Fused tetra-heterocyclic derivatives, pharmaceutical compositions thereof and uses thereof

Abstract

提供了一种式(I)所示双功能化合物，还公开了该化合物药学上可接受的盐、或其立体异构体、药物组合物及其用途。化合物对EED具有优异的降解作用，且对肿瘤细胞具有优异的细胞增殖抑制作用，具有潜在的肿瘤治疗作用。POI‑(L)n0‑ULM(I)。

Description

Fused tetracyclic heterocyclic derivatives and pharmaceutical compositions and uses thereof

[0001] This application claims priority to the Chinese patent application with application number 202311632052.6 filed with the China Patent Office on November 30, 2023, entitled “Fused tetra-heterocyclic derivatives and their pharmaceutical compositions and uses”, the Chinese patent application with application number 202311861488.2 filed with the China Patent Office on December 29, 2023, entitled “Fused tetra-heterocyclic derivatives and their pharmaceutical compositions and uses”, and the Chinese patent application with application number 202410854815.X filed with the China Patent Office on June 27, 2024, entitled “Fused tetra-heterocyclic derivatives and their pharmaceutical compositions and uses”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] 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. Background Art

[0003] The Polycomb group (PcG) protein, the Polycomb repressive complex 2 (PRC2), performs a core function of transcriptional repression in the body, achieving gene silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27me3). In tumors, it can promote tumor development by inhibiting the expression of tumor suppressor genes. The catalytic subunit of PRC2, EZH2, is an important representative of the third generation of epigenetic regulation precision therapy targets. Compared with first- and second-generation pan-epigenetic regulation targets, current therapeutic targets can target tumors with specific mutation types, significantly improving both efficacy and safety. Although EZH2 is an ideal target for directly shutting down abnormal PRC2 activity, as a complex protein, the function and activity of PRC2 is highly dependent on the scaffold and the regulation of another core subunit, EED. Interfering with the protein-protein interaction (PPI) between EZH2 and EED can also inhibit the methyltransferase activity of the PRC2 complex. 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.

[0004] The rise of targeted protein degradation (TPD) technology has provided a new path for small molecule drug development. Among them, proteolysis targeting chimeras (PROTACs) are the most mature system. Their mechanism of action is to connect a small molecule inhibitor and an E3 ubiquitin ligase ligand through a linker chain to form a targeted protein degradation conjugate. In vivo, the inhibitor portion of this bifunctional molecule can recognize the target protein, while the E3 enzyme ligand portion can recognize the ubiquitin ligase, ultimately degrading the target protein through the ubiquitin-proteasome pathway. Protein degraders can target "undruggable" targets, improve target selectivity and inhibitory activity, prolong the drug's duration of action, and reduce drug-resistant mutations. They are particularly suitable for drug development against traditionally undruggable targets (such as transcription factors and scaffold proteins), targets prone to acquired resistance mutations during targeted tumor therapy, targets with gene amplification and / or protein overexpression, targets with different protein isoforms, scaffold proteins, protein polymers, etc. Currently, small molecule inhibitors targeting EZH2 have been approved for marketing, clinically validating the feasibility of PRC2 as an anti-tumor drug target. However, the efficacy of EZH2 small molecule inhibitors in solid tumors remains limited, and several small molecule inhibitors of EZH2 and EED are still under clinical investigation. Considering the structural and functional characteristics of PRC2 and the advantages of protein degradation drugs, the use of protein degradation technology for drug development targeting this target may bring new directions and breakthroughs.

[0005] 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. Summary of the Invention

[0006] The object of the present invention is to provide a PROTAC compound. The compound of the present invention 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).

[0007] 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),

[0008] Among them, POI is the ligand that binds to the EED protein;

[0009] L is the connection link between POI and ULM;

[0010] ULM is the group that binds to the E3 ligase;

[0011] n0 is 0 or 1.

[0012] In some embodiments, n0 is 0.

[0013] In some embodiments, n0 is 1.

[0014] In some embodiments, POI is a structure represented by formula (A-1) or an isomer thereof,

[0015] in,

[0016] express (double bond) or (single bond);

[0017] W1, W2, W3 are each independently selected from a bond, -CH2-, -(CH2)2-, -CH=CH-, -CH=N-, -N=N-, -(CH2)3-, -C(O)NH-, -NHC(O)-, -C(O)-, -NH-, -CH- and -N-;

[0018] W4 and W5 are each independently selected from -CH-, -N- and -C-;

[0019] A1 ring is selected from C 3-15 Cycloalkyl ring (preferably C 3-12 Cycloalkyl ring, more preferably C 3-10 Cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, 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 C 6-14 aromatic rings;

[0020] (R1) p1 represents that the hydrogen on the A1 ring is replaced by p1 R1, p1 is 0, 1, 2 or 3, each R1 is the same or different and is independently selected from X1, hydrogen, deuterium, cyano, carboxyl, nitro, formyl, sulfonic acid, halogen (preferably fluorine, chlorine or bromine), C 1-10Alkyl (preferably C 1-8 Alkyl, more preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), halogenated C 1-10 Alkyl (preferably halogenated C 1-8 Alkyl, more preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 1-10 Alkoxy (preferably C 1-8 Alkoxy, more preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-10 Alkoxy (preferably halogenated C 1-8 Alkoxy, more preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -COC 1-10 Alkyl (preferably -COC 1-8 Alkyl, more preferably -COC 1-6 Alkyl, more preferably -COC 1-3 Alkyl), -COOC 1-10 Alkyl (preferably -COOC 1-8 Alkyl, more preferably -COOC 1-6 Alkyl, more preferably -COOC 1-3 alkyl), -CONH2, -CONHC 1-10 Alkyl (preferably -CONHC 1-8 Alkyl, more preferably -CONHC 1-6 Alkyl, more 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, more preferably -CON (C 1-3 Alkyl)2), -SOC 1-10 Alkyl (preferably -SOC 1-8 Alkyl, more preferably -SOC 1-6 Alkyl, more preferably -SOC 1-3 Alkyl), -SO2C 1-10 Alkyl (preferably -SO2C 1-8 Alkyl, more preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), -SO2NH2, -SO2NHC 1-10 Alkyl (preferably -SO2NHC 1-8Alkyl, more preferably -SO2NHC 1-6 Alkyl, more preferably -SO2NHC 1-3 Alkyl), -SO2N(C 1-10 Alkyl)2(preferably -SO2N(C 1-8 Alkyl)2, more preferably -SO2N(C 1-6 Alkyl) 2, more preferably -SO2N(C 1-3 Alkyl)2), C 3-8 Cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 15-membered heterocycloalkyl (preferably 4 to 12-membered heterocycloalkyl, more preferably 4 to 8-membered heterocycloalkyl, further preferably 4 to 6-membered heterocycloalkyl), 5 to 10-membered heteroaryl (preferably 5 to 6-membered heteroaryl) and C 6-14 Aryl; the C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, -COC 1-10 Alkyl, -COOC 1-10 Alkyl, -CONH2, -CONHC 1-10 Alkyl, -CON(C 1-10 Alkyl)2, -SOC 1-10 Alkyl, -SO2C 1-10 Alkyl, -SO2NH2, -SO2NHC 1-10 Alkyl, -SO2N(C 1-10 Alkyl)2, C 3-8 Cycloalkyl, 3 to 15 membered heterocycloalkyl, 5 to 10 membered heteroaryl, C 6-14 Aryl is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, halogen, 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, C 3-6Cycloalkyl, 3- to 15-membered heterocycloalkyl (preferably 4- to 12-membered heterocycloalkyl, more preferably 4- to 8-membered heterocycloalkyl, further preferably 4- to 6-membered heterocycloalkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl), phenyl, and naphthyl;

[0021] (R2) p2 Indicates that the hydrogen on the A2 ring is replaced by p2 R2, p2 is 0, 1, 2 or 3, each R2 is the same or different and is independently selected from X1, hydrogen, deuterium, C 1-10 Alkyl (preferably C 1-8 Alkyl, more preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-10 Alkoxy (preferably C 1-8 Alkoxy, more preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-10 Alkyl (preferably halogenated C 1-8 Alkyl, more preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), halogenated C 1-10 Alkoxy (preferably halogenated C 1-8 Alkoxy, more preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), C 3-8 Cycloalkyl (preferably C 3-6 cycloalkyl), 3 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 5 to 10-membered heteroaryl (preferably 5 to 6-membered heteroaryl) and C 6-14 Aryl (preferably C 6-12 Aryl); the C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, 5- to 10-membered heteroaryl, C 3-8 Cycloalkyl, 3 to 15 membered heterocycloalkyl, C 6-14 Aryl is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), hydroxy, carboxyl, nitro, formyl, sulfonic acid, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, 5- to 6-membered heteroaryl, C 3-8Cycloalkyl, 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);

[0022] (R3) p3 represents that the hydrogen on the 2,3-dihydrobenzofuran ring is replaced by p3 R3, p3 is 0, 1 or 2, each R3 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), -CONH2, -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), -SO2C 1-8 Alkyl (preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), -SO2NH2, -SO2NHC 1-8 Alkyl (preferably -SO2NHC 1-6 Alkyl, more preferably -SO2NHC 1-3 Alkyl), -SO2N(C 1-8Alkyl)2(preferably -SO2N(C 1-6 Alkyl)2, more preferably -SO2N(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 and / or two adjacent R3 and the carbon atom connected thereto form C 3-8 Cycloalkyl ring (preferably C 3-6 cycloalkyl ring), 3 to 8-membered heterocycloalkyl ring (preferably 3 to 6-membered heterocycloalkyl ring, 4 to 5-membered heterocycloalkyl ring), 5 to 10-membered heteroaryl ring (preferably 5 to 6-membered heteroaryl ring), 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, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -SO2NH2, -SO2NHC 1-8 Alkyl, -SO2N(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 The cycloalkyl ring, 3- to 8-membered heterocycloalkyl ring, 5- to 10-membered heteroaryl ring, and benzene ring are unsubstituted or substituted with 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, C3-8 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);

[0023] (R4) p4 represents that the hydrogen on the imidazo[1,5-c]pyrimidine ring is replaced by p4 R4, p4 is 0, 1 or 2, each R4 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), -CONH2, -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), -SO2C 1-8 Alkyl (preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), -SO2NH2, -SO2NHC 1-8 Alkyl (preferably -SO2NHC 1-6 Alkyl, more preferably -SO2NHC 1-3 Alkyl), -SO2N(C1-8 Alkyl)2(preferably -SO2N(C 1-6 Alkyl)2, more preferably -SO2N(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); 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, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -SO2NH2, -SO2NHC 1-8 Alkyl, -SO2N(C 1-8 Alkyl)2, C 3-8 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 6-14 Aryl 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(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), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl) and C 6-14 Aryl (preferably C 6-12 aryl);

[0024] Wherein, X1 is the connection site between POI and L or ULM, and at least one of R1 and R2 is X1.

[0025] In some embodiments, W1, W2, W3 are each independently selected from a bond, -CH2-, -C(O)NH-, and -NHC(O)-.

[0026] In some embodiments, W4 and W5 are each independently selected from -CH- and -C-.

[0027] In some embodiments, the structure represented by formula (A-1) is the structure represented by formula (A-2) or an isomer thereof,

[0028] In some embodiments, p1 is 0.

[0029] In some embodiments, p1 is 1.

[0030] In some embodiments, R1 is selected from X1, 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, -CH2-cyclopropyl, -CH2-tetrahydropyrrolyl, -CH2-pyrrolyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-quinolyl, and -CH2-cyclohexenyl.

[0031] In some embodiments, R1 is selected from X1, hydrogen, -CN, -COOH, -NO2, -CHO, -SO3H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OC H2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -COC H3, -COOCH3, -CONH2, -CONHCH3, -CON(CH3)2, -SOCH3, -SO2CH3, -SO2NH2, -SO2NHCH3, and -SO2N(CH3)2.

[0032] In some embodiments, R1 is selected from X1, hydrogen, -CH3, -CHF2, -CF3, -CH2OH, -OCH3, -OCH2CH3, -COCH3, -COOCH3, -CONH2, -CONHCH3, -CON(CH3)2, -SOCH3, -SO2CH3, -SO2NH2, -SO2NHCH3 and -SO2N(CH3)2.

[0033] In some embodiments, R1 is selected from X1, -CH3, and -CF3.

[0034] In some embodiments, R1 is selected from X1 and -CF3.

[0035] In some embodiments, p1 is 1 and R1 is X1 or -CF3.

[0036] In some embodiments, p1 is 1 and R1 is X1.

[0037] In some embodiments, p1 is 1 and R1 is -CF3.

[0038] In some embodiments, p2 is 0.

[0039] In some embodiments, p2 is 1.

[0040] In some embodiments, R2 is selected from X1, 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 3-6 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, quinolinyl, naphthyl, -CH2-cyclopropyl, -CH2-tetrahydropyrrolyl, -CH2-pyrrolyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-quinolinyl, -CH2-cyclohexenyl, -CH2-azetidine, -CH2-piperidine, -CH2-piperazine, tetrahydro-2H-pyran and -CH2-(tetrahydro-2H-pyran).

[0041] In some embodiments, R2 is selected from X1, 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).

[0042] In some embodiments, R2 is selected from X1, 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).

[0043] In some embodiments, R2 is selected from X1, -CH3, -CH2CHF2, -CH2CF2CH3, and -CH(CH3)2.

[0044] In some embodiments, R2 is selected from X1 and -CH(CH3)2.

[0045] In some embodiments, R2 is X1.

[0046] In some embodiments, R2 is -CH(CH3)2.

[0047] In some embodiments, p2 is 1 and R2 is X1 or -CH(CH3)2.

[0048] In some embodiments, p2 is 1 and R2 is X1.

[0049] In some embodiments, p2 is 1 and R2 is -CH(CH3)2.

[0050] In some embodiments, p3 is 0.

[0051] In some embodiments, p3 is 1.

[0052] In some embodiments, p3 is 3.

[0053] In some embodiments, R3 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, quinolinyl, naphthyl, -CH2-cyclopropyl, -CH2-tetrahydropyrrolyl, -CH2-pyrrolyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-quinolinyl, -CH2-cyclohexenyl, -CH2-azetidine, -CH2-piperidine, -CH2-piperazine, tetrahydro-2H-pyran and -CH2-(tetrahydro-2H-pyran).

[0054] 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.

[0055] In some embodiments, p3 is 1 and R3 is fluoro.

[0056] In some embodiments, the structure for

[0057] In some embodiments, two adjacent R3 and the carbon atom to which they are attached form C 3-6 a cycloalkyl ring, a 3- to 6-membered heterocycloalkyl ring, or a 5- to 6-membered heteroaryl ring.

[0058] 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.

[0059] In some embodiments, two adjacent R3 groups and the carbon atom to which they are attached form a cyclopropane ring.

[0060] In some embodiments, p3 is 3, wherein one R3 is fluorine, and the other two R3 and the carbon atom to which they are attached form a cyclopropane ring.

[0061] In some embodiments, the structure for

[0062] In some embodiments, the structure for

[0063] In some embodiments, the C in the A1 ring 3-15 The cycloalkyl 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.

[0064] 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 2,5-dihydro-1H-pyrrole ring, a 2,3-dihydro-1H-azacyclopentane ring, a 2,3-dihydro-1H-azacyclopentane ring, a 2,3-dihydro-1H-azacyclopentane ring, a 2,3-dihydro-1H-azacyclopentane ring, a 2,3-dihydro-1H-azacyclopentane ring, a 2,3-dihydro-1H-azacyclopentane ring, a 2,3-dihydro-1H-azacyclopentane ring, a 2,3-dihydro-1H-aza flat ring, 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.

[0065] 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 pyrimidopyrazole ring, a pyridazinopyrazole ring, a pyrimidopyrazole ring, a pyridazinoimidazole ring, a pyrazinoimidazole ring, a quinoline ring, an isoquinoline ring, and a 9H-pyrido[2,3-b]indole ring.

[0066] In some embodiments, the C in the A1 ring 6-14The aromatic ring is selected from a benzene ring and a naphthalene ring.

[0067] 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.

[0068] In some embodiments, the A1 ring is selected from a benzene ring, a pyridine ring, and a pyrazole ring.

[0069] In some embodiments, the A1 ring is selected from a benzene ring and a pyridine ring.

[0070] In some embodiments, the structure Selected from Wherein, R1, R2, and p1 are as defined in the specification, and at least one of R1 and R2 is X1.

[0071] In some embodiments, the structure Selected from: Wherein, R1, R2, and p1 are as defined in the specification, and at least one of R1 and R2 is X1.

[0072] In some embodiments, the structure Selected from

[0073] In some embodiments, the structure Selected from:

[0074] In some embodiments, the structure Selected from wherein Y1, Y2, and Y3 are each independently CH or N, (R1) p1 , R2, and A1 are as described in the specification, and X1 is the connection site between POI and L or ULM.

[0075] In some embodiments, Y1, Y2, and Y3 are each independently CH.

[0076] In some embodiments, Y2 and Y3 are each independently CH, and Y1 is N.

[0077] In some embodiments, Y1 and Y3 are each independently CH, and Y2 is N.

[0078] In some embodiments, Y1 and Y2 are each independently CH, and Y3 is N.

[0079] In some embodiments, Y1 and Y2 are each independently N, and Y3 is CH.

[0080] In some embodiments, Y2 and Y3 are each independently N, and Y1 is CH.

[0081] In some embodiments, Y1, Y2, and Y3 are each independently N.

[0082] In some embodiments, the structure Selected from Where X1 is the connection site between POI and L or ULM.

[0083] In some embodiments, the structure Selected from Where X1 is the connection site between POI and L or ULM.

[0084] In some embodiments, the structure Selected from: Where X1 is the connection site between POI and L or ULM.

[0085] In some embodiments, the structure Selected from: Where X1 is the connection site between POI and L or ULM.

[0086] In some embodiments, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.

[0087] In some embodiments, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.

[0088] In some embodiments, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.

[0089] In some embodiments, the compound represented by formula (I) is represented by formula (IC),

[0090] in W1, W2, W3, W4, W5, A1 ring, R1, R2, R3, R4, L, ULM, p1, p2, p3, p4, and n0 are as defined in the specification, and R1 and R2 are not X1.

[0091] In some embodiments, the compound represented by formula (I) is represented by formula (ID),

[0092] in W1, W2, W3, W4, W5, A1 ring, R1, R2, R3, R4, L, ULM, p1, p2, p3, p4, and n0 are as defined in the specification, and R1 and R2 are not X1.

[0093] In some embodiments, the compound represented by formula (I) is a structure represented by formula (IE),

[0094] in W1, W2, W3, W4, W5, A1 ring, R1, R3, R4, L, ULM, p1, p3, p4, and n0 are as defined in the specification, and R1 is not X1.

[0095] In some embodiments, the compound represented by formula (I) is represented by formula (IF),

[0096] in W1, W2, W3, W4, W5, A1 ring, R2, R3, R4, L, ULM, p2, p3, p4, and n0 are as defined in the specification, and R2 is not X1.

[0097] In some embodiments, the compound represented by formula (I) is represented by formula (IA),

[0098] in A1 ring, R1, R3, R4, L, ULM, p1, p3, p4, and n0 are as defined in the specification, and R1 is not X1.

[0099] In some embodiments, the compound represented by formula (I) is represented by formula (IB),

[0100] in Ring A1, R1, R2, R3, R4, L, ULM, p1, p3, p4, and n0 are as defined in the specification, and R1 and R2 are not X1.

[0101] In some embodiments, the compound represented by formula (I) is represented by formula (IB-1),

[0102] in R1, R2, R3, R4, L, ULM, p1, p3, p4, n0, Y1, Y2, and Y3 are as defined in the specification, and R1 and R2 are not X1.

[0103] In some embodiments, the compound represented by formula (I) is selected from the following structures: wherein R1, R2, R3, L, ULM, p1, p3, and n0 are as defined in the specification, and R1 and R2 are not X1.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] In some embodiments, L is a structure represented by formula (L-1) or an isomer thereof, a ) m1 - (L-1),

[0108] wherein m1 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0109] L a Each occurrence 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, more preferably C 1-3 Alkylene), C 1-10 Alkyleneoxy (preferably C 1-8 Alkyleneoxy, more preferably C 1-6 Alkyleneoxy, more preferably C 1-3 Alkyleneoxy), C 2-10 Alkenylene (preferably C 2-8 Alkenylene, more preferably C 2-6Alkenylene, more preferably C 2-4 Alkenylene), C 2-10 Alkyne group (preferably C 2-8 Alkyne, more preferably C 2-6 Alkyne group, more preferably C 2-4 Alkynylidene), C 3-15 Cycloalkyl ring (preferably C 3-10 Cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 15-membered heteroaryl ring (preferably a 5- to 14-membered heteroaryl ring, more preferably a 5- to 12-membered heteroaryl ring, further preferably a 5- to 10-membered heteroaryl ring, further preferably a 5- to 6-membered heteroaryl ring) and C 6-14 Aromatic ring (preferably a benzene ring or a naphthalene ring); the C 1-10 Alkylene, C 1-10 Alkyleneoxy, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-15 Cycloalkyl ring, 3- to 15-membered heterocycloalkyl ring, 5- to 15-membered heteroaryl ring, C 6-14 The aromatic ring is unsubstituted or substituted with 1, 2, 3 or 4 R L2 Substituted, the R L2 are independently selected from deuterium, halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, amino, carboxyl, formyl, oxo, sulfonic acid, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 alkyl, 3 to 6 membered heterocycloalkyl, 3 to 6 membered heterocycloalkylC 1-6 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroarylC 1-6 Alkyl, phenyl, phenyl C 1-6 Alkyl, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONH2, -CONHC 1-6Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl and -SO2N(C 1-6 Alkyl)2;

[0110] R L1 Each occurrence is independently selected from hydrogen, deuterium, 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), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy) and halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl).

[0111] In some embodiments, R L1 Each occurrence 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.

[0112] In some embodiments, R L1 Each occurrence is independently selected from hydrogen, methyl, ethyl, difluoromethyl and monofluoromethyl.

[0113] In some embodiments, R L1 For hydrogen.

[0114] In some embodiments, R L2are each 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, -C H2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-cyclohexenyl, -CH2-cyclopentenyl, -CH2-tetrahydropyrrolyl, -CH2-tetrahydrofuranyl, -CH2-phenyl, -CH2-pyrrolyl, -CH2-triazolyl, -CH2-tetrazolyl, -CH2-pyridyl, -CH2-pyrazinyl, -CH2-triazinyl, methoxy, ethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethoxy, acetyl, acetylamino and sulfonamido.

[0115] In some embodiments, R L2 Each 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(CH3)2, -SOCH3, -SO2CH3, -SO2NH2, -SO2NHCH3 and -SO2N(CH3)2.

[0116] In some embodiments, R L2 Each 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.

[0117] In some embodiments, R L2Each is independently selected from fluorine, chlorine, bromine, methyl, hydroxyl and hydroxymethyl.

[0118] In some embodiments, the L a Each independently selected from the following structures or isomers thereof: -C(O)-, -C(O)NH-, -O-, -S-, -NH-, C 1-10 Alkylene, C 1-10 Alkyleneoxy, C 3-12 Cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring; said C 3-12 The cycloalkyl ring, the 4- 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 R L2 Substituted, the R L2 Selected from fluorine, methyl, hydroxy and hydroxymethyl.

[0119] In some embodiments, the L a Each is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH2) m2 -、-O(CH2) m2 -、-(CH2) 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.

[0120] In some embodiments, the L aEach is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH2) m2 -、-O(CH2) m2 -、-(CH2) 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-aza 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 each occurrence of m2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0121] In some embodiments, the L a Each 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-, -CH2CH2O-, 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,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.

[0122] In some embodiments, the L aEach 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-, -CH2CH2O-,

[0123] In some embodiments, the L a Each 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-, -CH2CH2O-,

[0124] In some embodiments, the L a Each is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -NH-, -CH2-,

[0125] In some embodiments, the L a Each independently selected from the following structures or isomers thereof: -CONH-, -CO-, -CH2-, -NH-,

[0126] In some embodiments, the L a Each independently selected from the following structures or isomers thereof: -CONH-, -CH2-, -NH-, -CO-,

[0127] In some embodiments, the L a Each is independently selected from the following structures or isomers thereof: -CH2-, -NH-, -CONH-, -CO-,

[0128] 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 -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-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) m3 O(CH2) m3 -、-Cy0-C(O)-(CH2) m3 -、-NH-Cy0-(CH2) m3 -Cy0- and -(CH2) m3 -Cy0-O-Cy0-O(CH2) m3 -; wherein, m3 each occurrence is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Cy0 each occurrence is independently selected from C 3-12 Cycloalkyl ring (preferably C 3-10 Cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, further preferably a 3- to 6-membered heterocycloalkyl ring), a 5- to 6-membered heteroaryl ring and a benzene ring; the C 3-12 The 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 R L2 Replacement, R L2 Each occurrence is independently selected from deuterium, halogen, hydroxyl, cyano, amino, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated 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, C3-6 Cycloalkyl C 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -CONH2, -CONHC 1-3 Alkyl and -CON(C 1-3 Alkyl)2.

[0129] In some embodiments, the CyO 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 , 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, 1,1,3,3-tetramethylcyclobutane, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,3-difluoropiperidine.

[0130] In some embodiments, the CyO 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.

[0131] In some embodiments, the CyO 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.

[0132] In some embodiments, the CyO 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.

[0133] In some embodiments, the CyO 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.

[0134] In some embodiments, the CyO is each independently selected from the following structures or isomers thereof:

[0135] In some embodiments, the CyO is each independently selected from the following structures or isomers thereof:

[0136] In some embodiments, the CyO is each independently selected from the following structures or isomers thereof:

[0137] In some embodiments, the CyO is each independently selected from the following structures or isomers thereof:

[0138] In some embodiments, the CyO is each independently selected from the following structures or isomers thereof:

[0139] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00It is the connection site between L and ULM or POI.

[0140] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection site between L and ULM or POI.

[0141] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection site between L and ULM or POI.

[0142] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection site between L and ULM or POI.

[0143] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection site between L and ULM or POI.

[0144] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection site between L and ULM or POI.

[0145] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 It is the site where L is connected to ULM.

[0146] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 It is the site where L is connected to ULM.

[0147] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 It is the site where L is connected to ULM.

[0148] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 It is the site where L is connected to ULM.

[0149] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 It is the site where L is connected to ULM.

[0150] In some embodiments, the ULM is a compound represented by formula (U-1) or an isomer thereof:

[0151] in,

[0152] express (double bond) or (single bond);

[0153] U0 is a bond, -N(R U0 )-、-CON(R U0 )-, -CH2- or -(CH2)2-;

[0154] R U0 Each occurrence is independently hydrogen or C 1-3 alkyl;

[0155] B ring is absent or 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), C 3-15 Cycloalkyl ring and C 6-10 an aromatic ring (preferably a benzene ring);

[0156] S1, S3, S5 are each independently selected from a bond, -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-, and -SO2-;

[0157] S2 and S4 are each independently selected from -N-, -NH-, -CH- and -CH2-;

[0158] S6 is selected from C, -CH- and N;

[0159] (R B1 ) b1 Indicates that the hydrogen on the B ring is replaced by b1 R B1 Substitution, b1 is 0, 1, 2 or 3, each R B1 are the same or different, each independently selected from X2, 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), -SO2C 1-8 Alkyl (preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), amino-substituted C 1-8 Alkyl (preferably amino substituted C 1-6 Alkyl, more preferably amino substituted 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), hydroxy substituted C 1-8 Alkyl (preferably hydroxy substituted C 1-6 Alkyl, more preferably hydroxy substituted C 1-3 Alkyl), carboxyl substituted C 1-8 Alkyl (preferably carboxyl substituted C 1-6Alkyl, more preferably carboxyl substituted C 1-3 Alkyl), -COC 1-8 Alkyl (preferably -COC 1-6 Alkyl, more preferably -COC 1-3 Alkyl), -COOC 1-8 Alkyl-CONR a2 R b2 (Preferably -COOC 1-6 Alkyl-CONR a2 R b2 , more preferably -COOC 1-3 Alkyl-CONR a2 R b2 ), -SO2NR a2 R b2 、C 3-15 Cycloalkyl ring (preferably C 3-10 Cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, 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 C 6-10 Aromatic ring (preferably a benzene ring or a naphthalene ring); or two adjacent R B1 The carbon atom connected to it forms C 3-15 Cycloalkyl ring (preferably C 3-10 Cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 6-membered heteroaryl ring or a benzene ring; the C 3-15 The cycloalkyl ring, 3- to 15-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring or benzene ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of X2, 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, -SO2C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -COC 1-6Alkyl, -COOC 1-6 Alkyl, -CONR a2 R b2 and -SO2NR a2 R b2 ;

[0160] (R B2 ) b2 Indicates that the hydrogen on the C ring is replaced by b2 R B2 Substituted, b2 is 0, 1, 2, 3 or 4, each R B2 are the same or different, each independently selected from X2, deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, -NR a1 R b1 、C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONR a2 R b2 、-OC(O)C 1-6 Alkyl substituted C 1-6 Alkyl and -COOC 1-6 Alkyl substituted C 1-6 alkyl;

[0161] R a1 、R b1 、R a2 、R b2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, -COC 1-6 Alkyl and -COOC 1-6 alkyl;

[0162] Among them, X2 is the connection site between ULM and L or POI, and R B1 and R B2 At least one of them is X2.

[0163] In some embodiments, R B1 and R B2 Not X2 at the same time.

[0164] In some embodiments, the B ring is absent.

[0165] In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzopyrrole, benzofuran, benzothiophene, benzopyrazole, benzimidazole, benzothiazole, benzoxazole, pyridine, a pyrrole ring, a pyridofuran ring, a pyridothiophene ring, a pyridopyrazole ring, a pyridoimidazole ring, a pyridothiazole ring, a pyridoxazole ring, a pyrimidopyrrole ring, a pyridazinopyrrole 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.

[0166] In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from a pyridine ring and a benzopyrazole ring.

[0167] In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in Indicates covalent linkage to U0.

[0168] In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in Indicates covalent linkage to U0.

[0169] In some embodiments, the C in Ring B 6-10 The aromatic ring is selected from a benzene ring and a naphthalene ring.

[0170] In some embodiments, the C in Ring B 6-10 The aromatic ring is a benzene ring.

[0171] In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from: in Indicates covalent linkage to U0.

[0172] In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Q1, Q2, Q3, and Q4 are each independently selected from -CH-, N, and NO; S7 and S8 are each independently selected from a bond, -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-, and -SO2-; Indicates covalent linkage to U0.

[0173] In some embodiments, Q1, Q2, Q3, and Q4 are each independently -CH-.

[0174] In some embodiments, S8 is selected from -CH=N-, -N=N-, -CH2C(O)-, -C(O)O-, -CONH-, and -CH=CH-.

[0175] In some embodiments, S7 and S8 are each independently selected from -CH2- and -C(O)-.

[0176] In some embodiments, S7 is -CH2- and S8 is -C(O)-.

[0177] In some embodiments, S7 is -C(O)- and S8 is -C(O)-.

[0178] In some embodiments, S7 is -CH2- and S8 is -C(S)-.

[0179] In some embodiments, S7 is -C(O)- and S8 is -C(S)-.

[0180] In some embodiments, S7 is a bond and S8 is -CONH-.

[0181] In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0182] 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 C 4-8 Cycloalkyl ring, 4- to 8-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring and benzene ring; S9, S 10 are each independently selected from a bond, -CH2-, and -C(O)-; Indicates covalent linkage to U0.

[0183] In some embodiments, the structure Selected from in Indicates covalent linkage to U0.

[0184] 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 C 5-7Cycloalkyl ring and 5- to 7-membered heterocycloalkyl ring, Q1, Q2, Q3, Q4, S7, S8 are as described in the specification, Indicates covalent linkage to U0.

[0185] In some embodiments, Ring B3, Ring B4, and Ring B5 are each independently selected from a partially unsaturated C 5-7 cycloalkyl ring and partially unsaturated 5- to 7-membered heterocycloalkyl ring.

[0186] In some embodiments, Ring B3, Ring B4, and 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.

[0187] In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is selected from in Indicates covalent linkage to U0.

[0188] In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is in Indicates covalent linkage to U0.

[0189] In some embodiments, Ring B3 is a 5- to 7-membered nitrogen-containing heterocycloalkyl ring.

[0190] In some embodiments, Ring B3 is a partially unsaturated 5- to 7-membered nitrogen-containing heterocycloalkyl ring.

[0191] 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.

[0192] In some embodiments, the structure Selected from in Indicates covalent linkage to U0.

[0193] In some embodiments, the structure Selected from in Indicates covalent linkage to U0.

[0194] 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, Q5, Q6, Q7, Q8, and Q9 are each independently selected from C, -CH-, and N, Indicates covalent linkage to U0.

[0195] In some embodiments, Ring B7 is 1,3-dioxole.

[0196] In some embodiments, the structure Selected from in Indicates covalent linkage to U0.

[0197] 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 Each is independently selected from -C-, -N-, -S-, -O-, -NH-; S7 and S8 are as described in the specification, Indicates covalent linkage to U0.

[0198] In some embodiments, Ring B6 is a benzene ring.

[0199] In some embodiments, Q 11 Selected from -S-, -O-, -NH-, Q 12 , Q 13 are each independently selected from -C-.

[0200] In some embodiments, the structure Selected from: in Indicates covalent linkage to U0.

[0201] In some embodiments, Ring B is selected from: in Indicates covalent linkage to U0.

[0202] In some embodiments, Ring B is selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0203] In some embodiments, Ring B is selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0204] In some embodiments, R B1 Each 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)2OH, -(CH2)3OH, -CH2COOH, -(CH2)2COOH, -(CH2)3COOH, -COCH3, -COCH2CH3, -COOCH3, -COOCH2CH3, -CONH2 or -SO2NH2; or two adjacent R B1 The carbon atom connected thereto forms 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-azapine 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, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclopentene ring, cyclohexene ring, cycloheptene ring, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydro The thiophene 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 with 1, 2, 3 or 4 substituents selected from the group consisting of X2, deuterium, fluorine, chlorine, bromine, cyano, carboxyl, hydroxyl, nitro, amino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -SCH3, -SOCH3, -SO2CH3, -COCH3, -COOCH3, -CONH2 and -SO2NH2.

[0205] In some embodiments, R B1 is selected from fluorine, chlorine, hydroxy, methyl, trifluoromethyl and methoxy.

[0206] In some embodiments, b1 is 1, R B1For fluorine.

[0207] In some embodiments, b1 is 1, R B1 is X2.

[0208] In some embodiments, Selected from: Where X2 is the connection site between ULM and L or POI, Indicates covalent linkage to U0.

[0209] 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 linkage to U0.

[0210] 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 linkage to U0.

[0211] In some embodiments, U0 is a bond, -NH-, -CONH-, or -CH2-.

[0212] In some embodiments, U0 is a bond.

[0213] In some embodiments, U0 is -NH-.

[0214] In some embodiments, U0 is -CONH-.

[0215] In some embodiments, U0 is -CH2-.

[0216] In some embodiments, S1 and S3 are -C(O)-, S2 is -NH-, and S4 and S5 are -CH2-.

[0217] In some embodiments, S6 is CH.

[0218] In some embodiments, S6 is N.

[0219] In some embodiments, b2 is 0.

[0220] In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0221] In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] In some embodiments, the ULM is a structure represented by formula (U-2) or an isomer thereof:

[0228] in,

[0229] (R U7 ) r1 Indicates that the hydrogen on the tetrahydropyrrole ring is replaced by r1 R U7 Substitution, r1 is 0, 1, 2 or 3, each R U7 The same or different, each 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;

[0230] R U1 -C(R U3 R U4 )-U1;

[0231] U1 is selected from the following structures or isomers thereof: X2, -NHCO-X2, -NHCOCH3, 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 X2, 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 -COCH3), -COOC 1-6 Alkyl (preferably -COOCH3), -CONH2, -CONHC 1-6 Alkyl (preferably -CONHCH3), -CON(C 1-6 Alkyl) 2 (preferably -CON (CH3) 2) and hydroxy substituted C 1-6 Alkyl (preferably -CH2OH);

[0232] R Ua is selected from hydrogen, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxy, 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;

[0233] R U3 、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 C1-3 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 、R U4 Together with the carbon atom to which it is connected, it forms C 3-7 Cycloalkyl (preferably C 3-6 cycloalkyl) and 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 Cycloalkyl, 3- to 7-membered heterocycloalkyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X2, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl and hydroxyl;

[0234] R U5 、R U6 Each is independently selected from X2, 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), CONHC 1-6 Alkyl substituted C 1-6 Alkyl, CON(C 1-6 Alkyl)2 substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl and COOC 1-6 Alkyl substituted C 1-6 alkyl;

[0235] (R U2 ) r2 Indicates that the hydrogen on the D ring is replaced by r2 R U2 Substituted, r2 is 0, 1, 2 or 3, each R U2 are the same or different, each independently selected from X2, hydrogen, deuterium, halogen (preferably fluorine, chlorine), nitro, cyano, carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkoxy C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SC 1-6 Alkyl, 5- to 6-membered heteroaryl and phenyl; the 5- to 6-membered heteroaryl and phenyl 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 hydroxy substituted C 1-3 Alkyl), C 1-6 Alkoxy 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), -NH2, -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), -CONH2, -NHCONH2, -CONHC 1-6 Alkyl, -NHCONHC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl and -SC 1-6 alkyl;

[0236] D ring is selected from benzene ring, 5 to 6 membered heteroaryl ring, C3-10 Cycloalkyl ring (preferably C 3-8 Cycloalkyl ring, more preferably 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);

[0237] R a3 、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), -CONH2, -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 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), -CONH2, -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl) and -CON(C 1-6 Alkyl)2 (preferably -CON(C 1-3 alkyl)2);

[0238] Among them, X2 is the connection site between ULM and L or POI, and U1, R U5、R U6 and R U2 At least one of them is X2, or R U1 Contains at least one X2.

[0239] In some embodiments, U1, R U5 、R U6 and R U2 One of them is X2.

[0240] In some embodiments, R U1 Contains one X2.

[0241] In some embodiments, r1 is 2, R U7 Selected from fluorine and hydroxy.

[0242] In some embodiments, the structure represented by formula (U-2) is the structure represented by formula (U-2-1) or an isomer thereof:

[0243] In some embodiments, R U7 Selected from hydroxy, amino, -OCH3, -OCF3 and -OCOCH3.

[0244] In some embodiments, R U7 It is a hydroxyl group.

[0245] In some embodiments, R Ua is selected from fluoro, cyano, methyl, ethyl, trifluoromethyl and trifluoromethoxy.

[0246] In some embodiments, R Ua Selected from fluorine and cyano.

[0247] In some embodiments, U1 is selected from X2, -NHCO-X2, -NHCOCH3, Where X2 is the connection site between ULM and L or POI.

[0248] In some embodiments, U1 is selected from -NHCO-X2 and Where X2 is the connection site between ULM and L or POI.

[0249] In some embodiments, R U3 、R U4 are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; or R U3 、R U4 The carbon atom to which it is connected forms a C 3-6 Cycloalkyl ring.

[0250] In some embodiments, R U3 、R U4 Each is independently hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2F, -OCH3, -OCH(CH3)2, -OC(CH3)3, -OCF3, -OCHF2, -OCH2F, fluoroisopropyl or fluorotert-butyl; or R U3 、R U4 The carbon atom to which it is attached forms a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.

[0251] In some embodiments, R U3 、R U4 Each is independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3; or R U3 、R U4 The carbon atom to which it is attached forms a cyclopropyl ring.

[0252] In some embodiments, R U3 、R U4 Each is independently hydrogen, -CH(CH3)2 or -C(CH3)3.

[0253] In some embodiments, R U1 Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

[0254] In some embodiments, R U1 Selected from the following structures: Where X2 is the connection site between ULM and L or POI.

[0255] In some embodiments, R U1 Selected from the following structures: Where X2 is the connection site between ULM and L or POI.

[0256] In some embodiments, R U5 、R U6 Each independently represents X2, 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.

[0257] In some embodiments, R U5 、R U6 are independently hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0258] In some embodiments, R U5 、R U6 Each is independently hydrogen, -CH3, -OCH3, -CF3, -OCF3, -CHF2, -CH2F, -OCHF2 or -OCH2F.

[0259] In some embodiments, R U5 、R U6 are each independently hydrogen or -CH3.

[0260] In some embodiments, r2 is 0.

[0261] In some embodiments, r2 is 1.

[0262] In some embodiments, r2 is 2.

[0263] In some embodiments, R U2 is a 5- to 6-membered heteroaryl or phenyl group, wherein 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 deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHCOC 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -CONH2, -NHCONH2, -CONHC 1-3 Alkyl, -NHCONHC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl and -SC 1-3 alkyl.

[0264] In some embodiments, the 5- to 6-membered heteroaryl is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazolyl.

[0265] In some embodiments, the 5- to 6-membered heteroaryl group is selected from

[0266] In some embodiments, the 5- to 6-membered heteroaryl group is

[0267] 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.

[0268] In some embodiments, R U2 It is a cyano group.

[0269] In some embodiments, R a3 、R b3 Each is 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, -COCH3 and -CONH2.

[0270] In some embodiments, R U2 NHR a3 , where 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 with 1, 2 or 3 substituents selected from the group consisting of: C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, -SC 1-3 Alkyl and -OCOC 1-3 alkyl.

[0271] In some embodiments, R U2 NHR a3 , where R a3 is thiazolyl; the 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.

[0272] In some embodiments, R U2 NHR a3 , where R a3is thiazolyl; said thiazolyl is substituted by 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl and isopropyl.

[0273] In some embodiments, R U2 Selected from the following structures: cyano,

[0274] In some embodiments, r2 is 1, R U2 Selected from cyano,

[0275] In some embodiments, r2 is 1, R U2 for

[0276] In some embodiments, r2 is 2, R U2 X2 and Where X2 is the connection site between ULM and L or POI.

[0277] In some embodiments, the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-6 cycloalkyl rings and 3- to 6-membered heterocycloalkyl rings.

[0278] In some embodiments, the D ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring.

[0279] 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.

[0280] In some embodiments, the D ring is selected from a benzene ring and a pyridine ring.

[0281] In some embodiments, Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

[0282] In some embodiments, Selected from the following structures or isomers thereof:

[0283] 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.

[0284] 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.

[0285] 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.

[0286] In some embodiments, the ULM is a structure represented by formula (U-3) or an isomer thereof:

[0287] Among them, R n1 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; said 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, hydroxy, 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, -SO2C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 heterocycloalkyl;

[0288] R n2 、R n3 Together with the connected N, a 4- to 12-membered heterocycloalkyl ring is formed; the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of X2, halogen, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, C 1-6Alkyl, -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, -SO2C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-14 aryl, 5- to 10-membered heteroaryl.

[0289] In some embodiments, R n1 Selected from tert-butyl, morpholino-substituted tert-butyl, thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane; the thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the following group: halogen, cyano, hydroxyl, nitro, trifluoromethyl, difluoromethyl, monofluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, -SCH3, -SOCH3, -SO2CH3, -NHCH3, -N(CH3)2, -COCH3.

[0290] In some embodiments, R n1 Selected from tert-butyl and pyridyl, wherein the pyridyl is substituted by bromine.

[0291] In some embodiments, R n2 、R n3 Together with the connected N, a 4- to 12-membered heterocycloalkyl ring is formed, 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 by 1, 2, 3 or 4 substituents selected from the group consisting of X2, fluorine, chlorine, bromine, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, methyl, tert-butyl, methoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, -NH(CH3), -N(CH3)2, -NHCOCH3, -COCH3, -COOCH3, -SOCH3, -SO2CH3, and cyclopropyl.

[0292] In some embodiments, R n2 、R n3 Together with the connected N, it forms a piperidine ring.

[0293] In some embodiments, the ULM is selected from the following structures:

[0294] In some embodiments, the compound of formula (I) is a specific compound selected from the Examples.

[0295] In some embodiments, the compound of formula (I) is a compound selected from the group consisting of:

[0296] In some embodiments, the compound of formula (I) is a compound selected from the group consisting of:

[0297] 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.

[0298] 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.

[0299] In some embodiments, the EED-mediated disease is a tumor or an autoimmune disease.

[0300] In some embodiments, the EED-mediated disease is cancer.

[0301] 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.

[0302] 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.

[0303] In some embodiments, the EED-mediated disease is a tumor or an autoimmune disease.

[0304] In some embodiments, the EED-mediated disease is cancer.

[0305] 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.

[0306] In a fifth aspect, 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0307] 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.

[0308] FIG1 is a Western blot image showing the degradation of EED protein by compound H39 in Karpas-422 cells;

[0309] FIG2 is a graph showing the dose-degradation activity of compound H39 on EED protein in Karpas-422 cells;

[0310] FIG3 is a graph showing the in vivo anti-tumor activity of compound D1 and compound H39;

[0311] FIG4 is a graph showing the effects of compound D1 and compound H39 on mouse body weight;

[0312] FIG5 is a graph showing the in vivo anti-tumor activity of compound D1 and compound H80;

[0313] FIG6 is a graph showing the effects of compound D1 and compound H80 on the body weight of mice. DETAILED DESCRIPTION

[0314] After extensive and in-depth research, the inventors unexpectedly discovered a bifunctional compound that targets and / or inhibits EED protein. This compound exhibits excellent EED protein degradation, excellent tumor cell (e.g., wsuDLCL-2 cells, Pfeiffer cells, etc.) proliferation inhibition, excellent pharmacokinetic characteristics, good CYP450 activity, and good safety, making it particularly suitable for treating diseases or conditions characterized by abnormal EED protein activity (e.g., proliferative diseases such as cancer). Based on this, the inventors completed the present application.

[0315] Definition of terms

[0316] In order to more clearly understand the technical content of the present invention, the terms of this application are further explained below.

[0317] 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 connecting 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 degradation (and / or inhibiting) the effect 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.

[0318] "Alkyl" refers to straight-chain and branched saturated aliphatic hydrocarbon groups. 1-10 "Alkyl" refers to an alkyl group having 1 to 10 carbon atoms, preferably C 1-8 Alkyl; more preferably C 1-6 Alkyl; more preferably C 1-3Alkyl; Non-limiting examples of alkyl groups 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-methylhexyl 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.

[0319] "Alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C). 2-10 "Alkenyl" refers to an alkenyl group having 2 to 10 carbon atoms, preferably C 2-8 Alkenyl, more preferably C 2-6 Alkenyl, more preferably C 2-4 Alkenyl is similarly defined; non-limiting examples of alkenyl include ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.

[0320] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-10 "Alkynyl" refers to an alkynyl group having 2 to 10 carbon atoms, preferably C 2-8 Alkynyl, more preferably C 2-6 Alkynyl, more preferably C 2-4 Alkynyl is similarly defined; non-limiting examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.

[0321] "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)-. In certain embodiments, C1-10 Alkylene, more preferably C 1-8 Alkylene, more preferably C 1-6 Alkylene, most preferably C 1-3 Alkylene. For example, C 1-3 Alkylene groups include -CH2-, -(CH2)2-, -CH(CH3)-, -(CH2)3-, -CH(CH2CH3)-, -CH2CH(CH3)-, and -C(CH3)2-. In certain embodiments, the alkylene group can 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, and the like. Without 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.

[0322] "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 a carbon atom can only be part of one C-C double bond. Formally, in the alkylene group defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valences are saturated to form a second bond, thereby forming the corresponding alkenylene group. In certain embodiments, preferably C 2-10 Alkenylene, more preferably C 2-8 Alkenylene, more preferably C 2-6 Alkenylene, most preferably C 2-4 Alkenylene. In certain embodiments, 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 general terms propenylene, butenylene, pentenylene, hexenylene, etc. 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 can optionally be present in cis or trans or E or Z form with respect to one or more double bonds.

[0323] "Alkyne" 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 valences are saturated to form two additional bonds to form the corresponding alkynyl group. In certain embodiments, preferably C 2-10 Alkynylidene, more preferably C 2-8 Alkyne group, more preferably C 2-6 Alkynylidene, most preferably C 2-4 Alkynylene. 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. In the absence of any further definition, the generic terms propynylene, butynylene, pentynylene, hexynylene, etc. are intended to refer to 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.

[0324] "Alkyleneoxy" refers to a divalent alkoxy group. In certain embodiments, C 1-10 Alkyleneoxy, more preferably C 1-8 Alkyleneoxy, more preferably C 1-6 Alkyleneoxy, most preferably C 1-3 Alkyleneoxy. In certain embodiments, the alkyleneoxy group can be -OCH2-, -OCH(CH3)CH2-, -OCH2CH2O-, -CH2CH2O-, etc. In the absence of any further definition, the general terms propyleneoxy, butyleneoxy, pentyleneoxy, hexyleneoxy, etc. are intended to refer to 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-.

[0325] "Cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to a monocyclic or polycyclic hydrocarbon group, which may be fused to an aryl or heteroaryl group. The cycloalkyl ring may be optionally substituted. In certain embodiments, the cycloalkyl ring is a spirocyclic 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 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. are preferred. 3-7 Cycloalkyl, such as cycloheptane, spiro[3.3]heptane, etc., more preferably C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. They may be saturated cycloalkyl groups such as cyclohexyl and cyclopropyl. They may also be partially unsaturated cycloalkyl groups such as cyclohexene and 1,2-diethylcyclopent-1-ene.

[0326] "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 no ring has a completely conjugated π electron system. Spirocycles are classified as bispirocycles or polyspirocycles based on the number of rings, preferably bispirocycles. More preferred are 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bispirocycles. For example:

[0327] Spiroheterocycle refers to a polycyclic hydrocarbon ring in which one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. These may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro heterocycles are classified as bispiro heterocycles or polyspiro heterocycles according to the number of rings, preferably bispiro heterocycles. More preferably, they are 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bispiro heterocycles. For example:

[0328] "Bridged ring" refers to a polycyclic group that shares two or more carbon atoms. The shared carbon atoms are called bridgehead carbons. The bridgehead carbons can be connected by 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:

[0329] "Bridged heterocycle" refers to a polycyclic group that shares two or more atoms, one or more of which are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2) with 1 heteroatom, and the remaining ring atoms are carbon. These may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, a bicyclic or tricyclic bridged heterocycle is used. For example:

[0330] "Heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which group may be fused to 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 spiroheterocycle 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 group, more preferably a 3 to 7 membered heterocycloalkyl group, further more preferably a 3 to 7 membered heterocycloalkyl group, further preferably a 3 to 6 membered heterocycloalkyl group. Non-limiting examples of heterocycloalkyl groups 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, pyrrolidin-2-one, pyrrolidin-2,5-dione, dihydrofuran-2,5-dione, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazin-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.

[0331] "Aryl" and "aromatic ring" are used interchangeably and refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 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 aromatic group having 6 to 14 ring carbon atoms. "C 6-10 "Aryl" refers to an aromatic group having 6 to 10 ring carbon atoms. Non-limiting examples include phenyl, naphthyl, anthracenyl.

[0332] "Heteroaryl" and "heteroaryl 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 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 to 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 group 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 group 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, isoquinolinyl, benzopyrrolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzimidazolyl, benzotriazolyl, benzotetrazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, pyridopyrrolyl, pyridofuranyl, pyridothiphenyl, pyridopyrazolyl, pyridoimidazolyl, pyridotriazolyl, pyridotetrazolyl, pyridooxazolyl, pyridisoxazolyl, pyridooxadiazolyl, pyridothiazolyl, pyridothiadiazolyl, pyrimidopyrrolyl, pyrimido furanyl, pyrimidothiphenyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidotriazolyl, pyrimidotetrazolyl, pyrimidooxazolyl, pyrimidoisoxazolyl, pyrimidooxadiazolyl, pyrimidothiazolyl, pyrimidothiadiazolyl, pyrimidothiazolyl, pyrimidothiadiazolyl, pyrimidothiadiazolyl, pyridazinopyrrolyl, pyridazinofuranyl, pyridazinothienyl, pyridazinopyrazolyl, pyridazinoimidazolyl, pyridazinotriazolyl, pyridazinotetrazolyl, pyridazinooxazolyl, pyridazinoisoxazolyl, pyridazinooxadiazolyl, pyridazinothiazolyl, pyridazinothiadiazolyl, pyrazinopyrrolyl, pyrazinofuranyl , pyrazinothiophenyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyrazinotriazolyl, pyrazinotetrazolyl, pyrazinooxazolyl, pyrazinoisoxazolyl, pyrazinooxadiazolyl, pyrazinothiazolyl, pyrazinothiadiazolyl, triazinopyrrolyl, triazinofuranyl, triazinothiophenyl, triazinopyrazolyl, triazinoimidazolyl, triazinotriazolyl, triazinotetrazolyl, triazinooxazolyl, triazinoisoxazolyl, triazinooxadiazolyl, triazinothiazolyl, triazinothiadiazolyl, benzoquinolinyl, benzoisoquinolinyl, carbazole. "Heteroatom" means nitrogen, oxygen or sulfur.In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits.Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0333] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0334] "Halo" refers to a group in which one or more (eg, 1, 2, 3, or all) hydrogen atoms are replaced by halogen.

[0335] "Haloalkyl" refers to an alkyl group substituted with one or more (such as 1, 2, 3 or all) halogens, wherein the definition of alkyl is as described above. 1-8 Alkyl, more preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 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.

[0336] "Alkoxy" refers to an -O-alkyl group, 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.

[0337] "Alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy groups are as defined above. 1-6 Alkoxy C 1-6 Alkyl, more preferably C 1-3 Alkoxy C 1-3 Alkyl. Non-limiting examples of alkoxyalkyl include -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, and the like.

[0338] "Cycloalkylalkyl" refers to an alkyl group substituted by one or more cycloalkyl groups, wherein the definitions of alkyl and cycloalkyl are as described above. 3-6 Cycloalkyl C 1-6 Alkyl, more preferably C 3-6 Cycloalkyl C 1-3 Alkyl. Non-limiting examples of cycloalkylalkyl include -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclobutyl, and the like.

[0339] "Alkenylalkyl" refers to an alkyl group substituted with one or more alkenyl groups, wherein the alkyl and alkenyl groups are as defined above.2-8 Alkenyl C 1-10 Alkyl, more preferably C 2-8 Alkenyl C 1-8 Alkyl, more preferably C 2-8 Alkenyl C 1-6 Alkyl, more preferably C 2-8 Alkenyl C 1-3 Non-limiting examples of cycloalkylalkyl groups include wait.

[0340] "Alkynylalkyl" refers to an alkyl group substituted with one or more alkynyl groups, wherein the alkyl and alkynyl groups are as defined above. 2-8 Alkynyl C 1-10 Alkyl, more preferably C 2-8 Alkynyl C 1-8 Alkyl, more preferably C 2-8 Alkynyl C 1-6 Alkyl, more preferably C 2-8 Alkynyl C 1-3 Non-limiting examples of cycloalkylalkyl groups include wait.

[0341] "Heterocycloalkylalkyl" refers to an alkyl group substituted by one or more heterocycloalkyl groups, wherein alkyl and heterocycloalkyl are as defined above. Preferably, the alkyl group is a 4- to 10-membered heterocycloalkyl group C 1-6 Alkyl, more preferably 4 to 8 membered heterocycloalkyl C 1-3 Alkyl, more preferably 3 to 6 membered heterocycloalkyl C 1-3 Alkyl, more preferably 4 to 6 membered heterocycloalkyl C 1-3 Non-limiting examples of heterocycloalkylalkyl include -CH2-tetrahydropyrrolyl, -CH2-azetidinyl, -CH2-piperidinyl, -CH2-piperazinyl, and the like.

[0342] "Hydroxy-substituted alkyl" means an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above. Preferably, the C 1-10 Alkyl, more preferably hydroxy substituted C 1-8 Alkyl, more preferably hydroxy-substituted C 1-6 Alkyl, more preferably hydroxy substituted C 1-3 Alkyl. Non-limiting examples of "hydroxy-substituted alkyl" include -CH2OH, -CH2CH2OH, -CH(OH)CH3, and the like.

[0343] "Cyano-substituted alkyl" means an alkyl group substituted with one or more cyano groups, wherein the alkyl group is as defined above. Preferably, the cyano-substituted C 1-10 Alkyl, more preferably cyano-substituted C 1-8Alkyl, more preferably cyano-substituted C 1-6 Alkyl, more preferably cyano-substituted C 1-3 Alkyl. Non-limiting examples of "cyano-substituted alkyl" include -CH2CN, -CH2CH2CN, -CH(CN)CH3, and the like.

[0344] "Carboxyl substituted alkyl" means an alkyl group substituted with one or more carboxyl groups, wherein the alkyl group is as defined above. 1-10 Alkyl, more preferably carboxyl substituted C 1-8 Alkyl, more preferably carboxyl substituted C 1-6 Alkyl, more preferably carboxyl substituted C 1-3 Alkyl. Non-limiting examples of "carboxy-substituted alkyl" include -CH2COOH, -CH2CH2COOH, -CH(COOH)CH3, and the like.

[0345] "Amino-substituted alkyl" means an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined above. Preferably, the amino-substituted C 1-10 Alkyl, more preferably amino substituted C 1-8 Alkyl, more preferably amino-substituted C 1-6 Alkyl, more preferably amino-substituted C 1-3 Alkyl. Non-limiting examples of "amino-substituted alkyl" include -CH2NH2, -CH2CH2NH2, -CH(NH2)CH3, and the like.

[0346] "Haloalkoxy" refers to an alkoxy group substituted by one or more (eg, 1, 2, 3, 4, or 5) halogen groups, wherein the definition of alkoxy is as described above. 1-10 Alkoxy, more preferably halogenated C 1-8 Alkoxy, more preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy. Haloalkoxy includes, but is not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0347] "Amino" refers to -NH2, "cyano" refers to -CN, "nitro" refers to -NO2, "benzyl" refers to -CH2-phenyl, "oxo" refers to =O, "carboxy" refers to -C(O)OH, "acetyl" refers to -C(O)CH3, "acetamido" refers to -C(O)NH2, "hydroxymethyl" refers to -CH2OH, "hydroxyethyl" refers to -CH2CH2OH or -CHOHCH3, "hydroxy" refers to -OH, "thiol" refers to -SH; "formyl" refers to -CHO; "sulfonate" refers to -SO3H.

[0348] The term "linking site" as used herein refers to the point at which one group is connected to another group via a covalent bond. For example, in the definition of "when R2 is X1, X1 is the linking site between POI and L or ULM" in this application, it means that POI is connected to L or ULM via a covalent bond, and X1 is the point of connection with L or ULM. This definition is similar to "structure is wherein X1 is the connection site between POI and L or ULM” has the same meaning.

[0349] 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 n0 is 0 or 1, the meaning is the same.

[0350] 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 n0 is 0 or 1, the meaning is the same.

[0351] For example, for the compound of formula (I), the connecting chain structure X 10 When indicating a connection point with a POI, X 20 Indicates the connection point with ULM, its meaning and structure The meaning is the same.

[0352] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5 hydrogen atoms, and more preferably 1 to 3 hydrogen atoms, in a group 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) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0353] 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.

[0354] Unless otherwise defined, the "substituents independently selected from..." described 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.

[0355] 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 independently selected from deuterium, halogen (preferably fluorine, chlorine), cyano, hydroxyl, carboxyl, C 1-8Alkyl (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, halo 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 、-SO2C 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 substituted 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, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, NR A0 R B0 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR A10 RB10 、-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;

[0356] R A10 、R B10 are each independently hydrogen or C 1-3 Alkyl; or R A10 、R B10 Together with the nitrogen atom to which it is connected, it forms a 4- to 6-membered saturated monocyclic heterocycle; the 4- to 6-membered saturated monocyclic heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents 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, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -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 Cycloalkyloxy, 3- to 6-membered heterocycloalkyl;

[0357] R A0 、R B0 are independently hydrogen, C 1-3 Alkyl or acetyl; or R A0 、R B0 Together with the nitrogen atom to which it is connected, it forms a 4- to 6-membered saturated monocyclic heterocycle; the 4- to 6-membered saturated monocyclic heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents 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, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C1-3 Alkyl)2, -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.

[0358] In the present invention, when two or more “preferably” appear in one embodiment, any two “preferably” may be independent of each other.

[0359] In the present invention, when the number of substituents is greater than 1, any two substituents may be the same or different. For example, the substituents may be two halogens that are the same or different, or one halogen and one hydroxyl group.

[0360] Each type of substituent group described herein above can itself be substituted with the groups described herein.

[0361] Pharmaceutical composition

[0362] Typically, the compounds of the present invention or their pharmaceutically acceptable salts, or their stereoisomers can be administered in a suitable dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral administration, rectal administration, topical administration, oral administration, and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.

[0363] "Pharmaceutically acceptable carrier" means 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.

[0364] The compositions of the present invention are formulated, dosed and administered in a manner consistent with standard 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.

[0365] "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.

[0366] "Patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0367] "Treatment" refers to alleviating, slowing the progression of, attenuating, preventing, or maintaining 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.

[0368] The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0369] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other adverse effects.

[0370] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases and salts with organic bases.

[0371] 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 compound is represented by a wedge-shaped bond. " represents the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are encompassed within the scope of this application.

[0372] The enantiomers, diastereomers and mixtures of these isomers of the compounds of the present invention are all within the scope of protection of the present invention. Enantiomers and diastereomers can be separated by methods known in the art, such as crystallization and chiral chromatography.

[0373] Preparation method

[0374] The present invention provides methods for preparing compounds of formula (I), which can be synthesized using standard synthetic 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 skill in the art. The reactions can be used sequentially to provide compounds of the present invention, or they can be used to synthesize fragments that are subsequently added by the methods described herein and / or methods known in the art.

[0375] 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 based on the properties of the compounds involved in the reactions without causing any difficulties to those skilled in the art.

[0376] The compounds described in the present invention can be synthesized using appropriate optional starting materials using methods similar to those described below or the exemplary methods described in the examples, or relevant 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 described in the present invention can be used to prepare them. Compounds 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.

[0377] 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 and tumor cell proliferation inhibition effects, 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).

[0378] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or 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 may be applied to the present invention.

[0379] Reagents and instruments

[0380] 1 H NMR: Bruker AVANCE-400 nuclear magnetic spectrometer, internal standard is tetramethylsilane (TMS).

[0381] 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.

[0382] Preparative high performance liquid chromatography (pre-HPLC): GX-281 (manufacturer: Gilson).

[0383] An ISCO Combiflash-Rf75 or Rf200 automatic column analyzer and Agela 4g, 12g, 20g, 40g, 80g, or 120g disposable silica gel columns were used.

[0384] Known starting materials can be synthesized by 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.

[0385] In the embodiments, reaction progress can be monitored by thin layer chromatography (TLC), and compound purification can be performed by column chromatography. The developing solvent system used in column chromatography or TLC can be selected from: a dichloromethane and methanol system, a n-hexane and ethyl acetate system, a petroleum ether and ethyl acetate system, and an acetone system, etc. The volume ratio of the solvent is adjusted according to the polarity of the compound.

[0386] As used herein, PE: petroleum ether, EA: ethyl acetate, THF: tetrahydrofuran, H2O: water, DMF: N,N-dimethylformamide, DME: dimethyl ether, DCM: dichloromethane, MeOH: methanol, EtOH: ethanol, DMSO: dimethyl sulfoxide, ACN: acetonitrile, DIPEA: N,N-diisopropylethylamine, TEA / Et3N: triethylamine, TFA: trifluoroacetic acid, FA: formic acid, SOCl2: thionyl chloride, CCl4: carbon tetrachloride, AcOH / CH3COOH: 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)BH3 or NaBH3CN: sodium cyanoborohydride, NaBH(OAc)3: sodium triacetoxyborohydride, NaBH: sodium borohydride, (Boc)2O: di-tert-butyl dicarbonate, PdOH / C: palladium hydroxide / carbon, Pd / C: palladium on carbon, Pd(dppf)Cl2: 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride; Pd(OAc)2: palladium acetate, Ruphos-Pd-G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, Pd2(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'-diisopropoxy-1,1'-biphenyl, K2CO3: potassium carbonate, Cs2CO3: cesium carbonate, NaHCO3: sodium bicarbonate, t-BuOK: potassium tert-butoxide, t-BuONa: sodium tert-butoxide, (Pin)2B2: bis(pinacol)diboron, NBS: N-bromosuccinimide, AIBN: azobisisobutyronitrile, LiHMDS: lithium bis(trimethylsilyl)amide, NH4HCO3: ammonium bicarbonate, NH4Cl: ammonium chloride, NaH: sodium hydride, NaOH: sodium hydroxide, KOAc: potassium acetate, CuBr: cuprous bromide, BnBr: benzyl bromide, PTSA: p-toluenesulfonamide.

[0387] Unless otherwise specified, percentages used herein refer to mass percentages for solid-liquid mixtures and solid-solid mixtures, and volume percentages for liquid-liquid mixtures. Unless otherwise specified, the solvent used is water.

[0388] As used herein, room temperature refers to about 20-30°C.

[0389] As used herein, "overnight" means about 10 to 16 hours.

[0390] Preparation of intermediate Z1

[0391] Step 1: Methyl 4-bromo-3-formylbenzoate (5 g, 20.57 mmol) and propan-2-amine (2.43 g, 41.14 mmol) were dissolved in ethanol (60 mL), followed by the addition of 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)BH3 (2.59 g, 41.14 mmol) was added, and the mixture was stirred at 0°C for 3 h. After completion, the reaction was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a CombiFlash (80 g, 0-100% EA / PE) to afford product Z1-a (5.4 g, pale yellow solid) in a 91.73% yield. MS m / z (ESI): 286.1 [M+H] + .

[0392] Step 2: Z1-a (5.4 g, 18.87 mmol) was dissolved in DCM (60 mL), and Et3N (7.64 g, 75.48 mmol) was added. The temperature was lowered to 0°C, and (Boc)2O (6.18 g, 28.31 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. After completion of the reaction, the reaction mixture was concentrated and purified using CombiFlash (40 g, 0-35% EA / PE) to afford Z1-b (4.7 g, colorless oil) in a yield of 64.48%. MS m / z (ESI): 286.1 [M-100+H]. + .

[0393] 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), followed by the addition of Pd(OAc)2 (51.58 mg, 229.75 μmol), CataCXium A (164.75 mg, 459.51 μmol), K2CO3 (1.27 g, 9.19 mmol) and (Pin)2B2 (1.17 g, 4.60 mmol). The reaction was stirred at 70°C for 18 h. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and then purified using 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] + .

[0394] Step 4: Dissolve Z1-c (950 mg, 1.44 mmol) in DCM (15 mL), then add TFA (163.70 mg, 1.44 mmol, 2.5 mL). Stir the reaction at 20°C for 3 h. After completion, concentrate the reaction mixture to afford Z1-d (806 mg, crude oil) in a 99.97% yield. MS m / z (ESI): 562.2 [M+H] + .

[0395] 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 completion of the reaction, cool to room temperature, filter, and adjust the pH of the filtrate to 2-3 with dilute hydrochloric acid (3 mol / L). Concentrate to afford intermediate Z1 (2.1 g, brown solid, crude product). MS m / z (ESI): 520.2 [M+H] + .

[0396] Preparation of intermediate Z2

[0397] Step 1: Dissolve 5-bromo-4-methylpicolinic acid (12.5 g, 57.86 mmol) in MeOH (250 mL), then add SOCl2 (17.15 g, 144.14 mmol, 10.47 mL) and stir at 84°C for 2 h. After completion, cool to room temperature, quench with saturated aqueous sodium bicarbonate, and extract with ethyl acetate (3 x 500 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford Z2-a (13 g, white solid, crude product) in a 97.66% yield. MS m / z (ESI): 230.0 [M+H] + .

[0398] Step 2: Dissolve Z2-a (5 g, 21.73 mmol) in CCl4 (70 mL), then add NBS (11.60 g, 65.20 mmol) and AIBN (356.88 mg, 2.17 mmol), and stir at 80°C for 18 h. After completion of the reaction, cool to room temperature, filter, and concentrate the filtrate to obtain Z2-b (8.43 g, pale yellow oil, crude product) in a yield of 100.00%. MS m / z (ESI): 385.8 [M+H] + .

[0399] Step 3: Dissolve Z2-b (8 g, 20.63 mmol) in THF (100 mL), cool to 0-5°C, and add diethyl phosphite (3.11 g, 22.69 mmol) and DIPEA (4 g, 30.94 mmol, 5.39 mL) dropwise. The mixture is then reacted at 25°C for 1 h. After completion of the reaction, the reaction solution is concentrated and purified via CombiFlash (120 g, 0-50% PE / EA) to afford Z2-c (4.2 g, white solid) in a yield of 65.91%. MS m / z (ESI): 307.9 [M+H] + .

[0400] 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), and allow to warm to room temperature. Stir 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]. + .

[0401] Step 5: Dissolve Z2-d (1.86 g, 6.48 mmol) in DCM (20 mL). Add Et3N (3.28 g, 32.39 mmol) under ice-cold water, followed by (Boc)2O (3.53 g, 9.72 mmol, 60% purity). Warm to room temperature and continue stirring for 18 h. After completion of the reaction, concentrate the reaction solution and purify it via CombiFlash (24 g, 0-50% EA / PE) to obtain Z2-e (2.4 g, colorless oil) in a yield of 95.68%. MS m / z (ESI): 387.1 [M+H]. + .

[0402] Step 6: Z2-e (500 mg, 1.15 mmol) and 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (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), K2CO3 (793.86 mg, 5.74 mmol) and (Pin)2B2 (875.15 mg, 3.45 mmol) were added and stirred at 70 °C for 18 h. After the reaction, the reaction mixture was filtered, the filtrate was concentrated, and then 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] + .

[0403] Step 7: Z2-f (300 mg, 452.69 μmol) was dissolved in DCM (15 mL), followed by the addition of TFA (4 mL) and stirring at room temperature for 18 h. After completion of the reaction, the mixture was neutralized with aqueous sodium bicarbonate and extracted with a mixture of dichloromethane and methanol (10:1; 3 × 70 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford Z2-g (248 mg, pale yellow solid, crude product) in a yield of 99.87%. MS m / z (ESI): 563.3 [M+H] + .

[0404] Step 8: Dissolve Z2-g (248.44 mg, 441.59 μmol) in THF (20 mL) and water (5 mL), then add LiOH (317.26 mg, 13.25 mmol) and stir at 75°C for 18 h. After completion of the reaction, cool to room temperature, filter, and adjust the pH of the filtrate to 2-3 with dilute hydrochloric acid (3 mol / L). Concentrate and lyophilize to obtain intermediate Z2 (763 mg, khaki solid, 30% content), yield: 99.63%. MS m / z (ESI): 521.2 [M+H] + .

[0405] Preparation of intermediate Z3

[0406] Step 1: Dissolve 2-bromo-5-nitrobenzaldehyde (5.0 g, 21.74 mmol) and propan-2-amine (1.67 g, 28.26 mmol) in DCM (40 mL) and methanol (4 mL) at room temperature. Then, add acetic acid (1.69 g, 28.69 mmol) and stir at 25°C for 16 hours. Then, add NaBH4 (1.64 g, 43.47 mmol) and continue stirring at 25°C for 2 hours. After the reaction is complete, pour the reaction solution into saturated aqueous sodium bicarbonate (50 mL). The aqueous phase is extracted with dichloromethane (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 50-60%) to afford Z3-a (3.70 g, yellow oil). Yield: 62.32%. MS m / z (ESI): 273.0 [M+H]. + .

[0407] 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)2O (4.63 g, 21.24 mmol), and heat to 40°C with stirring for 4 hours. After the reaction is complete, the reaction solution is concentrated and purified by silica gel column chromatography (EA / PE = 10-20%) to obtain Z3-b (3.60 g, white solid) in a yield of 90.84%. MS m / z (ESI): 373.2 [M+H] + .

[0408] Step 3: 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (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)2B2 (613 mg, 2.41 mmol) were added. The mixture was stirred at 70 ° C under nitrogen atmosphere for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography (MeOH / DCM = 3-5%) to give Z3-c (200 mg, yellow solid). Yield: 38.34%. MS m / z(ESI):649.3[M+H] + .

[0409] 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 completion of the reaction, the reaction solution was concentrated to afford Z3-d (165 mg, yellow oil) in a yield of 97.56%. MS m / z (ESI): 549.4 [M+H] + .

[0410] Step 5: Z3-d (165 mg, 0.30 mmol) was dissolved in THF (6 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide monohydrate (126 mg, 3.01 mmol) was added and stirred at 70°C for 12 hours. After completion of the reaction, the reaction solution was concentrated and purified using a reverse phase column chromatography (C18, MeCN / 0.1% FA in H2O = 40% to 60%) to obtain Z3-e (60 mg, yellow solid) in a yield of 38.32%. MS m / z (ESI): 521.2 [M+H] + .

[0411] Step 6: Z3-e (60 mg, 0.12 mmol) was dissolved in DMF (3 mL), and HATU (88 mg, 0.23 mmol) and DIPEA (74 mg, 0.58 mmol) were added sequentially. The mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give Z3-f (50 mg, yellow solid, crude product) in a yield of 86.33%. MS m / z (ESI): 503.2 [M+H] + .

[0412] 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 completion of the reaction, filter the reaction mixture through celite, wash the filter cake with methanol (6 mL x 2), dilute the filtrate with water (20 mL), extract with ethyl acetate (20 mL x 2), and combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain intermediate Z3 (40 mg, yellow solid, crude product) in a yield of 85.08%. MS m / z (ESI): 473.0 [M+H] + .

[0413] Example 1 Preparation of Compound H1

[0414] 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)butanoic 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, followed by the addition of TCHF (781.99 mg, 2.79 mmol) and stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated and purified using CombiFlash (24 g, 0-10%, MeOH / DCM) to afford product H1-a (1.3 g, white solid) in a yield of 90.90%. MS m / z(ESI):616.4[M+H] + .

[0415] Step 2: H1-a (1.3 g, 2.11 mmol) was dissolved in DCM (12 mL), followed by the addition of TFA (2.41 g, 21.11 mmol). The reaction was stirred at 20°C for 18 h. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane and methanol (10:1; 3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford H1-b (1 g, viscous light yellow, crude product) in a 91.86% yield. MS m / z (ESI): 516.3 [M+H] + .

[0416] Step 3: Intermediate Z1 (300 mg) was dissolved in THF (20 mL), followed by the addition of 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, followed by the addition of H1-b (387.11 mg, 750.70 μmol) and continued stirring for 3 h. Upon completion, the reaction solution was concentrated and purified via CombiFlash (12 g, 0-15% MeOH / DCM). The product was then purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 35% to 68% acetonitrile) to afford H1 (123.78 mg) in a yield of 21.45%. MS m / z(ESI):500.3[M / 2+H] + . 1 H 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).

[0417] Example 2 Preparation of Compound H2

[0418] 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) and stir at room temperature for 18 h. Then cool to -10°C and add Na(CN)BH3 (2.72 g, 43.31 mmol). Stir at 0°C for 2 h. After completion of the reaction, neutralize the mixture with saturated aqueous sodium bicarbonate. 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]. + .

[0419] Step 2: Dissolve H2-a (6.6 g, 15.06 mmol) and (Boc)2O (4.93 g, 22.59 mmol) in DCM (100 mL). Add Et3N (6.10 g, 60.24 mmol) and stir at room temperature for 1 h. After completion of the reaction, concentrate the reaction solution and purify it via CombiFlash (80 g, 0-70% EA / PE) to afford H2-b (4.7 g, colorless solid) in a 57.97% yield. MS m / z (ESI): 560.2 [M+Na] + .

[0420] 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), K2CO3 (2.54 g, 18.38 mmol) and (Pin)2B2 (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, concentrated, and purified using CombiFlash (80 g, 0-100% EA / PE) to obtain H2-c (2 g, pale yellow solid). The yield was 53.48%. MS m / z (ESI): 814.4 [M+H] + .

[0421] Step 4: Dissolve H2-c (2 g, 2.46 mmol) in DCM (25 mL), add TFA (2.80 g, 24.57 mmol), and stir at room temperature for 36 h. After completion, neutralize with aqueous sodium bicarbonate solution and extract with a mixed solvent of dichloromethane and methanol (10:1). The organic phase is dried over anhydrous sodium sulfate and concentrated to afford H2-d (1.2 g, pale yellow solid, crude product) in a yield of 79.58%. MS m / z (ESI): 614.3 [M+H] + .

[0422] Step 5: Dissolve H2-d (1.2 g, 1.96 mmol) in THF (20 mL) and water (5 mL), add LiOH (1.41 g, 58.67 mmol), and stir at 75°C for 18 h. After the reaction is complete, cool the reaction solution to room temperature, filter, and adjust the pH of the filtrate to 2-3 with dilute hydrochloric acid (3 mol / L) and concentrate to obtain H2-e (3.3 g). MS m / z (ESI): 586.2 [M+H] + .

[0423] 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. The mixture was stirred at room temperature for 3 h. After completion, the reaction was quenched with aqueous solution and extracted three times with dichloromethane and methanol (10:1). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified using CombiFlash (24 g, 0-23%, MeOH / DCM + 1% Et3N) to afford H2-f (270 mg, pale yellow solid) in a yield of 29.95%. MS m / z (ESI): 568.2 [M+H]. + .

[0424] Step 7: H2-f (70 mg, 123.34 μmol) and 1-(2-(2,6-dioxapiperidin-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 NaBH3CN (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 completion of the reaction, the mixture was cooled to room temperature, concentrated, and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 56%-86% acetonitrile) to obtain H2 (54.01 mg) in a yield of 45.26%. MS m / z (ESI): 921.3 [M+H] + . 1 H 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).

[0425] Example 3 Preparation of Compound H3

[0426] 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-butoxycarbonylamino)cyclobutanecarboxylic acid (522.88 mg, 2.43 mmol) were dissolved in DMF (7 mL). DIPEA (313.96 mg, 2.43 mmol, 423.12 μL) and HATU (641.53 mg, 1.70 mmol) were then added. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated and purified on a CombiFlash (24 g, 0-10% MeOH / DCM) to afford H3-a (430 mg, white solid) in a 55.16% yield. MS m / z(ESI):542.3[M-100+H] + .

[0427] Step 2: Dissolve H3-a (430 mg, 669.97 μmol) in EtOH (5 mL), then add dilute hydrochloric acid (4 mol / L, 2 mL). Stir the reaction at room temperature for 18 h. After completion, the reaction solution was concentrated to afford H3-b (320 mg, yellow solid, crude product) in an 88.17% yield. MS m / z (ESI): 542.3 [M+H] + .

[0428] Step 3: Intermediate Z1 (100 mg, 192.48 μmol) was dissolved in DMF (5 mL), and DIPEA (348.28 mg, 2.69 mmol, 469.38 μL) and HATU (326.78 mg, 866.18 μmol) were added. 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 another 2 h. After completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (12 g, 0-15% MeOH / DCM). The product was then purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 35%-68% acetonitrile) to afford H3 (14.19 mg, purity: 100%) in a yield of 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,1 H),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=8.6,3.9H z,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).

[0429] Example 4 Preparation of Compound H4

[0430] 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), followed by the addition of DIPEA (784.90 mg, 6.07 mmol, 1.06 mL) and HATU (1.15 g, 3.04 mmol). The reaction was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and purified on a CombiFlash (24 g, 0-10% MeOH / DCM) to afford H4-a (0.89 g, pale yellow solid) in a yield of 66.83%. MS m / z(ESI):558.3[M-100+H] + .

[0431] Step 2: Dissolve H4-a (0.89 g, 1.35 mmol) in DCM (10 mL), then add dilute hydrochloric acid (4 mol / L, 3 mL). Stir the reaction at room temperature for 30 minutes. After completion, concentrate the reaction solution to obtain H4-b (800 mg, light yellow solid, hydrochloride salt) in a yield of 99.52%. MS m / z (ESI): 558.3 ​​[M+H] + .

[0432] 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 stirring continued for 1 h. After completion of the reaction, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-13% MeOH / DCM), followed by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 40%-48% acetonitrile) to obtain H4 (7.9 mg, 100% purity) in a yield of 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),7.5 7(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).

[0433] Example 5 Preparation of Compound H5

[0434] Step 1: 4-((tert-Butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.35 g, 5.57 mmol) and (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), followed by the addition of HATU (2.12 g, 5.57 mmol) and DIPEA (2 mL). The mixture was stirred at room temperature for 10 minutes and purified by silica gel column chromatography (DCM / MeOH 0-10%) to afford H5-a (2.27 g, yield: 75.4%). MS m / z (ESI): 670 [M+H]. + .

[0435] 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. The mixture was stirred at room temperature for 1 h and concentrated to afford H5-b (1.76 g). Yield: 95.6%. MS m / z (ESI): 570 [M+H] + .

[0436] Step 3: Z1 (100 mg, 0.192 mmol) was dissolved in DMF (3 mL), followed by the addition of DIPEA (2 mL) and HATU (218 mg, 0.576 mmol). The mixture was stirred at room temperature for 10 minutes, and then H5-b (109 mg, 0.192 mmol) was added and stirred for 20 minutes. The mixture was concentrated and purified by high-pressure liquid chromatography (HPLC) (waters-sunfire-10 μm-19*150 mm column (mobile phase: 28%-38% (v / v) acetonitrile and formic acid in water) to give H5 (3.76 mg) in a yield of 2.9%. MS m / z (ESI): 527.3 [M / 2+H]. + . 1 H 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),4.9 5-4.84(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).

[0437] Example 6 Preparation of Compound H6

[0438] 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), and 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 stirred at room temperature for 5 h. After the reaction, the reaction mixture was poured into water and extracted with dichloromethane (30 mL x 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 H6-a (510 mg, yellow solid) in a yield of 75.36%. MS m / z (ESI): 602 [M+H] + .

[0439] Step 2: Dissolve H6-a (600 mg, 997.08 μmol) in DCM (10 mL). Add dilute hydrochloric acid (4 mol / L, 5 mL) with stirring at room temperature and stir for 2 h. After the reaction, concentrate the reaction solution to obtain H6-b (500.18 mg, yellow solid). Yield: 100.00%. MS m / z (ESI): 502 [M+H] + .

[0440] Step 3: H10-a (100 mg, 192.48 μmol) was dissolved in DMF (5 mL), and 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. The mixture was stirred at room temperature overnight. H6-b (193.12 mg, 384.97 μmol) was added and stirred at room temperature for 5 hours. After the reaction, the reaction mixture was poured into water and extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, then purified by silica gel column chromatography (MeOH:DCM = 0-10%). The product was then purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-70% acetonitrile) to obtain H6 (9.86 mg, purity: 98.32%) in a yield of 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).

[0441] Example 7 Preparation of Compound H7

[0442] Step 1: Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 9.99 mmol) and azetidin-3-ol (1.46 g, 13.33 mmol, HCl) in DMF (10 mL). Add KCO (4.14 g, 29.98 mmol) and stir at 80°C for 18 h. After completion of the reaction, filter, concentrate the filtrate, and purify it on a CombiFlash (40 g, 0-10% DCM / ACN) to afford H7-a (1.1 g, a yellow viscous substance) in a yield of 33.43%. MS m / z (ESI): 330.1 [M+H]. + .

[0443] Step 2: Dissolve H7-a (0.9 g, 2.73 mmol) in DCM (30 mL) and add Dess-Martin periodinane (2.32 g, 5.47 mmol). Stir at room temperature for 4 h. After completion of the reaction, filter, concentrate the filtrate, and purify it on a CombiFlash (20 g, 0-10% DCM / THF) to afford H7-b (250 mg, yellow solid) in a yield of 27.95%. MS m / z (ESI): 328.0 [M+H] + .

[0444] 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 stirred for 1 hour. Na(CN)BH3 (58.46 mg, 930.34 μmol) was then added and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 0.04% FA H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 35%-68% acetonitrile) to obtain H7 (47.40 mg) in a yield of 44.96%. MS m / z (ESI): 879.3 [M+H] + . 1 H 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),2.97-2.7 8(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).

[0445] Example 8 Preparation of Compound H8

[0446] Step 1: Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 9.99 mmol) and azetidin-3-ylmethanol (2.47 g, 19.98 mmol, hydrochloride) in DMF (10 mL). Add KCO (5.52 g, 39.97 mmol) and stir at 70°C for 18 h. After completion of the reaction, filter, concentrate the filtrate, and purify it via CombiFlash (40 g, 0-50% DCM / ACN) to afford H8-a (230 mg, yellow solid) in a 6.70% yield. MS m / z (ESI): 344.1 [M+H]. + .

[0447] Step 2: H8-a (0.23 g, 669.90 μmol) was dissolved in DCM (30 mL) and Dess-Martin periodinane (852.40 mg, 2.01 mmol) was added. The mixture was stirred at room temperature for 18 h, filtered, and the filtrate was concentrated and purified using a CombiFlash (12 g, 0-10% MeOH / DCM) to afford H8-b (130 mg, yellow solid) in a yield of 56.86%. MS m / z (ESI): 342.1 [M+H] + .

[0448] 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 stirred for 1 hour. Na(CN)BH3 (57.58 mg, 916.24 μmol) was then added and stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 0.04% FA H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 26%-56% acetonitrile) to obtain H8 (48.90 mg) in a yield of 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),2.4 0-2.11(m,2H),2.05-1.93(m,1H),1.68(s,1H),1.02(d,J=11.6Hz,1H).

[0449] Example 9 Preparation of Compound H9

[0450] 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)butanoic acid (251.42 mg, 1.24 mmol) were dissolved in DMF (5 mL). 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 completion of the reaction, the reaction solution was concentrated and purified on CombiFlash (24 g, 0-10% MeOH / DCM) to afford H9-a (430 mg, light yellow solid) in a yield of 60.71%. MS m / z(ESI):530.3[M-100+H] + .

[0451] Step 2: Dissolve H9-a (430 mg, 682.75 μmol) in DCM (10 mL), then add dilute hydrochloric acid (4 mol / L, 3 mL) and stir at room temperature for 30 minutes. After the reaction, concentrate the reaction solution to obtain H9-b (386 mg, yellow solid, hydrochloride salt) in a yield of 99.86%. MS m / z (ESI): 530.3 [M+H] + .

[0452] Step 3: Intermediate Z2 (210 mg, 30% content, 134.48 μmol) was dissolved in DMF (5 mL), and DIPEA (1.48 g, 11.48 mmol, 2 mL) and (202.95 mg, 537.93 mmol) were added. The mixture was stirred at room temperature for 0.5 h, followed by the addition of H9-b (110 mg, 194.29 μmol, hydrochloride salt) and continued stirring at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH / DCM) and then by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mm NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 46% to 57% acetonitrile) to obtain H9 (4.26 mg) in a yield of 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=7.0 Hz,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=14.3,7.0 Hz,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,2 H),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).

[0453] Example 10 Preparation of Compound H10

[0454] Step 1: Dissolve 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 completion of the reaction, pour the reaction solution into water and extract with ethyl acetate (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH:DCM = 0-30%) to obtain H10-a (154 mg, yellow solid) in a yield of 53.18%. MS m / z (ESI): 502.2 [M+H] + .

[0455] Step 2: Dissolve H10-a (570 mg, 1.14 mmol) and 1-methylimidazole (280 mg, 3.41 mmol) in acetonitrile (10 mL). Add TCFH (383 mg, 1.36 mmol). Stir for 10 minutes, then add methyl 4-aminobenzoate (344 mg, 2.27 mmol). Continue stirring at room temperature for 20 hours. After completion of the reaction, pour the reaction solution into water and extract with ethyl acetate (30 mL x 2). The combined organic phases are 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) in a yield of 20.79%. MS m / z (ESI): 635.3 [M+H]. + .

[0456] Step 3: Dissolve H10-b (120 mg, 0.19 mmol) in MeOH (15 mL) and water (3 mL), add LiOH (80 mg, 1.89 mmol), and stir at room temperature overnight. After the reaction, concentrate the reaction solution and adjust the pH to 5 with dilute hydrochloric acid (1 mol / L). Extract with dichloromethane (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford H10-c (25 mg) in a yield of 21.30%. Use directly in the next reaction. MS m / z (ESI): 621.2 [M+H] + .

[0457] Step 4: H10-c (23 mg, 0.037 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-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 completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-60% acetonitrile) to obtain H10 (4.95 mg) in a yield of 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=8.8H z,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).

[0458] Example 11 Preparation of Compound H11

[0459] Step 1: Dissolve intermediate Z1 (100 mg, 192.48 μmol) in DMF (5 mL). Add DIPEA (1.48 g, 11.48 mmol, 2 mL) until completely dissolved, then add HATU (217.86 mg, 577.45 μmol). Stir at room temperature for half an hour until the starting material reacts completely. Then, add tert-butyl 4-aminopiperidine-1-carboxylate (192.75 mg, 962.42 μmol) and allow to react for an additional hour at room temperature. The reaction solution is concentrated and purified via CombiFlash (12 g, 0-10% MeOH / DCM) to afford H11-a (100 mg, pale yellow solid) in a yield of 75.98%. MS m / z (ESI): 683.8 [M+H]. + .

[0460] Step 2: H11-a (100 mg, 146.25 μmol) was dissolved in DCM (5 mL), and TFA (146.25 μmol, 0.8 mL) was added. The mixture was stirred at room temperature for 18 h. After completion of the reaction, the mixture was neutralized with saturated NaHCO₃ and extracted with a mixed solvent of dichloromethane and methanol (10:1; 3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford H11-b (85 mg, pale yellow oil, crude product) in a yield of 99.58%. MS m / z (ESI): 584.3 [M+H] + .

[0461] 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). The mixture was stirred in a microwave oven at 80°C for 30 minutes. After cooling to room temperature, NaBH3CN (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: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 38%-40% acetonitrile) to obtain H11 (4.83 mg, purity 99.04%) in a yield of 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=1 4.9Hz,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),1.9 3(dd,J=46.0,41.0Hz,4H), 1.27(d,J=6.7Hz,4H), 1.13(d,J=6.8Hz,3H).

[0462] Example 12 Preparation of Compound H12

[0463] Step 1: Intermediate Z1 (100 mg, 192.48 μmol) was dissolved in DMF (5 mL). DIPEA (1.48 g, 11.48 mmol, 2 mL) was added and allowed to dissolve completely. HATU (217.86 mg, 577.45 μmol) was then added and stirred at room temperature for 0.5 h. After the reaction was complete, tert-butyl piperazine-1-carboxylate (107.55 mg, 577.45 μmol) was added and the reaction continued at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and purified using a CombiFlash (12 g, 0-10% MeOH / DCM) to afford H12-a (70 mg, pale yellow solid) in a yield of 54.30%. MS m / z (ESI): 670.3 [M+H]. + .

[0464] 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 completion of the reaction, the reaction solution was concentrated, neutralized with sodium bicarbonate, and extracted with a mixed solvent of dichloromethane and methanol (10:1; 3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford H12-b (57 mg, pale yellow oil, crude product) in a yield of 95.74%. MS m / z (ESI): 570.2 [M+H] + .

[0465] 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). The mixture was stirred in a microwave oven at 80°C for 30 minutes. After cooling to room temperature, NaBH3CN (60 mg, 954.78 μmol) was added and stirred at room temperature for 0.5 hour. After the reaction was complete, the reaction solution was purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 40%-48% acetonitrile) to obtain H12 (14.06 mg) in a yield of 15.06%. MS m / z (ESI): 895.3 [M+H] + . 1 H 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).

[0466] Example 13 Preparation of Compound H13

[0467] Procedure: H11-b (50 mg, 85.67 μmol) and 1-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-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 completion of the reaction, the reaction solution was purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 0.04% FA H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 38%-48% acetonitrile) to obtain H13 (2.43 mg, purity: 94.41%) in a yield of 2.90%. MS m / z (ESI): 923.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.74(s,1H),8.58(s,1H),8.32(d,J=7.3 Hz,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),4.0 0-3.87(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).

[0468] Example 14 Preparation of Compound H14

[0469] 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 5-(tert-butoxycarbonylamino)pentanoic acid (175.93 mg, 809.74 μmol) were dissolved in DMF (5 mL). HATU (381.86 mg, 1.01 mmol) and DIPEA (436.05 mg, 3.37 mmol, 587.67 μL) were added sequentially with stirring at room temperature. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0-10%) to obtain H14-a (380 mg, yellow solid) in a yield of 87.47%.

[0470] MS m / z(ESI):644[M+H] + .

[0471] Step 2: Dissolve H14-a (350 mg, 543.62 μmol) in DCM (5 mL) and add dilute hydrochloric acid (4 mol / L, 3 mL) with stirring at room temperature. Stir at room temperature for 2 h. After the reaction, concentrate the reaction solution to obtain H14-b (295.58 mg, yellow solid) in a yield of 100.00%. MS m / z (ESI): 544 [M+H] + .

[0472] Step 3: 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. The mixture was stirred at room temperature for 2 hours, followed by the addition of H14-b (209.31 mg, 384.97 μmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0-10%). The product was then purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-75% acetonitrile) to obtain H14 (2.1 mg, purity: 97.26%), yield: 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(d d,J=8.7,3.8Hz,1H),5.21-4.07(m,14H),3.58(s,2H),2.47-0.80(m,33H).

[0473] Example 15 Preparation of Compound H15

[0474] Procedure: H12-b (68 mg, 119.38 μmol) and 1-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-5-yl)azetidine-3-carboxylic acid (63.98 mg, 179.06 μmol) were dissolved in DMF (5 mL). 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 completion of the reaction, the reaction solution was concentrated and purified using CombiFlash (12 g, 0-10% MeOH / DCM) to afford H15 (13.57 mg) in a yield of 12.46%. MS m / z (ESI): 909.3 [M+H] + . 1 H 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),3.5 6(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).

[0475] Example 16 Preparation of Compound H16

[0476] 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-butoxycarbonylpiperidine-4-carboxylic acid (515.70 mg, 2.25 mmol) were dissolved in DMF (10 mL). 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 completion of the reaction, the reaction solution was concentrated and purified on CombiFlash (24 g, 0-10% MeOH / DCM) to afford H16-a (354 mg) in a yield of 47.99%. MS m / z(ESI):556.3[M-100+H] + .

[0477] Step 2: Dissolve H16-a (354 mg, 539.76 μmol) in DCM (10 mL), add dilute hydrochloric acid (4 mol / L, 2 mL), and stir at 20°C for 1 h. After completion of the reaction, concentrate the reaction solution to obtain H16-b (299.96 mg, yellow solid) in a yield of 100.00%. MS m / z (ESI): 556.3 [M+H] + .

[0478] Step 3: Intermediate Z1 (100 mg, 192.48 μmol) and DIPEA (1.48 g, 11.48 mmol, 2 mL) were dissolved in DMF (5 mL). HATU (254.16 mg, 673.69 μmol) was added and stirred at room temperature for 0.5 h. H16-b (213.94 mg, 384.97 μmol) was then added and stirred at room temperature for another 0.5 h. After completion of the reaction, the reaction solution was concentrated and purified using a CombiFlash (12 g, 0-10% MeOH / DCM) to afford H16 (18.29 mg) in a 9.14% yield. 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,1 H),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).

[0479] Example 17 Preparation of Compound H17

[0480] 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). 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 completion of the reaction, the reaction solution was concentrated and purified on a CombiFlash (24 g, 0-10% MeOH / DCM) to afford H17-a (1.1 g, 1.83 mmol) in a yield of 92.75%. MS m / z (ESI): 601.4 [M+H]. + .

[0481] Step 2: H17-a (1.1 g, 1.83 mmol) was dissolved in THF (10 mL), and dilute hydrochloric acid (4 mol / L, 12 mL) was added. The mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was neutralized with saturated aqueous sodium bicarbonate solution and extracted with a mixed solvent of dichloromethane and methanol (10:1, 30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford H17-b (412 mg, colorless viscous material, crude product). Yield: 41.31%. MS m / z (ESI): 545.3 [M+H]. + .

[0482] Step 3: H2-f (70 mg, 123.34 μmol) and H17-b (80.61 mg, 148.01 μmol) were dissolved in DMF (4 mL). 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 completion, the reaction solution was purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 44% to 74% acetonitrile) to obtain H17 (33.57 mg) in a yield of 24.87%. MS m / z (ESI): 547.8 [M / 2+H]. + . 1 H 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),3.1 1-2.79(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).

[0483] Example 18 Preparation of Compound H18

[0484] Step 1: Dissolve 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) in DMF (10 mL). Add KCO (2.02 g, 14.59 mmol) and stir at 50°C for 18 h. After completion of the reaction, cool the reaction mixture to room temperature, filter, and concentrate the filtrate. Purify the filtrate using CombiFlash (12 g, 0-100% EA / PE) to afford H18-a (335 mg, colorless oil) in an 18.32% yield. MS m / z (ESI): 402.2 [M-100+H]. + .

[0485] Step 2: Dissolve H18-a (335 mg, 667.90 μmol) in DCM (20 mL) and add HCl (4 mol / L in ethyl acetate, 3 mL). Stir at room temperature for 18 h. After completion of the reaction, concentrate the reaction solution to obtain H18-b (268 mg, white solid) in a yield of 99.95%. MS m / z (ESI): 402.2 [M+H] + .

[0486] Step 3: Intermediate Z1 (100 mg, 192.48 μmol) was dissolved in DMF (1.02 mL), and DIPEA (199.02 mg, 1.54 mmol, 268.22 μL) and HATU (363.09 mg, 962.42 μmol) were added. The mixture was stirred at room temperature for 18 hours, followed by the addition of H18-b (149.18 mg, 371.61 μmol). Stirring was continued at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% ACN / DCM). The product was then purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 47% to 78% acetonitrile) to afford H18 (34.59 mg) in a yield of 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,1 H),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).

[0487] Example 19 Preparation of Compound H19

[0488] Procedure: 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 with stirring at room temperature and stirred overnight. 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 mixture was poured into water and extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH:DCM = 0-10%). The product was then purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-65% acetonitrile) to afford H19 (6.14 mg, purity: 99.41%) in a yield of 3.42%. MS m / z (ESI): 929 [M+H] + . 1 H 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),2.0 4(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).

[0489] Example 20 Preparation of Compound H20

[0490] 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 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 x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by combifax (MeOH:DCM = 0-10%) to obtain H20-a (565 mg, yellow solid) in a yield of 61.04%. MS m / z (ESI): 586.4 [M-100+H] + .

[0491] Step 2: Dissolve H20-a (565 mg, 823.72 μmol) in THF (5 mL). Add dioxane hydrochloride solution (4 mol / L, 5.01 mL) under ice-cooling (0°C) and stir at room temperature for 4 hours. After the reaction, concentrate the reaction solution to obtain H20-b (482 mg, yellow solid, crude product), which is used directly in the next step. MS m / z (ESI): 586.3 [M+H] + .

[0492] 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), and 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 completion of the reaction, the reaction solution was concentrated and purified by combiflash (MeOH:DCM = 0-14%). It was then purified by alkaline preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 48%-53% acetonitrile). It was then purified by acidic preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 0.04% TFA / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 41%-71% acetonitrile) to obtain H2O (2.17 mg, 100% purity) in a yield of 0.94%. MS m / z (ESI): 535.3 [M / 2+H]. + .1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.74(s,1H),8.57(s,1H),8.48(t,J=5.6H z,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),4.30-4.1 2(m,3H),3.59(d,J=3.8Hz,2H),2.43(s,3H),2.29-2.17(m,1H),2.10(q,J=7.0H z,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).

[0493] Example 21 Preparation of Compound H21

[0494] Step 1: Dissolve H10-a (190 mg, 378.86 μmol) and tert-butyl 4-aminopiperidine-1-carboxylate (151.75 mg, 757.71 μmol) in DMF (10 mL). Add HATU (285.86 mg, 757.71 μmol) and DIPEA (146.89 mg, 1.14 mmol, 197.97 μL). Stir at room temperature for 16 hours. After completion of 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). The crude product was used directly in the next reaction. MS m / z (ESI): 683.8 [M+H] + .

[0495] 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. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, DCM (20 mL) was added to the reaction solution, followed by a saturated aqueous sodium bicarbonate solution (50 mL). The mixture was stirred for 5 minutes. A solid precipitated and was filtered. The filter cake was concentrated to obtain H11-b (95 mg, yellow solid, crude product). The product was used directly in the next step without further purification. MS m / z (ESI): 583.8 [M+H] + .

[0496] Step 3: H11-b (40 mg, 68.53 μmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde (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, and cooled to room temperature naturally. NaBH3CN (43.07 mg, 685.34 μmol) was added at room temperature, and stirring was continued at room temperature for 2 h. After the reaction, the reaction mixture was concentrated, and the crude product was purified by alkaline preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 47%-52% acetonitrile) to obtain H21 (16.28 mg, purity: 97.01%) in a yield of 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=10.3,8.7 Hz,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).

[0497] Example 22 Preparation of Compound H22

[0498] 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)propanoic acid (153.21 mg, 809.74 μmol) were dissolved in DMF (5 mL). HATU (381.86 mg, 1.01 mmol) and DIPEA (436.05 mg, 3.37 mmol, 587.67 μL) were added sequentially with stirring at room temperature. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0-10%) to afford H22-a (260 mg, yellow solid) in a yield of 62.57%. MS m / z(ESI):616[M+H] + .

[0499] Step 2: Dissolve H22-a (260 mg, 422.23 μmol) in DCM (5 mL). Add HCl in ethyl acetate (4.0 mol / L, 3 mL) with stirring at room temperature. Stir at room temperature for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain H22-b (217.73 mg, yellow solid). Yield: 100.00%. MS m / z (ESI): 516 [M+H] + .

[0500] Step 3: H10-a (100 mg, 192.48 μmol) and H22-b (198.52 mg, 384.97 μmol) were 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 sequentially with stirring at room temperature. The mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0-10%). The product was then purified by HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-85% acetonitrile) to obtain H22 (1.84 mg, 100% purity) in a yield of 0.96%. MS m / z(ESI):500.3[M / 2+H] + . 1 H 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).

[0501] Example 23 Preparation of Compound H23

[0502] 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). 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 completion of the reaction, the reaction solution was concentrated and purified on CombiFlash (24 g, 0-10% MeOH / DCM) to afford H23-a (180 mg, white solid) in a yield of 26.08%. MS m / z(ESI):628.3[M+H] + .

[0503] Step 2: Dissolve H23-a (170 mg, 270.79 μmol) in DCM (10 mL) and add 4 M HCl in ethyl acetate (2 mL). Stir at room temperature for 1 hour. After the reaction, concentrate the reaction mixture to obtain H23-b (142 mg, yellow solid, HCl) in a yield of 92.95%. MS m / z (ESI): 528.3 [M+H] + .

[0504] Step 3: Intermediate Z1 (100 mg, 192.48 μmol) and DIPEA (1.48 g, 11.48 mmol, 2 mL) were dissolved in DMF (5 mL). HATU (290.47 mg, 769.94 μmol) was added and stirred at room temperature for 0.5 h. H23-b (142 mg, 251.71 μmol, HCl) was then added and stirred at room temperature for another 0.5 h. After completion of the reaction, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-10% MeOH / DCM) and then by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 40% to 45% acetonitrile) to obtain H23 (1.93 mg) in a yield of 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,3 H),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).

[0505] Example 24 Preparation of Compound H24

[0506] 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. 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 give H24-a (220 mg, white solid) in a yield of 43.77%. MS m / z (ESI): 559.4 [M+H]. + .

[0507] Step 2: Intermediate Z3 (18 mg, 0.04 mmol) and H24-a (26 mg, 0.05 mmol) were dissolved in DMF (1.5 mL), and HATU (22 mg, 0.06 mmol) and DIPEA (15 mg, 0.11 mmol) were added. 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 give H24 (6 mg) in a yield of 15.54%. MS m / z (ESI): 1014.6 [M+H] + . 1 H 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).

[0508] Example 25 Preparation of Compound H25

[0509] 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 the mixture was heated in a microwave oven at 80°C for 0.5 h. The mixture was then cooled to room temperature and NaBH3CN (8 mg, 0.12 mmol) was added. Stirring was continued at room temperature for 20 h. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-70% acetonitrile) to obtain H25 (14.64 mg) in a yield of 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,2 H),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),5.1 6-4.98(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).

[0510] Example 26 Preparation of Compound H26

[0511] Procedure: H27-e (100 mg, 185.36 μmol) and H8-b (253.07 mg, 741.45 μmol) were dissolved in DCM (6 mL) and stirred at room temperature for 2 hours. NaBH(OAc)3 (196.43 mg, 926.81 μmol) was then added and stirred at room temperature for an additional 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by CombiFlash (12 g, 0-15% MeOH / DCM). The product was then purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 48%-55% acetonitrile) to afford H26 (20.43 mg) in a yield of 11.81%. MS m / z (ESI): 865.3 [M+H] + . 1 H 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,1 H),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).

[0512] Example 27 Preparation of Compound H27

[0513] 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) and stir at room temperature for 18 hours. Then, add NaBH3CN (3.46 g, 55.12 mmol) and continue stirring at room temperature for 3 hours. After completion, quench the reaction by adding saturated aqueous ammonium chloride. Extract with dichloromethane (100 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford H27-a (4.5 g, pale yellow oil, crude product) in a yield of 99.51%. MS m / z (ESI): 354.0 [M-56+H]. + .

[0514] Step 2: Dissolve H27-a (4.5 g, 10.97 mmol) and Et3N (7.77 g, 76.79 mmol, 11.10 mL) in DCM (88.90 mL), add (Boc)2O (7.18 g, 32.91 mmol), and stir at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (40 g, 0-15% EA / PE) to afford H27-b (3 g, colorless oil) in a yield of 53.59%. MS m / z (ESI): 398.0 [M-112+H] + .

[0515] 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), K2CO3 (1.91 g, 13.79 mmol) and (Pin)2B2 (1.75 g, 6.89 mmol) were added and stirred at 70 °C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and purified using CombiFlash (80 g, 0-100% EA / PE) to obtain H27-c (1.87 g, pale yellow solid). Yield: 69.05%. MS m / z (ESI): 674.2 [M-112+H] + .

[0516] 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. The mixture was stirred at room temperature for 18 hours. After completion, the reaction was quenched with aqueous sodium bicarbonate and extracted with a mixture of DCM and MeOH (DCM:MeOH = 10:1, 100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified using CombiFlash (24 g, 5-20% DCM + 1% Et3N / MeOH) to afford H27-d (486 mg, white solid) in a yield of 34.88%. MS m / z (ESI): 586.2 [M+H] + .

[0517] Step 5: Dissolve H27-d (460 mg, 785.58 μmol) in EtOH (3 mL), add CH3ONa (424.40 mg, 7.86 mmol), and stir at 80°C for 2 hours. After completion, the reaction solution was poured into saturated aqueous ammonium chloride, filtered, and the filter cake was dried to obtain the product H27-e (360 mg, white solid) in a yield of 84.94%. MS m / z (ESI): 540.2 [M+H] + .

[0518] 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 hour, then cooled to room temperature, and then NaBH3CN (69.89 mg, 1.11 mmol) was added and stirring was continued at room temperature for 0.5 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with aqueous solution, and extracted with a mixture of DCM and MeOH (DCM:MeOH = 10:1, 100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, then purified by CombiFlash (12 g, 0-15% MeOH / DCM) and preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 55%-60% acetonitrile) to obtain H27 (2.01 mg) in a yield of 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,2 H),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).

[0519] Example 28 Preparation of Compound H28

[0520] Procedure: H27-e (100 mg, 185.36 μmol) and 1-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-5-yl)azetidine-3-carboxylic acid (99.35 mg, 278.04 μmol) were dissolved in DMF (5 mL), and 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 completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (12 g, 0-15% MeOH / DCM), followed by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 0.04% FA / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 42%-62% acetonitrile) to afford H28 (21.30 mg) in a yield of 12.61%. MS m / z (ESI): 879.3 [M+H] + .1 H 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),6.9 7-6.89(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).

[0521] Example 29 Preparation of Compound H29

[0522] Step 1: Dissolve 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) in DCM (20 mL). Add NaBH(OAc)3 (2.50 g, 11.81 mmol) with stirring at room temperature. Stir at room temperature for 1 hour. Add NaBH3CN (1.24 g, 19.68 mmol) and continue stirring at room temperature for 1 hour. After completion of the reaction, pour the reaction solution into water and extract with ethyl acetate (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to yield H29-a (1.65 g, yellow oil) in a yield of 98.79%. MS m / z (ESI): 424 [M+H]. + .

[0523] Step 2: Dissolve H29-a (1.5 g, 3.54 mmol) and tert-butyl tert-butoxycarbonyl carbonate (2.31 g, 10.61 mmol) in DCM (20 mL). Add triethylamine (2.14 g, 21.21 mmol) with stirring at room temperature. Heat to 45°C and stir for 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (EA:PE = 0-53) to obtain H29-b (700 mg, yellow oil) in a yield of 37.76%. MS m / z (ESI): 468, 470 [M+H-56]. + .

[0524] 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 H2O (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)2B2, (583.43 mg, 2.30 mmol) were added and 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) in a yield of 27.21%.

[0525] Step 4: Dissolve H29-c (250 mg, 312.57 μmol) in DCM (10 mL) and add 2,2,2-trifluoroacetic acid (35.64 mg, 312.57 μmol, 3 mL) with stirring at room temperature. Stir at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain H29-d (187.41 mg, yellow solid) in a yield of 100.00%. MS m / z (ESI): 600 [M+H] + .

[0526] Step 5: Dissolve H29-d (540.62 mg, 10.01 mmol) in methanol (20 mL), add sodium methoxide (540.62 mg, 10.01 mmol), and heat to 70°C with stirring overnight. Pour the reaction solution into saturated sodium carbonate and extract with EA (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to give H29-e (184.63 mg, yellow solid, crude product) in a yield of 100.00%, which is used directly in the next step. MS m / z (ESI): 554 [M+H] + .

[0527] Step 6: Dissolve H29-e (200 mg, 361.33 μmol) and H8-b (246.66 mg, 722.66 μmol) in DCM (20 mL). Add NaBH(OAc)3 (382.90 mg, 1.81 mmol) with stirring at room temperature, and stir overnight at room temperature. The reaction mixture was poured into water and extracted with DCM (30 mL x 2). The filtrate and the solid on the separatory funnel during extraction were combined and purified by silica gel column chromatography (MeOH:DCM 0-10%) and then by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-70% acetonitrile) to obtain H29 (8.49 mg, purity: 100%), yield: 1.79%. MS m / z(ESI):879[M+H] + . 1 H 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,1 H), 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).

[0528] Example 30 Preparation of Compound H30

[0529] Step 1: Dissolve 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) in DCM (15 mL). Add NaBH(OAc)3 (2.50 g, 11.81 mmol) with stirring at room temperature, and stir overnight at room temperature. The reaction mixture was poured into water and extracted with EA (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE = 0-30%) to afford H30-a (1.77 g, colorless oil) in a yield of 100.00%. MS m / z (ESI): 450, 452 [M+H]. + .

[0530] Step 2: Dissolve H30-a (1.7 g, 3.78 mmol) in DCM (20 mL). Add triethylamine (1.14 g, 11.33 mmol) and (Boc)2O (1.03 g, 4.73 mmol) with stirring at room temperature. Stir overnight at room temperature. The reaction mixture 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]. + .

[0531] 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), and (Pin)2B2 (816.81 mg, 3.22 mmol) were added and stirred at 70 °C for 18 hours. The reaction solution was purified by CombiFlash (80 g, 0-100% EA / PE) to afford H30-c (700 mg, light yellow solid) in a yield of 52.70%. MS m / z (ESI): 770 [M+H-56] + .

[0532] Step 4: Dissolve H30-c (700 mg, 847.62 μmol, 1 mL) in DCM (10 mL). Add trifluoroacetic acid (96.65 mg, 847.62 μmol, 3 mL) with stirring at room temperature. Stir at room temperature for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain H30-d (530.28 mg, yellow solid) in a yield of 100.00%. MS m / z (ESI): 626 [M+H] + .

[0533] Step 5: Dissolve H30-d (600 mg, 959.06 μmol) in methanol (25 mL), add sodium methoxide (1.55 g, 28.77 mmol), and heat to 70°C with stirring overnight. After the reaction, pour the reaction solution into saturated sodium carbonate and extract with EA (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to obtain H30-e (555.82 mg, crude product, yellow solid) in a yield of 100.00%, which is used directly in the next step. MS m / z (ESI): 580 [M+H] + .

[0534] Step 6: Dissolve H30-e (300 mg, 517.65 μmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carbaldehyde (382.41 mg, 1.04 mmol) in DCM (20 mL). Add sodium acetate borohydride (548.55 mg, 2.59 mmol) with stirring at room temperature. Stir at room temperature overnight. After completion of the reaction, pour the reaction mixture into water and extract with DCM (30 mL x 2). The filtrate and the solid from the separatory funnel during extraction were combined and purified sequentially by alkaline preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-70% acetonitrile) and acid preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM formic acid / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-75% acetonitrile) to obtain H30 (32.32 mg, purity: 94.9%) in a yield of 6.35%. MS m / z (ESI): 467 [M / 2+H]. + . 1 H 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,1 H),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,1 H),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).

[0535] Example 31 Preparation of Compound H31

[0536] Step 1: Dissolve 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) in DCM (15 mL). Add NaBH(OAc)3 (2.50 g, 11.81 mmol) with stirring at room temperature, and stir at room temperature for 1 hour. Then add NaBH3CN (1.24 g, 19.68 mmol) and stir at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EA (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE = 0-30%) to afford H31-a (1.88 g, colorless oil) in a yield of 100.00%. MS m / z (ESI): 478, 480 [M+H]. + .

[0537] Step 2: Dissolve H31-a (1.8 g, 3.76 mmol) and tert-butyl tert-butoxycarbonyl carbonate (1.48 g, 6.77 mmol) in DCM (20 mL). Add triethylamine (1.14 g, 11.29 mmol) with stirring at room temperature. Stir overnight at room temperature. The reaction mixture was concentrated and purified by silica gel column chromatography (EA:PE = 0-30%) to obtain H31-b (1.85 g, yellow oil) in an 84.99% yield. MS m / z (ESI): 478 [M+H-100] + .

[0538] 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), K2CO3 (889.12 mg, 6.43 mmol), and (Pin)2B2 (816.81 mg, 3.22 mmol) were added and stirred at 70 °C for 18 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated, and purified by CombiFlash (80 g, 0-100% EA / PE) to afford H31-c (750 mg, light yellow solid) in a yield of 54.61%. MS m / z (ESI): 854 [M+H] + .

[0539] Step 4: Dissolve H31-c (700 mg, 819.77 μmol) in DCM (10 mL) and add 2,2,2-trifluoroacetic acid (93.47 mg, 819.77 μmol, 3.0 mL) with stirring at room temperature. Stir at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain H31-d (512.86 mg, yellow solid) in a yield of 100.00%. MS m / z (ESI): 654 [M+H] + .

[0540] Step 5: Dissolve H31-d (600 mg, 917.90 μmol) in methanol (25 mL), add sodium methoxide (1.49 g, 27.54 mmol), and heat to 70°C with stirring overnight. After the reaction, pour the reaction solution into saturated sodium carbonate and extract with EA (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to give H31-e (557.71 mg, crude product, yellow solid) in a yield of 100.00%, which is used directly in the next step. MS m / z (ESI): 608 [M+H] + .

[0541] Step 6: Dissolve H31-e (300 mg, 493.75 μmol) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carbaldehyde (364.75 mg, 987.49 μmol) in DCM (20 mL). Add NaBH(OAc)3 (523.22 mg, 2.47 mmol) with stirring at room temperature and stir overnight at room temperature. After completion of the reaction, pour the reaction mixture into water and extract with DCM (30 mL x 2). The DCM and the solid adhering to the separatory funnel during extraction were combined and purified by alkaline preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH₄HCO₃H₂O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-70% acetonitrile) followed by acid preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM formic acid H₂O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-75% acetonitrile) to afford H31 (8.49 mg, purity: 100%) in a yield of 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).

[0542] Example 32 Preparation of Compound H32

[0543] Step 1: Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (300 mg, 1.09 mmol) and 4-tert-butoxycarbonylaminopiperidine (326 mg, 1.63 mmol) in DMF (3 mL) and add DIPEA (702 mg, 5.43 mmol). Heat the reaction mixture to 80°C and stir overnight. After completion of the reaction, pour the mixture into water and extract with EA (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH:DCM = 0-10%) to afford H32-a (240 mg, yellow solid) in a yield of 48.41%. MS m / z (ESI): 457.2 [M+H]. + .

[0544] Step 2: Dissolve H32-a (240 mg, 0.53 mmol) in DCM (10 mL) and add HCl in ethyl acetate (4 mol / L, 5.26 mmol). Stir at room temperature for 4 hours. After the reaction, concentrate the reaction solution to obtain H32-b (185 mg, crude product) in a yield of 98.74%, which was used directly in the next reaction. MS m / z (ESI): 357.1 [M+H] + .

[0545] Step 3: Intermediate Z1 (30 mg, 0.058 mmol) was dissolved in DMF (5 mL), and DIPEA (223 mg, 1.72 mmol) and HATU (100 mg, 0.27 mmol) were added. The mixture was stirred at room temperature for 0.5 hours, followed by the addition of H32-b (31 mg, 0.087 mmol). The reaction mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was concentrated and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-60% acetonitrile) to obtain H32 (4.99 mg) in a yield of 9.86%. MS m / z (ESI): 840.3 [M+H] + . 1 H 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,2 H),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),1.96-1.8 6(m,2H),1.69-1.56(m,2H),1.25(d,J=6.7Hz,3H),1.16(d,J=6.9Hz,3H).

[0546] Example 33 Preparation of Compound H33

[0547] 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 completion of the reaction, the reaction solution was concentrated and purified using a CombiFlash (24 g, 0-10% MeOH / DCM) to afford H33-a (220 mg, pale yellow solid) in an 89.20% yield. MS m / z (ESI): 641.3 [M+H] + .

[0548] Step 2: H33-a (220 mg, 343.37 μmol) was dissolved in THF (4 mL) and water (1 mL), and LiOH (65.79 mg, 2.75 mmol) was added. The mixture was stirred at 75°C for 18 hours. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated, and the pH was adjusted to 3-4 with dilute hydrochloric acid (2 mol / L). The mixture was extracted with dichloromethane (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford H33-b (145 mg, pale yellow solid, crude product) in a yield of 68.93%. MS m / z (ESI): 613.3 [M+H] + .

[0549] 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). DIPEA (101.26 mg, 783.48 μmol, 136.47 μL) was added and stirred at room temperature for 0.5 h. HATU (110.84 mg, 293.81 μmol) was then added and stirring was continued at room temperature for 1 h. After the reaction of the starting materials was complete, the reaction solution was purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 0.04% FA / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 40%-60% acetonitrile) to obtain H33 (2.02 mg) in a yield of 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=7.6H z,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).

[0550] Example 34 Preparation of Compound H34

[0551] Procedure: Intermediate Z1 (100 mg, 0.192 mmol) was dissolved in DMF (3 mL), followed by the addition of DIPEA (2 mL) and HATU (218 mg, 0.576 mmol). The mixture was stirred at room temperature for 10 minutes. TLC analysis revealed the formation of the intermediate product. H3-b (104 mg, 0.192 mmol) was then added and stirring continued for 20 minutes. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC (waters-sunfire-10 μm-19*150 mm column (mobile phase: 28%-38% (v / v) acetonitrile and formic acid in water) to afford H34 (20 mg) in a 6.6% yield. 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).

[0552] Example 35 Preparation of Compound H35

[0553] 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 completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (24 g, 0-10% MeOH / DCM) to afford H35-a (220 mg, pale yellow solid) in an 89.20% yield. MS m / z (ESI): 643.3 [M+H]. + .

[0554] Step 2: H35-a (220 mg, 342.30 μmol) was dissolved in EtOH (4 mL) and H2O (2 mL), and p-TsOH (176.83 mg, 1.03 mmol) was added. The mixture was stirred at 90°C for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and diluted to 30 mL with water. Saturated aqueous sodium bicarbonate was added to adjust the pH to 8, and the mixture was extracted with dichloromethane (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (10 g, 0-10% MeOH / DCM) to afford H35-b (187 mg, black, viscous solid) in a yield of 91.56%. MS m / z (ESI): 597.3 [M+H]. + .

[0555] Step 3: H35-b (100 mg, 167.60 μmol) and 2-(2,6-dioxopiperidine-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 stirred at 90 ° C in a microwave for 0.5 hour. Then CH3COOH (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, NaBH3CN (52.66 mg, 838.01 μmol) was added and stirred at room temperature for 3 hours. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with dichloromethane (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified using CombiFlash (4 g, 0-15% MeOH / DCM) to afford H35-c (107 mg, pale yellow solid) in a yield of 72.64%. MS m / z (ESI): 879.3 [M+H]. + .

[0556] Step 4: H35-c (107 mg, 121.74 μmol) was dissolved in EtOH (10 mL), and NaBH3CN (76.50 mg, 1.22 mmol) was added. The mixture was stirred at 20°C for 4 hours. After completion of the reaction, the reaction solution was purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-60% acetonitrile) to obtain H35 (1.03 mg, white solid) in a yield of 0.84%. MS m / z (ESI): 880.3 [M+H] + .

[0557] Example 36 Preparation of Compound H36

[0558] Step 1: tert-Butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (717 mg, 3 mmol) was added to dioxane (1 mL), followed by dioxane hydrochloride solution (4 mol / L, 10 mL), 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 naturally dried to obtain H36-a (525 mg) in a yield of 100%. MS m / z (ESI): 176 [M+H] + .

[0559] Step 2: H36-a (525 mg, 3 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (828 mg, 3 mmol) were added to DMF (2 mL). DIPEA (1 mL) was added, and the mixture was heated to 125°C and stirred at 125°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated and purified by silica gel column chromatography (PE / EA 0-60%) to obtain H36-b (790 mg) in a 66.7% yield. MS m / z (ESI): 396 [M+H] + .

[0560] Step 3: Dissolve H36-b (790 mg, 2 mmol) in ammonia-dioxane solution (10 mL, 1.6 mol / L), add tetraisopropyl titanate (1136 mg, 4 mmol), and stir at room temperature for 2 hours. Then, add NaBH (150 mg) and continue stirring for 30 minutes. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (0-5% DCM / MeOH) to obtain H36-c (475 mg) in a 75% yield. MS m / z (ESI): 397.2 [M+H] + .

[0561] Step 4: H36-c (100 mg, 250 μmol) and H10-a (126 mg, 250 μmol) were dissolved in DMF (2 mL), and TCFH (16 mg, 55 μmmol) and N-methylimidazole (1 mL) were added and stirred at room temperature. The resulting mixture was pumped dry and the filtrate was purified by high-pressure liquid chromatography (HPLC) (Waters-Sunfire 10 μm-19*150 mm column (mobile phase: 28%-38% (v / v) acetonitrile and formic acid in water) to obtain H36 (14 mg) in a 6% yield. 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,2 H), 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).

[0562] Example 37 Preparation of Compound H37

[0563] Step 1: Dissolve intermediate Z3 (50 mg, 0.11 mmol) and N-tert-butyloxycarbonyl-4-piperidone (42 mg, 0.21 mmol) in DCM (2 mL) at room temperature. Add acetic acid (20 mg, 0.33 mmol) and NaBH(OAc)3 (67 mg, 0.32 mmol). Stir at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (DCM / MeOH = 0-10%) to afford H37-a (30 mg, yellow oil). Yield: 43.23%. MS m / z (ESI): 656.2 [M+H]. + .

[0564] Step 2: Dissolve H37-a (30 mg, 0.05 mmol) in methanol (1 mL), add hydrochloric acid / methanol solution (1 mL, 4 mol / L), and stir at room temperature for 3 hours. After the reaction is complete, the reaction solution is concentrated to obtain H37-b (25 mg, yellow oil) in a yield of 98.35%. MS m / z (ESI): 556.2 [M+H] + .

[0565] Step 3: H37-b (20 mg, 0.04 mmol) and 1-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-5-yl)piperidine-4-carbaldehyde (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 completion of the reaction, the reaction solution was concentrated and purified on a preparative silica gel plate (DCM:MeOH = 8:1) to afford H37 (3 mg, light yellow solid) in a 6.11% yield. MS m / z (ESI): 909.4 [M+H]. + . 1 H 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).

[0566] Example 38 Preparation of Compound H38

[0567] 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 NaHCO 3 aqueous 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 give H2-a (13.4 g, yellow liquid) in a yield of 81.6%. MS m / z(ESI):382.0[M-56+H] + .

[0568] Step 2: To a solution of H2-a (13.4 g, 24.5 mmol) in DCM (150 mL) at 0°C were added (Boc)2O (8.01 g, 36.7 mmol) and triethylamine (10.2 mL, 73.4 mmol). The mixture was stirred at 60°C under a nitrogen atmosphere for 18 hours. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography (PE:EA = 10:1-3:1) to afford H2-b (12.4 g, white solid) in a 94.2% yield. MS m / z (ESI): 438.0 [M-100+H]. + .

[0569] Step 3: H2-b (4.45 g, 8.27 mmol) was dissolved in DME (40 mL) and water (4 mL), and 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), bis(Pin)2B2 (2.33 g, 9.19 mmol), CataCXium A (329 mg, 0.92 mmol), Pd(OAc)2 (103 mg, 0.46 mmol) and K2CO3 (2.54 g, 18.4 mmol) were added. The mixture was stirred at 70°C under a nitrogen atmosphere for 18 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1-30:1) to give H2-c (2 g, white solid) in a yield of 53.5%. MS m / z(ESI):714.3[M-100+H] + .

[0570] Step 4: To a solution of H2-c (2 g, 2.46 mmol) in EA (15 mL) was added ethyl acetate (4 mol / L, 15 mL) and stirred at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated to afford H2-d (1.8 g, yellow solid) in a 95.9% yield. MS m / z (ESI): 614.2 [M+H] + .

[0571] Step 5: To a solution of H2-d (500 mg, 0.66 mmol) in MeOH (10 mL) and water (2 mL) was added lithium hydroxide hydrate (412 mg, 9.84 mmol) and stirred at 70°C under a nitrogen atmosphere for 3 hours. After completion of the reaction, the mixture was concentrated, 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, supplemented with 0.025% formic acid) to afford H2-e (260 mg, white solid) in a yield of 67.7%. MS m / z (ESI): 586.2 [M+H] + .

[0572] Step 6: To a solution of H2-e (250 mg, 0.43 mmol) in DMF (4 mL) and THF (20 mL) was added HATU (194 mg, 0.51 mmol) and DIPEA (276 mg, 2.13 mmol). The mixture was stirred at 25°C for 30 minutes under a nitrogen atmosphere. After completion of the reaction, the mixture was concentrated and diluted with water (10 mL). The filter cake was filtered and dried to afford H2-f (150 mg, red solid) in a yield of 30.9%. MS m / z (ESI): 568.2 [M+H] + .

[0573] Step 7: To a solution of H2-f (50 mg, 0.04 mmol) in DMF (2 mL) was added 1-(2-(2,6-dioxapiperidin-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), 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, 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-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),3.1 5-2.96(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).

[0574] Example 39 Preparation of Compound H39

[0575] 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. LiHMDS (1 mol / L, 4.11 mL, 4.11 mmol) was added with stirring at room temperature under nitrogen atmosphere, and the reaction was carried out at 80 ° C for 2 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 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) in a yield of 63.67%. MS m / z (ESI): 417.2 [M+H] + .

[0576] Step 2: H39-a (218 mg, 0.520 mmol) and THF (1.5 mL) were added to a single-necked flask at room temperature. Dilute hydrochloric acid (2 mol / L, 1.50 mL, 3.00 mmol) was added with stirring at room temperature and the mixture was reacted at 70°C for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction system, and the pH was adjusted to 7 with saturated aqueous NaHCO₃. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain H39-b (140 mg, yellow solid) in a yield of 72.69%. MS m / z (ESI): 371.0 [M+H] + .

[0577] 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-necked vial at room temperature. NaBH3CN (76.7 mg, 1.28 mmol) and acetic acid (45.9 μL, 0.800 mmol) were added with 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) in a yield of 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).

[0578] Example 40 Preparation of Compound H40

[0579] Step 1: Dissolve 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) in DMSO (10 mL) at room temperature. Add DIPEA (702 mg, 5.43 mmol) and stir at 120°C for 2 hours. After the reaction is complete, pour the reaction solution into water (30 mL). The aqueous phase is extracted with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford H40-a (690 mg, yellow solid) in a yield of 91.75%. MS m / z (ESI): 416.2 [M+H]. + .

[0580] Step 2: Dissolve H40-a (690 mg, 1.66 mmol) in THF (4 mL), add aqueous hydrochloric acid (2 mol / L, 4 mL), and heat to 70°C with stirring for 1 hour. After the reaction is complete, add water (20 mL) to the reaction solution, adjust the pH to ~7 with saturated aqueous sodium bicarbonate solution, and extract with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to obtain H40-b (450 mg, yellow solid, 80% purity) in a yield of 73.35%. MS m / z (ESI): 370.2 [M+H] + .

[0581] Step 3: H40-b (34 mg, 0.07 mmol, 80% purity) and H2-f (30 mg, 0.04 mmol) were dissolved in DMSO (3 mL) and EtOH (1 mL), and NaBH3CN (18 mg, 0.30 mmol) and acetic acid (11 mg, 0.19 mmol) were added. The mixture was microwaved at 95°C for 1 hour. After completion of the reaction, 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 give H40 (10 mg, yellow solid) in a yield of 29.34%. MS m / z (ESI): 921.6 [M+H] + . 1 H 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),7.5 8(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),2.36-2.3 1(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).

[0582] Example 43 Preparation of Compound H43

[0583] Referring to the preparation method of Example 39, H43 was prepared according to the above synthetic route. Preparative HPLC purification conditions were as follows: a 21.2 x 250 mm C18 column; a 10 mM NH4HCO3 / H2O-acetonitrile system; a wavelength of 254 / 214 nm; and a gradient of 5% to 95% acetonitrile. H43 (14.68 mg, 98.93% purity) was obtained in a yield of 30.29%. MS m / z (ESI): 454.3 [M / 2+H].+ . 1 H 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).

[0584] Example 45 Preparation of Compound H45

[0585] 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-cooling (0°C). Slowly warm the mixture to room temperature and stir for 1 hour. Add 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindoline-1,3-dione (20 mg, 58.59 μmol) at 0°C and continue stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated to yield H45-a (105 mg, 189.67 μmol). MS m / z (ESI): 453.9 [M-100+H]. + .

[0586] 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. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain H45-b (86 mg, white solid, crude product), which was used directly in the next reaction without further purification. MS m / z (ESI): 453.9 [M-100+H] + .

[0587] 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 stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 62% to 67% acetonitrile) to obtain H45 (1.62 mg, purity 96.56%) in a yield of 1.62%. MS m / z (ESI): 936.6 [M+H] + . 1 H 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).

[0588] Example 46 Preparation of Compound H46

[0589] 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). Pd2(dba)3 (183.00 mg, 199.85 μmol), XPhos (190.54 mg, 399.69 μmol) and Cs2CO3 (1.30 g, 4.00 mmol) were added under argon protection, and the temperature was raised to 100°C and stirred overnight. After completion of the reaction, the reaction mixture was concentrated, and water and ethyl acetate were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was purified by CombiFlash (12 g, 0-40% EA / PE) to afford H46-a (0.9 g, brown oil) in a yield of 77.82%. MS m / z (ESI): 579.3 [M+H] + .

[0590] Step 2: H46-a (0.9 g, 1.56 mmol) was dissolved in CF3CH2OH (20 mL), and TFA (212.80 mg, 1.87 mmol) and Pd / C (165.51 mg, 155.52 μmol, 10% purity) were added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered, concentrated, and dissolved in THF. The pH was adjusted to a weak base with triethylamine. The product was concentrated and purified via CombiFlash (12 g, 0-10% MeOH / DCM) to afford H46-b (0.35 g, brown oil) in a yield of 56.20%. MS m / z (ESI): 401.3 [M+H] + .

[0591] Step 3: Dissolve H46-b (300 mg, 749.12 μmol) in DCM (5 mL) and add a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 5 mL). Stir at room temperature for 20 minutes. After completion of the reaction, concentrate the reaction mixture and dissolve it in dichloromethane. Add a small amount of triethylamine and purify it via CombiFlash (4 g, 0-10% MeOH / DCM) to obtain H46-c (0.2 g, light yellow solid). Yield: 75.33%. MS m / z (ESI): 355.2 [M+H] + .

[0592] 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). NaBH3CN (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 in a microwave oven and stirred for 45 minutes. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) 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-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).

[0593] Example 47 and Example 48 Preparation of Compound H47 and Compound H48

[0594] 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 CH3COOH (312.08 mg, 5.20 mmol) and stir at room temperature for 18 hours. Then cool to 0°C and add NaBH3CN (598.72 mg, 9.53 mmol). Stir at 0°C for 2 hours. After completion of the reaction, add saturated aqueous sodium bicarbonate to the reaction mixture. Concentrate to remove the organic solvent, and extract the aqueous phase with dichloromethane (80 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford H47-a (1.98 g, pale yellow oil, crude product) in a yield of 100.00%. MS m / z (ESI): 400.0 [M-56+H]. + .

[0595] Step 2: Dissolve H47-a (1.98 g, 4.34 mmol) in DCM (30 mL), add Et3N (1.76 g, 17.36 mmol) and (Boc)2O (1.89 g, 8.68 mmol), and stir at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (12 g, 0-10% EA / PE) to afford H47-b (2.1 g, colorless oil) in an 86.98% yield. MS m / z (ESI): 444.0 [M-56-56+H]. + .

[0596] 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), K2CO3 (3.49 g, 25.27 mmol) and (Pin)2B2 (3.21 g, 12.64 mmol) were added and stirred at 70 °C for 18 hours. After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated and purified via CombiFlash (40 g, 0-50% EA / PE) to afford H47-c (1.4 g, pale yellow solid) in a yield of 33.30%. MS m / z (ESI): 732.0 [M-100+H] + .

[0597] Step 4: Dissolve H47-c (2.8 g, 3.37 mmol) in DCM (20 mL) and add HCl / 1,4-dioxane (4 mol / L, 10.10 mL). Stir at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated to afford H47-d (2.13 g, pale yellow solid). Yield: 100.00%. MS m / z (ESI): 632.3 [M+H]. + .

[0598] Step 5: Dissolve H47-d (2.1 g, 3.32 mmol) in DCM (25 mL), add (Boc)2O (870.78 mg, 3.99 mmol) and Et3N (336.45 mg, 3.32 mmol), and stir at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (24 g, 0-40% DCM / EA) to afford H47-e (2.2 g, pale yellow solid) in a yield of 90.43%. MS m / z (ESI): 733.3 [M+H] + .

[0599] 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 stirred at 80°C for 18 hours. After completion of the reaction, the reaction solution was concentrated and the pH was adjusted to 5-6 with dilute hydrochloric acid (1 mol / L). The mixture was filtered and the filter cake was dried under vacuum to obtain H47-f (1.7 g, yellow solid). Yield: 73.66%. MS m / z (ESI): 704.3 [M+H]. + .

[0600] Step 7: Dissolve H47-f (1.7 g, 2.42 mmol) in DMF (10 mL), add Et3N (2.44 g, 24.16 mmol) and HATU (1.82 g, 4.83 mmol), and stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution and purify it via CombiFlash (24 g, 0-10% MeOH / DCM) to obtain H47-g (320 mg, light yellow solid) in a yield of 19.32%. MS m / z (ESI): 630.2 [M-56+H]. + .

[0601] Step 8: H47-g (320 mg, 466.72 μmol) was dissolved in MeOH (1 mL) and DCM (12 mL), and HCl / 1,4-dioxane (4 mol / L, 2 mL) was added. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (80 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford H47-h (270 mg, light yellow solid). Yield: 98.80%. MS m / z (ESI): 586.2 [M+H] + .

[0602] 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. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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) to obtain H47 (50.26 mg), MS m / z (ESI): 470.7 [M / 2+H] + . 1 H 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),6.9 8-6.86(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,3 H),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); and 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).

[0603] Example 49 Preparation of Compound H49

[0604] Step 1: Dissolve 3-fluoroisonicotinaldehyde (12 g, 95.92 mmol) in toluene (200 mL), add PTSA (1.65 g, 9.59 mmol) and MeOH (19.98 g, 575.54 mmol, 25.22 mL), and reflux with stirring at 120°C for 18 hours. After completion, the reaction solution was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (300 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (120 g, 0-50% EA / PE) to afford H49-a (11.3 g, colorless oil) in a yield of 68.82%. MS m / z (ESI): 172.1 [M+H]. + .

[0605] Step 2: H49-a (11.3 g, 66.02 mmol) was dissolved in acetone (100 mL), and BnBr (12.98 g, 75.92 mmol) was added. The mixture was stirred at 70°C for 18 hours. After completion of the reaction, the reaction solution was concentrated and slurried with ethyl acetate (70 mL). The mixture was 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]. + .

[0606] Step 3: Dissolve H49-b (15 g, 57.19 mmol, HBr) in MeOH (120 mL), lower the temperature to 0°C, and add NaBH4 (4.33 g, 114.37 mmol) portionwise. Stir at 0°C for 4 hours. After completion of the reaction, concentrate the reaction solution, add water (100 mL), and extract with ethyl acetate (300 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (60 g, 0-100% PE / DCM + 1% Et3N) to afford H49-c (11.7 g, colorless oil) in a yield of 77.11%. MS m / z (ESI): 266.2 [M+H]. + .

[0607] Step 4: H49-c (11.7 g, 44.10 mmol) was dissolved in EtOH (120 mL), and PdOH / C (10.89 g, 20% purity) and ammonium formate (55.61 g, 881.95 mmol) were added. The mixture was stirred at 90°C for 18 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to afford H49-d (5.5 g, viscous oil) in a yield of 70.38%. MS m / z (ESI): 178.1 [M+H] + .

[0608] 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). LiHMDS (1 mol / L, THF solution, 14.79 mmol, 14.79 mL) was added under nitrogen protection and stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (24 g, 0-10% MeOH / DCM) to afford H49-e (380 mg, pale yellow solid) in a yield of 29.58%. MS m / z (ESI): 435.2 [M+H] + .

[0609] 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 completion of the reaction, the reaction solution was concentrated to afford H49-f (130 mg, red viscous product) in a yield of 99.57%. MS m / z (ESI): 389.2 [M+H] + .

[0610] 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. The mixture was stirred at room temperature for 18 hours. After completion of the reaction, 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) to obtain H49 (3.94 mg) in a yield of 2.24%. MS m / z (ESI): 470.7 [M / 2+H] + . 1 H 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=37.6,26.6H z,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),2.9 7-2.80(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).

[0611] Example 51 Preparation of Compound H51

[0612] Step 1: Dissolve tert-butyl 3,3-difluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.98 mmol) in DCM (20 mL). Add hydrogen chloride in ethyl acetate (4.0 mol / L, 10 mL) with stirring at room temperature. Stir at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to afford H51-a (601.56 mg, yellow solid) in a yield of 100.00%. MS m / z (ESI): 152 [M+H] + .

[0613] 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. The mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and benzyl chloroformate (678.92 mg, 3.98 mmol) was added. The mixture was stirred at 0°C for 2 hours. After completion of the reaction, 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] + .

[0614] Step 3: Dissolve H51-b (1.0 g, 3.51 mmol) in DCM (20 mL) and add (1,1-diacetoxy-3-oxo-1,2-benzoxol-1-yl) acetate (1.78 g, 4.21 mmol) with stirring at room temperature. Stir at room temperature for 2 hours. After completion of the reaction, filter the reaction solution, concentrate the filtrate, and purify it 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] + .

[0615] Step 4: Dissolve H51-c (850 mg, 3.00 mmol) in MeOH (20 mL). Add trimethoxymethane (1.59 g, 15.00 mmol) and p-TSOH (25.84 mg, 0.15 mmol) with stirring at room temperature. Stir overnight at room temperature. After the reaction is complete, the reaction solution is concentrated and purified by silica gel column chromatography (EA:PE = 0-50%) to obtain H51-d (800 mg, yellow oil) in an 81% yield. MS m / z (ESI): 330 [M+H] + .

[0616] Step 5: Dissolve H51-d (830 mg, 2.52 mmol) in MeOH (20 mL), add Pd / C (576.39 mg, 541.62 μmol, 10% purity), and stir at room temperature under a hydrogen atmosphere for 2 hours. After completion of the reaction, filter the reaction solution, and concentrate the filtrate to obtain H51-e (300 mg, colorless oil) in a yield of 60.98%. MS m / z (ESI): 196 [M+H] + .

[0617] Steps 6-8 were prepared according to the preparation method of Example 39, and H51 was prepared according to the above synthetic route. MS m / z (ESI): 958 [M+H] + .

[0618] Example 56 Preparation of Compound H56

[0619] Steps 1 to 5 were prepared according to the preparation method of Example 88, and H56-e was prepared according to the above synthetic route. MS m / z (ESI): 545.3 [M+H] + .

[0620] 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. The mixture was reacted at 85°C for 16 h. After completion of the reaction, water was added to the reaction solution and extracted twice with DCM:MeOH (10:1). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified using 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] + .

[0621] 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). The mixture was heated to 85°C and stirred for 30 min under microwave conditions. NaBH(OAc)3 (31.88 mg, 150.44 μmol) was then added, and the mixture was heated to 85°C and stirred for 30 min under microwave conditions. After completion of the reaction, the reaction solution was concentrated and initially purified by CombiFlash (4 g, 0-12% MeOH / DCM). It was then purified by preparative HPLC (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5% to 95% acetonitrile change) to obtain H56 (1.9 mg, purity 95.3%) in a yield of 4.23%. MS m / z(ESI):427.3[M / 2+H] + . 1 HNMR(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).

[0622] Example 61 Preparation of Compound H61

[0623] Referring to the preparation method of Example 39, compound H61 was prepared according to the above synthetic route. Its preparative HPLC purification conditions were: waters-sunfire-10 μm-19×150 mm column (mobile phase: 28%-38% (v / v) acetonitrile and formic acid / water). MS m / z (ESI): 962 [M+H] + . 1 H 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,2 H),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).

[0624] Example 62 Preparation of Compound H62

[0625] 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. NaBH3CN (51.71 mg, 822.91 μmol) was then added, and the mixture was heated to 90°C and stirred for 20 minutes under microwave. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) to obtain H62 (28.14 mg, 100% purity) in a yield of 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,2 H),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).

[0626] Example 65 Preparation of Compound H65

[0627] Step 1: The 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-dioxaborolan-2-yl)pyridine (1460 mg, 3.5 mmol), Pd(dppf)Cl2 (120 mg, 0.16 mmol), and Cs2CO3 (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 completion of the reaction, the product was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (50 mL x 1), concentrated, and purified by silica gel column chromatography (PE / EA = 0-50%) to afford H65-a (1036 mg) in a 57% yield. MS m / z (ESI): 518 [M+H] + .

[0628] Step 2: H65-a (1036 mg, 2 mmol) was added to MeOH (5 mL), followed by the addition of Pd / C (200 mg, 10 wt%). The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to afford H65-b (680 mg) in a 100% yield. MS m / z (ESI): 340 [M+H] + .

[0629] Step 3: H65-b (680 mg, 2 mmol), 4-(dimethoxymethyl)piperidine (477 mg, 3 mmol), Ruphos-Pd-G3 (340 mg, 0.41 mmol), and Cs2CO3 (1952 mg, 6 mmol) were added sequentially to 1,4-dioxane (10 mL). The atmosphere was purged with nitrogen three times, and the mixture was heated at 120°C with stirring for 15 hours. After completion of the reaction, the mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL x 1). The organic phases were 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] + .

[0630] Step 4: H65-c (84 mg, 0.2 mmol) was added to DCM (5 mL), followed by TFA (2 mL), and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to afford H65-d (74.5 mg) in a 100% yield. MS m / z (ESI): 373 [M+H] + .

[0631] Step 5: H2-f (113 mg, 0.2 mmol) was added to DMSO (5 mL), and 3 drops of acetic acid and H65-d (74.5 mg, 0.2 mmol) were added. The mixture was heated in a microwave oven at 90°C for 1 hour. NaBH(OAc)3 (100 mg) was then added and the mixture was heated in a microwave oven at 90°C for another 1 hour. After completion of the reaction, the mixture was purified by preparative HPLC (waters-sunfire-10 μm-19*150 mm column (mobile phase: 28%-38% (v / v) acetonitrile and formic acid / water) to obtain H65 (2 mg). Yield: 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),2.74-2.5 6(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).

[0632] Example 66 Preparation of Compound H66

[0633] 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 Cs2CO3 (2928 mg, 1.5 mmol) were added sequentially to 1,4-dioxane (15 mL). The atmosphere was purged with nitrogen three times and then heated to 120°C with stirring for 15 hours. After completion of the reaction, 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] + .

[0634] 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 completion of the reaction, concentrate to obtain H66-b (82 mg). Yield: 100%. MS m / z (ESI): 412 [M+H] + .

[0635] 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. The reaction was stirred at room temperature for 10 minutes, and then H10-a (82 mg, 0.2 mmol) was added and the reaction was continued for 1 hour. After completion of the reaction, 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 (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).

[0636] Example 67 Preparation of Compound H67

[0637] Step 1: 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) were dissolved in dioxane (20 mL). Pd2(dba)3 (274.50 mg, 299.77 μmol), X-Phos (285.81 mg, 599.54 μmol) and Cs2CO3 (1.95 g, 6.00 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 then added with water and ethyl acetate. The product 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, 0-40% EA / PE) to obtain H67-a (2 g, brown oil) with a yield of 99.01%.

[0638] 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. The mixture was stirred at 40°C overnight under a hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration and the mixture was concentrated to afford H67-b (1 g, gray solid, crude product) in a yield of 67.98%. The product was directly used in the next step without purification. MS m / z (ESI): 496.3 [M+H] + .

[0639] Step 3: Dissolve H67-b (1 g, 2.02 mmol) in hydrogen chloride in 1,4-dioxane (4 mol / L, 15 mL) and stir at room temperature for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain H67-c (0.7 g, gray solid, crude product, HCl) in an 80.32% yield. This product was used directly in the next step without purification. MS m / z (ESI): 396.2 [M+H] + .

[0640] Step 4: Intermediate Z1 (833.33 mg, 481.21 μmol) was dissolved in DMF (5 mL), HATU (907.73 mg, 2.41 mmol) and DIPEA (1.24 g, 9.62 mmol, 1.68 mL) were added, and the mixture was stirred at room temperature for 20 min. H67-c (285.48 mg, 721.82 μmol) was added, and stirring was continued at room temperature for 2 h. After completion of the reaction, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated, and purified by preparative HPLC (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile). Further preparative HPLC (preparative column: 21.2 × 250 mm C18 column; system: 10 mM FA / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) was performed to obtain H67 (5.56 mg, purity 99.45%) in a yield of 1.31%. MS m / z (ESI): 440.3 [M / 2+H]. + . 1 H 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),4.7 1(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).

[0641] Example 68 Preparation of Compound H68

[0642] Compound H68 was prepared according to the synthetic route described above, with reference to the preparation method of Example 66. Preparative HPLC purification conditions were as follows (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile). MS m / z (ESI): 440.8 [M / 2+H] + . 1 H 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),7.4 4-7.36(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).

[0643] Example 69 Preparation of Compound H69

[0644] Compound H69 was prepared according to the synthetic route described in Example 66. Preparative HPLC purification conditions were as follows: 21.2 x 250 mm C18 column; 10 mM NH₄HCO₃ / H₂O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile. 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).

[0645] Example 70 Preparation of Compound H70

[0646] 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. Stir at room temperature for 16 hours. After completion of the reaction, pour the reaction solution into water and extract with DCM (100 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford H70-a (11 g, light yellow oil) in a yield of 96.61%. This product was used directly in the next step without purification. MS m / z (ESI): 354.0 [M+H] + .

[0647] Step 2: Dissolve H70-a (11 g, 31.07 mmol) and (Boc)2O (13.56 g, 62.14 mmol, 15.07 mL) in DCM (150 mL). Add TEA (9.43 g, 93.21 mmol, 13.00 mL) with stirring at room temperature. Stir at room temperature for 3 hours. After completion of the reaction, 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) in an 85.04% yield. MS m / z (ESI): 397.9 [M-56+H]. + .

[0648] 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). Pd(dppf)Cl2 (322.24 mg, 440.39 μmol) and K2CO3 (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 completion of the reaction, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (20 g, 0-20% EA / PE) to afford H70-c (1.6 g, light yellow oil) in a yield of 71.31%. MS m / z (ESI): 353.0 [M-156+H] + .

[0649] Step 4: H70-c and (Pin)2B2 (1.20 g, 4.71 mmol) were dissolved in 1,4-dioxane (30 mL). KOAc (924.64 mg, 9.42 mmol) and Pd(dppf)Cl2 (229.79 mg, 314.05 μmol) were added. The mixture was heated to 95°C and stirred overnight under an argon atmosphere. After completion of the reaction, the solid was filtered off, and the filtrate was concentrated and purified via CombiFlash (20 g, 0-20% EA / PE) to afford H70-d (1.5 g, light brown solid) in an 85.82% yield. MS m / z (ESI): 401.3 [M-156+H]. + .

[0650] Step 5: Dissolve H70-d (1.45 g, 2.61 mmol) in MeOH (20 mL), add Pd / C (277.27 mg, 260.54 μmol, 10% purity), and stir at room temperature under a hydrogen atmosphere for 1 hour. After completion of the reaction, filter out the catalyst, and concentrate the filtrate to obtain H70-e (1.3 g, light yellow solid) in an 89.33% yield. This was used directly in the next step without purification. MS m / z (ESI): 403.3 [M-156+H] + .

[0651] Step 6: H70-e (1.3 g, 2.33 mmol) and 8-bromo-5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester (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). Pd(dppf)Cl2 (170.30 mg, 232.74 μmol) and K2CO3 (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 completion of the reaction, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using CombiFlash (20 g, 0-70% EA / PE) to obtain H70-f (1.4 g, light yellow solid) in a yield of 76.44%. MS m / z (ESI): 687.4 [M-100+H]. + .

[0652] 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. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and slurried with PE and EA to obtain H70-g (1 g, pale yellow solid, crude product). Yield: 95.81%. The product was directly reacted in the next step without purification. MS m / z (ESI): 587.3 [M+H] + .

[0653] Step 8: H70-g (0.4 g, 641.89 μmol, HCl) was dissolved in MeOH (5 mL), and sodium methoxide (2.31 g, 12.84 mmol, 30% purity) was added. The mixture was heated to 80°C and stirred for 16 hours. After completion of the reaction, the reaction solution was concentrated, and water and dichloromethane were added. 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 H70-h (0.2 g, light yellow solid, crude product). Yield: 57.63%. The product was directly used in the next step without purification. MS m / z (ESI): 541.3 [M+H] + .

[0654] 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. The mixture was heated to 100°C and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2×250 mm C18 column; system: 10 mM NH₄HCO₃ / H₂O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) 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-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),2.63-2.5 1(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).

[0655] Example 71 Preparation of Compound H71

[0656] Step 1: Dissolve 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. Stir overnight at room temperature. After completion of the reaction, concentrate the reaction solution and purify it 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]. + .

[0657] 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). Pd2(dba)3 (85.36 mg, 93.21 μmol), Xantphos (53.94 mg, 93.21 μmol), and t-BuONa (223.96 mg, 2.33 mmol) were added sequentially under argon. The mixture was heated to 120°C and stirred for 2 hours in a microwave oven. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0-10%) to obtain H71-b (150 mg, yellow solid) in a yield of 50.15%. MS m / z (ESI): 642 [M+H] + .

[0658] Step 3: Dissolve H71-b (130 mg, 202.58 μmol) in DCM (9.96 mL) and MeOH (2.99 mL). Add hydrogen chloride in ethyl acetate (4.0 mol / L, 5 mL) with stirring at room temperature. Stir at room temperature for 3 hours. After completion of the reaction, concentrate the reaction solution to obtain H71-c (109.72 mg, yellow solid). Yield: 100.00%. MS m / z (ESI): 542 [M+H]. + .

[0659] Step 4: Dissolve 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) in NMP (5 mL). Add DIPEA (477.25 mg, 3.69 mmol, 643.19 μL). Heat to 120°C and stir for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to obtain H71 (4.54 mg, 100% purity) in a yield of 3.08%. MS m / z (ESI): 798 [M+H]. + . 1 H 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=13.6,8.6H z,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).

[0660] Example 74 Preparation of Compound H74

[0661] 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). Pd2(dba)3 (68.29 mg, 74.57 μmol), Xantphos (43.15 mg, 74.57 μmol), and t-BuONa (215.00 mg, 2.24 mmol) were added under argon. The mixture was heated to 120°C and stirred for 3 hours in a microwave oven. After completion of the reaction, 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) in a yield of 43.63%. MS m / z (ESI): 615 [M+H] + .

[0662] Step 2: Dissolve H74-a (20 mg, 32.54 μmol) in DCM (5 mL) and add TFA (3.71 mg, 32.54 μmol, 2 mL) with stirring at room temperature. Stir at room temperature for 3 hours. After completion of the reaction, concentrate the reaction solution to obtain H74-b (18.50 mg, yellow solid). Yield: 100.00%. MS m / z (ESI): 569 [M+H] + .

[0663] Step 3: H74-b (20 mg, 35.17 μmol) and H99-b (24.08 mg, 70.34 μmol) were dissolved in DCM (5 mL). NaBH(OAc)3 (7.45 mg, 35.17 μmol) was added with stirring at room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC to obtain H74 (1.67 mg, 94.53% purity) in a yield of 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,2 H),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),3.07-2.5 2(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).

[0664] Example 76 Preparation of Compound H76

[0665] Step 1: Dissolve H10-a (337 mg, 0.67 mmol) in DMF (10 mL), add DIPEA (522.42 mg, 4.04 mmol) and HA TU (508 mg, 1.35 mmol), and stir at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (0-10% MeOH / DCM) to afford H76-a (300 mg, yellow solid) in a yield of 81.77%. MS m / z (ESI): 545.3 [M+H] + .

[0666] Step 2: Dissolve H76-a (300 mg, 0.55 mmol) in THF (30 mL), add LAH (2.5 mol / L, 0.88 mL) at -78°C, and stir under argon for 2 hours. After completion, quench the reaction with sodium sulfate decahydrate, filter, and concentrate the filtrate to obtain H76-b (225 mg) in an 84.12% yield, which was used directly in the next reaction. MS m / z (ESI): 486.2 [M+H] + .

[0667] 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 stirred at room temperature for 1 hour. NaBH(OAc)3 (70 mg, 0.33 mmol) was then added and stirred overnight. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-60% acetonitrile) to obtain H76 (3.2 mg) in a yield of 2.25%. MS m / z (ESI): 433.2 [M / 2+H] + . 1 H 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=4.8 Hz,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).

[0668] Example 78 Preparation of Compound H78

[0669] Step 1: Dissolve 3,3,5,5-tetramethylpiperidin-4-one (3.7 g, 19.30 mmol, HCl) and K2CO3 (8.00 g, 57.90 mmol) in DMF (40.00 mL). Add BnBr (4.95 g, 28.95 mmol, 3.44 mL) and stir overnight at 60°C. After completion, cool the reaction mixture to room temperature, add water and ethyl acetate, and extract three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (40 g, 0-5% DCM / PE) to afford H78-a (4.7 g, colorless oil) in a yield of 99.25%. MS m / z (ESI): 246.2 [M+H]. + .

[0670] 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), and NaOAc (7.86 g, 95.78 mmol) was added. 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. 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%. The product was directly used in the next step without purification. MS m / z (ESI): 261.2 [M+H] + .

[0671] Step 3: H78-b (4.5 g, 17.28 mmol) was dissolved in THF (80 mL), and LiAlH4 (3.94 g, 103.70 mmol) was added. The mixture was heated to 70°C and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of THF was added. Water (4 mL), 15% NaOH (4 mL), and water (12 mL) were slowly added dropwise under an ice bath. The mixture was stirred for another half hour. Anhydrous sodium sulfate was added and stirred for 10 minutes. The solid was filtered off, and the filtrate was concentrated to obtain H78-c (4.2 g, light yellow oil, crude product) in a yield of 98.63%. The product was used directly in the next step without purification. MS m / z (ESI): 247.2 [M+H] + .

[0672] Step 4: Dissolve H78-c (4.2 g, 17.05 mmol) in DCM (60 mL), add (Boc)2O (7.44 g, 34.09 mmol, 7.83 mL) and TEA (5.17 g, 51.14 mmol, 7.13 mL), and stir at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (40 g, 0-100% DCM / PE) to afford H78-d (5 g, light yellow solid) in a yield of 84.65%. MS m / z (ESI): 347.3 [M+H] + .

[0673] Step 5: H78-d (1 g, 2.89 mmol) was dissolved in THF (20 mL), and Pd / C (305.91 mg, 288.60 μmol, 10% purity) was added. The atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature under a hydrogen balloon for 16 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain H78-e (0.6 g, pale white solid, crude product) in a yield of 81.09%. The product was directly used in the next step without purification. MS m / z (ESI): 257.2 [M+H] + .

[0674] 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). Pd2(dba)3 (91.50 mg, 99.92 μmol), X-Phos (95.27 mg, 199.85 μmol) and Cs2CO3 (651.14 mg, 2.00 mmol) were added under argon protection, and the temperature was raised to 100°C and stirred overnight. After completion of the reaction, the reaction mixture was concentrated, and water and ethyl acetate were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was purified by CombiFlash (12 g, 0-30% EA / PE) to obtain H78-f (250 mg, light brown oil) in a yield of 37.02%. MS m / z (ESI): 676.3 [M+H]. + .

[0675] 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). The mixture was heated to 40°C and stirred for 4 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to obtain H78-g (180 mg, light yellow solid) in a yield of 97.79%. The mixture was used in the next step without purification. MS m / z (ESI): 498.3 [M+H] + .

[0676] Step 8: Dissolve H78-g (180 mg, 361.72 μmol) in DCM (3 mL), add TFA (1 mL), and stir at room temperature for 1 hour. After completion of the reaction, filter the reaction solution, and concentrate the filtrate to obtain H78-h (0.1 g, pale yellow solid, crude product) in a yield of 69.55%. This product was used directly in the next step without purification. MS m / z (ESI): 398.3 [M+H] + .

[0677] 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 the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was purified by CombiFlash (4 g, 0-10% MeOH / DCM) and then by preparative HPLC (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) to obtain H78 (15.27 mg, purity 96.71%) in a yield of 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).

[0678] Example 80 Preparation of Compound H80

[0679] 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 h, then NaBH(OAc)3 (1.53 g, 7.21 mmol) was added and stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, ethyl acetate and aqueous sodium bicarbonate solution were added, the solid was filtered, and the mother liquor was extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product and filter cake were mixed and separated by CombiFlash column chromatography (12 g, 0-10% MeOH / DCM) to afford the crude product. This crude product was then purified by preparative liquid chromatography (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) to afford H80 (1.1 g, 1.23 mmol, 51.11% yield) as a white solid. 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=15.2 Hz,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).

[0680] 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. The mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure to yield a pale yellow solid. The solid was then sonicated with purified water and lyophilized to yield the pale yellow solid product H80-a (1.14 g, 1.20 mmol, 97.52% yield, 97.52% purity, hydrochloride). 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=8.0 Hz,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).

[0681] Example 88 Preparation of Compound H88

[0682] Step 1: Dissolve 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) in DMF (15 mL). Add DIPEA (1.87 g, 14.48 mmol, 2.52 mL) and stir at 100°C for 18 hours. After completion of the reaction, concentrate the reaction mixture, add water and ethyl acetate (80 mL), separate the organic phase, and extract the aqueous phase with ethyl acetate (80 mL x 2). The combined organic phases are washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (20 g, 0-30% EA / PE) to afford H88-a (480 mg) in a yield of 25.87%. MS m / z (ESI): 513.3 [M+H]. + .

[0683] Step 2: Dissolve H88-a (0.48 g, 936.41 μmol) in DCM (12 mL) and add a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 6 mL). Stir at room temperature for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain H88-b (420 mg, yellow solid, HCl) in a yield of 99.91%. MS m / z (ESI): 413.3 [M-HCl+H] + .

[0684] 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) and stir at room temperature for 18 hours. Then, add NaBH(OAc)3 (12.56 g, 59.25 mmol) and continue stirring at room temperature for 4 hours. After completion of the reaction, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (80 mL × 3), dried over anhydrous sodium sulfate, and concentrated to afford H88-c (9 g, light yellow oil) in a yield of 98.60%. MS m / z (ESI): 308.0 [M+H] + .

[0685] Step 4: Dissolve H88-c (9 g, 29.21 mmol) and Et3N (19.12 g, 87.63 mmol) in DCM (50 mL). Stir at room temperature and add (Boc)2O (19.12 g, 87.63 mmol). Heat to 45°C and stir overnight. After completion of the reaction, concentrate the reaction solution and purify it via CombiFlash (120 g, 0-40% DCM / PE) to obtain H88-d (7.2 g, yellow oil) in a yield of 60.38%. MS m / z (ESI): 352.0 [M-56+H]. + .

[0686] Step 5: H88-d (7.2 g, 17.64 mmol), KOAc (6.06 g, 61.73 mmol), B2(pin)2 (8.96 g, 35.27 mmol), and Pd(dppf)2Cl2 (1.29 g, 1.76 mmol) were dissolved in 1,4-dioxane (100 mL) and stirred at 95°C for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature, quenched with water, and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (120 g, 0-20% DCM / PE) to afford H88-e (6.2 g, colorless oil) in a yield of 77.21%. MS m / z (ESI): 356.2 [M-100+H].+ .

[0687] 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 water (8 mL), a mixed solution of DMSO (5 mL) and 1,4-dioxane (40 mL), and Pd(dppf)2Cl2 (504.34 mg, 689.26 μmol) and K2CO3 (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 complete, the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (300 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (40 g, 0-100% EA / PE) to afford H88-f (4.2 g, yellow solid) in a yield of 89.13%. MS m / z (ESI): 628.2 [M-56+H] + .

[0688] Step 7: Dissolve H88-f (4.2 g, 6.14 mmol) in DCM (30 mL) and add a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 10 mL). Stir at room temperature for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain H88-g (3.8 g, yellow solid, HCl). Yield: 99.76%. MS m / z (ESI): 584.2 [M-HCl+H] + .

[0689] Step 8: H88-g (3.8 g, 6.51 mmol) was dissolved in a mixture of THF (40 mL) and water (10 mL). LiOH (3.12 g, 130.24 mmol) was added and stirred at 80°C for 18 hours. After completion of the reaction, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid (2 mol / L). The mixture was then filtered and the filter cake was washed with water. 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]. + .

[0690] 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 stirred at room temperature for 10 minutes. H88-b (99.49 mg, 221.62 μmol, HCl) was added and stirred at room temperature overnight. After completion of the reaction, 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) to obtain H88 (40.09 mg) in a yield of 23.65%. MS m / z (ESI): 459.7 [M / 2+H] + . 1 H 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=8.6,3.8 Hz,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).

[0691] Example 91 Preparation of Compound H91

[0692] Step 1: 6-Bromo-3-iodo-2-methyl-2H-indole (1.3 g, 3.86 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.45 g, 3.47 mmol) were dissolved in THF (30 mL) and water (5 mL). Pd(dppf)Cl2 (282.30 mg, 385.81 μmol) and Cs2CO3 (2.51 g, 7.72 mmol) were added under argon protection, and the temperature was raised to 80°C and stirred overnight. After the reaction was complete, the reaction solution was cooled to room temperature, and then water and ethyl acetate were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified using CombiFlash (12 g, 0-20% EA / PE) to obtain H91-a (1.6 g, pale white solid) in a yield of 82.88%. MS m / z (ESI): 500.1 [M+H] + .

[0693] Steps 2-5: Compound H91 was prepared according to the synthetic route described in Example 46. Preparative HPLC purification conditions were as follows: a 21.2 x 250 mm C18 column; a 10 mM NH₄HCO₃ / H₂O-acetonitrile system; a wavelength of 254 / 214 nm; and a gradient of 5% to 95% acetonitrile. MS m / z (ESI): 453.8 [M / 2+H] + . 1 H 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=8.8 Hz,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,1 H),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).

[0694] Example 92 Preparation of Compound H92

[0695] Step 1-Step 2: Referring to the preparation method of Example 46, according to the above synthetic route, H92-b was prepared, MS m / z (ESI): 311.1 [M+H] + .

[0696] 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. The mixture was heated to 70°C and stirred for 2 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and then purified via CombiFlash (4 g, 0-10% MeOH / DCM) to afford H92-c (90 mg, light yellow solid) in a yield of 60.39%. MS m / z (ESI): 309.1 [M+H] + .

[0697] Step 4: Referring to the preparation method of Example 46, H92 was prepared according to the above synthetic route. The preparative HPLC purification conditions were: preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile. MS m / z (ESI): 860.3 [M+H] + . 1 H 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).

[0698] Example 93 Preparation of Compound H93

[0699] 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] + .

[0700] Step 3-Step 5: Referring to the preparation method of Example 67, according to the above synthetic route, H93 was prepared, MS m / z (ESI): 868 [M+H] + . 1 H 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).

[0701] Example 94 Preparation of Compound H94

[0702] Step 1: Dissolve 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (300 mg, 1.09 mmol) and benzyl N-(3-azabicyclo[3.2.1]octan-8-yl)carbamate (311.02 mg, 1.19 mmol) in NMP (951.94 mL), warm to 120°C, and stir for 1.5 hours. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0-10%) to obtain H94-a (100 mg, yellow solid) in a yield of 17.82%. MS m / z (ESI): 517 [M+H]. + .

[0703] Step 2: Dissolve H94-a (90 mg, 174.23 μmol) in MeOH (5 mL), add palladium on carbon (185.42 mg, 174.23 μmol, 10% purity), and stir at room temperature under hydrogen for 6 hours. After completion of the reaction, filter the reaction solution, and concentrate the filtrate to obtain H94-b (50 mg, yellow solid) in a yield of 75.04%. MS m / z (ESI): 383 [M+H] + .

[0704] Step 3: Intermediate Z1 (100 mg, 192.48 μmol) was dissolved in DMF (3 mL). 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. The mixture was stirred at room temperature for 20 minutes. H94-b (73.61 mg, 192.48 μmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (MeOH:DCM = 0-10%) to obtain H94 (5.51 mg, 98.8% purity) in a yield of 3.27%. MS m / z (ESI): 866 [M+H] + . 1 H 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).

[0705] Example 96 Preparation of Compound H96

[0706] Step 1: Intermediate Z1 (120 mg, 0.23 mmol) was dissolved in DMF (2.82 mL). DIPEA (180 mg, 1.39 mmol) and HA TU (261.43 mg, 692.94 μmol) were added and stirred at room temperature for 0.5 h. Tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (74 mg, 0.35 mmol) was then added and stirred at room temperature overnight. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (0-10% MeOH / DCM) to afford H96-a (69 mg, yellow solid) in a yield of 42.81%. MS m / z (ESI): 698.3 [M+H]. + .

[0707] Step 2: Dissolve H96-a (30 mg, 0.043 mmol) in DCM (5 mL), add HCl / EA (4 mol / L, 0.5 mL), and stir at room temperature for 2 hours. After completion of the reaction, concentrate the reaction solution to obtain H96-b (25 mg, crude product) in a yield of 97.3%. Use directly in the next reaction. MS m / z (ESI): 598.3 [M+H] + .

[0708] Step 3: H96-b (23.54 mg, 39.39 μmol) was dissolved in DCM (8 mL), and acetic acid (6.76 mg, 112.55 μmol) was added. The mixture was stirred at room temperature for 1 hour, followed by the addition of NaBH(OAc)₃ (23.85 mg, 112.55 μmol) and continued stirring overnight. After completion of the reaction, the reaction solution was concentrated and purified by preparative HPLC (preparative column: 21.2 x 250 mm C₁₈ column; system: 10 mM NH₄HCO₃ / H₂O-acetonitrile; wavelength: 254 / 214 nm; gradient: 0%-60% acetonitrile) to obtain H96 (1.39 mg) in a yield of 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=1 4.8Hz,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).

[0709] Example 98 Preparation of Compound H98

[0710] Step 1: Dissolve 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) with stirring at room temperature. Stir at room temperature for 5 minutes. Add tert-butyl 4-amino-3,3-difluoro-piperidine-1-carboxylate (272.86 mg, 1.15 mmol) and stir at room temperature for 2 hours. After completion of the reaction, the reaction solution was 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) in a yield of 86.62%. MS m / z (ESI): 720 [M+H] + .

[0711] Step 2: H98-a (180 mg, 250.09 μmol) was dissolved in MeOH (5 mL) and DCM (10 mL). A solution of hydrogen chloride in ethyl acetate (4.0 mol / L, 7.50 mL) was added with stirring at room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated and dissolved in a small amount of methanol. Saturated aqueous sodium carbonate was added and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford H98-b (100 mg, yellow solid). Yield: 64.53%. MS m / z (ESI): 620 [M+H]. + .

[0712] 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). 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 completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (EA:PE = 0-50%, then MeOH:DCM = 0-10%) and then by preparative HPLC to obtain H98 (9.81 mg, 95.44% purity) in a yield of 5.52%. MS m / z (ESI): 876 [M+H] + . 1 H 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).

[0713] Example 99 Preparation of Compound H99

[0714] Referring to the preparation method of Example 66, H99 was prepared according to the above synthetic route. Preparative HPLC purification conditions were: a 21.2 x 250 mm C18 column; a 10 mM NH₄HCO₃ / H₂O-acetonitrile system; a wavelength of 254 / 214 nm; and a gradient of 5% to 95% acetonitrile. MS m / z (ESI): 812.3 [M+H] + . 1 H 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),4.7 1(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).

[0715] Example 101 Pre...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: POI-(L) n0 —ULM (I), in, L is the connection link between POI and ULM; ULM is the group that binds to the E3 ligase; n0 is 0 or 1; POI is a ligand that binds to the EED protein and has a structure represented by formula (A-1) or an isomer thereof. in, express (double bond) or (single bond); W1, W2, W3 are each independently selected from a bond, -CH2-, -(CH2)2-, -CH=CH-, -CH=N-, -N=N-, -(CH2)3-, -C(O)NH-, -NHC(O)-, -C(O)-, -NH-, -CH- and -N-; W4 and W5 are each independently selected from -CH-, -N- and -C-; A1 ring is selected from C 3-15 Cycloalkyl ring (preferably C 3-12 A cycloalkyl ring, more preferably C 3-10 Cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, 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 C 6-14 Aromatic rings; (R1) p1 represents that the hydrogen on the A1 ring is replaced by p1 R1, p1 is 0, 1, 2 or 3, each R1 is the same or different, and each is independently selected from X1, 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, more preferably C 1-3 Alkyl), halogenated C 1-10 Alkyl (preferably halogenated C 1-8 Alkyl, more preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 1-10 Alkoxy (preferably C 1-8 Alkoxy, more preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-10 Alkoxy (preferably halogenated C 1-8 Alkoxy, more preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -COC 1-10 Alkyl (preferably -COC 1-8 Alkyl, more preferably -COC 1-6 Alkyl, more preferably -COC 1-3 Alkyl), -COOC 1-10 Alkyl (preferably -COOC 1-8 Alkyl, more preferably -COOC 1-6 Alkyl, more preferably -COOC 1-3 alkyl), -CONH2, -CONHC 1-10 Alkyl (preferably -CONHC 1-8 Alkyl, more preferably -CONHC 1-6 Alkyl, more 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, more preferably -CON(C 1-3 Alkyl)2), -SOC 1-10 Alkyl (preferably -SOC 1-8 Alkyl, more preferably -SOC 1-6 Alkyl, more preferably -SOC 1-3 Alkyl), -SO2C 1-10 Alkyl (preferably -SO2C 1-8 Alkyl, more preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), -SO2NH2, -SO2NHC 1-10 Alkyl (preferably -SO2NHC 1-8 Alkyl, more preferably -SO2NHC 1-6 Alkyl, more preferably -SO2NHC 1-3 Alkyl), -SO2N(C 1-10 Alkyl)2 (preferably -SO2N(C 1-8 Alkyl)2, more preferably -SO2N(C 1-6 Alkyl)2, more preferably -SO2N(C 1-3 Alkyl)2), C 3-8 Cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 15-membered heterocycloalkyl (preferably 4 to 12-membered heterocycloalkyl, more preferably 4 to 8-membered heterocycloalkyl, further preferably 4 to 6-membered heterocycloalkyl), 5 to 10-membered heteroaryl (preferably 5 to 6-membered heteroaryl) and C 6-14 Aryl; said C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, -COC 1-10 Alkyl, -COOC 1-10 Alkyl, -CONH2, -CONHC 1-10 Alkyl, -CON(C 1-10 Alkyl)2, -SOC 1-10 Alkyl, -SO2C 1-10 Alkyl, -SO2NH2, -SO2NHC 1-10 Alkyl, -SO2N(C 1-10 Alkyl)2, C 3-8 Cycloalkyl, 3- to 15-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 6-14 The aryl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, halogen, 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, C 3-6 Cycloalkyl, 3- to 15-membered heterocycloalkyl (preferably 4- to 12-membered heterocycloalkyl, more preferably 4- to 8-membered heterocycloalkyl, further preferably 4- to 6-membered heterocycloalkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl), phenyl and naphthyl; (R2) p2 represents that the hydrogen on the A2 ring is replaced by p2 R2, p2 is 0, 1, 2 or 3, each R2 is the same or different, and each is independently selected from X1, hydrogen, deuterium, C 1-10 Alkyl (preferably C 1-8 Alkyl, more preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-10 Alkoxy (preferably C 1-8 Alkoxy, more preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-10 Alkyl (preferably halogenated C 1-8 Alkyl, more preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), halogenated C 1-10 Alkoxy (preferably halogenated C 1-8 Alkoxy, more preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), C 3-8 Cycloalkyl (preferably C 3-6 cycloalkyl), 3 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 5 to 10-membered heteroaryl (preferably 5 to 6-membered heteroaryl) and C 6-14 Aryl (preferably C 6-12 Aryl); said C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, 5- to 10-membered heteroaryl, C 3-8 Cycloalkyl, 3- to 15-membered heterocycloalkyl, C 6-14 Aryl is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), hydroxy, carboxyl, nitro, formyl, sulfonic acid, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated 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 represents that the hydrogen on the 2,3-dihydrobenzofuran ring is replaced by p3 R3, p3 is 0, 1 or 2, each R3 is the same or different, and each 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), -CONH2, -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), -SO2C 1-8 Alkyl (preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), -SO2NH2, -SO2NHC 1-8 Alkyl (preferably -SO2NHC 1-6 Alkyl, more preferably -SO2NHC 1-3 Alkyl), -SO2N(C 1-8 Alkyl)2 (preferably -SO2N(C 1-6 Alkyl)2, more preferably -SO2N(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 and / or two adjacent R3 and the carbon atom connected thereto form a C 3-8 Cycloalkyl ring (preferably C 3-6 cycloalkyl ring), 3 to 8 membered heterocycloalkyl ring (preferably 3 to 6 membered heterocycloalkyl ring, 4 to 5 membered heterocycloalkyl ring), 5 to 10 membered heteroaryl ring (preferably 5 to 6 membered heteroaryl ring), 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, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -SO2NH2, -SO2NHC 1-8 Alkyl, -SO2N(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 The cycloalkyl ring, 3- to 8-membered heterocycloalkyl ring, 5- to 10-membered heteroaryl ring, and benzene ring 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(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 represents that the hydrogen on the imidazo[1,5-c]pyrimidine ring is replaced by p4 R4, p4 is 0, 1 or 2, each R4 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), -CONH2, -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), -SO2C 1-8 Alkyl (preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), -SO2NH2, -SO2NHC 1-8 Alkyl (preferably -SO2NHC 1-6 Alkyl, more preferably -SO2NHC 1-3 Alkyl), -SO2N(C 1-8 Alkyl)2 (preferably -SO2N(C 1-6 Alkyl)2, more preferably -SO2N(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); said 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, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -SO2NH2, -SO2NHC 1-8 Alkyl, -SO2N(C 1-8 Alkyl)2, C 3-8 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 6-14 The aryl 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(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), 5 to 10 membered heteroaryl (preferably 5 to 6 membered heteroaryl) and C 6-14 Aryl (preferably C 6-12 Aryl); Wherein, X1 is the connection site between POI and L or ULM, and at least one of R1 and R2 is X1.

2. 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, 3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R is selected from X, 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, -CH2-cyclopropyl, -CH2-tetrahydropyrrolyl, -CH2-pyrrolyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-quinolyl and -CH2-cyclohexenyl; Preferably, R1 is selected from X1, hydrogen, -CN, -COOH, -NO2, -CHO, -SO3H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2C H2CH3, -OCH(CH3)2, -OC(CH3)3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -COCH 3. -COOCH3, -CONH2, -CONHCH3, -CON(CH3)2, -SOCH3, -SO2CH3, -SO2NH2, -SO2NHCH3 and -SO2N(CH3)2; Preferably, R1 is selected from X1, hydrogen, -CH3, -CHF2, -CF3, -CH2OH, -OCH3, -OCH2CH3, -COCH3, -COOCH3, -CONH2, -CONHCH3, -CON(CH3)2, -SOCH3, -SO2CH3, -SO2NH2, -SO2NHCH3 and -SO2N(CH3)2; Preferably, R1 is selected from X1, -CH3 and -CF3; Preferably, R1 is selected from X1 and -CF3.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: p1 is 1, and R1 is X1 or -CF3.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R2 is selected from X1, 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 3-6 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 -CH2-(tetrahydro-2H-pyran); Preferably, R2 is selected from X1, 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); Preferably, R2 is selected from X1, 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); Preferably, R2 is selected from X1, -CH3, -CH2CHF2, -CH2CF2CH3 and -CH(CH3)2; Preferably, R2 is selected from X1 and -CH(CH3)2.

6. 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 R2 is X1 or -CH(CH3)2.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R is selected from the group consisting of 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, -CH2-cyclopropyl, -CH2-tetrahydropyrrolyl, -CH2-pyrrolyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-quinolyl, -CH2-cyclohexenyl, -CH2-azetidine, -CH2-piperidine, -CH2-piperazine, tetrahydro-2H-pyran and -CH2-(tetrahydro-2H-pyran); Preferably, 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.

8. 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, R3 is fluorine; Preferably, the structure for 9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Two adjacent R3 and the carbon atom connected to them form a C 3-6 a cycloalkyl ring, a 3- to 6-membered heterocycloalkyl ring, or a 5- to 6-membered heteroaryl ring; Preferably, two adjacent R3 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; Preferably, two adjacent R3 and the carbon atom to which they are connected form a cyclopropane ring.

10. 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 R3 is fluorine, and the other two R3 and the carbon atoms connected thereto form a cyclopropane ring; Preferably, the structure for Preferably, the structure for 11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: C in the A1 ring 3-15 The cycloalkyl ring is selected from the group consisting of 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 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 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 C in the A1 ring 6-14 The aromatic ring is selected from a benzene ring and a naphthalene ring; 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; Preferably, the A1 ring is selected from a benzene ring, a pyridine ring and a pyrazole ring; Preferably, the A1 ring is selected from a benzene ring and a pyridine ring; Preferably, the structure Selected from Preferably, the structure Selected from: Preferably, the structure Selected from wherein R1, R2, p1, and X1 are as defined in claim 1, and at least one of R1 and R2 is X1; Preferably, the structure Selected from: Wherein, R1, R2, p1, and X1 are as defined in claim 1, and at least one of R1 and R2 is X1.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Selected from wherein Y1, Y2, and Y3 are each independently CH or N, and R1, R2, p1, A1, and X1 are as defined in claim 1; Preferably, the structure Selected from Where X1 is the connection site between POI and L or ULM; Preferably, the structure Selected from Where X1 is the connection site between POI and L or ULM; Preferably, the structure Selected from: Where X1 is the connection site between POI and L or ULM; Preferably, the structure Selected from: Where X1 is the connection site between POI and L or ULM.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: POIs are selected from the following structure: Where X1 is the connection site between POI and L or ULM; Preferably, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM; Preferably, the POI is selected from the following structures: Where X1 is the connection site between POI and L or ULM.

14. 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), wherein m1 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L a Each occurrence 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, more preferably C 1-3 Alkylene), C 1-10 Alkyleneoxy (preferably C 1-8 Alkyleneoxy, more preferably C 1-6 Alkyleneoxy, more preferably C 1-3 Alkyleneoxy), C 2-10 Alkenylene (preferably C 2-8 Alkenylene, more preferably C 2-6 Alkenylene, more preferably C 2-4 Alkenylene), C 2-10 Alkyne (preferably C 2-8 Alkyne, more preferably C 2-6 Alkyne, more preferably C 2-4 Alkyne), C 3-15 Cycloalkyl ring (preferably C 3-10 A cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 15-membered heteroaryl ring (preferably a 5- to 14-membered heteroaryl ring, more preferably a 5- to 12-membered heteroaryl ring, further preferably a 5- to 10-membered heteroaryl ring, further preferably a 5- to 6-membered heteroaryl ring) and C 6-14 Aromatic ring (preferably a benzene ring or a naphthalene ring); the C 1-10 Alkylene, C 1-10 Alkyleneoxy, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-15 Cycloalkyl ring, 3- to 15-membered heterocycloalkyl ring, 5- to 15-membered heteroaryl ring, C 6-14 The aromatic ring is unsubstituted or substituted with 1, 2, 3 or 4 R L2 Substitute, the R L2 are each independently selected from deuterium, halogen, hydroxyl, cyano, amino, carboxyl, formyl, oxo, sulfonic acid, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkylC 1-6 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroarylC 1-6 Alkyl, phenyl, phenyl C 1-6 Alkyl, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl and -SO2N(C 1-6 Alkyl)2; R L1 Each occurrence is independently selected from hydrogen, deuterium, 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), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy) and halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl).

15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R L1 each occurrence 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; Preferably, R L1 Each occurrence is independently selected from hydrogen, methyl, ethyl, difluoromethyl and monofluoromethyl; Preferably, R L1 For hydrogen.

16. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R L2 each 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 yl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-cyclohexenyl, -CH2-cyclopentenyl, -CH2-tetrahydropyrrolyl, -CH2-tetrahydrofuranyl, -CH2-phenyl, -CH2-pyrrolyl, -CH2-triazolyl, -CH2-tetrazolyl, -CH2-pyridyl, -CH2-pyrazinyl, -CH2-triazinyl, methoxy, ethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethoxy, acetyl, acetylamino, and sulfonamido; Preferably, R L2 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(CH3)2, -SOCH3, -SO2CH3, -SO2NH2, -SO2NHCH3 and -SO2N(CH3)2; Preferably, R L2 each 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; Preferably, R L2 Each is independently selected from fluorine, chlorine, bromine, methyl, hydroxyl and hydroxymethyl.

17. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The L a Each is independently selected from the following structures or isomers thereof: -C(O)-, -C(O)NH-, -O-, -S-, -NH-, C 1-10 Alkylene, C 1-10 Alkyleneoxy, C 3-12 Cycloalkyl ring, 4 to 12 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring and benzene ring; said C 3-12 The cycloalkyl ring, the 4- 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 R L2 Substitute, the R L2 is selected from fluorine, methyl, hydroxyl and hydroxymethyl; Preferably, the L a Each is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH2) m2 -、-O(CH2) m2 -、-(CH2) 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; Preferably, the L a Each is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH2) m2 -、-O(CH2) m2 -、-(CH2) 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; Preferably, the L a Each 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-, -CH2CH2O-, 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,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; Preferably, the L a Each 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-, -CH2CH2O-, Preferably, the L a Each 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-, -CH2CH2O-, Preferably, the L a Each is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -NH-, -CH2-, Preferably, the L a Each is independently selected from the following structures or isomers thereof: -CONH-, -CO-, -CH2-, -NH-, Preferably, the L a Each is independently selected from the following structures or isomers thereof: -CONH-, -CH2-, -NH-, -CO-, Preferably, the L a Each is independently selected from the following structures or isomers thereof: -CH2-, -NH-, -CONH-, -CO-, 18. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The 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 -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-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) m3 O(CH2) m3 -、-Cy0-C(O)-(CH2) m3 -、-NH-Cy0-(CH2) m3 -Cy0- and -(CH2) m3 -Cy0-O-Cy0-O(CH2) m3 -; wherein m3 each occurrence is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Cy0 each occurrence is independently selected from C 3-12 Cycloalkyl ring (preferably C 3-10 A cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably C 3-6 cycloalkyl ring), 3 to 12 membered heterocycloalkyl ring (preferably 3 to 10 membered heterocycloalkyl ring, more preferably 3 to 8 membered heterocycloalkyl ring, further preferably 3 to 6 membered heterocycloalkyl ring), 5 to 6 membered heteroaryl ring and benzene ring; the C 3-12 The 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 R L2 Replacement, R L2 Each occurrence is independently selected from deuterium, halogen, hydroxyl, cyano, amino, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated 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, -CONH2, -CONHC 1-3 Alkyl and -CON(C 1-3 Alkyl)2; Preferably, CyO 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, 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, 1,1,3,3-tetramethylcyclobutane, 3-fluoropiperidine, (S)-3-fluoropiperidine, (R)-3-fluoropiperidine, 3,3-difluoropiperidine; Preferably, the Cy0 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; Preferably, the Cy0 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; Preferably, the Cy0 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; Preferably, the Cy0 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; Preferably, the Cy0 is independently selected from the following structures or isomers thereof: Preferably, the Cy0 is independently selected from the following structures or isomers thereof: Preferably, the Cy0 is independently selected from the following structures or isomers thereof: Preferably, the Cy0 is independently selected from the following structures or isomers thereof: Preferably, the Cy0 is independently selected from the following structures or isomers thereof:

19. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: 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; 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; 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; 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; 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; 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; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 is the site where L is connected to ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 is the site where L is connected to ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 is the site where L is connected to ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 is the site where L is connected to ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection site between L and POI, X 20 It is the site where L connects to ULM.

20. 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: in, express U0 is a bond, -N(R U0 )-、-CON(R U0 )-, -CH2- or -(CH2)2-; R U0 Each occurrence is independently hydrogen or C 1-3 alkyl; B ring 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), C 3-15 Cycloalkyl ring and C 6-10 An aromatic ring (preferably a benzene ring); S1, S3, S5 are each independently selected from a bond, -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- and -SO2-; S2 and S4 are each independently selected from -N-, -NH-, -CH- and -CH2-; S6 is selected from C, -CH- and N; (R B1 ) b1 Indicates that the hydrogen on the B ring is replaced by b1 R B1 Substitution, b1 is 0, 1, 2 or 3, each R B1 are the same or different and are independently selected from X2, 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), -SO2C 1-8 Alkyl (preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), amino-substituted C 1-8 Alkyl (preferably amino substituted C 1-6 Alkyl, more preferably amino substituted 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), hydroxy substituted C 1-8 Alkyl (preferably hydroxy substituted C 1-6 Alkyl, more preferably hydroxy substituted C 1-3 Alkyl), carboxyl substituted C 1-8 Alkyl (preferably carboxyl substituted C 1-6 Alkyl, more preferably carboxyl substituted C 1-3 Alkyl), -COC 1-8 Alkyl (preferably -COC 1-6 Alkyl, more preferably -COC 1-3 Alkyl), -COOC 1-8 Alkyl-CONR a2 R b2 (preferably -COOC 1-6 Alkyl-CONR a2 R b2 , more preferably -COOC 1-3 Alkyl-CONR a2 R b2 ), -SO2NR a2 R b2 , C 3-15 Cycloalkyl ring (preferably C 3-10 A cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, 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 C 6-10 Aromatic ring (preferably benzene ring or naphthalene ring); or two adjacent R B1 The carbon atom it is connected to forms C 3-15 Cycloalkyl ring (preferably C 3-10 A cycloalkyl ring, more preferably C 3-8 Cycloalkyl ring, more preferably 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, further preferably a 4- to 6-membered heterocycloalkyl ring), a 5- to 6-membered heteroaryl ring or a benzene ring; the C 3-15 The cycloalkyl ring, 3- to 15-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring or benzene ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of X2, 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, -SO2C 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 -SO2NR a2 R b2 ; (R B2 ) b2 Indicates that the hydrogen on the C ring is replaced by b2 R B2 Substitution, b2 is 0, 1, 2, 3 or 4, each R B2 are the same or different and are independently selected from X2, deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, -NR a1 R b1 , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONR a2 R b2 、-OC(O)C 1-6 Alkyl substituted C 1-6 Alkyl and -COOC 1-6 Alkyl substituted C 1-6 alkyl; R a1 , R b1 , R a2 , R b2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, -COC 1-6 Alkyl and -COOC 1-6 alkyl; Among them, X2 is the connection site between ULM and L or POI, and R B1 and R B2 At least one of them is X2.

21. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Ring B is absent; or 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 Preferably, the 5- to 15-membered heteroaryl ring in ring B is selected from a pyridine ring and a benzopyrazole ring; Preferably, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in indicates covalent attachment to U0; Preferably, the 5- to 15-membered heteroaryl ring in Ring B is selected from: in indicates covalent attachment to U0; C in B ring 6-10 The aromatic ring is selected from a benzene ring and a naphthalene ring; or Preferably, the C in ring B 6-10 The aromatic ring is a benzene ring; The 3 to 15-membered heterocycloalkyl ring in Ring B is selected from: in indicates a covalent bond to U0; or The 3- to 15-membered heterocycloalkyl ring in Ring B is Wherein, Q1, Q2, Q3, and Q4 are each independently selected from -CH-, N, and NO; S7 and S8 are each independently selected from a bond, -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- and -SO2-; indicates a covalent bond to U0; or Preferably, Q1, Q2, Q3, and Q4 are each independently -CH-; Preferably, S8 is selected from -CH=N-, -N=N-, -CH2C(O)-, -C(O)O-, -CONH- and -CH=CH-; Preferably, S7 and S8 are each independently selected from -CH2- and -C(O)-; Preferably, S7 is -CH2-, and S8 is -C(O)-; Preferably, S7 is -C(O)-, and S8 is -C(O)-; Preferably, S7 is -CH2-, and S8 is -C(S)-; Preferably, S7 is -C(O)-, and S8 is -C(S)-; Preferably, S7 is a bond and S8 is -CONH-; Preferably, the structure Selected from the following structures or isomers thereof: in indicates covalent attachment to U0; The 3- to 15-membered heterocycloalkyl ring in Ring B is Wherein, ring B1 and ring B2 are each independently selected from C 4-8 Cycloalkyl ring, 4- to 8-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring and benzene ring; S9, S 10 are each independently selected from a bond, -CH2-, and -C(O)-; indicates a covalent bond to U0; or Preferably, the structure Selected from in indicates covalent attachment to U0; 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 C 5-7 cycloalkyl rings and 5- to 7-membered heterocycloalkyl rings, indicates a covalent bond to U0; or 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; Preferably, the 3 to 15 membered heterocycloalkyl ring in Ring B is selected from in indicates covalent attachment to U0; Preferably, the 3 to 15 membered heterocycloalkyl ring in Ring B is in indicates covalent attachment to U0; Preferably, Ring B3 is a 5- to 7-membered nitrogen-containing heterocycloalkyl ring; 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; Preferably, the structure Selected from in indicates covalent attachment to U0; 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 Each is independently selected from -C-, -N-, -S-, -O-, -NH-; indicates a covalent bond to U0; or Preferably, the structure Selected from: in indicates covalent attachment to U0; The 3- to 15-membered heterocycloalkyl ring in Ring B is wherein Ring B7 is a 5- to 10-membered heterocycloalkyl ring, Q5, Q6, Q7, Q8, Q9 are each independently selected from C, -CH- and N, indicates covalent attachment to U0; Preferably, ring B7 is 1,3-dioxole; Preferably, the structure Selected from in Indicates covalent linkage to U0.

22. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Ring B is selected from: in indicates covalent attachment to U0; Preferably, the B ring is selected from the following structures or isomers thereof: in indicates covalent attachment to U0; Preferably, the B ring is selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

23. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R B1 Each 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)2OH, -(CH2)3OH, -CH2COOH, -(CH2)2COOH, -(CH2)3COOH, -COCH3, -COCH2CH3, -COOCH3, -COOCH2CH3, -CONH2 or -SO2NH2; or two adjacent R B1 The carbon atom connected thereto forms 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, and the cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclopentene ring, cyclohexene ring, cycloheptene ring, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydro The thiophene 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 with 1, 2, 3 or 4 substituents selected from the group consisting of X2, deuterium, fluorine, chlorine, bromine, cyano, carboxyl, hydroxyl, nitro, amino, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -SCH3, -SOCH3, -SO2CH3, -COCH3, -COOCH3, -CONH2 and -SO2NH2; Preferably, R B1 is selected from fluorine, chlorine, hydroxy, methyl, trifluoromethyl and methoxy.

24. 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, R B1 For fluorine.

25. 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 U0; 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 U0; Preferably, Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI, Indicates covalent linkage to U0.

26. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: U0 is a bond, -NH-, -CONH- or -CH2-.

27. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: S1 and S3 are -C(O)-, S2 is -NH-, and S4 and S5 are -CH2-; Preferably, the structure Selected from the following structures or isomers thereof: in indicates covalent attachment to U0; Preferably, the structure Selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

28. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

29. 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: in, (R U7 ) r1 Indicates that the hydrogen on the tetrahydropyrrole ring is replaced by r1 R U7 Substitution, r1 is 0, 1, 2 or 3, each R U7 are the same or different and are each 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; R U1 -C(R U3 R U4 )-U1; U1 is selected from the following structures or isomers thereof: X2, -NHCO-X2, -NHCOCH3, 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 X2, 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 -COCH3), -COOC 1-6 Alkyl (preferably -COOCH3), -CONH2, -CONHC 1-6 Alkyl (preferably -CONHCH3), -CON(C 1-6 alkyl)2 (preferably -CON(CH3)2) and hydroxy-substituted C 1-6 Alkyl (preferably -CH2OH); Preferably, U1 is selected from X2, -NHCO-X2, -NHCOCH3, Preferably, U1 is selected from -NHCO-X2 and 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; Preferably, R Ua is selected from fluoro, cyano, methyl, ethyl, trifluoromethyl and trifluoromethoxy; Preferably, R Ua is selected from fluorine and cyano; R U3 , 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 , R U4 Together with the carbon atom to which it is attached, it forms C 3-7 Cycloalkyl (preferably C 3-6 cycloalkyl) and 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 Cycloalkyl, 3- to 7-membered heterocycloalkyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X2, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl and hydroxyl; R U5 , R U6 Each is independently selected from X2, 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), CONHC 1-6 Alkyl substituted C 1-6 Alkyl, CON(C 1-6 Alkyl)2-substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl and COOC 1-6 Alkyl substituted C 1-6 alkyl; (R U2 ) r2 Indicates that the hydrogen on the D ring is replaced by r2 R U2 substituted, r2 is 0, 1, 2 or 3, each R U2 are the same or different, each independently selected from X2, hydrogen, deuterium, halogen (preferably fluorine, chlorine), nitro, cyano, carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, 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, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SC 1-6 alkyl, 5- to 6-membered heteroaryl and phenyl; the 5- to 6-membered heteroaryl and phenyl 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 hydroxy substituted C 1-3 Alkyl), C 1-6 Alkoxy 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), -NH2, -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), -CONH2, -NHCONH2, -CONHC 1-6 Alkyl, -NHCONHC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl and -SC 1-6 alkyl; The D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-10 Cycloalkyl ring (preferably C 3-8 A cycloalkyl ring, more preferably 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 , 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), -CONH2, -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 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), -CONH2, -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl) and -CON(C 1-6 Alkyl)2 (preferably -CON(C 1-3 Alkyl)2); Preferably, R a3 , R b3 Each is 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 by 1 or 2 substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, -COCH3 and -CONH2; Among them, X2 is the connection site between ULM and L or POI, and U1, R U5 , R U6 and R U2 At least one of them is X2, or R U1 Contains at least one X2.

30. 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 its isomer: Preferably, R U7 Selected from hydroxyl, amino, -OCH3, -OCF3 and -OCOCH3; Preferably, R U7 It is hydroxyl.

31. The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U3 , R U4 are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; or R U3 , R U4 The carbon atom to which it is attached forms a C 3-6 Cycloalkyl ring; Preferably, R U3 , R U4 Each is independently hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2F, -OCH3, -OCH(CH3)2, -OC(CH3)3, -OCF3, -OCHF2, -OCH2F, fluoroisopropyl or fluorotert-butyl; or R U3 , R U4 Forms a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring with the carbon atom to which it is attached; Preferably, R U3 , R U4 Each is independently hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3; or R U3 , R U4 It forms a cyclopropyl ring with the carbon atom to which it is attached; Preferably, R U3 , R U4 Each is independently hydrogen, -CH(CH3)2 or -C(CH3)3.

32. The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U1 Selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI; Preferably, R U1 Select from the following structures: Where X2 is the connection site between ULM and L or POI; Preferably, R U1 Select from the following structures: Where X2 is the connection site between ULM and L or POI.

33. The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U5 , R U6 Each independently represents X2, 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; Preferably, R U5 , R U6 are independently hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; Preferably, R U5 , R U6 Each is independently hydrogen, -CH3, -OCH3, -CF3, -OCF3, -CHF2, -CH2F, -OCHF2 or -OCH2F; Preferably, R U5 , R U6 Each is independently hydrogen or -CH3.

34. 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 phenyl group, wherein 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 deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHCOC 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -CONH2, -NHCONH2, -CONHC 1-3 Alkyl, -NHCONHC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl and -SC 1-3 alkyl; or R U2 is cyano; or R U2 NHR a3 , where 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 with 1, 2 or 3 substituents selected from the group consisting of: C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, -SC 1-3 Alkyl and -OCOC 1-3 alkyl; Preferably, the 5- to 6-membered heteroaryl group is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, tetrazolyl and triazolyl; Preferably, the 5- to 6-membered heteroaryl group is selected from Preferably, the 5- to 6-membered heteroaryl group is 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; Preferably, R U2 NHR a3 , where R a3 is thiazolyl; the 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; Preferably, R U2 NHR a3 , where R a3 is thiazolyl; the thiazolyl is substituted by 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl and isopropyl; Preferably, R U2 Selected from the following structures: cyano, 35. 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 Selected from cyano, Preferably, r2 is 1, R U2 for Preferably, r2 is 2, R U2 X2 and Where X2 is the connection site between ULM and L or POI.

36. The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-6 Cycloalkyl rings and 3- to 6-membered heterocycloalkyl rings; Preferably, the D ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring; 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; Preferably, the D ring is selected from a benzene ring and a pyridine ring.

37. 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 X2 is the connection site between ULM and L or POI; Preferably, Selected from the following structures or isomers thereof:

38. The compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The ULM is selected from the following structures or isomers thereof: ; Wherein X2 is the connection site between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection site between ULM and L or POI.

39. 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: Among them, R n1 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; said C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-14 Aryl, 5- to 10-membered heteroaryl is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, 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, -SO2C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl; Preferably, R n1 Selected from tert-butyl, tert-butyl substituted by morpholinyl, thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane; the thiazole, pyrazole, oxazole, isoxazole, benzene ring, pyridine, benzothiazole, cyclobutane is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the following group: halogen, cyano, hydroxyl, nitro, trifluoromethyl, difluoromethyl, monofluoromethyl, methyl, ethyl, propyl, isopropyl, methoxy, -SCH3, -SOCH3, -SO2CH3, -NHCH3, -N(CH3)2, -COCH3; Preferably, R n1 is selected from tert-butyl and pyridyl, wherein the pyridyl is substituted by bromine; R n2 , R n3 Together with the connected N, it forms 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 X2, 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, -SO2C 1-6 Alkyl, C 3-12 Cycloalkyl, C 3-12 Heterocycloalkyl, C 6-14 Aryl, 5- to 10-membered heteroaryl; Preferably, R n2 , R n3 Together with the connected N, a 4- to 12-membered heterocycloalkyl ring is formed, 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 by 1, 2, 3 or 4 substituents selected from the group consisting of X2, fluorine, chlorine, bromine, nitro, cyano, hydroxyl, carboxyl, oxo, -CHO, amino, methyl, tert-butyl, methoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, -NH(CH3), -N(CH3)2, -NHCOCH3, -COCH3, -COOCH3, -SOCH3, -SO2CH3, cyclopropyl; Preferably, R n2 , R n3 Together with the connected N, it forms a piperidine ring.

40. The compound of formula (I) according to claim 39, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: ULM is selected from the following structures:

41. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (I) has the structure represented by formula (IA), in, A1 ring, R1, R3, R4, p1, p3, p4, L, ULM, n0 are as defined in claim 1, and R1 is not X1.

42. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (I) has the structure represented by formula (IB), in, A1 ring, R1, R2, R3, R4, p1, p3, p4, L, ULM, n0 are as defined in claim 1, and R1 and R2 are not X1; Preferably, the compound represented by formula (I) is a compound represented by formula (IB-1), Wherein, Y1, Y2, and Y3 are each independently CH or N, R1, R2, R3, R4, L, ULM, p1, p3, p4, n0 are as defined in claim 1, and R1 and R2 are not X1.

43. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (I) is selected from the following structures: wherein R1, R2, R3, p1, p3, L, ULM, n0 are as defined in claim 1, and R1 and R2 are not X1; Preferably, the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, n0 are as defined in claim 1; Preferably, the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, n0 are as defined in claim 1; Preferably, the compound represented by formula (I) is selected from the following structures: Wherein L, ULM, and n0 are as defined in claim 1.

44. 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:

45. 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.

46. ​​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.

47. The use according to 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.

48. 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.

49. 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.

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