded twice a week.

动物状态观察：如动物出现腹泻、精神萎靡等，需记录。Observation of animal condition: If the animal has diarrhea, lethargy, etc., it needs to be recorded.

相对肿瘤增殖率(T/C％)：用于评价药物抗肿瘤活性的作用，相对肿瘤增殖率T/C(％)＝治疗组(T)RTV平均值/阴性对照组(C)RTV平均值×100％。Relative tumor proliferation rate (T/C%): used to evaluate the anti-tumor activity of drugs, relative tumor proliferation rate T/C (%) = average RTV value of treatment group (T)/average RTV value of negative control group (C) × 100%.

肿瘤生长抑制率(TGI)(％)：(阴性对照组平均肿瘤增长体积–治疗组平均肿瘤增长体积)/阴性对照组平均肿瘤增长体积×100％。Tumor growth inhibition rate (TGI) (%): (average tumor growth volume of negative control group - average tumor growth volume of treatment group)/average tumor growth volume of negative control group × 100%.

阴性对照组为对照组，治疗组为给药D1、H39或H80组，结果将以平均值±S.E.M的方式呈现。两组间比较将用Dunnett’s multi-comparison test(邓尼特多重比较测验)进行检验。如果p<0.05则认为有统计学显著性差异。The negative control group is the control group, and the treatment group is the D1, H39 or H80 group. The results will be presented as mean ± S.E.M. The comparison between the two groups will be tested using Dunnett’s multi-comparison test. If p < 0.05, it is considered to be statistically significant.

测试一结果见图3-图4及表18所示。其中图3为化合物D1和化合物H39在体内的抗肿瘤活性结果图，*P<0.05,**P<0.01和***P<0.001表示显著不同于G1；图4为化合物D1和化合物H39对小鼠体重的影响结果图，*P<0.05,**P<0.01和***P<0.001表示显著不同于G1。表18示出了待测化合物对人B细胞非霍奇金淋巴瘤Karpas-422裸小鼠移植瘤的试验治疗作用。The results of test 1 are shown in Figures 3-4 and Table 18. Figure 3 is a graph showing the anti-tumor activity of compound D1 and compound H39 in vivo, *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences from G1; Figure 4 is a graph showing the effects of compound D1 and compound H39 on mouse body weight, *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences from G1. Table 18 shows the experimental therapeutic effects of the test compounds on human B-cell non-Hodgkin's lymphoma Karpas-422 nude mouse transplant tumors.

测试二结果见图5-图6及表19所示。其中图5为化合物D1和化合物H80在体内的抗肿瘤活性结果图，*P<0.05,**P<0.01和***P<0.001表示显著不同于G1，CRs为肿瘤完全缓解；图6为化合物D1和化合物H80对小鼠体重的影响结果图，*P<0.05,**P<0.01和***P<0.001表示显著不同于G1。表19示出了待测化合物对人B细胞非霍奇金淋巴瘤Karpas-422裸小鼠移植瘤的试验治疗作用。The results of test 2 are shown in Figures 5-6 and Table 19. Figure 5 is a graph showing the anti-tumor activity of compound D1 and compound H80 in vivo, *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences from G1, and CRs indicate complete tumor remission; Figure 6 is a graph showing the effects of compound D1 and compound H80 on mouse body weight, *P<0.05, **P<0.01 and ***P<0.001 indicate significant differences from G1. Table 19 shows the experimental therapeutic effects of the test compounds on human B-cell non-Hodgkin's lymphoma Karpas-422 nude mouse transplant tumors.

表18测试一中待测化合物对人B细胞非霍奇金淋巴瘤Karpas-422裸小鼠移植瘤的试验治疗
Table 18 Experimental treatment of human B cell non-Hodgkin's lymphoma Karpas-422 nude mouse transplant tumor by the test compound in test 1

表19测试二中待测化合物对人B细胞非霍奇金淋巴瘤Karpas-422裸小鼠移植瘤的试验治疗
Table 19 Experimental treatment of human B cell non-Hodgkin's lymphoma Karpas-422 nude mouse transplant tumor by the test compound in test 2

从上表18和图3可以看出，本公开的化合物具有很强的体内抗肿瘤活性。化合物D1在50mg/kg每天给一次药(QD)剂量下能有效抑制肿瘤生长，化合物H39在5mg/kg和25mg/kg每两天给一次药(Q2D)剂量下能有效抑制肿瘤生长。从图4可以看出，测试小鼠的体重均没有较大的波动(体重减轻在15％范围内)，说明本公开的化合物在有效抗肿瘤的同时也对小鼠本身无明显毒性。As can be seen from Table 18 and Figure 3 above, the compounds disclosed herein have strong in vivo anti-tumor activity. Compound D1 can effectively inhibit tumor growth at a dose of 50 mg/kg once a day (QD), and compound H39 can effectively inhibit tumor growth at doses of 5 mg/kg and 25 mg/kg once every two days (Q2D). As can be seen from Figure 4, the body weight of the test mice did not fluctuate significantly (weight loss was within 15%), indicating that the compounds disclosed herein are effective in anti-tumor and have no obvious toxicity to the mice themselves.

从上表19和图5可以看出，本公开的化合物具有很强的体内抗肿瘤活性。化合物D1在50mg/kg每天给一次药(QD)剂量下能有效抑制肿瘤生长，化合物H80在1mg/kg、5mg/kg和25mg/kg每两天给一次药(Q2D)剂量下均能有效抑制肿瘤生长。从图6可以看出，测试小鼠的体重均没有较大的波动(体重减轻在15％范围内)，说明本公开的化合物在有效抗肿瘤的同时也对小鼠本身无明显毒性。As can be seen from Table 19 and Figure 5 above, the compounds of the present disclosure have strong in vivo anti-tumor activity. Compound D1 can effectively inhibit tumor growth at a dose of 50 mg/kg once a day (QD), and compound H80 can effectively inhibit tumor growth at doses of 1 mg/kg, 5 mg/kg and 25 mg/kg once every two days (Q2D). As can be seen from Figure 6, the body weight of the test mice did not fluctuate significantly (weight loss was within 15%), indicating that the compounds of the present disclosure are effective in anti-tumor and have no obvious toxicity to the mice themselves.

其中，化合物D1为(CAS：2585648-55-9)，可通过参照现有技术制备得到或者通过市售获得。Wherein, compound D1 is (CAS: 2585648-55-9), which can be prepared by referring to the prior art or obtained from the market.

在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (49)

一种式(I)所示化合物、或其药学上可接受的盐、或其立体异构体：
POI—(L)n0—ULM
(I)，A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
POI—(L) n0 —ULM
(I) 其中，L为连接POI和ULM的连接链；Where L is the connection link connecting POI and ULM; ULM为与E3连接酶结合的基团；ULM is the group that binds to the E3 ligase; n0为0或1；n0 is 0 or 1; POI为与EED蛋白结合的配体，其具有式(A-1)所示的结构或其异构体，
POI is a ligand that binds to the EED protein and has a structure represented by formula (A-1) or an isomer thereof.
其中，in, 表示(双键)或(单键)； express (double bond) or (single bond); W1、W2、W3各自独立地选自键、-CH2-、-(CH2)2-、-CH＝CH-、-CH＝N-、-N＝N-、-(CH2)3-、-C(O)NH-、-NHC(O)-、-C(O)-、-NH-、-CH-和-N-；W 1 , W 2 , and W 3 are each independently selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -CH=CH-, -CH=N-, -N=N-, -(CH 2 ) 3 -, -C(O)NH-, -NHC(O)-, -C(O)-, -NH-, -CH-, and -N-; W4、W5各自独立地选自-CH-、-N-和-C-；W 4 and W 5 are each independently selected from -CH-, -N- and -C-; A1环选自C3-15环烷基环(优选为C3-12环烷基环，更优选为C3-10环烷基环，进一步优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环，进一步优选为4至6元杂环烷基环)、5至15元杂芳基环(优选为5至12元杂芳基环，更优选为5至10元杂芳基环，进一步优选为5至6元杂芳基环)和C6-14芳环；The A1 ring is selected from a C3-15 cycloalkyl ring (preferably a C3-12 cycloalkyl ring, more preferably a C3-10 cycloalkyl ring, further preferably a C3-8 cycloalkyl ring, further preferably a C3-6 cycloalkyl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 4- to 12-membered heterocycloalkyl ring, more preferably a 4- to 10-membered heterocycloalkyl ring, further preferably a 4- to 8-membered heterocycloalkyl ring, further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 15-membered heteroaryl ring (preferably a 5- to 12-membered heteroaryl ring, more preferably a 5- to 10-membered heteroaryl ring, further preferably a 5- to 6-membered heteroaryl ring) and a C6-14 aromatic ring; (R1)p1表示A1环上的氢被p1个R1取代，p1为0、1、2或3，每个R1相同或不同，各自独立地选自X1、氢、氘、氰基、羧基、硝基、甲酰基、磺酸基、卤素(优选为氟、氯或溴)、C1-10烷基(优选为C1-8烷基，更优选为C1-6烷基，进一步优选为C1-3烷基)、卤代C1-10烷基(优选为卤代C1-8烷基，更优选为卤代C1-6烷基，进一步优选为卤代C1-3烷基)、C1-10烷氧基(优选为C1-8烷氧基，更优选为C1-6烷氧基，进一步优选为C1-3烷氧基)、卤代C1-10烷氧基(优选为卤代C1-8烷氧基，更优选为卤代C1-6烷氧基，进一步优选为卤代C1-3烷氧基)、-COC1-10烷基(优选为-COC1-8烷基，更优选为-COC1-6烷基，进一步优选为-COC1-3烷基)、-COOC1-10烷基(优选为-COOC1-8烷基，更优选为-COOC1-6烷基，进一步优选为-COOC1-3烷基)、-CONH2、-CONHC1-10烷基(优选为-CONHC1-8烷基，更优选为-CONHC1-6烷基，进一步优选为-CONHC1-3烷基)、-CON(C1-10烷基)2(优选为-CON(C1-8烷基)2，更优选为-CON(C1-6烷基)2，进一步优选为-CON(C1-3烷基)2)、-SOC1-10烷基(优选为-SOC1-8烷基，更优选为-SOC1-6烷基，进一步优选为-SOC1-3烷基)、-SO2C1-10烷基(优选为-SO2C1-8烷基，更优选为-SO2C1-6烷基，进一步优选为-SO2C1-3烷基)、-SO2NH2、-SO2NHC1-10烷基(优选为-SO2NHC1-8烷基，更优选为-SO2NHC1-6烷基，进一步优选为-SO2NHC1-3烷基)、-SO2N(C1-10烷基)2(优选为-SO2N(C1-8烷基)2，更优选为-SO2N(C1-6烷基)2，进一步优选为-SO2N(C1-3烷基)2)、C3-8环烷基(优选为C3-6环烷基)、3至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基；所述的C1-10烷基、卤代C1-10烷基、C1-10烷氧基、卤代C1-10烷氧基、-COC1-10烷基、-COOC1-10烷基、-CONH2、-CONHC1-10烷基、-CON(C1-10烷基)2、-SOC1-10烷基、-SO2C1-10烷基、-SO2NH2、-SO2NHC1-10烷基、-SO2N(C1-10烷基)2、C3-8环烷基、3至15元杂环烷基、5至10元杂芳基、C6-14芳基为未取代或被1、2或3个选自下组的取代基取代：氰基、羟基、羧基、硝基、甲酰基、磺酸基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、C3-6环烷基、3至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)、苯基和萘基；(R 1 ) p1 represents that the hydrogen on the A1 ring is replaced by p1 R 1s , p1 is 0, 1, 2 or 3, each R 1 is the same or different and is independently selected from X 1 , hydrogen, deuterium, cyano, carboxyl, nitro, formyl, sulfonic acid , halogen (preferably fluorine, chlorine or bromine), C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-6 alkyl, and further preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-8 alkyl, more preferably halogenated C 1-6 alkyl, and further preferably halogenated C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, and further preferably C 1-3 alkoxy), halogenated C 1-10 alkoxy (preferably halogenated C 1-8 alkoxy, more preferably halogenated C 1-6 alkoxy, and further preferably halogenated C -COC 1-10 alkyl (preferably -COC 1-8 alkyl, more preferably -COC 1-6 alkyl, further preferably -COC 1-3 alkyl), -COOC 1-10 alkyl (preferably -COOC 1-8 alkyl, more preferably -COOC 1-6 alkyl, further preferably -COOC 1-3 alkyl), -CONH 2 , -CONHC 1-10 alkyl (preferably -CONHC 1-8 alkyl, more preferably -CONHC 1-6 alkyl, further preferably -CONHC 1-3 alkyl), -CON(C 1-10 alkyl ) 2 (preferably -CON(C 1-8 alkyl) 2 , more preferably -CON(C 1-6 alkyl) 2 , further preferably -CON(C 1-3 alkyl) 2 ), -SOC 1-10 alkyl (preferably -SOC 1-8 alkyl, more preferably -SOC 1-6 alkyl, further preferably -SOC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-8 alkyl, more preferably -SO 2 C 1-6 alkyl, further preferably -SO 2 C 1-3 alkyl), -SO 2 NH 2 , -SO 2 NHC 1-10 alkyl (preferably -SO 2 NHC 1-8 alkyl, more preferably -SO 2 NHC 1-6 alkyl, further preferably -SO 2 NHC 1-3 alkyl), -SO 2 N(C 1-10 alkyl) 2 (preferably -SO 2 N(C 1-8 alkyl) 2 , more preferably -SO 2 N(C 1-6 alkyl) 2 , further preferably -SO 2 N(C 1-3 alkyl) 2 ), C 3-8 cycloalkyl (preferably C 3-8 cycloalkyl) 2 The C 1-10 alkyl, the halogenated C 1-10 alkyl, the C 1-10 alkoxy, the halogenated C 1-10 alkoxy, -COC 1-10 alkyl, -COOC 1-10 alkyl, -CONH 2 , -CONHC 1-10 alkyl, -CON(C 1-10 alkyl) 2 , -SOC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-10 alkyl, -SO 2 N(C 1-10 alkyl) 2 , C 1-10 alkyl, -COC 1-10 alkyl, -COOC 1-10 alkyl, -CONH 2 , -CONHC 1-10 alkyl, -CON(C 1-10 alkyl) 2 , -SOC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-10 alkyl, -SO 2 N(C 1-10 alkyl) 2 , C the C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C 3-6 -membered cycloalkyl, 3- to 15-membered heterocycloalkyl (preferably 4- to 12-membered heterocycloalkyl, more preferably 4- to 8-membered heterocycloalkyl, and further preferably 4- to 6-membered heterocycloalkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl), phenyl and naphthyl; (R2)p2表示A2环上的氢被p2个R2取代，p2为0、1、2或3，每个R2相同或不同，各自独立地选自X1、氢、氘、C1-10烷基(优选为C1-8烷基，更优选为C1-6烷基，进一步优选为C1-3烷基)、C1-10烷氧基(优选为C1-8烷氧基，更优选为C1-6烷氧基，进一步优选为C1-3烷氧基)、卤代C1-10烷基(优选为卤代C1-8烷基，更优选为卤代C1-6烷基，进一步优选为卤代C1-3烷基)、卤代C1-10烷氧基(优选为卤代C1-8烷氧基，更优选为卤代C1-6烷氧基，进一步优选为卤代C1-3烷氧基)、C3-8环烷基(优选为C3-6环烷基)、3至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)和5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；所述的C1-10烷基、C1-10烷氧基、卤代C1-10烷基、卤代C1-10烷氧基、5至10元杂芳基、C3-8环烷基、3至15元杂环烷基、C6-14芳基为未取代或被1、2、3或4个选自下组的取代基取代：卤素(优选为氟、氯或溴)、羟基、羧基、硝基、甲酰基、磺酸基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、5至6元杂芳基、C3-8环烷基、4至15元杂环烷基(优选为4至12元杂环烷基，更优选为4至8元杂环烷基，进一步优选为4至6元杂环烷基)和C6-14芳基(优选为C6-12芳基)；(R 2 ) p2 represents that the hydrogen on the A2 ring is replaced by p2 R 2 , p2 is 0, 1, 2 or 3, each R 2 is the same or different and is independently selected from X 1 , hydrogen, deuterium, C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-6 alkyl, and further preferably C 1-3 alkyl ), C 1-10 alkoxy (preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, and further preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-8 alkyl, more preferably halogenated C 1-6 alkyl, and further preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-8 alkoxy, more preferably halogenated C 1-6 alkoxy, and further preferably halogenated C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C The C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, 5-10 membered heteroaryl, C 3-8 cycloalkyl, 3-15 membered heterocycloalkyl, C 6-14 aryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), hydroxyl, carboxyl , nitro, formyl, sulfonic acid, C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkyl , halogenated C 1-6 alkoxy , C 1-6 alkoxy, 5- to 6-membered heteroaryl, C 3-8 cycloalkyl, 4- to 15-membered heterocycloalkyl (preferably 4- to 12-membered heterocycloalkyl, more preferably 4- to 8-membered heterocycloalkyl, further preferably 4- to 6-membered heterocycloalkyl) and C 6-14 aryl (preferably C 6-12 aryl); (R3)p3表示2,3-二氢苯并呋喃环上的氢被p3个R3取代，p3为0、1或2，每个R3相同或不同，各自独立地选自氢、氘、卤素(优选为氟、氯或溴)、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、-COC1-8烷基(优选为-COC1-6烷基，更优选为-COC1-3烷基)、-COOC1-8烷基(优选为-COOC1-6烷基，更优选为-COOC1-3烷基)、-CONH2、-CONHC1-8烷基(优选为-CONHC1-6烷基，更优选为-CONHC1-3烷基)、-CON(C1-8烷基)2(优选为-CON(C1-6烷基)2，更优选为-CON(C1-3烷基)2)、-SOC1-8烷基(优选为-SOC1-6烷基，更优选为-SOC1-3烷基)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、-SO2NH2、-SO2NHC1-8烷基(优选为-SO2NHC1-6烷基，更优选为-SO2NHC1-3烷基)、-SO2N(C1-8烷基)2(优选为-SO2N(C1-6烷基)2，更优选为-SO2N(C1-3烷基)2)、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；和/或相邻的两个R3以及与其相连的碳原子形成C3-8环烷基环(优选为C3-6环烷基环)、3至8元杂环烷基环(优选为3至6元杂环烷基环、4至5元杂环烷基环)、5至10元杂芳基环(优选为5至6元杂芳基环)、苯环；所述的C1-8烷基、卤代C1-8烷基、C1-8烷氧基、卤代C1-8烷氧基、-COC1-8烷基、-COOC1-8烷基、-CONH2、-CONHC1-8烷基、-CON(C1-8烷基)2、-SOC1-8烷基、-SO2C1-8烷基、-SO2NH2、-SO2NHC1-8烷基、-SO2N(C1-8烷基)2、C3-8环烷基、3至12元杂环烷基、5至10元杂芳基、C6-14芳基、C3-8环烷基环、3至8元杂环烷基环、5至10元杂芳基环、苯环为未取代或被1、2或3个选自下组的取代基取代：卤素、氰基、羟基、羧基、硝基、甲酰基、磺酸基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)和5至10元杂芳基(优选为5至6元杂芳基)；(R 3 ) p3 represents that the hydrogen on the 2,3-dihydrobenzofuran ring is replaced by p3 R 3 , p3 is 0, 1 or 2, each R 3 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -COC 1-8 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -COOC 1-8 alkyl (preferably -COOC 1-6 alkyl, more preferably -COOC 1-3 alkyl), -CONH 2 , -CONHC 1-8 alkyl (preferably -CONHC 1-6 alkyl, more preferably -CONHC 1-3 alkyl), -CON(C 1-8 alkyl) 2 (preferably -CON(C 1-6 alkyl) 2 , more preferably -CON(C 1-3 alkyl) 2 ), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NH 2 , -SO 2 NHC 1-8 alkyl (preferably -SO 2 NHC 1-6 alkyl, more preferably -SO 2 NHC 1-3 alkyl), -SO 2 N(C 1-8 alkyl) 2 (preferably -SO 2 N(C 1-6 alkyl) 2 , more preferably -SO 2 N(C 1-3 alkyl) 2 ), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 12 membered heterocycloalkyl (preferably 4 to 8 membered heterocycloalkyl, more preferably 4 to 6 membered heterocycloalkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl) and C 6-14 aryl (preferably C 6-12 aryl); and/or two adjacent R 3 and the carbon atom connected thereto form a C 3-8 cycloalkyl ring (preferably a C 3-6 cycloalkyl ring), a 3 to 8 membered heterocycloalkyl ring (preferably a 3 to 6 membered heterocycloalkyl ring, a 4 to 5 membered heterocycloalkyl ring), a 5 to 10 membered heteroaryl ring (preferably a 5 to 6 membered heteroaryl ring), a benzene ring; the C 1-8 alkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, -COC 1-8 alkyl, -COOC 1-8 alkyl, -CONH 2 , -CONHC 1-8 alkyl, -CON( C wherein the alkyl group is unsubstituted or substituted by 1 , 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy , carboxyl, nitro , formyl , sulfonic acid, C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-8 alkyl) 2 , C 3-8 cycloalkyl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, C 6-14 aryl, C 3-8 cycloalkyl ring, 3 to 8 membered heterocycloalkyl ring, 5 to 10 membered heteroaryl ring, and benzene ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C -SOC 1-6 alkyl), -SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N (C 1-6 alkyl) 2 , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 12 membered heterocycloalkyl (preferably 4 to 8 membered heterocycloalkyl, more preferably 4 to 6 membered heterocycloalkyl) and 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl); (R4)p4表示咪唑并[1,5-c]嘧啶环上的氢被p4个R4取代，p4为0、1或2，每个R4相同或不同，各自独立地选自氢、氘、卤素(优选为氟、氯或溴)、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、-COC1-8烷基(优选为-COC1-6烷基，更优选为-COC1-3烷基)、-COOC1-8烷基(优选为-COOC1-6烷基，更优选为-COOC1-3烷基)、-CONH2、-CONHC1-8烷基(优选为-CONHC1-6烷基，更优选为-CONHC1-3烷基)、-CON(C1-8烷基)2(优选为-CON(C1-6烷基)2，更优选为-CON(C1-3烷基)2)、-SOC1-8烷基(优选为-SOC1-6烷基，更优选为-SOC1-3烷基)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、-SO2NH2、-SO2NHC1-8烷基(优选为-SO2NHC1-6烷基，更优选为-SO2NHC1-3烷基)、-SO2N(C1-8烷基)2(优选为-SO2N(C1-6烷基)2，更优选为-SO2N(C1-3烷基)2)、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；所述的C1-8烷基、卤代C1-8烷基、C1-8烷氧基、卤代C1-8烷氧基、-COC1-8烷基、-COOC1-8烷基、-CONH2、-CONHC1-8烷基、-CON(C1-8烷基)2、-SOC1-8烷基、-SO2C1-8烷基、-SO2NH2、-SO2NHC1-8烷基、-SO2N(C1-8烷基)2、C3-8环烷基、3至12元杂环烷基、5至10元杂芳基、C6-14芳基为未取代或被1、2或3个选自下组的取代基取代：卤素、氰基、羟基、羧基、硝基、甲酰基、磺酸基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、C3-8环烷基(优选为C3-6环烷基)、3至12元杂环烷基(优选为4至8元杂环烷基，更优选为4至6元杂环烷基)、5至10元杂芳基(优选为5至6元杂芳基)和C6-14芳基(优选为C6-12芳基)；(R 4 ) p4 represents that the hydrogen on the imidazo[1,5-c]pyrimidine ring is replaced by p4 R 4 , p4 is 0, 1 or 2, each R 4 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -COC 1-8 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -COOC 1-8 alkyl (preferably -COOC 1-6 alkyl, more preferably -COOC 1-3 alkyl), -CONH 2 , -CONHC 1-8 alkyl (preferably -CONHC 1-6 alkyl, more preferably -CONHC 1-3 alkyl), -CON(C 1-8 alkyl) 2 (preferably -CON(C 1-6 alkyl) 2 , more preferably -CON(C 1-3 alkyl) 2 ), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NH 2 , -SO 2 NHC 1-8 alkyl (preferably -SO 2 NHC 1-6 alkyl, more preferably -SO 2 NHC 1-3 alkyl), -SO 2 N(C 1-8 alkyl) 2 (preferably -SO 2 N(C 1-6 alkyl) 2 , more preferably -SO 2 N(C 1-6 alkyl) 2 C 1-8 alkyl) 2 ), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 12 membered heterocycloalkyl (preferably 4 to 8 membered heterocycloalkyl, more preferably 4 to 6 membered heterocycloalkyl), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl) and C 6-14 aryl (preferably C 6-12 aryl); the C 1-8 alkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, -COC 1-8 alkyl, -COOC 1-8 alkyl, -CONH 2 , -CONHC 1-8 alkyl, -CON(C 1-8 alkyl) 2 , -SOC 1-8 alkyl, -SO 2 C 1-8 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-8 alkyl, -SO 2 N ( C 1-8 alkyl) 2 , C The C 3-8 cycloalkyl, 3 to 12 membered heterocycloalkyl, 5 to 10 membered heteroaryl, and C 6-14 aryl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3-12 membered heterocycloalkyl (preferably 4-8 membered heterocycloalkyl, more preferably 4-6 membered heterocycloalkyl), 5-10 membered heteroaryl (preferably 5-6 membered heteroaryl) and C 6-14 aryl (preferably C 6-12 aryl); 其中，X1为POI与L或ULM的连接位点，且R1和R2中至少一个为X1。Wherein, X 1 is the connection site between POI and L or ULM, and at least one of R 1 and R 2 is X 1 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(A-1)所示的结构为式(A-2)所示的结构或其异构体，
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the structure represented by formula (A-1) is the structure represented by formula (A-2) or an isomer thereof,
如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，R1选自X1、氢、氰基、羧基、硝基、甲酰基、磺酸基、甲基、乙基、丙基、异丙基、叔丁基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、羟甲基、羟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、环己烯基、环戊烯基、四氢吡咯基、四氢呋喃基、哌啶基、哌嗪基、吡啶基、吡嗪基、哒嗪基、三嗪基、苯基、-CH2-环丙基、-CH2-四氢吡咯基、-CH2-吡咯基、-CH2-苯基、-CH2-吡啶基、-CH2-喹啉基和-CH2-环己烯基；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R 1 is selected from X 1 , hydrogen, cyano, carboxyl, nitro, formyl, sulfonic acid, methyl, ethyl, propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, phenyl, -CH 2 -cyclopropyl, -CH 2 -tetrahydropyrrolyl, -CH 2 -pyrrolyl, -CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -quinolinyl and -CH 2 -cyclohexenyl; 优选地，R1选自X1、氢、-CN、-COOH、-NO2、-CHO、-SO3H、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2OH、-CH2CH2OH、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-OC(CH3)3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-COCH3、-COOCH3、-CONH2、-CONHCH3、-CON(CH3)2、-SOCH3、-SO2CH3、-SO2NH2、-SO2NHCH3和-SO2N(CH3)2； Preferably , R 1 is selected from the group consisting of ​ ​ ​ ​ ​ ​ ​ ​ 2 CHF 2 , -CH 2 CF 3 , -CH 2 OH, -CH 2 CH 2 OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 F. -OCH 2 CHF 2 , -OCH 2 CF 3 , -COCH 3 , -COOCH 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -SOCH 3 , -SO 2 CH 3 , -SO 2 NH 2 , -SO 2 NHCH 3 and -SO 2 N(CH 3 ) 2 ; 优选地，R1选自X1、氢、-CH3、-CHF2、-CF3、-CH2OH、-OCH3、-OCH2CH3、-COCH3、-COOCH3、-CONH2、-CONHCH3、-CON(CH3)2、-SOCH3、-SO2CH3、-SO2NH2、-SO2NHCH3和-SO2N(CH3)2；Preferably, R 1 is selected from X 1 , hydrogen, —CH 3 , —CHF 2 , —CF 3 , —CH 2 OH, —OCH 3 , —OCH 2 CH 3 , —COCH 3 , —COOCH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —SOCH 3 , —SO 2 CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 and —SO 2 N(CH 3 ) 2 ; 优选地，R1选自X1、-CH3和-CF3；Preferably, R 1 is selected from X 1 , -CH 3 and -CF 3 ; 优选地，R1选自X1和-CF3。Preferably, R 1 is selected from X 1 and -CF 3 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，p1为1，R1为X1或-CF3。The compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that p1 is 1, and R 1 is X 1 or -CF 3 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，R2选自X1、氢、氘、C1-3烷基(优选为甲基、乙基、异丙基)、卤代C1-3烷基(优选为三氟甲基、二氟乙基、三氟乙基、二氟丙基)、C3-6环烷基(优选为环丙基、环丁基)和4至6元杂环烷基；所述的C1-3烷基、卤代C1-3烷基、C3-6环烷基、4至6元杂环烷基为未取代或被1、2、3或4个选自下组的取代基取代：氟、氯、溴、羟基、羧基、硝基、甲酰基、磺酸基、甲基、乙基、异丙基、甲氧基、乙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基、环丙基、环丁基、环戊基、环己基、环己烯基、吡咯基、吡唑基、吡啶基、苯基、嘧啶基、喹啉基、萘基、-CH2-环丙基、-CH2-四氢吡咯基、-CH2-吡咯基、-CH2-苯基、-CH2-吡啶基、-CH2-喹啉基、-CH2-环己烯基、-CH2-氮杂环丁烷、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R 2 is selected from X 1 , hydrogen, deuterium, C 1-3 alkyl (preferably methyl, ethyl, isopropyl), halogenated C 1-3 alkyl (preferably trifluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl), C 3-6 cycloalkyl (preferably cyclopropyl, cyclobutyl) and 4 to 6 membered heterocycloalkyl; the C 1-3 alkyl, halogenated C 1-3 alkyl, C The 3-6- membered cycloalkyl and 4- to 6-membered heterocycloalkyl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, carboxyl, nitro, formyl, sulfonic acid, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl, quinolyl, naphthyl, -CH2-cyclopropyl, -CH2 - tetrahydropyrrolyl, -CH2 -pyrrolyl, -CH2 -phenyl, -CH2 -pyridinyl, -CH2 -quinolyl, -CH2 - cyclohexenyl, -CH2-azetidine, -CH2 -piperidine, -CH2 -piperazine, tetrahydro-2H-pyran and -CH 2 -(tetrahydro-2H-pyran); 优选地，R2选自X1、氢、氘、甲基、乙基、丙基、异丙基、叔丁基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、二氟丙基、环丙基、环丁基、环戊基、环己基、氮杂环丁烷基、四氢吡咯基、哌啶基、哌嗪基、-CH2-环丙基、-CH2-氮杂环丁烷、-CH2-四氢吡咯、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)；Preferably, R 2 is selected from X 1 , hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, -CH 2 -cyclopropyl, -CH 2 -azetidine, -CH 2 -tetrahydropyrrole, -CH 2 -piperidine, -CH 2 -piperazine, tetrahydro-2H-pyran and -CH 2 - (tetrahydro-2H-pyran); 优选地，R2选自X1、氢、氘、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CF2CH3、环丙基、环丁基、环戊基、环己基、氮杂环丁烷基、四氢吡咯基、哌啶基、哌嗪基、-CH2-环丙基、-CH2-氮杂环丁烷、-CH2-四氢吡咯、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)；Preferably, R 2 is selected from X 1 , hydrogen, deuterium, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, -CH 2 -cyclopropyl, -CH 2 -azetidine, -CH 2 -tetrahydropyrrole, -CH 2 -piperidine, -CH 2 -piperazine, tetrahydro-2H-pyran and -CH 2 -(tetrahydro-2H-pyran); 优选地，R2选自X1、-CH3、-CH2CHF2、-CH2CF2CH3和-CH(CH3)2；Preferably, R 2 is selected from X 1 , -CH 3 , -CH 2 CHF 2 , -CH 2 CF 2 CH 3 and -CH(CH 3 ) 2 ; 优选地，R2选自X1和-CH(CH3)2。Preferably, R 2 is selected from X 1 and -CH(CH 3 ) 2 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，p2为1，R2为X1或-CH(CH3)2。The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that p2 is 1, and R 2 is X 1 or -CH(CH 3 ) 2 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，R3选自氢、氘、氟、氯、溴、碘、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲氧基、二氟甲氧基、三氟甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、环丙基、环丁基、环戊基、环己基、环己烯基、吡咯基、吡唑基、吡啶基、苯基、嘧啶基、喹啉基、萘基、-CH2-环丙基、-CH2-四氢吡咯基、-CH2-吡咯基、-CH2-苯基、-CH2-吡啶基、-CH2-喹啉基、-CH2-环己烯基、-CH2-氮杂环丁烷、-CH2-哌啶、-CH2-哌嗪、四氢-2H-吡喃和-CH2-(四氢-2H-吡喃)；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R 3 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl, quinolyl, naphthyl, -CH 2 -cyclopropyl, -CH 2 -tetrahydropyrrolyl, -CH 2 -pyrrolyl, -CH 2 -phenyl, -CH 2 -pyridinyl, -CH 2 -quinolyl, -CH 2 -cyclohexenyl, -CH 2 -azetidine, -CH 2 - 2 -piperidine, -CH2 -piperazine, tetrahydro-2H-pyran and -CH2- (tetrahydro-2H-pyran); 优选地，R3选自氢、氘、氟、氯、溴、碘、-CH3、-CH2CH3、-CH(CH3)2、-CH2CH2CH3、-CH2F、-CHF2、-CF3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-OCH2F、-OCHF2、-OCF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-OCH2CH2F、-OCH2CHF2和-OCH2CF3。Preferably, R 3 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 F, -OCHF 2 , -OCF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 and -OCH 2 CF 3 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，p3为1，R3为氟；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that p3 is 1, and R 3 is fluorine; 优选地，结构为 Preferably, the structure for 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，相邻的两个R3以及与其相连的碳原子形成C3-6环烷基环、3至6元杂环烷基环或5至6元杂芳基环；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that two adjacent R 3 and the carbon atom to which they are connected form a C 3-6 cycloalkyl ring, a 3- to 6-membered heterocycloalkyl ring, or a 5- to 6-membered heteroaryl ring; 优选地，相邻的两个R3以及与其相连的碳原子形成环丙烷环、环丁烷环、环戊烷环、环己烷环、环己烯环、环戊烯环、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、吡咯环、呋喃环、噻吩环、恶唑环、噻唑环、吡唑环、咪唑环、三唑环、吡啶环、嘧啶环、哒嗪环、吡嗪环或三嗪环；Preferably, two adjacent R 3 and the carbon atom connected thereto form a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cyclohexene ring, a cyclopentene ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, a thiazole ring, a pyrazole ring, an imidazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring or a triazine ring; 优选地，相邻的两个R3以及与其相连的碳原子形成环丙烷环。Preferably, two adjacent R 3 and the carbon atom to which they are attached form a cyclopropane ring. 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，p3为3，其中一个R3为氟，另两个R3以及与其相连的碳原子形成环丙烷环；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that p3 is 3, one R 3 is fluorine, and the other two R 3 and the carbon atoms connected thereto form a cyclopropane ring; 优选地，结构为 Preferably, the structure for 优选地，结构为 Preferably, the structure for 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，A1环中所述的C3-15环烷基环选自环丙烷环、环丁烷环、环戊烷环、双环戊烷环、环己烷环、螺[3.3]庚烷环、螺环[3.4]辛烷环、螺[3.5]壬烷环、萘烷环、十四氢蒽环、八氢-1'H-螺[环戊烷-1，2'-萘]环、环己烯环和螺[4.5]癸-6-烯环；或The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the C 3-15 cycloalkyl ring in the A1 ring is selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a bicyclopentane ring, a cyclohexane ring, a spiro[3.3]heptane ring, a spiro[3.4]octane ring, a spiro[3.5]nonane ring, a decalin ring, a tetradecahydroanthracene ring, an octahydro-1'H-spiro[cyclopentane-1,2'-naphthalene] ring, a cyclohexene ring and a spiro[4.5]dec-6-ene ring; or A1环中所述的3至15元杂环烷基环选自氮杂环丁烷环、四氢吡咯环、四氢呋喃环、四氢噻吩环、哌啶环、哌嗪环、2,5-二氢-1H-吡咯环、2,3-二氢-1H-吡咯环、1,2,3,6-四氢吡啶环、1,2,3,4-四氢吡啶环、3,4-二氢-2H-1,4-恶嗪环、1,3-二氧杂环戊烯环、2,3,6,7-四氢-1H-氮平环、2,3,4,7-四氢-1H-氮平环、2,3,4,5-四氢-1H-氮平环、2-氮杂螺[3.3]庚烷环、6-氮杂螺[3.4]辛烷环、7-氮杂螺[3.5]壬烷环、2,6-二氮杂螺[3.3]庚烷环、2,6-二氮杂螺[3.4]辛烷环、2,7-二氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环和2-氮杂螺[4.5]癸-6-烯环；或The 3- to 15-membered heterocycloalkyl ring in the A1 ring is selected from an azetidine ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a piperazine ring, a 2,5-dihydro-1H-pyrrole ring, a 2,3-dihydro-1H-pyrrole ring, a 1,2,3,6-tetrahydropyridine ring, a 1,2,3,4-tetrahydropyridine ring, a 3,4-dihydro-2H-1,4-oxazine ring, a 1,3-dioxole ring, a 2,3,6,7-tetrahydro-1H-azepine ring, a 2,5-dihydro-1H-azepine ring, a 2,3-dihydro-1H-azepine ring, a 1,2,3,6-tetrahydropyridine ring, a 1,2,3,4-tetrahydropyridine ring, a 3,4-dihydro-2H-1,4-oxazine ring, a 1,3-dioxole ring, a 2,3,6,7-tetrahydro-1H-azepine ring, a 2,3 3,4,7-tetrahydro-1H-azapine ring, 2,3,4,5-tetrahydro-1H-azapine ring, 2-azaspiro[3.3]heptane ring, 6-azaspiro[3.4]octane ring, 7-azaspiro[3.5]nonane ring, 2,6-diazaspiro[3.3]heptane ring, 2,6-diazaspiro[3.4]octane ring, 2,7-diazaspiro[3.5]nonane ring, 2-azaspiro[3.5]nonane ring and 2-azaspiro[4.5]dec-6-ene ring; or A1环中所述的5至15元杂芳基环选自吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、三唑环、四唑环、噁唑环、噻唑环、恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环、苯并吡咯环、苯并呋喃环、苯并噻吩环、苯并吡唑环、苯并咪唑环、苯并噻唑环、苯并噁唑环、吡啶并吡咯环、吡啶并呋喃环、吡啶并噻吩环、吡啶并吡唑环、吡啶并咪唑环、吡啶并噻唑环、吡啶并噁唑环、嘧啶并吡咯环、哒嗪并吡咯环、吡嗪并吡咯环、嘧啶并吡唑环、哒嗪并吡唑环、吡嗪并吡唑环、嘧啶并咪唑环、哒嗪并咪唑环、吡嗪并咪唑环、喹啉环、异喹啉环和9H-吡啶并[2,3-b]吲哚环；或The 5- to 15-membered heteroaryl ring in Ring A1 is selected from the group consisting of a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a benzopyrrole ring, a benzofuran ring, a benzothiophene ring, a benzopyrazole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a pyridopyrrole ring, a , a pyridofuran ring, a pyridothiophene ring, a pyridopyrazole ring, a pyridoimidazole ring, a pyridothiazole ring, a pyridooxazole ring, a pyrimidopyrrole ring, a pyridazinopyrrole ring, a pyrazinopyrrole ring, a pyrimidopyrazole ring, a pyridazinopyrazole ring, a pyrazinopyrazole ring, a pyrimidoimidazole ring, a pyridazinoimidazole ring, a quinoline ring, an isoquinoline ring and a 9H-pyrido[2,3-b]indole ring; or A1环中所述的C6-14芳环选自苯环和萘环；The C 6-14 aromatic ring in the A1 ring is selected from a benzene ring and a naphthalene ring; 优选地，A1环选自苯环、吡啶环、嘧啶环、哒嗪环、吡嗪环、三嗪环、吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、噁唑环和噻唑环；Preferably, the A1 ring is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring and a thiazole ring; 优选地，A1环选自苯环、吡啶环和吡唑环；Preferably, the A1 ring is selected from a benzene ring, a pyridine ring and a pyrazole ring; 优选地，A1环选自苯环、吡啶环；Preferably, the A1 ring is selected from a benzene ring and a pyridine ring; 优选地，结构选自 Preferably, the structure Selected from 优选地，结构选自： Preferably, the structure Selected from: 优选地，结构选自 其中，R1、R2、p1、X1如权利要求1中所定义，且R1和R2中至少一个为X1；Preferably, the structure Selected from wherein R 1 , R 2 , p1, and X 1 are as defined in claim 1 , and at least one of R 1 and R 2 is X 1 ; 优选地，结构选自：其中，R1、R2、p1、X1如权利要求1中所定义，且R1和R2中至少一个为X1。Preferably, the structure Selected from: Wherein, R 1 , R 2 , p1, and X 1 are as defined in claim 1 , and at least one of R 1 and R 2 is X 1 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，结构选自其中Y1、Y2、Y3各自独立地为CH或N，R1、R2、p1、A1、X1如权利要求1所定义；The compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the structure Selected from wherein Y 1 , Y 2 , and Y 3 are each independently CH or N, and R 1 , R 2 , p1, A1, and X 1 are as defined in claim 1; 优选地，结构选自 其中X1为POI与L或ULM的连接位点；Preferably, the structure Selected from Where X 1 is the connection site between POI and L or ULM; 优选地，结构选自、 其中X1为POI与L或ULM的连接位点；Preferably, the structure Selected from Where X 1 is the connection site between POI and L or ULM; 优选地，结构选自： 其中X1为POI与L或ULM的连接位点；Preferably, the structure Selected from: Where X 1 is the connection site between POI and L or ULM; 优选地，结构选自： 其中X1为POI与L或ULM的连接位点。Preferably, the structure Selected from: Where X1 is the connection site between POI and L or ULM. 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，POI选自以下结构： 其中X1为POI与L或ULM的连接位点；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein POI is selected from the following structures: Where X 1 is the connection site between POI and L or ULM; 优选地，POI选自以下结构： 其中X1为POI与L或ULM的连接位点；Preferably, the POI is selected from the following structures: Where X 1 is the connection site between POI and L or ULM; 优选地，POI选自以下结构： 其中X1为POI与L或ULM的连接位点。Preferably, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM. 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，L为式(L-1)所示的结构或其异构体，
-(La)m1-
(L-1)，The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that L is a structure represented by formula (L-1) or an isomer thereof,
-(L a ) m1 -
(L-1), 其中，m1独立的为0、1、2、3、4、5、6、7、8、9或10；wherein m1 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; La每次出现，各自独立地选自键、-C(O)-、-C(O)NRL1-、-NRL1-、-O-、-S-、C1-10亚烷基(优选为C1-8亚烷基，更优选为C1-6亚烷基，进一步优选为C1-3亚烷基)、C1-10亚烷氧基(优选为C1-8亚烷氧基、更优选为C1-6亚烷氧基、进一步优选为C1-3亚烷氧基)、C2-10亚烯基(优选为C2-8亚烯基，更优选为C2-6亚烯基，进一步优选为C2-4亚烯基)、C2-10亚炔基(优选为C2-8亚炔基，更优选为C2-6亚炔基，进一步优选为C2-4亚炔基)、C3-15环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环、进一步优选为4至6元杂环烷基环)、5至15元杂芳基环(优选为5至14元杂芳基环，更优选为5至12元杂芳基环，进一步优选为5至10元杂芳基环，进一步优选为5至6元杂芳基环)和C6-14芳环(优选为苯环或萘环)；所述的C1-10亚烷基、C1-10亚烷氧基、C2-10亚烯基、C2-10亚炔基、C3-15环烷基环、3至15元杂环烷基环、5至15元杂芳基环、C6-14芳环为未取代或被1、2、3或4个RL2取代，所述的RL2各自独立地选自氘、卤素、羟基、氰基、氨基、羧基、甲酰基、氧代基、磺酸基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、氨基取代的C1-6烷基、C1-6烷氧基C1-6烷基、C3-6环烷基、C3-6环烷基C1-6烷基、3至6元杂环烷基、3至6元杂环烷基C1-6烷基、5至6元杂芳基、5至6元杂芳基C1-6烷基、苯基、苯基C1-6烷基、-COC1-6烷基、-COOC1-6烷基、-OCOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基和-SO2N(C1-6烷基)2；Each occurrence of L a is independently selected from a bond, -C(O)-, -C(O)NR L1 -, -NR L1 -, -O-, -S-, C 1-10 alkylene (preferably C 1-8 alkylene, more preferably C 1-6 alkylene, and further preferably C 1-3 alkylene), C 1-10 alkyleneoxy (preferably C 1-8 alkyleneoxy, more preferably C 1-6 alkyleneoxy, and further preferably C 1-3 alkyleneoxy), C 2-10 alkenylene (preferably C 2-8 alkenylene, more preferably C 2-6 alkenylene, and further preferably C 2-4 alkenylene), C 2-10 alkynylene (preferably C 2-8 alkynylene, more preferably C 2-6 alkynylene, and further preferably C 2-4 alkynylene), C 3-15 cycloalkyl ring (preferably C 3-10 cycloalkyl ring, more preferably C 3-8 cycloalkyl ring, and further preferably C wherein the C 1-10 alkylene group, C 1-10 alkylene group, C 2-10 alkenylene group, C 2-10 alkynylene group, C 3-15 cycloalkyl ring, 3-15 membered heterocycloalkyl ring, 5-15 membered heteroaryl ring and C 6-14 aromatic ring are unsubstituted or substituted with 1 , 2 , 3 or 4 R L2 , wherein R L2 is each independently selected from deuterium, halogen, hydroxyl, cyano, amino, carboxyl, formyl, oxo, sulfonic acid, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, hydroxy-substituted C1-6 alkyl, cyano-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, 3 to 6-membered heterocycloalkyl, 3 to 6 - membered heterocycloalkyl C1-6 alkyl, 5 to 6-membered heteroaryl, 5 to 6-membered heteroaryl C1-6 alkyl, phenyl, phenyl C1-6 alkyl, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl, -CONH2 , -CONHC1-6 alkyl, -CON( C1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, and -SO 2 N(C 1-6 alkyl) 2 ; RL1每次出现，各自独立地选自氢、氘、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)和卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)。Each occurrence of RL1 is independently selected from hydrogen, deuterium, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), halo-substituted C1-8 alkoxy (preferably halo-substituted C1-6 alkoxy, more preferably halo-substituted C1-3 alkoxy) and halo-substituted C1-8 alkyl (preferably halo-substituted C1-6 alkyl, more preferably halo-substituted C1-3 alkyl). 如权利要求14所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，RL1每次出现，各自独立地选自氢、甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基、叔丁氧基、三氟甲基、二氟甲基、一氟甲基、三氟乙基、二氟乙基、一氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、三氟乙氧基、二氟乙氧基和一氟乙氧基；The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that each occurrence of R L1 is independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoroethoxy, difluoroethoxy and monofluoroethoxy; 优选地，RL1每次出现，各自独立地选自氢、甲基、乙基、二氟甲基和一氟甲基；Preferably, each occurrence of R L1 is independently selected from hydrogen, methyl, ethyl, difluoromethyl and monofluoromethyl; 优选地，RL1为氢。Preferably, R L1 is hydrogen. 如权利要求14所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，RL2各自独立地选自氘、卤素、羟基、氰基、氨基、羧基、羟甲基、羟乙基、甲基、乙基、二氟甲基、一氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、环丙基、环丁基、环戊基、环己基、环己烯基、环戊烯基、四氢吡咯基、四氢呋喃基、苯基、吡咯基、呋喃基、噻吩基、噻唑基、噁唑基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-环己烯基、-CH2-环戊烯基、-CH2-四氢吡咯基、-CH2-四氢呋喃基、-CH2-苯基、-CH2-吡咯基、-CH2-三唑基、-CH2-四唑基、-CH2-吡啶基、-CH2-吡嗪基、-CH2-三嗪基、甲氧基、乙氧基、二氟甲氧基、一氟甲氧基、三氟甲氧基、乙酰基、乙酰氨基和磺酰胺基；The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that RL2 is independently selected from deuterium, halogen, hydroxyl, cyano, amino, carboxyl, hydroxymethyl, hydroxyethyl, methyl, ethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, -CH2 -cyclohexenyl, -CH2 -cyclopentenyl, -CH2 -tetrahydropyrrolyl, -CH 2 -tetrahydrofuranyl, -CH 2 -phenyl, -CH 2 -pyrrolyl, -CH 2 -triazolyl, -CH 2 -tetrazolyl, -CH 2 -pyridinyl, -CH 2 -pyrazinyl, -CH 2 -triazinyl, methoxy, ethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethoxy, acetyl, acetamido and sulfonamido ; 优选地，RL2各自独立地选自氘、-F、-Cl、-Br、-OH、-CN、-CHO、-COOH、-NH2、-CH2OH、-CH2CH2OH、-CH3、-CH2CH3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-OCH3、-OCH2CH3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-COCH3、-CH2-环丙基、环丙基、-CONH2、-COOCH3、-OCOCH3、-CONHCH3、-CON(CH3)2、-SOCH3、-SO2CH3、-SO2NH2、-SO2NHCH3和-SO2N(CH3)2；Preferably, RL2 is each independently selected from deuterium, -F, -Cl, -Br, -OH , -CN , -CHO, -COOH , -NH2 , -CH2OH , -CH2CH2OH , -CH3 , -CH2CH3 , -CH2F , -CHF2 , -CF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3, -OCH3 , -OCH2CH3 , -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2 , -OCH2CF3, -COCH3 , -CH2 - cyclopropyl, cyclopropyl , -CONH2 , -COOCH3 , -OCOCH3 , -CONHCH3 , -CON(CH 3 ) 2 , -SOCH 3 , -SO 2 CH 3 , -SO 2 NH 2 , -SO 2 NHCH 3 and -SO 2 N(CH 3 ) 2 ; 优选地，RL2各自独立地选自氘、-F、-Cl、-Br、-OH、-CN、-COOH、-NH2、-CH2OH、-CH2CH2OH、-CH3、-CH2CH3、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-OCH3、-OCH2CH3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-COCH3、-CH2-环丙基、环丙基和-CONH2；Preferably, each RL2 is independently selected from deuterium, -F, -Cl, -Br , -OH , -CN , -COOH , -NH2 , -CH2OH, -CH2CH2OH, -CH3, -CH2CH3 , -CH2F , -CHF2 , -CF3 , -CH2CH2F , -CH2CHF2, -CH2CF3 , -OCH3 , -OCH2CH3 , -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2 , -OCH2CF3 , -COCH3 , -CH2 - cyclopropyl, cyclopropyl and -CONH2 ; 优选地，RL2各自独立地选自氟、氯、溴、甲基、羟基和羟甲基。Preferably, R L2 are each independently selected from fluorine, chlorine, bromine, methyl, hydroxyl and hydroxymethyl. 如权利要求14所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述的La各自独立地选自以下结构或其异构体：-C(O)-、-C(O)NH-、-O-、-S-、-NH-、C1-10亚烷基、C1-10亚烷氧基、C3-12环烷基环、4至12元杂环烷基环、5至6元杂芳基环和苯环；所述的C3-12环烷基环、4至12元杂环烷基环、5至6元杂芳基环、苯环为未取代或被1、2、3或4个RL2取代，所述的RL2选自氟、甲基、羟基和羟甲基；The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the La is independently selected from the following structures or isomers thereof: -C(O)-, -C(O)NH-, -O-, -S-, -NH-, C1-10 alkylene, C1-10 alkyleneoxy, C3-12 cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring; the C3-12 cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring are unsubstituted or substituted with 1, 2, 3 or 4 RL2 , and the RL2 is selected from fluorine, methyl, hydroxyl and hydroxymethyl; 优选地，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-(CH2)m2-、-O(CH2)m2-、-(CH2)m2O-、环丙烷环、环丁烷环、双环戊烷环、环戊烷环、环己烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、羟基取代的哌啶环、羟基取代的哌嗪环、羟甲基取代的哌啶环、羟甲基取代的哌嗪环、2-氮杂螺[3.3]庚烷环、6-氮杂螺[3.4]辛烷环、7-氮杂螺[3.5]壬烷环、2,6-二氮杂螺[3.3]庚烷环、2,6-二氮杂螺[3.4]辛烷环、2,7-二氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环、螺[3.3]庚烷环、螺[3.4]辛烷环、螺[3.5]壬烷环、苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、三嗪环、噻吩环、呋喃环、吡咯环、噻唑环、噁唑环、吡唑环、咪唑环、三唑环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷；其中，m2每次出现，各自独立地为1、2、3、4、5、6、7、8、9或10；Preferably, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH 2 ) m2 -, -O(CH 2 ) m2 -, -(CH 2 ) m2 O-, cyclopropane ring, cyclobutane ring, bicyclopentane ring, cyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, 2-azaspiro[3.3]heptane ring, 6-azaspiro[3.4]octane ring, 7-azaspiro[3.5]nonane ring, 2,6-diazaspiro[3.3]heptane ring, 2,6-diazaspiro[3.4]octane ring, 2,7-diazaspiro[3.5]nonane ring, 2-azaspiro[3.5]nonane ring, spiro[3.3]heptane ring, spiro[3.4]octane ring, spiro[3.5]nonane ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, triazine ring, thiophene ring, furan ring, pyrrole ring, thiazole ring, oxazole ring, pyrazole ring, imidazole ring, triazole ring, (2S,6R)-2,6-dimethylpiperazine, 3-azabicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane and 3,9-diazaspiro[5.5]undecane; wherein m2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it occurs; 优选地，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-(CH2)m2-、-O(CH2)m2-、-(CH2)m2O-、环丙烷环、环丁烷环、环戊烷环、双环戊烷环、环己烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、羟基取代的哌啶环、羟基取代的哌嗪环、羟甲基取代的哌啶环、羟甲基取代的哌嗪环、2-氮杂螺[3.3]庚烷环、7-氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环、苯环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷；其中，m2每次出现，各自独立地为1、2、3、4、5、6、7、8、9或10；Preferably, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH 2 ) m2 -, -O(CH 2 ) m2 -, -(CH 2 ) m2 O-, cyclopropane ring, cyclobutane ring, cyclopentane ring, bicyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, 2-azaspiro[3.3]heptane ring, 7-azaspiro[3.5]nonane ring, 2-azaspiro[3.5]nonane ring, benzene ring, (2S,6R)-2,6-dimethylpiperazine, 3-azaspiro[3.5]nonane ring, heterobicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane and 3,9-diazaspiro[5.5]undecane; wherein m2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 at each occurrence; 优选地，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)7-、-(CH2)8-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、氮杂环丁烷环、四氢吡咯环、哌啶环、哌嗪环、羟基取代的哌啶环、羟基取代的哌嗪环、羟甲基取代的哌啶环、羟甲基取代的哌嗪环、环丁烷环、环戊烷环、环己烷环、苯环、双环戊烷环、2-氮杂螺[3.3]庚烷环、2-氮杂螺[3.4]辛烷环、2-氮杂螺[3.5]壬烷环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷；Preferably, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH- , -CH2- , -(CH2) 2- , -(CH2) 3- , -( CH2 ) 4- , -( CH2 ) 5- , - ( CH2 ) 7- , -( CH2 ) 8- , -OCH2- , -OCH2CH2- , -CH2O-, -CH2CH2 O-, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, benzene ring, bicyclopentane ring, 2-azaspiro[3.3]heptane ring, 2-azaspiro[3.4]octane ring, 2-azaspiro[3.5]nonane ring, (2S,6 R)-2,6-dimethylpiperazine, 3-azabicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane, and 3,9-diazaspiro[5.5]undecane; 优选地，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)7-、-(CH2)8-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、 Preferably, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, 优选地，所述的La各自独立地选自以下结构或其异构体：-O-、-S-、-NH-、-C(O)-、-C(O)NH-、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)7-、-(CH2)8-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、 Preferably, the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, 优选地，所述的La各自独立地选自以下结构或其异构体：-CONH-、-CO-、-NH-、-CH2-、 Preferably, the La is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -NH-, -CH 2 -, 优选地，所述的La各自独立地选自以下结构或其异构体：-CONH-、-CO-、-CH2-、-NH-、 Preferably, the La is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -CH 2 -, -NH-, 优选地，所述的La各自独立地选自以下结构或其异构体：-CONH-、-CH2-、-NH-、-CO-、 Preferably, the La is independently selected from the following structures or isomers thereof: -CONH-, -CH2- , -NH-, -CO-, 优选地，所述的La各自独立地选自以下结构或其异构体：-CH2-、-NH-、-CONH-、-CO-、 Preferably, the La is independently selected from the following structures or isomers thereof: -CH2- , -NH-, -CONH-, -CO-, 如权利要求14所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述的L选自以下结构或其异构体：-(CH2)m3-、-C(O)-(CH2)m3-、-C(O)NH-(CH2)m3-、-C(O)NH-(CH2)m3-O-、-Cy0-NH-(CH2)m3-、-C(O)NH-Cy0-、-C(O)-Cy0-、-(CH2)m3-C(O)-Cy0-、-(CH2)m3-Cy0-、-(CH2)m3-C(O)NH-(CH2)m3O-Cy0-O(CH2)m3-、-Cy0-Cy0-、-Cy0-CH2-Cy0-、-C(O)-Cy0-CH2-Cy0-、-C(O)NH-Cy0-CH2-Cy0-、-Cy0-C(O)-Cy0-、-C(O)-Cy0-C(O)-Cy0-、-C(O)NH-Cy0-C(O)-Cy0-、-Cy0-O-Cy0-、-Cy0-C(O)NH-Cy0-、-NH(CH2)m3-、-(CH2)m3O(CH2)m3-、-Cy0-C(O)-(CH2)m3-、-NH-Cy0-(CH2)m3-Cy0-和-(CH2)m3-Cy0-O-Cy0-O(CH2)m3-；其中，m3每次出现，独立地为0,1,2,3,4,5,6,7,8,9或10；Cy0每次出现，独立地选自C3-12环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至12元杂环烷基环(优选为的3至10元杂环烷基环，更优选为3至8元杂环烷基环，进一步优选为3至6元杂环烷基环)、5至6元杂芳基环和苯环；所述C3-12环烷基环、3至12元杂环烷基环、5至6元杂芳基环、苯环为未取代或被1、2、3或4个RL2取代，RL2每次出现，各自独立地选自氘、卤素、羟基、氰基、氨基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、羟基取代的C1-3烷基、氰基取代的C1-3烷基、氨基取代的C1-3烷基、C1-3烷氧基C1-3烷基、C3-6环烷基、C3-6环烷基C1-3烷基、-COC1-3烷基、-COOC1-3烷基、-OCOC1-3烷基、-CONH2、-CONHC1-3烷基和-CON(C1-3烷基)2；The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is characterized in that L is selected from the following structures or isomers thereof: -( CH2 ) m3- , -C(O)-( CH2 ) m3- , -C(O)NH-( CH2 ) m3- , -C(O)NH-( CH2 ) m3 -O-, -Cy0 -NH-( CH2 ) m3- , -C(O)NH- Cy0- , -C(O) -Cy0- , -( CH2 ) m3 -C(O)-Cy0-, -( CH2 ) m3 - C(O) -Cy0- , -( CH2 )m3-Cy0-, -( CH2 ) m3 -C(O)NH-(CH2) m3O - Cy0 -O( CH2 ) m3- , -Cy0- Cy0- , -Cy0 - CH2 -Cy 0 -, -C(O)-Cy 0 -CH 2 -Cy 0 -, -C(O)NH-Cy 0 -CH 2 -Cy 0 -, -Cy 0 -C(O)-Cy 0 -, -C(O)-Cy 0 -C(O)-Cy 0 -, -C(O)NH-Cy 0 -C(O)-Cy 0 -, -Cy 0 -O-Cy 0 -, -Cy 0 -C(O)NH-Cy 0 -, -NH(CH 2 ) m3 -, -(CH 2 ) m3 O(CH 2 ) m3 -, -Cy 0 -C(O)-(CH 2 ) m3 -, -NH-Cy 0 -(CH 2 ) m3 -Cy 0 -and -(CH 2 ) m3 -Cy 0 -O-Cy 0 -O(CH 2 ) m3- ; wherein, m3 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it appears; Cy0 is independently selected from C3-12 cycloalkyl ring (preferably C3-10 cycloalkyl ring, more preferably C3-8 cycloalkyl ring, and further preferably C3-6 cycloalkyl ring), 3 to 12 membered heterocycloalkyl ring (preferably 3 to 10 membered heterocycloalkyl ring, more preferably 3 to 8 membered heterocycloalkyl ring, and further preferably 3 to 6 membered heterocycloalkyl ring), 5 to 6 membered heteroaryl ring and benzene ring; the C3-12 cycloalkyl ring, 3 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring, and benzene ring are unsubstituted or substituted with 1, 2, 3 or 4 RL2 , and RL2 is independently selected from deuterium, halogen, hydroxyl, cyano, amino, carboxyl, C1-3 alkyl, C1-3 alkoxy, halogenated C C 1-3 alkyl, halogenated C 1-3 alkoxy, hydroxy-substituted C 1-3 alkyl, cyano-substituted C 1-3 alkyl, amino-substituted C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, -COC 1-3 alkyl, -COOC 1-3 alkyl, -OCOC 1-3 alkyl, -CONH 2 , -CONHC 1-3 alkyl and -CON(C 1-3 alkyl) 2 ; 优选地，Cy0各自独立地自环丙烷环、环丁烷环、环戊烷环、双环戊烷环、环己烷环、氮杂环丁烷环、四氢吡咯环、哌啶环、羟基取代的哌啶环、羟甲基取代的哌啶环、哌嗪环、2-氮杂螺[3.3]庚烷环、6-氮杂螺[3.4]辛烷环、7-氮杂螺[3.5]壬烷环、2,6-二氮杂螺[3.3]庚烷环、2,6-二氮杂螺[3.4]辛烷环、2,7-二氮杂螺[3.5]壬烷环、2-氮杂螺[3.5]壬烷环、螺[3.3]庚烷环、螺环[3.4]辛烷环、螺[3.5]壬烷环、苯环、吡啶环、嘧啶环、吡嗪环、哒嗪环、三嗪环、噻吩环、呋喃环、吡咯环、噻唑环、噁唑环、吡唑环、咪唑环、三唑环、(2S,6R)-2,6-二甲基哌嗪、3-氮杂双环[3.2.1]辛烷、3,5-二甲基哌啶、3,3,5,5-四甲基哌啶、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,8-二氮杂螺[4.5]癸烷和3,9-二氮杂螺[5.5]十一烷、1,1,3,3-四甲基环丁烷、3-氟哌啶、(S)-3-氟哌啶、(R)-3-氟哌啶、3,3-二氟哌啶；Preferably, Cy O is each independently selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a bicyclopentane ring, a cyclohexane ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a hydroxy-substituted piperidine ring, a hydroxymethyl-substituted piperidine ring, a piperazine ring, a 2-azaspiro[3.3]heptane ring, a 6-azaspiro[3.4]octane ring, a 7-azaspiro[3.5]nonane ring, a 2,6-diazaspiro[3.3]heptane ring, a 2,6-diazaspiro[3.4]octane ring, a 2,7-diazaspiro[3.5]nonane ring, a 2-azaspiro[3.5]nonane ring, a spiro[3.3]heptane ring, a spiro[3.4]octane ring, a spiro[3.5]nonane ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridinium ... azine ring, a triazine ring, a thiophene ring, a furan ring, a pyrrole ring, a thiazole ring, an oxazole ring, a pyrazole ring, an imidazole ring, a triazole ring, (2S,6R)-2,6-dimethylpiperazine, 3-azabicyclo[3.2.1]octane, 3,5-dimethylpiperidine, 3,3,5,5-tetramethylpiperidine, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,8-diazaspiro[4.5]decane and 3,9-diazaspiro[5.5]undecane, 1,1,3,3-tetramethylcyclobutane, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,3-difluoropiperidine; 优选地，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、哌嗪环、3,3,5,5-四甲基哌啶、环己烷环、环丁烷环、1,1,3,3-四甲基环丁烷、氮杂环丁烷环、3,3-二氟哌啶、3-氟哌啶、(S)-3-氟哌啶、(R)-3-氟哌啶、3,5-二甲基哌啶、2,6-二甲基哌嗪、3,9-二氮杂螺[5.5]十一烷、2-氮杂螺[3.5]壬烷、2-氮杂螺[3.3]庚烷、7-氮杂螺[3.5]壬烷、2,7-二氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、3-氮杂双环[3.2.1]辛烷；Preferably, the Cy 0 is each independently selected from the following structures or isomers thereof: piperidine ring, piperazine ring, 3,3,5,5-tetramethylpiperidine, cyclohexane ring, cyclobutane ring, 1,1,3,3-tetramethylcyclobutane, azetidine ring, 3,3-difluoropiperidine, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,5-dimethylpiperidine, 2,6-dimethylpiperazine, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 3-azabicyclo[3.2.1]octane; 优选地，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、哌嗪环、3,3,5,5-四甲基哌啶、3,3-二氟哌啶、3-氟哌啶、(S)-3-氟哌啶、(R)-3-氟哌啶、3,3-二甲基哌啶、2,6-二甲基哌嗪、氮杂环丁烷环、1,1,3,3-四甲基环丁烷、环己烷环、3,9-二氮杂螺[5.5]十一烷、2-氮杂螺[3.5]壬烷、2-氮杂螺[3.3]庚烷、7-氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷、2,7-二氮杂螺[3.5]壬烷、3-氮杂双环[3.2.1]辛烷；Preferably, the Cy 0 is each independently selected from the following structures or isomers thereof: piperidine ring, piperazine ring, 3,3,5,5-tetramethylpiperidine, 3,3-difluoropiperidine, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,3-dimethylpiperidine, 2,6-dimethylpiperazine, azetidine ring, 1,1,3,3-tetramethylcyclobutane, cyclohexane ring, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.2.1]octane; 优选地，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、3,3-二氟哌啶、3,9-二氮杂螺[5.5]十一烷、7-氮杂螺[3.5]壬烷、3-氮杂双环[3.2.1]辛烷；Preferably, the Cy 0 is independently selected from the following structures or isomers thereof: piperidine ring, 3,3-difluoropiperidine, 3,9-diazaspiro[5.5]undecane, 7-azaspiro[3.5]nonane, 3-azabicyclo[3.2.1]octane; 优选地，所述Cy0各自独立地选自以下结构或其异构体：哌啶环、3,3-二氟哌啶、3,9-二氮杂螺[5.5]十一烷、7-氮杂螺[3.5]壬烷；Preferably, the Cy 0 is independently selected from the following structures or isomers thereof: piperidine ring, 3,3-difluoropiperidine, 3,9-diazaspiro[5.5]undecane, 7-azaspiro[3.5]nonane; 优选地，所述Cy0各自独立地选自以下结构或其异构体： Preferably, the Cy 0 is independently selected from the following structures or isomers thereof: 优选地，所述Cy0各自独立地选自以下结构或其异构体： Preferably, the Cy 0 is independently selected from the following structures or isomers thereof: 优选地，所述Cy0各自独立地选自以下结构或其异构体： Preferably, the Cy 0 is independently selected from the following structures or isomers thereof: 优选地，所述Cy0各自独立地选自以下结构或其异构体： Preferably, the Cy 0 is independently selected from the following structures or isomers thereof: 优选地，所述Cy0各自独立地选自以下结构或其异构体： Preferably, the Cy 0 is independently selected from the following structures or isomers thereof: 如权利要求14所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点；The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein L is selected from the following structures or isomers thereof: Among them, X 00 is the connection site between L and ULM or POI; 优选地，所述的L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点；Preferably, the L is selected from the following structures or isomers thereof: Among them, X 00 is the connection site between L and ULM or POI; 优选地，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 00 is the connection site between L and ULM or POI; 优选地，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 00 is the connection site between L and ULM or POI; 优选地，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 00 is the connection site between L and ULM or POI; 优选地，所述L选自以下结构或其异构体： 其中，X00为L与ULM或POI的连接位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 00 is the connection site between L and ULM or POI; 优选地，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, and X 20 is the connection site between L and ULM; 优选地，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, and X 20 is the connection site between L and ULM; 优选地，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, and X 20 is the connection site between L and ULM; 优选地，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点；Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, and X 20 is the connection site between L and ULM; 优选地，所述L选自以下结构或其异构体： 其中，X10为L与POI的连接位点，X20为L与ULM连接的位点。Preferably, L is selected from the following structures or isomers thereof: Among them, X10 is the connection site between L and POI, and X20 is the connection site between L and ULM. 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，ULM为式(U-1)所示结构或其异构体：
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that ULM is a structure represented by formula (U-1) or an isomer thereof:
其中，in, 表示 express U0为键、-N(RU0)-、-CON(RU0)-、-CH2-或-(CH2)2-； U0 is a bond, -N(R U0 )-, -CON(R U0 )-, -CH 2 - or -(CH 2 ) 2 -; RU0每次出现，各自独立地为氢或C1-3烷基；Each occurrence of R U0 is independently hydrogen or C 1-3 alkyl; B环不存在、或选自5至15元杂芳基环(优选为6至12元杂芳基环，更优选为6至10元杂芳基环)、3至15元杂环烷基环(优选为5至12元杂环烷基环，更优选为5至10元杂环烷基环)、C3-15环烷基环和C6-10芳环(优选为苯环)；Ring B is absent or is selected from a 5- to 15-membered heteroaryl ring (preferably a 6- to 12-membered heteroaryl ring, more preferably a 6- to 10-membered heteroaryl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 5- to 12-membered heterocycloalkyl ring, more preferably a 5- to 10-membered heterocycloalkyl ring), a C 3-15 cycloalkyl ring, and a C 6-10 aromatic ring (preferably a benzene ring); S1、S3、S5各自独立地选自键、-O-、-NH-、-N-、-CH2-、-CH-、-C(O)-、-C(O)O-、-C(O)S-、-CH2C(O)-、-CH2C(S)-、-C(S)-、-CONH-、-CH＝N-、-N＝N-、-CH＝CH-、-SO-和-SO2-；S 1 , S 3 , and S 5 are each independently selected from a bond, -O-, -NH-, -N-, -CH 2 -, -CH-, -C(O)-, -C(O)O-, -C(O)S-, -CH 2 C(O)-, -CH 2 C(S)-, -C(S)-, -CONH-, -CH=N-, -N=N-, -CH=CH-, -SO-, and -SO 2 -; S2、S4各自独立地选自-N-、-NH-、-CH-和-CH2-；S 2 and S 4 are each independently selected from -N-, -NH-, -CH- and -CH 2 -; S6选自C、-CH-和N；S 6 is selected from C, -CH- and N; (RB1)b1表示B环上的氢被b1个RB1取代，b1为0、1、2或3，每个RB1相同或不同，各自独立地选自X2、氘、卤素(优选为氟、氯或溴)、氰基、羧基、羟基、硝基、-NRa1Rb1、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、-SC1-8烷基(优选为-SC1-6烷基，更优选为-SC1-3烷基)、-SOC1-8烷基(优选为-SOC1-6烷基，更优选为-SOC1-3烷基)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、氨基取代的C1-8烷基(优选为氨基取代的C1-6烷基，更优选为氨基取代的C1-3烷基)、氰基取代的C1-8烷基(优选为氰基取代的C1-6烷基，更优选为氰基取代的C1-3烷基)、羟基取代的C1-8烷基(优选为羟基取代的C1-6烷基，更优选为羟基取代的C1-3烷基)、羧基取代的C1-8烷基(优选为羧基取代的C1-6烷基，更优选为羧基取代的C1-3烷基)、-COC1-8烷基(优选为-COC1-6烷基，更优选为-COC1-3烷基)、-COOC1-8烷基-CONRa2Rb2(优选为-COOC1-6烷基-CONRa2Rb2，更优选为-COOC1-3烷基-CONRa2Rb2)、-SO2NRa2Rb2、C3-15环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环、进一步优选为4至6元杂环烷基环)、5至10元杂芳基环(优选为5至6元杂芳基环)和C6-10芳环(优选为苯环或萘环)；或相邻的两个RB1与其相连的碳原子形成C3-15环烷基环(优选为C3-10环烷基环，更优选为C3-8环烷基环，进一步优选为C3-6环烷基环)、3至15元杂环烷基环(优选为4至12元杂环烷基环，更优选为4至10元杂环烷基环，进一步优选为4至8元杂环烷基环、进一步优选为4至6元杂环烷基环)、5至6元杂芳基环或苯环；所述的C3-15环烷基环、3至15元杂环烷基环、5至6元杂芳基环或苯环为未取代或被1、2、3或4个选自下组的取代基取代：X2、氘、卤素(优选为氟、氯或溴)、氰基、羧基、羟基、硝基、-NRa1Rb1、C1-6烷基、C1-6烷氧基、-SC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-CONRa2Rb2和-SO2NRa2Rb2；(R B1 ) b1 represents that the hydrogen on the B ring is replaced by b1 R B1s , b1 is 0, 1, 2 or 3, each R B1 is the same or different and is independently selected from X 2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, -NR a1 R b1 , C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-8 alkyl), C 1-8 alkyl-CONR a2 R b2 (preferably -COC 1-6 alkyl , more preferably -COC 1-3 alkyl) ; C 1-8 alkyl - CONR a2 R b2 ( preferably -COC 1-6 alkyl , more preferably -COC 1-3 alkyl ) ; R 1-6 alkyl-CONR a2 R b2 , more preferably -COOC 1-3 alkyl-CONR a2 R b2 ), -SO 2 NR a2 R b2 , a C 3-15 cycloalkyl ring (preferably a C 3-10 cycloalkyl ring, more preferably a C 3-8 cycloalkyl ring, and further preferably a C 3-6 cycloalkyl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 4- to 12-membered heterocycloalkyl ring, more preferably a 4- to 10-membered heterocycloalkyl ring, further preferably a 4- to 8-membered heterocycloalkyl ring, and further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 10-membered heteroaryl ring (preferably a 5- to 6-membered heteroaryl ring) and a C 6-10 aromatic ring (preferably a benzene ring or a naphthalene ring); or two adjacent R B1s and the carbon atom to which they are attached form a C 3-15 cycloalkyl ring (preferably a C 3-10 cycloalkyl ring, more preferably a C 3-8 cycloalkyl ring, and further preferably a C wherein the C 3-15 cycloalkyl ring, the 3-15 membered heterocycloalkyl ring, the 5-6 membered heteroaryl ring or the benzene ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of X 2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, -NR a1 R b1 , C 1-6 alkyl, C 1-6 alkoxy, -SC 1-6 alkyl, -SOC 1-6 alkyl , -SO 2 C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -COOC 1-6 alkyl, -CONR a2 R b2 and -SO 2 NR a2 R b2 ; (RB2)b2表示C环上的氢被b2个RB2取代，b2为0、1、2、3或4，每个RB2相同或不同，各自独立地选自X2、氘、卤素(优选为氟、氯或溴)、氰基、羧基、羟基、-NRa1Rb1、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-COC1-6烷基、-COOC1-6烷基、-OCOC1-6烷基、-CONRa2Rb2、-OC(O)C1-6烷基取代的C1-6烷基和-COOC1-6烷基取代的C1-6烷基；( RB2 ) b2 represents that the hydrogen on the C ring is replaced by b2 RB2 , b2 is 0, 1, 2, 3 or 4, each RB2 is the same or different and is independently selected from X2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, -NRa1Rb1 , C1-6 alkyl , C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, -COC1-6 alkyl, -COOC1-6 alkyl, -OCOC1-6 alkyl , -CONRa2Rb2, C1-6 alkyl substituted with -OC (O) C1-6 alkyl and C1-6 alkyl substituted with -COOC1-6 alkyl; Ra1、Rb1、Ra2、Rb2各自独立地选自氢、C1-6烷基、卤代C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、羧基取代的C1-6烷基、氨基取代的C1-6烷基、-COC1-6烷基和-COOC1-6烷基； Ra1 , Rb1 , Ra2 , and Rb2 are each independently selected from hydrogen, C1-6 alkyl, halogenated C1-6 alkyl, hydroxy-substituted C1-6 alkyl, cyano-substituted C1-6 alkyl, carboxyl-substituted C1-6 alkyl, amino-substituted C1-6 alkyl, -COC1-6 alkyl, and -COOC1-6 alkyl; 其中，X2为ULM与L或POI的连接位点，且RB1和RB2中至少一个为X2。Wherein, X2 is the connection site between ULM and L or POI, and at least one of RB1 and RB2 is X2 . 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: B环不存在；或Ring B is absent; or B环中所述的5至15元杂芳基环选自吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、三唑环、四唑环、噁唑环、噻唑环、恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环、苯并吡咯环、苯并呋喃环、苯并噻吩环、苯并吡唑环、苯并咪唑环、苯并噻唑环、苯并噁唑环、吡啶并吡咯环、吡啶并呋喃环、吡啶并噻吩环、吡啶并吡唑环、吡啶并咪唑环、吡啶并噻唑环、吡啶并噁唑环、嘧啶并吡咯环、哒嗪并吡咯环、吡嗪并吡咯环、嘧啶并吡唑环、哒嗪并吡唑环、吡嗪并吡唑环、嘧啶并咪唑环、哒嗪并咪唑环、吡嗪并咪唑环、喹啉环、异喹啉环和9H-吡啶并[2,3-b]吲哚环；或The 5- to 15-membered heteroaryl ring in Ring B is selected from the group consisting of a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a benzopyrrole ring, a benzofuran ring, a benzothiophene ring, a benzopyrazole ring, a benzimidazole ring, a benzothiazole ring, a benzoxazole ring, a pyridopyrrole ring, a pyridofuran ring, a pyridothiophene ring, a pyridopyrazole ring, a pyridoimidazole ring, a pyridothiazole ring, a pyridooxazole ring, a pyrimidopyrrole ring, a pyridazinopyrrole ring, a pyrazinopyrrole ring, a pyrimidopyrazole ring, a pyridazinopyrazole ring, a pyrazinopyrazole ring, a pyrimidoimidazole ring, a pyridazinoimidazole ring, a pyrazinoimidazole ring, a quinoline ring, an isoquinoline ring, and a 9H-pyrido[2,3-b]indole ring; or 优选地，B环中所述的5至15元杂芳基环选自吡啶环和苯并吡唑环；Preferably, the 5- to 15-membered heteroaryl ring in ring B is selected from a pyridine ring and a benzopyrazole ring; 优选地，B环中所述的5至15元杂芳基环选自： 其中表示与U0的共价连接；Preferably, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in indicates covalent attachment to U 0 ; 优选地，B环中所述的5至15元杂芳基环选自：其中表示与U0的共价连接；Preferably, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in Indicates covalent attachment to U 0 ; B环中所述的C6-10芳环选自苯环和萘环；或The C 6-10 aromatic ring in ring B is selected from a benzene ring and a naphthalene ring; or 优选地，B环中所述的C6-10芳环为苯环；Preferably, the C 6-10 aromatic ring in ring B is a benzene ring; B环中所述的3至15元杂环烷基环选自：其中表示与U0的共价连接；或The 3 to 15-membered heterocycloalkyl ring in Ring B is selected from: in represents a covalent bond to U 0 ; or B环中所述的3至15元杂环烷基环为 The 3- to 15-membered heterocycloalkyl ring in Ring B is 其中，Q1、Q2、Q3、Q4各自独立地选自-CH-、N和N-O；wherein Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from -CH-, N, and NO; S7、S8各自独立地选自键、-O-、-NH-、-CH2-、-C(O)-、-C(O)O-、-C(O)S-、-CH2C(O)-、-CH2C(S)-、-C(S)-、-CONH-、-CH＝N-、-N＝N-、-CH＝CH-、-SO-和-SO2-；S 7 and S 8 are each independently selected from a bond, -O-, -NH-, -CH 2 -, -C(O)-, -C(O)O-, -C(O)S-, -CH 2 C(O)-, -CH 2 C (S)-, -C(S)-, -CONH-, -CH=N-, -N=N-, -CH=CH-, -SO- and -SO 2 -; 表示与U0的共价连接；或 represents a covalent bond to U 0 ; or 优选地，Q1、Q2、Q3、Q4各自独立地为-CH-；Preferably, Q 1 , Q 2 , Q 3 , and Q 4 are each independently -CH-; 优选地，S8选自-CH＝N-、-N＝N-、-CH2C(O)-、-C(O)O-、-CONH-和-CH＝CH-；Preferably, S 8 is selected from -CH=N-, -N=N-, -CH 2 C(O)-, -C(O)O-, -CONH- and -CH=CH-; 优选地，S7、S8各自独立地选自-CH2-和-C(O)-；Preferably, S 7 and S 8 are each independently selected from -CH 2 - and -C(O)-; 优选地，S7为-CH2-，S8为-C(O)-；Preferably, S 7 is -CH 2 -, and S 8 is -C(O)-; 优选地，S7为-C(O)-，S8为-C(O)-；Preferably, S7 is -C(O)-, and S8 is -C(O)-; 优选地，S7为-CH2-，S8为-C(S)-；Preferably, S 7 is -CH 2 -, and S 8 is -C(S)-; 优选地，S7为-C(O)-，S8为-C(S)-；Preferably, S7 is -C(O)-, and S8 is -C(S)-; 优选地，S7为键，S8为-CONH-；Preferably, S7 is a bond and S8 is -CONH-; 优选地，结构选自下组所示结构或其异构体： 其中表示与U0的共价连接；Preferably, the structure Selected from the following structures or isomers thereof: in indicates covalent attachment to U 0 ; B环中所述的3至15元杂环烷基环为 The 3- to 15-membered heterocycloalkyl ring in Ring B is 其中，环B1、环B2各自独立地选自C4-8环烷基环、4至8元杂环烷基环、5至6元杂芳基环和苯环；wherein Ring B1 and Ring B2 are each independently selected from a C 4-8 cycloalkyl ring, a 4- to 8-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring and a benzene ring; S9、S10各自独立地选自键、-CH2-和-C(O)-；S 9 and S 10 are each independently selected from a bond, -CH 2 - and -C(O)-; 表示与U0的共价连接；或 represents a covalent bond to U 0 ; or 优选地，结构选自其中表示与U0的共价连接；Preferably, the structure Selected from in Indicates covalent attachment to U 0 ; B环中所述的3至15元杂环烷基环选自 其中环B3、环B4、环B5各自独立地选自C5-7环烷基环和5至7元杂环烷基环，表示与U0的共价连接；或The 3 to 15-membered heterocycloalkyl ring in Ring B is selected from wherein Ring B3, Ring B4, and Ring B5 are each independently selected from a C 5-7 cycloalkyl ring and a 5- to 7-membered heterocycloalkyl ring, represents a covalent bond to U 0 ; or 优选地，环B3、环B4、环B5各自独立地选自2,5-二氢-1H-吡咯、2,3-二氢-1H-吡咯、1,2,3,6-四氢吡啶、1,2,3,4-四氢吡啶、3,4-二氢-2H-1,4-恶嗪、1,3-二氧杂环戊烯、2,3,6,7-四氢-1H-氮平、2,3,4,7-四氢-1H-氮平和2,3,4,5-四氢-1H-氮平；Preferably, Ring B3, Ring B4, Ring B5 are each independently selected from 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-1,4-oxazine, 1,3-dioxole, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine and 2,3,4,5-tetrahydro-1H-azepine; 优选地，B环中所述的3至15元杂环烷基环选自 Preferably, the 3 to 15 membered heterocycloalkyl ring in ring B is selected from 其中表示与U0的共价连接；in indicates covalent attachment to U 0 ; 优选地，B环中所述的3至15元杂环烷基环为其中表示与U0的共价连接；Preferably, the 3 to 15 membered heterocycloalkyl ring in Ring B is in Indicates covalent attachment to U 0 ; 优选地，环B3为5至7元含氮杂环烷基环；Preferably, Ring B3 is a 5- to 7-membered nitrogen-containing heterocycloalkyl ring; 优选地，环B3选自2,5-二氢-1H-吡咯、2,3-二氢-1H-吡咯、1,2,3,6-四氢吡啶、1,2,3,4-四氢吡啶、2,3,6,7-四氢-1H-氮平、2,3,4,7-四氢-1H-氮平和2,3,4,5-四氢-1H-氮平；Preferably, Ring B3 is selected from 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine and 2,3,4,5-tetrahydro-1H-azepine; 优选地，结构选自 其中表示与U0的共价连接；Preferably, the structure Selected from in indicates covalent attachment to U 0 ; B环中所述的3至15元杂环烷基环为其中环B6选自5至6元杂芳基环和苯环；Q11、Q12、Q13各自独立地选自-C-、-N-、-S-、-O-、-NH-；表示与U0的共价连接；或The 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B6 is selected from a 5- to 6-membered heteroaryl ring and a benzene ring; Q 11 , Q 12 , and Q 13 are each independently selected from -C-, -N-, -S-, -O-, and -NH-; represents a covalent bond to U 0 ; or 优选地，结构选自：其中表示与U0的共价连接；Preferably, the structure Selected from: in Indicates covalent attachment to U 0 ; B环中所述的3至15元杂环烷基环为其中环B7为5至10元杂环烷基环，Q5、Q6、Q7、Q8、Q9各自独立地选自C、-CH-和N，表示与U0的共价连接；The 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B7 is a 5- to 10-membered heterocycloalkyl ring, Q 5 , Q 6 , Q 7 , Q 8 , and Q 9 are each independently selected from C, -CH-, and N, Indicates covalent attachment to U 0 ; 优选地，环B7为1，3-二氧杂环戊烯；Preferably, ring B7 is 1,3-dioxole; 优选地，结构选自其中表示与U0的共价连接。Preferably, the structure Selected from in Indicates covalent attachment to U 0 . 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，B环选自： 其中表示与U0的共价连接；The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring B is selected from: in indicates covalent attachment to U 0 ; 优选地，B环选自以下结构或其异构体：其中表示与U0的共价连接；Preferably, the B ring is selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 ; 优选地，B环选自以下结构或其异构体：其中表示与U0的共价连接。Preferably, the B ring is selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 . 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，RB1各自独立地为X2、氘、氟、氯、溴、氰基、羧基、羟基、硝基、-NH2、-N(CH3)2、-NHCH3、-NHCOCH3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、异丙氧基、三氟甲基、二氟甲基、一氟甲基、三氟甲氧基、二氟甲氧基、一氟甲氧基、-SCH3、-SOCH3、-SO2CH3、-CH2NH2、-(CH2)2NH2、-(CH2)3NH2、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH2COOH、-(CH2)2COOH、-(CH2)3COOH、-COCH3、-COCH2CH3、-COOCH3、-COOCH2CH3、-CONH2或-SO2NH2；或相邻的两个RB1与其相连的碳原子形成环丁烷基环、环戊烷基环、环己烷基环、环庚烷基环、环戊烯环、环己烯环、环庚烯环、四氢吡咯环、四氢呋喃环、四氢噻吩环、哌啶环、吡嗪环、1,2,3,4-四氢吡啶环、1,2,3,4-四氢吡喃环、3,4-二氢-2H-1,4-恶嗪环、2,3,4,5-四氢-1H-氮平环、吡咯环、吡唑环、噁唑环、噻唑环、吡喃环、吡啶环、哒嗪环、嘧啶环或苯环，所述的环丁烷基环、环戊烷基环、环己烷基环、环庚烷基环、环戊烯环、环己烯环、环庚烯环、四氢吡咯环、四氢呋喃环、四氢噻吩环、哌啶环、吡嗪环、1,2,3,4-四氢吡啶环、1,2,3,4-四氢吡喃环、3,4-二氢-2H-1,4-恶嗪环、2,3,4,5-四氢-1H-氮平环、吡咯环、吡唑环、噁唑环、噻唑环、吡喃环、吡啶环、哒嗪环、嘧啶环或苯环为未取代或被1、2、3或4个选自下组的取代基取代：X2、氘、氟、氯、溴、氰基、羧基、羟基、硝基、氨基、甲基、三氟甲基、甲氧基、三氟甲氧基、-SCH3、-SOCH3、-SO2CH3、-COCH3、-COOCH3、-CONH2和-SO2NH2；The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that RB1 is independently X2 , deuterium, fluorine, chlorine, bromine, cyano, carboxyl, hydroxyl, nitro, -NH2 , -N( CH3 ) 2 , -NHCH3 , -NHCOCH3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, -SCH3 , -SOCH3 , -SO2CH3 , -CH2NH2 , -( CH2 ) 2NH2 , -( CH2 ) 3NH2 , -CH2CN, -(CH2)2CN , - ( CH2 ) 3CN , -CH2OH , -( CH2 ) 2 OH, -(CH 2 ) 3 OH, -CH 2 COOH, -(CH 2 ) 2 COOH, -(CH 2 ) 3 COOH, -COCH 3 , -COCH 2 CH 3 , -COOCH 3 , -COOCH 2 CH 3 , -CONH 2 or -SO 2 NH 2 ; or two adjacent R B1 and the carbon atom to which it is connected form a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring, a pyrazine ring, a 1,2,3,4-tetrahydropyridine ring, a 1,2,3,4-tetrahydropyran ring, a 3,4-dihydro-2H-1,4-oxazine ring, a 2,3,4,5-tetrahydro-1H-azepine ring, a pyrrole ring, a pyrazole ring, an oxazole ring, a thiazole ring, a pyran ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a benzene ring. The cyclobutane ring , cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, cyclopentene ring, cyclohexene ring, cycloheptene ring, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, pyrazine ring, 1,2,3,4-tetrahydropyridine ring, 1,2,3,4-tetrahydropyran ring, 3,4-dihydro-2H-1,4-oxazine ring, 2,3,4,5-tetrahydro-1H-azepine ring, pyrrole ring, pyrazole ring, oxazole ring, thiazole ring, pyran ring, pyridine ring, pyridazine ring, pyrimidine ring or benzene ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: X 2 , deuterium, fluorine, chlorine, bromine, cyano, carboxyl, hydroxyl, nitro, amino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -SCH 3 , -SOCH 3 , -SO 2 CH 3 , -COCH 3 , -COOCH 3 , -CONH 2 , and -SO 2 NH 2 ; 优选地，RB1选自氟、氯、羟基、甲基、三氟甲基和甲氧基。Preferably, R B1 is selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl and methoxy. 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，b1为1，RB1为氟。The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that b1 is 1 and RB1 is fluorine. 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，选自： 其中X2为ULM与L或POI的连接位点，表示与U0的共价连接；The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Selected from: Where X2 is the connection site between ULM and L or POI, Indicates covalent attachment to U 0 ; 优选地，选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点，表示与U0的共价连接；Preferably, Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI, indicates covalent attachment to U 0 ; 优选地，选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点，表示与U0的共价连接。Preferably, Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI, Indicates covalent attachment to U 0 . 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，U0为键、-NH-、-CONH-或-CH2-。The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein U 0 is a bond, -NH-, -CONH- or -CH 2 -. 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，S1、S3为-C(O)-，S2为-NH-，S4、S5为-CH2-；The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that S 1 and S 3 are -C(O)-, S 2 is -NH-, and S 4 and S 5 are -CH 2 -; 优选地，结构选自下组所示结构或其异构体： 其中表示与U0的共价连接；Preferably, the structure Selected from the following structures or isomers thereof: in indicates covalent attachment to U 0 ; 优选地，结构选自下组所示结构或其异构体： 其中表示与U0的共价连接。Preferably, the structure Selected from the following structures or isomers thereof: in Indicates covalent attachment to U 0 . 如权利要求20所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，ULM选自以下结构或其异构体：


其中X2为
ULM与L或POI的连接位点；The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein ULM is selected from the following structures or isomers thereof:


Where X2 is
The attachment site of ULM to L or POI; 优选地，ULM选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点；Preferably, the ULM is selected from the following structures or isomers thereof: Where X 2 is the connection site between ULM and L or POI; 优选地，ULM选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点；Preferably, the ULM is selected from the following structures or isomers thereof: Where X 2 is the connection site between ULM and L or POI; 优选地，ULM选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点；Preferably, the ULM is selected from the following structures or isomers thereof: Where X 2 is the connection site between ULM and L or POI; 优选地，ULM选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点。Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI. 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，ULM为式(U-2)所示结构或其异构体：
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that ULM is a structure represented by formula (U-2) or an isomer thereof:
其中，in, (RU7)r1表示四氢吡咯环上的氢被r1个RU7取代，r1为0、1、2或3，每个RU7相同或不同，各自独立地选自卤素(优选为氟、氯或溴)、羟基、氨基、C1-3烷氧基、卤代C1-3烷氧基和-OCOC1-3烷基；(R U7 ) r1 represents that the hydrogen on the tetrahydropyrrole ring is replaced by r1 R U7 , r1 is 0, 1, 2 or 3, each R U7 is the same or different, and each is independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, amino, C 1-3 alkoxy, halogenated C 1-3 alkoxy and -OCOC 1-3 alkyl; RU1为-C(RU3RU4)-U1； RU1 is -C ( RU3RU4 ) -U1 ; U1选自以下结构或其异构体：X2、-NHCO-X2、-NHCOCH3、5至6元杂芳基环、 所述的5至6元杂芳基环、为未取代或被1、2或3个选自下组的取代基取代：X2、卤素、羟基、氰基、氨基、羧基、C1-6烷基(优选为甲基、乙基、异丙基)、C1-6烷氧基(优选为甲氧基、乙氧基、异丙氧基)、卤代C1-6烷基(优选为三氟甲基)、卤代C1-6烷氧基(优选为三氟甲氧基)、-COC1-6烷基(优选为-COCH3)、-COOC1-6烷基(优选为-COOCH3)、-CONH2、-CONHC1-6烷基(优选为-CONHCH3)、-CON(C1-6烷基)2(优选为-CON(CH3)2)和羟基取代的C1-6烷基(优选为-CH2OH)；U 1 is selected from the following structures or isomers thereof: X 2 , -NHCO-X 2 , -NHCOCH 3 , 5- to 6-membered heteroaryl ring, The 5- to 6-membered heteroaryl ring, is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X 2 , halogen, hydroxy, cyano, amino, carboxyl, C 1-6 alkyl (preferably methyl, ethyl, isopropyl), C 1-6 alkoxy (preferably methoxy, ethoxy, isopropoxy), halogenated C 1-6 alkyl (preferably trifluoromethyl), halogenated C 1-6 alkoxy (preferably trifluoromethoxy), -COC 1-6 alkyl (preferably -COCH 3 ), -COOC 1-6 alkyl (preferably -COOCH 3 ), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHCH 3 ), -CON(C 1-6 alkyl) 2 (preferably -CON(CH 3 ) 2 ) and hydroxy-substituted C 1-6 alkyl (preferably -CH 2 OH); 优选地，U1选自X2、-NHCO-X2、-NHCOCH3、 Preferably, U 1 is selected from X 2 , -NHCO-X 2 , -NHCOCH 3 , 优选地，U1选自-NHCO-X2和 Preferably, U 1 is selected from -NHCO-X 2 and RUa选自氢、卤素(优选为氟、氯或溴)、氰基、羟基、羧基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-COC1-6烷基、-NHCOC1-6烷基、-N(C1-6烷基)COC1-6烷基、-NHC1-6烷基和-N(C1-6烷基)2；R Ua is selected from hydrogen, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxyl, carboxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 ; 优选地，RUa选自氟、氰基、甲基、乙基、三氟甲基和三氟甲氧基；Preferably, R Ua is selected from fluoro, cyano, methyl, ethyl, trifluoromethyl and trifluoromethoxy; 优选地，RUa选自氟和氰基；Preferably, R Ua is selected from fluorine and cyano; RU3、RU4各自独立地选自氢、氘、卤素、氰基、羧基、羟基、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、卤代C1-6烷基(优选为C1-3烷氧基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)和-SC1-6烷基(优选为-SC1-3烷基)；或RU3、RU4与所连接的碳原子共同形成C3-7环烷基(优选为的C3-6环烷基)和3至7元杂环烷基(优选为4至6元杂环烷基)；所述的C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-SC1-6烷基、C3-7环烷基、3至7元杂环烷基为未取代或被1、2或3个选自下组的取代基取代：X2、卤素(优选为氟、氯或溴)、氰基、羧基和羟基；R U3 and R U4 are each independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably C 1-3 alkoxy), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy) and -SC 1-6 alkyl (preferably -SC 1-3 alkyl); or R U3 and R U4 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl (preferably C 3-6 cycloalkyl) and a 3 to 7 membered heterocycloalkyl (preferably 4 to 6 membered heterocycloalkyl); the C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -SC 1-6 alkyl, C 3-7 -membered cycloalkyl, 3- to 7-membered heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X 2 , halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl and hydroxyl; RU5、RU6各自独立地选自X2、氢、氘、卤素、氨基、氰基、羧基、羟基、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(卤代C1-3烷氧基)、-SC1-6烷基(优选为-SC1-3烷基)、CONHC1-6烷基取代的C1-6烷基、CON(C1-6烷基)2取代的C1-6烷基、羧基取代的C1-6烷基和COOC1-6烷基取代的C1-6烷基；R U5 and R U6 are each independently selected from X 2 , hydrogen, deuterium, halogen, amino, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (halogenated C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), C 1-6 alkyl substituted by CONHC 1-6 alkyl, C 1-6 alkyl substituted by CON(C 1-6 alkyl) 2 , C 1-6 alkyl substituted by carboxyl, and C 1-6 alkyl substituted by COOC 1-6 alkyl; (RU2)r2表示D环上的氢被r2个RU2取代，r2为0、1、2或3，每个RU2相同或不同，各自独立地选自X2、氢、氘、卤素(优选为氟、氯)、硝基、氰基、羧基、羟基、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷基、羟基取代的C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、-NRa3Rb3、-COC1-6烷基、-COOC1-6烷基、-OCOC1-6烷基、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-SOC1-6烷基、-SO2C1-6烷基、-SC1-6烷基、5至6元杂芳基和苯基；所述的5至6元杂芳基、苯基为未取代或被1、2或3个选自下组的取代基取代：氢、氘、卤素、氰基、羧基、羟基、C1-6烷基(优选为C1-3烷基)、羟基取代的C1-6烷基(优选为羟基取代的C1-3烷基)、C1-6烷氧基C1-6烷基(优选为C1-3烷氧基C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)、-NH2、-NHCOC1-6烷基(优选为-NHCOC1-3烷基)、-COC1-6烷基(优选为-COC1-3烷基)、-COOC1-6烷基(优选为-COOC1-3烷基)、-OCOC1-6烷基(优选为-OCOC1-3烷基)、-CONH2、-NHCONH2、-CONHC1-6烷基、-NHCONHC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基和-SC1-6烷基；(R U2 ) r2 represents that the hydrogen on the D ring is replaced by r2 R U2 , r2 is 0, 1, 2 or 3, each R U2 is the same or different and is independently selected from X 2 , hydrogen, deuterium, halogen (preferably fluorine, chlorine), nitro, cyano, carboxyl, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkyl substituted with hydroxyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NR a3 R b3 , -COC 1-6 alkyl, -COOC 1-6 alkyl, -OCOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SC The 5- to 6-membered heteroaryl and phenyl groups are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), hydroxy-substituted C 1-6 alkyl (preferably C 1-3 alkoxy C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl ), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy) , -NH 2 , -NHCOC 1-6 alkyl (preferably -NHCOC 1-3 alkyl), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -COOC 1-6 alkyl (preferably -COOC 1-3 alkyl), -OCOC 1-6 alkyl (preferably -OCOC 1-3 alkyl), -CONH 2 , -NHCONH 2 , -CONHC 1-6 alkyl, -NHCONHC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl and -SC 1-6 alkyl; D环选自苯环、5至6元杂芳基环、C3-10环烷基环(优选为C3-8环烷基环，更优选为C3-6环烷基环)和3至10元杂环烷基环(优选为3至8元杂环烷基环，更优选为3至6元杂环烷基环)；The D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-10 cycloalkyl ring (preferably a C 3-8 cycloalkyl ring, more preferably a C 3-6 cycloalkyl ring) and a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring); Ra3、Rb3各自独立地选自氢、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、-SC1-6烷基(优选为-SC1-3烷基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)、-COC1-6烷基(优选为-COC1-3烷基)、-CONH2、-CONHC1-6烷基(优选为-CONHC1-3烷基)、-CON(C1-6烷基)2(优选为-CON(C1-3烷基)2)、5至6元杂芳基和苯基；其中，所述5至6元杂芳基、苯基各自独立地为未被取代或被1、2或3个选自下组的取代基取代：氢、C1-6烷基(优选为C1-3烷基)、C1-6烷氧基(优选为C1-3烷氧基)、-SC1-6烷基(优选为-SC1-3烷基)、卤代C1-6烷基(优选为卤代C1-3烷基)、卤代C1-6烷氧基(优选为卤代C1-3烷氧基)、-COC1-6烷基(优选为-COC1-3烷基)、-CONH2、-CONHC1-6烷基(优选为-CONHC1-3烷基)和-CON(C1-6烷基)2(优选为-CON(C1-3烷基)2)；R a3 and R b3 are each independently selected from hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHC 1-3 alkyl), -CON(C 1-6 alkyl) 2 (preferably -CON(C 1-3 alkyl) 2 ), 5- to 6-membered heteroaryl and phenyl; wherein the 5- to 6-membered heteroaryl and phenyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), C -SC 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHC 1-3 alkyl) and -CON(C 1-6 alkyl) 2 (preferably -CON(C 1-3 alkyl) 2 ); 优选地，Ra3、Rb3各自独立地选自氢、5至6元杂芳基和苯基；所述的5至6元杂芳基为噻唑基、噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、三唑基和四唑基；所述的5至6元杂芳基和苯基为未取代或被1或2个选自下组的取代基取代：氢、甲基、乙基、异丙基、三氟甲基、三氟甲氧基、-COCH3和-CONH2；Preferably, R a3 and R b3 are each independently selected from hydrogen, 5- to 6-membered heteroaryl and phenyl; the 5- to 6-membered heteroaryl is thiazolyl, oxazolyl, pyrazolyl, imidazolyl, thienyl, furyl, pyrrolyl, triazolyl and tetrazolyl; the 5- to 6-membered heteroaryl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, -COCH 3 and -CONH 2 ; 其中，X2为ULM与L或POI的连接位点，且U1、RU5、RU6和RU2中至少一个为X2，或RU1至少含一个X2。Wherein, X 2 is the connection site between ULM and L or POI, and at least one of U 1 , RU5 , RU6 and RU2 is X 2 , or RU1 contains at least one X 2 . 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(U-2)所示结构为式(U-2-1)所示结构或其异构体：
The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the structure represented by formula (U-2) is the structure represented by formula (U-2-1) or an isomer thereof:
优选地，RU7选自羟基、氨基、-OCH3、-OCF3和-OCOCH3；Preferably, R U7 is selected from hydroxy, amino, -OCH 3 , -OCF 3 and -OCOCH 3 ; 优选地，RU7为羟基。Preferably, R U7 is hydroxy. 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，RU3、RU4各自独立地为氢、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基；或RU3、RU4与其所连接的碳原子形成C3-6环烷基环；The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R U3 and R U4 are each independently hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy; or R U3 and R U4 form a C 3-6 cycloalkyl ring with the carbon atom to which they are attached; 优选地，RU3、RU4各自独立的为氢、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3、-CF3、-CHF2、-CH2F、-OCH3、-OCH(CH3)2、-OC(CH3)3、-OCF3、-OCHF2、-OCH2F、氟代异丙基或氟代叔丁基；或RU3、RU4与其所连接的碳原子形成环丙基环、环丁基环、环戊基环或环己基环；Preferably, R U3 and R U4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, fluoroisopropyl or fluorotert-butyl; or R U3 , R U4 and the carbon atom to which they are connected form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring; 优选地，RU3、RU4各自独立的为氢、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2或-C(CH3)3；或RU3、RU4与其所连接的碳原子形成环丙基环；Preferably, R U3 and R U4 are each independently hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -C(CH 3 ) 3 ; or R U3 , R U4 and the carbon atom to which they are attached form a cyclopropyl ring; 优选地，RU3、RU4各自独立地为氢、-CH(CH3)2或-C(CH3)3。Preferably, R U3 and R U4 are each independently hydrogen, -CH(CH 3 ) 2 or -C(CH 3 ) 3 . 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，RU1选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点；The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R U1 is selected from the following structures or isomers thereof: Where X 2 is the connection site between ULM and L or POI; 优选地，RU1选自以下结构： 其中X2为ULM与L或POI的连接位点；Preferably, R U1 is selected from the following structures: Where X 2 is the connection site between ULM and L or POI; 优选地，RU1选自以下结构：其中X2为ULM与L或POI的连接位点。Preferably, R U1 is selected from the following structures: Wherein X2 is the connection site between ULM and L or POI. 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，RU5、RU6各自独立地为X2、氢、氘、卤素、羟基、羧基、氰基、氨基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基或卤代C1-3烷氧基；The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R U5 and R U6 are each independently X 2 , hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl or halogenated C 1-3 alkoxy; 优选地，RU5、RU6各自独立地为氢、C1-3烷基或卤代C1-3烷基；Preferably, R U5 and R U6 are each independently hydrogen, C 1-3 alkyl or halogenated C 1-3 alkyl; 优选地，RU5、RU6各自独立地为氢、-CH3、-OCH3、-CF3、-OCF3、-CHF2、-CH2F、-OCHF2或-OCH2F；Preferably, R U5 and R U6 are each independently hydrogen, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 , -CHF 2 , -CH 2 F, -OCHF 2 or -OCH 2 F; 优选地，RU5、RU6各自独立地为氢或-CH3。Preferably, R U5 and R U6 are each independently hydrogen or -CH 3 . 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，RU2为5至6元杂芳基或苯基，所述的5至6元杂芳基或苯基为未取代或被1、2或3个选自下组的取代基取代：氘、卤素(优选为氟、氯)、氰基、羧基、羟基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、-NH2、-NHCOC1-3烷基、-COC1-3烷基、-COOC1-3烷基、-OCOC1-3烷基、-CONH2、-NHCONH2、-CONHC1-3烷基、-NHCONHC1-3烷基、-SOC1-3烷基、-SO2C1-3烷基和-SC1-3烷基；The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R U2 is a 5- to 6-membered heteroaryl or a phenyl group, wherein the 5- to 6-membered heteroaryl or the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, carboxyl, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NH 2 , -NHCOC 1-3 alkyl, -COC 1-3 alkyl, -COOC 1-3 alkyl, -OCOC 1-3 alkyl, -CONH 2 , -NHCONH 2 , -CONHC 1-3 alkyl, -NHCONHC 1-3 alkyl, -SOC 1-3 alkyl, -SO 2 C 1-3 alkyl and -SC 1-3 alkyl; 或RU2为氰基；or R U2 is cyano; 或RU2为-NHRa3，其中Ra3为5至6元杂芳基或苯基，所述的5至6元杂芳基选自噻唑基、咪唑基、吡唑基、噁唑基、吡啶基和嘧啶基；所述的5至6元杂芳基或苯基为未被取代或被1、2或3个选自下组的取代基取代：C1-3烷氧基、卤代C1-3烷氧基、C1-3烷基、卤代C1-3烷基、-SC1-3烷基和-OCOC1-3烷基；or R U2 is -NHR a3 , wherein R a3 is a 5- to 6-membered heteroaryl or phenyl group, wherein the 5- to 6-membered heteroaryl group is selected from thiazolyl, imidazolyl, pyrazolyl, oxazolyl, pyridinyl and pyrimidinyl; the 5- to 6-membered heteroaryl or phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkyl, halo C 1-3 alkyl, -SC 1-3 alkyl and -OCOC 1-3 alkyl; 优选地，所述的5至6元杂芳基选自噻唑基、噁唑基、吡唑基、咪唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、四氮唑基和三氮唑基；Preferably, the 5- to 6-membered heteroaryl group is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, tetrazolyl and triazolyl; 优选地，所述的5至6元杂芳基选自 Preferably, the 5- to 6-membered heteroaryl group is selected from 优选地，所述的5至6元杂芳基为 Preferably, the 5- to 6-membered heteroaryl group is 优选地，所述的5至6元杂芳基环选自噻唑环、噁唑环、吡唑环、咪唑环、吡咯环、吡啶环、嘧啶环、哒嗪环、吡嗪环、四氮唑环和三氮唑环；Preferably, the 5- to 6-membered heteroaryl ring is selected from a thiazole ring, an oxazole ring, a pyrazole ring, an imidazole ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a tetrazole ring and a triazole ring; 优选地，RU2为-NHRa3，其中Ra3为噻唑基；所述的噻唑基被1、2或3个选自下组的取代基取代：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、一氟甲氧基、二氟甲氧基、三氟甲氧基、一氟乙氧基、二氟乙氧基和三氟乙氧基；Preferably, R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl is substituted by 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy and trifluoroethoxy; 优选地，RU2为-NHRa3，其中Ra3为噻唑基；所述的噻唑基被1、2或3个选自下组的取代基取代：甲基、乙基、丙基和异丙基；Preferably, R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl is substituted by 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl and isopropyl; 优选地，RU2选自以下结构：氰基、 Preferably, R U2 is selected from the following structures: cyano, 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，r2为1，RU2选自氰基、 The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that r2 is 1, R U2 is selected from cyano, 优选地，r2为1，RU2为 Preferably, r2 is 1, R U2 is 优选地，r2为2，RU2分别为X2和其中X2为ULM与L或POI的连接位点。Preferably, r2 is 2, R U2 is X 2 and Where X2 is the connection site between ULM and L or POI. 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，D环选自苯环、5至6元杂芳基环、C3-6环烷基环和3至6元杂环烷基环；The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-6 cycloalkyl ring, and a 3- to 6-membered heterocycloalkyl ring; 优选地，D环选自苯环和5至6元杂芳基环；Preferably, the D ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring; 优选地，D环选自苯环、吡咯环、噻吩环、呋喃环、吡唑环、咪唑环、三唑环、噻唑环、噁唑环、吡啶环、嘧啶环、吡嗪环、哒嗪环、环丙烷基环、环丁烷基环、环戊烷基环、环己烷基环、哌啶环、哌嗪环和四氢吡咯环；Preferably, the D ring is selected from a benzene ring, a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a triazole ring, a thiazole ring, an oxazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a piperidine ring, a piperazine ring and a tetrahydropyrrole ring; 优选地，D环选自苯环和吡啶环。Preferably, the D ring is selected from a benzene ring and a pyridine ring. 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，选自以下结构或其异构体： 其中X2为ULM与L或POI的连接位点；The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Selected from the following structures or isomers thereof: Where X 2 is the connection site between ULM and L or POI; 优选地，选自以下结构或其异构体： Preferably, Selected from the following structures or isomers thereof: 如权利要求29所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，ULM选自以下结构或其异构体：


；其中X2为ULM与L或POI的连接位点；The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein ULM is selected from the following structures or isomers thereof:


; wherein X 2 is the connection site between ULM and L or POI; 优选地，ULM选自以下结构或其异构体：其中X2为ULM与L或POI的连接位点；Preferably, the ULM is selected from the following structures or isomers thereof: Where X 2 is the connection site between ULM and L or POI; 优选地，ULM选自以下结构或其异构体：其中X2为ULM与L或POI的连接位点。Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI. 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，ULM为式(U-3)所示结构或其异构体：
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that ULM is a structure represented by formula (U-3) or an isomer thereof:
其中，Rn1选自C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-SC1-6烷基、C3-12环烷基、C3-12杂环烷基、C6-14芳基、5至10元杂芳基；所述C1-6烷基、C3-12环烷基、C3-12杂环烷基、C6-14芳基、5至10元杂芳基为未取代或被1,2,3或4个选自下组的取代基取代：卤素、硝基、氰基、羟基、羧基、氧代基、-CHO、氨基、C1-6烷基、-SC1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NHCOC1-6烷基、-COC1-6烷基、-COOC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、C3-12环烷基、C3-12杂环烷基；wherein R n1 is selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -SC 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5 to 10 membered heteroaryl; the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5 to 10 membered heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, C 1-6 alkyl, -SC 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NHCOC C 1-6 alkyl, -COC 1-6 alkyl, -COOC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl; 优选地，Rn1选自叔丁基、吗啉基取代的叔丁基、噻唑、吡唑、恶唑、异恶唑、苯环、吡啶、苯并噻唑、环丁烷；所述的噻唑、吡唑、恶唑、异恶唑、苯环、吡啶、苯并噻唑、环丁烷为未取代或被1,2,3或4个选自下组的取代基取代：卤素、氰基、羟基、硝基、三氟甲基、二氟甲基、一氟甲基、甲基、乙基、丙基、异丙基、甲氧基、-SCH3、-SOCH3、-SO2CH3、-NHCH3、-N(CH3)2、-COCH3；Preferably, R n1 is selected from tert-butyl, tert-butyl substituted with morpholinyl, thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane; the thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, nitro, trifluoromethyl, difluoromethyl, monofluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, -SCH 3 , -SOCH 3 , -SO 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -COCH 3 ; 优选地，Rn1选自叔丁基、吡啶基，所述的吡啶基被溴取代；Preferably, R n1 is selected from tert-butyl and pyridyl, and the pyridyl is substituted by bromine; Rn2、Rn3与相连的N共同形成4至12元杂环烷基环；所述的杂环烷基为未取代或被1,2,3或4个选自下组的取代基取代：X2、卤素、硝基、氰基、羟基、羧基、氧代基、-CHO、氨基、C1-6烷基、-SC1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NHCOC1-6烷基、-COC1-6烷基、-COOC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、C3-12环烷基、C3-12杂环烷基、C6-14芳基、5至10元杂芳基；R n2 , R n3 and the connected N together form a 4- to 12-membered heterocycloalkyl ring; the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of X 2 , halogen, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, C 1-6 alkyl, -SC 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -COC 1-6 alkyl, -COOC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 6-14 aryl, 5- to 10-membered heteroaryl; 优选地，Rn2、Rn3与相连的N共同形成4至12元杂环烷基环，所述的4至12元杂环烷基环选自四氢吡咯环、哌啶环、吗啉环、哌嗪环、3,6-二氮杂双环[3.1.1]庚烷、2,5-二氮杂双环[2.2.1]庚烷、(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷、1,4-二氮杂卓、3,9-二氮杂螺[5.5]十一烷、4,7-二氮杂螺[2.5]辛烷；所述的4至12元杂环烷基环未取代或被1,2,3或4个选自下组的取代基取代：X2、氟、氯、溴、硝基、氰基、羟基、羧基、氧代基、-CHO、氨基、甲基、叔丁基、甲氧基、叔丁氧基、三氟甲基、三氟甲氧基、-NH(CH3)、-N(CH3)2、-NHCOCH3、-COCH3、-COOCH3、-SOCH3、-SO2CH3、环丙基；Preferably, R n2 , R n3 and the connected N together form a 4- to 12-membered heterocycloalkyl ring, wherein the 4- to 12-membered heterocycloalkyl ring is selected from tetrahydropyrrole ring, piperidine ring, morpholine ring, piperazine ring, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, (1R,5S)-3,8-diazabicyclo[3.2.1]octane, 1,4-diazapine, 3,9-diazaspiro[5.5]undecane, 4,7-diazaspiro[2.5]octane; the 4- to 12-membered heterocycloalkyl ring is unsubstituted or substituted by 1,2,3 or 4 substituents selected from the group consisting of: X 2 , fluorine, chlorine, bromine, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, methyl, tert-butyl, methoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, -NH(CH 3 ), -N(CH 3 ) 2 , -NHCOCH 3 , -COCH 3 , -COOCH 3 , -SOCH 3 , -SO 2 CH 3 , cyclopropyl; 优选地，Rn2、Rn3与相连的N共同形成哌啶环。Preferably, R n2 , R n3 and the connected N together form a piperidine ring. 如权利要求39所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，ULM选自以下结构： The compound of formula (I) according to claim 39, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein ULM is selected from the following structures: 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(I)所示化合物为式(I-A)所示结构，
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula (I) is a structure represented by formula (IA),
其中，A1环、R1、R3、R4、p1、p3、p4、L、ULM、n0如权利要求1所定义，且R1不为X1。in, Ring A1, R 1 , R 3 , R 4 , p1, p3, p4, L, ULM and n0 are as defined in claim 1 , and R 1 is not X 1 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(I)所示化合物为式(I-B)所示结构，
The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula (I) has a structure as shown in formula (IB),
其中，A1环、R1、R2、R3、R4、p1、p3、p4、L、ULM、n0如权利要求1所定义，且R1、R2不为X1；in, A1 ring, R 1 , R 2 , R 3 , R 4 , p1, p3, p4, L, ULM, n0 are as defined in claim 1 , and R 1 and R 2 are not X 1 ; 优选地，式(I)所示化合物为式(I-B-1)所示结构，
Preferably, the compound represented by formula (I) is a compound represented by formula (IB-1),
其中，Y1、Y2、Y3各自独立地为CH或N，R1、R2、R3、R4、L、ULM、p1、p3、p4、n0如权利要求1所定义，且R1、R2不为X1。wherein Y 1 , Y 2 , and Y 3 are each independently CH or N, R 1 , R 2 , R 3 , R 4 , L, ULM, p1, p3, p4, n0 are as defined in claim 1 , and R 1 and R 2 are not X 1 . 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(I)所示化合物选自以下结构： 其中R1、R2、R3、p1、p3、L、ULM、n0如权利要求1所定义，且R1、R2不为X1；The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula (I) is selected from the following structures: wherein R 1 , R 2 , R 3 , p1, p3, L, ULM, and n0 are as defined in claim 1 , and R 1 and R 2 are not X 1 ; 优选地，式(I)所示化合物选自以下结构： 其中L、ULM、n0如权利要求1所定义；Preferably, the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, n0 are as defined in claim 1; 优选地，式(I)所示化合物选自以下结构： 其中L、ULM、n0如权利要求1所定义；Preferably, the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, n0 are as defined in claim 1; 优选地，式(I)所示化合物选自以下结构： 其中L、ULM、n0如权利要求1所定义。Preferably, the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, and n0 are as defined in claim 1. 如权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(I)化合物选自下列化合物或其立体异构体：











The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula (I) is selected from the following compounds or their stereoisomers:











一种药物组合物，包括权利要求1-44所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体；以及药学上可接受的载体。A pharmaceutical composition comprising a compound of formula (I) as described in claims 1-44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier. 权利要求1-44所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，或权利要求45所述的药物组合物在制备预防和/或治疗EED介导的疾病的药物中的用途。Use of the compound of formula (I) according to claims 1-44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 45 in the preparation of a medicament for preventing and/or treating EED-mediated diseases. 如权利要求46所述的用途，其特征在于，所述EED介导的疾病为肿瘤或自身免疫疾病；优选地，所述EED介导的疾病为癌症；优选地，所述癌症选自多发性骨髓瘤、白血病、非小细胞肺癌、结肠癌、中枢神经系统癌症、黑素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌。The use as claimed in claim 46, characterized in that the EED-mediated disease is a tumor or an autoimmune disease; preferably, the EED-mediated disease is cancer; preferably, the cancer is selected from multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer and breast cancer. 一种预防和/或治疗EED介导的疾病的方法，包括给予受试者治疗有效量的权利要求1-44所述的式(I)所示化合物、或其药学上可接受的盐、或其立体异构体，或者权利要求45所述的药物组合物。A method for preventing and/or treating EED-mediated diseases, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as described in claims 1-44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition as described in claim 45. 如权利要求48所述的方法，其特征在于，所述EED介导的疾病为肿瘤或自身免疫疾病；优选地，所述EED介导的疾病为癌症；优选地，所述癌症选自多发性骨髓瘤、白血病、非小细胞肺癌、结肠癌、中枢神经系统癌症、黑素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌。The method of claim 48, wherein the EED-mediated disease is a tumor or an autoimmune disease; preferably, the EED-mediated disease is cancer; preferably, the cancer is selected from multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer and breast cancer.
PCT/CN2024/135781 2023-11-30 2024-11-29 Fused tetraheterocyclic derivative, pharmaceutical composition thereof, and use thereof Pending WO2025113665A1 (en)

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