Bicyclic fused heteroaromatic ring derivative, and pharmaceutical composition and use thereof

Abstract

Provided in the present application is a bifunctional compound as shown in formula (I). In addition, further disclosed in the present application are a pharmaceutically acceptable salt or a stereoisomer, a pharmaceutical composition and the use of the compound. The compound of the present application has a good degradation effect on EED, has a good inhibition effect on cell proliferation of tumor cells, and has a potential treatment effect on tumors. POI—(L)n0—ULM (I)

Description

Bicyclic fused heteroaromatic ring derivatives and pharmaceutical compositions and uses thereof

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on December 22, 2023, with application number 202311789109.3 and title “Bicyclic fused heteroaromatic derivatives and their pharmaceutical compositions and uses”, and the Chinese patent application filed with the China Patent Office on June 6, 2024, with application number 202410735064.X and title “Bicyclic fused heteroaromatic derivatives and their pharmaceutical compositions and uses”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to the field of medical technology, and in particular to a bicyclic fused heteroaromatic ring 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 purpose of this application is to provide a PROTAC compound, which can degrade and / or inhibit EED protein, has excellent degradation / inhibition effect on EED protein and excellent tumor cell proliferation inhibition effect, and has excellent pharmacokinetic characteristics, small toxic side effects, good safety, and is more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).

[0007] In a first aspect, the present application provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0008] POI—(L) n0 —ULM

[0009] (I),

[0010] Wherein, POI is the ligand that binds to the EED protein; L is the connecting chain connecting POI and ULM; ULM is the group that binds to the E3 ligase; and n0 is 0 or 1.

[0011] In some embodiments, n0 is 0.

[0012] In some embodiments, n0 is 1.

[0013] In some embodiments, POI is a structure represented by formula (A-1) or an isomer thereof:

[0014] wherein the A1 ring is a 5- to 20-membered heterocycloalkyl ring (preferably a 5- to 6-membered heterocycloalkyl ring, preferably a 15- to 20-membered heterocycloalkyl ring, more preferably a 15- to 18-membered heterocycloalkyl ring, further preferably an 18-membered heterocycloalkyl ring) or a 5- to 10-membered heteroaryl ring (preferably an 8- to 10-membered heteroaryl ring, more preferably a 9-membered heteroaryl ring, more preferably a 10-membered heteroaryl ring);

[0015] A2 ring is absent, 3 to 15 membered heterocycloalkyl ring, C 3-10 a cycloalkyl 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, and further preferably a 5- to 6-membered heteroaryl ring), or a C 6-10 an aryl ring (preferably a benzene ring or a naphthalene ring);

[0016] (R1) n1 It means that the hydrogen on the 2,3-dihydrobenzofuran ring is replaced by n1 R1, n1 is 0, 1 or 2, each R1 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), oxo, 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), -OCOC 1-8Alkyl (preferably -OCOC 1-6 Alkyl, more preferably -OCOC 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), -OSO2C 1-8 Alkyl (preferably -OSO2C 1-6 Alkyl, more preferably -OSO2C 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 R1 and the carbon atom to which they are connected together form 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) or a 3- to 15-membered heterocycloalkyl ring (preferably a 3- to 10-membered heterocycloalkyl ring, more preferably a 3- to 8-membered heterocycloalkyl ring, and further preferably a 3- to 6-membered heterocycloalkyl ring); the C 1-8 Alkyl, halogenated C1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy, -COC 1-8 Alkyl, -COOC 1-8 Alkyl, -OCOC 1-8 Alkyl, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -OSO2C 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 3-15 The cycloalkyl ring and the 3- to 15-membered heterocycloalkyl 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, -OCOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 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);

[0017] (R2) n2 Indicates that the hydrogen on the A1 ring is replaced by n2 R2, n2 is 0, 1 or 2, each R2 is the same or different, and is independently selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), halogenated C1-8 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), -NHC 1-8 Alkyl (preferably -NHC 1-6 Alkyl, more preferably -NHC 1-3 Alkyl), -N(C 1-8 Alkyl)2(preferably -N(C 1-6 Alkyl)2, more preferably -N(C 1-3 Alkyl)2), -COC 1-8 Alkyl (preferably -COC 1-6 Alkyl, more preferably -COC 1-3 Alkyl), -OCOC 1-8 Alkyl (preferably -OCOC 1-6 Alkyl, more preferably -OCOC 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), -PO(C 1-8 Alkyl)2(preferably -PO(C 1-6 Alkyl)2, more preferably -PO(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), -OSO2C 1-8 Alkyl (preferably -OSO2C 1-6 Alkyl, more preferably -OSO2C 1-3 Alkyl), -SC1-6 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); the C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -COC 1-8 Alkyl, -OCOC 1-8 Alkyl, -COOC 1-8 Alkyl, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -PO(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -OSO2C 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, NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COC 1-6 Alkyl, -OCOC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6Alkyl, -CON(C 1-6 Alkyl)2, -PO(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 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);

[0018] Or R1, R2, and the carbon atoms connected thereto together form a 6- to 15-membered heterocycloalkyl ring; the 6- to 15-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, carboxyl, nitro, formyl, sulfonic acid, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COC 1-6 Alkyl, -OCOC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -PO(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 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);

[0019] (R3) n3Indicates that the hydrogen on the A2 ring is replaced by n3 R3, n3 is 0, 1, 2 or 3, each R3 is the same or different, and is independently selected from X1, hydrogen, deuterium, cyano, carboxyl, nitro, formyl, sulfonic acid, halogen, oxo, 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), -OCOC 1-10 Alkyl (preferably -OCOC 1-8 Alkyl, more preferably -OCOC 1-6 Alkyl, more preferably -OCOC 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 1-6Alkyl, 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), -OSO2C 1-10 Alkyl (preferably -OSO2C 1-8 Alkyl, more preferably -OSO2C 1-6 Alkyl, more preferably -OSO2C 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; the C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, -COC 1-10 Alkyl, -OCOC 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, -OSO2C 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, C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 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;

[0020] X1 in R2 and R3 is the connection point between POI and L or ULM, and at least one of R2 and R3 is X1.

[0021] In some embodiments, the A1 ring is an 8- to 10-membered heteroaryl ring.

[0022] In some embodiments, the A1 ring is a 9-membered heteroaryl ring or a 10-membered heteroaryl ring.

[0023] In some embodiments, the A1 ring is a 9-membered nitrogen-containing heteroaryl ring or a 10-membered nitrogen-containing heteroaryl ring.

[0024] In some embodiments, the A1 ring is selected from an indolizine ring, a pyrazolopyridine ring, an imidazopyridine ring, a triazolopyridine ring, a tetraazolopyridine ring, a pyrrolopyridazine ring, a pyrazolopyridazine ring, an imidazopyridazine ring, a triazolopyridazine ring, a tetraazolopyridazine ring, a pyrrolopyrimidine ring, a pyrazolopyrimidine ring, an imidazopyrimidine ring, a triazolopyrimidine ring, a tetraazolopyrimidine ring, a pyrrolopyrazine ring, a pyrazolopyrazine ring, an imidazopyrazine ring, a triazolopyrazine ring, a pyridopyridine ring, a pyridopyrazine ring, a pyridopyrazine ring, a pyridotriazine ring, a pyridopyrimidine ring, and a tetraazolopyrazine ring.

[0025] In some embodiments, the Al ring is selected from [1,2,4]triazolo[4,3-c]pyrimidine, imidazo[1,5-c]pyrimidine, imidazo[1,2-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, and pyrido[3,4-d]pyridazine.

[0026] In some embodiments, the A1 ring is a 5- to 6-membered heterocycloalkyl ring.

[0027] In some embodiments, the A1 ring is selected from pyrimidin-4(3H)-one, 1,6-dihydropyrimidine, pyridin-2(1H)-one, 1,2-dihydropyridine, 3,8-diazabicyclo[3.2.1]octane.

[0028] In some embodiments, the A1 ring is an 18-membered heterocycloalkyl ring.

[0029] In some embodiments, the A1 ring is a partially unsaturated 18-membered heterocycloalkyl ring.

[0030] In some embodiments, the Al ring is selected from 2,3-dihydro-7'H-spiro[indene-1,8'-pyrido[3,4-d]pyridazin]-7'-one and 2,3-dihydro-7'H-spiro[indene-1,8'-pyrido[4,3-c]pyridazin]-7'-one.

[0031] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0032] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0033] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0034] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0035] In some embodiments, POI is a structure represented by formula (A-2-1) or an isomer thereof:

[0036] Wherein, W1, W2, W3, W4, W5, and W6 are each independently CH or N; A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0037] In some embodiments, POI is a structure represented by formula (A-2-2) or an isomer thereof:

[0038] Wherein, W1, W2, W3, W4, and W5 are each independently CH or N; A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0039] In some embodiments, POI is a structure represented by formula (A-3) or an isomer thereof:

[0040] Wherein, the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0041] In some embodiments, POI is a structure represented by formula (A-4) or an isomer thereof:

[0042] Wherein, the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0043] In some embodiments, POI is a structure represented by formula (A-5) or an isomer thereof:

[0044] Wherein, the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0045] In some embodiments, POI is a structure represented by formula (A-6) or an isomer thereof:

[0046] Wherein, the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0047] In some embodiments, POI is a structure represented by formula (A-7) or an isomer thereof:

[0048] Wherein, the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0049] In some embodiments, POI is a structure represented by formula (A-8) or an isomer thereof:

[0050] Wherein, the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in the specification, and at least one of R2 and R3 is X1.

[0051] In some embodiments, the A2 ring is selected from the group consisting of: absent, a 4- to 8-membered heterocycloalkyl ring, a C4-8 cycloalkyl ring, 5- to 10-membered heteroaryl ring, 10- to 15-membered heterocycloalkyl ring and benzene ring.

[0052] In some embodiments, the A2 ring is selected from absent, a 4- to 8-membered heterocycloalkyl ring, a saturated C 4-8 cycloalkyl ring, 5- to 10-membered heteroaryl ring, partially unsaturated 10- to 15-membered heterocycloalkyl ring and benzene ring.

[0053] In some embodiments, the A2 ring is selected from the group consisting of: absent, cyclobutane ring, cyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, pyrazolidine ring, imidazolidine ring, piperidine ring, hexahydropyridazine ring, hexahydropyrimidine ring, piperazine ring, benzene ring, pyrazole ring, oxazole ring, imidazole ring, triazole ring, tetrazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indolizine ring, pyrazolopyridine, imidazopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyridazine, ... Azolopyridazine, imidazopyridazine, triazolopyridazine, tetrazolopyridazine, pyrrolopyrimidine, pyrazolopyrimidine, imidazopyrimidine, triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrazine, pyrazolopyrazine, imidazopyrazine, triazolopyrazine, tetrazolopyrazine, pyridopyridine, pyridopyrazine, pyridopyrazine, pyridotriazine, pyridopyrimidine, 3,8-diazabicyclo[3.2.1]octane, 2,3-dihydrospiro[indene-1,4'-piperidine].

[0054] In some embodiments, the A2 ring is selected from the group consisting of absent, a saturated 6-membered heterocycloalkyl ring, a partially unsaturated 12-membered heterocycloalkyl ring, a cyclohexane ring, a 5- to 6-membered heteroaryl ring, a 9-membered heteroaryl ring, and a benzene ring.

[0055] In some embodiments, the A2 ring is selected from absent, a cyclohexane ring, a piperidine ring, a piperazine ring, a benzene ring, a pyridine ring, a pyrazole ring, a triazolopyridine ring, and 2,3-dihydrospiro[indene-1,4'-piperidine].

[0056] In some embodiments, the A2 ring is selected from a benzene ring, a pyridine ring, and a pyrazole ring.

[0057] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0058] In some embodiments, the structure Selected from the following structures:

[0059] In some embodiments, the structure for

[0060] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0061] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0062] In some embodiments, n1 is 0.

[0063] In some embodiments, n1 is 1 or 2.

[0064] In some embodiments, n1 is 1.

[0065] In some embodiments, R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropyloxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl, -CH2-cyclopropyl, -CH2-tetrahydropyrrolyl, -CH2-pyrrolyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-cyclohexenyl, -CH2-azetidine, -CH2-piperidine, -CH2-piperazine, tetrahydro-2H-pyran, and -CH2-(tetrahydro-2H-pyran).

[0066] In some embodiments, R1 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.

[0067] In some embodiments, n1 is 1 and R1 is fluoro.

[0068] In some embodiments, the structure for

[0069] In some embodiments, the structure for

[0070] In some embodiments, two R1 and the carbon atom to which they are attached together form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, or a piperazine ring.

[0071] In some embodiments, two R1 groups and the carbon atom to which they are attached together form a cyclopropyl ring.

[0072] 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.

[0073] In some embodiments, the structure for

[0074] In some embodiments, the structure for

[0075] In some embodiments, R2 is selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -PO(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0076] In some embodiments, R2 is selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -PO(C 1-3 Alkyl)2, -SOC1-3 Alkyl, -SO2C 1-3 Alkyl, -OSO2C 1-3 Alkyl, -SC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy.

[0077] In some embodiments, R2 is selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHCH3, -N(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -COCH3, -COC(CH3)3, -COOCH3, -COOCH2CH3, -COOC(CH3)3, -OCOCH3, -OCOCH2CH3, -OCOC(CH3)3, -PO(CH3)2, -PO(CH2CH3)2, -SOCH3, -SOCH2CH3, -SOC(CH3)3, -SO2CH3, -SO2CH2CH3, -SO2C(CH3)3, -OSO2CH3, - OSO2CH2CH3, -OSO2C(CH3)3, -SCH3, -SCH2CH3, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, monofluoroisopropyl, difluoroisopropyl, trifluoroisopropyl, monofluorotert-butyl, difluorotert-butyl, trifluorotert-butyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy, trifluoropropoxy, monofluoroisopropoxy, difluoroisopropoxy, trifluoroisopropoxy, monofluorotert-butoxy, difluorotert-butoxy, trifluorotert-butoxy.

[0078] In some embodiments, R2 is selected from X1, hydrogen, halogen, cyano, -SO2C 1-6 Alkyl, -OSO2C 1-6 alkyl.

[0079] In some embodiments, R2 is selected from X1, hydrogen, halogen, cyano, -SO2C 1-3 Alkyl, -OSO2C 1-3 alkyl.

[0080] In some embodiments, R2 is selected from X1, hydrogen, fluoro, chloro, bromo, iodo, cyano, -SO2CH3, -OSO2CH3.

[0081] In some embodiments, R2 is selected from cyano, fluoro, chloro, bromo, iodo, -CH3, -CF3, -SO2CH3, hydrogen, -PO(CH3)2.

[0082] In some embodiments, R2 is selected from cyano, chloro, bromo, -SO2CH3, hydrogen.

[0083] In some embodiments, n2 is 1, and R2 is selected from X1, hydrogen, fluorine, chlorine, bromine, iodine, -CH3, cyano, -SO2CH3, -OSO2CH3, -PO(CH3)2.

[0084] In some embodiments, n2 is 1, and R2 is selected from cyano, fluoro, chloro, bromo, iodo, -CH3, -CF3, -SO2CH3, hydrogen, -PO(CH3)2.

[0085] In some embodiments, n2 is 1, and R2 is selected from cyano, chloro, bromo, -SO2CH3, and hydrogen.

[0086] In some embodiments, the structure Selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM.

[0087] In some embodiments, the structure Selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM.

[0088] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0089] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0090] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0091] In some embodiments, R1, R2, and the carbon atom to which they are attached together form a 6- to 15-membered heterocycloalkyl ring selected from 5,8-dihydro-4H-1,4-oxazine, 4,5,8,9-tetrahydro-1,4-oxazolone, 5,8,9,10-tetrahydro-4H-1,4-oxazine, 1-oxa-4-azacycloundecane-2,6-diene; the 6- to 15-membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, chlorine, bromine , iodine, cyano, hydroxyl, carboxyl, nitro, formyl, sulfonic acid, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, -COCH3, -COCH2CH3, -COCH(CH3)2, -COC(CH3)3, -OCOCH3, -OCOCH2C H3, -OCOCH(CH3)2, -OCOC(CH3)3, -CONH2, -CONHCH3, -CONHCH2CH3, -CONHCH(CH3)2, -CONHC(CH3)3, -CON( CH3)2, -CON(CH2CH3)2, -SOCH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -SO2C(CH3)3, -OSO2CH3, -OSO2CH2C H3, -OSO2CH(CH3)2, -OSO2C(CH3)3, -SO2NH2, -SO2NHCH3, -SO2NHCH2CH3, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(CH2CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl.

[0092] In some embodiments, R1, R2, and the carbon atom to which they are attached together form 4,5,8,9-tetrahydro-1,4-oxazolone, 5,8-dihydro-4H-1,4-oxazine, 5,8,9,10-tetrahydro-4H-1,4-oxazine, or 1-oxa-4-azacycloundec-2,6-diene.

[0093] In some embodiments, R1, R2, and the carbon atom to which they are attached together form (2Z,6Z)-4,5,8,9-tetrahydro-1,4-oxazolone, (2E,6Z)-4,5,8,9-tetrahydro-1,4-oxazolone, (2E,6E)-4,5,8,9-tetrahydro-1,4-oxazolone, (2Z,6E)-4,5,8,9-tetrahydro-1,4-oxazolone, (2Z,6Z)-5,8-dihydro-4H-1,4-oxazine, (2E,6Z)-5,8-dihydro-4H-1,4-oxazine, (2Z,6E)-5,8-dihydro-4H-1,4-oxazine, (2E,6E)-5,8-dihydro-4H-1,4-oxazine , (2Z,6Z)-5,8,9,10-tetrahydro-4H-1,4-oxazine, (2E,6Z)-5,8,9,10-tetrahydro-4H-1,4-oxazine, (2Z,6E)-5,8,9,10-tetrahydro-4H-1,4-oxazine, (2E,6E)-5,8,9,10-tetrahydro-4H-1,4-oxazine, (2Z,6Z)-1-oxa-4-azacycloundeca-2,6-diene, (2E,6Z)-1-oxa-4-azacycloundeca-2,6-diene, (2Z,6E)-1-oxa-4-azacycloundeca-2,6-diene or (2E,6E)-1-oxa-4-azacycloundeca-2,6-diene.

[0094] In some embodiments, R1, R2, and the carbon atom to which they are attached together form (2Z,6Z)-4,5,8,9-tetrahydro-1,4-oxazolone, (2Z,6Z)-5,8-dihydro-4H-1,4-oxazine, (2Z,6Z)-5,8,9,10-tetrahydro-4H-1,4-oxazine, or (2Z,6Z)-1-oxa-4-azacycloundeca-2,6-diene.

[0095] In some embodiments, the structure Selected from in express (single key) or (double bond); n1 is 0 or 1, n2 is 0 or 1.

[0096] In some embodiments, the structure Selected from Where n1 is 0 or 1, and n2 is 0 or 1.

[0097] In some embodiments, the structure Selected from

[0098] In some embodiments, the structure Selected from

[0099] In some embodiments, the structure Selected from

[0100] In some embodiments, R3 is selected from X1, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl) 2, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl and phenyl; said C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl) 2, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl and phenyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, -COC 1-3Alkyl, -COOC 1-3 Alkyl, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, -OSO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl.

[0101] In some embodiments, R3 is selected from X1, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl) 2, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl and phenyl; the C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6alkyl), 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and phenyl are unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -COCH, -OCOCH, -COOCH, -CONH, -CONHCH, -CON(CH), -SOCH, -SOCH, -SONH, -SONHCH, -SON(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and phenyl.

[0102] In some embodiments, R3 is selected from X1, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 1-6 Alkyl, -COOC 1-6 Alkyl, -CO2NH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl) 2, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl and phenyl.

[0103] In some embodiments, R3 is selected from X1, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, -COCH3, -COCH2CH3, -COC(CH3)3, -OCOCH3, -OCOCH2CH3, -OCOC(CH3)3, -COOCH3, -COOCH2CH 3, -COOC(CH3)3, -CONH2, -CONHCH3, -CON(CH3)2, -SOCH3, -SO2CH3, -SO2C(CH3)3, -OSO2CH3, -OSO2C(CH3)3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, azetidinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl and phenyl.

[0104] In some embodiments, R3 is selected from X1, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 Alkyl, -COC 1-6 alkyl.

[0105] In some embodiments, R3 is selected from X1, C 1-3 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-3 Alkyl, -COC 1-3 alkyl.

[0106] In some embodiments, R3 is selected from X1, methyl, cyclopropyl, trifluoromethyl, -COCH3.

[0107] In some embodiments, R3 is selected from X1, fluoro, methyl.

[0108] In some embodiments, n3 is 0.

[0109] In some embodiments, n3 is 1, and R3 is selected from X1, methyl, cyclopropyl, trifluoromethyl, -COCH3.

[0110] In some embodiments, n3 is 1 and R3 is selected from methyl.

[0111] In some embodiments, n3 is 2, and R3 is X1 and methyl, respectively.

[0112] In some embodiments, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM.

[0113] In some embodiments, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM.

[0114] In some embodiments, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM.

[0115] In some embodiments, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM.

[0116] In some embodiments, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM.

[0117] In some embodiments, the POI is selected from the following structures or isomers thereof:

[0118] Where X1 is the connection point with L or ULM.

[0119] In some embodiments, the POI is selected from the following structures or isomers thereof:

[0120] Where X1 is the connection point with L or ULM.

[0121] In some embodiments, the POI is selected from the following structures or isomers thereof:

[0122] Where X1 is the connection point with L or ULM.

[0123] In some embodiments, the POI is selected from the following structures or isomers thereof:

[0124] Where X1 is the connection point with L or ULM.

[0125] In some embodiments, the POI is selected from the following structures or isomers thereof:

[0126] Where X1 is the connection point with L or ULM.

[0127] In some embodiments, L is a structure represented by formula (L-1) or an isomer thereof,

[0128] -(L a ) m1 -

[0129] (L-1),

[0130] wherein m1 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0131] L a Each occurrence is independently selected from a chemical 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 group (preferably C 2-8 Alkynylidene, more preferably C 2-6 Alkyne group, more preferably C 2-4 Alkynylidene), C 3-15 Cycloalkylene ring (preferably C 3-10 Cycloalkylene ring, more preferably C 3-8 Cycloalkylene ring, more preferably C 3-6 cycloalkylene ring), a 3- to 15-membered heterocycloalkylene ring (preferably a 4- to 12-membered heterocycloalkylene ring, more preferably a 4- to 10-membered heterocycloalkylene ring, further preferably a 4- to 8-membered heterocycloalkylene ring, further preferably a 4- to 6-membered heterocycloalkylene ring), a 5- to 15-membered heteroarylene ring (preferably a 5- to 14-membered heteroarylene ring, more preferably a 5- to 12-membered heteroarylene ring, further preferably a 5- to 10-membered heteroarylene ring, further preferably a 5- to 6-membered heteroarylene ring) and C6-14 Arylene ring (preferably phenylene ring or naphthylene ring); the C 1-10 Alkylene, C 1-10 Alkyleneoxy, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-15 Cycloalkylene ring, 3 to 15 membered heterocycloalkylene ring, 5 to 15 membered heteroarylene ring, C 6-14 The arylene 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 1-6 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;

[0132] 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 1-6Alkoxy, 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).

[0133] 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.

[0134] In some embodiments, R L1 Each occurrence is independently selected from hydrogen, methyl, ethyl, difluoromethyl and monofluoromethyl.

[0135] In some embodiments, R L1 For hydrogen.

[0136] In some embodiments, R L2 are 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.

[0137] In some embodiments, R L2Each 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.

[0138] 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.

[0139] In some embodiments, R L2 Each is independently selected from fluorine, chlorine, bromine, hydroxyl and hydroxymethyl.

[0140] 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 Cycloalkylene ring, 4 to 12 membered heterocycloalkylene ring, 5 to 6 membered heteroarylene ring and phenylene ring; the C 3-12 The cycloalkylene ring, the 4- to 12-membered heterocycloalkylene ring, the 5- to 6-membered heteroarylene ring, and the phenylene ring are unsubstituted or substituted with 1, 2, 3, or 4 R L2 Substituted, the R L2 Selected from fluorine, hydroxy and hydroxymethyl.

[0141] 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-, or a subunit form selected from the following cyclic groups: 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, 3,3,5,5-tetramethylpiperidine, 3,3-difluoropiperidine, 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, 3,9-diazaspiro[5.5]undecane, 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 and triazole ring; wherein, each occurrence of m2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0142] In some embodiments, the L a Each is independently selected from the following structures or isomers thereof: -(CH2)-, -(CH2)2-, -(CH2)5-, -C(O)-, -(CH2)3-, -C(O)NH-, -(CH2)8-, -O-, -NH-,

[0143] In some embodiments, the L a Each is independently selected from the following structures or isomers thereof: -(CH2)-,

[0144] 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-Cy0-, -Cy0-NH-(CH2) m3 -、-Cy0-(CH2) m3 -NH-, -Cy0-(CH2) m3-O-, -C(O)NH-Cy0-, -(CH2) m3 -C(O)NH-(CH2) m3 -O-Cy0-O-(CH2) m3 -、-Cy0-Cy0-、-(CH2) m3 -Cy0-O-Cy0-O-(CH2) m3 -, -Cy0-C(O)NH-Cy0-, -Cy0-(CH2) m3 -Cy0-, -Cy0-O-Cy0-, -Cy0-C(O)-Cy0-, -(CH2) m3 -Cy0-Cy0, -C(O)NH-(CH2) m3 -Cy0-(CH2) m3 -Cy0; wherein, each occurrence of m3 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each occurrence of Cy0 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, 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.

[0145] In some embodiments, 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 hydroxy-substituted azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a hydroxy-substituted piperidine ring, a hydroxymethyl-substituted piperidine ring, a 4-fluoropiperidine ring, a 3,3-difluoropiperidine, a 3,3,5,5-tetramethylpiperidine, a piperazine ring, a 2-azaspiro[3.3]heptane ring, a 6-azaspiro[3.4]octane ring, a 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, 3,9-diazaspiro[5.5]undecane, 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 and triazole ring.

[0146] In some embodiments, the CyO are each independently selected from a cyclobutane ring, a bicyclopentane ring, a benzene ring, an azetidine ring, a piperidine ring, a piperazine ring, and 3,9-diazaspiro[5.5]undecane.

[0147] In some embodiments, the CyO are each independently selected from a cyclobutane ring, an azetidine ring, a benzene ring, and a piperidine ring.

[0148] In some embodiments, the CyO is each independently selected from the following structures or isomers thereof:

[0149] In some embodiments, the CyO is each independently selected from the following structures or isomers thereof:

[0150] In some embodiments, L is selected from the following structures or isomers thereof:

[0151] Among them, X 00 It is the connection point between L and ULM or POI.

[0152] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection point between L and ULM or POI.

[0153] In some embodiments, L is selected from the following structures or isomers thereof:

[0154] Among them, X 00 It is the connection point between L and ULM or POI.

[0155] In some embodiments, L is selected from the following structures or isomers thereof:

[0156] Among them, X 00 It is the connection point between L and ULM or POI.

[0157] In some embodiments, L is selected from the following structures or isomers thereof:

[0158] Among them, X 00 It is the connection point between L and ULM or POI.

[0159] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection point between L and ULM or POI.

[0160] In some embodiments, L is selected from the following structures or isomers thereof:

[0161] Among them, X 10 is the connection point between L and POI, X 20 It is the connection point of L and ULM.

[0162] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point of L and ULM.

[0163] In some embodiments, L is selected from the following structures or isomers thereof:

[0164] Among them, X 10 is the connection point between L and POI, X 20 It is the connection point of L and ULM.

[0165] In some embodiments, L is selected from the following structures or isomers thereof:

[0166] Among them, X 10is the connection point between L and POI, X 20 It is the connection point of L and ULM.

[0167] In some embodiments, L is selected from the following structures or isomers thereof:

[0168] Among them, X 10 is the connection point between L and POI, X 20 It is the connection point of L and ULM.

[0169] In some embodiments, L is selected from the following structures or isomers thereof:

[0170] Among them, X 10 is the connection point between L and POI, X 20 It is the connection point of L and ULM.

[0171] In some embodiments, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point of L and ULM.

[0172] In some embodiments, the ULM is a compound represented by formula (U-1) or an isomer thereof:

[0173] in,

[0174] express (double bond) or (single bond);

[0175] U0 is a chemical bond, -N(R U0 )-、-CON(R U0 )-, -CH2- or -(CH2)2-;

[0176] R U0 Each occurrence is independently hydrogen or C 1-3 alkyl;

[0177] Ring B is selected from the group consisting of: absent, 5- to 15-membered heteroaryl ring (preferably 6- to 12-membered heteroaryl ring, more preferably 6- to 10-membered heteroaryl ring), 3- to 15-membered heterocycloalkyl ring (preferably 5- to 12-membered heterocycloalkyl ring, more preferably 5- to 10-membered heterocycloalkyl ring), C 3-15 Cycloalkyl ring and C 6-10 an aromatic ring (preferably a benzene ring);

[0178] S1, S3, and S5 are each independently selected from a chemical 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-;

[0179] S2 and S4 are each independently selected from -N-, -NH-, -CH- and -CH2-;

[0180] S6 is selected from C, -CH- and N;

[0181] (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 1-6Alkyl, 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 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 、C1-6 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 ;

[0182] (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;

[0183] 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;

[0184] R B1 、R B2X2 in the figure is the connection point between ULM and L or POI, and R B1 and R B2 At least one of them is X2.

[0185] In some embodiments, R B1 and R B2 Not X2 at the same time.

[0186] In some embodiments, the B ring is absent.

[0187] 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.

[0188] In some embodiments, the 5- to 15-membered heteroaryl ring in Ring B is selected from a benzopyrazole ring.

[0189] In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is

[0190] wherein Q1, Q2, Q3, and Q4 are each independently selected from -CH-, N, and NO;

[0191] S7 and S8 are each independently selected from a chemical 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-;

[0192] Indicates covalent linkage to U0.

[0193] In some embodiments, Q1, Q2, Q3, and Q4 are each independently -CH-.

[0194] In some embodiments, S7 and S8 are each independently selected from -CH2- and -C(O)-.

[0195] In some embodiments, S7 is -CH2- and S8 is -C(O)-.

[0196] In some embodiments, S7 is -C(O)- and S8 is -C(O)-.

[0197] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0198] in Indicates covalent linkage to U0.

[0199] In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0200] In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is

[0201] 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;

[0202] S9, S 10 are each independently selected from a bond, -CH2-, and -C(O)-;

[0203] Indicates covalent linkage to U0.

[0204] In some embodiments, the structure Selected from in Indicates covalent linkage to U0.

[0205] In some embodiments, the 3- to 15-membered heterocycloalkyl ring in Ring B is Wherein, the B3 ring is a 3- to 7-membered heterocycloalkyl ring, Indicates covalent linkage to U0.

[0206] In some embodiments, Ring B3 is a 5- to 7-membered nitrogen-containing heterocycloalkyl ring.

[0207] In some embodiments, Ring B3 is a partially unsaturated 5- to 7-membered nitrogen-containing heterocycloalkyl ring.

[0208] 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.

[0209] In some embodiments, the structure Selected from in Indicates covalent linkage to U0.

[0210] In some embodiments, the structure Selected from in Indicates covalent linkage to U0.

[0211] In some embodiments, Ring B is selected from the group consisting of: a benzene ring, in Indicates covalent linkage to U0.

[0212] In some embodiments, Ring B is selected from the group consisting of: a benzene ring, in Indicates covalent linkage to U0.

[0213] In some embodiments, Ring B is selected from: in Indicates covalent linkage to U0.

[0214] 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 B1The 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; 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.

[0215] In some embodiments, R B1 is selected from the group consisting of X2, fluorine, chlorine, hydroxy, methyl, trifluoromethyl and methoxy.

[0216] In some embodiments, b1 is 1, R B1 For fluorine.

[0217] In some embodiments, b1 is 1, R B1 It is a methyl group.

[0218] In some embodiments, Selected from: Where X2 is the connection point between ULM and L or POI, Indicates covalent linkage to U0.

[0219] In some embodiments, Selected from: Where X2 is the connection point between ULM and L or POI, Indicates covalent linkage to U0.

[0220] In some embodiments, Selected from: Where X2 is the connection point between ULM and L or POI, Indicates covalent linkage to U0.

[0221] In some embodiments, U0 is a chemical bond.

[0222] In some embodiments, U0 is -NH-.

[0223] In some embodiments, U0 is -CONH-.

[0224] In some embodiments, U0 is -CH2-.

[0225] In some embodiments, S1 and S3 are -C(O)-, S2 is -NH-, and S4 and S5 are -CH2-.

[0226] In some embodiments, S6 is -CH-.

[0227] In some embodiments, S6 is N.

[0228] In some embodiments, b2 is 0.

[0229] In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0230] In some embodiments, the structure Selected from the following structures or isomers thereof: in Indicates covalent linkage to U0.

[0231] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0232] Where X2 is the connection point between ULM and L or POI.

[0233] In some embodiments, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

[0234] In some embodiments, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

[0235] In some embodiments, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

[0236] In some embodiments, the ULM is a structure represented by formula (U-2) or an isomer thereof:

[0237] in,

[0238] r1 is 0, 1, or 2;

[0239] D ring is selected from benzene ring, 5 to 6 membered heteroaryl ring, C 3-10 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);

[0240] (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 1-3Alkoxy 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 (preferably -CONHC 1-3 Alkyl), -NHCONHC 1-6 Alkyl (preferably -NHCONHC 1-3 Alkyl), -SOC 1-6 Alkyl (preferably -SOC 1-3 Alkyl), -SO2C 1-6 Alkyl (preferably -SO2C 1-3 Alkyl) and -SC 1-6 Alkyl (preferably -SC 1-3 alkyl);

[0241] R U1 -C(R U3 R U4 )-U1;

[0242] 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), -COOC1-6 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);

[0243] 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;

[0244] 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 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;

[0245] RU5 、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;

[0246] R U7 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl; or R U7 , and R U7 The connected nitrogen atoms, R U6 and R U6 The connected carbon atoms together form a 3- to 8-membered heterocycloalkyl ring or a 5- to 6-membered heteroaryl ring;

[0247] R U8 Selected from hydroxyl, amino, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -OCOC 1-6 alkyl;

[0248] 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 1-3Alkoxy), -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);

[0249] R U2 、R U1 、R U5 、R U6 X2 in the figure is the connection point between ULM and L or POI, and R U1 、R U5 、R U6 and R U2 At least one of them is X2.

[0250] In some embodiments, r1 is 0.

[0251] In some embodiments, r1 is 1.

[0252] In some embodiments, r1 is 2.

[0253] In some embodiments, the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 5-9 cycloalkyl rings and 5- to 9-membered heterocycloalkyl rings.

[0254] In some embodiments, the D ring is selected from a benzene ring, 2,3-dihydro-1H-indene.

[0255] In some embodiments, the D ring is selected from a benzene ring.

[0256] In some embodiments, Ring D is selected from 2,3-dihydro-1H-indene.

[0257] In some embodiments, the D ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring.

[0258] 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.

[0259] In some embodiments, the D ring is selected from a benzene ring and a pyridine ring.

[0260] In some embodiments, r1 is 0, and Ring D is 2,3-dihydro-1H-indene.

[0261] In some embodiments, r1 is 1, and the D ring is a benzene ring.

[0262] In some embodiments, r2 is 0.

[0263] In some embodiments, r2 is 1.

[0264] In some embodiments, r2 is 2.

[0265] 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.

[0266] In some embodiments, the 5- to 6-membered heteroaryl is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazolyl.

[0267] In some embodiments, the 5- to 6-membered heteroaryl group is selected from

[0268] In some embodiments, the 5- to 6-membered heteroaryl group is

[0269] 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.

[0270] In some embodiments, R U2 It is a cyano group.

[0271] 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.

[0272] 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.

[0273] In some embodiments, R U2 NHR a3 , where R a3is 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.

[0274] In some embodiments, R U2 NHR a3 , where R a3 is thiazolyl; said thiazolyl is substituted by 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl and isopropyl.

[0275] In some embodiments, R U2 Selected from the following structures: cyano,

[0276] In some embodiments, r2 is 1, R U2 Selected from cyano,

[0277] In some embodiments, r2 is 1, R U2 for

[0278] In some embodiments, r2 is 2, R U2 X2 and

[0279] In some embodiments, Selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

[0280] In some embodiments, Selected from the following structures or isomers thereof:

[0281] In some embodiments, R U1 、R U5 、R U6 and R U2 One of them is X2.

[0282] In some embodiments, R Ua is selected from fluoro, cyano, methyl, ethyl, trifluoromethyl and trifluoromethoxy.

[0283] In some embodiments, R Ua Selected from fluorine and cyano.

[0284] In some embodiments, U1 is selected from X2, -NHCO-X2, -NHCOCH3, Where X2 is the connection point between ULM and L or POI.

[0285] In some embodiments, U1 is selected from -NHCO-X2 and Where X2 is the connection point between ULM and L or POI.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] In some embodiments, R U3 、R U4 Each is independently hydrogen, -CH(CH3)2 or -C(CH3)3.

[0290] In some embodiments, R U1 Selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

[0291] In some embodiments, R U1 Selected from the following structures: Where X2 is the connection point between ULM and L or POI.

[0292] In some embodiments, R U1 Selected from the following structures: Where X2 is the connection point between ULM and L or POI.

[0293] 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; or R U5 Together with the carbon atoms on the D ring, it forms C 3-6 Cycloalkyl ring; said C 3-6 The cycloalkyl ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, formyl, sulfonic acid, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, 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, amino substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, -COC 1-6 Alkyl, -CO2NH2, -CO2NH(C 1-6 alkyl), -CO2N(C 1-6 Alkyl)2, -SO2NH2, -SO2NH(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, C 3-8 cycloalkyl ring, 4- to 10-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring and benzene ring.

[0294] In some embodiments, R U5 、R U6 are independently hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0295] In some embodiments, R U5 、R U6 Each is independently hydrogen, -CH3, -OCH3, -CF3, -OCF3, -CHF2, -CH2F, -OCHF2 or -OCH2F.

[0296] In some embodiments, R U5 、R U6 are each independently hydrogen or -CH3.

[0297] In some embodiments, R U7 Selected from hydrogen, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl.

[0298] In some embodiments, R U7 For hydrogen.

[0299] In some embodiments, R U7 , and R U7 The connected nitrogen atoms, R U6 and R U6 The connected carbon atoms together form a partially unsaturated 3- to 8-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring, or a benzene ring.

[0300] In some embodiments, R U7 , and R U7 The connected nitrogen atoms, R U6 and R U6 The connected carbon atoms together form a tetrahydropyrrole ring, a pyrazolidine ring, an imidazolidine ring, a piperazine ring, a piperidine ring, a 2,3-dihydro-1H-pyrrole ring, a 2,3-dihydro-1H-pyrazole ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring or a benzene ring.

[0301] In some embodiments, R U7 , and R U7 The connected nitrogen atoms, R U6 and R U6 The connected carbon atoms together form a 4- to 6-membered heterocycloalkyl ring.

[0302] In some embodiments, R U7 , and R U7 The connected nitrogen atoms, R U6 and R U6 The connected carbon atoms together form a 5-membered heterocycloalkyl ring.

[0303] In some embodiments, R U7 , and R U7 The connected nitrogen atoms, R U6 and R U6 The connected carbon atoms together form a tetrahydropyrrole ring.

[0304] In some embodiments, the structure Selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

[0305] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0306] In some embodiments, R U8 Selected from hydroxyl, amino, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy, fluorinated C 1-3 Alkoxy and -OCOC 1-3 alkyl.

[0307] In some embodiments, R U8 Selected from hydroxy, amino, -NH(CH3), -N(CH3)2, -OCH3, -OCF3 and -OCOCH3.

[0308] In some embodiments, R U8 It is a hydroxyl group.

[0309] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0310] Where X2 is the connection point between ULM and L or POI.

[0311] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0312] Where X2 is the connection point between ULM and L or POI.

[0313] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0314] Where X2 is the connection point between ULM and L or POI.

[0315] In some embodiments, the compound represented by formula (I) is represented by formula (IA),

[0316] wherein, A1 ring, A2 ring, R1, n1, R2, n2, R3, n3, L, n0, and ULM are as defined in the specification, and R2 and R3 are not X1.

[0317] In some embodiments, the compound represented by formula (I) is represented by formula (IB),

[0318] wherein, A1 ring, A2 ring, R1, n1, R2, n2, R3, n3, L, n0, and ULM are as defined in the specification, and R2 and R3 are not X1.

[0319] In some embodiments, the compound represented by formula (I) is selected from the following structures or isomers thereof:

[0320] wherein, the A2 ring, R1, n1, R2, n2, R3, n3, L, n0, and ULM are as defined in the specification, and R2 and R3 are not X1.

[0321] In some embodiments, the compound represented by formula (I) is selected from the following structures or isomers thereof:

[0322] Wherein, L, n0, and ULM are as defined in the specification.

[0323] In some embodiments, the compound represented by formula (I) is selected from the following structures or isomers thereof:

[0324] Wherein, L, n0, and ULM are as defined in the specification.

[0325] In some embodiments, the compound represented by formula (I) is selected from the following structures or isomers thereof:

[0326] Wherein, L, n0, and ULM are as defined in the specification.

[0327] In some embodiments, the compound represented by formula (I) is selected from the following structures or isomers thereof:

[0328] Wherein, L, n0, and ULM are as defined in the specification.

[0329] In some embodiments, the compound of formula (I) is a specific compound selected from the Examples.

[0330] In some embodiments, the compound of formula (I) is a compound selected from Table A or a stereoisomer thereof:

[0331] Table A

[0332] In some embodiments, the compound of formula (I) is a compound selected from Table B or a stereoisomer thereof:

[0333] Table B

[0334] 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.

[0335] 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 preventing and / or treating EED-mediated diseases.

[0336] In some embodiments, the EED-mediated disease is a tumor or an autoimmune disease.

[0337] In some embodiments, the EED-mediated disease is cancer.

[0338] 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.

[0339] 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.

[0340] In some embodiments, the EED-mediated disease is a tumor or an autoimmune disease.

[0341] In some embodiments, the EED-mediated disease is cancer.

[0342] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0343] 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.

[0344] FIG1 is a graph showing the in vivo anti-tumor activity of compound D1 and compound H105;

[0345] FIG2 is a graph showing the effects of compound D1 and compound H105 on the body weight of mice. DETAILED DESCRIPTION

[0346] 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, excellent 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.

[0347] Definition of terms

[0348] In order to more clearly understand the technical content of this application, the terms of this application are further explained below.

[0349] 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 2homologue) 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.

[0350] "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.

[0351] "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.

[0352] "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.

[0353] "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.

[0354] "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.

[0355] "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 Alkyne, 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.

[0356] "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-.

[0357] "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 includes one or more of a spirocyclic ring and 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 includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It can be a saturated cycloalkyl, such as cyclohexyl, cyclopropyl, etc. It can be a partially unsaturated cycloalkyl, such as cyclohexene, 1,2-diethylcyclopent-1-ene, etc. "Spiro" refers to a polycyclic group in which a carbon atom (called spiro atom) is shared between the monocyclic rings. These may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spirocycles are divided into bispirocycles or polyspirocycles according to the number of rings, preferably bispirocycles. More preferably, it is a 4-membered / 5-membered, 5-membered / 5-membered or 5-membered / 6-membered bispirocycle. For example:

[0358] "Cycloalkylene" and "cycloalkylene ring" are used interchangeably and are both divalent, requiring two binding partners. Formally, the second valency is generated by removing a hydrogen atom from a cycloalkyl group, e.g.

[0359] 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:

[0360] "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:

[0361] "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:

[0362] "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 includes one or more of a spiroheterocycle and a bridged heterocycle. In certain embodiments, the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups comprising 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.

[0363] "Heterocycloalkylene" and "heterocycloalkylene ring" are used interchangeably and are both divalent, requiring two binding partners. Formally, the second valency is generated by removing a hydrogen atom from a cycloalkyl group, e.g.

[0364] "Aryl" and "aromatic ring" are used interchangeably and refer to a group having 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) with ring carbon atoms. In this application, 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.

[0365] "Arylene" and "arylene ring" are used interchangeably and are both divalent, requiring two binding partners. Formally, the second valency is generated by removing a hydrogen atom from a cycloalkyl group, e.g.

[0366] "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 application, 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.

[0367] "Heteroarylene" and "heteroarylene ring" are used interchangeably and are both divalent, requiring two binding partners. Formally, the second valency is generated by removing a hydrogen atom from a cycloalkyl group, e.g.

[0368] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0369] "Halo" refers to a group in which one or more (eg, 1, 2, 3, or all) hydrogen atoms are replaced by halogen.

[0370] "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.

[0371] "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.

[0372] "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.

[0373] "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 1-3Alkyl. Non-limiting examples of cycloalkylalkyl include -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclobutyl, and the like.

[0374] "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 Alkyl. Non-limiting examples of cycloalkylalkyl include -H2C-HC=CH2, -CH2CH2-HC=CH2, wait.

[0375] "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 Alkyl. Non-limiting examples of cycloalkylalkyl include -H2C-C≡CH, -CH2CH2-C≡CH, wait.

[0376] "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.

[0377] "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 1-3Alkyl. Non-limiting examples of "hydroxy-substituted alkyl" include -CH2OH, -CH2CH2OH, -CH(OH)CH3, and the like.

[0378] "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 1-8 Alkyl, 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.

[0379] "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.

[0380] "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.

[0381] "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.

[0382] "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.

[0383] For example, in the definition of this application, "when R2 or R3 is X1, X1 is the connection point between POI and L or ULM" means that POI is connected to L or ULM through a covalent bond, and X1 is the connection point with L or ULM. For the compound of formula (I), when POI is 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. Similarly, for the compound of formula (I), when ULM is In the example, X2 is the connection point between ULM and L or POI, and its meaning is the same as that of When n0 is 0 or 1, the meaning is the same.

[0384] "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.

[0385] When the number of substituents is not indicated in the present application, it means that the substituents are optionally substituted.

[0386] Unless otherwise defined, the "substituents independently selected from..." mentioned herein means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be of the same or different types, and the substituents selected are of independent types.

[0387] 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 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C1-6 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 R B10 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C3-6 Cycloalkyl, C 3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl;

[0388] 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;

[0389] 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(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3- to 6-membered heterocycloalkyl.

[0390] In this application, when two or more “preferably” appear in one solution, any two “preferably” may be independent of each other.

[0391] In the present application, 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.

[0392] Each type of substituent group described herein above can itself be substituted with the groups described herein.

[0393] Pharmaceutical composition

[0394] Generally, 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 administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.

[0395] "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.

[0396] The compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0397] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will induce 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.

[0398] "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.

[0399] "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.

[0400] The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0401] "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.

[0402] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases and salts with organic bases.

[0403] 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.

[0404] The enantiomers, diastereomers and mixtures of these isomers of the compounds of the present application 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.

[0405] Preparation method

[0406] The application provides a preparation method of a compound of formula (I), which can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. The solvent, temperature, and other reaction conditions provided herein can be changed according to the art. The reactions can be used in sequence to provide compounds of the application, or they can be used to synthesize fragments, which are subsequently added by methods described herein and / or methods known in the art.

[0407] The reactions in the above schemes can be adaptively adjusted by those skilled in the art with reference to the specific embodiments described in this application 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.

[0408] The compounds described herein can be prepared using methods similar to those described below or the illustrative methods described in the examples, or related open literature used by those skilled in the art, by using appropriate selectable starting materials to synthesize compounds. The starting materials or intermediates for synthesizing the compounds described herein 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 application can be used to prepare them. Compounds such as those described herein 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 compounds disclosed herein 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 herein.

[0409] Compared with the prior art, the main advantages of the present application are that the compounds of the present application have excellent EED protein degradation and tumor cell proliferation inhibition effects, and have excellent pharmacokinetic characteristics, have excellent effects on cytochrome P450, have good safety, and are more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).

[0410] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples 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 according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the present application.

[0411] Reagents and instruments

[0412] 1 H NMR: Bruker AVANCE-400 nuclear magnetic spectrometer, internal standard is tetramethylsilane (TMS).

[0413] 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.

[0414] Preparative high performance liquid chromatography (pre-HPLC): GX-281 (manufacturer: Gilson).

[0415] An ISCO Combiflash-Rf75 or Rf200 automatic column analyzer and Agela 4g, 12g, 20g, 40g, 80g, or 120g disposable silica gel columns were used.

[0416] 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.

[0417] 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.

[0418] As used herein, PE: petroleum ether, EA: ethyl acetate, THF: tetrahydrofuran, H2O: water, DMF: N,N-dimethylformamide, DCM: dichloromethane, MeOH: methanol, EtOH: ethanol, DMSO: dimethyl sulfoxide, DCE: 1,2-dichloroethane, NMP: N-methylpyrrolidone, DME: dimethyl ether, DMAC: N,N-dimethylacetamide, TFA: trifluoroacetic acid, FA: formic acid, AcOH: acetic acid, CH3COOH: acetic acid, SOCl2: thionyl chloride, POCl3: trichloromethane Phosphorus oxide, PCy3: tricyclohexylphosphine, Et3N: triethylamine, LiOH: lithium hydroxide, LiAlH: lithium aluminum hydride, NaOH: sodium hydroxide, NaHCO3: sodium bicarbonate, NaH: sodium hydride, KOAc: potassium acetate, K2CO3: potassium carbonate, Cs2CO3: cesium carbonate, NH4HCO3: ammonium bicarbonate, TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HOBT: 1 -Hydroxybenzotriazole, EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Pd(dppf)Cl2: 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride; DIPEA: N,N-diisopropylethylamine, mCPBA: m-chloroperbenzoic acid, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, Pd2(dba)3: tris(dibenzylideneacetone)dipalladium, Pd(dba)2: bis(dibenzylideneacetonepalladium), Pd(OAc2: palladium acetate, Xantphos: 4,5-bis(diphenylphosphine-9, 9-Dimethylxanthene, NIS: N-iodosuccinimide, NBS: N-bromosuccinimide, CuI: cuprous iodide, PPh3: triphenylphosphine, DEAD: diethyl azodicarboxylate, NaBH3CN: sodium cyanoborohydride, NaBH(OAc)3: sodium triacetoxyborohydride, B2Pin2: bis(pinacolato)diboron, X-Phos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, Selectfluor: 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2].2-octane bis(tetrafluoroborate), Ruphos-Pd-G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, DIBAL-H: diisobutylaluminum hydride, DIEA: N,N-diisopropylethylamine, DMAP: 4-dimethylaminopyridine, Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, LiHMD S: lithium bis(trimethylsilylamide), TEA: triethylamine, MeCN: acetonitrile, Boc2O: di-tert-butyl dicarbonate, Dess-Martin periodinane: Dess-Martin periodinane, (Pin)2B2: pinacol diboronate, n-BuLi: n-butyllithium, Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium dichloride, t-BuOH: tert-butyl alcohol, DIAD: diisopropyl azodicarboxylate, TBSCl: tert-butyldimethylsilyl chloride, CataCXium A: n-butylbis(1-adamantyl)phosphine, RhCl(PPh3)3: triphenylphosphine rhodium chloride, TsOH: p-toluenesulfonic acid, PtO2: platinum dioxide, Pd(aMphos)Cl2: dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II).

[0419] 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.

[0420] As used herein, rt means room temperature, which refers to about 20-30°C.

[0421] As used herein, "overnight" means about 10 to 16 hours.

[0422] Preparation of intermediate Z1

[0423] Step 1: 8-Bromo-5-(methylthio)-[1,2,4]triazolo[4,3-c]pyrimidine (5 g, 20.40 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (5 g, 29.91 mmol) were mixed and pre-sonicated for 5 minutes, followed by stirring at 85°C in a microwave oven for 3 hours. After completion of the reaction, DCM (100 mL) was added and ultrasonically filtered. The filter cake was dried naturally to afford Z1-a (5.5 g) in a 50.50% yield. MS m / z (ESI): 364 [M+H] + , 366[M+H] + .

[0424] Step 2: Z1-a (300 mg, 823.8 μmol) and ethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (455 mg, 1.65 mmol) were mixed and added to a 1,4-dioxane aqueous solution (5 mL, 20%), followed by the addition of K2CO3 (342 mg, 2.47 mmol) and catalyst Pd(dppf)Cl2 (73.1 mg, 0.1 mmol). The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 12 h. After completion of the reaction, the reaction solution was purified by column chromatography (PE / EA = 15%-100%) to give Z1-b (200 mg) in a yield of 56.10%. MS m / z (ESI): 434 [M+H] + .

[0425] Step 3: Z1-b (200 mg, 0.46 mmol) was added to a THF / H2O solution (2 mL, 50%), followed by the addition of LiOH (40 mg) and stirred at room temperature for 12 hours. After completion of the reaction, the pH was adjusted to neutral with dilute hydrochloric acid (2 mol / L), and then purified by column chromatography (DCM / MeOH = 0-10%) to afford intermediate Z1 (160 mg) in 86.9% yield. MS m / z (ESI): 406 [M+H] + .

[0426] Preparation of intermediate Z2

[0427] Referring to the preparation method of intermediate Z1, ethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was replaced with methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate to prepare intermediate Z2, MS m / z (ESI): 407 [M+H] + .

[0428] Preparation of intermediate Z3

[0429] Step 1: Add ethyl 4-hydrazino-2-(methylthio)pyrimidine-5-carboxylate (2.5 g, 10.96 mmol) to trimethyl orthoformate (5 mL), add one drop of TFA, and heat under reflux with stirring for 2 hours. After completion of the reaction, concentrate to obtain Z3-a (2.2 g) in an 84.3% yield. MS m / z (ESI): 239 [M+H] + .

[0430] Step 2: Z3-a (2.2 g, 9.24 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (2.2 g) were added to a microwave tube and reacted at 60°C for 30 min. DCM was added and ultrasonically dispersed, followed by filtration to obtain Z3-b (1 g). Yield: 30.3%. MS m / z (ESI): 358 [M+H] + .

[0431] Step 3: Z3-b (1 g, 2.8 mmol) was added to a tetrahydrofuran aqueous solution (5 mL, 50%), followed by the addition of LiOH (150 mg) and stirred at room temperature for 3 hours. After the reaction was complete, hydrochloric acid solution (2 mol / L) was added to adjust the pH to neutral, and then purified by column chromatography (DCM / MeOH = 2%-10%) to obtain Z3 (500 mg) in a yield of 54.2%. MS m / z (ESI): 330 [M+H] + .

[0432] Preparation of intermediate Z4

[0433] Step 1: Dissolve 6-amino-5-bromopyrimidin-2(1H)-one (50 g, 263.16 mmol) and ethyl 3-bromopyruvate (128.30 g, 657.90 mmol) in AcOH (500 mL). Stir the reaction at 120°C for 3 h. After completion, cool to room temperature, concentrate to remove most of the acetic acid, add water, and extract four times with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified using a CombiFlash (120 g, 0-10% MeOH / DCM) to afford Z4-a (13 g, yellow solid) in a 17.27% yield. MS m / z (ESI): 286.0 [M+H]. + .

[0434] Step 2: Z4-a (13 g, 45.44 mmol) was dissolved in MeOH (130 mL), and then aqueous NaOH solution (6.36 g, 159.05 mmol, 50 mL) was added. The reaction was stirred at 50°C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to remove the MeOH. The aqueous phase was cooled to 0°C and the pH was adjusted to 2-3 with dilute hydrochloric acid (2 mol / L). A solid precipitated and was filtered. The filter cake was washed three times with water and dried under vacuum to obtain Z4-b (4.8 g, brown solid, crude product) in a yield of 40.94%. MS m / z (ESI): 258.0 [M+H] + .

[0435] Step 3: To a suspension of Z4-b (4.8 g, 18.60 mmol) in SOCl2 (65.52 g, 550.73 mmol, 40 mL) was added DMF (67.99 mg, 930.13 μmol, 72.02 μL). The mixture was stirred at 80°C for 2 h. The reaction solution was then concentrated and dissolved in DCM (29.93 mL). Ammonia (13.04 g, 372.05 mmol) was added dropwise at 0°C to the resulting mixture, and the mixture was stirred at 25°C for 1 h. After completion of the reaction, the mixture was filtered, and the filter cake was washed with MeOH. The filter cake was then dried under vacuum to afford Z4-c (3.5 g, brown solid) in a 73.20% yield. MS m / z (ESI): 257.0 [M+H]. + .

[0436] Step 4: Z4-c (3.5 g, 13.62 mmol) was dissolved in POCl3 (67.85 g, 442.53 mmol, 40 mL), and DIPEA (8.80 g, 68.08 mmol, 11.86 mL) was added dropwise. The reaction was stirred at 120°C for 14 h. After completion, the reaction was cooled to room temperature, concentrated, and purified via CombiFlash (80 g, 0-25% EA / PE) to afford Z4-d (1.2 g, pale yellow solid) in a 34.23% yield. MS m / z (ESI): 256.9 [M+H] + .

[0437] Step 5: Dissolve Z4-d (1.2 g, 4.66 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (935.00 mg, 5.59 mmol) in DCM (15 mL), and then add DIPEA (1.20 g, 9.32 mmol, 1.62 mL). The reaction was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated and purified by CombiFlash (24 g, 0-100% EA / PE) to afford Z4-e (1.78 g, pale yellow solid) in 98.38% yield. MS m / z (ESI): 388.0 [M+H] + .

[0438] Step 6: Z4-e (300 mg, 772.81 μmol) and 4-formylphenylboronic acid pinacol ester (269.03 mg, 1.16 mmol) were dissolved in a mixture of water (1.5 mL) and 1,4-dioxane (7.5 mL). Pd(dppf)Cl2 (56.55 mg, 77.28 μmol) and NaHCO3 (324.61 mg, 3.86 mmol) were then added. The reaction was stirred at 100°C for 1.5 h. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and purified on a CombiFlash (12 g, 0-5% MeOH / DCM) to afford intermediate Z4 (201 mg, pale yellow solid) in a 62.91% yield. MS m / z (ESI): 414.1 [M+H] + .

[0439] Preparation of intermediate Z5

[0440] Step 1: Under nitrogen, NaH (1.67 g, 41.75 mmol) was dissolved in DMSO (16 mL), then cooled to 0°C. A solution of diphenylmethyleneglycine ethyl ester (6.14 g, 22.96 mmol) in DMSO (16 mL) was added. The mixture was stirred at 0°C for 5 minutes, and the reaction solution turned orange. 2-Methylthio-4-chloro-5-bromopyrimidine (5 g, 20.88 mmol) was dissolved in DMSO (16 mL) and added dropwise to the reaction solution at 0°C. The reaction solution was then slowly heated to 25°C and stirred under nitrogen for 2 hours, and the reaction solution turned dark red. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 9-11%) to obtain Z5-a (9.8 g, yellow oil) in a yield of 99.80%. MS m / z (ESI): 470.2, 472.2 [M+H] + .

[0441] Step 2: Z5-a (5 g, 10.63 mmol) was dissolved in a mixture of THF (50 mL) and water (30 mL). After cooling the solution to 0°C, concentrated hydrochloric acid (10 mL, 120.00 mmol) was slowly added. The reaction solution was stirred at 0°C for 10 minutes, then slowly heated to 25°C and the reaction continued for 1 hour. After completion of the reaction, the pH of the reaction solution was adjusted to 8-9 with aqueous NaOH (20 wt%). The aqueous phase was then extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 50-55%) to obtain Z5-b (3.2 g, yellow oil) in a yield of 98.32%. MS m / z (ESI): 306.0, 308.0 [M+H] + .

[0442] Step 3: Formic acid (6 mL, 159.06 mmol) and acetic anhydride (6 mL, 64.06 mmol) were mixed and stirred at 50°C for 1 hour. The reaction mixture was then cooled to 25°C. Z5-b (3.2 g, 10.45 mmol) was dissolved in DCM (30 mL) and added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 8-9 with aqueous NaOH (20 wt%). The aqueous phase was then extracted with DCM (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 55-60%) to afford Z5-c (3.25 g, white solid) in a yield of 93.05%. MS m / z (ESI): 334.0 [M+H]. + ,336.0[M+H] + .

[0443] Step 4: Dissolve Z5-c (3.2 g, 9.58 mmol) in 1,4-dioxane (50 mL), add POCl3 (2.67 mL, 28.73 mmol), and stir the reaction mixture at 110°C for 1 h. After completion of the reaction, concentrate the reaction mixture and adjust the pH to 8-9 with saturated sodium bicarbonate solution. Extract the aqueous phase with ethyl acetate (100 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 55-60%) to obtain Z5-d (3 g, light yellow solid). Yield: 99.09%. MS m / z (ESI): 316.0 [M+H] + ,318.0[M+H] + .

[0444] Step 5: Z5-d (1 g, 3.16 mmol) was dissolved in DCM (15 mL) at room temperature, followed by the addition of mCPBA (2.18 g, 12.64 mmol). The reaction mixture was stirred at 25°C for 3 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (PE / EA = 40-50%) to afford Z5-e (900 mg, yellow solid) in a yield of 81.73%. MS m / z (ESI): 348.0 [M+H] + ,350.0[M+H] + .

[0445] Step 6: Dissolve (5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methanamine (247.77 mg, 1.48 mmol) and Z5-e (430 mg, 1.24 mmol) in DCM (10 mL) at room temperature. Stir on ice for 15 minutes, then add triethylamine (342.39 μL, 2.47 mmol). The reaction mixture is stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture is concentrated and purified by column chromatography (PE / EA = 40-50%) to obtain Z5-f (300 mg, yellow solid). Yield: 55.81%. MS m / z (ESI): 434.8 [M+H] + ,436.8[M+H] + .

[0446] Step 7: Z5-f (60 mg, 0.14 mmol) was dissolved in a mixture of MeOH (1 mL) and THF (1 mL), and 10% wet palladium on carbon (14.67 mg, 0.01 mmol) was added. The reaction mixture was stirred at 25°C for 4 h. After the reaction was complete, the mixture was filtered, and the filter cake was washed with MeOH (10 mL) and EA (10 mL). The filtrates were combined and concentrated to give Z5-g (40 mg, white solid, crude product). Yield: 81.43%. MS m / z (ESI): 356.9 [M+H] + .

[0447] Step 8: Z5-g (40 mg, 0.11 mmol) was dissolved in a mixture of MeOH (1 mL), water (1 mL), and THF (1 mL). LiOH (23.07 mg, 0.55 mmol) was then added, and the reaction mixture was stirred at 60°C for 18 h. After completion of the reaction, the pH of the reaction mixture was adjusted to 3-4 with hydrochloric acid (2 mol / L). The aqueous phase was then extracted with ethyl acetate (20 mL x 2). The combined organic phases were concentrated to afford intermediate Z5 (30 mg, white solid) in an 81.41% yield. MS m / z (ESI): 329.0 [M+H] + .

[0448] Preparation of intermediate Z6

[0449] Step 1: Under nitrogen protection, Z5-f (200 mg, 0.46 mmol) and 6-cyclopropylpyridine-3-boronic acid pinacol ester (168.96 mg, 0.69 mmol) were dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (1 mL). K2CO3 (190.51 mg, 1.38 mmol) and Pd(dppf)Cl2 (34.09 mg, 0.05 mmol) were then added. The mixture was stirred at 100°C under nitrogen protection for 2 h. After completion of the reaction, the reaction solution was poured into water (10 mL), the aqueous phase was extracted with ethyl acetate (100 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 50-80%) to obtain Z6-a (200 mg, white solid) in a yield of 91.92%. MS m / z(ESI):474.2[M+H] + .

[0450] Step 2: Dissolve Z6-a (200 mg, 0.42 mmol) in a mixture of THF (3 mL) / methanol (1 mL) / water (1 mL). Add LiOH (88.61 mg, 2.11 mmol) and heat to 60°C with stirring for 18 h. After completion of the reaction, concentrate the reaction solution to afford intermediate Z6 (180 mg, white solid, crude product) in a 95.67% yield. MS m / z (ESI): 445.9 [M+H] + .

[0451] Preparation of intermediate Z7

[0452] Step 1: The compound 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (300 mg, 823.8 umol) and the compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylic acid ethyl ester (462 mg, 1.65 mmol) were mixed and added to a dioxane aqueous solution (5 mL, v / v = 20%), K2CO3 (342 mg, 2.47 mmol) and Pd(dppf)Cl2 (73.1 mg, 0.1 mmol), and the mixture was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was purified by column chromatography (15%-100% PE / EA) to obtain Z7-a (200 mg) with a yield of 56.10%. MS m / z (ESI): 438 [M+H] + .

[0453] Step 2: Z7-a (200 mg, 0.46 mmol) was added to MeOH, followed by 10% palladium on carbon (20 mg). The mixture was heated to 40°C and stirred for 5 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to afford Z7-b (200 mg) in a 100% yield. MS m / z (ESI): 440 [M+H] + .

[0454] Step 3: Z7-b (200 mg, 0.46 mmol) was added to a THF / H2O solution (2 mL, v / v = 50%), followed by the addition of lithium hydroxide (40 mg). The mixture was stirred at room temperature for 3 hours. After completion of the reaction, aqueous hydrochloric acid (2 mol / L) was added to adjust the pH to neutral. The mixture was purified by column chromatography (0-10% DCM / MeOH) to afford intermediate Z7 (150 mg) in a 79.3% yield. MS m / z (ESI): 412 [M+H] + .

[0455] Preparation of intermediate Z8

[0456] Step 1: To a solution of 8-bromo-5-(methylthio)imidazo[1,5-c]pyrimidine (1 g, 4.10 mmol) in DCM (20 mL) was added m-chloroperbenzoic acid (1.08 g, 5.33 mmol). The mixture was stirred at 0°C under a nitrogen atmosphere for 5 hours. Triethylamine (2.84 mL, 20.5 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (0.68 g, 4.10 mmol) were then added at 0°C. The mixture was stirred at 25°C under a nitrogen atmosphere for 18 hours. After completion of the reaction, the mixture was concentrated and purified by silica gel chromatography (DCM:MeOH = 100:1 to 40:1) to afford Z8-a (1 g, yellow solid) in a 67.1% yield. MS m / z (ESI): 365.0 [M+H] + .

[0457] Step 2: To a solution of Z8-a (500 mg, 1.38 mmol) in 1,4-dioxane (20 mL) and water (4 mL) were added ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (763 mg, 2.75 mmol), K2CO3 (380 mg, 2.75 mmol) and Pd(PPh3)4 (318 mg, 0.28 mmol), and the mixture was stirred at 90 ° C. under a nitrogen atmosphere for 7 hours. After completion of the reaction, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM: MeOH = 100: 1 to 20: 1) to give Z8-b (260 mg, yellow solid) in a yield of 43.6%. MS m / z(ESI):434.1[M+H] + .

[0458] Step 3: To a solution of Z8-b (160 mg, 0.37 mmol) in DMF (6 mL) was slowly added NIS (141 mg, 0.63 mmol) at 0°C under a nitrogen atmosphere. The reaction was stirred at 25°C under a nitrogen atmosphere for 2 hours. After completion of the reaction, the reaction solution was poured into ice water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 500:1-40:1) to obtain Z8-c (88 mg, red solid) in a yield of 42.6%. MS m / z (ESI): 559.8 [M+H] + .

[0459] Step 4: To a solution of Z8-c (59 mg, 0.11 mmol) in DMSO (2.5 mL) were added sodium methanesulfinate (32 mg, 0.32 mmol) and CuI (60 mg, 0.32 mmol). The mixture was heated in a microwave oven at 120°C for 20 min and then at 100°C for 3 h under a nitrogen atmosphere. After completion of the reaction, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to obtain Z8-d (50 mg, yellow solid) in a yield of 92.7%. MS m / z (ESI): 511.9 [M+H] + .

[0460] Step 5: To a solution of Z8-d (40 mg, 0.08 mmol) in methanol (4 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (40 mg, 0.95 mmol) and stirred at 25°C for 5 h. After completion of the reaction, the mixture was concentrated and diluted with water (5 mL), adjusted to pH 7 with aqueous hydrochloric acid (2 mol / L), extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to afford intermediate Z8 (35 mg, yellow solid) in a yield of 92.5%. MS m / z (ESI): 483.9 [M+H] + .

[0461] Preparation of intermediate Z9

[0462] Step 1: Z10-a (80.0 mg, 0.180 mmol), methanol (5 mL), and water (0.5 mL) were added to a single-necked flask at room temperature. Lithium hydroxide monohydrate (80.0 mg, 1.91 mmol) was added with stirring and the mixture was allowed to react at 25°C for 3 hours. After completion of the reaction, the reaction solution was poured into water (20 mL), filtered, and the filter cake was washed with water (5 mL) and dried to obtain intermediate Z9 (68 mg, light yellow solid) in a yield of 90.88%. MS m / z (ESI): 406.2 [M+H] + .

[0463] Preparation of intermediate Z10

[0464] Step 1: 8-Bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (400 mg, 1.10 mmol) and methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (580 mg, 2.20 mmol) were dissolved in 1,4-dioxane (15 mL) and water (2 mL), and Pd(PPh3)4 (255 mg, 0.22 mmol) and K2CO3 (304.43 mg, 2.20 mmol) were added, and the mixture was stirred at 90 °C under argon protection for 20 hours. After the reaction was complete, 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 using CombiFlash (PE / EA = 0-90%) to obtain Z10-a (78 mg, yellow solid) in a yield of 16.89%. MS m / z (ESI): 420.1 [M+H] + .

[0465] Step 2: Dissolve Z10-a (78 mg, 0.19 mmol) in DMF (5 mL), cool to 0°C, add NIS (42 mg, 0.19 mmol), and stir at room temperature for 0.5 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 via CombiFlash (PE / EA = 0-100%) to obtain Z10-b (70 mg, yellow solid) in a yield of 69%. MS m / z (ESI): 546.0 [M+H] + .

[0466] Step 3: Dissolve Z10-b (50 mg, 0.092 mmol) in methanol (12 mL) and water (3 mL), add lithium hydroxide monohydrate (39 mg, 0.92 mmol), and stir at room temperature for 20 hours. Adjust the pH to 5 with dilute hydrochloric acid (1 mol / L), extract with dichloromethane (30 mL x 3), and combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain intermediate Z10 (35 mg, yellow solid, crude product) in a yield of 71.8%. MS m / z (ESI): 532.0 [M+H] + .

[0467] Preparation of intermediate Z11

[0468] Step 1: Dissolve Z8-a (1 g, 2.75 mmol), di-tert-butyl dicarbonate (1.20 g, 5.51 mmol), triethylamine (0.83 g, 8.25 mmol), and 4-dimethylaminopyridine (0.34 g, 2.75 mmol) in anhydrous DCM (20 mL) and stir at 35°C for 2 hours under nitrogen. After completion, pour the reaction solution into water and extract twice with dichloromethane. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain Z11-a (1.13 g, pale yellow solid) in an 88.6% yield. MS m / z (ESI): 463.2 [M+H] + .

[0469] Step 2: Z11-a (460 mg, 0.99 mmol), tert-butyl piperazine-1-carboxylate (50.90 mg, 0.32 mmol), cesium carbonate (970.48 mg, 2.98 mmol), Xantphos (229.80 mg, 0.40 mmol), and Pd2(dba)3 (181.83 mg, 0.20 mmol) were dissolved in 1,4-dioxane (5 mL). The atmosphere was purged with nitrogen three times, the temperature was raised to 90°C, and the mixture was stirred at 90°C for 18 hours. After completion of the reaction, the reaction solution was poured into water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 3:1) to afford Z11-b (440 mg, light yellow solid) in a yield of 77.9%. MS m / z (ESI): 569.5 [M+H] + .

[0470] Step 3: Dissolve Z11-b (200 mg, 0.35 mmol) in DMF (8 mL), cool to 0°C, then add NIS (134.52 mg, 0.60 mmol). Slowly warm to 25°C and continue stirring for 18 hours. After completion, pour the reaction solution into water and extract twice with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain Z11-c (50 mg, light yellow solid) in a yield of 20.47%. MS m / z (ESI): 695.6 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),6.90(s,1H),6.646.53(m,1H),6.48(dd,J=8.7,4.0Hz,1H),4.92(s,2H) ,4.47(t,J=8.7Hz,2H),3.60-3.72(m,4H),3.15-3.25(m,2H),2.90-2.99(m,4H),1.42(s,9H),1.28(s,9H).

[0471] Step 4: Z11-c (25 mg, 0.05 mmol) was dissolved in DMSO (2 mL), and then CuI (17.14 mg, 0.09 mmol) and sodium methanesulfinate (8.82 mg, 0.09 mmol) were added. The mixture was microwaved at 120°C for 20 minutes and then at 100°C for 3 hours. After the reaction was completed, the reaction solution was poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give Z11-d (18 mg, light yellow solid, crude product), which was used in the next step without further purification. MS m / z (ESI): 647.3 [M+H] + .

[0472] Step 5: Dissolve Z11-d (50 mg, 0.08 mmol) in ethyl acetate (2 mL), add hydrochloric acid in ethyl acetate (4 mol / L, 2 mL), and stir at 25°C for 18 hours. After completion of the reaction, filter, wash the filter cake twice with ethyl acetate, and dry the filter cake to obtain intermediate Z11 (36 mg, white solid) in a 96.4% yield. MS m / z (ESI): 447.2 [M+H] + .

[0473] Preparation of intermediate Z12

[0474] Step 1: Dissolve 3-bromo-6-chloro-2-fluoropyridine (8.8 g, 41.82 mmol) in ethanol (40 mL), add hydrazine hydrate (2.96 g, 50.18 mmol, 85% purity), heat to 80°C, and stir overnight at 80°C. After completion of the reaction, concentrate the reaction solution to obtain Z12-a (9.3 g) in a yield of 99.96%. Use directly in the next reaction. MS m / z (ESI): 221.9 [M+H] + .

[0475] Step 2: Dissolve Z12-a (9.3 g, 41.80 mmol) in trimethyl orthoformate (90 mL) and stir at 100°C under argon for 4 hours. After the reaction is complete, filter the reaction mixture and dry the filter cake to obtain Z12-b (8.5 g) in an 87.47% yield. MS m / z (ESI): 231.9 [M+H] + .

[0476] Step 3: Combine Z12-b (2 g, 8.60 mmol), (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (3.31 g, 19.79 mmol), and ethanol (1 mL) and stir at 85°C for 20 hours. After completion of the reaction, the reaction solution was concentrated and purified via CombiFlash (0-10% MeOH / DCM) to afford intermediate Z12 (1.2 g, yellow solid) in a 38.40% yield. MS m / z (ESI): 365.0 [M+2H] + .

[0477] Preparation of intermediate Z13

[0478] Step 1: To a solution of 8-bromo-5-(((5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl)amino)imidazo[4,3-f]pyrimidine (100 mg, 0.28 mmol) in ethylene glycol dimethyl ether (2 mL) and water (0.2 mL) was added methyl 5-bromo-6-methylpyridine-2-carboxylate (126 mg, 0.55 mmol), 4,4,5,5-tetramethyl-2-(4,4,5 A mixture of 1,3,2-dioxaborolane (174 mg, 0.69 mmol), n-butyldi(1-adamantyl)phosphine (39 mg, 0.11 mmol), KCO (152 mg, 1.10 mmol), and Pd(OAC) (12 mg, 0.06 mmol) was stirred at 70°C under a nitrogen atmosphere for 18 hours. The reaction solution was concentrated and purified by silica gel chromatography (eluent: DCM:MeOH = 100:1 to 20:1) to obtain Z13-a (45 mg, black solid) in a yield of 37.1%. MS m / z (ESI): 434.1 [M+H] + .

[0479] Step 2: To a solution of Z13-a (25 mg, 0.06 mmol) in DMF (1.5 mL) was added NIS (22 mg, 0.10 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C under nitrogen atmosphere for 30 minutes. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give Z13-b (20 mg, yellow liquid, crude product) in a yield of 43.3%. MS m / z (ESI): 560.1 [M+H] + .

[0480] Step 3: To a solution of Z13-b (20 mg, 0.03 mmol) in methanol (1 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (10 mg, 0.43 mmol). The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated to afford intermediate Z13 (22 mg, yellow solid) in a 96.7% yield. MS m / z (ESI): 546.0 [M+H] + .

[0481] Preparation of intermediate Z15

[0482] Step 1: Dissolve Z10-a (190 mg, 453.02 μmol) in DCM (50 mL), cool to 0°C under argon, add NBS (80.63 mg, 453.02 μmol), and stir at 0°C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH:DCM = 0-10%) to obtain Z15-a (45 mg, 90.31 μmol, yellow solid) in a yield of 19.93%. MS m / z (ESI): 498 [M+H] + .

[0483] Step 2: Dissolve Z15-a (45 mg, 90.31 μmol) in MeOH (5 mL). Add a solution of NaOH (3.61 mg, 90.31 μmol) in methanol / water (5 mL / 0.5 mL) with stirring at room temperature. Stir at room temperature for 3 hours. After completion of the reaction, adjust the pH to 4-5 with concentrated hydrochloric acid in an ice bath and concentrate to obtain intermediate Z15 (43.73 mg, yellow solid, crude product). Yield: 100.00%. MS m / z (ESI): 484 [M+H] + .

[0484] Preparation of intermediate Z16

[0485] Step 1: Dissolve intermediate Z9 (170 mg, 419.36 μmol) in DMF (10 mL) and slowly add NCS (56.00 mg, 419.36 μmol) in portions under an ice bath. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford intermediate Z16 (150 mg, yellow solid) in an 81.3% yield. MS m / z (ESI): 440.1 [M+H] + .

[0486] Preparation of intermediate Z17

[0487] Step 1: Dissolve Z10-a (323 mg, 0.77 mmol) in ultra-dry DCM (15 mL) and add select-Fluor (409 mg, 1.16 mmol). Stir at room temperature for 20 hours. After completion, pour the reaction mixture into water and extract with dichloromethane (30 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified via CombiFlash (0-10% MeOH / DCM) to afford Z17-a (35 mg, yellow solid) in a yield of 10.39%. MS m / z (ESI): 438.1 [M+H] + .

[0488] Step 2: Dissolve Z17-a (35 mg, 0.08 mmol) in a mixture of MeOH and water (6 mL / 1 mL). Add lithium hydroxide monohydrate (20 mg, 0.48 mmol). Stir the reaction mixture at room temperature for 20 hours. After completion, neutralize the reaction mixture with HCl (6 mol / L) to pH 5 and concentrate to obtain intermediate Z17 (33 mg, crude product) in a yield of 97.41%. MS m / z (ESI): 424.1 [M+H] + .

[0489] Preparation of intermediate Z18

[0490] Referring to the preparation method of intermediate Z6, Z5-f was replaced with 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine to prepare intermediate Z18, MS m / z (ESI): 439.1 [M+H] + .

[0491] Preparation of intermediate Z19

[0492] Step 1: 8-Bromo-1-chloro-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (0.9 g, 2.26 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carboxylic acid methyl ester (896.60 mg, 3.40 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and Ruphos-Pd-G3 (379.06 mg, 452.68 μmol) and K3PO4 (672.63 mg, 3.17 mmol) were added. The reaction solution was stirred at 100 ° C under argon protection for 20 hours. After the reaction was complete, the reaction mixture was poured into water and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified using CombiFlash (0-100% EA / PE) to obtain Z19-a (415 mg, yellow solid) in a yield of 40.31%. MS m / z (ESI): 455.1 [M+H] + .

[0493] Step 2: Dissolve Z19-a (415 mg, 912.41 μmol) in THF (8.81 mL), cool to -78°C, add DIBAL-H (1 mol / L, 3.01 mL), and continue stirring at -78°C for 1 hour. After completion, the reaction solution was quenched with saturated aqueous NH4Cl solution, filtered, and the filtrate extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to yield intermediate Z19 (360 mg, crude product) in a yield of 92.88%. MS m / z (ESI): 425.1 [M+H] + .

[0494] Preparation of intermediate Z20

[0495] Step 1: Dissolve 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (1 g, 2.75 mmol) in 1,4-dioxane (4 mL) of water. Add 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (302.20 mg, 413.01 μmol), potassium carbonate (761.08 mg, 5.51 mmol), and tert-butyl 4-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate (1.33 g, 3.30 mmol). Incubate at 90°C for 16 h. Monitor the reaction by LCMS. Filter the reaction mixture and spin dry. The residue was combiflashed with PE:EA=1:2 to give compound Z20-1 (1.11 g, 1.99 mmol, 72.16% yield) as a yellow solid. MS m / z (ESI): 559.3 [M+H] + .

[0496] Step 2: Dissolve compound Z20-1 (200 mg, 358.01 μmol) in DMF (2 mL). Add N-iodosuccinimide (80.54 mg, 358.01 μmol) under ice-cooling conditions and stir at room temperature for 15 minutes. LC-MS analysis confirmed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified on a silica gel column (EA:PE = 0-100%) to afford compound Z20-2 (180 mg, 262.95 μmol, 73.45% yield) as a yellow solid. MS m / z (ESI): 685.1 [M+H] + .

[0497] Step 3: Dissolve compound Z20-2 (200 mg, 292.17 μmol) in DMSO (4 mL). Under argon, add sodium bisulfite (89.40 mg, 876.50 μmol) and cuprous iodide (166.93 mg, 876.50 μmol). Heat to 100°C and stir for 1 hour. LCMS monitored the reaction completion. The reaction mixture was filtered and dried. The residue was combi-flashed with DCM:MeOH (10:1) to afford compound Z20-3 (150 mg, 235.58 μmol, 80.63% yield) as a yellow solid. MS m / z (ESI): 637.3 [M+H] + .

[0498] Step 4: Compound Z20-3 (150 mg, 235.58 μmol) was dissolved in trifluoroacetic acid (1 mL) in dichloromethane (5 mL). The reaction was allowed to react at room temperature for 1 h. LCMS monitored the reaction completion, and the reaction solution was spun down to dryness. The residue was combiflashed with DCM:MeOH = 10:1 to afford compound Z20 (110 mg, 204.99 μmol, 87.1% yield) as a yellow solid. MS m / z (ESI): 537.2 [M+H] + .

[0499] Preparation of intermediate Z21

[0500] Step 1: Dissolve 5-bromo-2-iodopyrimidine (5 g, 17.55 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.97 g, 19.31 mmol) in water (15 mL) and 1,4-dioxane (100 mL). Add 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.92 g, 2.63 mmol) and potassium carbonate (7.28 g, 52.65 mmol) under argon. Heat to 80°C and stir for 16 hours. Monitor the reaction by LCMS. Filter the reaction mixture and spin dry. The residue was combiflashed with PE:EA = 2:1 to give tert-butyl 4-(5-bromopyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5 g, 14.70 mmol, 83.74% yield) as a yellow solid. MS m / z (ESI): 342.1 [M+H] + .

[0501] Step 2: Dissolve tert-butyl 4-(5-bromopyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.94 mmol) and pinacol diboron (1.12 g, 4.41 mmol) in 1,4-dioxane (20 mL). Add 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (322.30 mg, 440.90 μmol) and potassium acetate (865.39 mg, 8.82 mmol). Replace the atmosphere with argon three times, raise the temperature to 95°C, and stir overnight. LCMS indicates product formation. Filter the solids, and concentrate the mother liquor under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column chromatography (20 g, 0-20% EA / PE) to afford tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 2.07 mmol, 70.28% yield). MS m / z (ESI): 330.3 [M-56+H] +.

[0502] Step 3: Dissolve tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.58 mmol) and 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (1.03 g, 2.58 mmol) in water (3 mL) and 1,4-dioxane (20 mL). Add 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (283.40 mg, 387.32 μmol) and potassium carbonate (713.72 mg, 5.16 mmol) under argon. Heat to 80 ° C and stir for 16 hours. LCMS monitoring of the reaction was complete, and the reaction solution was filtered and dried. The residue was combiflashed with PE:EA = 2:1 to give compound Z21-1 (1 g, 1.73 mmol, 67.00% yield) as a yellow solid. MS m / z (ESI): 522.2 [M-56+H] + .

[0503] Step 4: Dissolve compound Z21-1 (200 mg, 346.00 μmol) in ethyl acetate (10 mL), add Pd / C (42.02 mg, 346.00 μmol), and stir at room temperature for 2 hours under hydrogen protection. LC-MS analysis was performed. The reaction mixture was filtered and concentrated under reduced pressure to dryness to obtain compound Z21-2 (190 mg, 327.56 μmol, 94.67% yield) as a colorless oil. MS m / z (ESI): 524.2 [M-56+H] + .

[0504] Step 5: Compound Z21-2 (200 mg, 344.80 μmol) was dissolved in trifluoroacetic acid (3 mL), and dichloromethane (6 mL) was added. The mixture was allowed to react at room temperature for 2 h. LCMS monitoring of the reaction was performed. The reaction solution was dried, adjusted to pH 8 with aqueous sodium bicarbonate solution, extracted twice with DCM, washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness. The residue was combined with DCM:MeOH in a ratio of 5:1 to afford compound Z21 (75 mg, 156.27 μmol, 45.32% yield) as a pale yellow solid. MS m / z (ESI): 480.2 [M+H] + .

[0505] Preparation of intermediate Z22

[0506] Step 1: Dissolve 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (320 mg, 804.77 μmol) and Z22-a (312.50 mg, 804.77 μmol) in dioxane (10 mL), dimethyl sulfoxide (1 mL), and water (1 mL). Under argon, add Pd(dppf)Cl2 (58.89 mg, 80.48 μmol) and K2CO3 (333.67 mg, 2.41 mmol). Heat to 90°C and stir for 3 hours. Add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column (12 g, 0-40% EA / PE) to give compound Z22-b (350 mg, 604.42 μmol, 75.11% yield) as a light yellow solid. MS m / z (ESI): 579.3 [M+H] + .

[0507] Step 2: Compound Z22-b (350 mg, 604.42 μmol) was dissolved in DCM (6 mL) and TFA (2 mL) was added. Stir at room temperature for 1 hour. The mixture was concentrated under reduced pressure to remove the solvent, then dissolved in dichloromethane. The pH was adjusted to greater than 8 with aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane and methanol (10:1). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product Z22 (240 mg, 501.10 μmol, 82.91% yield) as a light yellow solid, which was directly reacted in the next step without purification. MS m / z (ESI): 479.2 [M+H] + .

[0508] Preparation of intermediate Z23-d

[0509] Step 1: Under argon, 1,4-dibromobenzene (1 g, 4.24 mmol), compound Z23-a (786.44 mg, 2.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (310.17 mg, 423.90 μmol), potassium carbonate (1.76 g, 12.72 mmol), 1,4-dioxane (20 mL), and water (5 mL) were mixed and heated at 85°C for 2 hours. The reaction mixture was filtered, and the filtrate was added to water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 75%:25%) to obtain compound Z23-b (540 mg, 1.60 mmol, yield 37.66%) as a colorless liquid, which was used directly in the next step. MS m / z(ESI):282.0[M+H-56]+ .

[0510] Step 2: Under argon, compound Z23-b (490 mg, 1.45 mmol), pinacol diboron (919.69 mg, 3.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (106.00 mg, 144.87 μmol), potassium acetate (426.53 mg, 4.35 mmol), and 1,4-dioxane (35 mL) were mixed and heated at 90°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 85%:15%) to obtain compound Z23-c (420 mg, 1.09 mmol, yield 75.24%) as a yellow solid. MS m / z (ESI): 330.2 [M+H-56] + .

[0511] Step 3: Under a hydrogen atmosphere, palladium on carbon (11.05 mg, 103.81 μmol) was added to a solution of compound Z23-c (400 mg, 1.04 mmol) and methanol (10 mL). The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated to dryness to obtain compound Z23-d (380 mg, 981.10 μmol, 94.51% yield) as a colorless oil. The crude product was directly used in the next step. MS m / z (ESI): 332.2 [M+H-56] + .

[0512] Preparation of intermediate Z24

[0513] Step 1: Dissolve tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2 g, 7.86 mmol) in toluene (30 mL) and add 1,4-dibromobenzene (5.56 g, 23.59 mmol), cesium carbonate (7.67 g, 23.59 mmol), bis(dibenzylideneacetone)palladium (719.99 mg, 786.26 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (908.92 mg, 1.57 mmol). React at 110°C overnight and monitor the disappearance of the starting material using LCMS. Add water to the reaction solution, extract twice with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, and spin-dry. The product was then purified by CombiFlash (40 g, 0-40% EA / PE) to obtain a yellow solid compound Z24-a (1.3 g, 3.18 mmol, yield: 40.39%). MS m / z (ESI): 409.2 [M+H] + .

[0514] Step 2: Compound Z24-a (1.3 g, 3.18 mmol) was dissolved in 1,4-dioxane (15 mL) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (464.29 mg, 635.14 μmol) and pinacol diboron (1.61 g, 6.35 mmol) were added. The argon atmosphere was replaced three times and the reaction was carried out at 100°C for 16 h. LCMS monitoring indicated the disappearance of the starting material and the formation of the product. The reaction solution was added with water, extracted twice with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spun down. The product was then purified using a CombiFlash (20 g, 0-40% EA / PE) to obtain compound Z24-b (1 g, 2.19 mmol, yield: 68.99%) as a yellow solid. MS m / z (ESI): 457.3 [M+H] + .

[0515] Step 3: Compound Z24-b (250 mg, 628.73 μmol) and 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine were dissolved in 1,4-dioxane (10 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (68.94 mg, 94.31 μmol) and potassium carbonate (260.68 mg, 1.89 mmol) were added. The argon atmosphere was replaced three times and the reaction was carried out at 100°C for 16 h. LCMS monitoring indicated the disappearance of the starting material and the formation of the product. The reaction mixture was filtered and dried, and the residue was purified by CombiFlash (12 g, 0-25% EA / PE) to afford compound Z24-c as a yellow solid (400 mg, 618.07 μmol, yield: 98.30%). MS m / z(ESI):647.1[M+H] + .

[0516] Step 4: Compound Z24-c (300 mg, 463.55 μmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (2 mL) was added. The reaction was allowed to react overnight at room temperature. LCMS monitored the product formation and the disappearance of the starting material. The reaction solution was spin-dried to dryness, and the residue was dissolved in TEA and DCM, and the sample was stirred. The product was then purified by CombiFlash (12 g, 0-50% MeOH / DCM) to obtain compound Z24 (250 mg, 456.98 μmol, yield: 98.58%) as a yellow solid. MS m / z (ESI): 547.3 [M+H] + .

[0517] Preparation of intermediate Z25

[0518] Step 1: Compound 8-bromo-1-chloro-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (200 mg, 502.98 μmol) and tert-butyl 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (194.81 mg, 502.98 μmol) were dissolved in dioxane (5 mL) and water (0.5 mL). Under argon protection, bis(2-diphenylphosphinocyclopenta-2,4-dien-1-yl)iron; palladium dichloride (73.61 mg, 100.60 μmol) and potassium carbonate (139.03 mg, 1.01 mmol) were added in sequence, and the temperature was raised to 95 degrees and stirred for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (DCM:EA=0-80%) to give a yellow solid Z25-a (200 mg, 345.98 μmol, 68.78% yield). MS m / z (ESI): 578 [M+H] + .

[0519] Step 2: Compound Z25-a (150 mg, 259.48 μmol) was dissolved in dichloromethane (8.53 mL) and methanol (3.41 mL). A 4.0 M solution of hydrogen chloride in ethyl acetate (64.87 μL) was added with stirring at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to dryness to obtain a yellow solid Z25 (124.02 mg, 259.48 μmol, 100.00% yield). MS m / z (ESI): 478 [M+H] +

[0520] Preparation of intermediate Z26

[0521] Step 1: Ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (554 mg, 2 mmol), 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (792 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol), and the catalyst 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (146 mg, 0.2 mmol) were added to a mixture of 5 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with nitrogen three times and heated at 100°C for 5 hours. After the reaction, silica gel was added and the mixture was filtered through a 30-100% PE / EA column. The desired product was concentrated to obtain compound Z26-a (467 mg, 1 mmol). Yield: 50%. MS m / z(ESI):468[M+H] + .

[0522] Step 2: Compound Z26-a (467 mg, 1 mmol) and 100 mg of lithium hydroxide were added to a mixture of 5 ml of tetrahydrofuran and 2 ml of water. After stirring at room temperature for 2 hours, 2 M aqueous hydrochloric acid was added dropwise to adjust the pH to a weakly acidic state. The mixture was extracted with ethyl acetate three times (20 ml x 3). The combined organic phases were concentrated to obtain compound Z26-b (330 mg, 0.75 mmol). Yield: 75%. MS m / z (ESI): 440 [M+H] + .

[0523] Step 3: Compound Z26-b (330 mg, 0.75 mmol), 1 ml of DIEA, and HATU (285 mg, 0.75 mmol) were added sequentially to 5 ml of DMF. The reaction was stirred at room temperature for 10 minutes, followed by the addition of tert-butyl 4-aminopiperidine-1-carboxylate (200 mg, 1 mmol) and the reaction continued for 1 hour. Silica gel was added to the resulting mixture, and the mixture was filtered through a PE / EA (10-100%) column to afford Z26-c (156 mg, 0.25 mol). Yield: 33%. MS m / z (ESI): 622 [M+H] + .

[0524] Step 4: Compound Z26-c (156 mg, 0.25 mol) was added to a mixture of 5 mL of dichloromethane and 1 mL of TFA, stirred at room temperature for 1 hour, and then concentrated to dryness to afford compound Z26 (120 mg, 0.23 mmol). Yield: 92%. MS m / z (ESI): 522 [M+H] + .

[0525] Preparation of intermediate Z27

[0526] Step 1: 8-Bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (1090 mg, 3 mmol) was added to 3 ml of pyridine, followed by the addition of 100 mg of DMAP and di-tert-butyl dicarbonate (1090 mg, 5 mmol). The mixture was stirred at room temperature for 5 hours. After completion of the reaction, silica gel was added and the mixture was purified by column chromatography using PE / EA (25-100%) to afford Z27-a (926 mg, 2 mmol). Yield: 66%. MS m / z (ESI): 464 [M+H]. + .

[0527] Step 2: Compound Z27-a (926 mg, 2 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.36 mmol), 100 mg of Xantphos, 100 mg of Pd2(dba)3, and cesium carbonate were added sequentially to 10 ml of 1,4-dioxane. The atmosphere was purged with nitrogen three times, and the mixture was heated at 110°C with stirring for 10 hours. After the reaction, silica gel was added and the sample was filtered through a PE / EA (10-100%) column to obtain compound Z27-b (595 mg, 1 mmol). Yield: 50%. MS m / z (ESI): 596 [M+H] + .

[0528] Step 3: Compound Z27-b (595 mg, 1 mmol) was added to 5 ml of dichloromethane, followed by 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to obtain compound Z27-c (394 mg, 1 mmol). Yield: 100%. MS m / z (ESI): 396 [M+H] + .

[0529] Step 4: Compound Z27-c (394 mg, 1 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (213 mg, 1 mmol) were added to 5 ml of DMSO, followed by the addition of 3 drops of acetic acid. The mixture was microwaved at 50°C for 30 min, and then 80 mg of sodium acetate borohydride was added. The mixture was stirred and microwaved at 50°C for 1 hour. After the reaction, silica gel was added and the mixture was filtered through a PE / EA (10-100%) column to afford compound Z27-d (355 mg, 0.6 mmol). Yield: 60%. MS m / z (ESI): 593 [M+H]. + .

[0530] Step 5: Compound Z27-d (355 mg, 0.6 mmol) was added to 5 ml of dichloromethane, followed by 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to obtain compound Z27 (295 mg, 0.6 mmol). Yield: 60%. MS m / z (ESI): 493 [M+H] + .

[0531] Preparation of intermediate Z28

[0532] Step 1: Dissolve compound Z28-a (3 g, 14.32 mmol) and KOH (1.61 g, 28.65 mmol) in THF (30 mL). Add dimethyl sulfate (3.61 g, 28.65 mmol, 2.71 mL) dropwise and stir at room temperature for 1 hour. Filter the solids and concentrate under reduced pressure to obtain the crude product. The residue is separated by a CombiFlash column (40 g, 0-20% EA / PE) to afford Z28-b (0.7 g, 3.13 mmol, 21.87% yield) as a white solid. MS m / z (ESI): 223.0 [M+H] + .

[0533] Step 2: Dissolve Z28-b (0.5 g, 2.24 mmol) and NaHCO3 (375.94 mg, 4.48 mmol) in ethanol (15 mL), add (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (486.30 mg, 2.91 mmol), and heat to 60°C with stirring for 1 hour. Add water and dichloromethane, extract three times with DCM:MeOH ~10:1, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Then, slurry with ethyl acetate, filter to obtain a filter cake, and dry the filter cake to obtain the product Z28-c (0.6 g, 1.69 mmol, 75.71% yield) as a white solid. The product was directly reacted in the next step without purification. MS m / z (ESI): 354.0 [M+H] + .

[0534] Step 3: Dissolve Z28-c (80 mg, 225.88 μmol) and tert-butyl 4-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate (99.97 mg, 248.47 μmol) in dioxane (5 mL), DMSO (0.5 mL), and water (1 mL). Add Pd(dppf)Cl2 (16.53 mg, 22.59 μmol) and K2CO3 (62.44 mg, 451.76 μmol) under argon. Heat to 100°C and stir for 2 hours. Concentrate under reduced pressure to remove the solvent, add water and ethyl acetate, and extract three times with ethyl acetate. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column (4 g, 0-80% EA / PE) to give Z28-d (30 mg, 54.58 μmol, 24.16% yield) as a brown oil. MS m / z (ESI): 550.3 [M+H] + .

[0535] Step 4: Dissolve Z28-d (30 mg, 54.58 μmol) in DCM (2 mL), add TFA (0.8 mL), and stir at room temperature for 1 hour. Concentrate under reduced pressure to remove the solvent, add aqueous sodium bicarbonate and ethyl acetate, and extract three times with ethyl acetate. The organic phases are combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product Z28 (24 mg, 53.39 μmol, 97.82% yield) as a light yellow solid. Used in the next step without purification. MS m / z (ESI): 450.2 [M+H] + .

[0536] Preparation of intermediate Z29

[0537] Step 1: Z29-a (12 g, 51.01 mmol) and benzylamine (5.47 g, 51.01 mmol) were dissolved in DCM (100 mL), and sodium triacetoxyborohydride (21.62 g, 102.03 mmol) was added. The reaction was stirred at room temperature for 18 hours. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (200 mL × 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain the oily product Z29-b (16.65 g, 51.01 mmol, 100.00% yield). MS m / z (ESI): 327.2 [M+H] + .

[0538] Step 2: Z29-b (16.65 g, 51.01 mmol) and benzaldehyde (8.12 g, 76.52 mmol) were dissolved in DCM (100 mL), and sodium triacetoxyborohydride (21.62 g, 102.03 mmol) was added. The reaction was stirred at room temperature for 18 hours. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product Z29-c (6.4 g, 15.37 mmol, 30.12% yield) was obtained as a white solid. MS m / z (ESI): 417.3 [M+H] + .

[0539] Step 3: Z29-c (6.4 g, 15.37 mmol) was dissolved in DCM (35 mL), and HCl (4 M in dioxane, 25 mL) was added. The reaction was stirred at room temperature for 18 hours. After completion, the reaction solution was concentrated and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the product Z29-d (4.6 g, 14.54 mmol, 94.62% yield) as a white solid. MS m / z (ESI): 317.2 [M+H] + .

[0540] Step 4: 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol) and Z29-d (1.50 g, 4.73 mmol) were dissolved in toluene (60 mL), and then Ruphos (275.99 mg, 591.44 μmol) and Ruphos-Pd-G3 (495.26 mg, 591.44 μmol) were added thereto. LiHMDS (1 M in 4% NaOH) was added under nitrogen. The reaction mixture was stirred at 90°C for 2 hours in THF (14.79 mL). After completion of the reaction, the mixture was cooled to room temperature and poured into water (60 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product Z29-e was obtained as a yellow solid (1.1 g, 1.92 mmol, 64.85% yield) after separation on a CombiFlash column (24 g, 0-100% EA / PE). MS m / z (ESI): 574.2 [M+H] + .

[0541] Step 5: Z29-e (1.1 g, 1.92 mmol) and Pd / C (300 mg, 10% purity and 50% water) were dissolved in THF (30 mL). The reaction was stirred at 50°C under a hydrogen balloon for 6 hours, filtered through celite, and the filter cake was washed with a small amount of methanol. The filtrate was concentrated to obtain the product Z29 (690 mg, 1.75 mmol, 91.47% yield) as a pale yellow solid. MS m / z (ESI): 394.1 [M+H] + .

[0542] Preparation of intermediate Z30

[0543] Step 1: Dissolve Z30-a (0.5 g, 1.48 mmol) and 4-N-BOC-4-N-benzyl-piperidine (515.26 mg, 1.77 mmol) in toluene (10 mL). Add Ruphos-Pd-G3 (123.81 mg, 147.86 μmol) and Ruphos (137.99 mg, 295.72 μmol). Replace the atmosphere with argon three times. Add LiHMDS (1 M, 7.39 mL), replace the atmosphere with argon three more times, and heat to 80°C with stirring for 2 hours. Cool to room temperature, add water and ethyl acetate, and extract three times with ethyl acetate. The organic phases are combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The residue is purified by a CombiFlash column (12 g, 0-60% EA / PE) to afford Z30-b (0.5 g, 913.00 μmol, 61.75% yield) as a pale yellow solid. MS m / z(ESI):548.3[M+H] +

[0544] Step 2: Dissolve Z30-b (0.4 g, 730.40 μmol) in HCl / dioxane (4 M) (10 mL) and stir at room temperature for 1 hour. Concentrate under reduced pressure to remove the solvent to obtain a crude product, which is then dissolved in dichloromethane:methanol (10:1), washed with aqueous sodium bicarbonate solution, and the organic phase is dried and concentrated under reduced pressure to remove the solvent to obtain crude product Z30-c (0.3 g, 670.35 μmol, 91.78% yield) as a white solid. This product is used directly in the next step without purification. MS m / z (ESI): 448.2 [M+H] +

[0545] Step 3: Dissolve Z30-c (0.3 g, 670.35 μmol) in THF (5 mL) and add Pd / C (713.39 mg, 670.35 μmol, 10% purity). Replace the mixture three times with hydrogen balloon and stir at room temperature overnight. Filter the catalyst, and concentrate the mother liquor under reduced pressure to obtain crude Z30 (0.1 g, 279.79 μmol, 41.74% yield) as a pale white solid. This was used in the next step without purification. MS m / z (ESI): 358.2 [M+H] +

[0546] Preparation of intermediate Z31

[0547] Step 1: Dissolve Z31-a (7 g, 29.90 mmol) and TEA (9.08 g, 89.70 mmol, 12.51 mL) in DCM (946.01 μL) and add ethyl oxalyl chloride (4.08 g, 29.90 mmol, 3.34 mL) at 0°C. Stir at room temperature for 1 hour. Add water and extract three times with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is slurried with PE:EA ~1:1 and filtered to obtain a filter cake. The filter cake is dried to obtain the product Z31-b (3.5 g, 10.47 mmol, 35.03% yield) as a white solid. MS m / z (ESI): 334.0 [M+H] + .

[0548] Step 2: Phosphorus oxychloride (4.11 g, 26.82 mmol, 2.50 mL) was added dropwise to a solution of Z31-b (3.5 g, 10.47 mmol) in dioxane (40 mL). The mixture was heated to 110 ° C and stirred for 8 hours. The mixture was cooled to room temperature and concentrated. It was slowly added to a saturated aqueous NaHCO3 solution. The precipitated solid was filtered, the filter cake was washed twice with water, and the solid was vacuum dried to obtain a crude product. It was then slurried with petroleum ether to obtain a crude product Z31-c (3.3 g, 10.44 mmol, 99.66% yield), a light brown solid. It was directly reacted in the next step without purification. MS m / z (ESI): 315.9 [M+H] +

[0549] Step 3: Dissolve Z31-c (3.3 g, 10.44 mmol) in DCM (50 mL) and add m-chloroperbenzoic acid (4.24 g, 20.87 mmol, 85% purity) at 0°C. Stir at low temperature for 1 hour. Filter the solids. The mother liquor contains Z31-d (3.4 g, 10.24 mmol, 98.07% yield) as a light yellow solution, which is directly reacted in the next step without purification. MS m / z (ESI): 332.0 [M+H] + .

[0550] Step 4: Dissolve (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (3.42 g, 20.47 mmol) and DIEA (3.97 g, 30.71 mmol, 5.35 mL) in DCM (1.03 mL). Add Z31-d (3.4 g, 10.24 mmol) at 0°C and stir at room temperature for 1 hour. Add water and extract three times with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was purified by a CombiFlash column (40 g, 0-40% EA / PE) to afford Z31-e (1.8 g, 4.14 mmol, 40.40% yield) as a light yellow solid. MS m / z (ESI): 435.0 [M+H] + .

[0551] Step 5: Dissolve Z31-e (1.8 g, 4.14 mmol) in 7 M NH3 / MeOH (30 mL) and stir at room temperature overnight. The reaction mixture was filtered and the filter cake dried to give a white solid product, Z31-f (1.2 g, 2.95 mmol, 71.43% yield). The white solid was used in the next step without purification. MS m / z (ESI): 406.0 [M+H] + .

[0552] Step 6: Dissolve Z31-f (0.5 g, 1.23 mmol) in phosphorus oxychloride (10 mL) and heat to 120°C under argon and stir for 4 hours. Concentrate under reduced pressure to remove the solvent, then adjust the pH to greater than 8 with saturated sodium bicarbonate solution. Extract three times with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue is separated by a CombiFlash column (12 g, 0-10% MeOH / DCM) to obtain Z31-g (0.3 g, 772.81 μmol, 62.78% yield) as a dark green solid. MS m / z (ESI): 388.0 [M+H] + .

[0553] Step 7: Dissolve Z31-g (0.15 g, 386.41 μmol) and 4-(1-BOC-4-piperidinyl)phenylboronic acid pinacol ester (179.59 mg, 463.69 μmol) in dioxane (5 mL) and water (0.5 mL). Under argon, add Pd(dppf)Cl2 (56.55 mg, 77.28 μmol) and K2CO3 (160.21 mg, 1.16 mmol). Heat to 100°C and stir for 2 hours. Cool to room temperature, add water and ethyl acetate, and extract three times with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue is purified by CombiFlash column chromatography (4 g, 0-10% MeOH / DCM) to afford Z31-h (0.1 g, 175.86 μmol, 45.51% yield) as a pale yellow solid. MS m / z(ESI):569.1[M+H] + .

[0554] Step 8: Z31-h (0.15 g, 263.79 μmol) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure to yield the product, adjusted to a pH greater than 7 with saturated sodium bicarbonate, and extracted three times with dichloromethane:methanol (10:1). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The residue was 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% to 95% acetonitrile) to yield Z31 (15 mg, 32.02 μmol, 12.14% yield) as a light yellow solid. MS m / z(ESI):469.2[M+H] + .

[0555] Preparation of intermediate Z32

[0556] Step 1: Dissolve Z32-a (3.5 g, 27.02 mmol) and NaHCO3 (6.81 g, 81.05 mmol) in MeCN (80 mL). Add ethyl 3-bromopyruvate (9.88 g, 40.53 mmol, 6.37 mL) under argon and stir at 80°C for 16 hours. Concentrate under reduced pressure to remove the solvent, add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue is purified by a CombiFlash column (20 g, 0-10% MeOH / DCM) to obtain the crude product. The product is then slurried with petroleum ether and ethyl acetate and filtered to obtain the product Z32-b (4.5 g, 19.94 mmol, 73.82% yield) as a light yellow solid. MS m / z (ESI): 226.0 [M+H] + .

[0557] Step 2: Dissolve Z32-b (4.5 g, 19.94 mmol) and TEA (6.05 g, 59.83 mmol, 8.35 mL) in ethanol (100 mL), add (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (6.67 g, 39.89 mmol, 5.33 mL), and heat to 90°C with stirring for 16 hours. The solvent was removed by concentration under reduced pressure to obtain the crude product. The residue was separated by a CombiFlash column (80 g, 0-40% EA / PE) to obtain the product, which was then slurried with petroleum ether, filtered, and the filter cake was dried to obtain the product Z32-c (4.5 g, 12.63 mmol, 63.32% yield) as a light white solid. MS m / z (ESI): 357.1 [M+H] +

[0558] Step 3: Dissolve Z32-c (4 g, 11.22 mmol) in DCM (80 mL) and add pyridinium tribromide (3.59 g, 11.22 mmol) at 0°C. Stir at 0°C for 1 hour. Add water and extract three times with dichloromethane. Wash with saturated aqueous sodium sulfite solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue is separated by a CombiFlash column (40 g, 0-10% EA / DCM) to afford Z32-d (4 g, 9.19 mmol, 81.87% yield) as a white solid. MS m / z (ESI): 435.0 [M+H] +

[0559] Step 4: Dissolve Z32-d (2 g, 4.60 mmol) in NH3 / MeOH (50 mL) and heat to 50°C with stirring for 20 hours. Concentrate under reduced pressure to remove the solvent to give the crude product Z32-e (1.5 g, 3.69 mmol, 80.36% yield) as a white solid, which was directly used in the next step without purification. MS m / z (ESI): 406.0 [M+H] +

[0560] Step 5: Dissolve Z32-e (1.3 g, 3.20 mmol) in phosphorus oxychloride (15 mL) and heat to 120°C under argon and stir for 4 hours. Concentrate under reduced pressure to remove the solvent, then adjust the pH to greater than 8 with saturated sodium bicarbonate aqueous solution, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was slurried with petroleum ether and ethyl acetate, and the filter cake was concentrated to dryness to obtain the white solid product Z32-f (1 g, 2.58 mmol, 80.49% yield). MS m / z (ESI): 388.0 [M+H] +

[0561] Step 6: Dissolve Z32-f (0.5 g, 1.29 mmol) and 4-(1-BOC-4-piperidinyl)phenylboronic acid pinacol ester (748.31 mg, 1.93 mmol) in dioxane (5 mL) and water (1 mL). Under argon, add Pd(dppf)Cl2 (94.24 mg, 128.80 μmol) and K2CO3 (534.03 mg, 3.86 mmol). Heat to 100°C and stir for 2 hours. Concentrate under reduced pressure to obtain the crude product. Add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue is purified by a CombiFlash column (12 g, 0-50% EA / PE) to afford Z32-g (0.6 g, 1.06 mmol, 81.92% yield) as a light yellow solid. MS m / z(ESI):569.3[M+H] +

[0562] Step 7: Dissolve Z32-g (0.1 g, 175.86 μmol) in DCM (3 mL), add TFA (1 mL), and stir at room temperature for 1 hour. Concentrate under reduced pressure to remove the solvent, add dichloromethane and saturated aqueous sodium bicarbonate solution, and extract three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude Z32 (80 mg, 170.75 μmol, 97.09% yield) as a light yellow solid, which is used directly in the next step without purification. MS m / z (ESI): 469.3 [M+H] +

[0563] Preparation of intermediate Z33

[0564] Z33 was prepared by following steps 6-7 of intermediate Z32. MS m / z (ESI): 487.2 [M+H] + .

[0565] Preparation of intermediate Z34

[0566] Z34 was prepared by following steps 6-7 of intermediate Z32. MS m / z (ESI): 516.2 [M+H] + .

[0567] Preparation of intermediate Z35

[0568] Step 1: 4-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (762 mg, 3 mmol), pinacol diboron (774 mg, 3 mmol), potassium acetate (2.7 g, 9 mmol), and the catalyst 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (146 mg, 0.2 mmol) were added to 5 ml of dioxane. The atmosphere was purged with nitrogen three times, and then heated to 110°C with stirring for 15 hours. After the reaction, silica gel was added and the mixture was filtered through a 30-100% PE / EA column. The target product was concentrated to obtain 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (890 mg, 2 mmol). Yield: 66%. MS m / z(ESI):446[M+H] + .

[0569] Step 2: Compound 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (890 mg, 2 mmol), 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (792 mg, 3 mmol), potassium carbonate (828 mg, 6 mmol), catalyst 1,1-bis(diphenylphosphine)dichloroferric palladium (146 mg, 0.2 mmol) and 1 ml of water were added to 5 ml of dioxane in sequence, and the atmosphere was replaced with nitrogen three times, and then heated at 100° C. and stirred for 15 hours. After the reaction, silica gel was directly added and the sample was stirred. 30-100% The product was purified by column chromatography with PE / EA and concentrated to afford tert-butyl 4-(4-(1-chloro-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (952 mg, 1.5 mmol). Yield: 75%. MS m / z (ESI): 636 [M+H]. + .

[0570] Step 3: tert-Butyl 4-(4-(1-chloro-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (952 mg, 1.5 mmol) was added to a mixture of 5 mL of dichloromethane and 1 mL of trifluoroacetic acid, stirred at room temperature for 1 hour, and then concentrated to dryness to afford compound Z35 (802 mg, 0.5 mmol). Yield: 100%. MS m / z (ESI): 536 [M+H] + .

[0571] Preparation of intermediate Z36

[0572] Step 1: Dissolve 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (0.6 g, 1.51 mmol) and 2-fluoro-6-methylpyridine-5-boronic acid (350.68 mg, 2.26 mmol) in dioxane (15 mL), water (2 mL), and DMSO (1 mL). Under argon, add Pd(dppf)Cl2 (110.41 mg, 150.89 μmol) and K2CO3 (625.63 mg, 4.53 mmol). Heat to 100°C and stir for 2 hours. Cool to room temperature, add water and ethyl acetate, and extract three times with ethyl acetate. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column (12 g, 0-30% EA / PE) to give Z36-a (0.55 g, 1.29 mmol, 85.20% yield) as a light brown solid. MS m / z (ESI): 428.1 [M+H] + .

[0573] Step 2: Dissolve Z36-a (100 mg, 233.74 μmol) and tert-butyl piperazine-1-carboxylate (217.67 mg, 1.17 mmol) in NMP (3 mL). Add DIEA (90.63 mg, 701.21 μmol, 122.14 μL) and microwave the mixture to 200°C with stirring for 2 hours. Cool to room temperature and add Boc2O (153.04 mg, 701.21 μmol) dropwise. Stir at room temperature for 0.5 hour. Add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was purified by CombiFlash column chromatography (4 g, 0-30% EA / DCM) to afford Z36-b (80 mg, 134.66 μmol, 57.61% yield) as a light yellow solid. MS m / z(ESI):594.3[M+H] + .

[0574] Step 3: Dissolve Z36-b (80 mg, 134.66 μmol) in DCM (2 mL), add TFA (1 mL), and stir at room temperature for 1 hour. Concentrate under reduced pressure to remove the solvent, add dichloromethane and saturated aqueous sodium bicarbonate solution, and extract three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product Z36 (60 mg, 121.47 μmol, 90.20% yield) as a light yellow solid, which is directly reacted in the next step without purification. MS m / z (ESI): 494.2 [M+H] + .

[0575] Preparation of intermediate Z37

[0576] Step 1: 6-bromo-3-iodo-1-methyl-1H-indazole (5.2 g, 15.43 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.41 g, 17.75 mmol) were dissolved in 1,4-dioxane (80 mL) and water (20 mL), and then Pd(dppf)Cl2 (1.13 g, 1.54 mmol) and Cs2CO3 (10.06 g, 30.86 mmol) were added thereto, and nitrogen was replaced. The reaction was stirred at 100 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature, quenched with aqueous solution, and then extracted with ethyl acetate (120 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure. It was separated by CombiFlash column (24 g, 0-100%). EA / PE) to successfully obtain white solid product Z37-a (4.9 g, 63.45% yield). MS m / z (ESI): 500.1 [M+H] + .

[0577] Step 2: Dissolve Z37-a (1.5 g, 3.00 mmol) and tert-butyl piperazine-1-carboxylate (837.48 mg, 4.50 mmol) in dioxane (15 mL). Under argon, add 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). Heat to 100°C and stir overnight. Concentrate under reduced pressure to remove the solvent, then add water and ethyl acetate. Extract three times with ethyl acetate. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue is purified by a CombiFlash column (20 g, 0-30% EA / PE) to afford Z37-b (1.7 g, 2.81 mmol, 93.62% yield) as a light brown solid. MS m / z(ESI):606.3[M+H] + .

[0578] Step 3: Dissolve Z37-b (1.7 g, 2.81 mmol) in ethanol (30 mL) and THF (30 mL), add Pd / C (297.50 mg, 280.66 μmol, 10% purity), and replace with a hydrogen balloon three times. Stir at room temperature overnight. Filter the catalyst, and concentrate the mother liquor under reduced pressure to give the crude product Z37-c (1.1 g, 2.57 mmol, 91.68% yield) as a light yellow solid. Use the product in the next step without purification. MS m / z (ESI): 428.2 [M+H] + .

[0579] Step 4: Dissolve Z37-c (0.5 g, 1.17 mmol) in DCM (6 mL), add TFA (2 mL), and stir at room temperature for 1 hour. Concentrate under reduced pressure to remove the solvent, add dichloromethane and saturated aqueous sodium bicarbonate solution, and extract three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude Z37 (0.25 g, 763.64 μmol, 65.29% yield) as a light yellow solid. Used in the next step without purification. MS m / z (ESI): 328.2 [M+H] + .

[0580] Preparation of intermediate Z38

[0581] Step 1: Dissolve Z36-a (150 mg, 350.60 μmol) and 4-(dimethoxymethyl)-piperidine (279.12 mg, 1.75 mmol) in NMP (3 mL). Add DIEA (135.94 mg, 1.05 mmol, 183.20 μL) and microwave at 200°C with stirring for 1 hour. Add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column (4 g, 0-40% EA / PE) to obtain Z38-a (150 mg, 264.53 μmol, 75.45% yield) as a light yellow solid. MS m / z (ESI): 567.3 [M+H] + .

[0582] Step 2: Dissolve Z38-a (150 mg, 264.53 μmol) in DCM (3 mL), add TFA (1 mL), and stir at room temperature for 1 hour. Concentrate under reduced pressure to remove the solvent, add dichloromethane and saturated aqueous sodium bicarbonate solution, and extract three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product Z38 (0.1 g, 191.94 μmol, 72.56% yield) as a light yellow solid, which is used directly in the next step without purification. MS m / z (ESI): 521.2 [M+H] + .

[0583] Preparation of intermediate Z39

[0584] Z39 was prepared using Z37-a as starting material according to the method of Z37. MS m / z (ESI): 424.3 [M+H] + .

[0585] Preparation of intermediate Z40

[0586] Z40 was prepared using Z37-a as the starting material according to the method of Z37. MS m / z (ESI): 426.3 [M+H] + .

[0587] Preparation of intermediate Z41

[0588] Step 1: Compound 8-bromo-1-chloro-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (150 mg, 377.24 μmol) and tert-3-hydroxy-3-[6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]azetidine-1-carboxylic acid The butyl ester (147.23 mg, 377.24 μmol) was dissolved in dioxane (5 mL) and water (0.5 mL). Under argon, bis(2-diphenylphosphinocyclopenta-2,4-dien-1-yl)iron dichloropalladium (276.03 mg, 377.24 μmol) and potassium carbonate (52.14 mg, 377.24 μmol) were added sequentially. The temperature was raised to 95°C and stirred overnight. The reaction was monitored by LC-MS. The reaction solution was concentrated to dryness under reduced pressure and purified on a silica gel column (MeOH:DCM = 0-10%) to afford Z41-a (110 mg, 189.32 μmol, 50.19% yield) as a yellow solid. MS m / z (ESI): 581 [M+H] + .

[0589] Step 2: Z41-a (113.11 mg, 194.68 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.83 g, 16.08 mmol, 1 mL) was added with stirring at room temperature. The mixture was stirred at room temperature for 2 hours and analyzed by LC-MS. The reaction mixture was concentrated to dryness under reduced pressure, saturated sodium carbonate was added, and the mixture was extracted with EA (30 ml × 2). The mixture was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a yellow solid Z41 (60 mg, 124.76 μmol, 64.09% yield). MS m / z (ESI): 481 [M+H] + .

[0590] Preparation of intermediate Z42

[0591] Step 1: Dissolve 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.04 g, 5.15 mmol), and tri-n-butylphosphine cyanide (1.24 g, 5.15 mmol) in toluene (10 mL). After purging the mixture with argon, stir at 90°C for 16 hours to produce the product. The reaction mixture was concentrated to dryness under reduced pressure and the concentrate was purified by combiflash (EA:PE = 0-40%) to give the yellow oily product Z42-a (550 mg, crude). MS m / z (ESI): 378.3 [M+H] + .

[0592] Step 2: 8-Bromo-1-chloro-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (150 mg, 377.24 μmol) and Z42-a (426.98 mg, 1.13 mmol) were dissolved in a mixed solution of 1,4-dioxane (10 mL), H2O (2 mL) and DMSO (0.5 mL), and PdCl2(dppf) (82.81 mg, 113.17 μmol) and potassium carbonate (260.69 mg, 1.89 mmol) were added. After the mixed solution was replaced with argon, it was stirred at 95 ° C for 3 hours and the raw materials were completely reacted. The reaction mixture was concentrated under reduced pressure to dryness to obtain a crude product, which was then purified by combiflash (EA:PE = 0-40%) to give a yellow oily product Z42-b (105 mg, yield: 49.00%). MS m / z (ESI): 512.2 [M-56+H] + .

[0593] Step 3: Dissolve Z42-b (105 mg, 184.85 μmol) in DCM (5 mL) and add trifluoroacetic acid (21.08 mg, 184.85 μmol, 1 mL). The mixture was stirred at room temperature (25°C) for 2 hours until the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and triethylamine (1 ml) was added to alkalize the product. The product was further concentrated to dryness under reduced pressure to obtain crude Z42 (86 mg, crude product) as a yellow oil. The product was used directly in the next step without further purification. MS m / z (ESI): 468.1 [M+H] + .

[0594] Preparation of intermediate Z43

[0595] Z43 was obtained by following the above route and referring to the preparation method of Z42. MS m / z (ESI): 468.1 [M+H] + .

[0596] Preparation of intermediate Z44

[0597] Z44 was obtained by following the above route and referring to the preparation method of Z42. MS m / z (ESI): 468.1 [M+H] + .

[0598] Preparation of intermediate Z45

[0599] Step 1: 8-Bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (2 g, 5.51 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.04 g, 6.61 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL). Pd(dppf)Cl2 (805.88 mg, 1.10 mmol) and K2CO3 (2.28 g, 16.52 mmol) were then added. The reaction was stirred at 100°C for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure and the product Z45-a (2.2 g, 85.82% yield) was obtained as a pale yellow solid. MS m / z (ESI): 466.2 [M+H] + .

[0600] Step 2: Z45-a (2.2 g, 4.73 mmol) was dissolved in MeOH (40 mL), and Pd(OH)2 / C (774.70 mg, 1.26 mmol, 20% purity) was added. The reaction was stirred under hydrogen at room temperature for 18 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to give the crude product Z45-b (2.1 g, 95.04% yield) as a pale yellow solid. MS m / z (ESI): 468.2 [M+H] + .

[0601] Step 3: Compound Z45-b (2.1 g, 4.49 mmol) was dissolved in DMF (40 mL). NCS (599.78 mg, 4.49 mmol) was added under ice-cooling. The mixture was then allowed to warm to room temperature and stirred overnight. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and separated by a CombiFlash column (12 g, 0-40% EA / DCM) to afford the off-white solid product Z45-c (2.1 g, 93.14% yield). MS m / z (ESI): 502.2 [M+H] +.

[0602] Step 4: Z45-c (2.1 g, 4.18 mmol) was dissolved in DCM (30 mL), and HCl (4 M in dioxane, 10 mL) was added. The reaction was stirred at room temperature for 2 hours. After completion, the reaction solution was concentrated and neutralized with saturated aqueous sodium bicarbonate to produce a solid. The solid was filtered, washed twice with water, and then twice with a small amount of methanol. The filter cake was vacuum dried to yield the crude product Z45-d (1.3 g, 77.33% yield) as a pale yellow solid. MS m / z (ESI): 402.1 [M+H] + .

[0603] Step 5: Z45-d (500 mg, 1.24 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.49 g, 7.47 mmol) were dissolved in DMSO (9 mL) and EtOH (3 mL). NaBH3CN (781.88 mg, 12.44 mmol) and AcOH (373.58 mg, 6.22 mmol) were then added. The reaction was stirred in a microwave oven at 85°C for 0.7 h. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethane (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was separated by passing through a CombiFlash column (24 g, 0-100% THF / PE) to obtain the product Z45-e (620 mg, 85.17% yield) as a light yellow solid. MS m / z (ESI): 585.3 [M+H] + .

[0604] Step 6: Z45-e (620 mg, 1.06 mmol) was dissolved in DCM (20 mL), and CF3COOH (120.82 mg, 1.06 mmol, 6 mL) was added. The reaction was stirred at room temperature for 2 hours. After completion, the reaction was concentrated and neutralized with aqueous sodium bicarbonate to produce a solid. The solid was filtered, and the filter cake was washed with water and dichloromethane. The filter cake was vacuum dried to give the product Z45 (420 mg, 81.73% yield) as a pale yellow solid. MS m / z (ESI): 485.2 [M+H] + .

[0605] Preparation of intermediate Z46

[0606] Step 1: Dissolve 4-bromo-1H-pyrazole (7 g, 47.63 mmol) and tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (9.96 g, 50.01 mmol) in DMSO (100 mL) and add Cs2CO3 (31.04 g, 95.26 mmol). The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was filtered and washed, and the filtrate was diluted with EA and washed three times with saturated brine. The mixture was concentrated under reduced pressure, and the crude product was separated by a CombiFlash column (0-70% EA / PE) to obtain tert-butyl 4-(4-bromopyrazol-1-yl)-3-hydroxy-piperidine-1-carboxylate (15.46 g, 93.76% yield) as a yellow solid. MS m / z (ESI): 290.0 [M+H-56] + .

[0607] Step 2: Dissolve tert-butyl 4-(4-bromopyrazol-1-yl)-3-hydroxy-piperidine-1-carboxylate (2.9 g, 8.38 mmol) in DCM (20 mL) and add Dess-martin oxidant (5.33 g, 12.56 mmol). The reaction mixture was stirred at room temperature for 20 hours. The mixture was poured into water and neutralized with saturated NaHCO₃ solution. The mixture was filtered, washed, extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by a CombiFlash column (0-70% EA / PE) to afford tert-butyl 4-(4-bromopyrazol-1-yl)-3-oxo-piperidine-1-carboxylate (2.4 g, 83.24% yield) as a yellow solid. MS m / z (ESI): 288.0 [M+H-56] + .

[0608] Step 3: Dissolve tert-butyl 4-(4-bromopyrazol-1-yl)-3-oxo-piperidine-1-carboxylate (3.95 g, 11.48 mmol) in DCM (40 mL), cool to -78°C, and add N-ethyl-N-(trifluorothio)ethylamine (5.55 g, 34.43 mmol, 4.55 mL). Stir the reaction mixture at room temperature for 20 hours. Pour the mixture into water, extract with DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated by a CombiFlash column (0-70% EA / PE) to afford tert-butyl 4-(4-bromopyrazol-1-yl)-3,3-difluoro-piperidine-1-carboxylate (2.5 g, 59.49% yield) as a yellow solid. MS m / z (ESI): 310.0 [M+H-56] + .

[0609] Step 4: 8-Bromo-1-chloro-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (360 mg, 905.37 μmol) and tert-butyl 4-(4-bromopyrazol-1-yl)-3,3-difluoro-piperidine-1-carboxylate (663.09 mg, 1.81 mmol) were dissolved in DME (15 mL) and water (1.5 mL). Palladium acetate (40.65 mg, 181.07 μmol), n-butyldi(1-adamantyl)phosphine (129.84 mg, 362.15 μmol), K2CO3 (501 mg, 3.62 mmol), and (Pin)2B2 (919.63 mg, 3.62 mmol) were added. The reaction mixture was reacted at 70°C under argon for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by CombiFlash column chromatography (0-100% EA / PE) to give 4-[4-[1-chloro-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]pyrazol-1[yl]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (177 mg, 32.37% yield) as a yellow solid. MS m / z (ESI): 548.2 [M+H-56]. + .

[0610] Step 5: Dissolve 4-[4-[1-chloro-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]pyrazol-1[-yl]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (177 mg, 293.04 μmol) in DCM (15.00 mL) and add trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, neutralized with NaHCO₃ solution, extracted with DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product, 1-chloro-8-[1-(3,3-difluoro-4-piperidinyl)pyrazol-4-yl]-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (130 mg, 88.04% yield), was used directly in the next reaction. MS m / z (ESI): 504.2 [M+H] + .

[0611] Preparation of intermediate Z47

[0612] Step 1: 8-Bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (0.8 g, 2.20 mmol) was dissolved in THF (30 mL) and n-BuLi (2.5 M, 4.39 mL) was added dropwise at -78°C for 1 hour. Triisopropyl borate (4.96 g, 26.36 mmol, 6.08 mL) was then slowly added dropwise for 1 hour. The reaction mixture was quenched with 1N HCl and stirred at room temperature for 0.5 hour. The mixture was extracted twice with ethyl acetate and the residue was evaporated to dryness. The mixture was then combined with DCM:MeOH (10:1) to afford Z47-a (22 mg, 66.85 μmol, 3.04% yield) as a yellow oil. MS m / z (ESI): 412.1 [M+H] + .

[0613] Step 2: Under argon, tert-butyl 4-(6-bromopyridazin-3-yl)piperidine-1-carboxylate (100 mg, 292.20 μmol), Z47-a (400.67 mg, 438.30 μmol), Pd(dppf)Cl2 (21.38 mg, 29.22 μmol), potassium carbonate (121.15 mg, 876.60 μmol), 1,4-dioxane (4 mL), and water (1 mL) were heated at 115°C for 2 hours. The reaction mixture was filtered, the aqueous layer was separated, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 30%:70%) to obtain crude Z47-b (135 mg, 29.64 μmol, yield 10.14%) as a yellow solid. MS m / z (ESI): 547.3 [M+H] + .

[0614] Step 3: Z47-b (125 mg, 228.69 μmol), TFA (0.5 mL), and DCM (0.5 mL) were mixed at room temperature and reacted for 1 hour. The reaction mixture was concentrated to obtain the crude product, which was dissolved in DCM:MeOH (10:1) and adjusted to pH 7-8 by adding saturated sodium bicarbonate solution. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to obtain Z47 (100 mg, 223.97 μmol, 97.94% yield) as a yellow oil. The crude product was directly used in the next step. MS m / z (ESI): 447.2 [M+H] + .

[0615] Preparation of intermediate Z48

[0616] Step 1: tert-Butyl 4-formyl-3,6-dihydropyridine-1(2H)-carboxylate (5 g, 23.44 mmol) was dissolved in ethanol (50 mL), and then hydroxylamine hydrochloride (2.45 g, 35.28 mmol) and pyridine (2.45 g, 31.03 mmol, 2.50 mL) were added thereto. The reaction was stirred at room temperature for 6 hours. After completion of the reaction, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate (150 ml × 3), washed with saturated brine (100 ml), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The product was successfully obtained by CombiFlash column separation (40 g, 0-10% DCM / MeOH) as a white solid product (E)-tert-butyl 4-((hydroxyimino)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 22.42% yield). MS m / z(ESI):129.2[M-100+H] + .

[0617] Step 2: (E)-4-((hydroxyimino)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (559.47 mg, 2.45 mmol) and 1-chloro-8-ethyl-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (280 mg, 816.91 μmol) were dissolved in methanol (60 mL) and THF (15 mL), and then ([bis(trifluoroacetoxy)iodo]benzene) (1.23 g, 2.86 mmol) was added. The reaction was stirred at room temperature for 20 hours. After the reaction was completed, the aqueous solution was quenched and extracted with ethyl acetate (70 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was separated by CombiFlash column (12 g, 0-50%). EA / PE) successfully obtained the light yellow solid product Z48-a (87 mg, 18.72% yield). MS m / z (ESI): 569.2 [M+H] + .

[0618] Step 3: Z48-a (87 mg, 152.89 μmol) was dissolved in DCM (4 mL), and CF3COOH (1.05 g, 9.17 mmol, 1 mL) was added. The reaction was stirred at room temperature for 1 hour. After completion, the reaction was neutralized with saturated sodium bicarbonate and extracted with dichloromethane (70 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the product Z48 (65 mg, 90.66% yield) as a light yellow solid. MS m / z (ESI): 469.2 [M+H] + .

[0619] Preparation of intermediate Z49

[0620] 8-Bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (726 mg, 2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzaldehyde (464 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol), and the catalyst 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (146 mg, 0.2 mmol) were added to a mixture of 5 mL of 1,4-dioxane and 1 mL of water. The atmosphere was purged with nitrogen three times, then heated at 100°C with stirring for 5 hours. After the reaction, silica gel was added and the sample was filtered through a 30-100% PE / EA column and concentrated to yield the desired product Z49 (391 mg, 1 mmol). Yield: 50%. MS m / z(ESI):390[M+H] + .

[0621] Preparation of intermediate Z50

[0622] Z50 was obtained by referring to the preparation method of Z49. MS m / z (ESI): 428.1 [M+H] + .

[0623] Preparation of intermediate Z51

[0624] Z51 was obtained by referring to the preparation method of Z49. MS m / z (ESI): 437.1 [M+H] + .

[0625] Preparation of intermediate Z52

[0626] Z52 was obtained by referring to the preparation method of Z49. MS m / z (ESI): 404.1 [M+H] + .

[0627] Preparation of intermediate Z53

[0628] Step 1: Dissolve tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-1-carboxylate (240 mg, 541.16 μmol) in DCM (15 mL) and add trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, neutralized with NaHCO3 solution until alkaline, extracted with dichloromethane (30 ml × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 3-(3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione (180 mg, 96.87% yield), which was used directly in the next reaction. MS m / z (ESI): 344.2 [M+H] + .

[0629] Step 2: Dissolve 3-(3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione (180 mg, 524.20 μmol) and tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (185 mg, 786.30 μmol) in toluene (6 mL) and acetonitrile (3 mL). Add sodium acetate (175.40 mg, 1.31 mmol) and acetic acid (293.72 mg, 4.89 mmol). Stir the reaction mixture at 120°C for 20 hours. The reaction mixture was poured into water and neutralized with saturated NaHCO₃ solution until alkaline. The mixture was extracted with dichloromethane (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]-3,3-difluoro-1-piperidinecarboxylate (280 mg, 94.94% yield), which was used directly in the next reaction. MS m / z (ESI): 561.3 [M+H] + .

[0630] Step 3: Dissolve tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperazin-1-yl]-3,3-difluoro-1-piperidinecarboxylate (280 mg, 499.47 μmol) in dichloroethane (10 mL) and methanol (10 mL). Add AcOH (73.32 mg, 1.22 mmol) and NaBH3CN (156.94 mg, 2.50 mmol). The reaction mixture is stirred at room temperature overnight. The reaction mixture was poured into water, neutralized with saturated NaHCO₃, extracted with dichloromethane (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]-3,3-difluoro-1-piperidinecarboxylate (100 mg, 35.59% yield), which was used directly in the next reaction. MS m / z (ESI): 563.3 [M+H] + .

[0631] Step 4: Dissolve tert-butyl 4-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]-3,3-difluoro-1-piperidinecarboxylate (100 mg, 177.74 μmol) in DCM (15 mL) and add trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, neutralized with NaHCO3 solution until alkaline, extracted with dichloromethane (30 ml*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product Z53 (80 mg, 97.32% yield), which was used directly in the next reaction. MS m / z (ESI): 463.2 [M+H] + .

[0632] Preparation of intermediate Z54

[0633] Step 1: Dissolve 8-bromo-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (191 mg, 0.5 mmol) and ethynyl(triisopropyl)silane (0.46 g, 2.52 mmol) in THF (5 mL). Then, add cuprous iodide (29 mg, 0.15 mmol), Pd(PPh3)2Cl2 (71 mg, 0.1 mmol), and diisopropylamine (0.51 g, 5.03 mmol, 0.69 mL). After nitrogen substitution three times, the reaction mixture was reacted at 75°C under argon protection for 48 hours. After the reaction, silica gel was added and the sample was stirred. Column chromatography with 30-100% PE / EA was performed, and the target product was concentrated to obtain 1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-((triisopropylsilyl)ethynyl)imidazo[1,5-c]pyrimidin-5-amine (170 mg, 0.35 mmol). Yield: 70%. MS m / z (ESI): 483 [M+H]. + .

[0634] Step 2: Add 1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-((triisopropylsilyl)ethynyl)imidazo[1,5-c]pyrimidin-5-amine (170 mg, 0.35 mmol) to a 0.5 M TBAF-THF solution (3 mL) and stir at room temperature for 2 hours. After the reaction, add silica gel and mix the sample. Purify the mixture through a 30-100% PE / EA column and concentrate to obtain the desired product, 8-ethynyl-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (65 mg, 0.2 mmol). Yield: 57%. MS m / z (ESI): 327 [M+H]. + .

[0635] Step 3: Compound 8-ethynyl-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (65 mg, 0.2 mmol) and tert-butyl 4-azidopiperidine-1-carboxylate (130 mg, 0.58 mmol) were dissolved in t-BuOH (5 mL) and water (1 mL), and sodium ascorbate (12 mg, 70 μmol) and CuSO4 5H2O (7 mg, 29 μmol) were added. After argon replacement, the mixed solution was stirred at 70 ° C for 12 hours. After the reaction was complete, silica gel was added to the sample and the mixture was passed through a column using 30-100% PE / EA. The product was concentrated to yield tert-butyl 4-(4-(1-fluoro-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (10 mg, 18 μmol). Yield: 9%. MS m / z (ESI): 553 [M+H]. + .

[0636] Step 4: Compound 4-(4-(1-fluoro-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (10 mg, 18 μmol) was added to a mixture of 2 mL of dichloromethane and 0.5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour, and the solvent was removed by rotary evaporation to obtain crude compound Z54 (8.1 mg, 18 μmol). Yield: 100%. MS m / z (ESI): 453 [M+H]. + .

[0637] Preparation of intermediate Z55

[0638] Z55 was obtained by following the above synthetic route and referring to the preparation method of Z54. MS m / z (ESI): 436.2 [M+H] + .

[0639] Preparation of intermediate Z56

[0640] Step 1: Dissolve 4,5-dibromo-2H-triazole (5 g, 22.04 mmol) and tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate (6.46 g, 23.14 mmol) in DMF (110 mL) and add Cs2CO3 (21.54 g, 66.12 mmol). The reaction mixture was stirred at 100°C overnight. The reaction mixture was poured into water and extracted with ethyl acetate (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by CombiFlash (0-50% EA / PE) to obtain tert-butyl 4-(4,5-dibromotriazol-2-yl)piperidine-1-carboxylate (6.27 g, 69.37% yield) as a colorless oil. MS m / z (ESI): 352.9 [M+H-56] + .

[0641] Step 2: Dissolve tert-butyl 4-(4,5-dibromotriazol-2-yl)piperidine-1-carboxylate (6.27 g, 15.29 mmol) in tetrahydrofuran (45 mL), cool to -78°C, and slowly add n-BuLi (2.5 M, 6.07 mL) dropwise. The reaction mixture is stirred at -78°C for 1 hour. NH4Cl solution is added to quench the reaction. Extract with ethyl acetate (30 ml x 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated by CombiFlash (0-60% EA / PE) to obtain tert-butyl 4-(4-bromotriazol-2-yl)piperidine-1-carboxylate (980 mg, 19.35% yield) as an anhydrous oily liquid. MS m / z (ESI): 275.0 [M+H-56] + .

[0642] Step 3: Dissolve tert-butyl 4-(4-bromotriazol-2-yl)piperidine-1-carboxylate (490 mg, 1.48 mmol) in THF (20 mL), cool to -78°C, and slowly add n-BuLi (2.5 M, 769.30 μL) dropwise. Stir the reaction at -78°C for 0.5 h, then add 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (551 mg, 2.96 mmol). Slowly warm the reaction to room temperature and continue stirring for 2 h. Cool the reaction to 0°C and quench the reaction by dropwise addition of saturated NH4Cl solution. Ethyl acetate (30 ml x 3) was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)triazol-2-yl]piperidine-1-carboxylate (550 mg, 98.28% yield), which was used directly in the next reaction. MS m / z (ESI): 197.1 [M+H-182] + .

[0643] Step 4: 8-Bromo-1-chloro-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (100 mg, 251.49 μmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)triazol-2-yl]piperidine-1-carboxylate (114.16 mg, 301.79 μmol) were dissolved in dioxane (12 mL) and water (2 mL). PdCl2(dppf) (18.40 mg, 25.15 μmol) and potassium carbonate (69.51 mg, 502.98 μmol) were added. The reaction mixture was stirred at 100°C overnight. The reaction mixture was poured into water, added with ethyl acetate (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by CombiFlash column chromatography (0-80% EA / PE) to afford tert-butyl 4-[4-[1-chloro-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]triazol-2-yl]piperidine-1-carboxylate (22 mg, 15.37% yield) as a yellow solid. MS m / z (ESI): 513.2 [M+H-56]. + .

[0644] Step 5: Dissolve tert-butyl 4-[4-[1-chloro-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]triazol-2-yl]piperidine-1-carboxylate (22 mg, 38.66 μmol) in dichloromethane (10 mL) and add trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, neutralized with NaHCO3 solution to alkalinity, extracted with dichloromethane (30 ml × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product Z56 (18 mg, 99.29% yield), which was used directly in the next reaction. MS m / z (ESI): 469.2 [M+H] + .

[0645] Preparation of intermediate Z57

[0646] Step 1: Compound 8-bromo-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (570 mg, 1.5 mmol), n-butyldi(1-adamantyl)phosphine (214 mg, 598 umol), diacetoxypalladium (67 mg, 300 μmol), K2CO3 (620 mg, 4.48 mmol) and (Pin)2B2 (1140 mg, 4.48 mmol) were added sequentially to a mixed solution of DME (100 mL) and water (10 mL). After nitrogen replacement three times, the reaction solution was reacted at 70 ° C under argon protection for 20 hours. After the reaction, silica gel was added and the sample was stirred. The product was then purified by column chromatography using 30-100% PE / EA and concentrated to yield tert-butyl 4-(3-(1-fluoro-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (83 mg, 0.15 mmol). Yield: 10%. MS m / z (ESI): 553 [M+H]. + .

[0647] Step 2: Compound 4-(3-(1-fluoro-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (83 mg, 0.15 mmol) was added to a mixture of 5 mL of dichloromethane and 1 mL of trifluoroacetic acid, stirred at room temperature for 1 hour, and then concentrated to dryness to obtain compound Z57 (68 mg, 0.15 mmol). Yield: 100%. MS m / z (ESI): 453 [M+H] + .

[0648] Preparation of intermediate Z58

[0649] Step 1: Dissolve 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (1 g, 2.75 mmol) in THF (30 mL) and add n-BuLi (2.5 M, 5.49 mL) dropwise at -78°C for 1 hour. Slowly add isopropyl pinacol borate (6.13 g, 32.95 mmol, 6.72 mL) dropwise and stir at low temperature for 1 hour. The reaction mixture is quenched with saturated ammonium chloride solution, stirred at room temperature for 0.5 hour, and extracted twice with ethyl acetate. The organic phases are combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM FA H2O / acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) to obtain Z58-a (0.2 g, 607.73 μmol, 22.13% yield) as a pale yellow solid. MS m / z (ESI): 330.1 [M+H] + .

[0650] Step 2: Dissolve Z58-a (198.72 mg, 603.85 μmol) and tert-butyl 4-(3-bromo-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (200 mg, 603.85 μmol) in dioxane (8 mL) and water (1 mL). Add Pd(dppf)Cl2 (44.18 mg, 60.38 μmol) and K2CO3 (166.92 mg, 1.21 mmol) under argon. Heat to 120°C and stir for 2 hours. Concentrate under reduced pressure to remove the solvent, add water and ethyl acetate, extract three times with ethyl acetate, wash with the combined organic solution with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column (4 g, 0-10% MeOH / DCM) to give Z58-b (40 mg, 74.69 μmol, 12.37% yield) as a light yellow solid. MS m / z (ESI): 536.3 [M+H] + .

[0651] Step 3: Dissolve Z58-b (40 mg, 74.69 μmol) in DCM (3 mL) and add TFA (1 mL). Stir at room temperature for 1 hour. Concentrate under reduced pressure to remove the solvent to give crude Z58 (30 mg, 68.89 μmol, 92.24% yield) as a pale yellow solid. Use the product in the next step without purification. MS m / z (ESI): 436.2 [M+H] + .

[0652] Preparation of intermediate Z61

[0653] Z61 was obtained by referring to the preparation method of Z49. MS m / z (ESI): 424.1 [M+H] + .

[0654] Preparation of intermediate Z62

[0655] Step 1: Dissolve 5-bromo-6-methylpicolinic acid (2 g, 9.26 mmol) and dimethylhydroxylamine hydrochloride (993.35 mg, 10.18 mmol, HCl) in THF (30 mL). Add TEA (3.75 g, 37.03 mmol, 5.16 mL) and HATU (4.19 g, 11.11 mmol) and stir at room temperature for 2 hours. Add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was purified by a CombiFlash column (20 g, 0-30% EA / PE) to afford Z62-a (2.2 g, 8.49 mmol, 91.72% yield) as a light yellow oil. MS m / z (ESI): 259.0 [M+H] + .

[0656] Step 2: Dissolve Z62-a (2.2 g, 8.49 mmol) and pinacol diboronate (3.23 g, 12.74 mmol) in dioxane (30 mL). Under argon, add potassium acetate (2.50 g, 25.47 mmol) and Pd(dppf)Cl2 (621.29 mg, 849.09 μmol). Heat to 95°C and stir overnight. Filter the solids and concentrate under reduced pressure to obtain the crude product. The residue is separated by a CombiFlash column (20 g, 0-30% EA / PE) to obtain Z62-b (2.4 g, 7.84 mmol, 92.32% yield) as a light yellow solid. MS m / z (ESI): 307.2 [M+H] + .

[0657] Step 3: Dissolve 8-bromo-1-chloro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (0.5 g, 1.26 mmol) and Z62-b (577.48 mg, 1.89 mmol) in dioxane (10 mL) and water (2 mL). Under argon, add KCO (347.57 mg, 2.51 mmol) and Pd(dppf)Cl (92.01 mg, 125.75 μmol). Heat to 100°C and stir for 3 hours. Add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column (12 g, 0-30% EA / PE) to give Z62-c (0.4 g, 804.96 μmol, 64.01% yield) as a light yellow solid. MS m / z (ESI): 497.2 [M+H] + .

[0658] Step 4: Dissolve Z62-c (0.3 g, 603.72 μmol) in THF (10 mL), cool to -78°C under argon, and slowly add DIBAL-H (1 M, 2.41 mL) dropwise. Stir at low temperature for 3 hours. Quench the reaction by adding saturated aqueous ammonium chloride dropwise at low temperature. Add a large amount of anhydrous sodium sulfate and ethyl acetate, filter out the solid, and concentrate the mother liquor under reduced pressure to obtain the crude product. The residue is separated by a CombiFlash column (4 g, 0-60% EA / PE) to obtain Z62 (0.2 g, 456.77 μmol, 75.66% yield) as a light yellow solid. MS m / z (ESI): 438.1 [M+H] + .

[0659] Preparation of intermediate Z63

[0660] Prepared according to the method of Z47 step 2. MS m / z (ESI): 438.1 [M+H] + .

[0661] Preparation of intermediate Z64

[0662] Step 1: Under argon, 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (1 g, 2.75 mmol) was dissolved in THF (50 mL) and n-BuLi (2.5 M, 5.49 mL) was added dropwise at -78°C. After reacting at -78°C for 1 hour, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was slowly added dropwise, and the mixture was reacted at -78°C for another 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution, stirred at room temperature for 0.5 hour, extracted twice with ethyl acetate, and dried to obtain the crude product. The crude product was purified by prep-HPLC to afford Z64-a (200 mg, 486.34 μmol, 17.71% yield) as a white solid. MS m / z (ESI): 330.1 [M+H] + .

[0663] Step 2: 6-Bromo-3-iodo-2-methylpyridine (1 g, 3.36 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.04 g, 3.36 mmol) were dissolved in 1,4-dioxane (20 mL), water (4 mL), and DMSO (2 mL). Pd(dppf)Cl2 (245.60 mg, 335.66 μmol) and K2CO3 (927.84 mg, 6.71 mmol) were then added. The reaction was stirred at 65°C for 3 hours. The reaction mixture was concentrated, and water and ethyl acetate were added. The mixture was extracted with ethyl acetate, washed three times with saturated brine, dried, filtered, and concentrated. CombiFlash column separation (petroleum ether:ethyl acetate = 70%:30%) afforded Z64-b (1.2 g, 3.16 mmol, 94.20% yield) as a colorless oil. MS m / z (ESI): 353.1 [M+H] + .

[0664] Step 3: Under argon, Z64-b (153.50 mg, 434.53 μmol), Z64-a (110 mg, 334.25 μmol), Pd(dppf)Cl2 (43.17 mg, 66.85 μmol), K2CO3 (115.49 mg, 835.63 μmol), 1,4-dioxane (10 mL), and water (0.5 mL) were mixed and heated at 100°C for 3 hours. Water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with saturated brine, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20%:80%) to obtain Z64-c (170 mg, 304.87 μmol, yield 91.21%) as a yellow oil. MS m / z (ESI): 558.3 ​​[M+H]+ .

[0665] Step 4: Z64-c (70 mg, 125.53 μmol), platinum dioxide (2.85 mg, 12.55 μmol), methanol (2 mL), and EA (2 mL) were stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered and concentrated to afford Z64-d (70 mg, 125.08 μmol, 99.64% yield) as a yellow solid oil. The crude product was used directly in the next step. MS m / z (ESI): 560.3 [M+H] + .

[0666] Step 5: Z64-d (70 mg, 125.08 μmol), TFA (1 mL), and DCM (1 mL) were stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a crude product, which was dissolved in dichloromethane and adjusted to pH 9-10 by adding saturated sodium bicarbonate. The product was then extracted with dichloromethane:methanol (10:1) (10 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain Z64 (50 mg, 108.81 μmol, yield 86.99%) as a yellow solid. MS m / z (ESI): 460.2 [M+H] + .

[0667] Preparation of intermediate Z65

[0668] Z65 was obtained by following the above synthetic route and referring to the preparation method of Z56. MS m / z (ESI): 492.2 [M+H] + .

[0669] Preparation of intermediate Z66

[0670] Step 1: Z66-a (200 mg, 401.36 μmol) was dissolved in DMF (4 mL), and trimethylboroxine (3.5 M, 1 mL), K2CO3 (443.76 mg, 3.21 mmol), and Pd(dppf)Cl2 (88.10 mg, 120.41 μmol) were added. The reaction was stirred in a microwave oven at 120°C for 3 hours. After completion, the solvent was evaporated under reduced pressure and separated on a CombiFlash (12 g, 0-100% DCM / EA) to afford the product Z66-b (127 mg, 293.01 μmol, 73.00% yield) as a pale yellow solid. MS m / z (ESI): 434.1 [M+H] + .

[0671] Step 2: Z66-b (127 mg, 293.01 μmol) was dissolved in THF (6 mL) and water (2 mL), and LiOH (70.17 mg, 2.93 mmol) was added. The reaction was stirred at room temperature for 2 hours, neutralized with dilute hydrochloric acid (2N), filtered, and the solid was vacuum-dried to obtain the yellow solid product Z66 (87 mg, 207.44 μmol, 70.79% yield). MS m / z (ESI): 420.2 [M+H] + .

[0672] Preparation of intermediate Z67

[0673] Step 1: 4-(tert-Butyloxycarbonyl)amino)butyric acid (502.84 mg, 2.47 mmol) and (2S,4R)-1-((S)-2-amino-3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1 g, 2.25 mmol) were dissolved in DMF (25 mL). DIPEA (872.09 mg, 6.75 mmol, 1.18 mL) and HATU (1.27 g, 3.37 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction solution was then evaporated to dryness under reduced pressure and purified by CombiFlash column chromatography (24 g, 0-10% MeOH / DCM) to afford the product Z67-a (0.8 g, 1.27 mmol, 56.47% yield) as a pale yellow solid. MS m / z(ESI):530.3[M-100+H] + .

[0674] Step 2: Z67-a (0.8 g, 1.27 mmol) was dissolved in DCM (20 mL), and HCl (4 M in EA, 5 mL) was added. The reaction was stirred at room temperature for 1 hour, and the reaction solution was concentrated to obtain the yellow solid product Z67-b (719 mg, 1.27 mmol, 99.98% yield, HCl). MS m / z (ESI): 530.3 [M+H] + .

[0675] Step 3: 5-Bromo-4-chloro-2-(methylthio)pyrimidine (9.66 g, 43.84 mmol) was dissolved in DMF (120 mL), the temperature was lowered to 0°C, and NaH (3.19 g, 83.34 mmol, 60% purity) was added in portions. The reaction was stirred at 0°C for 1 hour. Then, a solution of 5-bromo-4-chloro-2-methylaminopyrimidine (10 g, 41.75 mmol) in DMF (120 mL) was added dropwise to the reaction solution. The mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (250 mL × 3), washed with water (100 mL × 3), and washed with saturated brine (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give an oily crude product Z67-c (15 g, 35.43 mmol, 84.87% yield). MS m / z(ESI):423.0[M+H] + .

[0676] Step 4: To a solution of Z67-c (15 g, 35.43 mmol) in THF (200 mL) was added a 3 M aqueous solution of HCl (30 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then concentrated and basified to pH 8-9 with a Na2CO3 aqueous solution. The mixture was extracted with DCM (500 mL x 2) and washed with saturated brine (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the red oily product Z67-d (8.5 g, 32.80 mmol, 92.57% yield). MS m / z (ESI): 259.0 [M+H] + .

[0677] Step 5: A mixture of formic acid (39 g, 720.26 mmol, 31.97 mL, 85% purity) and acetic anhydride (34.8 g, 328.21 mmol, 32.01 mL) was heated at 50°C for 1 hour. The reaction mixture was then cooled to room temperature and added to a solution of Z67-d (8.5 g, 32.80 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, water (500 mL) was added, and then extracted with DCM (500 mL × 3). The organic phases were combined, washed sequentially with water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to successfully obtain the product Z67-e (8.5 g, 29.60 mmol, 90.25% yield) as a light yellow solid. MS m / z (ESI): 287.0 [M+H] + .

[0678] Step 6: To a solution of Z67-e (8.5 g, 29.60 mmol) in dioxane (83.96 mL) was added POCl3 (9.05 g, 50.18 mmol, 7.42 mL, 85% purity) dropwise. The reaction mixture was then heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and concentrated, diluted with DCM (100 mL), and adjusted to pH 8 with saturated aqueous NaHCO3. The mixture was extracted with DCM (200 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product Z67-f (6.5 g, 24.15 mmol, 81.59% yield) was successfully obtained as a pale yellow solid. MS m / z (ESI): 269.0 [M+H] + .

[0679] Step 7: Z67-f (1.6 g, 5.95 mmol) was dissolved in DCM (35 mL) at 0°C, and m-CPBA (3.73 g, 18.39 mmol, 85% purity) was added. The reaction was allowed to warm to room temperature and stirred for 18 hours. (5-Fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (1.19 g, 7.13 mmol) and sodium carbonate (3.14 g, 29.60 mmol) were then added and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and separated using a CombiFlash (12 g, 0-60% DCM / MeOH) to obtain the product Z67-g (600 mg, 1.55 mmol, 26.00% yield) as a pale yellow solid. MS m / z (ESI): 388.0 [M+H] + .

[0680] Step 8: Z67-g (225 mg, 579.61 μmol) and (6-methoxycarbonyl-3-pyridyl)boronic acid (209.76 mg, 1.16 mmol) were dissolved in dioxane (10 mL) and water (3 mL). KCO (400.53 mg, 2.90 mmol) and Pd(dppf)Cl (127.23 mg, 173.88 μmol) were then added. The reaction was stirred at 105°C for 2 hours. After completion, the mixture was extracted twice with water (25 mL x 2). The aqueous phases were combined and neutralized with 2N HCl. The resulting solid was filtered and dried in vacuo to yield Z67 (170 mg, 394.99 μmol, 68.15% yield) as a brown solid. MS m / z (ESI): 431.1 [M+H] + .

[0681] Preparation of intermediate Z68

[0682] Step 1: Dissolve 8-bromo-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (300 mg, 0.83 mmol) and methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (652 mg, 2.48 mmol) in 1,4-dioxane (20 mL) and water (3 mL). Add tetrakistriphenylphosphine palladium (191 mg, 0.16 mmol) and potassium carbonate (228 mg, 1.65 mmol). Stir the reaction mixture at 100°C for 20 hours. The solvent was concentrated under reduced pressure, and the crude product was separated by CombiFlash (0-10% MeOH / DCM) to give methyl 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylate (340 mg, 98.14% yield) as a yellow solid. MS m / z (ESI): 420.1 [M+H] + .

[0683] Step 2: Dissolve methyl 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylate (323 mg, 0.77 mmol) in tetrahydrofuran (10 mL), cool to 0°C, and add N-iodosuccinimide (173 mg, 0.77 mmol). Stir the reaction mixture at 0°C for 1 hour. The reaction mixture was poured into water, extracted with DCM (100 ml x 3), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting crude product was separated by CombiFlash (0-10% MeOH / DCM) to obtain a yellow solid product, 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-1-iodoimidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylic acid methyl ester (350 mg, 83.34% yield). MS m / z (ESI): 546.1 [M+H] + .

[0684] Step 3: Dissolve methyl 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-1-iodoimidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylate (350 mg, 0.64 mmol) in DMF (15 mL), add CuI (1.22 g, 6.42 mmol), PdCl2(dppf) (47 mg, 0.064 mmol), and methyl 2,2-difluoro-2-fluorosulfonylacetate (1.23 g, 6.42 mmol). The reaction mixture is stirred at 90°C overnight under argon. The reaction mixture was filtered, washed, and the solvent was concentrated under reduced pressure. The resulting crude product was separated using CombiFlash (0-10% MeOH / DCM) to afford methyl 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-1-(trifluoromethyl)imidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylate (200 mg, 63.93% yield) as a yellow solid. MS m / z (ESI): 488.1 [M+H] + .

[0685] Step 4: Dissolve methyl 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-1-(trifluoromethyl)imidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylate (100 mg, 0.21 mmol) in tetrahydrofuran (15 mL) and add potassium trimethylsilanol (40 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was separated by CombiFlash (0-80% MeOH / DCM) to obtain the product Z68 (50 mg, 51.48% yield) as a yellow solid. MS m / z (ESI): 474.1 [M+H] + .

[0686] Preparation of intermediate H159-b

[0687] Step 1: Compound 8-bromo-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (760 mg, 2 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (754 mg, 2 mmol), potassium carbonate (828 mg, 6 mmol) and catalyst 1,1-bis(diphenylphosphino)dichloroferroni palladium (146 mg, 0.2 mmol) were added to a mixed solvent of 5 ml 1,4-dioxane and 1 ml water, and nitrogen was replaced three times. The mixture was then heated at 100° C. and stirred for 5 hours. After the reaction was completed, silica gel was directly added and the sample was stirred. 30-100% The product was purified by column chromatography with PE / EA and concentrated to afford compound H159-a (552 mg, 1 mmol). Yield: 50%. MS m / z (ESI): 552 [M+H] + .

[0688] Step 2: Compound H159-a (552 mg, 1 mmol) was added to a mixture of 5 mL of dichloromethane and 1 mL of trifluoroacetic acid, stirred at room temperature for 1 hour, and then concentrated to dryness to afford compound H159-b (451 mg, 1 mmol). Yield: 100%. MS m / z (ESI): 452 [M+H] + .

[0689] Preparation of intermediate H80-d

[0690] Step 1: Under argon, 1-bromo-4-iodobenzene (8.20 g, 28.98 mmol), methyl 3-aminocyclobutanecarboxylate hydrochloride (4 g, 24.15 mmol), L-proline (1.11 g, 9.66 mmol), cuprous iodide (919.95 mg, 4.83 mmol), potassium carbonate (6.68 g, 48.30 mmol), and DMSO (40 mL) were mixed and heated at 80°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80%:20%) to obtain H80-a (4.6 g, 16.19 mmol, yield 67.03%) as a yellow solid. MS m / z (ESI): 284.1 [M+H] + .

[0691] Step 2: Under argon, H80-a (730 mg, 2.01 mmol), 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (628.25 mg, 2.21 mmol), palladium acetate (90.25 mg, 402.00 μmol), n-butyldi(1-adamantyl)phosphine (144.13 mg, 402.00 μmol), potassium carbonate (1.11 g, 8.04 mmol), bis(pinacol)diboronate (1.02 g, 4.02 mmol), DME (20 mL), and water (2 mL) were mixed and heated at 70°C for 16 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20%:80%) to give H80-b (540 mg, 1.11 mmol, yield 55.11%) as a yellow solid. MS m / z (ESI): 488.3 [M+H] + .

[0692] Step 3: Combine H80-b (490 mg, 804.06 μmol), THF (20 mL), and TFA (2 mL), stir at room temperature for 5 minutes, then cool to -15°C and add N-iodosuccinimide (180.90 mg, 804.06 μmol). After addition, maintain the mixture at -15°C for 15 minutes. Pour the reaction mixture into ice water, adjust the pH to >7 with sodium bicarbonate solution, and extract with ethyl acetate (10 mL x 2). The combined organic layers are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product is purified by column chromatography (petroleum ether:ethyl acetate = 50%:50%) to yield H80-c (55 mg, 89.66 μmol, yield 11.15%) as a yellow solid. MS m / z (ESI): 614.1 [M+H] + .

[0693] Step 4: Lithium hydroxide (5.86 mg, 244.53 μmol) was added to a solution of H80-c (50 mg, 81.51 μmol) in THF (2 mL) and water (0.5 mL) at room temperature. The mixture was allowed to react for 1 hour. The reaction mixture was concentrated and adjusted to pH <3 by adding 1N HCl. The aqueous phase was lyophilized to afford H80-d (48 mg, 80.08 μmol, 98.25% yield) as a white solid. MS m / z (ESI): 600.2 [M+H] + .

[0694] Preparation of intermediate H87-h

[0695] Step 1: Under argon, 1-bromo-4-iodobenzene (13.33 g, 47.10 mmol), 4-(dimethoxymethyl)piperidine (5 g, 31.40 mmol), L-proline (1.45 g, 12.56 mmol), cuprous iodide (1.20 g, 6.28 mmol), potassium carbonate (8.68 g, 62.80 mmol), and DMSO (50 mL) were mixed and heated at 80°C for 16 hours. The reaction mixture was filtered, the filtrate added to water, and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed three times with water and once with saturated brine, then concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 70%:30%) to afford H87-a (6.1 g, 19.41 mmol, yield 61.82%) as a yellow solid. MS m / z (ESI): 314.1 [M+H] + .

[0696] Step 2: Add TFA (5 mL) to a solution of H87-a (6.1 g, 19.41 mmol) in DCM (10 mL) at room temperature. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to obtain a crude product. The crude product was dissolved in dichloromethane and washed once with saturated sodium bicarbonate solution and once with saturated brine. The product was dried over anhydrous sodium sulfate and concentrated to obtain H87-b (5 g, 18.65 mmol, 96.05% yield) as a yellow liquid. The crude product was directly used in the next step. MS m / z (ESI): 268.1 [M+H] + .

[0697] Step 3: Add NaBH(OAC)3 (13.66 g, 64.43 mmol) to a solution of tert-butyl piperazine-1-carboxylate (3 g, 16.11 mmol), H87-b (4.75 g, 17.72 mmol), DCM (50 mL), and AcOH (0.5 mL). The mixture was allowed to react at room temperature for 3 hours. The reaction solution was poured into water and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with saturated brine and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80%:20%) to obtain H87-c (4.8 g, 10.95 mmol, yield 67.97%) as a yellow solid. MS m / z (ESI): 438.0 [M+H] + .

[0698] Step 4: Add TFA (10 mL) to a solution of H87-c (4.8 g, 10.95 mmol) in DCM (20 mL) at room temperature. Allow to react at room temperature for 1 hour. Concentrate the reaction mixture, then add dichloromethane. Adjust the pH to >8 with saturated sodium bicarbonate solution. Collect the organic phase, dry it over anhydrous sodium sulfate, and concentrate to obtain H87-d (4 g, 8.84 mmol, 80.77% yield, TFA) as a yellow solid. The crude product was directly used in the next step. MS m / z (ESI): 338.2 [M+H] + .

[0699] Step 5: Combine H87-d (4 g, 8.84 mmol), methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (6.38 g, 13.27 mmol), DIPEA (3.43 g, 26.53 mmol, 4.62 mL), and DMSO (50 mL) and heat at 110°C for 16 hours. Pour the reaction mixture into ice water and extract with ethyl acetate (30 mL x 2). The combined organic layers are washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by column chromatography (dichloromethane:ammonia / methanol = 95%:5%) to obtain H87-e (4.3 g, 8.28 mmol, yield 93.60%) as a brown liquid. MS m / z (ESI): 519.2 [M+H] + .

[0700] Step 6: Dissolve H87-e (1 g, 1.93 mmol) and pinacol diboronate (1.47 g, 5.78 mmol) in 1,4-dioxane (20 mL). Under argon, add Pd(dba)2 (218.28 mg, 385.01 μmol) and PCy3 (259.12 mg, 924.01 μmol). Heat to 120°C and stir for 24 hours. The reaction mixture is filtered, and the filtrate is concentrated to obtain the crude product. The crude product is purified by column chromatography (petroleum ether / triethylamine:dichloromethane = 85%:15%) to obtain H87-f (700 mg, 1.24 mmol, yield 64.18%) as a yellow solid. MS m / z (ESI): 567.4 [M+H] + .

[0701] Step 7: Under argon protection, 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (400 mg, 1.10 mmol), H87-f (684.50 mg, 1.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80.37 mg, 109.84 μmol), potassium carbonate (455.41 mg, 3.30 mmol), 1,4-dioxane (20 mL), and DMSO (1 mL) were mixed and heated at 100°C for 2 hours. The reaction solution was filtered, and the filtrate was added with ethyl acetate and saturated brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate / triethylamine = 80%:20% to 0:100%) to afford H87-g (470 mg, 649.32 μmol, yield 59.12%) as a yellow solid. MS m / z (ESI): 724.4 [M+H] + .

[0702] Step 8: LiOH (76.10 mg, 3.18 mmol) was added to a solution of H87-g (460 mg, 635.50 μmol), THF (6 mL), methanol (4 mL), and water (2 mL) at room temperature. The mixture was allowed to react at room temperature for 1 hour. The pH of the reaction solution was adjusted to 5-6 with 1N aqueous HCl. Ethyl acetate was added to precipitate a large amount of yellow solid. The solid was collected and dried to obtain H87-h (400 mg, 563.53 μmol, 88.67% yield) as a yellow solid. MS m / z (ESI): 710.4 [M+H] + .

[0703] Preparation of intermediates H66-b and H86-b

[0704] Step 1: Ethyl 1-(4-(5-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)phenyl)azetidine-3-carboxylate (700 mg, 1.44 mmol) was dissolved in THF (10 mL), the temperature was lowered to 0°C, and N-iodosuccinimide (226.13 mg, 1.01 mmol) was added. The reaction was stirred at 0°C for 0.5 hours, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (70 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product, which was separated by CombiFlash (12 g, 0-50% EA / PE) to successfully obtain a mixture of light yellow solid products H86-a and H66-a (88 mg, 143.46 μmol, 9.99% yield). MS m / z(ESI):614.2[M+H] + .

[0705] Step 2: A mixture of H86-a and H66-a (80 mg, 130.42 μmol) was dissolved in THF (8 mL) and water (2 mL), and then LiOH (62.46 mg, 2.61 mmol) was added. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was neutralized with dilute hydrochloric acid (2N) to a pH of 3-4, and the solvent was then dried under reduced pressure to obtain a mixture of white solid products H86-b and H66-b (66 mg, 112.75 μmol, 86.45% yield). MS m / z (ESI): 586.1 [M+H] + .

[0706] Preparation of intermediate H64-b

[0707] Step 1: Dissolve dibromohydroxycarbonate (25 g, 123.25 mmol) in EA (250 mL) and water (25 mL). Add 3-butyn-1-ol (34.56 g, 493.02 mmol) and NaHCO₃ (31.80 g, 369.76 mmol) and allow to react at room temperature for 3 hours. Filter the reaction mixture, add water, separate the layers, and extract twice with ethyl acetate. Wash once with saturated brine, dry over anhydrous sodium sulfate, filter, and spin-dry to obtain the crude product. The crude product is purified by column chromatography (petroleum ether:dichloromethane = 50%:50% to 0:100%) to yield 2-(3-bromoisoxazol-5-yl)ethanol-1-ol (18 g, 93.74 mmol, yield 76.06%) as a yellow liquid. MS m / z (ESI): 192.0 [M+H] + .

[0708] Step 2: Dissolve 2-(3-bromoisoxazol-5-yl)ethanol-1-ol (18 g, 93.74 mmol) in acetone (150 mL) at 0°C and add Jones reagent (100 mL). React at room temperature for 16 hours. The reaction solution is slowly poured into ice water and extracted twice with ethyl acetate. The combined organic phases are washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2-(3-bromoisoxazol-5-yl)acetic acid (16.8 g, 81.56 mmol, yield 87.00%) as a brown liquid. The crude product is directly used in the next step. MS m / z (ESI): 203.7 [M+H] + .

[0709] Step 3: Dissolve 2-(3-bromoisoxazol-5-yl)acetic acid (16 g, 77.67 mmol) in methanol (100 mL) and add concentrated sulfuric acid (2 mL). The mixture is allowed to react at 70°C for 1 hour. The reaction solution is concentrated to a small volume, then water is added and extracted with dichloromethane (50 mL x 2). The mixture is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product is purified by column chromatography (petroleum ether:dichloromethane = 30%:70%) to obtain methyl 2-(3-bromoisoxazol-5-yl)acetate (14 g, 63.63 mmol, yield 81.92%) as a white solid. MS m / z (ESI): 220.0 [M+H] + .

[0710] Step 4: Dissolve methyl 2-(3-bromoisoxazol-5-yl)acetate (14 g, 63.63 mmol) in THF (150 mL) under ice-cooling. Add potassium tert-butoxide (10.69 g, 95.27 mmol) and stir for 10 min. Slowly add 2-iodopropane (14.06 g, 82.72 mmol, 8.26 mL) dropwise. After addition, react at room temperature for 16 hours. Pour the reaction solution into ice-water, extract twice with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, and spin-dry to obtain crude methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (8 g, 30.52 mmol, 47.97% yield) as a yellow oil. The crude product was directly used in the next step. MS m / z (ESI): 262.0 [M+H] + .

[0711] Step 5: Methyl 2-(3-bromoisoxazol-5-yl)-3-methylbutanoate (8 g, 30.52 mmol), potassium hydroxide (8.56 g, 152.61 mmol), methanol (45 mL), and water (5 mL) were added to an autoclave and reacted at 110°C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and ice water was added. The aqueous phase was washed once with ethyl acetate and collected. The pH of the aqueous phase was adjusted to <4 with concentrated hydrochloric acid at 0°C, and then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (5.1 g, 25.60 mmol, yield 83.88%) as a yellow liquid. The crude product was directly used in the next step. MS m / z (ESI): 200.2 [M+H] + .

[0712] Step 6: Heat 2-(3-methoxyisoxazol-5-yl)-3-methylbutanoic acid (5 g, 25.10 mmol) and HBr / AcOH (20 mL) at 80°C for 0.5 h. Concentrate the reaction mixture to obtain 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (4.6 g, 24.84 mmol, 98.97% yield) as a yellow liquid. The crude product was used directly in the next step. MS m / z (ESI): 186.1 [M+H] + .

[0713] Step 7: Add thionyl chloride (13.30 g, 111.78 mmol, 8.12 mL) dropwise to a solution of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (4.6 g, 24.84 mmol) in methanol (50 mL). Allow to react at room temperature for 2 hours. Concentrate the reaction mixture to dryness, add water, and extract with ethyl acetate (20 mL x 2). The combined organic layers are washed with saturated brine and concentrated to obtain the crude product. The crude product is purified by column chromatography (petroleum ether: dichloromethane = 50%:50%) to obtain methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (3.8 g, 19.08 mmol, yield 76.79%) as a brownish-red liquid. MS m / z (ESI): 200.1 [M+H] + .

[0714] Step 8: Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (3.8 g, 19.08 mmol), potassium carbonate (5.27 g, 38.15 mmol), and acetonitrile (100 mL) were mixed and perfluorobutylsulfonyl fluoride (6.63 g, 21.94 mmol) was added dropwise. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: dichloromethane = 80%:20%) to obtain methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (3 g, 6.23 mmol, yield 32.68%) as a colorless liquid. MS m / z (ESI): 482.0 [M+H] + .

[0715] Step 9: Under argon, 1-bromo-4-iodobenzene (7.29 g, 25.77 mmol), tert-butyl piperazine-1-carboxylate (4 g, 21.48 mmol, HCl), L-proline (989.03 mg, 8.59 mmol), cuprous iodide (818.04 mg, 4.30 mmol), potassium carbonate (5.94 g, 42.95 mmol), and DMSO (40 mL) were mixed and heated at 80°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80%:20%) to obtain tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (3 g, 8.79 mmol, 40.94% yield) as a yellow solid. MS m / z(ESI):285.1[M+H-56] + .

[0716] Step 10: Add TFA (2.5 mL) to a solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (1 g, 2.93 mmol) and DCM (5 mL) at room temperature. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to dryness to afford 1-(4-bromophenyl)piperazine (700 mg, 2.90 mmol, 99.06% yield) as a yellow solid. The crude product was used directly in the next step. MS m / z (ESI): 241.1 [M+H] + .

[0717] Step 11: 1-(4-bromophenyl)piperazine (500 mg, 2.07 mmol), methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (798.40 mg, 1.66 mmol), DIPEA (803.99 mg, 6.22 mmol, 1.08 mL), and DMSO (15 mL) were heated at 110°C for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed three times with water and once with saturated brine, then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:ammonia / methanol 4M = 98%:2%) to afford methyl 2-(3-(4-(4-bromophenyl)piperazin-1-yl)isoxazol-5-yl)-3-methylbutanoate (268 mg, 634.60 μmol, 30.60% yield) as a brown oil. MS m / z (ESI): 422.1 [M+H] + .

[0718] Step 12: Under argon protection, 2-(3-(4-(4-bromophenyl)piperazin-1-yl)isoxazol-5-yl)-3-methylbutanoate (255.12 mg, 604.11 μmol), 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (200 mg, 549.19 μmol) were added to the mixture. mol), palladium acetate (24.66 mg, 109.84 μmol), n-butyldi(1-adamantyl)phosphine (39.38 mg, 109.84 μmol), potassium carbonate (303.60 mg, 2.20 mmol), pinacol diboronate (278.92 mg, 1.10 mmol), DME (25 mL), and water (5 mL) were heated at 85°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and water was added. The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine and concentrated to a crude product. The crude product was purified by column chromatography (dichloromethane:ammonia / methanol 4M = 95%:5%) to obtain H64-a (150 mg, 239.36 μmol, 43.58% yield) as a brown oil. MS m / z (ESI): 627.3 [M+H] + .

[0719] Step 13: Lithium hydroxide (9.36 mg, 390.95 μmol) was added to a solution of H64-a (140 mg, 78.19 μmol) in THF (2 mL), methanol (2 mL), and water (1 mL) at room temperature. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated, washed once with ethyl acetate, and the pH was adjusted to 6-7 with 1N HCl. Ethyl acetate was added for extraction (5 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain H64-b (45 mg, 73.45 μmol, yield 93.94%) as a yellow oil. MS m / z (ESI): 613.3 [M+H] + .

[0720] Preparation of intermediate H64-f

[0721] Step 1: Under argon, tert-butyl (S)-(1-(4-bromophenyl)ethyl)carbamate (5 g, 16.66 mmol), 4-methylthiazole (3.30 g, 33.31 mmol), palladium acetate (37.39 mg, 166.56 μmol), potassium acetate (3.27 g, 33.31 mmol), and DMA (10 mL) were mixed and heated at 150°C for 4 hours. The reaction mixture was filtered, and the filtrate was added to ice water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 75:%:25%) to obtain H64-c (5.2 g, 16.33 mmol, yield 98.04%) as a yellow solid. MS m / z (ESI): 319.1 [M+H] + .

[0722] Step 2: Add HCl / 1,4-dioxane (15 mL) to a solution of H64-c (5.1 g, 16.02 mmol) and DCM (30 mL) at room temperature. Allow to react for 2 hours. Filter the reaction mixture and collect the solid to yield H64-d (4 g, 15.70 mmol, 98.03% yield, HCl) as a yellow solid. MS m / z (ESI): 219.1 [M+H] + .

[0723] Step 3: At room temperature, H64-d (4.34 g, 18.76 mmol), HATU (7.81 g, 20.54 mmol), DIPEA (6.93 g, 53.59 mmol, 9.33 mL), and DMF (50 mL) were mixed, followed by the addition of rac-(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine (3.9 g, 17.86 mmol). The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 95%:5%) to obtain H64-e (6 g, 13.90 mmol, yield 77.83%) as a white solid. MS m / z (ESI): 432.2 [M+H] + .

[0724] Step 4: Dissolve H64-e (1 g, 2.32 mmol) in HCl / 1,4-dioxane (4 M) (20 mL) and stir at room temperature for 2 hours. Concentrate under reduced pressure to remove the solvent to give crude H64-f (720 mg, 2.17 mmol, 93.75% yield) as a pink solid. The crude product was directly used in the next reaction. MS m / z (ESI): 332.2 [M+H] + .

[0725] Preparation of intermediate H65-g

[0726] Step 1: Under argon, 1-bromo-4-iodobenzene (6.40 g, 22.61 mmol), 4-(dimethoxymethyl)piperidine (3 g, 18.84 mmol, HCl), L-proline (867.68 mg, 7.54 mmol), cuprous iodide (717.66 mg, 3.77 mmol), potassium carbonate (5.21 g, 37.68 mmol), and DMSO (40 mL) were mixed and heated at 80°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100% to 80%:20%) to obtain H65-a (3.2 g, 10.18 mmol, yield 54.05%) as a yellow solid. MS m / z (ESI): 314.1 [M+H] + .

[0727] Step 2: Under argon, 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (500 mg, 1.37 mmol), H65-a (474.55 mg, 1.51 mmol), palladium acetate (61.65 mg, 274.60 μmol), n-butyldi(1-adamantyl)phosphine (98.45 mg, 274.60 μmol), potassium carbonate (759.01 mg, 5.49 mmol), diboronic acid pinacol ester (697.30 mg, 2.75 mmol), DME (20 mL), and water (2 mL) were mixed and heated at 85°C for 16 hours. The reaction mixture was filtered, the aqueous layer was separated, and the crude product was obtained by concentration. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50%:50% to 0%:100%) to give H65-b (120 mg, 231.40 μmol, yield 16.85%) as a yellow solid. MS m / z (ESI): 519.3 [M+H] + .

[0728] Step 3: Add TFA (0.5 mL) to a solution of H65-b (50 mg, 96.42 μmol) and DCM (1 mL) at room temperature. Allow to react for 1 hour. Concentrate the reaction mixture to afford H65-c (36 mg, 76.19 μmol, 79.02% yield) as a yellow solid. The crude product was used directly in the next step. MS m / z (ESI): 473.2 [M+H] + .

[0729] Step 4: tert-Butyl piperazine-1-carboxylate (400 mg, 2.15 mmol), methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (930.27 mg, 1.93 mmol), DIPEA (832.68 mg, 6.44 mmol, 1.12 mL), and DMSO (15 mL) were heated at 110°C for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed three times with water and once with saturated brine, then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:ammonia / methanol 4M = 95%:5%) to obtain H65-d (700 mg, 1.91 mmol, yield 88.71%) as a brown oil. MS m / z (ESI): 312.1 [M+H-56] + .

[0730] Step 5: H65-d (200 mg, 544.31 μmol), NaOH (78.21 mg, 1.96 mmol), THF (6 mL), and water (2 mL) were stirred at room temperature for 16 hours. The reaction solution was concentrated and adjusted to pH 4-5 with 1N HCl. The mixture was then extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with saturated brine and concentrated to afford H65-e (90 mg, 254.66 μmol, 46.79% yield) as a brown solid. MS m / z (ESI): 298.1 [M+H-56] + .

[0731] Step 6: At room temperature, H65-e (80 mg, 226.36 μmol), H64-f (75.02 mg, 226.36 μmol), DIPEA (87.77 mg, 679.09 μmol, 118.29 μL), and DMF (5 mL) were mixed, followed by the addition of HATU (102.48 mg, 271.64 μmol). The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was filtered, the filtrate was added to ice water, and then extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with saturated brine and concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:ammonia / methanol 4M = 95%:5%) to obtain H65-f (100 mg, 149.96 μmol, yield 66.25%) as a brown solid. MS m / z (ESI): 611.3 [M+H-56] + .

[0732] Step 7: Add TFA (1 mL) to a solution of H65-f (90 mg, 134.97 μmol) and DCM (2 mL) at room temperature. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated to dryness, and the residue was dissolved in ethyl acetate. Saturated sodium bicarbonate solution was then added to adjust the pH to >8. The organic layer was separated and concentrated to afford H65-g (55 mg, 97.05 μmol, 71.91% yield) as a yellow solid. The crude product was directly used in the next step. MS m / z (ESI): 567.3 [M+H] + .

[0733] Preparation of the intermediate 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid

[0734] Step 1: Dissolve 5-bromo-6-aminopyridine-2-carboxylic acid methyl ester (4.0 g, 17.31 mmol) in toluene (40 mL), followed by the addition of N,N-dimethylformamide dimethyl acetal (4.63 mL, 34.62 mmol). The mixture was stirred at 110 ° C for 4 hours. The crude product reaction solution was concentrated to give the crude product (E)-5-bromo-6-(((dimethylamino)methylene)amino)picolinic acid methyl ester (5.1 g, yellow solid, crude product), which was directly used in the next step without purification. MS m / z (ESI): 286.0 [M+H] + .

[0735] Step 2: (E)-5-bromo-6-(((dimethylamino)methylene)amino)picolinic acid methyl ester (5.1 g, crude product 17.82 mmol) was dissolved in ethanol (50 mL), followed by the addition of sodium acetate (2.92 g, 35.65 mmol) and hydroxylamine hydrochloride (2.48 g, 35.65 mmol). The mixture was stirred at 50 ° C for 4 hours. The crude product reaction solution was concentrated to give the crude product ((E)-5-bromo-6-(N'-hydroxycarbamimidoyl)picolinic acid methyl ester (10 g, yellow oil, crude product), which was directly used in the next step without purification. MS m / z (ESI): 273.8 [M+H] + .

[0736] Step 3: Methyl ((E)-5-bromo-6-(N'-hydroxycarbamimidoyl)picolinate (10.0 g, crude) was dissolved in tetrahydrofuran (100 mL), followed by the addition of trifluoroacetic anhydride (17.30 g, 35.65 mmol). The mixture was stirred at 75°C for 3 hours. After cooling to room temperature, the reaction solution was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated. Purification by silica gel column chromatography (PE / EA = 750 / 50) afforded methyl 8-bromo-[1,2,4]triazolo[1,5-A]pyridine-5-carboxylate (3.55 g, white solid, 80.0% yield over three steps). MS m / z (ESI): 258.0 [M+H] + .

[0737] Step 4: At 25°C under a nitrogen atmosphere, 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (1.50 g, 4.13 mmol), potassium acetate (1.22 g, 12.39 mmol) and biboronic acid pinacol ester (2.10 g, 8.26 mmol) were dissolved in 1,4-dioxane (50 mL), and then tetrakistriphenylphosphine palladium (0.95 g, 0.83 mmol) was added all at once. The mixture was stirred at 100°C for 18 hours. The crude product reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane:methanol = 1:0 to 10:1) to give N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)imidazo[1,5-c]pyrimidin-5-amine (400.0 mg, yellow solid). Yield: 23.61%. MS m / z (ESI): 411.2 [M+H] + .

[0738] Step 5: At 25 ° C, under a nitrogen atmosphere, N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-c]pyrimidin-5-amine (370 mg, 0.90 mmol), 8-bromo-[1,2,4]triazolo[1,5-A]pyridine-5-carboxylic acid methyl ester (461.9 mg, 1.80 mmol) and potassium carbonate (373.9 mg, 2.71 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL) and water (2 mL), and then tetrakistriphenylphosphine palladium (104.2 mg, 0.09 mmol) was added in one portion, and the mixture was stirred at 80 ° C for 2 hours. The crude product reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane:methanol = 1:0 to 10:1) to give methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate (16.0 mg, yellow solid). Yield: 38.61%. MS m / z (ESI): 460.2 [M+H] + .

[0739] Step 6: At 25 ° C, under a nitrogen atmosphere, 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (53 mg, 0.12 mmol) and lithium hydroxide (24.2 mg, 0.58 mmol) were dissolved in methanol (2 mL) and water (0.5 mL), and the mixture was stirred at 25 ° C for 2 hours. The crude product reaction solution was concentrated to obtain a crude product. The crude product was used directly in the next step. MS m / z (ESI): 446.2 [M+H] + .

[0740] Preparation of the intermediate 5'-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-7'-oxo-spiro[indan-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylic acid

[0741] Step 1: Dissolve 5-bromoindane-1-carbonitrile (3.0 g, 13.51 mmol) in methanol (100 mL). Under argon, add molybdenum hexacarbonyl (5.35 g, 20.26 mmol), triethylamine (5.46 g, 54.03 mmol, 7.52 mL), palladium acetate (303.28 mg, 1.35 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.68 g, 2.70 mmol) in sequence. Seal the tube, heat to 70°C, and stir for 2 hours. The reaction mixture is filtered, concentrated to dryness under reduced pressure, and purified on a silica gel column (EA:PE = 0-50%) to afford methyl 1-cyanoindane-5-carboxylate (600 mg, 2.98 mmol, 22.07% yield) as a yellow solid. MS m / z (ESI): 202 [M+H] + .

[0742] Step 2: Compound 1-cyanoindan-5-carboxylic acid methyl ester (1.0 g, 4.97 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C under argon protection, and sodium hydroxide (795.07 mg, 19.88 mmol, 60% purity) was added portionwise. After addition, the mixture was stirred at 0°C for 1 hour. 3-chloropyridazine-4-carbonitrile (832.17 mg, 5.96 mmol) dissolved in tetrahydrofuran (5 mL) was added dropwise. After addition, the mixture was stirred at 0°C for 2 hours, and then the mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was poured into ice water, extracted with EA (30 ml x 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified on a silica gel column (EA:PE = 0-100%) to give methyl 1-cyano-1-(4-cyanopyridazin-3-yl)indane-5-carboxylate (300 mg, 985.86 μmol, 19.84% yield) as a yellow solid. MS m / z (ESI): 305 [M+H] + .

[0743] Step 3: Compound 1-cyano-1-(4-cyanopyridazin-3-yl)indane-5-carboxylic acid methyl ester (300 mg, 985.86 μmol) was dissolved in concentrated hydrochloric acid (97.15 mg, 985.86 μmol, 15 mL, 37% purity), heated to 80°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain 5',7'-dioxaspiro[indane-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylic acid (304.90 mg, 985.85 μmol, 100.00% yield) as a gray solid. MS m / z (ESI): 305 [M+H] + .

[0744] Step 4: Compound 5',7'-dioxaspiro[indane-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylic acid (300 mg, 970.01 μmol) was dissolved in tetrahydrofuran (10 mL). 2-tert-Butyl-1,3-diisopropylisourea (971.56 mg, 4.85 mmol) was added with stirring at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified on a silica gel column (EA:PE = 0-100%) to give tert-butyl 5',7'-dioxaspiro[indane-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylate (320 mg, 875.80 μmol, 90.29% yield) as a yellow solid. MS m / z (ESI): 366 [M+H] + .

[0745] Step 5: Dissolve tert-butyl 5',7'-dioxaspiro[indane-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylate (226.03 mg, 618.62 μmol) in acetonitrile (10 mL). Under argon, add phosphorus oxychloride (474.27 mg, 3.09 mmol) and diisopropylethylamine (799.52 mg, 6.19 mmol, 1.08 mL). Heat to 80°C and stir for 25 minutes. Cool to room temperature. Add (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (517.10 mg, 3.09 mmol) and stir at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified on a silica gel column (MeOH:DCM = 0-10%) to give tert-butyl 5'-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-7'-oxo-spiro[indan-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylate (60 mg, 116.61 μmol, 18.85% yield) as a yellow solid. MS m / z (ESI): 515 [M+H] + .

[0746] Step 6: Compound 5'-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-7'-oxo-spiro[indane-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylic acid tert-butyl ester (50 mg, 97.17 μmol) was dissolved in dichloromethane (10 mL). A solution of hydrogen chloride in ethyl acetate (4.0 M, 10.00 mL) was added with stirring at room temperature and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to dryness to obtain 5'-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-7'-oxo-spiro[indane-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylic acid (44.55 mg, 97.18 μmol, 100.00% yield) as a yellow solid. MS m / z (ESI): 459 [M+H] + .

[0747] Preparation of the intermediate 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undec-3-yl)isoindole-1,3-dione

[0748] Step 1: Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (500 mg, 1.81 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (506.49 mg, 1.99 mmol) in DMSO (5 mL). Add DIPEA (467.90 mg, 3.62 mmol, 630.59 μL). Stir the mixture at 90°C under nitrogen for 15 hours until the reaction is complete. Add H2O (50 mL) to the reaction solution, extract three times with ethyl acetate (25 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by combiflash (EA:PE = 0-60%) to give tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (765 mg, yield: 82.77%) as a yellow oil. MS m / z (ESI): 510.9 [M+H] + .

[0749] Step 2: Dissolve tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (715 mg, 1.40 mmol) in dioxane (10 mL). Add 4M HCl in dioxane (10 mL) at room temperature (25°C). The mixture was stirred at room temperature (25°C) for 5 hours until the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecane-3-yl)isoindole-1,3-dione (570 mg, crude) as a yellow solid. The product was used directly in the next step without further purification. MS m / z (ESI): 411.2 [M+H] + .

[0750] Preparation of the intermediate 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxaldehyde

[0751] Step 1: Compound 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (5.0 g, 14.79 mmol) and 4-(dimethoxymethyl)piperidine (4.71 g, 29.57 mmol) were dissolved in toluene (150 mL). Under argon protection, methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (2.48 g, 2.96 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (1.38 g, 2.96 mmol), [bis(trimethylsilyl)amino]lithium (1.0 M, 73.93 mL) were added in sequence, and the temperature was raised to 80 degrees and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride, extracted with EA (30 ml x 2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 0-100%) to obtain 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione as a yellow solid. MS m / z (ESI): 417 [M+H] + .

[0752] Step 2: 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (5.3 g, 12.73 mmol) was dissolved in formic acid (122.00 g, 2.65 mol, 100 mL) and the reaction was stirred at 50 ° C for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure. The red solid product 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxaldehyde (4.71 g, 12.72 mmol, 100.00% yield) was obtained. MS m / z (ESI): 371 [M+H] + .

[0753] Preparation of the intermediate 1-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde

[0754] Step 1: 6-bromo-5-fluoro-1-methyl-1H-indazole (1140 mg, 5 mmol) was added to 5 ml of DMSO, followed by N-iodosuccinimide (1125 mg, 5 mmol). The mixture was stirred at 120°C for 3 hours. After completion of the reaction, the mixture was poured into water and extracted three times with 30 ml of ethyl acetate. The organic phases were combined and washed once with 50 ml of saturated sodium chloride. The organic phases were concentrated to obtain 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1239 mg, 3.5 mmol). Yield: 70%. MS m / z (ESI): 354.9 [M+H]. + .

[0755] Step 2: 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), 120 mg Pd(dppf)Cl2 and 3.41 g of cesium carbonate were added sequentially to 10 ml of 1,4-dioxane, followed by 2 ml of water. The nitrogen atmosphere was replaced three times, and the mixture was heated to 110°C with stirring for 15 hours. After the reaction, the mixture was poured into water and extracted three times with 30 ml of ethyl acetate. The organic phases were combined and washed once with 50 ml of saturated sodium chloride. An appropriate amount of silica gel was added to the resulting organic phase, and the mixture was filtered through a PE / EA (0-50%) column to obtain the compound 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (1036 mg, 2 mmol). Yield: 57%. MS m / z (ESI): 518 [M+H]. + .

[0756] Step 3: Compound 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (1036 mg, 2 mmol) was added to 5 ml of methanol, followed by the addition of 200 mg of 10 wt% Pd / C. The hydrogen atmosphere was replaced three times, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to obtain compound 3-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (680 mg, 2 mmol). Yield: 100%. MS m / z (ESI): 340 [M+H] + .

[0757] Step 4: Compound 3-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (680 mg, 2 mmol), 4-(dimethoxymethyl)piperidine (477 mg, 3 mmol), 340 mg of Ruphos-Pd-G3 and cesium carbonate (1952 mg, 6 mmol) were added sequentially to 10 ml of 1,4-dioxane, the nitrogen atmosphere was replaced three times, and the mixture was heated at 120° C. with stirring for 15 hours. After the reaction, the mixture was poured into water and then extracted three times with 30 ml of ethyl acetate. The organic phases were combined and washed once with 50 ml of saturated brine. An appropriate amount of silica gel was added to the organic phase and the sample was mixed. The mixture was then passed through a column with PE / EA (0-100%) to obtain 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (84 mg, 0.2 mmol). Yield: 10%. MS m / z (ESI): 419 [M+H] + .

[0758] Step 5: Compound 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (84 mg, 0.2 mmol) was added to 5 ml of dichloromethane, followed by 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was pumped dry to obtain 1-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde (74.5 mg, 0.2 mmol). Yield: 100%. MS m / z (ESI): 373 [M+H]. + .

[0759] Preparation of the intermediate 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde

[0760] Step 1: Dissolve 6-bromo-3-iodo-1-methylindazole (3000 mg, 8.90 mmol) in 24 mL of 1,4-dioxane and water (8 mL). Then add 2,6-bis(benzyloxyalkyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.72 g, 8.90 mmol), cesium carbonate (5.80 g, 17.81 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.73 g, 0.98 mmol). The atmosphere was replaced with nitrogen three times and stirred at 95°C under a nitrogen balloon for 2 hours. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to give 3-{6-[4-(2,4-dioxolane-3-yl)hexahydropyridin-1-yl]-1-methylindazol-3-yl}pyridine-2,6-diol (4.00 g, 7.99 mmol) as a white solid. Yield: 89.78%

[0761] Step 2: Dissolve 3-[2,6-bis(benzyloxyalkyl)pyridin-3-yl]-6-bromo-1-methylindazole (1000 mg, 2.00 mmol) in 20 mL of 1,4-dioxane, then add (hexahydropyridin-4-yl)dimethoxymethane (0.47 mL, 0.20 mmol), cesium carbonate (1953 mg, 6.00 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.20 mmol), and Xphos (95 mg, 0.25 mmol). Replace the atmosphere with nitrogen three times and stir at 100°C under a nitrogen balloon for 2 hours. Pour the reaction solution into 50 mL of water and extract with ethyl acetate (30 mL x 3). Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and filter to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 1:1) to afford 3-{6-[4-(2,4-dioxolane-3-yl)hexahydropyridin-1-yl]-1-methylindazol-3-yl}pyridine-2,6-diol (1000 mg, 2.51 mmol) as a yellow oil in a yield of 86.47%. MS m / z (ESI): 579.3 [M+H] + .

[0762] Step 3: 3-{6-[4-(2,4-dioxapentacyclopentane-3-yl)hexahydropyridine-1-yl]-1-methylindazole-3-yl}pyridine-2,6-diol (1000 mg, 2.51 mmol) was dissolved in 10 mL of trifluoroethanol, followed by the addition of 5-trifluoroacetic acid (0.02 mL, 0.25 mmol) and palladium carbon (30 mg, 0.25 mmmol). The mixture was replaced with hydrogen three times, stirred at room temperature for 3 hours under the protection of a hydrogen balloon, and then transferred to 50 degrees for 16 hours. The reaction solution was filtered, and the filtrate was spin-dried to obtain a yellow crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane:methanol = 20:1 to 10:1) to give 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (300 mg, yellow oil) in a yield of 29.85%. MS m / z (ESI): 401.2 [M+H] + .

[0763] Step 4: Dissolve 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (300 mg, 0.75 mmol) in 10 mL of tetrahydrofuran, then add 5 mL of hydrochloric acid. The mixture was reacted at 50°C for 3 hours. The reaction solution was neutralized with saturated sodium bicarbonate to pH 8, and ethyl acetate (30 mL x 3) was added. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane:methanol = 20:1 to 10:1) to obtain 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde (120 mg, yellow oil) in a yield of 45.20%. MS m / z (ESI): 355.2 [M+H] + .

[0764] Preparation of the intermediate 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)azetidine-3-carbaldehyde

[0765] Step 1: Dissolve 3-(hydroxymethyl)azetidine-1-carboxylic acid benzyl ester (5.0 g, 22.60 mmol) in dichloromethane (60 mL). Add (1,1-diacetoxy-3-oxo-1,2-benzoiodine-1-yl) acetate (14.38 g, 33.90 mmol) with stirring at room temperature. Stir at room temperature for 2 hours. Filter the reaction mixture after LC-MS analysis and concentrate under reduced pressure at 25°C to obtain a yellow solid, 3-formylazetidine-1-carboxylic acid benzyl ester (4.95 g, 22.58 mmol, 100.00% yield), which is directly used in the next step. MS m / z (ESI): 220 [M+H]+ .

[0766] Step 2: Dissolve the compound 3-formylazetidine-1-carboxylic acid benzyl ester (5.0 g, 22.81 mmol) in methanol (100 mL). Add trimethyl orthoformate (12.10 g, 114.03 mmol) and 4-methylbenzenesulfonic acid (196.37 mg, 1.14 mmol) with stirring at room temperature. Stir overnight at room temperature. LC-MS analysis. The reaction solution was concentrated to dryness under reduced pressure and purified on a silica gel column (EA:PE = 0-50%) to obtain 3-(dimethoxymethyl)azetidine-1-carboxylic acid benzyl ester (4.2 g, 15.83 mmol, 69.41% yield) as a yellow oil. MS m / z (ESI): 266 [M+H] + .

[0767] Step 3: Dissolve benzyl 3-(dimethoxymethyl)azetidine-1-carboxylate (668.62 mg, 2.52 mmol) in methanol (20 mL), add palladium on carbon (576.39 mg, 541.62 μmol, 10% purity), and stir at room temperature for 2 hours under hydrogen protection. LC-MS analysis. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(dimethoxymethyl)azetidine (330 mg, 2.52 mmol, 99.82% yield) as a colorless oil. MS m / z (ESI): 132 [M+H] + .

[0768] Step 4: 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methylindazole (1 g, 2.00 mmol) and 3-(dimethoxymethyl)azetidine (340.79 mg, 2.60 mmol) were dissolved in dioxane (20 mL). Tris(dibenzylideneacetone)dipalladium (183.00 mg, 199.85 μmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (190.54 mg, 399.69 μmol) and cesium carbonate (1.30 g, 4.00 mmol) were added under argon protection. The temperature was raised to 100 ° C and stirred overnight. LCMS showed that the product was generated. The solvent was concentrated under reduced pressure, and then water and ethyl acetate were added. The mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was separated on a silica gel column (24 g, 0-40% EA / PE) to give 3-(2,6-dibenzyloxy-3-pyridyl)-6-[3-(dimethoxymethyl)azetidin-1-yl]-1-methylindazole (0.8 g, 1.45 mmol, 72.70% yield). MS m / z (ESI): 551 [M+H] + .

[0769] Step 5: 3-(2,6-dibenzyloxy-3-pyridyl)-6-[3-(dimethoxymethyl)azetidin-1-yl]-1-methylindazole (0.8 g, 1.45 mmol) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL), and palladium on carbon (154.61 mg, 145.28 μmol, 10% purity) was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The hydrogen atmosphere was replaced again, and the mixture was heated to 40 degrees and stirred for 4 hours. LCMS showed that the product was formed. The catalyst was filtered off, and the solvent was concentrated under reduced pressure to obtain the crude product 3-[6-[3-(dimethoxymethyl)azetidin-1-yl]-1-methylindazol-3-yl]piperidine-2,6-dione (350 mg, 939.81 μmol, 64.69% yield).

[0770] Step 6: Compound 3-[6-[3-(dimethoxymethyl)azetidin-1-yl]-1-methylindazol-3-yl]piperidine-2,6-dione (426.64 mg, 1.15 mmol) was dissolved in formic acid (10 mL), heated to 40 degrees and stirred for 2 hours. LCMS showed product formation. The reaction solution was concentrated under reduced pressure to dryness to give a yellow solid 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)azetidine-3-carbaldehyde (373.87 mg, 1.15 mmol, 100.00% yield). MS m / z (ESI): 327 [M+H] + .

[0771] Preparation of the intermediate 1-(4-(2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carboxaldehyde

[0772] Step 1: At 25 ° C, under a nitrogen atmosphere, (hexahydropyridin-4-yl) dimethoxymethane (1.0 g, 6.28 mmol), 1,2-difluoro-4-nitrobenzene (1.10 g, 6.91 mmol) and potassium carbonate (1.30 g, 9.42 mmol) were dissolved in N, N-dimethylformamide (60 mL), and the mixture was stirred at 25 ° C for 18 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 1: 0 to 10: 1) to obtain [1- (2-fluoro-4-nitrophenyl) hexahydropyridin-4-yl] dimethoxymethane (1.8 g, yellow solid). Yield: 96.08%. MS m / z(ESI):299.1[M+H] + .

[0773] Step 2: [1-(2-Fluoro-4-nitrophenyl)piperidin-4-yl]dimethoxymethane (1.8 g, 6.03 mmol) and palladium on carbon (180 mg) were dissolved in tetrahydrofuran (20 mL) at 25°C under air. The atmosphere was replaced with hydrogen three times, and the mixture was stirred at 25°C for 18 hours. The mixture was filtered and concentrated to give [1-(4-amino-2-fluorophenyl)piperidin-4-yl]dimethoxymethane (1.6 g, yellow solid). Yield: 86.47%. MS m / z (ESI): 269.2 [M+H] + .

[0774] Step 3: [1-(4-amino-2-fluorophenyl)piperidin-4-yl]dimethoxymethane (1.6 g, 5.22 mmol), 2,6-bis(benzyloxyalkyl)-3-bromopyridine (1.93 g, 5.22 mmol), 2-(2-aminophenyl)-1-phenylmethanesulfonate palladium, {2-[2,6-bis(propan-2-yloxyalkyl)phenyl]phenyl}dicyclohexylphosphine (0.44 g, 0.52 mmol), and cesium carbonate (5.10 g, 15.65 mmol) were dissolved in 1,4-dioxane (50 mL), and the mixture was stirred at 100° C. under a nitrogen atmosphere for 18 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 1:1 to 0:1) to give [1-(4-{[2,6-bis(benzyloxyalkyl)pyridin-3-yl]amino}-2-fluorophenyl)hexahydropyridin-4-yl]dimethoxymethane (2.0 g, yellow solid). Yield: 68.70%. MS m / z (ESI): 558.6 [M+H] + .

[0775] Step 4: [1-(4-{[2,6-bis(benzyloxyalkyl)pyridin-3-yl]amino}-2-fluorophenyl)hexahydropyridin-4-yl]dimethoxymethane (2.0 g, 3.59 mmol) and palladium on carbon (2.0 g) were dissolved in tetrahydrofuran (30 mL) at 25°C under air atmosphere. The mixture was replaced with hydrogen three times and stirred at 25°C for 18 hours. The mixture was filtered and concentrated to give a crude product, which was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 1:1 to 0:1) to give 3-({4-[4-(2,4-dioxolan-3-yl)hexahydropyridin-1-yl]-3-fluorophenyl}amino)hexahydropyridine-2,6-dione (400 mg, blue solid). Yield: 29.25%. MS m / z (ESI): 380.2 [M+H] + .

[0776] Step 5: 3-({4-[4-(2,4-dioxolan-3-yl)piperidin-1-yl]-3-fluorophenyl}amino)piperidine-2,6-dione (200 mg, 0.530 mmol) and dichloromethane (2.5 mL) were added to a single-necked flask at room temperature. A 4.0 M hydrochloric acid-dioxane solution (1.25 mL, 5.00 mmol) was added with stirring at room temperature. The mixture was reacted at 25°C for 3 hours. After the reaction was complete, the reaction solution was concentrated to give 1-(4-(2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-4-carbaldehyde (196 mg, green solid). Yield: 100%. MS m / z (ESI): 334.1 [M+H]. + .

[0777] Preparation of the intermediate 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,3-difluoropiperidine-4-carbaldehyde

[0778] Step 1: Dissolve tert-butyl 3,3-difluoro-4-(hydroxymethyl)piperidin-1-carboxylate (1.0 g, 3.98 mmol) in dichloromethane (20 mL). Add hydrogen chloride in ethyl acetate (4.0 M, 10 mL) with stirring at room temperature. Stir at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressu...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: POI-(L) n0 —ULM (I), in, POI is the ligand that binds to the EED protein; L is the connection link between POI and ULM; ULM is the group that binds to the E3 ligase; n0 is 0 or 1.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: POI is a structure represented by formula (A-1) or an isomer thereof: in, A1 ring is a 5- to 20-membered heterocycloalkyl ring (preferably a 5- to 6-membered heterocycloalkyl ring, preferably a 15- to 20-membered heterocycloalkyl ring, more preferably a 15- to 18-membered heterocycloalkyl ring, and further preferably an 18-membered heterocycloalkyl ring) or a 5- to 10-membered heteroaryl ring; A2 ring is absent, 3 to 15-membered heterocycloalkyl ring, C 3-10 a cycloalkyl 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, and further preferably a 5- to 6-membered heteroaryl ring) or a C 6-10 an aryl ring (preferably a benzene ring or a naphthalene ring); (R1) n1 It means that the hydrogen on the 2,3-dihydrobenzofuran ring is replaced by n1 R1, n1 is 0, 1 or 2, each R1 is the same or different, and each is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), oxo, 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), -OCOC 1-8 Alkyl (preferably -OCOC 1-6 Alkyl, more preferably -OCOC 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), -OSO2C 1-8 Alkyl (preferably -OSO2C 1-6 Alkyl, more preferably -OSO2C 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 R1 and the carbon atom connected thereto together form 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) or a 3- to 15-membered heterocycloalkyl ring (preferably a 3- to 10-membered heterocycloalkyl ring, more preferably a 3- to 8-membered heterocycloalkyl ring, and further preferably a 3- to 6-membered heterocycloalkyl ring); 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, -OCOC 1-8 Alkyl, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -OSO2C 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 3-15 The cycloalkyl ring and the 3- to 15-membered heterocycloalkyl 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, -OCOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 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); (R2) n2 represents that the hydrogen on the A1 ring is replaced by n2 R2, n2 is 0, 1 or 2, each R2 is the same or different, and each is independently selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, 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), -NHC 1-8 Alkyl (preferably -NHC 1-6 Alkyl, more preferably -NHC 1-3 Alkyl), -N(C 1-8 Alkyl)2 (preferably -N(C 1-6 Alkyl)2, more preferably -N(C 1-3 Alkyl)2), -COC 1-8 Alkyl (preferably -COC 1-6 Alkyl, more preferably -COC 1-3 Alkyl), -OCOC 1-8 Alkyl (preferably -OCOC 1-6 Alkyl, more preferably -OCOC 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), -PO(C 1-8 Alkyl)2 (preferably -PO(C 1-6 Alkyl)2, more preferably -PO(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), -OSO2C 1-8 Alkyl (preferably -OSO2C 1-6 Alkyl, more preferably -OSO2C 1-3 Alkyl), -SC 1-6 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, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -COC 1-8 Alkyl, -OCOC 1-8 Alkyl, -COOC 1-8 Alkyl, -CONH2, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -PO(C 1-8 Alkyl)2, -SOC 1-8 Alkyl, -SO2C 1-8 Alkyl, -OSO2C 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, NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COC 1-6 Alkyl, -OCOC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -PO(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 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); or R1, R2, and the carbon atoms connected thereto together form a 6- to 15-membered heterocycloalkyl ring; the 6- to 15-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, carboxyl, nitro, formyl, sulfonic acid, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COC 1-6 Alkyl, -OCOC 1-6 Alkyl, -COOC 1-6 Alkyl, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -PO(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 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); (R3) n3 represents that the hydrogen on the A2 ring is replaced by n3 R3, n3 is 0, 1, 2 or 3, each R3 is the same or different, and each is independently selected from X1, hydrogen, deuterium, cyano, carboxyl, nitro, formyl, sulfonic acid, halogen, oxo, 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), -OCOC 1-10 Alkyl (preferably -OCOC 1-8 Alkyl, more preferably -OCOC 1-6 Alkyl, more preferably -OCOC 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), -OSO2C 1-10 Alkyl (preferably -OSO2C 1-8 Alkyl, more preferably -OSO2C 1-6 Alkyl, more preferably -OSO2C 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, -OCOC 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, -OSO2C 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, -OCOC 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, -OSO2C 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; X1 in R2 and R3 is the connection point between POI and L or ULM, and at least one of R2 and R3 is X1.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: A1 ring is an 8- to 10-membered heteroaryl ring, a 5- to 6-membered heterocycloalkyl ring, or an 18-membered heterocycloalkyl ring; Preferably, the A1 ring is a 9-membered heteroaryl ring or a 10-membered heteroaryl ring; Preferably, the A1 ring is a 9-membered nitrogen-containing heteroaryl ring or a 10-membered nitrogen-containing heteroaryl ring; Preferably, the A1 ring is selected from an indolizine ring, a pyrazolopyridine ring, an imidazopyridine ring, a triazolopyridine ring, a tetraazolopyridine ring, a pyrrolopyridazine ring, a pyrazolopyridazine ring, an imidazopyridazine ring, a triazolopyridazine ring, a tetraazolopyridazine ring, a pyrrolopyrimidine ring, a pyrazolopyrimidine ring, an imidazopyrimidine ring, a triazolopyrimidine ring, a tetraazolopyrimidine ring, a pyrrolopyrazine ring, a pyrazolopyrazine ring, an imidazopyrazine ring, a triazolopyrazine ring, a pyridopyrazine ring, a pyridopyridine ring, a pyridopyrazine ring, a pyridopyridazine ring, a pyridotriazine ring, a pyridopyrimidine ring and a tetraazolopyrazine ring; Preferably, the A1 ring is selected from [1,2,4]triazolo[4,3-c]pyrimidine, imidazo[1,5-c]pyrimidine, imidazo[1,2-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine and pyrido[3,4-d]pyridazine; Preferably, the A1 ring is selected from pyrimidin-4(3H)-one, 1,6-dihydropyrimidine, pyridin-2(1H)-one, 1,2-dihydropyridine, 3,8-diazabicyclo[3.2.1]octane; Preferably, the A1 ring is a partially unsaturated 18-membered heterocycloalkyl ring; Preferably, the A1 ring is selected from 2,3-dihydro-7'H-spiro[indene-1,8'-pyrido[3,4-d]pyridazin]-7'-one and 2,3-dihydro-7'H-spiro[indene-1,8'-pyrido[4,3-c]pyridazin]-7'-one.

4. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Selected from the following structures or isomers thereof: Preferably, the structure Selected from the following structures or isomers thereof: Preferably, the structure Selected from the following structures or isomers thereof: Preferably, the structure Selected from the following structures or isomers thereof:

5. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: POI is a structure represented by formula (A-2-1) or an isomer thereof: wherein W1, W2, W3, W4, W5, and W6 are each independently CH or N, the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in claim 2, and at least one of R2 and R3 is X1; Preferably, POI is a structure represented by formula (A-2-2) or an isomer thereof: Wherein, W1, W2, W3, W4, and W5 are each independently CH or N; the A2 ring, R1, n1, R2, n2, R3, and n3 are as defined in claim 2, and at least one of R2 and R3 is X1.

6. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: POI is selected from the following structures or isomers thereof: Wherein, ring A2, R1, n1, R2, n2, R3, and n3 are as defined in claim 2, and at least one of R2 and R3 is X1.

7. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: A2 ring is selected from the group consisting of: absent, 4- to 8-membered heterocycloalkyl ring, C 4-8 a cycloalkyl ring, a 5- to 10-membered heteroaryl ring, a 10- to 15-membered heterocycloalkyl ring, and a benzene ring; Preferably, the A2 ring is selected from the group consisting of an absent, 4- to 8-membered heterocycloalkyl ring, a saturated C 4-8 a cycloalkyl ring, a 5- to 10-membered heteroaryl ring, a partially unsaturated 10- to 15-membered heterocycloalkyl ring, and a benzene ring; Preferably, the A2 ring is selected from the group consisting of: absence, cyclobutane ring, cyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, pyrazolidine ring, imidazolidine ring, piperidine ring, hexahydropyridazine ring, hexahydropyrimidine ring, piperazine ring, benzene ring, pyrazole ring, oxazole ring, imidazole ring, triazole ring, tetrazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indolizine ring, pyrazolopyridine, imidazopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyridazine, pyrazolopyridine, Pyridazine, imidazopyridazine, triazolopyridazine, tetrazopyridazine, pyrrolopyrimidine, pyrazolopyrimidine, imidazopyrimidine, triazolopyrimidine, tetrazopyrimidine, pyrrolopyrazine, pyrazolopyrazine, imidazopyrazine, triazolopyrazine, tetrazopyrazine, pyridopyridine, pyridopyrazine, pyridopyrazine, pyridotriazine, pyridopyrimidine, 3,8-diazabicyclo[3.2.1]octane, 2,3-dihydrospiro[indene-1,4'-piperidine]; Preferably, the A2 ring is selected from the group consisting of absent, saturated 6-membered heterocycloalkyl ring, partially unsaturated 12-membered heterocycloalkyl ring, cyclohexane ring, 5- to 6-membered heteroaryl ring, 9-membered heteroaryl ring and benzene ring; Preferably, the A2 ring is selected from the group consisting of absent, cyclohexane ring, piperidine ring, piperazine ring, benzene ring, pyridine ring, pyrazole ring, triazolopyridine ring, 2,3-dihydrospiro[indene-1,4'-piperidine]; Preferably, the A2 ring is selected from a benzene ring, a pyridine ring, and a pyrazole ring.

8. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Selected from the following structures or isomers thereof: Preferably, the structure Select from the following structures: Preferably, the structure for Preferably, the structure Selected from the following structures or isomers thereof: Preferably, the structure Selected from the following structures or isomers thereof:

9. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R1 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, -CH2-cyclopropyl, -CH2-tetrakis R1, -CH2-pyrrolyl, -CH2-pyrrolyl, -CH2-phenyl, -CH2-pyridyl, -CH2-cyclohexenyl, -CH2-azetidine, -CH2-piperidine, -CH2-piperazine, tetrahydro-2H-pyran and -CH2-(tetrahydro-2H-pyran); or two R1 and the carbon atom to which they are attached together form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring or a piperazine ring; Preferably, R1 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; Preferably, two R1 and the carbon atom to which they are attached together form a cyclopropyl ring; Preferably, R1 is fluorine.

10. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure for Preferably, the structure for Preferably, the structure for 11. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R2 is selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -PO(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Preferably, R2 is selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -PO(C 1-3 Alkyl)2, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, -OSO2C 1-3 Alkyl, -SC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy; Preferably, R2 is selected from X1, hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHCH3, -N(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -COCH3, -COC(CH3)3, -COOCH3, -COOCH2CH3, -COOC(CH3)3, -OCOCH3, -OCOCH2CH3, -OCOC(CH3)3, -PO(CH3)2, -PO(CH2CH3)2, -SOCH3, -SOCH2CH3, -SOC(CH3)3, -SO2CH3, -SO2CH2CH3, -SO2C(CH3)3, -OSO2CH3, -OSO 2CH2CH3, -OSO2C(CH3)3, -SCH3, -SCH2CH3, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, monofluoroisopropyl, difluoroisopropyl, trifluoroisopropyl, monofluorotert-butyl, difluorotert-butyl, trifluorotert-butyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy, trifluoropropoxy, monofluoroisopropoxy, difluoroisopropoxy, trifluoroisopropoxy, monofluorotert-butoxy, difluorotert-butoxy, trifluorotert-butoxy; Preferably, R2 is selected from cyano, fluorine, chlorine, bromine, iodine, -CH3, -CF3, -SO2CH3, hydrogen; Preferably, R2 is selected from cyano, fluorine, chlorine, bromine, iodine, -SO2CH3, hydrogen; Preferably, R2 is selected from X1, hydrogen, halogen, cyano, -SO2C 1-6 Alkyl, -OSO2C 1-6 alkyl; Preferably, R2 is selected from X1, hydrogen, halogen, cyano, -SO2C 1-3 Alkyl, -OSO2C 1-3 alkyl; Preferably, R2 is selected from X1, hydrogen, fluorine, chlorine, bromine, iodine, cyano, -SO2CH3, -OSO2CH3.

12. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM; Preferably, the structure Selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM; Preferably, the structure Selected from the following structures or isomers thereof: Preferably, the structure Selected from the following structures or isomers thereof: Preferably, the structure Selected from the following structures or isomers thereof:

13. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R1, R2, and the carbon atoms connected thereto together form a 6- to 15-membered heterocycloalkyl ring, wherein the 6- to 15-membered heterocycloalkyl ring is selected from 5,8-dihydro-4H-1,4-oxazine, 4,5,8,9-tetrahydro-1,4-oxazolone, 5,8,9,10-tetrahydro-4H-1,4-oxazine, 1-oxa-4-azacycloundecane-2,6-diene; the 6- to 15-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxy , methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, -COCH3, -COCH2CH3, -COCH(CH3)2, -COC(CH3)3, -OCOCH3, -OCOCH2CH3, -O COCH(CH3)2, -OCOC(CH3)3, -CONH2, -CONHCH3, -CONHCH2CH3, -CONHCH(CH3)2, -CONHC(CH3)3, -CON(CH3) 2. -CON(CH2CH3)2, -SOCH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -SO2C(CH3)3, -OSO2CH3, -OSO2CH2CH3, -OSO2CH(CH3)2, -OSO2C(CH3)3, -SO2NH2, -SO2NHCH3, -SO2NHCH2CH3, -SO2NHCH(CH3)2, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(CH2CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl; Preferably, R1, R2, and the carbon atoms to which they are attached together form (2Z,6Z)-4,5,8,9-tetrahydro-1,4-oxazolone, (2E,6Z)-4,5,8,9-tetrahydro-1,4-oxazolone, (2E,6E)-4,5,8,9-tetrahydro-1,4-oxazolone, (2Z,6Z)-5,8-dihydro-4H-1,4-oxazine, (2E,6Z)-5,8-dihydro-4H-1,4-oxazine, (2Z,6E)-5,8-dihydro-4H-1,4-oxazine, (2E,6E)-5,8-dihydro-4H-1,4-oxazine, (2Z,6Z)-5,8-dihydro-4H-1,4-oxazine, (2 (2E,6Z)-5,8,9,10-tetrahydro-4H-1,4-oxazine, (2Z,6E)-5,8,9,10-tetrahydro-4H-1,4-oxazine, (2E,6E)-5,8,9,10-tetrahydro-4H-1,4-oxazine, (2Z,6Z)-1-oxa-4-azacycloundecane-2,6-diene, (2E,6Z)-1-oxa-4-azacycloundecane-2,6-diene, (2Z,6E)-1-oxa-4-azacycloundecane-2,6-diene or (2E,6E)-1-oxa-4-azacycloundecane-2,6-diene; Preferably, R1, R2, and the carbon atom to which they are attached together form (2Z,6Z)-4,5,8,9-tetrahydro-1,4-oxazolone, (2Z,6Z)-5,8-dihydro-4H-1,4-oxazine, (2Z,6Z)-5,8,9,10-tetrahydro-4H-1,4-oxazine or (2Z,6Z)-1-oxa-4-azacycloundecane-2,6-diene.

14. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Selected from in express (single key) or (double bond); n1 is 0 or 1, n2 is 0 or 1; Preferably, the structure Selected from Where n1 is 0 or 1, n2 is 0 or 1; Preferably, the structure Selected from Where n1 is 0 or 1, n2 is 0 or 1; Preferably, the structure Selected from Where n1 is 0 or 1, and n2 is 0 or 1.

15. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R3 is selected from X1, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl) 2, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl and phenyl; the C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl), 2- to 4-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, -OSO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and phenyl; Preferably, R3 is selected from X1, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl) 2, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl and phenyl; the C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)2, 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, carboxyl, nitro, formyl, sulfonic acid, halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -COCH3, -OCOCH3, -COOCH3, -CONH2, -CONHCH3, -CON(CH3)2, -SOCH3, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl and phenyl; Preferably, R3 is selected from X1, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, -COC 1-6 Alkyl, -OCOC 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, -OSO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 alkyl)2, 4 to 8 membered heterocycloalkyl, 5 to 6 membered heteroaryl and phenyl; Preferably, R3 is selected from X1, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, -COCH3, -COCH2CH3, -COC(CH3)3, -OCOCH3, -OCOCH2CH3, -OCOC(CH3)3, -COOCH3, -COOCH2CH3, - COOC(CH3)3, -CONH2, -CONHCH3, -CON(CH3)2, -SOCH3, -SO2CH3, -SO2C(CH3)3, -OSO2CH3, -OSO2C(CH3)3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, azetidinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl and phenyl; Preferably, R3 is selected from X1, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogenated C 1-6 Alkyl, -COC 1-6 alkyl; Preferably, R3 is selected from X1, C 1-3 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-3 Alkyl, -COC 1-3 alkyl; Preferably, R3 is selected from X1, methyl, cyclopropyl, trifluoromethyl, -COCH3; Preferably, R3 is selected from X1, fluorine, methyl.

16. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM; Preferably, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM; Preferably, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM; Preferably, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM; Preferably, the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM.

17. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The POI is selected from the following structures or isomers thereof: ; Where X1 is the connection point with L or ULM; Preferably, POI is selected from the following structures or isomers thereof: Preferably, POI is selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM; Preferably, POI is selected from the following structures or isomers thereof: ; Where X1 is the connection point with L or ULM; Preferably, POI is selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM.

18. 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 chemical 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 C 2-10 Alkyne (preferably C 2-8 Alkyne, more preferably C 2-6 Alkyne, more preferably C 2-4 Alkyne), C 3-15 Cycloalkylene ring (preferably C 3-10 A cycloalkylene ring, more preferably C 3-8 The cycloalkylene ring is preferably C 3-6 cycloalkylene ring), a 3- to 15-membered heterocycloalkylene ring (preferably a 4- to 12-membered heterocycloalkylene ring, more preferably a 4- to 10-membered heterocycloalkylene ring, further preferably a 4- to 8-membered heterocycloalkylene ring, further preferably a 4- to 6-membered heterocycloalkylene ring), a 5- to 15-membered heteroarylene ring (preferably a 5- to 14-membered heteroarylene ring, more preferably a 5- to 12-membered heteroarylene ring, further preferably a 5- to 10-membered heteroarylene ring, further preferably a 5- to 6-membered heteroarylene ring) and C 6-14 Arylene ring (preferably phenylene ring or naphthylene ring); the C 1-10 Alkylene, C 1-10 Alkyleneoxy, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-15 a cycloalkylene ring, a 3- to 15-membered heterocycloalkylene ring, a 5- to 15-membered heteroarylene ring, a C 6-14 The arylene ring is unsubstituted or substituted with 1, 2, 3 or 4 R L2 Substitute, the R L2 are each 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 1-6 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).

19. The compound of formula (I) according to claim 18, 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.

20. The compound of formula (I) according to claim 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R L2 are 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-pyridinyl, -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, hydroxyl and hydroxymethyl.

21. The compound of formula (I) according to claim 18, 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 a cycloalkylene ring, a 4- to 12-membered heterocycloalkylene ring, a 5- to 6-membered heteroarylene ring, and a phenylene ring; 3-12 The cycloalkylene ring, the 4- to 12-membered heterocycloalkylene ring, the 5- to 6-membered heteroarylene ring, and the phenylene ring are unsubstituted or substituted with 1, 2, 3 or 4 R L2 Substitute, the R L2 is selected from fluorine, 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-, or a subunit form selected from the following cyclic groups: 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, 3,3,5,5-tetramethylpiperidine, 3,3-difluoropiperidine, 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, 3,9-diazaspiro[5.5]undecane, 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 and triazole ring; wherein, each occurrence of m2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Preferably, the L a Each is independently selected from the following structures or isomers thereof: -(CH2)-, -(CH2)2-, -(CH2)5-, -C(O)-, -(CH2)3-, -C(O)NH-, -(CH2)8-, -O-, -NH-, Preferably, the L a Each is independently selected from the following structures or isomers thereof: -(CH2)-, 22. The compound of formula (I) according to claim 18, 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-Cy0-, -Cy0-NH-(CH2) m3 -、-Cy0-(CH2) m3 -NH-, -Cy0-(CH2) m3 -O-, -C(O)NH-Cy0-, -(CH2) m3 -C(O)NH-(CH2) m3 -O-Cy0-O-(CH2) m3 -、-Cy0-Cy0-、-(CH2) m3 -Cy0-O-Cy0-O-(CH2) m3 -, -Cy0-C(O)NH-Cy0-, -Cy0-(CH2) m3 -Cy0-, -Cy0-O-Cy0-, -Cy0-C(O)-Cy0-, -(CH2) m3 -Cy0-Cy0, -C(O)NH-(CH2) m3 -Cy0-(CH2) m3 -Cy0; wherein m3 each time appears, each is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Cy0 each time appears, 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), 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 hydroxy-substituted azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a hydroxy-substituted piperidine ring, a hydroxymethyl-substituted piperidine ring, a 4-fluoropiperidine ring, a 3,3-difluoropiperidine, a 3,3,5,5-tetramethylpiperidine, 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, 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, 3,9-diazaspiro[5.5]undecane, 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 and triazole ring; Preferably, the Cy0 are each independently selected from a cyclobutane ring, a dicyclopentane ring, a benzene ring, an azetidine ring, a piperidine ring, a piperazine ring, and 3,9-diazaspiro[5.5]undecane; Preferably, the Cy0 are each independently selected from a cyclobutane ring, an azetidine ring, a benzene ring, and a piperidine ring; 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:

23. The compound of formula (I) according to claim 18, 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 It is the connection point between L and ULM or POI; Preferably, the L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection point between L and ULM or POI; Preferably, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection point between L and ULM or POI; Preferably, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection point between L and ULM or POI; Preferably, L is selected from the following structures or isomers thereof: Among them, X 00 It is the connection point between L and ULM or POI; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point between L and ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point between L and ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point between L and ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point between L and ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point between L and ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point between L and ULM; Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection point between L and POI, X 20 It is the connection point of L and ULM.

24. 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 compound represented by formula (U-1) or an isomer thereof: in, express (double bond) or (single bond); U0 is a chemical 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 selected from the group consisting of absent, 5- to 15-membered heteroaryl ring (preferably 6- to 12-membered heteroaryl ring, more preferably 6- to 10-membered heteroaryl ring), 3- to 15-membered heterocycloalkyl ring (preferably 5- to 12-membered heterocycloalkyl ring, more preferably 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 chemical 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 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 1-6 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 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 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 1-6 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; R B1 , R B2 X2 in the figure is the connection point between ULM and L or POI, and R B1 and R B2 At least one of them is X2.

25. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R B1 and R B2 Not X2 at the same time.

26. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The B ring is absent; or the 5- to 15-membered heteroaryl ring in ring B is selected from pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, triazole ring, tetrazole ring, oxazole ring, thiazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, benzopyrrole ring, benzofuran ring, benzothiophene ring, benzopyrazole ring, benzimidazole ring, benzothiazole ring, benzoxazole ring, pyridopyrrole ring , pyridofuran ring, pyridothiophene ring, pyridopyrazole ring, pyridoimidazole ring, pyridothiazole ring, pyridooxazole ring, pyrimidopyrrole ring, pyridazinepyrrole ring, pyrazinepyrrole ring, pyrimidopyrazole ring, pyridazinepyrazole ring, pyrazinepyrazole ring, pyrimidoimidazole ring, pyridazineimidazole ring, pyrazineimidazole ring, quinoline ring, isoquinoline ring and 9H-pyrido[2,3-b]indole ring; Preferably, the 5- to 15-membered heteroaryl ring in ring B is selected from a benzopyrazole ring; 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 chemical 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 attachment to U0; Preferably, Q1, Q2, Q3, and Q4 are each independently -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, the structure Selected from the following structures or isomers thereof: in Indicates the common Valence connection; or 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 attachment to U0; Preferably, the structure Selected from in indicates covalent attachment to U0; or the 3 to 15-membered heterocycloalkyl ring in ring B is Wherein, the B3 ring is a 3- to 7-membered heterocycloalkyl ring, indicates covalent attachment to U0; Preferably, Ring B3 is a 5- to 7-membered nitrogen-containing heterocycloalkyl ring; Preferably, Ring B3 is a partially unsaturated 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 linkage to U0.

27. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Ring B is selected from: benzene ring, in indicates covalent attachment to U0; Preferably, the B ring is selected from: a benzene ring, in indicates covalent attachment to U0; Preferably, the B ring is selected from: in Indicates covalent linkage to U0.

28. The compound of formula (I) according to claim 24, 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; 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 by 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 the group consisting of X2, fluorine, chlorine, hydroxy, methyl, trifluoromethyl and methoxy.

29. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Selected from: Where X2 is the connection point between ULM and L or POI, indicates covalent attachment to U0; Preferably, Selected from: Where X2 is the connection point between ULM and L or POI, Indicates covalent linkage to U0.

30. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: U0 is a chemical bond, -NH-, -CONH- or -CH2-.

31. The compound of formula (I) according to claim 24, 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-.

32. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: S6 is CH or N.

33. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: 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.

34. The compound of formula (I) according to claim 24, 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 point between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

35. 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, r1 is 0, 1, or 2; 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 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 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 and are 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 (preferably -CONHC 1-3 Alkyl), -NHCONHC 1-6 Alkyl (preferably -NHCONHC 1-3 Alkyl), -SOC 1-6 Alkyl (preferably -SOC 1-3 Alkyl), -SO2C 1-6 Alkyl (preferably -SO2C 1-3 Alkyl) and -SC 1-6 Alkyl (preferably -SC 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); 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 U7 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl; or R U7 , and R U7 The connected nitrogen atom, R U6 and R U6 The connected carbon atoms together form a 3- to 8-membered heterocycloalkyl ring or a 5- to 6-membered heteroaryl ring; R U8 Selected from hydroxyl, amino, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -OCOC 1-6 alkyl; 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; R U2 , R U1 , R U5 , R U6 X2 in the figure is the connection point between ULM and L or POI, and R U1 , R U5 , R U6 and R U2 At least one of them is X2.

36. The compound of formula (I) according to claim 35, 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 5-9 Cycloalkyl rings and 5- to 9-membered heterocycloalkyl rings; Preferably, the D ring is selected from a benzene ring, 2,3-dihydro-1H-indene; Preferably, the D ring is selected from 2,3-dihydro-1H-indene; 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; Preferably, the D ring is selected from a benzene ring.

37. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: r1 is 1, and the D ring is a benzene ring.

38. The compound of formula (I) according to claim 35, 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; 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 It is cyano.

39. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: 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, 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.

40. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U2 Selected from the following structures: cyano, 41. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: r2 is 1, R U2 for 42. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: r2 is 2, R U2 X2 and 43. The compound of formula (I) according to claim 35, 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 point between ULM and L or POI; Preferably, Selected from the following structures or isomers thereof:

44. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U1 , R U5 , R U6 and R U2 One of them is X2.

45. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: U1 is selected from X2, -NHCO-X2, -NHCOCH3, Where X2 is the connection point between ULM and L or POI; Preferably, U1 is selected from -NHCO-X2 and Where X2 is the connection point between ULM and L or POI.

46. ​​The compound of formula (I) according to claim 35, 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.

47. The compound of formula (I) according to claim 35, 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 point between ULM and L or POI; Preferably, R U1 Select from the following structures: Where X2 is the connection point between ULM and L or POI; Preferably, R U1 Select from the following structures: Where X2 is the connection point between ULM and L or POI.

48. The compound of formula (I) according to claim 35, 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; or R U5 Together with the carbon atoms on the D ring, they form C 3-6 Cycloalkyl ring; said C 3-6 The cycloalkyl ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, formyl, sulfonic acid, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, 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, amino substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, -COC 1-6 Alkyl, -CO2NH2, -CO2NH(C 1-6 Alkyl), -CO2N(C 1-6 Alkyl)2, -SO2NH2, -SO2NH(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, C 3-8 a cycloalkyl ring, a 4- to 10-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring, and a benzene ring; 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.

49. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U7 Selected from hydrogen, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl; Preferably, R U7 For hydrogen.

50. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U7 , and R U7 The connected nitrogen atom, R U6 and R U6 The connected carbon atoms together form a partially unsaturated 3- to 8-membered heterocycloalkyl ring, a 5- to 6-membered heteroaryl ring, or a benzene ring; Preferably, R U7 , and R U7 The connected nitrogen atom, R U6 and R U6 The connected carbon atoms together form a tetrahydropyrrole ring, a pyrazolidine ring, an imidazolidine ring, a piperazine ring, a piperidine ring, a 2,3-dihydro-1H-pyrrole ring, a 2,3-dihydro-1H-pyrrole ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring or a benzene ring; Preferably, R U7 , and R U7 The connected nitrogen atom, R U6 and R U6 The connected carbon atoms together form a 4- to 6-membered heterocycloalkyl ring; Preferably, R U7 , and R U7 The connected nitrogen atom, R U6 and R U6 The connected carbon atoms together form a 5-membered heterocycloalkyl ring; Preferably, R U7 , and R U7 The connected nitrogen atom, R U6 and R U6 The connected carbon atoms together form a tetrahydropyrrole ring.

51. The compound of formula (I) according to claim 35, 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 point between ULM and L or POI; Preferably, the structure Selected from the following structures or isomers thereof:

52. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U8 Selected from hydroxyl, amino, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, C 1-3 Alkoxy, fluorinated C 1-3 Alkoxy and -OCOC 1-3 alkyl; Preferably, R U8 Selected from hydroxy, amino, -NH(CH3), -N(CH3)2, -OCH3, -OCF3 and -OCOCH3; Preferably, R U8 It is hydroxyl.

53. The compound of formula (I) according to claim 35, 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 point between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI; Preferably, the ULM is selected from the following structures or isomers thereof: Where X2 is the connection point between ULM and L or POI.

54. 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), Among them, A1 ring, A2 ring, R1, n1, R2, n2, R3, n3 are as defined in claim 2, L, n0, ULM are as defined in claim 1, and R2 and R3 are not X1.

55. 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), Among them, A1 ring, A2 ring, R1, n1, R2, n2, R3, n3 are as defined in claim 2, L, n0, ULM are as defined in claim 1, and R2 and R3 are not X1.

56. 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 or isomers thereof: Among them, A2 ring, R1, n1, R2, n2, R3, n3 are as defined in claim 2, L, n0, ULM are as defined in claim 1, and R2 and R3 are not X1.

57. 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 or isomers thereof: Preferably, the compound represented by formula (I) is selected from the following structures or isomers thereof: Preferably, the compound represented by formula (I) is selected from the following structures or isomers thereof:

58. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (I) is a compound selected from Table A or a stereoisomer thereof.

59. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (I) is a compound selected from Table B or a stereoisomer thereof.

60. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

61. Use of the compound (I) according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 60 in the preparation of a medicament for preventing and / or treating an EED-mediated disease; Preferably, the EED-mediated disease is a tumor or an autoimmune disease; Preferably, the EED-mediated disease is cancer; Preferably, the cancer is selected from the group consisting of multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer and breast cancer.

62. A method for preventing and / or treating an EED-mediated disease, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 60; Preferably, the EED-mediated disease is a tumor or an autoimmune disease; Preferably, the EED-mediated disease is cancer; Preferably, the cancer is selected from the group consisting of 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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