Substituted tricyclic derivative as well as pharmaceutical composition and application thereof

Abstract

A substituted tricyclic derivative as shown in formula (II) and pharmaceutically acceptable salts, stereoisomers, pharmaceutical compositions and uses thereof. The tricyclic derivative compound has a higher selective degradation effect on BRM, and has a higher application value.

Description

Substituted tricyclic derivatives and pharmaceutical compositions and uses thereof

[0001] This application claims priority to the Chinese patent application with application number 202310187769.8 filed with the China Patent Office on February 28, 2023, entitled “Substituted tricyclic derivatives, pharmaceutical compositions and uses thereof”, the Chinese patent application with application number 202310970002.2 filed with the China Patent Office on August 2, 2023, entitled “Substituted tricyclic derivatives, pharmaceutical compositions and uses thereof”, and the Chinese patent application with application number 202410076935.1 filed with the China Patent Office on January 18, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to a substituted tricyclic derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition and medical uses thereof. Background Art

[0003] The SWI / SNF chromatin remodeling complex is a multiprotein complex composed of 10–15 different subunits, including four core subunits: BRM (encoded by the SMARCA2 gene) or BRG1 (encoded by the SMARCA4 gene), BAF155 (encoded by the SMARCC1 gene), BAF170 (encoded by the SMARCC2 gene), INI1 (SNF5 or BAF47, encoded by the SMARCB1 gene), and non-core subunits. The SWI / SNF chromatin remodeling complex participates in numerous fundamental cellular processes, such as transcription, replication, and chromatin repair. It influences cellular processes such as metabolism, DNA repair, differentiation, adhesion, and apoptosis, and is involved in angiogenesis, cancer progression, and metastasis (Marquez-Vilendrer SB et al. Oncoscience. 2016;3:322-36).

[0004] BRM (encoded by the SMARCA2 gene) and BRG1 (encoded by the SMARCA4 gene) are two mutually exclusive catalytic subunits of the SWI / SNF complex and do not exist in the same protein complex. They both have a bromodomain and an ATP hydrolase domain and are highly homologous. Some tumors carry SMARCA4 mutations (10% of NSCLC, skin cancer, esophageal / gastric cancer, colon adenocarcinoma, head and neck squamous cell carcinoma). These tumors exhibit malignant characteristics such as poor differentiation, strong invasiveness, and insensitivity to chemotherapy and immunotherapy. In cancers with SMARCA4 mutations, the survival of cancer cells is highly dependent on the activity of SMARCA2. Inhibiting or degrading SMARCA2 will produce a strong synthetic lethality, leading to the death of SMARCA4-mutated tumor cells.

[0005] Therefore, there is a need to provide a BRM (encoded by SMARCA2 gene) degrader that may be useful for treating various disorders associated with BRM (encoded by SMARCA2 gene).

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a novel bifunctional compound (or PROTAC compound) with a higher selective degradation effect on BRM (encoded by the SMARCA2 gene).

[0008] The first aspect of the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0009] Among them, the A ring is selected from C 4-8 Cycloalkyl ring (preferably C 4-6 cycloalkyl ring), a 4- to 8-membered heterocycloalkyl ring (preferably a 4- to 6-membered heterocycloalkyl ring);

[0010] Y1, Y2, Y3, Y4 are each independently selected from a bond, -CH2-, -CH=CH-, -C(O)-, -NH-, -O-, -S-, -SO- and -SO2-;

[0011] The C ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring;

[0012] R1, R2, R3, R4, R5 are each independently selected from hydrogen, deuterium, hydroxyl, carboxyl, cyano, halogen (preferably fluorine, chlorine or bromine), C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), -NR a0 R b0 、-CONR a1 Rb1 、-COC 1-6 Alkyl (preferably -COC 1-3 alkyl), -C(O)OC 1-6 Alkyl (preferably -C(O)OC 1-3 Alkyl), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 Alkyl), C 2-4 Alkenyl, C 2-4 Alkynyl, -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), -SO2C 1-6 Alkyl (preferably -SO2C 1-3 alkyl), -S(O)C 1-6 Alkyl (preferably -S(O)C 1-3 Alkyl), C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl (preferably C 3-6 Cycloalkyl C 1-3 Alkyl), C 3-6 Cycloalkyloxy, 3 to 6 membered heterocycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, -COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OCOC 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SC 1-6 Alkyl, -SO2C 1-6 Alkyl, -S(O)C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 3-6 Cycloalkyloxy and 3- to 6-membered heterocycloalkyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), hydroxy, cyano, amino, and carboxyl;

[0013] R a0 、R b0 are each independently selected from deuterium, hydrogen, C 1-6 Alkyl (preferably C 1-3 Alkyl), -COC 1-6 Alkyl (preferably -COC 1-3 Alkyl), -COOC 1-6 Alkyl (preferably -COOC 1-3 alkyl), -CONH2, -CONHC 1-6Alkyl (preferably -CONHC 1-3 alkyl), -CON(C 1-6 Alkyl)2 (preferably -CON(C 1-3 alkyl)2);

[0014] R a1 、R b1 are each independently selected from deuterium, hydrogen, C 1-6 Alkyl (preferably C 1-3 Alkyl), -COC 1-6 Alkyl (preferably -COC 1-3 alkyl);

[0015] n1, n2, n3, n4, n5 are each independently 0, 1, 2, 3 or 4; L is a linking group;

[0016] ULM is a linker to E3 ligase.

[0017] In some embodiments, the C ring is a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an isothiazole ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, or a tetrazine ring.

[0018] In some embodiments, the C ring is a benzene ring, a pyridine ring, or a pyrimidine ring.

[0019] In some embodiments, Ring C is a benzene ring.

[0020] In some embodiments, the compound represented by formula (II) is represented by formula (II-A):

[0021] wherein Y5, Y6, and Y7 are each independently selected from CH and N;

[0022] R1, R2, R3, R4, R5, n1, n2, n3, n4, n5, Y1, Y2, Y3, Y4, L, ULM are as described in the specification.

[0023] In some embodiments, Y5, Y6, and Y7 are each independently CH.

[0024] In some embodiments, Y5 is N, and Y6 and Y7 are each independently CH.

[0025] In some embodiments, Y6 is N, and Y5 and Y7 are each independently CH.

[0026] In some embodiments, Y7 is N, and Y5 and Y6 are each independently CH.

[0027] In some embodiments, Y5 and Y7 are each independently N, and Y6 is CH.

[0028] In some embodiments, the compound represented by formula (II) is represented by formula (II-B):

[0029] Among them, Y8, Y9, Y 10 are each independently selected from CH and N;

[0030] R1, R2, R3, R4, R5, n1, n2, n3, n4, n5, Y1, Y2, Y3, Y4, L, ULM are as described in the specification.

[0031] In some embodiments, Y8, Y9, Y 10 Each is independently CH.

[0032] In some embodiments, Y8 is N, Y9, Y 10 Each is independently CH.

[0033] In some embodiments, Y9 is N, Y8, Y 10 Each is independently CH.

[0034] In some embodiments, Y 10 is N, and Y8 and Y9 are each independently CH.

[0035] In some embodiments, Y8, Y 10 Each is independently N, and Y9 is CH.

[0036] In some embodiments, Y1 is -CH2-, -O-, -SO2-, -CH=CH-, -NH-, or -C(O)-; preferably, Y1 is -CH2-;

[0037] Y2 is a bond, -CH2-, -NH-, -C(O)- or -O-; preferably, Y2 is -CH2- or -NH-; Y3 is a bond or -NH-; preferably, Y3 is a bond; Y4 is a bond.

[0038] In some embodiments, Y1 is -CH2-, -CH=CH-, or -C(O)-; Y2 is a bond, -CH2-, -NH-, or -O-; Y3 is a bond; and Y4 is a bond.

[0039] In some embodiments, Y1 is -CH=CH-, and Y2, Y3, and Y4 are each independently a bond.

[0040] In some embodiments, Y1 and Y2 are each independently -CH2-, and Y3 and Y4 are each independently a bond.

[0041] In some embodiments, Y1 is -CH2-, Y2 is -NH-, and Y3 and Y4 are each independently a bond.

[0042] In some embodiments, Y1 is -C(O)-, Y2 is -NH-, and Y3 and Y4 are each independently a bond.

[0043] In some embodiments, Y1 is -CH2-, Y2 is -O-, and Y3 and Y4 are each independently a bond.

[0044] In some embodiments, Y1 is -SO2-, Y2 is -NH-, and Y3 and Y4 are each independently a bond.

[0045] In some embodiments, Y1 is -O-, Y2 is -C(O)-, Y3 is -NH-, and Y4 is a bond.

[0046] In some embodiments, Y1 is -NH, Y2 is -C(O)-, and Y3 and Y4 are each independently a bond.

[0047] In some embodiments, Y1 is -NH-, Y2 is -CH2-, and Y3 and Y4 are each independently a bond.

[0048] In some embodiments, Ring A is a 4- to 8-membered nitrogen-containing heterocycloalkyl ring.

[0049] In some embodiments, Ring A is a 4- to 6-membered nitrogen-containing heterocycloalkyl ring.

[0050] In some embodiments, Ring A is a piperidine ring, a piperazine ring, a tetrahydropyrrole ring, a 1,4-dihydropyridine ring, a tetrahydropyrazine ring, an azetidine ring, or a tetrahydropyridine ring.

[0051] In some embodiments, Ring A is an azetidine ring.

[0052] In some embodiments, Ring A is a piperidine ring.

[0053] In some embodiments, the structure Select from the following structures:

[0054] In some embodiments, the structure Select from the following structures:

[0055] In some embodiments, the structure Select from the following structures:

[0056] In some embodiments, R1, R2, R3, R4, and R5 are each independently hydrogen, deuterium, hydroxyl, halogen (preferably fluorine or chlorine), carboxyl, amino, hydroxymethyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, cyclopropyl, difluoromethyl, monofluoromethyl, vinyl, ethynyl, cyano, -SCH3, -COCH3, -COCH2CH3, -COOCH3, -COOCH2CH3, -OCOCH3, -OCOCH2CH3, -NHCH3, -N(CH3)2, -NHCONH2, -NHCOCH2CH3, or -NHCOCH3.

[0057] In some embodiments, R1 is deuterium, fluorine, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, or -OCOCH3.

[0058] In some embodiments, R1 is hydroxy.

[0059] In some embodiments, R1 is fluoro or hydroxy.

[0060] In some embodiments, n1 is 1.

[0061] In some embodiments, n1 is 1 and R1 is hydroxy.

[0062] In some embodiments, n1 is 2.

[0063] In some embodiments, n1 is 2, and R1 is selected from fluoro and hydroxy.

[0064] In some embodiments, n1 is 3.

[0065] In some embodiments, n1 is 3, and R1 is selected from fluoro and hydroxy.

[0066] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0067] In some embodiments, R2 is deuterium, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, or -NHCONH2.

[0068] In some embodiments, R2 is -NH2.

[0069] In some embodiments, n2 is 1 and R2 is -NH2.

[0070] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0071] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0072] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0073] In some embodiments, R4 is hydrogen, deuterium, 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 or halogen.

[0074] In some embodiments, R4 is hydrogen, deuterium, C 1-3 Alkyl, fluorinated C 1-3 Alkyl, C 1-3 Alkoxy, fluorinated C 1-3 Alkoxy, -COC 1-3 Alkyl, -COOC 1-3 Alkyl or halogen.

[0075] In some embodiments, R4 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, monofluoropropoxy, difluoropropoxy, trifluoropropoxy, -COCH3, -COOCH3, fluorine, or chlorine.

[0076] In some embodiments, R4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, -C(O)CH3, or fluoro.

[0077] In some embodiments, n4 is 1, and R4 is methyl, ethyl, n-propyl, isopropyl, -C(O)CH3, or fluoro.

[0078] In some embodiments, R4 is methyl or isopropyl.

[0079] In some embodiments, n4 is 1 and R4 is methyl or isopropyl.

[0080] In some embodiments, n3 is 0.

[0081] In some embodiments, n5 is 0.

[0082] In some embodiments, R3, R4, and R5 are each independently hydrogen, deuterium, fluorine, chlorine, or C 1-3 alkyl.

[0083] In some embodiments, the structure Select from the following structures:

[0084] In some embodiments, the structure Select from the following structures:

[0085] In some embodiments, the structure Select from the following structures:

[0086] In some embodiments, ring A is a piperidine ring, a tetrahydropyrrole ring or an azetidine ring; preferably, ring A is an azetidine ring; ring C is a benzene ring or a pyridine ring, preferably, ring C is a benzene ring; Y1 is -CH2-, -O-, -SO2-, -CH=CH-, -NH- or -C(O)-; preferably, Y1 is -CH2-; Y2 is a bond, -CH2-, -NH-, -C(O)- or -O-; preferably, Y2 is -CH2- or -NH-; Y3 is a bond or -NH-; preferably, Y3 is a bond; Y4 is a bond; n3 is 0; n4 is 0, 1 or 2, and R4 is C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy or -C(O)C 1-6 Alkyl; preferably, R4 is methyl, ethyl, n-propyl, isopropyl or -C(O)CH3; n5 is 0; L, ULM are as described in the specification.

[0087] In some embodiments, the compound of formula (II) is represented by formula (III):

[0088] Among them, R3, R4, R5, n3, n4, n5, Y1, Y2, Y3, Y4, L, and ULM are as described in the specification.

[0089] In some embodiments, the compound of formula (II) is represented by formula (IV):

[0090] Among them, (R4) n4 represents n4 R4, n4 is 1 or 2, each R4 is the same or different, and each independently represents hydrogen, deuterium, fluorine, chlorine or C 1-3 Alkyl; L, ULM are as described in the specification.

[0091] In some embodiments, the compound represented by formula (II) is selected from the following structures:

[0092] wherein n4 is 1 or 2, each R4 is the same or different and is independently hydrogen, deuterium, fluorine, chlorine or C 1-3 Alkyl; L, ULM are as described in the specification.

[0093] In some embodiments, the compound represented by formula (II) is selected from the following structures:

[0094] Wherein, L and ULM are as described in the specification.

[0095] In some embodiments, the compound represented by formula (II) is represented by formula (V):

[0096] Among them, R1, n1, R4, n4, Y1, Y2, Y3, Y4, L, and ULM are as described in the specification.

[0097] In some embodiments, the compound represented by formula (II) is selected from the following structures:

[0098] Among them, R1, n1, R4, n4, Y1, Y2, Y3, Y4, L, and ULM are as described in the specification.

[0099] In some embodiments, L is a structure represented by formula (L-1) or an isomer thereof,

[0100] -(L1) m1 -(X1) p1 -(L2) m2 -(X2) p2 -(L3) m3 -(X3) p3 -(L4) m4 -(X4) p4 -,

[0101] (L-1)

[0102] Wherein, m1, m2, m3, m4, p1, p2, p3, p4 are each independently 0, 1 or 2;

[0103] L1, L2, L3, L4 are each independently selected from C3-15 Cycloalkyl ring (preferably C 3-10 Cycloalkyl ring, more preferably C 3-7 Cycloalkyl ring, more preferably C 3-6 cycloalkyl ring), 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), a 5- to 6-membered heteroaryl ring, a C 6-10 Aromatic ring (preferably a benzene ring); wherein the C 3-15 Cycloalkyl ring, 3 to 15 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring, C 6-10 The aromatic ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxyl, carboxyl, oxo, -NR a2 R b2 、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), -SC 1-10 Alkyl (preferably -SC 1-8 Alkyl, more preferably -SC 1-6 Alkyl, more preferably -SC 1-3 Alkyl), -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), 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 1-8Alkyl, 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), -CO2C 1-10 Alkyl (preferably -CO2C 1-8 Alkyl, more preferably -CO2C 1-6 Alkyl, more preferably -CO2C 1-3 Alkyl), C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl or C 6-10 Aryl (preferably phenyl);

[0104] X1, X2, X3, X4 are each independently selected from a bond, C 2-4 Alkynylidene, C 2-4 Alkenylene, 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(O)-, -O-, -N(R L1 )-, -S-, -S(O)-, -SO2-, -P(O)-, -P(O)O-, -C(O)O-, -OC(O)-, -N(R L1 )C(O)-、-C(O)N(R L1 )-、-N(R L1 )C(O)N(R L1 )-、-N(R L1 )S(O)- and -N(R L1 )SO2-; wherein, the C 2-4 Alkynylidene, C 2-4 Alkenylene, C 1-10 Alkylene, C 1-10 Each alkyleneoxy group is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, C 3-6 Cycloalkyl (preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), 3- to 6-membered heterocycloalkyl, hydroxy, carboxyl, -NR a2 R b2 、C1-6 Alkyl (preferably C 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), -SOC 1-6 Alkyl (preferably -SOC 1-3 Alkyl), -SO2C 1-6 Alkyl (preferably -SO2C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably halogenated C 1-3 Alkoxy), -COC 1-6 Alkyl (preferably -COC 1-3 Alkyl), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 Alkyl), -CO2C 1-6 Alkyl (preferably -CO2C 1-3 alkyl), 5- to 6-membered heteroaryl or C 6-10 Aryl (preferably phenyl);

[0105] R L1 Each occurrence is independently hydrogen, deuterium, 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 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl;

[0106] R a2 、R b2 Each independently represents hydrogen, deuterium, C 1-6 Alkyl (preferably C 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) or -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl); or R a2 、R b2and the nitrogen atom connected thereto together form a 3- to 10-membered heterocycloalkyl group (preferably a 3- to 8-membered heterocycloalkyl group, more preferably a 3- to 6-membered heterocycloalkyl group); the 3- to 10-membered heterocycloalkyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, -NH2, 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 (preferably halogenated C 1-3 Alkoxy), -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), -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 Alkyl), -NHC 1-6 Alkyl (preferably -NHC 1-3 Alkyl), -N(C 1-6 Alkyl)2(preferably -N(C 1-3 Alkyl)2), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 1-3 Alkyl), cyano-substituted C 1-6 Alkyl (preferably cyano-substituted C 1-3 Alkyl), -CONHC 1-6 Alkyl, -CON(C 1-6 alkyl)2 and -CONH2.

[0107] In some embodiments, X1, X2, X3, and X4 are each independently selected from a bond, C 2-4 Alkynylidene, C 2-4 Alkenylene, C 1-6 Alkylene, C 1-6 Alkyleneoxy, -C(O)-, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -N(CH2CH2Cl)-, -N(CH2CH2F)-, -S-, -S(O)-, -SO2-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)- and -NHSO2-; wherein, the C 2-4 Alkynylidene, C 2-4Alkenylene, C 1-6 Alkylene, C 1-6 Each alkyleneoxy radical is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, hydroxyl, carboxyl, -NH2, -NHCOCH3, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, -SC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -COC 1-3 Alkyl, -CO2C 1-3 alkyl, 5- to 6-membered heteroaryl, and phenyl.

[0108] In some embodiments, X1, X2, X3, X4 are each independently selected from a bond, C 2-4 Alkynylidene, C 2-4 Alkenylene, C 1-6 Alkylene, C 1-6 Alkyleneoxy, -C(O)NH-, -C(O)-, -O-, -NH-, and -S-.

[0109] In some embodiments, X1, X2, X3, X4 are each independently selected from a bond, C 2-4 Alkynylidene, C 2-4 Alkenylene, C 1-3 Alkylene, C 1-3 Alkyleneoxy, -C(O)-, -O-, -NH-, and -S-.

[0110] In some embodiments, X1, X2, X3, and X4 are each independently selected from a bond, ethenylene, propenylene, butenylene, ethynylene, propynylene, butynylene, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2O-, -(CH2)2O-, -(CH2)3O-, -C(O)-, -C(O)NH-, -O-, -NH-, -N(CH3)-, and -S-.

[0111] In some embodiments, X1, X2, X3, and X4 are each independently selected from a bond, -NH-, -O-, -C(O)-, -(CH2)4-, -(CH2)3-, -(CH2)2-, -CH2-, and -C(O)NH-.

[0112] In some embodiments, X1, X2, X3, and X4 are each independently selected from a bond, -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)5-, -C(O)NH-, or -O-.

[0113] In some embodiments, X1, X2, X3, and X4 are each independently selected from a bond, -C(O)-, -O-, -CH2-, and -CH2CH2-.

[0114] In some embodiments, said L1, L2, L3, L4 are each independently selected from C 3-15 Cycloalkyl ring (preferably C 3-10 Cycloalkyl ring, more preferably C 3-7 Cycloalkyl ring, more preferably C 3-6 cycloalkyl ring), 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), a 5- to 6-membered heteroaryl ring, a C 6-10 Aromatic ring (preferably a benzene ring); wherein the C 3-15 Cycloalkyl ring, 3 to 15 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring, C 6-10 The aromatic ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxyl, carboxyl, -NR a2 R b2 、C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, -SC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -CO2C 1-3 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl or phenyl.

[0115] In some embodiments, the C 3-15 The cycloalkyl ring is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, cycloheptene, cycloheptadiene, cycloheptatriene, spiro[2.4]heptane, spiro[3.4]octane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, dispiro[5.2.5] 9 .2 6 ]hexadecane and spiro[3.3]heptane.

[0116] In some embodiments, the 3- to 15-membered heterocycloalkyl ring is a heterocycle containing 0, 1, 2, or 3 heteroatoms, wherein the heteroatoms are O, S, -S(O)-, -SO2-, or N.

[0117] In some embodiments, the 3- to 15-membered heterocycloalkyl ring is selected from an aziridine ring, an oxirane ring, an azetidine ring, an oxetane ring, an oxazolidine ring, a 1,3-dioxolane ring, a dioxane ring, an imidazolidine ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide ring, a tetrahydropyran ring, a 1,2-dihydroazetidine ring, a 1,2-dihydrooxetadiene ring, a 2,5-dihydro-1H-pyrrole ring, a 2,5-dihydrofuran ring, a 2,3-dihydrofuran ring, a 2,3-dihydro-1H-pyrrole ring, a 3,4- dihydro-2H-pyran ring, 1,2,3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 1,3-oxazinyl ring, hexahydropyrimidine ring, 1,4-dioxanyl ring, 1,4-oxazacycloheptane ring, 1,3-oxazacycloheptane ring, 2-oxa-6-azaspiro[3.3]heptane ring, 1-azaspiro[2.4]heptane ring, 2-azaspiro[3.4]octane ring, 2-azaspiro[4.4]nonane ring, 8-azacyclo[4.5]decanyl ring, 2-azaspiro[3.3]heptane ring, 3-azaspiro[5.5]undecane ring, 3-azadispiro[5.2.5 9 .2 6 ] hexadecyl ring, 2,6-diazaspiro[3.3]heptyl ring, 3,9-diazaspiro[5.5]undecyl ring, 3,12-diazadispiro[5.2.5 9 .2 6 ]hexadecyl ring, 3,6-diazabicyclo[3.1.1]heptyl ring, 3,8-diazabicyclo[3.2.1]octyl ring, spiro[3.3]heptyl ring, 2,6-diazaspiro[3.3]heptyl ring, octahydropyrrolo[3,4-c]pyrrole ring, octahydrocyclopenta[c]pyrrole ring, 1,2,3,6-tetrahydropyridine ring, 2,5-diazabicyclo[2.2.1]heptyl ring, 3-azabicyclo[3.1.0]hexyl ring, 2,8-diazaspiro[4.5]decane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane and 3,9-diazaspiro[5.5]undecane.

[0118] In some embodiments, the 5- to 6-membered heteroaryl ring is selected from a thiophene ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an isothiazolyl group, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, and a tetrazine ring.

[0119] In some embodiments, L1, L2, L3, and L4 are each independently selected from a piperidine ring, a hydroxy-substituted piperidine ring, a piperazine ring, an azetidine ring, a tetrahydropyrrole ring, a 3,8-diazabicyclo[3.2.1]octyl ring, a pyrimidine ring, a pyridine ring, a benzene ring, a pyrazine ring, a cyclohexyl ring, a cyclobutane ring, a cyclopentane ring, a cyclopropane ring, a 2-azaspiro[3.3]heptane ring, a spiro[3.3]heptane ring, a 2,6-diazaspiro[3 .3]heptyl ring, octahydropyrrolo[3,4-c]pyrrole ring, octahydrocyclopenta[c]pyrrole ring, 1,2,3,6-tetrahydropyridine ring, 2,5-diazabicyclo[2.2.1]heptyl ring, 3-azabicyclo[3.1.0]hexyl ring, biscyclopentyl ring, 2,8-diazaspiro[4.5]decane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane and 3,9-diazaspiro[5.5]undecane.

[0120] In some embodiments, L1, L2, L3, and L4 are each independently a cyclobutane ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, 2-azaspiro[3.3]heptane, 2,8-diazaspiro[4.5]decane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, or 3,9-diazaspiro[5.5]undecane.

[0121] In some embodiments, L1, L2, L3, and L4 are each independently a cyclobutane ring, a piperidine ring, a piperazine ring, or 2-azaspiro[3.3]heptane.

[0122] In some embodiments, L1, L2, L3, and L4 are each independently selected from

[0123] In some embodiments, L1, L2, L3, and L4 are each independently selected from

[0124] In some embodiments, L1, L2, L3, and L4 are each independently selected from

[0125] In some embodiments, L1, L2, L3, and L4 are each independently

[0126] In some embodiments, L1, L2, L3, and L4 are each independently

[0127] In some embodiments, L1, L2, L3, and L4 are each independently

[0128] In some embodiments, said m1, m2, m3, and m4 are each independently 0, 1, or 2, and p1, p2, p3, and p4 are each independently 0, 1, or 2;

[0129] L1 is

[0130] L2 is

[0131] L3 is

[0132] L4 is

[0133] X1 is -CH2-, -NH-, -NHCH2- or -O-;

[0134] X2 is -C(O)-, C 1-6 Alkylene, -O-, -OCH2CH2- or -NH-;

[0135] X3 is -N(CH3CH2)-, -(CH2)2-, -NH-, -O-, -CH2-, propenylene, -(CH2)2O-, -(CH2)3O- or -CO-;

[0136] X4 is -O-, -CH2CH2- or -CH2-.

[0137] In some embodiments, said m1, m2, m3, and m4 are each independently 0 or 1, and p1, p2, p3, and p4 are each independently 0 or 1;

[0138] L1 is

[0139] L2 is

[0140] L3 is

[0141] L4 is

[0142] X1 is -NH- or -O-;

[0143] X2 is -O-, -C(O)-, C 1-6 Alkylene or -NH-;

[0144] X3 is C 1-6 Alkylene or -C(O)-;

[0145] X4 for C 1-6 Alkylene or -O-.

[0146] In some embodiments, m1, m2, and m4 are all 0, m3 is 0 or 1; p1 and p2 are both 1; p3 is 0 or 1; p4 is 0;

[0147] L3 is

[0148] X1 is -NH-;

[0149] X2 is -CH2-, -CO(CH2)2-, -(CH2)2-, -(CH2)3- or -(CH2)4-;

[0150] X3 is -N(CH3CH2)-.

[0151] In some embodiments, m3 is 1, m1, m2, and m4 are all 0, and p1, p2, p3, and p4 are all 0;

[0152] L3 is

[0153] In some embodiments, m3 is 1, m1, m2, and m4 are all 0, p2 is 1 or 2, and p1, p3, and p4 are all 0;

[0154] L3 is:

[0155] X2 is C 1-6 Alkylene or -CO-.

[0156] In some embodiments, m3 is 1, m1, m2, and m4 are all 0, p2 and p3 are all 1 or 2, and p1 and p4 are all 0;

[0157] L3 is

[0158] X2 is C1-6 Alkylene, -C(O)- or -NH-;

[0159] X3 is -O- or -CH2-.

[0160] In some embodiments, m2 and m3 are 1, m1 and m4 are 0, p3 is 0, 1 or 2, and p1, p2, and p4 are all 0;

[0161] L2 is

[0162] L3 is

[0163] X3 is C 1-6 Alkylene, -O- or -C(O)-.

[0164] In some embodiments, m2 and m3 are 1, m1 and m4 are 0, and p1, p2, p3, and p4 are all 1;

[0165] L2 is

[0166] L3 is

[0167] X1, X2 and X4 are all O;

[0168] X3 is a propenylene group.

[0169] In some embodiments, m2 and m3 are 1, m1 and m4 are 0, p1 is 0, 1 or 2, p2 is 1 or 2, and p3 and p4 are 0, 1 or 2;

[0170] L2 is:

[0171] L3 is

[0172] X1 is -CH2- or -NH-;

[0173] X2 is -O-, -CO-, -OCH2CH2-, -CH2- or -NH-;

[0174] X3 is -CO- or -(CH2)2-;

[0175] X4 is -CO- or -(CH2)2-.

[0176] In some embodiments, m2 and m3 are 1, m1 and m4 are 0, p1, p2, and p3 are 1, and p4 is 0;

[0177] L2 is

[0178] L3 is

[0179] L4 is

[0180] X1 and X2 are each independently -O-, -(CH2)2O- or -CO-;

[0181] X3 is -CH2-, -(CH2)2O- or -(CH2)3O-.

[0182] In some embodiments, m2, m3, and m4 are 1, m1 is 0, p1, p2, and p3 are 1, and p4 is 0;

[0183] L2 is:

[0184] L3 is:

[0185] L4 is:

[0186] X1 is -O- or -NH-;

[0187] X2 is -O-, -CH2- or -CO-;

[0188] X3 is -O-, -CO-, -CH2- or -(CH2)2-.

[0189] In some embodiments, m2, m3, and m4 are 1, m1 is 0, p1 and p3 are 1, p2 is 0 or 1, and p4 is 0;

[0190] L2 is

[0191] L3 is

[0192] L4 is

[0193] X1 is -CH2- or -NH-;

[0194] X2 is -CH2- or -O-;

[0195] X3 is -CH2- or -CO-.

[0196] In some embodiments, m2, m3, and m4 are 1, m1 is 0, p2, p3, and p4 are 1, and p1 is 0 or 1;

[0197] L2 is

[0198] L3 is

[0199] L4 is

[0200] X1 is -O-;

[0201] X2 is -CO- or -CH2-;

[0202] X3 is -O-;

[0203] X4 is -CH2- or -CH2CH2-.

[0204] In some embodiments, L is selected from the following structures or isomers thereof:

[0205] In some embodiments, L is selected from the following structures or isomers thereof:

[0206] In some embodiments, L is selected from the following structures or isomers thereof:

[0207] In some embodiments, L is selected from the following structures or isomers thereof:

[0208] In some embodiments, L is selected from the following structures or isomers thereof:

[0209] In some embodiments, L is selected from the following structures or isomers thereof:

[0210] In some embodiments, L is selected from the following structures or isomers thereof:

[0211] In some embodiments, L is selected from the following structures or isomers thereof:

[0212] Among them, X 10 is the connection key between L and POI, X 20 It is the connection key between L and ULM.

[0213] In some embodiments, L is selected from the following structures or isomers thereof:

[0214] In some embodiments, the ULM is a VHL (von Hippel-Lindau) binding (linking) group.

[0215] In some embodiments, the ULM is a structure represented by formula (V-1) or an isomer thereof:

[0216] in,

[0217] U1 is -CONR U7 C(R U5 R U6 )-, -CONHO-, -CONH-, or a substituted or unsubstituted 5- or 6-membered heteroaryl ring;

[0218] R U5 、R U6 Each is independently selected from X, hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), amino, cyano, carboxyl, hydroxyl, -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), -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 alkoxy), or R U5 、R U6 Together with the connected carbon atoms, it forms C 3-7 Cycloalkyl ring, 3 to 7 membered heterocycloalkyl ring; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7The cycloalkyl ring and the 3- to 7-membered heterocycloalkyl ring are each independently unsubstituted or substituted by 1, 2, or 3 substituents selected from the group consisting of halogen (preferably fluorine, chlorine, or bromine), hydroxyl, cyano, carboxyl, amino, C 1-6 Alkyl-substituted amino (preferably C 1-3 Alkyl-substituted amino), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), halogenated C 1-6 Alkoxy (preferably halogenated C 1-3 alkoxy);

[0219] 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;

[0220] D ring is C 6-10 Aromatic ring (preferably a benzene ring), a 5- to 6-membered heteroaryl ring (preferably a pyridine ring, a pyrimidine ring or a pyrazine ring), C 3-10 cycloalkyl ring, 3- to 10-membered heterocycloalkyl ring;

[0221] (R U1 ) r1 represents r1 R U1 , each R U1 The same or different, each independently deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, -NR a3 R b3 、-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONR a4 R b4 、-SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -SC 1-6 alkyl;

[0222] (R U2 )r2 represents r2 R U2 , each R U2 are the same or different and are each independently X, hydrogen, deuterium, halogen (preferably fluorine, chlorine), nitro, cyano, carboxyl, hydroxyl, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 1-6 Alkoxy C 1-6 Alkyl (preferably C 1-3 Alkoxy C 1-3 Alkyl), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 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), -NR a5 R b5 、-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, -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl), -CON(C 1-6 Alkyl)2 (preferably -CON(C 1-3 Alkyl)2), -SOC 1-6 Alkyl (preferably -SOC 1-3 Alkyl), -SO2C 1-6 Alkyl (preferably -SO2C 1-3 Alkyl), -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), C 2-4 Alkenyl, C 2-4 Alkynyl, 5- to 6-membered heteroaryl, C 6-10 Aryl, C 3-10 Cycloalkyl or 3 to 10 membered heterocycloalkyl; wherein said C 2-4 Alkenyl, C 2-4 Alkynyl, 5- to 6-membered heteroaryl, C 6-10 Aryl, C 3-10The cycloalkyl and 3- to 10-membered heterocycloalkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen (preferably fluorine, chlorine), 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), amino-substituted C 1-6 Alkyl (preferably amino substituted C 1-3 Alkyl), cyano-substituted C 1-6 Alkyl (preferably cyano-substituted C 1-3 Alkyl), carboxyl substituted C 1-6 Alkyl (preferably carboxyl 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, -NH(C 1-6 Alkyl) (preferably -NH(C 1-3 Alkyl)), -N(C 1-6 Alkyl)2(preferably -N(C 1-3 Alkyl)2), -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 Alkyl), -COC 1-6 Alkyl (preferably -COC 1-3 Alkyl), -COOC 1-6 Alkyl (preferably -COOC 1-3 Alkyl), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 alkyl), -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 1-6Alkyl (preferably -SC 1-3 alkyl);

[0223] W1 is selected from the following structures: X, -NHCO-X, -NHCOCH3,

[0224] R W1 、R W2 are each independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), 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) and halogenated C 1-6 Alkoxy (preferably halogenated C 1-3 alkoxy);

[0225] R U3 、R U4 are independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, -NR a3 R b3 、-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONR a4 R b4 、-SOC 1-6 Alkyl, -SO2C 1-6 Alkyl and -SC 1-6 Alkyl; or R U3 、R U4 Together with the carbon atom to which it is connected, it forms C 3-7 Cycloalkyl ring, 3 to 7 membered heterocycloalkyl ring; wherein, the C 3-7 The cycloalkyl ring and the 3- to 7-membered heterocycloalkyl ring are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C1-3 Alkoxy), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably halogenated C 1-3 Alkoxy), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 1-3 Alkyl), cyano-substituted C 1-6 Alkyl (preferably cyano-substituted C 1-3 Alkyl), carboxyl substituted C 1-6 Alkyl (preferably carboxyl substituted C 1-3 Alkyl), amino-substituted C 1-6 Alkyl (preferably amino substituted C 1-3 Alkyl), -NR a3 R b3 、-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), -CONR a4 R b4 、-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);

[0226] R a3 、R b3 Each independently represents hydrogen, deuterium, C 1-6 Alkyl (preferably C 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), -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl) or -CONH2; or R a3 、R b3Together with the nitrogen atom, it forms a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring); the 3- to 10-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the following: hydrogen, hydroxy, cyano, halogen, -NH2, 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 (preferably halogenated C 1-3 Alkoxy), -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), -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 Alkyl), -NHC 1-6 Alkyl (preferably -NHC 1-3 Alkyl), -N(C 1-6 Alkyl)2(preferably -N(C 1-3 Alkyl)2), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 1-3 Alkyl), cyano-substituted C 1-6 Alkyl (preferably cyano-substituted C 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);

[0227] R a4 、R b4 Each independently is hydrogen, deuterium or C 1-6 Alkyl (preferably C 1-3 alkyl); or R a4 、R b4 Together with the nitrogen atom, it forms a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring); the 3- to 10-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the following: hydrogen, hydroxy, cyano, halogen, -NH2, C 1-6 Alkyl (preferably C1-3 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), -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), -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 Alkyl), -NHC 1-6 Alkyl (preferably -NHC 1-3 Alkyl), -N(C 1-6 Alkyl)2(preferably -N(C 1-3 Alkyl)2), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 1-3 Alkyl), cyano-substituted C 1-6 Alkyl (preferably cyano-substituted C 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);

[0228] R a5 、R b5 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), -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl), -CON(C 1-6Alkyl)2 (preferably -CON(C 1-3 alkyl) 2), 5 to 6 membered heteroaryl and C 6-10 Aryl; wherein the 5 to 6 membered heteroaryl, the C 6-10 Each aryl group is independently unsubstituted or substituted with 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), -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl), -CON(C 1-6 Alkyl)2 (preferably -CON(C 1-3 Alkyl)2), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 alkyl);

[0229] r1 and r2 are each independently 0, 1, 2 or 3;

[0230] X is the connecting bond between ULM and L, and U1, R U2 , any structure of W1 contains X.

[0231] In some embodiments, U1 is -CONHC(R U5 R U6 )-.

[0232] In some embodiments, the ULM is a structure represented by formula (V-3) or an isomer thereof:

[0233] Among them, D ring, R U1 、R U2 、R U3 、R U4 、R U5 、R U6 , r2, W1 are as described in the instructions.

[0234] In some embodiments, W1 is selected from the following structures: X, -NHCO-X, -NHCOCH3,

[0235] In some embodiments, W1 is -NHCO-X.

[0236] In some embodiments, W1 is

[0237] In some embodiments, W1 is selected from the following structures:

[0238] In some embodiments, R U1 For hydroxyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, -SC 1-3 Alkyl or -OCOC 1-3 alkyl.

[0239] In some embodiments, R U1 It is hydroxy, -OCH3, -SCH3, -OCF3, -CH3, -CF3 or -OCOCH3.

[0240] In some embodiments, R U1 It is a hydroxyl group.

[0241] In some embodiments, R U2 is thiazole, oxazole, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, benzene ring, tetrazole or triazole, and the thiazole, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, benzene ring, tetrazole, triazole are each independently 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, -SC 1-3 alkyl.

[0242] In some embodiments, R U2Selected from the following structures: cyano, nitro, -NR a5 R b5 、

[0243] Among them, R Ua 、R Ub 、R Uc 、R Ud 、R Ue 、R Uf Each independently selected from deuterium, halogen (preferably fluorine, chlorine, bromine), amino, amino-substituted C 1-3 Alkyl, C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -SC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 alkyl;

[0244] t1, t2, t3, t4, t5, and t6 are each independently 0, 1, or 2;

[0245] R a5 、R b5 As described in the instructions.

[0246] In some embodiments, R U2 -NR a5 R b5 , where R a5 、R b5 is a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is thiazole, imidazole, pyrazole, oxazole, pyridine or pyrimidine; the 5- to 6-membered heteroaryl 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 or -OCOC 1-3 alkyl.

[0247] In some embodiments, R U2 NHR a5 , where R a5is a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is thiazole, imidazole, pyrazole, oxazole, pyridine or pyrimidine; the 5- to 6-membered heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -SC 1-6 Alkyl or -OCOC 1-6 alkyl.

[0248] In some embodiments, R U2 NHR a5 , where R a5 is a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is thiazole, imidazole, pyrazole, oxazole, pyridine or pyrimidine; the 5- to 6-membered heteroaryl 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 or -OCOC 1-3 alkyl.

[0249] In some embodiments, r2 is 1, R U2 -NR a5 R b5 、 Among them, R a5 、R b5 Each independently represents hydrogen, thiazole, wherein the thiazole is unsubstituted or substituted with 1 C 1-3 Alkyl, halogenated C 1-3 Alkyl substituted; t1 is 1, R Ua C 1-3 Alkyl, halogenated C 1-3 Alkyl or amino; t6 is 1, R Uf C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0250] In some embodiments, r2 is 1, R U2 For cyano, Among them, t1 is 1, R Ua C 1-3 Alkyl, halogenated C 1-3 Alkyl or amino; t3 is 2, R Uc C 1-3 Alkyl or halogenated C 1-3 Alkyl; t4 is 1, R Ud C 1-3 Alkyl or halogenated C1-3 alkyl.

[0251] In some embodiments, r2 is 1, R U2 for Among them, t1 is 1, R Ua C 1-3 Alkyl, amino or halogenated C 1-3 alkyl.

[0252] In some embodiments, r2 is 1, R U2 for Among them, t1 is 2, R Ua Selected from methyl, isopropyl, amino.

[0253] In some embodiments, R U2 Selected from the following structures: cyano,

[0254] In some embodiments, r2 is 1, R U2 for

[0255] In some embodiments, r2 is 1, R U2 For cyano,

[0256] In some embodiments, r2 is 1, R U2 for

[0257] In some embodiments, r2 is 2, R U2 X and Wherein, X is the bond connecting ULM and L.

[0258] In some embodiments, R U3 、R U4 are independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, -NH2, -NHCOC 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -CONH2, -NHCONH2, -CONHC 1-3Alkyl, -NHCONHC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, -SC 1-6 Alkyl; or R U3 、R U4 Together with the carbon atom to which it is connected, it forms a saturated C 3-7 Cycloalkyl ring, saturated 3- to 7-membered heterocycloalkyl ring.

[0259] In some embodiments, R U3 、R U4 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino substituted C 1-6 Alkyl, -NHCOC 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -CONHC 1-3 Alkyl, -NHCONHC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, -SC 1-6 Alkyl; or R U3 、R U4 Together with the carbon atom to which it is attached, it forms a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.

[0260] In some embodiments, R U3 、R U4 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or R U3 、R U4 The carbon atom to which it is connected forms a C 3-6 Cycloalkyl ring.

[0261] In some embodiments, R U3 、R U4 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0262] In some embodiments, R U3 、R U4 are each independently selected from hydrogen, C 1-3 Alkyl, halogenated C 1-3 alkyl.

[0263] In some embodiments, R U3 、R U4 are each independently hydrogen, -CH3, -CF3, -CHF2, -CH2F, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCF3, -OCHF2, -OCH2F, -OCH(CH3)2, -OC(CH3)3, fluoroisopropyl or fluorotert-butyl; or R U3 、R U4 Together with the carbon atom to which it is attached, it forms a cyclopropyl ring.

[0264] In some embodiments, R U3 、R U4 Each independently represents hydrogen, -CH(CH3)2, -CH2CH3 or -C(CH3)3; or R U3 、R U4 Together with the carbon atom to which it is attached, it forms a cyclopropyl ring.

[0265] In some embodiments, R U3 、R U4 are each independently hydrogen, -C(CH3)3 or -CH(CH3)2; or R U3 、R U4 The carbon atom to which it is attached forms a cyclopropyl ring.

[0266] In some embodiments, R U3 、R U4 Each is independently hydrogen, -CH(CH3)2 or -CH2CH3.

[0267] In some embodiments, R U3 、R U4 Each is independently hydrogen or -C(CH3)3.

[0268] In some embodiments, the D ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a cycloalkyl ring, a piperidine ring, a piperazine ring, a pyrrole ring, or 2,3-dihydro-1H-indene.

[0269] In some embodiments, the D ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, or 2,3-dihydro-1H-indene.

[0270] In some embodiments, the D ring is a benzene ring, a pyridine ring, or 2,3-dihydro-1H-indene.

[0271] In some embodiments, R U5 、R U6 are each independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), amino, cyano, carboxyl, hydroxyl, -NHCOC1-6 Alkyl, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONH2, -NHCONH2, -CONHC 1-6 Alkyl, -NHCONHC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SC 1-6 Alkyl, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 alkoxy), or R U5 、R U6 Together with the connected carbon atoms, it forms C 3-7 Cycloalkyl ring, 3 to 7 membered heterocycloalkyl ring; the C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 3-7 The cycloalkyl ring and the 3- to 7-membered heterocycloalkyl ring are each independently unsubstituted or substituted by 1, 2, or 3 substituents selected from the group consisting of halogen (preferably fluorine, chlorine, or bromine), hydroxyl, cyano, carboxyl, amino, C 1-3 Alkyl-substituted amino, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy.

[0272] In some embodiments, R U5 、R U6 Each is independently X, hydrogen, deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, -NH2, amino substituted C 1-6 Alkyl, -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 1-3Alkyl, -SO2C 1-3 Alkyl or -SC 1-6 Alkyl, wherein X is the bond connecting ULM and L.

[0273] In some embodiments, R U5 、R U6 are independently 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.

[0274] In some embodiments, R U5 、R U6 are independently hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0275] In some embodiments, R U5 、R U6 Each is independently hydrogen, -OCH3, -SCH3, -OCH2F, -OCHF2, -OCF3, -CH3, -CH2CH3, -CF3, -CHF2 or -CH2F.

[0276] In some embodiments, R U5 、R U6 Each is independently hydrogen, -OCH3, -SCH3, -OCF3, -CF3, -CHF2, -CH2F, -OCHF2, -OCH2F or -CH3.

[0277] In some embodiments, R U5 、R U6 Each is independently hydrogen, -CH3 or -CH2CH3.

[0278] In some embodiments, R U5 、R U6 are each independently hydrogen or -CH3.

[0279] In some embodiments, R U7 is hydrogen, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0280] In some embodiments, R U7 For hydrogen.

[0281] In some embodiments, R U7 , and R U7 The connected nitrogen atoms, R U6 and R U6The connected carbon atoms together form a 4- to 6-membered heterocycloalkyl ring or a 5- to 6-membered heteroaryl ring.

[0282] 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 or a pyrimidine ring.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0287] Wherein, X is the bond connecting ULM and L;

[0288] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0289] Wherein, X is the bond connecting ULM and L.

[0290] In some embodiments, the structure Selected from the following structures or isomers thereof:

[0291] Wherein, X is the bond connecting ULM and L.

[0292] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0293] Wherein, X is the bond connecting ULM and L.

[0294] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0295] Wherein, X is the connecting bond between ULM and L.

[0296] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0297] Wherein, X is the connecting bond between ULM and L.

[0298] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0299] Wherein, X is the bond connecting ULM and L.

[0300] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0301] Wherein, X is the bond connecting ULM and L.

[0302] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0303] Wherein, X is the bond connecting ULM and L.

[0304] In some embodiments, the ULM is selected from the following structures or isomers thereof:

[0305] Wherein, X is the bond connecting ULM and L.

[0306] In some embodiments, the compound of formula (II) is a specific compound selected from the Examples of the present invention.

[0307] In some embodiments, the compound of formula (II) is selected from the following compounds or stereoisomers thereof:

[0308] In some embodiments, the compound of formula (II) is selected from the following compounds or stereoisomers thereof:

[0309] The second aspect of the present invention provides a pharmaceutical composition comprising the compound represented by the above formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

[0310] The third aspect of the present invention provides the use of the compound represented by formula (II) described in the first aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a drug for treating diseases related to BRM (SMARCA2 gene editing) activity.

[0311] In some embodiments, the disease associated with BRM (SMARCA2 gene editing) activity is cancer.

[0312] In some embodiments, the various disorders associated with BRM activity are diseases associated with SMARCA4 mutations.

[0313] In some embodiments, the disease associated with SMARCA4 mutation is a disease caused by abnormal cell proliferation or hyperproliferation.

[0314] In some embodiments, the disease associated with SMARCA4 mutation is cancer.

[0315] In some embodiments, the cancer is non-small cell lung cancer, skin cancer, esophageal / gastric cancer, colon adenocarcinoma, or head and neck squamous cell carcinoma.

[0316] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is used in the preparation of a drug for treating cancer.

[0317] The fourth aspect of the present invention provides the use of the pharmaceutical composition described in the second aspect in the preparation of a drug for treating diseases related to BRM (SMARCA2 gene editing) activity.

[0318] In some embodiments, the disease associated with BRM (SMARCA2 gene editing) activity is cancer.

[0319] The fifth aspect of the present invention provides a method for treating a disease associated with BRM (SMARCA2 gene editing) activity, comprising administering to a patient a therapeutically effective amount of a compound of formula (II) according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to the second aspect of the present invention.

[0320] In some embodiments, the disease associated with BRM (SMARCA2 gene editing) activity is a disease associated with SMARCA4 mutation.

[0321] In some embodiments, the disease associated with SMARCA4 mutation is a disease caused by abnormal cell proliferation or hyperproliferation.

[0322] In some embodiments, the disease associated with SMARCA4 mutation is cancer.

[0323] In some embodiments, the cancer associated with a SMARCA4 mutation is a SMARCA4-deficient cancer or a cancer in which SMARCA4 expression is reduced relative to normal SMARCA4 expression.

[0324] In some embodiments, the cancer is non-small cell lung cancer, skin cancer, esophageal / gastric cancer, colon adenocarcinoma, or head and neck squamous cell carcinoma.

[0325] In some embodiments, a method for treating a disease caused by abnormal or excessive cell proliferation comprises administering to a patient a therapeutically effective amount of the compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the composition of the second aspect of the invention.

[0326] In some embodiments, the disease caused by abnormal or excessive cell proliferation is cancer.

[0327] In some embodiments, the cancer is non-small cell lung cancer, skin cancer, esophageal / gastric cancer, colon adenocarcinoma, or head and neck squamous cell carcinoma.

[0328] The sixth aspect of the present invention provides a compound of formula (N-1), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0329] wherein the NA ring is a 4- to 8-membered heterocycloalkyl ring (preferably a 4- to 6-membered heterocycloalkyl ring);

[0330] Z1, Z2, Z3, and Z4 are each independently a bond, -CH2-, -CH=CH-, -C(O)-, -NH-, -O-, -S-, -SO-, or -SO2-;

[0331] The NC ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring;

[0332] (R n1 ) q1 Indicates that the hydrogen on the NA ring is replaced by q1 R n1 Substitution, q1 is 0, 1, 2, 3 or 4, each R n1 the same or different, each independently selected from hydrogen, an amino protecting group (preferably -Boc, -Cbz, -Fomc), -C(O)C 1-6 Alkyl and oxo groups;

[0333] (R n2 ) q2 Indicates that the hydrogen on the NB ring is replaced by q2 R n2 Substitution, q2 is 0, 1, 2, 3 or 4, each R n2 The same or different, each independently selected from halogen (preferably fluorine, chlorine or bromine), oxo, hydroxy, carboxyl, amino, C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 1-6 Alkyl (preferably C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably halogenated C 1-3 Alkoxy), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 alkyl), -C(O)C 1-6 Alkyl (preferably -C(O)C 1-3 alkyl), -C(O)OC 1-6 Alkyl (preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-6 Alkyl (preferably -OC(O)C 1-3 Alkyl), C 3-6 Cycloalkyl, mesylate (-OMs), p-toluenesulfonate (-OTs), and amino protecting groups;

[0334] (R n3 ) q3 Indicates that the hydrogen on the NC ring is replaced by q3 R n3 substituted, q3 is 0, 1, 2, 3 or 4, each R n3 The same or different, each independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, carboxyl, amino, carboxyl, C 1-6 Aldehyde group (preferably C 1-3 Aldehyde), C 2-4 Ketone, C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 1-6 Alkyl (preferably C 1-3 Alkyl), -COC 1-6 Alkyl (preferably -COC1-3 Alkyl), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 Alkyl), -COOC 1-6 Alkyl (preferably -COOC 1-3 alkyl), -CONH2, -SO2NH2, -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 alkyl), 4,4,5,5-tetramethyl-1,3,2-dioxaboryl and -SO2C 1-6 Alkyl (preferably -SO2C 1-3 alkyl); wherein the C 1-6 Alkyl, C 1-6 Alkoxy, -COC 1-6 Alkyl, -OCOC 1-6 Alkyl, -COOC 1-6 Alkyl, -NHCOC 1-6 Alkyl, -SO2C 1-6 Each alkyl group is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen (preferably fluorine, chlorine, bromine), cyano or carboxyl.

[0335] In some embodiments, the NA ring is selected from a piperidine ring, a piperazine ring, a hexahydropyrimidine ring, a tetrahydropyrrole ring, a 1,4-dihydropyridine ring, a tetrahydropyrazine ring, an azetidine ring, and a tetrahydropyridine ring.

[0336] In some embodiments, the NA ring is an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a hexahydropyrimidine ring, or a piperazine ring.

[0337] In some embodiments, the NA ring is an azetidine ring.

[0338] In some embodiments, the NA ring is a piperidine ring.

[0339] In some embodiments, the NC ring is a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an isothiazole ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, or a tetrazine ring.

[0340] In some embodiments, the NC ring is a benzene ring, a pyridine ring, a pyrazine ring, a pyridazine ring, or a pyrimidine ring.

[0341] In some embodiments, the NC ring is a benzene ring or a pyridine ring.

[0342] In some embodiments, Z1 and Z2 are a bond, and Z3 and Z4 are each independently -C(O)-, -NH-, -O-, -S-, -SO-, or -SO2-.

[0343] In some embodiments, Z1 and Z2 are a bond, Z3 is -CH2-, and Z4 are each independently -C(O)-, -NH-, -O-, -S-, -SO-, or -SO2-.

[0344] In some embodiments, Z1 and Z2 are a bond, Z4 is -CH2-, and Z3 are each independently -C(O)-, -NH-, -O-, -S-, -SO-, or -SO2-.

[0345] In some embodiments, Z1 is a bond; Z2 is a bond or NH; preferably, Z2 is a bond; Z3 is -CH2-, -O-, -SO2-, -CH=CH-, or -C(O)-; preferably, Z3 is -CH2-; Z4 is a bond, -CH2-, -NH-, -C(O)-, or -O-; preferably, Z4 is -CH2- or -NH-.

[0346] In some embodiments, Z1, Z2, and Z3 are each independently a bond, and Z4 is -CH=CH-.

[0347] In some embodiments, Z1 and Z2 are each independently a bond, and Z3 and Z4 are both -CH2-.

[0348] In some embodiments, Z1 and Z2 are each independently a bond, Z3 is -CH2-, and Z4 is -NH-.

[0349] In some embodiments, Z1 and Z2 are each independently a bond, Z3 is -C(O)-, and Z4 is -NH-.

[0350] In some embodiments, Z1 and Z2 are each independently a bond, Z3 is -CH2-, and Z4 is -O-.

[0351] In some embodiments, Z1 and Z2 are each independently a bond, Z3 is -SO2-, and Z4 is -NH-.

[0352] In some embodiments, Z1 is a bond, Z2 is -O-, Z3 is -C(O)-, and Z4 is -NH-.

[0353] In some embodiments, Z1 and Z2 are each independently a bond, Z3 and Z4 are both -CH2-, and the NC ring is a pyridine ring.

[0354] In some embodiments, Z1, Z2, and Z3 are each independently a bond, Z4 is -CH=CH-, and the NC ring is a pyridine ring.

[0355] In some embodiments, Z1 and Z2 are each independently a bond, Z3 is -CH2-, Z4 is -NH-, and the NC ring is a benzene ring.

[0356] In some embodiments, Z1 and Z2 are each independently a bond, Z3 and Z4 are both -CH2-, and the NC ring is a benzene ring.

[0357] In some embodiments, R n1 is selected from hydrogen and an amino protecting group.

[0358] In some embodiments, R n1 is selected from hydrogen, -Boc, -Cbz, -Bn and -Fomc.

[0359] In some embodiments, R n2 is selected from halogen (preferably fluorine, chlorine or bromine), oxo, hydroxy, carboxyl, amino, C 1-6 Alkoxy, C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)C 1-6 Alkyl and amino protecting groups.

[0360] In some embodiments, R n2 Selected from C 1-3 Alkyl, fluorinated C 1-3 Alkyl, C 3-6 Cycloalkyl, -C(O)C 1-3 Alkyl, -OC(O)C 1-3 alkyl, 2-(trimethylsilyl)ethoxymethyl, -Boc, -Cbz, -Fomc, and -Bn.

[0361] In some embodiments, R n2 Selected from methyl, ethyl, n-propyl, isopropyl, difluoromethyl, monofluoromethyl, monofluoroethyl, cyclopropane, cyclobutane, -C(O)CH 3、 -C(O)CH2CH3, 2-(trimethylsilyl)ethoxymethyl, -Boc, -Cbz, -Bn, and -Fomc.

[0362] In some embodiments, R n3 Selected from chlorine, bromine, hydroxyl, amino, C 1-3 Alkoxy, hydroxy substituted C 1-3 Alkyl, amino substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl and C 1-3 Aldehyde group.

[0363] In some embodiments, R n3 Selected from chlorine, bromine, hydroxy, amino, methoxy, ethoxy, propoxy, isopropoxy, hydroxymethyl, hydroxyethyl, amino-substituted methyl, amino-substituted ethyl, cyano-substituted methyl, cyano-substituted ethyl, -CH(O)- and -CH2CH(O)-.

[0364] In some embodiments, R n3 is selected from chloro, bromo, hydroxy, amino, -CH2OH and -CH(O).

[0365] In some embodiments, the NA ring is a 4- to 8-membered heterocycloalkyl ring (preferably a 4- to 6-membered heterocycloalkyl ring);

[0366] Z1, Z2, Z3, and Z4 are each independently a bond, -CH2-, -CH=CH-, -C(O)-, -NH-, -O-, -S-, -SO-, or -SO2-;

[0367] (R n2 ) q2 Indicates that the hydrogen on the NB ring is replaced by q2 R n2 Substitution, q2 is 0, 1, 2, 3 or 4, each R n2 The same or different, each independently C 1-6 Alkyl (preferably C 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl (preferably -C(O)C 1-3 alkyl), -OC(O)C 1-6 Alkyl(-OC(O)C 1-3 alkyl), 2-(trimethylsilyl)ethoxymethyl, -Boc, -Cbz, -Fomc, oxo, -OH, -OMs or -OTs;

[0368] The NC ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring;

[0369] (R n1 ) q1 Indicates that the hydrogen on the NA ring is replaced by q1 R n1 Substitution, q1 is 0, 1, 2, 3 or 4, each R n1 The same or different, each independently hydrogen, an amino protecting group (preferably -Boc, -Cbz, -Fomc), -C(O)C 1-3 an alkyl group or an oxo group;

[0370] (R n3 )q3 Indicates that the hydrogen on the NC ring is replaced by q3 R n3 substituted, q3 is 0, 1, 2, 3 or 4, each R n3 The same or different, each independently halogen, hydroxyl, amino, cyano, C 1-6 Alkoxy (preferably C 1-3 Alkoxy), hydroxy substituted C 1-6 Alkyl (preferably C1-3 alkyl substituted with hydroxy), amino substituted C 1-6 Alkyl (preferably amino substituted C 1-3 Alkyl), cyano-substituted C 1-6 Alkyl (preferably cyano-substituted C 1-3 Alkyl), C 1-6 Aldehyde group (preferably C 1-3 aldehyde group).

[0371] In some embodiments, the compound of formula (N-1) is a structure represented by formula (M-1) or an isomer thereof:

[0372] Among them, (R m1 ) s1 Indicates s1 R m1 , s1 is 0, 1, 2, 3 or 4, each R m1 The same or different, each independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, carboxyl, amino, C 1-3 Aldehyde, C 2-4 Ketone, C 1-3 Alkoxy, C 1-3 Alkyl, -COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -CONH2, -SO2NH2, -NHCOC 1-3 Alkyl, 4,4,5,5-tetramethyl-1,3,2-dioxaboryl and -SO2C 1-3 Alkyl; wherein the C 1-3 Alkyl, C 1-3 Alkoxy, COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2C 1-3 Each alkyl group is independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen (preferably fluorine, chlorine, bromine), cyano or carboxyl;

[0373] (R m2 ) s2 Indicates s2 Rm2 , s2 is 0, 1, 2, 3 or 4, each R m2 The same or different, each independently selected from halogen, oxo, hydroxy, carboxyl, amino, C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkoxy and halogenated C 1-3 alkyl;

[0374] R m3 is selected from hydrogen and an amino protecting group;

[0375] Indicates a single bond or a double bond.

[0376] In some embodiments, the compound of formula (N-1) is a structure represented by formula (M-2) or an isomer thereof:

[0377] wherein Z5 and Z6 are each independently -CH-, -CH2-, -NH-, -N-, -O-, -C(O)-, -C(O)O- or -SO2-;

[0378] Z7, Z8, Z9, Z 10 are each independently -CH- or -N-;

[0379] (R m1 ) s1 Indicates that the hydrogen on the F ring is replaced by s1 R m1 Substitution, s1 is 0, 1, 2, 3 or 4, each R m1 The same or different, each independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, carboxyl, amino, C 1-3 Aldehyde, C 2-4 Ketone, C 1-3 Alkoxy, C 1-3 Alkyl, -COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -CONH2, -SO2NH2, -NHCOC 1-3 Alkyl, 4,4,5,5-tetramethyl-1,3,2-dioxaboryl and -SO2C 1-3 Alkyl; wherein the C 1-3 Alkyl, C 1-3 Alkoxy, COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2C 1-3Each alkyl group is independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen (preferably fluorine, chlorine, bromine), cyano or carboxyl;

[0380] (R m2 ) s2 Indicates that the hydrogen on the E ring is replaced by s2 R m2 Substitution, s2 is 0, 1, 2, 3 or 4, each R m2 The same or different, each independently selected from halogen, oxo, hydroxy, carboxyl, amino, C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkoxy and halogenated C 1-3 alkyl;

[0381] R m3 is selected from hydrogen and an amino protecting group;

[0382] Indicates a single bond or a double bond.

[0383] In some embodiments, Z7, Z8, Z9, Z 10 All are CH.

[0384] In some embodiments, Z7 is N, Z8, Z9, Z 10 All are CH.

[0385] In some embodiments, Z 10 is N, and Z7, Z8, and Z9 are all CH.

[0386] In some embodiments, Z9 is N, Z7, Z8, Z 10 All are CH.

[0387] In some embodiments, R m1 Each is independently selected from fluorine, chlorine, bromine, hydroxy, amino, methoxy, ethoxy, -CHO, -CH2OH, -COOC2H5 and 4,4,5,5-tetramethyl-1,3,2-dioxaboryl.

[0388] In some embodiments, R m2 Selected from C 1-6 Alkyl, halogen, -C(O)C 1-6 Alkyl, hydroxy, oxo.

[0389] In some embodiments, R m2 Selected from fluorine, oxo and hydroxy.

[0390] In some embodiments, R m2 Selected from methyl, ethyl, n-propyl, isopropyl, -C(O)CH3.

[0391] In some embodiments, R m3 is selected from hydrogen, -Boc, -Bn and -Cbz.

[0392] In some embodiments, the compound of formula (N-1) is selected from the compounds shown below or stereoisomers thereof:

[0393] In some embodiments, the compound of formula (N-1) is selected from the compounds shown below or stereoisomers thereof:

[0394] The seventh aspect of the present invention provides the use of a compound represented by formula (N-1), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a compound represented by formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described in the first aspect of the present invention.

[0395] In some embodiments, the compound of formula (N-1) is a structure represented by formula (M-1) or an isomer thereof.

[0396] In some embodiments, the compound of formula (N-1) is a structure represented by formula (M-2) or an isomer thereof.

[0397] The eighth aspect of the present invention provides a compound of formula (P-1), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0398] in,

[0399] Ring A, Ring C, Y1, Y2, Y3, Y4, (R1) n1 、(R2) n2 、(R3) n3 、(R4) n4 、(R5) n5 As described in the instructions.

[0400] In some embodiments, the compound of formula (P-1) is selected from the compounds shown below or stereoisomers thereof: DETAILED DESCRIPTION

[0401] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention is further described in detail with reference to the following embodiments. It is apparent that the described embodiments are only a portion of the embodiments of the present invention, rather than all of them. All other embodiments derived by those of ordinary skill in the art based on the embodiments of the present invention are intended to fall within the scope of protection of the present invention.

[0402] After extensive and in-depth research, the inventors unexpectedly discovered a novel bifunctional compound (or PROTAC compound) that has a higher selective degradation effect on BRM (encoded by the SMARCA2 gene) than BRG1 (encoded by the SMARCA4 gene). Based on this, the inventors completed the present invention.

[0403] Definition of terms

[0404] In order to more clearly understand the technical content of the present invention, the terms of the present invention are further explained below.

[0405] PROTAC compounds can be divided into three parts: targeting ligand, linker and E3 ligase linker. In the present invention, the targeting ligand is the part that specifically binds to BRM (SMARCA2 gene editing). That is, the POI in the present invention; the linking group (L) is a compound portion used to connect the targeting ligand and the E3 ligase linking (binding) group, such as shown in the chemical portion of L-1; the E3 ligase linking (binding) group (ULM) is a compound that can bind the E3 ubiquitin ligase to the target protein through the linking (binding) group and the targeting ligand to degrade the target protein through the ubiquitin proteasome system. In this article, the E3 ligase is the von Hippel-Lindau (VHL) tumor suppressor, for example, the compound portions (V-1), (V-3), and (V-5) defined in this article can specifically bind to VHL.

[0406] middle Represents adjacent atom pairs with other atoms.

[0407] "Alkyl" refers to straight-chain and branched saturated aliphatic hydrocarbon groups. 1-8 "Alkyl" refers to an alkyl group having 1 to 8 carbon atoms, 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.

[0408] "Alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C). 2-8 "Alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms, 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.

[0409] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-8 "Alkynyl" refers to an alkynyl group having 2 to 8 carbon atoms, 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.

[0410] "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 -CHCH3, etc. In certain embodiments, C 1-10 Alkylene, more preferably C 1-8 Alkylene, more preferably C1-6 Alkylene, most preferably C 1-3 Alkylene. For example, C 1-3 Alkylene includes -CH2-, -(CH2)2-, -CH(CH3)-, -(CH2)3-, -CH(CH2CH3), -CH2CH(CH3)-, and -C(CH3)2-. In certain embodiments, the alkylene 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. In the absence of any further definition, the generic terms propylene, butylene, pentylene, hexylene, and the like are intended to refer to 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.

[0411] "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.

[0412] "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.

[0413] "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(CH3)3-, -OCH2CH(CH3)-, -OC(CH3)2-, -OCH(CH3)CH2-, -OCH2CH(CH3)O-, -OC(CH3)2O-, and -OCH(CH3)CH2O-.

[0414] "Cycloalkyl", "cycloalkane ring" and "cycloalkyl ring" are used interchangeably and refer to a monocyclic or polycyclic hydrocarbon group, which may be fused to an aryl or heteroaryl group. The cycloalkyl ring may be optionally substituted. In certain embodiments, the cycloalkyl ring is a spirocyclic ring or a bridged ring. In certain embodiments, the cycloalkyl ring contains one or more carbonyl groups, such as an oxo group. "C 3-15"Cycloalkyl" refers to a monocyclic or polycyclic cycloalkyl group having 3 to 15 carbon atoms, such as spiro[4.5]decane, spiro[3.3]heptane, spiro[5.5]undecane, dispiro[5.2.59.26]hexadecane, decahydroazulene, 1,2-diethylcyclopent-1-ene, bicyclo[3.3.2]decane. Preferably C 3-8 Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. are preferred. 3-7 Cycloalkyl, such as cycloheptane, spiro[3.3]heptane, etc., more preferably C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. They may be saturated cycloalkyl groups such as cyclohexyl and cyclopropyl. They may also be partially unsaturated cycloalkyl groups such as cyclohexene and 1,2-diethylcyclopent-1-ene.

[0415] "Heterocycloalkyl", "heterocycloalkane ring" and "heterocycloalkyl ring" are used interchangeably and all refer to a cycloalkyl group comprising 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 optionally substituted. In certain embodiments, the heterocycloalkyl ring is a spiroheterocycle or a bridged heterocycle. In certain embodiments, the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups 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, more preferably a 3 to 7 membered heterocycloalkyl, further more preferably a 3 to 7 membered heterocycloalkyl, and most preferably a 3 to 6 membered heterocycloalkyl. In certain embodiments, the heterocycloalkyl ring is a saturated heterocycloalkyl ring or a partially unsaturated heterocycloalkyl ring. Non-limiting examples of heterocycloalkyl groups include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-onyl, oxetan-2-onyl, dihydrofuran-2(3H)-onyl, pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, dihydrofuran-2,5-dionyl, piperidin-2-onyl, tetrahydro-2H-pyran-2-onyl, piperazin-2-onyl, morpholin-3-onyl, and the like.

[0416] "Spiro" refers to a polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom). These may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spirocycles are classified as bispirocycles or polyspirocycles based on the number of rings, preferably bispirocycles. More preferred are 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bispirocycles. For example:

[0417] 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:

[0418] "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:

[0419] "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:

[0420] "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 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the present invention, heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. The heteroaryl ring may be optionally substituted. "5- to 6-membered heteroaryl" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. Non-limiting examples include thienyl, furyl, 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl. "Heteroatom" refers to nitrogen, oxygen or sulfur. In heteroaryl containing one or more nitrogen atoms, as long as valence allows, the point of attachment can be a carbon or nitrogen atom. Heteroaryl bicyclic system can include one or more heteroatoms in one or two rings.

[0421] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0422] "Halo" refers to a group in which one or more (eg, 1, 2, 3, or all) hydrogen atoms are replaced by halogen.

[0423] "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.

[0424] "Deuterated alkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms, wherein the definition of alkyl is as described above. 1-8 Alkyl, more preferably deuterated C 1-6 Alkyl, more preferably deuterated C 1-3 Examples of deuterated alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, dideuterated ethyl, trideuterated methyl, trideuterated ethyl, and the like.

[0425] "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.

[0426] "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.

[0427] "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 1-6 Alkyl, more preferably hydroxy substituted C 1-3 Alkyl. Non-limiting examples of "hydroxy-substituted alkyl" include -CH2OH, -CH2CH2OH, -CH(OH)CH3, and the like.

[0428] "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 1-6 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.

[0429] "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 1-6 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.

[0430] "Carboxyl substituted alkyl" means an alkyl group substituted with one or more carboxyl groups, wherein the alkyl group is as defined above. 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.

[0431] "Cycloalkyloxy" refers to an -O-cycloalkyl group, wherein the cycloalkyl group is as defined above. Preferably C 3-8 Cycloalkyloxy, more preferably C 3-6 Cycloalkyloxy. Non-limiting examples of cycloalkyloxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0432] "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. 1-8 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.

[0433] "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, "hydroxymethyl" refers to -CH2OH, "hydroxyethyl" refers to -CH2CH2OH or -CHOHCH3, "hydroxy" refers to -OH, "thiol" refers to -SH, and "carbonyl" refers to -CO- or -C(O)-.

[0434] An "amino-protecting group" refers to an easily removable group introduced onto an amino group to maintain the amino group intact during reactions elsewhere in the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl (-SEM), tetrahydropyranyl, tert-butyloxycarbonyl (-Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fomc), acetyl, p-toluenesulfonyl (Ts), benzyl (-Bn), allyl, p-methoxybenzyl, and tert-butyldimethylsilyl (TBS). These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy, or nitro.

[0435] "Hydroxy protecting group" refers to a group that is easily removed and introduced on a hydroxyl group, and is generally used to block or protect the hydroxyl group while reacting on other functional groups of the compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, tert-butyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl (such as methoxymethyl (MOM) and ethoxyethyl, etc.), (C 1-10 Alkyl or aromatic) acyl (such as formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.), (C 1-6 alkyl or 6 to 10 membered aryl)sulfonyl, (C1-6 alkoxy or 6 to 10-membered aryloxy)carbonyl, allyl, 2-tetrahydropyranyl (THP) and the like.

[0436] "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.

[0437] When the number of substituents is not indicated in the present invention, it means that the substituents may be substituted with the number of substituents that can be substituted.

[0438] Unless otherwise defined, the "substituents independently selected from..." described in the present invention means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different, and the substituents selected are independently of each other.

[0439] 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 C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), cyano substituted C 1-8 Alkyl (preferably cyano substituted C 1-6 Alkyl, more preferably cyano substituted C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), NR A0 R B0 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR A1 R B1 、-C(O)C 1-8Alkyl (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 A1 R B1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl;

[0440] R A1 、R B1 are each independently hydrogen or C 1-3 Alkyl; or R A1 、R B1 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 1-3Alkyl, -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;

[0441] 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, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3- to 6-membered heterocycloalkyl.

[0442] In the present invention, when two or more “preferably” appear in one embodiment, any two “preferably” may be independent of each other.

[0443] In the present invention, when the number of substituents is greater than 1, any two substituents may be the same or different. For example, the substituents may be two halogens that are the same or different, or one halogen and one hydroxyl group.

[0444] Each type of substituent group described herein above can itself be substituted with the groups described herein.

[0445] Pharmaceutical composition

[0446] Typically, the compounds of the present invention or their pharmaceutically acceptable salts, or their stereoisomers can be administered in a suitable dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral administration, rectal administration, topical administration, oral administration, and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.

[0447] "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.

[0448] The compositions of the present invention are formulated, dosed and administered in a manner consistent with standard medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0449] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0450] "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.

[0451] "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.

[0452] The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0453] "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.

[0454] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases and salts with organic bases.

[0455] 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. To indicate the absolute configuration of a stereocenter, use a wavy key. represents one of the absolute configurations of a stereocenter, e.g. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, they are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are encompassed within the scope of this application.

[0456] The enantiomers, diastereomers and mixtures of these isomers of the compounds of the present invention are all within the scope of protection of the present invention. Enantiomers and diastereomers can be separated by methods known in the art, such as crystallization and chiral chromatography.

[0457] Preparation method

[0458] The present invention provides methods for preparing compounds of formula (II), which can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. The solvents, temperatures, and other reaction conditions provided herein can be varied according to the skill in the art. The reactions can be used sequentially to provide compounds of the present invention, or they can be used to synthesize fragments that are subsequently added by the methods described herein and / or methods known in the art.

[0459] Scheme 1: When the linker is The linker to E3 ligase is It can be prepared by the following method,

[0460] Scheme 2: When the linker is and The linker to E3 ligase is When , it can be prepared by the following method.

[0461] Scheme 3: When the linker is and The linker to E3 ligase is When , it can be prepared by the following method.

[0462] Scheme 4: When the linker is The linker to E3 ligase is It can be prepared by the following method,

[0463] In the above schemes 1, 2, 3, and 4, linker is a connecting group, which is shown as (L-1) in the Summary of the Invention; degrader is a group connecting to the E3 ligase, which is shown as (V-1), (V-3), and (V-5) in the Summary of the Invention;

[0464] In the above schemes 1, 2, 3, and 4, PG is an amino protecting group, such as the amino protecting group described in the present invention;

[0465] In the above schemes 1, 2, 3, and 4, the G1 group (e.g., bromine) reacts with the nitrogen of the saturated heterocycle (e.g., Buchwald coupling reaction, SNAr reaction);

[0466] In the above schemes 1, 2, 3, and 4, G2 and G3 can be a pair of coupling groups, such as reactive groups that undergo Suzuki coupling reaction. For example, G2 is chlorine, and G3 is a boron-containing group (preferably boric acid or boric ester).

[0467] In the above schemes 1, 2, 3, and 4, the compound and the linker, the linker fragments, and the linker and the degrader can be connected through reactions between the following groups:

[0468] 1.R m1 It forms a pair of reactive groups with the G5 group in linker / linker-1. The linker / linker-1 can be connected through the reaction between the two. The common reactions are as follows:

[0469] (1)R m1 is an amino group, the corresponding G5 group in linker / linker-1 is -CHO, and the two compound fragments undergo reductive amination reaction. m1 The compound fragment containing the G5 group and the compound fragment containing the G5 group are reacted in a solvent in the presence of a reducing agent and an acid. The solvent can be one or more of tetrahydrofuran, dichloromethane, and methanol. The reducing agent can be NaBH(OAc)3. The acid can be acetic acid. The reaction temperature is -20 to 35°C, preferably -10 to 15°C. The reaction time can be 0.5 to 10 hours, preferably 1 to 3 hours.

[0470] (2)R m1 is bromine, and the G5 group in the corresponding linker / linker-1 is a boron-containing group, preferably boronic acid or boronic ester, containing R m1The compound fragment containing R and the compound fragment containing G5 group undergo Suzuki coupling reaction, and the reaction conditions can be appropriately adjusted according to the existing technology. m1 The compound fragment containing the G5 group and the compound fragment containing the G5 group react in a solvent in the presence of a base and a catalyst. The solvent can be a mixed solvent of dioxane and water. The base can be potassium carbonate, sodium carbonate, or cesium carbonate. The catalyst is a palladium catalyst, for example, PdCl2(dppf). The reaction time can be 0.5-24 hours, for example, 15 hours, depending on the needs. The reaction is carried out under the protection of an inert gas (such as nitrogen, argon, etc.). The reaction temperature can be 0-200°C, for example, 100°C, and can be adaptively adjusted according to the needs of the reaction.

[0471] (3)R m1 is bromine, the corresponding G5 group in linker / linker-1 is an amine (such as a primary amine or a secondary amine), and contains R m1 The compound fragment containing R and the compound fragment containing G5 group undergo N-containing nucleophilic substitution reaction, and the reaction conditions can be appropriately adjusted with reference to the existing technology. m1 The compound fragment containing the G5 group and the compound fragment containing the G5 group are reacted in a solvent in the presence of a base and a catalyst system. The solvent can be 1,4-dioxane. The base can be cesium carbonate or potassium carbonate. The catalyst system can be a palladium catalyst system, for example, Xphos / Pd2(dba)3, Xantphos / Pd2(dba)3, BrettPhos Pd G3, RuPhos Pd G3, etc. The reaction time can be 0.5-24 hours (preferably 10-20 hours) as needed, for example, 16 hours or 18 hours. The reaction is carried out under the protection of an inert gas (such as nitrogen, argon, etc.). The reaction temperature can be 0-200°C (preferably 80-120°C), for example, 100°C or 105°C.

[0472] (4)R m1 is a hydroxyl group, and the corresponding G5 group in the linker / linker-1 is a hydroxyl group, a halogen group (such as chlorine, bromine, iodine) or an activated group of a hydroxyl group (such as -OMs, -OTf, etc.), and the two compound fragments undergo an etherification reaction. The reaction conditions can refer to conventional operations in the art. m1When R is a hydroxyl group and G5 is a hydroxyl group, it can be converted into an ether through the Mitsunobu reaction. The reaction can utilize a conventional Mitsunobu reaction system. For example, the catalytic system used is a combination of azo reagents such as DEAD (diethyl azodicarboxylate), DIAD (diisopropyl azodicarboxylate), TMAD (azodicarbonamide) and phosphorus ligands such as triphenylphosphine, tri-n-butylphosphine, and tri-tert-butylphosphine, preferably TMAD / tri-n-butylphosphine and TMAD / tri-tert-butylphosphine. The solvent is THF, 1,4-dioxane, DCM, toluene, etc. When R m1 When it is a hydroxyl group and G5 is a halogen (such as chlorine, bromine, or iodine), it can be converted into an ether by a nucleophilic substitution reaction. For example, the reaction is carried out in the presence of a base (such as cesium carbonate, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, or lithium hydroxide) to obtain an etherification product.

[0473] (5)R m1 is a hydroxyl group, and the corresponding G5 group in linker / linker-1 is an amine (such as a primary amine or a secondary amine), and the two compound fragments undergo a nucleophilic substitution reaction. The reaction conditions can refer to conventional operations in the art. For example, when R m1 When G5 is a hydroxyl group and G5 is a secondary amine, the hydroxyl group can be activated to -OTf, and then undergo an affinity substitution reaction with the secondary amine. For example, the catalytic system used is Pd2(dba)3 / Xhpos, and the reaction is carried out in the presence of a base (such as cesium carbonate, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.). The reaction time and reaction temperature are adjusted according to actual needs. For example, the temperature can be 80-120°C and the reaction time is 12-24 hours. The hydroxyl group can also be converted into a halogen (such as chlorine, bromine or iodine) through a reaction, and then undergo a nucleophilic substitution reaction with an amine, such as using Pd2(dba)3 / Xhpos as a catalytic system to form an ether, or directly in the presence of a base (such as cesium carbonate, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.).

[0474] The above reaction can also occur in R m1 G with linker 11 Those skilled in the art can make adaptive adjustments based on the properties of the compounds in the synthetic fragments.

[0475] 2. G5 and G6 are a pair of reactive groups that react to connect the degrader fragment to the linker. Common reactions include:

[0476] (1) Reductive amination of amine with ketone / aldehyde group, such as using the reduction system of NaBH3CN / Ti(Oi-Pr)4, NaBH(OAc)3 / AcOH, NaBH(OAc)3 / Ti(Oi-Pr)4, NaB(OAc)4 / Ti(Oi-Pr)4, NaBH3CN, NaBH(OAc)3 or NaBH3CN / AcOH, and the solvent used can be one or more of tetrahydrofuran, dichloromethane, methanol and dichloroethane.

[0477] (2) A carbonyl linkage is formed between two amino groups via a triphosgene / Et3N or triphosgene / DIEA system, similar to the reaction shown in step 3 of Example 4. A carbonyl linkage can also be formed between two amino groups by introducing an activating group (e.g., 4-nitrophenylphosgene).

[0478] (3) Amide formation reaction between carboxyl groups and amino groups, such as using a catalyst (e.g., HATU, HBTU, HOBt, TCFH, etc.) and condensing in the presence of a base (e.g., DIEA, Et3N, NMI, etc.) to form an amide linkage. The solvent used can be DMF, THF, DCM, etc.

[0479] Similar reactions between G5 and G6 can also occur between G5 and G7, between G5 and G8, between G9 and G 10 Between G 12 and G 13 Those skilled in the art can make adaptive adjustments according to the properties of the compounds in the synthetic fragments.

[0480] In the above schemes 1-4, the corresponding Can be replaced by The corresponding compounds were prepared by referring to the synthetic routes in Schemes 1-4. During the synthesis process, those skilled in the art can make adaptive adjustments according to actual needs in combination with conventional technical means in the art without any difficulty.

[0481] The reactions in the above schemes can be adaptively adjusted by those skilled in the art with reference to the specific embodiments described in the present invention or according to existing literature based on the properties of the compounds involved in the reactions without causing any difficulties to those skilled in the art.

[0482] The compounds described in the present invention can be synthesized using appropriate optional starting materials using methods similar to those described below or the exemplary methods described in the examples, or relevant open literature used by those skilled in the art. The starting materials or intermediates used to synthesize the compounds described in the present invention can be synthesized or can be obtained from commercial sources. If the existing literature is not reported or cannot be obtained from commercial sources, similar existing preparation methods of analogs or similar preparation methods described in the present invention can be used to prepare them. Compounds as described in the present invention and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art. The general method for preparing the compounds disclosed in the present invention can be from reactions known in the art, and the reaction can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various parts into the molecules provided by the present invention.

[0483] Compared with the prior art, the main advantages of the present invention are: the present invention provides a novel PROTAC compound with a stronger degradation effect on BRM (encoded by the SMARCA2 gene) and / or better selectivity for SMARCA2 (compared to the degradation activity against SMACA4). The compounds of the present invention have a good degradation effect on BRM (encoded by the SMARCA2 gene), with some compounds achieving a Dmax of more than 70% for BRM degradation, some reaching more than 75%, some reaching more than 80%, and some even reaching more than 85%. The DC50 for BRM degradation is less than 20nM, some reaching less than 10nM, and some reaching less than 1nM.

[0484] Compared to their BRG1 degradation, the compounds of the present invention exhibit highly selective degradation of BRM. Selectivity for some compounds (dividing the DC50 values ​​for BRG1 and BRM degradation) is greater than 10-fold, for some compounds greater than 20-fold, for some compounds greater than 50-fold, and for some compounds even exceeding 1000-fold. Furthermore, the compounds of the present invention exhibit excellent inhibitory effects on tumor cell activity, with IC50 values ​​for the compounds against tumor cells below 100 nM, for some compounds below 70 nM, for some compounds below 50 nM, and even for some compounds below 10 nM. The compounds of the present invention are potentially useful for treating various conditions associated with BRM (encoded by the SMARCA2 gene).

[0485] In addition, the compounds of the present application have excellent pharmacokinetic properties and minimal toxic and side effects. Some compounds have AUCs 10-20 times that of prior art, while others have comparable pharmacokinetic properties to prior art but with minimal toxic and side effects. Furthermore, the compounds of the present application have low inhibitory effects on hERG potassium channels, with some compounds having IC50 values ​​above 40 μM, exhibiting minimal cardiotoxicity, and exhibiting improved safety. The present invention will be further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit its scope. Experimental methods in the following examples, where specific conditions are not specified, were generally performed according to 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 indicated, percentages and parts are by weight. Unless otherwise defined, terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein may be applied to the present invention. Unless otherwise noted, compounds of the present invention may exist as diastereoisomers when purified by pre-HPLC. Compound codes are determined based on the HPLC retention times of the compounds in the examples. For example, in the product obtained in Example 67, H-67-1 indicates that its retention time is shorter than that of H-67-2. Similarly, in the product obtained in Example 68, H-68-1 indicates that its retention time is shorter than that of H-68-2. As used herein, the term "about" is defined as being close to, as understood by one of ordinary skill in the art. In one non-limiting embodiment, the term is defined as within 10%, preferably within 5%, more preferably within 1%, and even more preferably within 0.5%.

[0486] Reagents and instruments

[0487] 1 H NMR: Bruker AVANCE-400 nuclear magnetic spectrometer, internal standard is tetramethylsilane (TMS).

[0488] LC-MS: Agilent 1290 HPLC System / 6130 / 6150 MS liquid chromatography-mass spectrometer (manufacturer: Agilent), column: Waters BEH / CHS, 50×2.1 mm, 1.7 μm.

[0489] Preparative high performance liquid chromatography (pre-HPLC): GX-281 (manufacturer: Gilson).

[0490] An ISCO Combiflash-Rf75 or Rf200 automatic column analyzer and Agela 4g, 12g, 20g, 40g, 80g, or 120g disposable silica gel columns were used.

[0491] 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.

[0492] 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.

[0493] As used herein, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, Xphos Pd G3: methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II), Xphos G3Pd: methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II), Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos G3Pd: methanesulfonate [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl]palladium(II) dichloromethane adduct, Brettphos Pd G3: methanesulfonate (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), t-BuXphos-Pd-G3: methanesulfonate (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, Cs2CO3: cesium carbonate, Pd2(dba)3: tris(dibenzylideneacetone)dipalladium, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, Pd(dppf)Cl2 / PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, EA: ethyl acetate, PE: petroleum ether, MeOH: methanol, THF: tetrahydrofuran, DCM: dichloromethane, Pd / C: palladium on carbon, DIEA: N,N-diisopropylethylamine, DMSO: dimethyl sulfoxide, K2CO3: potassium carbonate, LiOH·H2O: lithium hydroxide monohydrate , LiOH: lithium hydroxide, DMF: N,N-dimethylformamide, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, NH4HCO3: ammonium bicarbonate, H2O: water, MeCN / ACN: acetonitrile, EtOH: ethanol, Na2SO4: sodium sulfate, NaBH4: sodium borohydride, HOBt: 1-hydroxybenzotriazole, EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, FA: formic acid, TsOH·H2O: p-toluenesulfonic acid monohydrate, TFA: trifluoroacetic acid, NaHCO3: sodium bicarbonate, NaBH3CN: sodium cyanoborohydride, NH4Cl: ammonium chloride, DMAC: N,N-dimethylacetamide, DMA: N,N-dimethylacetamide, Pd(OAc)2: palladium acetate, CDCl3: deuterated chloroform, DMSO-d6: deuterated dimethyl sulfoxide, TBSCl: tert-butyldimethylchlorosilane, TIPSCl: triisopropylchlorosilane, LiHMDS: lithium bis(trimethylsilyl)amide, NaI: sodium iodide, CbzCl: benzyl chloroformate, (Boc)2O: di-tert-butyl dicarbonate, HCl: hydrogen chloride, NMP: N-methylpyrrolidone, LiAlH4: lithium aluminum hydride, NaOH : sodium hydroxide, LAH: lithium aluminum hydride, DIPEA: N,N-diisopropylethylamine, S-Phos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, TMAD: N,N,N',N'-tetramethylazodicarbonamide, DIAD: diisopropyl azodicarboxylate, DEAD: diethyl azodicarboxylate, 9-BBN: 9-borabicyclo[3.3.1]nonane, HOAT: N-hydroxy-7-azobenzotriazole, DCE: dichloroethane, R uphos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, DMAP: 4-dimethylaminopyridine, PPh3: triphenylphosphine, TCFH: tetramethylchlorouronium hexafluorophosphate, NaHMDS: sodium bis(trimethylsilyl)amide, LDA: lithium diisopropylamide, MsCl: methanesulfonyl chloride, AIBN: azobisisobutyronitrile, Et2O: diethyl ether, DCC: dicyclohexylcarbodiimide, PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate , DIBALH: diisobutylaluminum hydride, BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, Tf2O: trifluoromethanesulfonic anhydride, Vitride reagent: a solution composed of sodium dihydrogen bis(2-methoxyethoxy)aluminate and 30 vol% toluene, DAST: diethylaminosulfur trifluoride, cisapride: cisapride, HEPES: 4-hydroxyethylpiperazineethanesulfonic acid, EGTA: ethylene glycol bis(2-aminoethyl ether)tetraacetic acid, Hygromycin B: hygromycin B, Trypsin-EDTA: trypsin-ethylenediaminetetraacetic acid, EDTA-K2: dipotassium ethylenediaminetetraacetic acid.

[0494] 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.

[0495] As used herein, room temperature refers to about 20-30°C.

[0496] As used herein, "overnight" means about 10 to 16 hours.

[0497] Preparation of intermediate a

[0498] Step 1: Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (430 mg, 2.16 mmol) was dissolved in DMF (6 mL). Potassium carbonate (597 mg, 4.32 mmol) and 2-bromo-1,1-dimethoxyethane (0.3 mL, 2.59 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 15 hours, then diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was dried and the crude product was purified by silica gel column chromatography to afford a-1 (330 mg, colorless oil) in a yield of 53.21%. 1 H NMR (400MHz, CDCl3): δ (ppm) 5.93 (s, 1H), 4.73 (t, J = 5.2Hz, 1H), 4.25 (d, J = 5.2Hz, 2H), 3.72 (s, 3H), 3 .49(d,J=8.8Hz,1H),3.44(s,6H),2.40-2.30(m,1H),1.00(d,J=6.8Hz,3H),0.92(d,J=6.4Hz,3H).MS m / z(ESI):288.1[M+H] + .

[0499] Step 2: Dissolve a-1 (330 mg, 1.15 mmol) in methanol (4 mL) and water (2 mL). Add LiOH·H2O (193 mg, 4.59 mmol) at room temperature. The reaction mixture was heated to 40°C and stirred for 2 hours. The mixture was then spin-dried to dryness, diluted with water (5 mL), and the pH was adjusted to 2 with 1 mol / L hydrochloric acid. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were spin-dried to dryness to afford intermediate a (310 mg, yellow oil) in a 98.76% yield. MS m / z (ESI): 274.2 [M+H] + .

[0500] Referring to the preparation method of intermediate a, 2-bromo-1,1-dimethoxyethane was replaced by 3-bromo-1,1-dimethoxypropane to prepare intermediate b.

[0501] Preparation of intermediate c

[0502] Step 1: Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (3.12 g, 15.6 mmol), 1,3-dioxolane-2-one (2.76 g, 31.3 mmol), and potassium carbonate (4.33 g, 31.3 mmol) were dissolved in acetonitrile (30 mL) at room temperature and reacted at 90°C for 6 hours. The reaction solution was filtered, concentrated, and purified by silica gel column chromatography (MeOH / DCM = 0-3%) to obtain c-1 (2.2 g, colorless oil). Yield: 57.7%. MS m / z (ESI): 244.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 6.20 (s, 1H), 4.93-4.90 (m, 1H), 4.16-4, 15 (m, 2H), 3.71-3 .67(m,3H),3.66(s,3H),2.34-2.30(m,1H),0.93(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H).

[0503] Step 2: Oxalyl chloride (104.36 mg, 0.82 mmol) was dissolved in DCM (15 mL) at -78 ° C, DMSO (128.26 mg, 1.64 mmol) was added dropwise to the solution and stirred for 30 minutes. Then, a solution of c-1 (100 mg, 0.41 mmol) in DCM (2 mL) was slowly added. After 1.5 hours, triethylamine (290.64 mg, 2.88 mmol) was added and stirred at 25 ° C for 1 hour. The mixture was concentrated and diluted with saturated aqueous ammonium chloride solution (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated to give intermediate c (98 mg, crude product). Yield: 93.88%. MS m / z (ESI): 242.1 [M+H] + .

[0504] Preparation of intermediate d

[0505] Step 1: Dissolve 6-bromo-2,3-dihydro-1-hydro-inden-1-one (10 g, 47.39 mmol) in acetonitrile (150 mL). Add sodium iodide (7.11 g, 47.39 mmol) and triethylamine (23.93 g, 236.95 mmol, 32.8 mL). React at room temperature for 10 min. Add TBSCl (14.31 g, 94.78 mmol) and react at room temperature overnight. Filter the reaction solution, concentrate the filtrate, and wash with petroleum ether to obtain compound d-1 (14.6 g, crude, yellow solid). Yield: 94.2%.

[0506] Step 2: Dissolve d-1 (14.2 g, 43.6 mmol) in THF (200 mL). Under nitrogen, slowly add LiHMDS (108.9 mL). Stir at 0°C for 30 min. Add a solution of tert-butyl bis(2-chloroethyl)carbamate (11.6 g, 47.9 mmol) in THF (100 mL). React at 0°C for 1 hour, then warm to room temperature for 3 hours. Add saturated ammonium chloride solution (50 mL), extract with ethyl acetate (100 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford d-2 (16.4 g, yellow oil) in a yield of 76.01%. MS m / z (ESI): 494.1 [M+H]. + .

[0507] Step 3: Dissolve d-2 (16.4 g, 33.1 mmol) in DCM (200 mL). Slowly add TFA (40 mL) at 0°C and warm to room temperature for 2 h. Concentrate to afford d-3 (9 g, yellow oil) in a 97% yield. MS m / z (ESI): 280.2 [M+H] + .

[0508] Step 4: Dissolve d-3 (9 g, 32.1 mmol) in DCM (200 mL). Slowly add benzyloxycarbonyl chloride (7.7 g, 45 mmol, 6.5 mL) and triethylamine (22.3 mL) at 0°C. Allow to react overnight at room temperature. Extract with dichloromethane (100 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 1 / 0 to 1 / 1) to afford d-4 (9.8 g, yellow oil) in a yield of 66.4%. MS m / z (ESI): 416.06 [M+H]. + .

[0509] Step 5: Dissolve d-4 (5.5 g, 13.29 mmol) in methanol (150 mL). Add NaBH4 (1 g, 26.6 mmol) at 0°C and warm to room temperature for 1 h. Add saturated ammonium chloride solution (50 mL) and extract with dichloromethane (50 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford d-5 (5.5 g, yellow oil) in a 99% yield. MS m / z (ESI): 418.1 [M+H] + .

[0510] Step 6: Dissolve d-5 (5.5 g, 13.2 mmol) in toluene (80 mL), add TsOH·H2O (1.33 mg, 6.6 mmol), and react at 110°C for 1 h. Extract with ethyl acetate (60 mL x 3), wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purify by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain intermediate d (4.8 g, yellow oil) in a yield of 91.3%. MS m / z (ESI): 400.0 [M+H] + .

[0511] Preparation of intermediate e

[0512] Step 1: Dissolve intermediate d (2 g, 5 mmol) in dioxane (20 mL) and add pinacol diboronate (2.54 g, 10 mmol), Pd(dppf)Cl2 (366 mg, 10 mol%), and potassium acetate (1.47 g, 15 mmol) at room temperature. Under nitrogen, heat the reaction mixture to 100°C in an oil bath and stir for 16 hours. After completion of the reaction, cool the system to room temperature and quench with saturated brine (50 mL). Extract the mixture with ethyl acetate (100 mL x 2). The organic phase is dried over anhydrous sodium sulfate and concentrated to afford e-1 (1.80 g, white solid, crude product) in an 81% yield. MS m / z (ESI): 446.4 [M+H]. + .

[0513] Step 2: Dissolve e-1 (1.70 g, 3.8 mmol) in THF (20 ml). Add NaOH solution (1 mol / L, 10 mL) under an ice-water bath. Then, slowly add aqueous hydrogen peroxide (30%, 5 mL) in portions and stir for 6 hours. After the reaction, the system is quenched with sodium sulfite solution and extracted with ethyl acetate (50 mL x 2). The organic phase is concentrated and the crude product is purified by silica gel column chromatography using an eluent (PE:EA = 5:1-1:1) to obtain intermediate e (1.2 g, white solid) in a 93% yield. MS m / z (ESI): 336.2 [M+H] + .

[0514] Referring to the preparation method of intermediate d, the starting material 6-bromo-2,3-dihydro-1-hydro-inden-1-one was replaced with 5-bromo-2,3-dihydro-1-hydro-inden-1-one to prepare intermediate f shown below.

[0515] Referring to the preparation method of intermediate e, the starting material intermediate d was replaced by intermediate f to prepare intermediate g as shown below:

[0516] Preparation of intermediate h

[0517] Step 1-6: Referring to the preparation method of intermediate d, 5-methoxy-1-indanone was used to replace 6-bromo-2,3-dihydro-1-hydro-indan-1-one to prepare intermediate h-6. MS m / z (ESI): 350.2 [M+H] + .

[0518] Step 7: At 25°C, h-6 (3.60 g, 9.27 mmol) was dissolved in methanol (30 mL), and 10% Pd / C (200 mg, 9.27 mmol) was added portionwise. The resulting mixture was then stirred at 25°C under hydrogen (1 atm) for 18 hours. The mixture was extracted with ethyl acetate (30 mL × 3), and 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 give h-7 (2.13 g, 9.12 mmol) in a yield of 98.31%. MS m / z (ESI): 218.1 [M+H] + .

[0519] Step 8: h-7 (2.02 g, 9.30 mmol) was dissolved in DCM (10 mL) at -78°C, and tribromoborane (1.32 mL, 13.96 mmol) was added dropwise. The resulting mixture was then stirred at 25°C for 18 hours. The mixture was added with methanol, filtered, and the filtrate was concentrated to afford h-8 (1.99 g, 9.80 mmol) in a yield of 98.98%. MS m / z (ESI): 204.1 [M+H] + .

[0520] Step 9: h-8 (2 g, 9.84 mmol) was dissolved in DCM (10 mL), (Boc)2O (2.03 g, 9.35 mmol) was added, and the resulting mixture was stirred at 25°C for 2 hours. The mixture was concentrated and diluted with saturated aqueous ammonium chloride (20 mL), and extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain intermediate h (2000 mg, 6.59 mmol) in a yield of 67.00%. MS m / z (ESI): 248.1 [M-56+H] + .

[0521] Preparation of intermediate i

[0522] Step 1: Dissolve intermediate d (2.4 g, 6.0 mmol) in anhydrous ethanol (45 mL). Add Pd(dppf)Cl2 (0.45 g, 0.6 mmol) and triethylamine (0.9 mL, 18.0 mmol) at room temperature. Place the reaction mixture under a hydrogen atmosphere and stir at 85°C for 16 hours. After the reaction is complete, cool to room temperature, dilute with water (60 mL), and extract with ethyl acetate (45 mL x 2). The organic phase is concentrated and purified by silica gel column chromatography to obtain i-1 (1.9 g, colorless oil) in an 83% yield. MS m / z (ESI): 392.1 [M+H] + .

[0523] Step 2: i-1 (1.9 g, 4.8 mmol) was dissolved in anhydrous THF (25 mL). Lithium borohydride (0.95 g, 43.7 mmol) was added at room temperature. The reaction mixture was placed under a nitrogen atmosphere and stirred at 70°C for 16 hours. After the reaction was complete, the mixture was cooled to 0°C and quenched by slowly adding saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (45 mL x 3). The organic phase was concentrated and purified by silica gel column chromatography to obtain i-2 (1.2 g, colorless oil) in a 70% yield. MS m / z (ESI): 350.1 [M+H] + .

[0524] Step 3: Dissolve i-2 (410 mg, 1.1 mmol) in dichloroethane (16 mL). Add manganese dioxide (1160 mg, 10.0 mmol) at room temperature. Place the reaction mixture under a nitrogen atmosphere and stir at 50°C for 16 hours. After the reaction is complete, cool to room temperature, filter through celite, and concentrate the organic phase. Purify by silica gel column chromatography to obtain intermediate i (320 mg, colorless oil) in a 79% yield. MS m / z (ESI): 348.1 [M+H] + .

[0525] Preparation of intermediate j

[0526] Step 1: Under nitrogen, intermediate d (4.2 g, 10.6 mmol), benzophenone imine (2.09 g, 11.5 mmol), Pd2(dba)3 (970 mg, 1.06 mmol), Xphos (1.0 g, 2.12 mmol), and sodium tert-butoxide (2.0 g, 21.2 mmol) were dissolved in toluene (40 mL) and heated to 65°C overnight. The reaction was monitored by TLC. The reaction solution was concentrated and purified by column chromatography (EA / PE = 1:10) to obtain j-1 (4.8 g, yellow solid) in a 92% yield.

[0527] Step 2: Dissolve j-1 (4.2 g, 8.43 mmol) in methanol (60 mL) at room temperature, add aqueous hydrochloric acid (1 mol / L, 10 mL), and stir at 50°C for 1 hour. Monitor the reaction by TLC. Concentrate the reaction solution, add water (50 mL), adjust the pH to >7 with saturated aqueous sodium bicarbonate solution, and extract with ethyl acetate (50 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 1:1) to obtain j-2 (2.3 g, light yellow solid). Yield: 82%. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 7.45-7.32 (m, 5H), 7.03 (d, J = 7.9Hz, 1H), 6.94 (d, J = 5.6Hz, 1H), 6.66 (d, J = 5.6Hz, 1H), 6.55 (d, J = 2.1Hz,1H),6.38(dd,J=8.0,2.1Hz,1H),5.12(s,2H),4.89(s,2H),4.05(m,2H),3.2-3.15(m,2H),1.83(m,2H),1.26-1.14(m,2H).

[0528] Step 3: Dissolve j-2 (1.25 g, 3.738 mmol) in methanol (50 mL) with stirring. Add wet palladium on carbon (0.8 g, 7.476 mmol, 10% purity) and stir under a hydrogen atmosphere for 2 hours. Monitor the reaction by TLC. The reaction mixture is filtered and the filtrate is concentrated to afford intermediate j (755 mg, oil) in a yield of 99.85%.

[0529] Preparation of intermediate k

[0530] Step 1: Dissolve 5-bromo-2-fluoro-3-methylpyridine (15 g, 78.9 mmol) and 1-(tert-butyl)-4-ethylpiperidine-1,4-dicarboxylate (22.3 g, 86.8 mmol) in toluene (150 mL) at room temperature. Under nitrogen, add NaHMDS solution (1 mol / L, 118 mL, 118 mmol) dropwise to the reaction mixture at 0°C. The reaction mixture is allowed to react at room temperature for 18 hours. After the reaction is complete, pour the reaction mixture into saturated ammonium chloride solution (100 mL) and water (100 mL), extract with ethyl acetate (100 mL x 3), and combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (EA / PE = 0-50%) to obtain k-1 (16 g, yellow oil). Yield: 47.4%, MS m / z (ESI): 371.0 [M-56+H]. + .

[0531] Step 2: Dissolve k-1 (10.7 g, 25 mmol) in THF (100 mL) at 0°C. Add LDA (2 mol / L, 31.3 mL, 62.6 mmol) dropwise at 0°C. The reaction mixture is allowed to react at 0°C for 1 hour. After the reaction is complete, the reaction mixture is concentrated and purified by silica gel column chromatography (EA / PE = 0-60%) to obtain k-2 (2 g, red oil) in a yield of 20.9%. MS m / z (ESI): 325.0 [M-56+H]. + .

[0532] Step 3: K-2 (1.7 g, 4.46 mmol) was dissolved in MeOH (20 mL) at 0°C, and NaBH4 (0.34 g, 8.92 mmol) was added portionwise. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, saturated ammonium chloride solution (10 mL) and water (10 mL) were added to the reaction mixture, and the solution was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain K-3 (1.7 g, yellow solid). Yield: 99.4%. MS m / z (ESI): 327.0 [M-56+H]. + .

[0533] Step 4: Dissolve k-3 (900 mg, 2.35 mmol) in DCM (10 mL) at 0°C, add triethylamine (0.98 mL, 7.04 mmol) and MsCl (0.27 mL, 3.52 mmol), and incubate at room temperature for 1 hour. After completion of the reaction, concentrate the reaction mixture to afford crude product k-4 (900 mg, yellow solid) in an 83.1% yield. MS m / z (ESI): 405.0 [M-56+H]. + .

[0534] Step 5: At room temperature, k-4 (900 mg, 1.95 mmol) was dissolved in MeOH (10 mL), and potassium tert-butoxide (656 mg, 5.85 mmol) was added. The reaction solution was reacted at room temperature for 18 hours. After the reaction was complete, 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, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 0-100%) to obtain intermediate k (600 mg, colorless oil). Yield: 84.2%, MS m / z (ESI): 365.2 [M+H] + .

[0535] Referring to the preparation method of intermediate k, the starting material 5-bromo-2-fluoro-3-methylpyridine was replaced with 3-bromo-6-chloro-2-methylpyridine to prepare the intermediate m shown below.

[0536] Referring to the preparation method of intermediate k, the starting material 5-bromo-2-fluoro-3-methylpyridine was replaced with 5-bromo-2-chloro-4-methylpyridine to prepare intermediate y shown below.

[0537] Preparation of intermediate n

[0538] Step 1: Dissolve benzyl 4-formylpiperidine-1-carboxylate (9 g, 36.39 mmol) in DCM (180 mL). Add (4-bromophenyl)hydrazine hydrochloride (8.95 g, 40.03 mmol) at room temperature, followed by dropwise addition of TFA (9.2 mL, 120.10 mmol). The reaction mixture was heated to 40°C and stirred for 15 hours. After cooling, it was used directly in the next step to obtain n-1 (14.53 g) according to theoretical yield. MS m / z (ESI): 399.1 [M+H] + .

[0539] Step 2: The reaction mixture from Step 1 was cooled to 0°C, and MeOH (60 mL) was added, followed by the addition of NaBH4 (2.4 g, 63.18 mmol) in portions. The reaction mixture was stirred at 0°C for 2 hours, quenched by the addition of aqueous ammonia (100 mL), diluted with water (300 mL), and extracted with dichloromethane (300 mL x 2). The combined organic phases were concentrated and purified by silica gel column chromatography to obtain n-2 (11.6 g, off-white solid) in a yield of 79.43%. MS m / z (ESI): 401.2 [M+H] + .

[0540] Step 3: Dissolve n-2 (7 g, 17.44 mmol) in MeOH (170 mL). 37% aqueous formaldehyde (6.5 mL, 87.22 mmol), NaBHCN (3.29 g, 52.33 mmol), and acetic acid (5 mL) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 15 hours. Aqueous sodium bicarbonate (8 g / 200 mL) was slowly added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were concentrated and purified by silica gel column chromatography to obtain intermediate n (7 g, yellow oil) in a 96.62% yield. MS m / z (ESI): 415.2 [M+H] + .

[0541] Referring to the preparation method of intermediate n, the starting material 4-bromophenylhydrazine hydrochloride was replaced with 3-bromophenylhydrazine hydrochloride to prepare intermediate w as shown below.

[0542] Referring to step 3 of the preparation method of intermediate n, replace n-2 with 1-benzyl-6'-chloro-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine] to prepare intermediate af shown below.

[0543] Preparation of intermediate o

[0544] Step 1: Dissolve methyl 5-bromo-2,3-dihydro-1H-indene-1-carboxylate (4.2 g, 16.4 mmol), aqueous formaldehyde solution (38%, 3.90 g, 49.4 mmol), and potassium carbonate (6.82 g, 49.4 mmol) in DMSO (35 mL) and stir at room temperature for 16 hours. After the reaction, add saturated brine (50 mL) and extract with ethyl acetate (100 mL x 2). The aqueous phase is adjusted to pH 3-4 with hydrochloric acid (2 mol / L) and extracted with ethyl acetate (50 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford o-1 (2.1 g, brown oil). Yield: 69%. MS m / z (ESI): 269.0 [MH] - .

[0545] Step 2: Dissolve o-1 (2.1 g, 7.75 mmol), benzylamine (1.65 g, 15.5 mmol), EDCI (2.23 g, 11.6 mmol), HOBt (1.56 g, 11.6 mmol), and DIEA (2.99 g, 23.2 mmol) in DMF (20 mL) and stir at room temperature for 16 hours. After the reaction, extract with ethyl acetate (100 mL x 2). Combine all organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain o-2 (1.3 g, orange oil). Yield: 46.5%. MS m / z (ESI): 360.2 [M+H] + .

[0546] Step 3: Dissolve o-2 (2.1 g, 5.8 mmol) and triethylamine (793 mg, 6.96 mmol) in DCM (20 mL). Add MsCl (739 mg, 6.96 mmol) dropwise in an ice bath. Stir the reaction at room temperature for 1 hour. After the reaction is complete, extract with dichloromethane (50 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to yield o-3 (crude product, 2.9 g, brown oil). MS m / z (ESI): 437.9 [M+H] + .

[0547] Step 4: Dissolve o-3 (2.9 g, 5.8 mmol, crude) and K2CO3 (2.4 g, 17.4 mmol) in acetonitrile (20 mL) and stir at 60°C for 16 hours. After completion of the reaction, concentrate and extract with ethyl acetate (50 mL x 2). The combined organic phases are washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain o-4 (1.9 g, orange solid) in a yield of 95.9%. MS m / z (ESI): 342.0 [M+H] + .

[0548] Step 5: Aluminum trichloride (584 mg, 4.4 mmol) was dissolved in THF (30 mL). LAH (1 mol / L THF solution, 5.8 mL, 5.8 mmol) was slowly added dropwise under an ice bath. The mixture was stirred at 0°C for 20 minutes. A THF solution (2 mL) of o-4 (1.0 g, 2.9 mmol) was slowly added dropwise under an ice bath. The mixture was stirred at 0°C for 30 minutes. Ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate o (1 g, yellow oil) in a 62% yield. MS m / z (ESI): 328.2 [M+H] + .

[0549] Preparation of intermediate p

[0550] Step 1: Under nitrogen at -78°C, slowly add NaHMDS (260 mL, 0.52 mol) dropwise to a solution of methoxyindole (17 g, 0.104 mol) in THF (150 mL). The reaction is stirred for half an hour. A solution of N-benzyl-2-chloro-N-(2-chloroethyl)ethyl-1-amine (36.3 g, 0.156 mol) in THF (20 mL) is then added to the reaction mixture. The reaction is stirred at 25°C for 86 hours. The reaction is quenched by the addition of saturated ammonium chloride (300 mL) and extracted with ethyl acetate (400 mL x 2). The combined organic phases are washed with saturated brine (200 mL), concentrated, and purified by silica gel column chromatography to afford p-1 (6.5 g, yellow solid) in a yield of 19.3%. MS m / z (ESI): 345.2 [M+Na] + .

[0551] Step 2: Boron tribromide (72 mL, 72 mol) was added dropwise to a solution of p-1 (6 g, 18 mmol) in DCM (200 mL) at 0°C. The reaction mixture was stirred at room temperature for 5 hours. The pH of the reaction mixture was adjusted to 10 with aqueous ammonia (27%), ice water (200 mL) was added, and extraction was performed with ethyl acetate (1000 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. Methanol (30 mL) and diethyl ether (200 mL) were then added, stirred for half an hour, and filtered. The filter residue was dried to afford intermediate p (5 g, yellow solid) in an 87.7% yield. MS m / z (ESI): 309.1 [M+H] + .

[0552] Preparation of intermediate q

[0553] Step 1: Under nitrogen at -78°C, a solution of NaHMDS in tetrahydrofuran (113 mL, 0.23 mol) was added dropwise to a solution of 6-bromoindolin-2-one (10 g, 47.2 mmol) in THF (100 mL) and stirred for half an hour. A solution of N,N-bis(2-chloroethyl)benzylamine (16.4 g, 70.8 mmol) in THF (10 mL) was then added and stirred at room temperature for 40 hours. After the reaction was complete, saturated aqueous ammonium chloride (100 mL) was added to quench the mixture. The reaction solution was extracted with ethyl acetate (400 mL x 2). The combined organic phases were concentrated and then purified by silica gel column chromatography (PE / EA) to afford q-1 (10 g, red solid) in a yield of 56.8%. MS m / z (ESI): 371.0 [M+Na] + .

[0554] Step 2: Add iodomethane (1.75 ml, 28.2 mmol) dropwise to a solution of q-1 (9.5 g, 25.6 mmol) and cesium carbonate (25 g, 76.8 mmol) in DMF (15 mL) under an ice-water bath. Stir at room temperature for 1 hour. After the reaction is complete, add ethyl acetate (500 mL) and wash with saturated brine (200 mL x 2). The organic phase is concentrated and purified by silica gel column chromatography to obtain intermediate q (10 g, brown solid) in an 81.6% yield. MS m / z (ESI): 385.0 [M+H] + .

[0555] Preparation of intermediate t

[0556] Step 1: Dissolve intermediate d (4 g, 10.07 mmol) in dry acetonitrile (40 mL) at room temperature, add trifluoromethanesulfonic acid (4.47 mL, 50.37 mmol), and react at room temperature for 5 hours. After the reaction is complete, the reaction solution is added to a saturated aqueous NaHCO solution (600 mL). The aqueous phase is extracted with ethyl acetate (300 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford t-1 (2.20 g, colorless oil). Yield: 82.7%. MS m / z (ESI): 264.0 [M+H] + .

[0557] Step 2: Dissolve t-1 (2 g, 7.57 mmol) in acetonitrile (40 mL) at room temperature, add (Boc)2O (2.48 g, 11.36 mmol) and triethylamine (7.35 mL, 53 mmol), and react at room temperature for 30 minutes. The reaction solution was concentrated and purified by column chromatography (PE / EA = 0-30%) to obtain intermediate t (2.2 g, brown oil). Yield: 79.77%. MS m / z (ESI): 308.0 [M+H-56] + .

[0558] Referring to the preparation method of intermediate t, the starting material intermediate d was replaced by intermediate f to prepare intermediate v as shown below.

[0559] Preparation of intermediate u

[0560] Step 1: Dissolve (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (2 g, 9.85 mmol) in THF (30 mL). Add 2-bromo-5-methoxyphenol (2 g, 9.85 mmol), PPh3 (3.1 g, 11.8 mmol), and DIAD (2.4 g, 11.8 mmol) sequentially under ice-water bath. Stir at room temperature for 16 hours. After completion of the reaction, wash with water (30 mL) and extract with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5:1 to 2:1) to obtain u-1 (9 g, colorless oil) in a 93% yield. MS m / z (ESI): 387.9 [M+H] + .

[0561] Step 2: Dissolve u-1 (1.5 g, 3.87 mmol) in toluene (30 mL). Add tributyltin hydride (1.46 g, 5.03 mmol) and AIBN (318 mg, 1.94 mmol) at room temperature. Bubble nitrogen for 5 minutes. Then, heat the reaction to 125°C and reflux under nitrogen for 16 hours. Wash with water (100 mL) and extract with ethyl acetate (100 mL x 3). The combined organic phases are washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5:1 to 2:1) to obtain u-2 (1.2 g, yellow liquid). Yield: 99%. MS m / z (ESI): 310.3 [M+H]. + .

[0562] Step 3: Dissolve u-2 (1.2 g, 3.87 mmol) in DCM (20 mL). Slowly add boron tribromide solution (1 mol / L, 7.74 mL, 7.74 mmol) dropwise in an ice bath. Stir at room temperature for 4 hours. After the reaction, pour the reaction mixture into ice water and adjust the pH to 10-11 with saturated sodium bicarbonate solution. Extract with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to yield intermediate u (900 g, brown liquid, crude product). Yield: 79%. MS m / z (ESI): 296.1 [M+H]. + .

[0563] Preparation of intermediate x

[0564] Step 1: At room temperature, benzyl 4-formylpiperidine-1-carboxylate (24 g, 97.05 mmol) and 3-bromophenylhydrazine hydrochloride (21.69 g, 97.05 mmol) were added to DCM (400 mL). TFA (14.47 mL, 194 mmol) was added dropwise and stirred at room temperature overnight. Aqueous sodium carbonate (30.86 g, 291 mol) was added to the reaction solution. The organic phase was collected, washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give x-1 (30 g, 400 mmol) in a yield of 77%. MS m / z (ESI): 399.2 [M+H] + .

[0565] Step 2: Dissolve x-1 (38 g, 399 mmol) in MeOH (200 mL) and THF (200 mL) at room temperature, add NaBH (14.4 g, 380 mmol), and react at 70°C overnight. The reaction solution was concentrated and purified by column chromatography (PE:DCM = 1:1 to 0:1) to afford x-2 (4.8 g, 12 mmol) in a 12% yield. MS m / z (ESI): 401.2 [M+H] +.

[0566] Step 3: Add x-2 (500 mg, 1.25 mmol) to DMF (5 mL). Add NaH (99 mg, 2.49 mmol) at 0°C, stir at 0°C for 1 h, add iodoethane (388.66 mg, 2.49 mmol), and react at room temperature overnight. Pour the reaction mixture into ice water (20 mL) and extract with ethyl acetate (15 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:DCM = 1:2) to obtain intermediate x (300 mg, 0.70 mmol) in a yield of 56%.

[0567] Referring to the preparation method of intermediate x, the starting material iodoethane was replaced with iodopropane to prepare intermediate ab shown below.

[0568] Referring to the preparation method of intermediate x, the starting material iodoethane was replaced with 2-iodopropane to prepare intermediate ad shown below.

[0569] Preparation of intermediate z

[0570] Step 1: Under nitrogen protection in an ice-water bath, triethylamine (2.16 g, 21.36 mmol) was slowly added dropwise to a solution of (4-bromophenyl)methanesulfonyl chloride (4.8 g, 17.8 mmol) and tert-butyl hydroxycarbamate (2.49 g, 18.7 mmol) in diethyl ether (60 mL). Solids gradually precipitated from the reaction solution. Stir at 0°C for 3 hours until the reaction was complete. Ethyl acetate (300 mL) was added to the reaction solution, which was then washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA) to obtain z-1 (2.2 g, off-white solid) in an 84% yield. MS m / z (ESI): 365.9 [M+H] + .

[0571] Step 2: A solution of z-1 (3.6 g, 9.8 mmol), ferrous sulfate heptahydrate (36 mg, 0.11 mmol), and TFA (5.6 g, 49.2 mmol) in DCM (50 ml) was stirred at 40°C for 16 hours. Solids gradually precipitated during stirring. After the reaction was complete, the reaction solution was concentrated to afford z-2 (4.2 g, brown solid) in a 96.3% yield. MS m / z (ESI): 266.0 [M+H] + .

[0572] Step 3: A solution of z-2 (2.1 g, 7.89 mmol) and POCl3 (12 g, 78.9 mmol) in acetonitrile (120 ml) was stirred at 60°C under nitrogen for 24 hours. After the reaction was complete, the reaction solution was concentrated, the pH was adjusted to 7 with saturated sodium bicarbonate, water (30 mL) was added, and the mixture was extracted with dichloromethane (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain z-3 (1.2 g, light red solid) in a yield of 61%. MS m / z (ESI): 245.9 [MH] - .

[0573] Step 4: 2-(Trimethylsilyl)ethoxymethyl chloride (704 mg, 4.2 mmol) was slowly added dropwise to a solution of z-3 (950 mg, 3.83 mmol) and DIEA (1.5 g, 11.49 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 h. After the reaction was complete, the solution was concentrated and purified by column chromatography to afford z-4 (1.4 g, colorless oil) in a 96.6% yield. MS m / z (ESI): 375.9 [MH] - .

[0574] Step 5: Under nitrogen protection, add NaH (260 mg, 6.63 mmol) to a solution of z-4 (1 g, 2.65 mmol) and benzyl bis(2-bromoethyl)carbamate (1.16 g, 3.18 mmol) in NMP (10 mL) in an ice-water bath. Stir the mixture at 0°C for 2 h. After the reaction is complete, quench the reaction with saturated aqueous ammonium chloride (20 mL). Add water (100 mL). Extract with dichloromethane (300 mL × 3). The combined organic phases are washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain intermediate z (1.7 g, colorless liquid) in a yield of 99.9%. MS m / z (ESI): 581.0 [M+H] + .

[0575] Preparation of intermediate aa

[0576] Step 1: Dissolve 2,5-dibromoaniline (5 g, 0.6 mmol) in THF (50 mL). Add dibutyl dicarbonate (13 g, 36 mmol) and DMAP (250 mg, 2 mmol). Stir the solution at 40°C for 5 hours. After the reaction is complete, cool the reaction mixture to room temperature and concentrate to afford aa-1 (9.2 g, brown oil). The crude product is used directly in the next step.

[0577] Step 2: Dissolve aa-1 (9 g, 20 mmol) in acetonitrile (200 mL) and add lithium bromide (5.35 g, 61.5 mmol). Stir the solution at 65°C for 8 hours. After the reaction is complete, cool the reaction mixture to room temperature and concentrate. Purify by column chromatography (PE:EA = 5:1 to 1:1) to obtain aa-2 (5.2 g, white solid) in a 74% yield.

[0578] Step 3: Dissolve aa-2 (3 g, 8.55 mmol) in diethyl ether (90 mL) under nitrogen protection, cool to -50°C, slowly add methyllithium solution (6 mL, 9.81 mmol, 1.6 mol / L Et2O solution), then warm to -10°C, stir for 10 minutes, cool to -50°C again, slowly add n-butyllithium solution (6.6 mL, 12.2 mmol, 1.6 mol / L hexane solution) to obtain a light yellow liquid, and keep stirring at -50°C for 2 hours. The temperature was lowered to -78°C, and a solution of lanthanum(III) chloride bis(lithium chloride) complex (17.1 mL, 10.26 mmol, 0.6 mol / L THF solution) and N-tert-butyloxycarbonyl-4-piperidone (2.13 g, 12.2 mmol) dissolved in THF (30 mL) were slowly added. The mixture was then heated to 25°C and stirred for 1 hour. Potassium tert-butoxide (0.3 g, 2.7 mmol) dissolved in THF (20 mL) was added, and the temperature was raised to 70°C and stirred for 5 hours. After the reaction was complete, the reaction mixture was cooled to 0°C and saturated aqueous ammonium chloride (90 mL) was slowly added. The mixture was extracted with ethyl acetate (60 mL). The organic phase was washed with dilute hydrochloric acid (1 mol / L, 45 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain intermediate aa (1.1 g, white solid) in a 32% yield. MS m / z(ESI):398.3[M+H] + .

[0579] Preparation of intermediate ac

[0580] Step 1: At room temperature, x-2 (500 mg, 1.25 mmol) and sodium bicarbonate (1.3 g, 15 mmol) were added to DCM (10 mL). Acetyl chloride (0.18 mL, 2.5 mmol) was added dropwise and the mixture was allowed to react at room temperature for 2 h. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to give intermediate ac (618 mg), which was used directly in the next step. MS m / z (ESI): 443.3 [M+H] + .

[0581] Preparation of intermediate ae

[0582] Step 1: Dissolve 5-bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidine] (700 mg, 2.78 mmol) and triethylamine (842 mg, 8.34 mmol) in DCM (10 mL). Add (Boc)2O (729 mg, 3.34 mmol) dropwise at room temperature and stir for 2 hours. After completion of the reaction, extract with dichloromethane (50 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to afford intermediate ae (370 mg, colorless oil). Yield: 37.9%. MS m / z (ESI): 296 [M-56+H]. + .

[0583] Preparation of intermediate ag

[0584] Step 1: tert-Butyl 6-bromo-3,3-bis(hydroxymethyl)-2-oxoindoline-1-carboxylate (7.5 g, 20.2 mmol) and pyridine (5.1 g, 64.6 mmol) were added to DCM (300 mL). TfO (11.4 g, 40.4 mmol) was added dropwise under nitrogen and ice-cooled. The mixture was allowed to react for 1 hour. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (EA / PE = 5-15%) to afford ag-1 (7.1 g, light yellow oil) in a 55.5% yield. MS m / z (ESI): 652.9 [M+18].

[0585] Step 2: Dissolve ag-1 (7.1 g, 11.16 mmol) and benzylamine (1.19 g, 11.16 mmol) in acetonitrile (350 mL), add DIPEA (5.76 g, 44.64 mmol), and react at 82°C under nitrogen for 16 hours. After completion of the reaction, cool the reaction solution, concentrate, add water (150 mL), and extract with ethyl acetate (150 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to obtain ag-2 (6.8 g, light yellow oil, crude product). MS m / z (ESI): 443.1 [M+H] + .

[0586] Step 3: Dissolve ag-2 (6.8 g, crude product, 6.9 mmol) in DCM (65 mL). Add trifluoroacetic acid (13 mL) under nitrogen and ice-cool. React on ice for 1 hour. After completion, concentrate the reaction solution, dissolve in DCM (200 mL) and MeOH (20 mL), adjust the pH to 11 with aqueous ammonia, wash with water (150 mL), dry over anhydrous sodium sulfate, and concentrate. Purify by silica gel column chromatography (EA / PE = 10-70%) to obtain ag-3 (2.1 g, light gray solid) in an 88.6% yield. MS m / z (ESI): 343.1 [M+H]+ .

[0587] Step 4: Dissolve ag-3 (2 g, 5.83 mmol) in THF (100 mL). Add Vitride reagent (8.3 mL, 29.2 mmol) under nitrogen at room temperature and allow to react for 1 hour. After completion, add saturated sodium potassium tartrate aqueous solution (50 mL). Extract with ethyl acetate (100 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH / DCM = 0-12%) to afford intermediate ag (1.89 g, light yellow oil) in a 98.9% yield. MS m / z (ESI): 329.1 [M+H] + .

[0588] Preparation of intermediate 1

[0589] Step 1: Dissolve tert-butyl (2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate (1.7 g, 4.07 mmol) in methanol (10 mL). Add HCl / dioxane solution (12 mL, 4 mol / L). Stir the reaction mixture at room temperature for 2 hours. The mixture was then evaporated to dryness to afford 1-a (1.4 g, brown solid) in a 97.22% yield. MS m / z (ESI): 318.1 [M+H] + .

[0590] Step 2: 1-a (500 mg, 1.42 mmol) was dissolved in DMF (5 mL) at room temperature. (S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutanoic acid (308 mg, 1.42 mmol), DIEA (0.88 mL, 5.2 mmol), and HATU (536 mg, 1.42 mmol) were then added sequentially. The reaction mixture was stirred at room temperature for 16 hours. The mixture was washed with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried and the crude product was purified by silica gel column chromatography to afford 1-b (690 mg, light yellow liquid) in an 84.78% yield. MS m / z (ESI): 517.2 [M+H] + .

[0591] Step 3: Dissolve 1-b (690 mg, 1.34 mmol) in THF (8 mL). Add HCl / dioxane solution (15 mL, 4 mol / L) at room temperature. Stir the reaction mixture at room temperature for 1 hour. The reaction mixture is evaporated to dryness in vacuo to afford intermediate 1 (600 mg, yellow liquid). Yield: 99.03%. MS m / z (ESI): 417.2 [M+H] + .

[0592] Preparation of intermediate 2

[0593] Step 1: To a solution of (S)-tert-butyl (1-(4-bromophenyl)ethyl)carbamate (4.0 g, 13.3 mmol) in DMAC (120 mL) were added Pd(OAc)2 (0.3 g, 1.33 mmol), potassium acetate (2.7 g, 26.6 mmol), and 4-methylthiazole (2.7 g, 26.6 mmol). The atmosphere was purged with nitrogen three times. The reaction mixture was stirred at 95°C for 12 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (600 mL x 3). The organic phase was dried by rotary evaporation, and the crude product was purified by silica gel column chromatography to afford 2-a (3.1 g, white solid) in a 73% yield. MS m / z (ESI): 319 [M+H] + .

[0594] Step 2: Dissolve 2-a (3.1 g, 9.7 mmol) in methanol (30 mL). Add HCl / dioxane solution (30 mL, 4 M) at 0°C. Warm the reaction mixture to room temperature and stir for 2 hours. Concentrate the reaction mixture to give 2-b (2.8 g, light yellow, crude product). MS m / z (ESI): 219 [M+H] + .

[0595] Step 3: (2S,4R)-1-(tert-Butyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (3.2 g, 14.1 mmol) and HATU (7.3 g, 19.2 mmol) were stirred in DMF (100 mL) under ice-cooling for 20 minutes. DIEA (13 g, 102.5 mmol) and 2-b (2.8 g, crude product) were then added. The reaction mixture was stirred at room temperature overnight, and then water (50 mL) was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 2-c (3.2 g, light yellow solid). MS m / z (ESI): 432 [M+H] + .

[0596] Step 4: Dissolve 2-c (3.2 g, 7.4 mmol) in MeOH (30 mL) and add HCl / dioxane solution (30 mL, 4 M) at 0°C. The reaction mixture is warmed to room temperature and stirred for 2 hours. The reaction mixture is concentrated to give intermediate 2 (3.1 g, brown solid, crude product). MS m / z (ESI): 332 [M+H] + .

[0597] Preparation of intermediate 3

[0598] Step 1: 3-c (1.0 g, 3.4 mmol), 2-methylimidazole (560 mg, 6.8 mmol), and t-BuXphos-Pd-G3 (540 mg, 0.68 mmol) were added sequentially to 1,4-dioxane (10 mL), followed by the addition of potassium tert-butoxide (760 mg, 6.8 mmol) at room temperature. The reaction mixture was heated to 110°C in an oil bath and stirred for 2 hours. After cooling to room temperature, the reaction mixture was spin-dried and added to silica gel. Purification by silica gel column chromatography afforded 3-d (600 mg, white solid) in a 53% yield. MS m / z (ESI): 303.2 [M+H] + .

[0599] Step 2: 3-d (600 mg, 1.99 mmol) was added to an HCl / 1,4-dioxane solution (5 mL, 1 mol / L) and stirred at room temperature for 1 hour. The reaction mixture was then evaporated to dryness to obtain the crude product. (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (690 mg, 2.99 mmol) and DIEA (1.8 g, 13.93 mmol) were dissolved in DMF (5 mL) and added to the crude product at room temperature. After stirring for 10 minutes, HATU (1.5 g, 3.98 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added dropwise to water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 1), concentrated, and purified by silica gel column chromatography to obtain 3-e (460 mg, white solid) in a 54% yield. MS m / z(ESI):416.2[M+H] + .

[0600] Step 3: Dissolve 3-e (400 mg, 0.96 mmol) in HCl / 1,4-dioxane solution (2 mL, 1.0 mol / L), stir at room temperature for 1 hour, and concentrate the reaction solution to obtain intermediate 3 (380 mg, colorless oil). MS m / z (ESI): 316.1 [M+H] + .

[0601] Preparation of intermediate 4

[0602] Step 1: Add 4-bromobenzonitrile (11 g, 60.77 mmol), 4-methylthiazole (7.2 g, 72.9 mmol), potassium acetate (11.9 g, 121.5 mmol), and palladium acetate (1.36 g, 6.1 mmol) to NMP (200 mL) and stir at 110°C overnight under nitrogen. TLC monitors the reaction completion. The reaction solution is cooled to room temperature, water (300 mL) is added, and extraction is performed with ethyl acetate (400 mL x 3). Drying over anhydrous sodium sulfate, concentration, and purification by column chromatography (EA / PE = 1:4) affords compound 4-a (4.0 g, yellow solid) in a yield of 33%.

[0603] Step 2: At 0°C, 4-a (1.5 g, 7.490 mmol) and LiAlH4 (568.49 mg, 14.980 mmol) were added to THF (40 mL). The reaction temperature was raised to 60°C and stirred overnight. TLC monitored the reaction completion. The temperature was lowered to room temperature and water (1 mL) was added to quench the reaction. Aqueous NaOH solution (15 wt%) was added, followed by water (2 mL), and the mixture was filtered. The filtrate was concentrated and purified by column chromatography (EA / PE = 1:10-1:2) to give 4-b (400 mg) in a yield of 26.14%.

[0604] Step 3: 4-b (400 mg, 1.958 mmol), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (452.79 mg, 1.958 mmol), HATU (744.51 mg, 1.958 mmol), and DIEA (759.21 mg, 5.874 mmol) were added to DCM (3 mL) and stirred at room temperature overnight. The reaction was monitored for completion by TLC. The reaction solution was concentrated and purified by column chromatography (EA / PE = 1:10 to 1:1) to afford 4-c (200 mg, white solid) in a yield of 24.46%.

[0605] Step 4: 4-c (200 mg, 0.479 mmol) and HCl / ethyl acetate solution (2 mol / L, 87.33 mg, 2.395 mmol) were added to EA (10 mL) and stirred at room temperature for 4 hours. The reaction was monitored for completion by TLC. The reaction mixture was filtered and the filter cake was collected to obtain intermediate 4 (160 mg, white solid) in a yield of 94.39%.

[0606] Preparation of intermediate 5

[0607] Step 1: Dissolve 5-b (350 mg, 1.7 mmol) in a mixture of 1,4-dioxane (15 mL) and water (3 mL). Add tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (565.88 mg, 1.7 mmol), potassium carbonate (704.09 mg, 5.1 mmol), and Pd(dppf)Cl2 (124.25 mg, 0.17 mmol) sequentially at room temperature. The reaction mixture was stirred at 90°C under nitrogen for 16 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography to afford 5-c (300 mg, light yellow liquid) in a 53.3% yield. MS m / z (ESI): 333.1 [M+H] + .

[0608] Step 2: Dissolve 5-c (300 mg, 0.9 mmol) in methanol (3 mL) and add HCl / dioxane solution (3 mL, 12 mmol, 4 mol / L) at room temperature. Stir the reaction mixture at room temperature for 16 hours. Concentrate the reaction mixture to give 5-d (240 mg, yellow solid) in a 99.2% yield. MS m / z (ESI): 233.2 [M+H] + .

[0609] Step 3: Dissolve 5-d (240 mg, 0.893 mmol) in DMF (5 mL). Add (2S,4R)-1-(tert-Butyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (206.47 mg, 0.893 mmol), DIEA (0.55 mL, 3.3 mmol), and HATU (339.48 mg, 0.893 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The organic phase was concentrated, and the crude product was purified by silica gel column chromatography to afford 5-e (390 mg, light yellow solid) in a 98.17% yield. MS m / z (ESI): 446.1 [M+H] + .

[0610] Step 4: Dissolve 5-e (390 mg, 0.876 mmol) in methanol (4 mL). Add HCl / dioxane solution (4 mL, 16 mmol, 4 mol / L) at room temperature. Stir the reaction mixture at room temperature for 2 hours and then spin dry to obtain 5-f (330 mg, light yellow solid). Yield: 98.65%. MS m / z (ESI): 346.2 [M+H] + .

[0611] Step 5: Dissolve 5-f (330 mg, 0.865 mmol) in DMF (5 mL). Add (S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (199.8 mg, 0.865 mmol), DIEA (0.53 mL, 3.2 mmol), and HATU (328.7 mg, 0.865 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The organic phase was dried by rotary evaporation. The crude product was purified by silica gel column chromatography (PE / EA = 10:1) to afford 5-g (480 mg, yellow liquid) in a 99.5% yield. MS m / z (ESI): 559.2 [M+H] + .

[0612] Step 6: Dissolve 5-g in THF (5 mL) and add HCl / dioxane solution (12 mL, 4 mol / L) at room temperature. Stir the reaction mixture at room temperature for 2 hours and then spin dry to obtain intermediate 5 (424 mg, yellow liquid). Yield: 99.86%. MS m / z (ESI): 459.3 [M+H] + .

[0613] Preparation of intermediate 6

[0614] Referring to steps 1 to 4 in the preparation method of intermediate 5, according to the above synthetic route, intermediate 5-b was replaced with tert-butyl (S)-(1-(4-bromophenyl)ethyl)carbamate, and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate was replaced with 3,5-dimethylpyrazole-4-boronic acid pinacol ester to prepare intermediate 6. MS m / z (ESI): 329.2 [M+H] + .

[0615] Preparation of intermediate 7

[0616] Step 1: Dissolve tert-butyl (4-bromobenzyl)carbamate (9.00 g, 31.4 mmol) and 4-methyl-1,3-thiazole (5.72 mL, 62.9 mmol) in DMA (20 mL). Add palladium acetate (100 mg, 0.450 mmol) and potassium carbonate (3.08 g, 31.4 mmol). Stir at 150°C under nitrogen for 4 hours. After post-treatment, quench with saturated sodium chloride solution. Extract the aqueous phase with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 2 / 1) to afford 7-a (7.70 g, crude product) in an 80.4% yield. MS m / z (ESI): 305.0 [M+H].+ .

[0617] Step 2: Dissolve 7-a (1.50 g, 4.93 mmol) in DCM (2.00 mL) and add HCl / 1,4-dioxane solution (10.0 mL, 20.0 mmol, 2 mol / L). Stir the resulting mixture at 25°C for 3 hours. Concentrate to afford 7-b (1.41 g, crude product) in a 99.48% yield. MS m / z (ESI): 204.9 [M+H] + .

[0618] Step 3: 7-b (1.63 g, 6.79 mmol) was dissolved in DMF (50 mL), and (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.57 g, 6.79 mmol), HATU (3.10 g, 8.15 mmol), and DIEA (2.62 g, 20.4 mmol) were added. After the reaction was completed, the resulting mixture was stirred at 25 ° C for 5 hours. Purification by silica gel column chromatography (PE / EA = 2 / 1) gave 7-c (2.18 g, white solid). Yield: 76.88%. MS m / z (ESI): 418.5 [M+H] + .

[0619] Step 4: 7-c (2.18 g, 5.22 mmol) was added to a 4 mol / L HCl / dioxane solution (10 mL), and the resulting mixture was stirred at 25°C for 2 hours. After post-treatment, the reaction solution was concentrated to afford 7-d (1.97 g), which was used directly in the next step without further treatment. Yield: 99.95%. MS m / z (ESI): 318.2 [M+H] + .

[0620] Step 5: To a solution of 7-d (1.97 g, 5.59 mmol) in DMF (10 mL) were added (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (1.29 g, 5.49 mmol), HATU (2.54 g, 6.70 mmol), and DIEA (2.16 g, 16.7 mmol), and the resulting mixture was stirred at 25 ° C for 5 hours. The mixture was concentrated and diluted with water (20 mL) and extracted with dichloromethane (20 mL×3). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (PE / EA=2 / 1) to give 7-e (2.95 g). Yield: 99.51%. MS m / z (ESI): 531.6 [M+H] + .

[0621] Step 6: To a solution of 7-e (700 mg, 1.32 mmol) in DCM (5.00 mL) was added HCl / dioxane solution (4 mol / L, 10 mL). The resulting mixture was then stirred at 25°C for 3 hours. After post-treatment, the reaction solution was concentrated to afford intermediate 7 (690 mg) in a 97.2% yield. MS m / z (ESI): 431.2 [M+H] + .

[0622] Preparation of intermediate 8

[0623] Step 1: (S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (11.6 g, 50.0 mmol) and L-hydroxyproline methyl ester hydrochloride (10.0 g, 55.0 mmol) were dissolved in DCM (500 mL), HATU (25.0 g, 66.0 mmol), and DIPEA (42.6 g, 330.0 mmol). The mixture was reacted at room temperature for 4 hours. The reaction was monitored by TLC for completion. The reaction mixture was added with water (400 mL) and washed with 5% citric acid (200 mL x 2) and saturated sodium chloride solution (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography (MeOH / DCM = 1:50-1:20) to obtain 8-a (16.7 g, colorless liquid) in an 88% yield.

[0624] Step 2: Dissolve 8-a (2.0 g, 5.6 mmol) in DCM (30 mL), add HCl / dioxane solution (4 mol / L, 1.5 mL), stir at room temperature overnight, and monitor the reaction completion by TLC. Concentrate to obtain 8-b (1.6 g, colorless liquid) in a 97% yield, which is used directly in the next step.

[0625] Step 3: 8-b (1.6 g, 5.6 mmol) and 1-fluorocyclopropanecarboxylic acid (640 mg, 6.16 mmol) were dissolved in DMF (15 mL), and HATU (2.5 g, 6.7 mmol) and DIPEA (4.3 g, 33.6 mmol) were added. The mixture was reacted at room temperature for 4 hours. The reaction was monitored by TLC for completion. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The concentrate was purified by column chromatography (MeOH / DCM = 1:50-1:20) to obtain 8-c (1.5 g, yellow oil) in a yield of 78%.

[0626] Step 4: 8-c (1.5 g, 4.3 mmol) was dissolved in THF (30 mL) and water (10 mL), and LiOH·H2O (900 mg, 22.0 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC for completion. The THF was concentrated to remove the THF, solid sodium hydroxide was added to adjust the pH to 12, and ethyl acetate (100 mL) was added for extraction. The aqueous phase was collected, and the pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid solution (6 mol / L). The aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 8 (1.0 g, white solid). Yield: 70%.

[0627] Preparation of intermediate 9

[0628] Step 1: Dissolve (1S)-1-[4-(4-methyl-thiazol-5-yl)phenyl]ethyl-1-amine (500 mg, 1.962 mmol) in acetonitrile (8 mL), add (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (675.90 mg, 1.962 mmol) and N-methylimidazole (805.70 mg, 9.812 mmol), stir for 5 minutes, add TCFH (715.82 mg, 2.551 mmol), and stir the reaction at room temperature for 3 hours. The reaction is monitored by TLC to ensure completion. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE=0-70%) to give 9-a (500 mg, yellow solid) in a yield of 48.08%.

[0629] Step 2: Dissolve 9-a (500 mg, 0.942 mmol) in EA (20 mL) and HCl / ethyl acetate solution (2 mol / L, 20 mL). Allow to react overnight at room temperature. TLC monitors the reaction for completion. The reaction solution is spin-dried, and water (5 mL) and EA (5 mL) are added. The pH is adjusted to 6-7 with saturated sodium bicarbonate solution. The layers are separated, and ethyl acetate (20 mL x 3) is added to extract the aqueous phase. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated to afford intermediate 9 (300 mg, yellow solid). Yield: 73.17%.

[0630] Preparation of intermediate 10

[0631] Step 1: Dissolve 5-aminomethyl-2-bromopyridine (2.0 g, 10.693 mmol) in THF (30 mL) and water (10 mL), add (Boc)2O (2.57 g, 11.762 mmol) and sodium carbonate (2.27 g, 21.386 mmol), and react at 20°C for 1 hour. TLC monitors the reaction completion. Dilute with water (50 mL), extract with ethyl acetate (20 mL x 2), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (EA / PE = 1:20-1:10) to afford 10-a (3.0 g, light yellow solid) in a yield of 97.70%.

[0632] Step 2: 10-a (2.0 g, 6.965 mmol), 2-amino-4-methylthiazole (0.68 g, 5.920 mmol), cesium carbonate (6.80 g, 20.894 mmol) and BrettPhos-Pd-G3 (0.63 g, 0.696 mmol) were dissolved in 1,4-dioxane (20 mL), heated to 110 ° C and stirred for 12 hours. The reaction was completed after TLC monitoring. The product was diluted with water (50 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE=1:10-1:3) to give 10-b (1.15 g, light yellow solid). Yield: 51.57%.

[0633] Step 3: 10-b (160 mg, 0.499 mmol) was dissolved in DCM (10 mL), HCl / ethyl acetate solution (2 mol / L, 20 mL) was added, and the mixture was stirred at room temperature overnight. The reaction was completed after monitoring by TLC. The reaction solution was filtered, and the filter cake was dissolved in water (10 mL). The pH was adjusted to 6-7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give 10-c (110 mg, yellow solid). Yield: 100.00%, which was used directly in the next step.

[0634] Step 4: 10-c (100 mg, 0.454 mmol) was dissolved in acetonitrile (4 mL) and DMF (2 mL). (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (156.34 mg, 0.454 mmol) and N-methylimidazole (186.37 mg, 2.270 mmol) were added. The mixture was stirred for 5 minutes. TCFH (152.84 mg, 0.545 mmol) was added and stirred at room temperature for 3 hours. The reaction was monitored for completion by TLC. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The product was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 20:1) to give 10-d (247 mg, yellow solid). Yield: 99.53%.

[0635] Step 5: 10-d (247 mg, 0.452 mmol) was dissolved in DCM (4 mL), and HCl / ethyl acetate solution (2 mol / L, 5 mL) was added. The mixture was stirred at room temperature overnight. The reaction was completed by monitoring by TLC. The reaction solution was filtered, and the filter cake was dissolved in water (10 mL). The pH was adjusted to 6-7 with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to give intermediate 10 (190 mg, white solid). Yield: 94.17%.

[0636] Preparation of intermediate 11

[0637] Step 1: To a solution of 4-bromobenzonitrile (1.00 mL, 5.49 mmol) in THF (5 mL) at 0°C under a nitrogen atmosphere was added a solution of methylmagnesium bromide in THF (1 mol / L, 16.5 mL, 16.5 mmol). The mixture was stirred at 25°C for 30 minutes, followed by the dropwise addition of tetraisopropyltitanium oxide (1.7 mL, 5.68 mmol). The mixture was reacted at 50°C under a nitrogen atmosphere for 18 hours. After completion of the reaction, aqueous sodium hydroxide solution (10 wt%, 10 mL) was added dropwise to the mixture, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was extracted with methyl tert-butyl ether (30 mL). The organic phase was washed with aqueous NaOH solution (10 wt%, 10 mL) and saturated sodium chloride solution (10 mL). Aqueous hydrochloric acid solution (2 mol / L, 10 mL) was then added to the organic phase. The aqueous phase was extracted with methyl tert-butyl ether (30 mL x 2). Aqueous NaOH (10 wt%) was added to the aqueous phase to adjust the pH to 9. The aqueous phase was then extracted with methyl tert-butyl ether (30 mL x 2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated to afford 11-a (0.64 g, yellow oil) in a yield of 54.24%. MS m / z (ESI): 197.0 [M-17+H]+ .

[0638] Step 2: To a solution of 11-a (590 mg, 2.76 mmol) in DCM (20 mL) were added (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (765 mg, 3.31 mmol), HATU (1572 mg, 4.13 mmol) and DIPEA (1.44 mL, 8.26 mmol), and the mixture was stirred at 25 ° C. under a nitrogen atmosphere for 2 hours. The mixture was concentrated to obtain a crude product. The crude product was purified by pre-HPLC (eluent: 30%-60% (v / v) acetonitrile and aqueous solution containing 0.1 wt% NH4HCO3) to give 11-b (660 mg, colorless oil) in a yield of 56.05%. MS m / z (ESI): 327.0 [M-100+H] + .

[0639] Step 3: To a solution of 11-b (530 mg, 1.24 mmol) in DMA (8 mL) were added 4-methylthiazole (148 mg, 1.49 mmol), KOAc (245 mg, 2.50 mmol), and Pd(OAc)2 (28 mg, 0.12 mmol). The mixture was stirred at 110°C under a nitrogen atmosphere for 18 hours. After the reaction, the mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 100:1-20:1) to obtain 11-c (160 mg, yellow oil) in a yield of 27.51%. MS m / z (ESI): 446.2 [M+H] + .

[0640] Step 4: To a solution of 11-c (160 mg, 0.34 mmol) in 1,4-dioxane (5 mL) was added hydrochloric acid / dioxane (4 mol / L, 5 mL), and the mixture was stirred at 25°C for 2 hours. The mixture was concentrated to afford 11-d (130 mg, yellow solid) in a yield of 95.11%. MS m / z (ESI): 346.2 [M+H] + .

[0641] Step 5: To a solution of 11-d (130 mg, 0.36 mmol) in DCM (10 mL) at 0°C under a nitrogen atmosphere were added (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (99 mg, 0.43 mmol), HATU (204 mg, 0.54 mmol), and DIPEA (232 mg, 1.80 mmol). The mixture was stirred at 25°C for 2 hours. After the reaction, the mixture was poured into water (20 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH = 100:1-10:1) to obtain 11-e (158 mg, yellow solid) in a yield of 75.14%. MS m / z (ESI): 559.4 [M+H] + .

[0642] Step 6: To a solution of 11-e (158 mg, 0.27 mmol) in 1,4-dioxane (2.5 mL) was added HCl / dioxane (4 mol / L, 2.5 mL), and the mixture was reacted at 25°C for 2 hours. After the reaction, the mixture was concentrated to afford intermediate 11 (147 mg, yellow solid) in a yield of 99.47%. MS m / z (ESI): 459.2 [M+H] + .

[0643] Preparation of intermediate 12

[0644] Step 1: 4-Bromobenzylamine (500 mg, 14.657 mmol), 2-methylpyridine-4-boronic acid (441.62 mg, 3.225 mmol), potassium phosphate (1711.31 mg, 8.062 mmol), Pd2(dba)3 (73.83 mg, 0.081 mmol), and S-Phos (11.03 mg, 0.027 mmol) were dissolved in n-butanol (10 mL) and water (2 mL). The mixture was heated to 120°C under nitrogen for 16 hours. The reaction was monitored by TLC for completion. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, extracted, and separated. The organic phase was washed with saturated brine, concentrated, and purified by column chromatography to obtain 12-a (300 mg, yellow oil) in a yield of 56.30%.

[0645] Step 2: (2S,4R)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (286.62 mg, 0.832 mmol) was dissolved in DMF (2 mL), and DIEA (293.35 mg, 2.270 mmol) and TCFH (318.38 mg, 1.135 mmol) were added. The mixture was stirred at room temperature for 1 hour, and 12-a (1.0 g, 2.915 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction was monitored for completion by TLC. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 12-b (300 mg, light yellow oil) in a yield of 75.58%.

[0646] Step 3: Dissolve 12-b (200 mg, 0.381 mmol) in EA (1 mL) and HCl / ethyl acetate (4 mol / L, 0.1 mL) in an ice-water bath. Stir overnight at room temperature. Monitor the reaction for completion by TLC. The reaction solution was concentrated to afford intermediate 12 (100 mg, white solid) in a 56.93% yield, which was used directly in the next step.

[0647] Preparation of intermediate 13

[0648] Step 1: Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (1.00 g, 5.02 mmol) was dissolved in acetonitrile (10 mL) at room temperature. 3-Bromopropyne (0.48 mL, 5.52 mmol) and potassium carbonate (1.39 g, 10.0 mmol) were added. The reaction was incubated at 60°C for 18 hours. The reaction solution was concentrated and purified by column chromatography (EA / PE = 0-30%) to afford 13-a (0.50 g, yellow oil). Yield: 33.6%. MS m / z (ESI): 238.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ (ppm) 5.88 (s, 1H), 4.79 (d, J = 2.4Hz, 2H), 3.67-3.66 (m, 4H), 3.43 (d, J=8.6Hz,1H),2.52(t,J=2.4Hz,1H),2.32-2.22(m,1H),0.93(d,J=6.7Hz,3H),0.85(d,J=6.8Hz,3H).

[0649] Step 2: Dissolve 13-a (0.50 g, 2.11 mmol) in methanol (10 mL) and water (2 mL) at room temperature, add LiOH·H2O (265 mg, 6.32 mmol), and react at room temperature for 18 hours. The reaction solution is concentrated to afford 13-b (0.47 g, white solid) in a 99.9% yield. MS m / z (ESI): 224.0 [M+H] + .

[0650] Step 3: Dissolve 13-b (0.47 g, 2.11 mmol) in dry DCM (10 mL) at room temperature, add Intermediate 2 (837 mg, 2.53 mmol), DIEA (1.05 mL, 5.62 mmol), and HATU (800 mg, 2.11 mmol), and react at room temperature for 18 hours. The reaction solution was concentrated and purified by column chromatography (MeOH / DCM = 0-10%) to obtain Intermediate 13 (1 g, yellow oil). Yield: 88.5%. MS m / z (ESI): 537.2 [M+H] + .

[0651] Preparation of intermediate 15

[0652] Step 1: 3-Methyl-2-(3-(prop-2-yn-1-yloxy)isoxazol-5-yl)butanoic acid (140 mg, 0.63 mmol), (2S,4R)-N-((S)-1-(4-cyanophenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (186 mg, 0.63 mmol), and DIEA (0.52 mL, 3.14 mmol) were dissolved in DMF (6 mL). HATU (286 mg, 0.75 mmol) was added portionwise at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was concentrated and the crude product was purified by silica gel column chromatography to afford Intermediate 15 (219 mg, white solid) in a yield of 75.09%. MS m / z (ESI): 465.2 [M+H]. + .

[0653] Preparation of intermediate 16

[0654] Step 1: Dissolve tert-butyl (1-(4-bromophenyl)propyl)carbamate (2 g, 6.37 mmol) and 4-methylthiazole (1.26 g, 12.73 mmol) in DMF (15 mL). Add Pd(OAc)2 (143 mg, 0.64 mmol) and KOAc (1.25 g, 12.73 mmol). Stir the reaction mixture at 110°C overnight under argon. After completion, pour the reaction mixture into water and extract with ethyl acetate (10 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (0-60% EA / PE) to afford 16-a (1.36 g) in a yield of 64.27%. MS m / z (ESI): 333.1 [M+H]. + .

[0655] Step 2: Dissolve 16-a (1.36 g, 4.09 mmol) in MeOH (15 mL), add HCl / 1,4-dioxane (4 mol / L, 10 mL), and stir at room temperature for 4 hours. After the reaction is complete, the reaction solution is concentrated to obtain 16-b (1.06 g, crude product) in a yield of 96.03%, which is used directly in the next reaction. MS m / z (ESI): 233.1 [M+H] + .

[0656] Step 3: Dissolve 16-b (1.05 g, 4.52 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.57 g, 6.78 mmol) in DMF (20 mL). Then add DIPEA (1.75 g, 13.56 mmol) and HATU (2.56 g, 6.78 mmol) and stir at room temperature for 20 hours. After completion of the reaction, pour the reaction solution into water and extract with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash (0-10% MeOH / DCM) to afford 16-c (1.8 g) in a yield of 89.39%. MS m / z (ESI): 446.2 [M+H]. + .

[0657] Step 4: Dissolve 16-c (1.8 g, 4.04 mmol) in MeOH (20 mL), add HCl / EA (4 mol / L, 9 mL), and stir at room temperature for 20 hours. After completion of the reaction, concentrate the reaction solution to obtain 16-d (1.3 g, crude product) in a yield of 93.15%, which was used directly in the next reaction. MS m / z (ESI): 346.2 [M+H] + .

[0658] Step 5: Dissolve 16-d (1.5 g, 4.34 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (1.51 g, 6.51 mmol) in DMF (15 mL). Add DIPEA (3.37 g, 26.05 mmol) and HATU (2.46 g, 6.51 mmol). Stir at room temperature for 20 hours. After completion of the reaction, pour the reaction solution into water and extract with ethyl acetate (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by CombiFlash chromatography (0-10% MeOH / DCM) to afford 16-e (2 g) in 82.44% yield. MS m / z (ESI): 559.3 [M+H]. + .

[0659] Step 6: Dissolve 16-e (200 mg, 0.36 mmol) in MeOH (8 mL), add HCl / EA (4 mol / L, 4 mL), and stir at room temperature for 20 hours. After completion of the reaction, the reaction solution was concentrated to obtain intermediate 16 (145 mg, crude product) in an 88.33% yield, which was used directly in the next reaction. MS m / z (ESI): 459.3 [M+H] + .

[0660] Preparation method of intermediate 17

[0661] Step 1: Dissolve intermediate 2 (1.0 g, 3.02 mmol) in DMF (10 mL). Add (tert-Butyloxycarbonyl)-L-valine (655 mg, 3.02 mmol), DIPEA (1.95 g, 15.1 mmol), and HATU (1.12 g, 3.62 mmol) sequentially to the reaction mixture, and stir at room temperature for 1 hour. After completion, pour the reaction mixture into water (80 mL), filter, and concentrate the filter cake in vacuo to afford 17-a (837 mg, pale yellow solid, crude product) in a 52% yield. MS m / z (ESI): 531.3 [M+H] + .

[0662] Step 2: Dissolve 17-a (837 mg, 1.58 mmol) in MeOH (7.5 mL). Add dioxane hydrochloride (4 mol / L, 7.5 mL) at 0°C and warm to room temperature for 2 h. After completion of the reaction, concentrate the reaction solution to afford intermediate 17 (680 mg, light yellow oily liquid). Yield: 84.5%. MS m / z (ESI): 431.3 [M+H] + .

[0663] Preparation method of intermediate 18

[0664] Step 1: Dissolve 2-(4-bromophenyl)pyrrolidine (1 g, 4.42 mmol) in DCM (15 mL). Add triethylamine (1.34 g, 13.27 mmol) and (Boc)2O (1.079 g, 4.95 mmol) sequentially at room temperature. Stir at room temperature for 2 hours. After completion of the reaction, dilute with water (30 mL) and extract with dichloromethane (30 mL x 2). The combined organic phases were concentrated to afford 18-a (1.52 g, yellow oil, crude product) in a yield of 105.35%. MS m / z (ESI): 270.0 [M-56+H]. + .

[0665] Step 2: Batch 1: Dissolve 18-a (300 mg, 0.92 mmol) in NMP (4.5 mL). 4-Methylthiazole (109 mg, 1.10 mmol), KOAc (226 mg, 2.30 mmol), and Pd(OAc)2 (21 mg, 0.092 mmol) were added sequentially at room temperature. The mixture was stirred at 110°C under nitrogen for 5 hours. Batch 2: Dissolve 18-a (1.22 g, 3.74 mmol) in NMP (12 mL). 4-Methylthiazole (445 mg, 4.49 mmol), KOAc (918 mg, 9.35 mmol), and Pd(OAc)2 (84 mg, 0.37 mmol) were added sequentially at room temperature. The mixture was stirred at 110°C under nitrogen for 5 hours. After cooling to room temperature, the two reaction mixtures were combined, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain 18-b (1 g, yellow oil) in a yield of 62.31%. MS m / z (ESI): 345.1 [M+H] + .

[0666] Step 3: Dissolve 18-b (900 mg, 2.61 mmol) in MeOH (6 mL). Add a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 6 mL) at room temperature and stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution to obtain 18-c (733 mg, yellow solid) in a yield of 99.91%. MS m / z (ESI): 245.1 [M+H] + .

[0667] Step 4: Batch 1: 18-c (80 mg, 0.28 mmol) was dissolved in DMF (3 mL), and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (73 mg, 0.31 mmol), DIPEA (0.24 mL, 1.45 mmol), and HATU (120 mg, 0.31 mmol) were added sequentially at room temperature. The reaction was stirred at room temperature for 2 hours. Batch 2: 18-c (733 mg, 2.61 mmol) was dissolved in DMF (12 mL), and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (664 mg, 2.87 mmol), DIPEA (2.5 mL, 15.14 mmol), and HATU (1.09 g, 2.87 mmol) were added sequentially at room temperature. The reaction was stirred at room temperature for 1 hour. The two reaction solutions were combined, diluted with water (80 mL), and extracted with ethyl acetate (60 mL × 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain 18-d (920 mg, yellow solid) in a yield of 69.44%. MS m / z (ESI): 458.1 [M+H] + .

[0668] Step 5: Dissolve 18-d (200 mg, 0.44 mmol) in MeOH (3 mL) and add a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 2 mL) at room temperature. Stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution to obtain 18-e (170 mg, yellow solid) in a yield of 98.74%. MS m / z (ESI): 358.1 [M+H] + .

[0669] Step 6: Batch 1: 18-e (170 mg, 0.43 mmol) was dissolved in DMF (4 mL), and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (110 mg, 0.47 mmol), DIPEA (0.4 mL, 2.43 mmol), and HATU (180 mg, 0.47 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Batch 2: 18-e (620 mg, 1.57 mmol) was dissolved in DMF (8 mL), and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (400 mg, 1.73 mmol), DIPEA (1.46 mL, 8.85 mmol), and HATU (658 mg, 1.73 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The two reaction solutions were combined and slowly poured into water (60 mL). The precipitate was collected by filtration and then dried to give 18-f (790 mg, gray solid). Yield: 69.02%. MS m / z (ESI): 571.2 [M+H] + .

[0670] Step 7: Dissolve 18-f (690 mg, 1.71 mmol) in MeOH (6 mL). Add a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 4 mL) at room temperature and stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction mixture to obtain intermediate 18 (610 mg, yellow solid) in a yield of 99.50%. MS m / z (ESI): 471.2 [M+H] + .

[0671] Example 1 Preparation of Compound H-1

[0672] Step 1: Dissolve compound d (1.3 g, 3.27 mmol) and ethyl piperidine-4-carboxylate (1.03 g, 6.54 mmol) in 1,4-dioxane (40 mL) under nitrogen. Add Xphos (191 mg, 0.33 mmol), Cs2CO3 (2.66 g, 8.18 mmol), and Pd2(dba)3 (147 mg, 0.16 mmol) and react at 105°C for 16 hours. After cooling, add water (60 mL) and extract the aqueous phase with ethyl acetate (50 mL x 3). The organic phase is dried over anhydrous sodium sulfate, dried by spin drying, and purified by column chromatography (EA / PE = 20-70%) to afford H-1-a (950 mg, light yellow solid) in a yield of 61.3%. MS m / z (ESI): 475.0 [M+H]. + .

[0673] Step 2: Dissolve H-1-a (0.95 g, 2.0 mmol) in EA (15 mL) and MeOH (3 mL), add Pd / C (0.4 g, 10% purity), replace the hydrogen atmosphere (1 atm), and stir at 30°C for 16 hours. After the reaction is complete, filter and concentrate the filtrate to obtain H-1-b (710 mg, crude product, yellow oil). MS m / z (ESI): 343.2 [M+H] + .

[0674] Step 3: 4-Bromo-6-chloropyridazin-3-amine (0.52 g, 2.5 mmol) and DIEA (1.34 g, 10.4 mmol) were added to DMSO (20 mL), followed by H-1-b (0.71 g, 2.08 mmol). The mixture was reacted at 120°C under nitrogen for 16 hours. After cooling, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, dried, and purified by column chromatography (EtOAc / PE = 20-80%) to afford H-1-c (426 mg, light yellow solid) in a yield of 45.3%. MS m / z (ESI): 469.9 [M+H] + .

[0675] Step 4: Dissolve H-1-c (426 mg, 0.91 mmol), 2-hydroxyphenylboronic acid (140 mg, 1.0 mmol), Xphos G3Pd (93 mg, 0.11 mmol), and K2CO3 (315 mg, 2.28 mmol) in a mixture of 1,4-dioxane (33 mL) and water (6.6 mL) under nitrogen atmosphere at 90°C for 5 hours. After cooling, water (100 mL) was added, and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EtOAc / PE = 30-80%) to afford H-1-d (280 mg, light yellow solid) in a yield of 58.4%. MS m / z (ESI): 527.9 [M+H] + .

[0676] Step 5: Dissolve H-1-d (130 mg, 0.25 mmol) in a mixture of methanol (4 mL), water (4 mL), and THF (4 mL). Add LiOH·H2O (53 mg, 1.26 mmol) and stir at room temperature under nitrogen for 16 hours. After the reaction is complete, add hydrochloric acid (2 mol / L) dropwise to adjust the pH to 6-7. Concentrate the tetrahydrofuran, add 30 mL of water, and extract the aqueous phase with dichloromethane / methanol (v / v = 10:1) (50 mL x 3). Dry the organic phase over anhydrous sodium sulfate and concentrate to obtain H-1-e (78 mg, crude product, light yellow solid). MS m / z (ESI): 500.0 [M+H] +.

[0677] Step 6: H-1-e (78 mg, 0.16 mmol) was dissolved in DMF (6 mL) under nitrogen atmosphere. DIEA (62 mg, 0.48 mmol) and HATU (99 mg, 0.26 mmol) were added separately. The mixture was stirred for 2 minutes and then added dropwise to a solution of intermediate 7 (80 mg, 0.18 mmol) in DMF (6 mL). The mixture was allowed to react at room temperature for 2 hours. Water (30 mL) was added and the aqueous phase was extracted with dichloromethane / methanol (v / v = 10:1) (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting mixture was purified by pre-HPLC (A: H2O containing 0.1 wt% NH4HCO3; B: MeCN, preparative column: 19×150 mm C18 column; gradient: 20%-70% acetonitrile) to afford H-1 (16 mg) in a yield of 11.0%. MS m / z(ESI):912.1[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.31 (s, 1H), 8.99 (s, 1H), 8.57 (s, 1H), 7.96-7.85 (m, 2H), 7.59 (s, 1H), 7.44-7.38(m,4H),7.27-7.23(t,J=7.6Hz,1H),7.11-7.09(d,J=8.0Hz,1H),6.91-6.89 (m,2H),6.81-6.79(m,2H),6.27(s,2H),5.15(s,1H),4.56-4.53(d,J=9.2Hz,1H),4.47 -4.21(m,4H),3.67-3.65(m,4H),3.45-3.42(m,2H),2.92-2.84(m,4H),2.64-2.51(m,3 H),2.45(s,3H),2.12-2.06(m,5H),1.92-1.77(m,2H),1.68-1.54(m,5H),0.96(s,9H).

[0678] Example 2 Preparation of Compound H-2

[0679] Step 1: Intermediate g (900 mg, 2.7 mmol), methyl (1S,3S)-3-hydroxycyclobutanecarboxylate (0.57 mL, 5.4 mmol), and tri-n-butylphosphine (1.3 mL, 5.4 mmol) were dissolved in toluene (20 mL). TMAD (930 mg, 5.4 mmol) was added to the mixture in an ice-water bath. The mixture was heated to 110°C and stirred for 16 hours. Upon completion, the mixture was diluted with EA (36 mL), washed with saturated aqueous NaHCO₃, and extracted with EA several times. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 10:1-2:1) to afford H-2-a (470 mg, colorless oil) in a 39% yield. MS m / z (ESI): 448.1 [M+H] + .

[0680] Step 2: Dissolve H-2-a (470 mg, 1.05 mmol) in methanol (15 mL), add 10% wet palladium on carbon (100 mg, 0.21 mmol), and stir at room temperature under a 1 atm hydrogen atmosphere for 16 hours. Once the reaction is complete, filter through celite and concentrate the filtrate to obtain H-2-b (350 mg, colorless oil, crude product). Use directly in the next step without purification. MS m / z (ESI): 316.1 [M+H] + .

[0681] Step 3: Dissolve H-2-b (350 mg, 1.1 mmol) in DMSO (15 mL) and add 4-bromo-6-chloropyridazin-3-amine (277 mg, 1.3 mmol) and DIEA (0.73 mL, 4.4 mmol) at room temperature. Heat the reaction mixture to 120°C and stir for 16 hours. After the reaction is complete, cool to room temperature, dilute with water (80 mL), and extract with ethyl acetate (40 mL x 2). The organic phase is then dried and the crude product is purified by silica gel column chromatography to afford H-2-c (387 mg, yellow solid) in a 79% yield. MS m / z (ESI): 443.1 [M+H] + .

[0682] Step 4: H-2-c (387 mg, 0.87 mmol) was dissolved in dioxane (15 mL) and water (3 mL). (2-Hydroxyphenyl)boronic acid (417 mg, 1.74 mmol), potassium carbonate (361 mg, 2.61 mmol), and BrettPhos Pd G3 (220 mg, 0.26 mmol) were added sequentially at room temperature. The reaction mixture was stirred at 90°C under nitrogen for 5 hours. The mixture was then concentrated and the crude product was purified by silica gel column chromatography to afford H-2-d (343 mg, yellow solid) in a 79% yield. MS m / z (ESI): 501.3 [M+H] + .

[0683] Step 5: H-2-d (343 mg, 0.68 mmol) was dissolved in anhydrous DCM (4 mL), cooled to -78°C, and a toluene solution of diisobutylaluminum hydride (0.9 mL, 1.36 mmol, 1.5 mol / L) was slowly added dropwise. The mixture was stirred at -78°C for 1.5 hours. Upon completion, saturated aqueous ammonium chloride was slowly added to quench the reaction. The mixture was warmed to room temperature and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to afford H-2-e (90 mg, yellow solid) in a 28% yield. MS m / z (ESI): 471.1 [M+H]. + .

[0684] Step 6: H-2-k (75 mg, 0.16 mmol) was dissolved in DMF (4.5 mL), and intermediate 2 (55 mg, 0.17 mmol), DIEA (0.09 mL, 0.48 mmol), and HATU (76 mg, 0.20 mmol) were added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 × 50 mL). The collected organic phase was washed with saturated brine (3 × 50 mL), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 50:1-20:1) to obtain H-2-1 (120 mg, yellow solid) in a 94% yield. MS m / z (ESI): 765.3 [M+H] + .

[0685] Step 7: Dissolve H-2-1 (120 mg, 0.16 mmol) in dioxane (4.0 mL), cool to 0°C, slowly add HCl / 1,4-dioxane solution (0.16 mL, 0.64 mmol, 4 mol / L), warm to room temperature, and stir for 1 hour. After the reaction is complete, stop stirring, let stand, filter, and dry to obtain H-2-m (106 mg, yellow solid). MS m / z (ESI): 665.2 [M+H] + .

[0686] Step 8: Triethylamine (24 mg, 0.24 mmol) was added to H-2-m (56 mg, 0.08 mmol) and stirred at room temperature for 10 min. H-2-e (40 mg, 0.08 mmol) and glacial acetic acid (10 mg, 0.16 mmol) were then added and stirred at room temperature for 1 hour. Sodium acetate borohydride (85 mg, 0.4 mmol) was then added and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated and purified by column chromatography to give 46 mg of crude product. Preparative purification (A: H2O, 0.1 wt% NH4HCO3; B: MeCN, preparative column: 19 x 150 mm C18 column; gradient: 20%-70% acetonitrile) afforded the desired product H-2 (8.8 mg) in a 9% yield. MS m / z (ESI): 1119.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.05-9.03(m,1H),8.46-8.25(m,1H),8.00( d,J=8.0Hz,1H),7.65(s,1H),7.53-7.37(m,4H),7.30(t,J=7.4Hz,1H),7.1 4(d,J=8.4Hz,1H),6.97-6.95(m,2H),6.78(d,J=8.0Hz,1H),6.70-6.65(m ,1H),6.35(s,2H),6.19(d,J=4.4Hz,1H),5.16-5.05(m,1H),4.99-4.91(m, 1H),4.59-4.55(m,1H),4.49-4.41(m,1H),4.34(s,1H),3.79-3.73(m,1H) ,3.63-3.60(m,1H),2.99-2.86(m,8H),2.73-2.65(m,3H),2.47-2.42(m,3H ),2.23-2.10(m,10H),1.86-1.82(m,5H),1.74-1.72(m,1H),1.64-1.61(m, 2H),1.52-1.40(m,9H),1.30(s,3H),1.02-1.01(m,3H),0.93-0.80(m,5H).

[0687] Example 3 Preparation of Compound H-3

[0688] Step 1: Dissolve p-bromobenzaldehyde (7.5 g, 40.00 mmol) in NMP (50 mL), add 4-methylthiazole (8.0 g, 80.00 mol), palladium acetate (0.5 g, 2.00 mmol), and potassium acetate (7.8 g, 80.00 mol), and heat to 110°C for 4 hours. The reaction is monitored by TLC for completion. Water (300 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (300 mL × 3). The organic phase is washed with saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, and concentrated. The organic phase is purified by column chromatography (EA / PE = 1:10-1:5) to obtain H-3-a (7.0 g, yellow oil) in a yield of 86%.

[0689] Step 2: Take magnesium powder (50g) and add it to dilute hydrochloric acid solution (0.1mol / L, 200mL), stir for 30 minutes, filter with suction, and dry the filter cake under reduced pressure for 1 hour for standby use. Under nitrogen protection, add treated magnesium powder (1.0g), THF (10mL), and iodine (0.1g) into a 100mL three-necked flask, stir, raise the temperature to 65°C, add dropwise a solution of 5-bromo-1-pentene (5.1g) in tetrahydrofuran (10mL), complete the addition, keep warm at 65°C and stir for 2 hours, cool to room temperature, and standby use to obtain a 1.7M / L Grignard reagent solution.

[0690] Under nitrogen protection, H-3-a (1.6 g) was dissolved in THF (20 mL), the temperature was controlled at -10°C to 0°C, and 16 mL of the above-prepared Grignard reagent solution was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes at this temperature. The reaction was detected by TLC. Saturated ammonium chloride solution (50 mL) was added under ice-water bath to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated and the concentrate was purified by column chromatography (EA / PE = 95:5-75:25) to obtain H-3-b (1.1 g, light yellow oil) in a yield of 48%.

[0691] Step 3: Under nitrogen, H-3-b (1.0 g, 3.66 mmol) was dissolved in DCM (20 mL). Dess-Martin reagent (1.55 g, 3.66 mmol) was added at 0°C and stirred at room temperature for 1 hour. The reaction was monitored for completion by TLC. Ethyl acetate (50 mL) was added to the reaction solution, and a large amount of solid precipitated. The solution was filtered and washed with 5% sodium thiosulfate solution (100 mL × 2) and saturated sodium bicarbonate solution (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (EA / PE = 0:1-10:90) to obtain H-3-c (0.97 g, colorless oil) in a yield of 98%.

[0692] Step 4: Under nitrogen, H-3-c (9.2 g, 33.94 mmol) was dissolved in THF (100 mL) and 9-BBN tetrahydrofuran solution (0.5 mol / L, 102 mL, 51 mmol) was added dropwise with stirring. After the addition was complete, the temperature was raised to 65°C and stirred for 2 hours. The system was cooled to 0°C, ethanol (85 mL) and sodium hydroxide aqueous solution (4 mol / L, 17 mL) were added, and hydrogen peroxide (51 mL, 30 wt%) was slowly added dropwise. After the addition was complete, the mixture was stirred for 2 hours. TLC monitoring showed that the reaction was almost complete. The reaction solution was added with saturated sodium chloride solution (200 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 0:1-100:30) to obtain H-3-d (4.6 g, light yellow solid). Yield: 47%.

[0693] Step 5: Dissolve H-3-d (0.5 g, 1.728 mmol) in methanol (6 mL), and stir to add ammonium acetate (1.33 g, 17.258 mmol) and NaBHCN (0.22 g, 3.456 mmol). Stir overnight, and monitor the reaction for completion by TLC. The reaction solution is concentrated under reduced pressure, and water (20 mL) is added. The aqueous phase is adjusted to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (20 mL x 3). The organic phase is discarded, and the aqueous phase is adjusted to pH 10 with aqueous sodium hydroxide solution (10 mol / L, 5 mL). The aqueous phase is extracted with dichloromethane (20 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 99:1-90:10) to obtain H-3-e (157 mg, colorless oil).

[0694] Step 6: Dissolve compound H-3-e (450 mg, 1.549 mmol) in 20 mL of tetrahydrofuran. Add triethylamine (203.44 mg, 2.014 mmol) and (Boc)2O (405.33 mg, 1.859 mmol) at room temperature and stir for 3 hours. Monitor the reaction for completion by TLC. The reaction solution is concentrated and purified by column chromatography (DCM / MeOH = 50:1 to 20:1) to obtain H-3-f (170 mg, colorless oil) in a yield of 28%.

[0695] Step 7: H-3-f (78 mg, 0.200 mmol) was dissolved in DCM (2 mL), triethylamine (0.111 mL, 0.800 mmol) was added and stirred, and then an ice-water bath was cooled to 0°C. A mixture of sulfur trioxide pyridine (63.66 mg, 0.400 mmol), pyridine (0.032 mL, 0.400 mmol) and DMSO (0.5 mL) was slowly added dropwise. After the addition, the ice-water bath was removed, the mixture was warmed to room temperature and stirred for 3 hours. TLC was used to monitor the reaction completion. Water was added to the reaction solution, the aqueous phase was extracted with dichloromethane (20 mL × 3), the combined organic phases were washed with water (20 mL × 2), the organic phases were dried over anhydrous magnesium sulfate, concentrated, and purified by flash column chromatography (PE:EA = 1:1) to obtain H-3-g (58 mg, colorless oil) with a yield of 74.74%.

[0696] Step 8: H-3-g (140 mg, 0.360 mmol) was dissolved in DMF (5 mL) at room temperature, and H-23-e (164.17 mg, 0.360 mmol) and acetic acid (0.3 mL) were added. Stir for 20 minutes, and sodium triacetoxyborohydride (228.01 mg, 1.081 mmol) was added at 0°C. The mixture was slowly returned to room temperature and stirred overnight. TLC monitored the reaction completion. Sodium hydroxide solution (3 mol / L) was added to the reaction solution to adjust the pH to 11. The liquid was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water (10 mL × 2). Drying over anhydrous magnesium sulfate, the organic phase was concentrated, and purification was performed by flash column chromatography (DCM:MeOH = 15:1) to obtain H-3-h (65 mg, yellow solid) in a yield of 21.78%.

[0697] Step 9: Dissolve H-3-h (65 mg, 0.078 mmol) in DCM (5 mL), cool to 0°C, and add dioxane hydrochloric acid solution (4 mol / L, 0.3 mL). Slowly return to room temperature and stir for 3 hours. TLC monitors the reaction for completion. The reaction solution is concentrated to give H-3-i (60 mg, yellow solid) in a yield of 99.9%. MS m / z (ESI): 728.4 [M+H] + .

[0698] Step 10: H-3-i (60 mg, 0.083 mmol) and intermediate 8 (29.99 mg, 0.091 mmol) were dissolved in DMF (2 mL) at room temperature. With stirring, HATU (34.52 mg, 0.091 mmol), HOAT (12.36 mg, 0.091 mmol), and DIEA (85.33 mg, 0.660 mmol) were added and stirring continued for 1 hour. The reaction was monitored for completion by TLC. Water (1 mL) was added to quench the reaction. Purification by pre-HPLC (HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: aqueous solution containing 0.1 wt% FA, mobile phase B: acetonitrile) afforded H-3 (50 mg) in a yield of 57.9%. MS m / z (ESI): 520.9 [M / 2+H] + . 1 H-NMR (400MHz, Methanol-d4): δ (ppm) 8.90 (d, J = 3.2Hz, 1H), 8.48 (s, 1H), 7.82 (dd, J = 8.3, 1.7Hz, 1H), 7.56 (d, J = 17.5Hz, 2H), 7.50-7.40 (m, 3H), 7.2 8(td,J=8.2,2.3Hz,2H),7.20-7.04(m,2H),6.96(dd,J=8.0,6.1Hz,2H),4. 66-4.60(m,4H),4.57-4.37(m,2H),3.93-3.74(m,2H),3.66(dd,J=13.2,5. 7Hz,2H),3.55(dt,J=12.7,3.1Hz,2H),3.24-2.81(m,9H),2.50(d,J=2.0H z,3H),2.32-2.14(m,5H),2.07(q,J=12.0,9.4Hz,4H),1.95(ddt,J=19.4,1 0.2,4.6Hz,3H),1.82(d,J=8.5Hz,2H),1.70(d,J=12.9Hz,3H),1.57-1.44( m,3H),1.35(ddq,J=21.1,12.2,4.8,4.1Hz,6H),1.10(s,6H),0.97(s,4H).

[0699] Example 4 Preparation of Compound H-4

[0700] Step 1: H-23-e (100 mg, 0.219 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (112.73 mg, 0.658 mmol), and anhydrous sodium sulfate (276.03 mg, 2.190 mmol) were dissolved in a mixture of DCE (20 mL) and acetic acid (2 mL). The mixture was heated to 70°C for 8 hours, then cooled to room temperature. NaBH(OAc)3 (279.11 mg, 1.317 mmol) was added and heated to 70°C for 16 hours. The reaction was monitored by TLC and quenched by water (10 mL). The organic phase was separated and washed with saturated brine. The organic phase was concentrated and purified by column chromatography (MeOH:DCM = 1:10) to obtain H-4-a (130.0 mg, white oil) in a yield of 96.97%, which was used directly in the next step.

[0701] Step 2: Add H-4-a (130 mg, 0.213 mmol) to a 4 mol / L 1,4-dioxane solution (0.5 mL). Stir at room temperature for 10 minutes. Monitor the reaction by TLC. The reaction mixture is concentrated to afford H-4-b (100.00 mg, off-white solid) in a yield of 85.81%.

[0702] Step 3: H-4-b (83.00 mg, 0.163 mmol) and triethylamine (59 mg, 0.58 mol) were dissolved in THF (1 mL), cooled to 0-10°C, and triphosgene (2.97 mg, 0.010 mmol) was added. The mixture was stirred at 0-10°C for 30 minutes, and intermediate 7 (69.98 mg, 0.163 mmol) was added. The mixture was allowed to return to room temperature and stirred for 16 hours. The reaction was monitored for completion by TLC. Ethyl acetate (10 mL) and water (10 mL) were added, the layers were separated, and the organic phase was washed with saturated brine. The organic phase was concentrated to obtain the crude product, which was purified by pre-HPLC (column: HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: 0.1 wt% FA in water, mobile phase B: ACN) to afford H-4 (4.67 mg) in a yield of 2.97%. MS m / z (ESI): 484.3 [M / 2+H]. + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 10.50 (s, 1H), 8.99 (s, 1H), 8.55 (t, J = 6.1Hz, 1H), 7.61 (d, J = 7.7Hz, 1H), 7.50 (s, 1H) ),7.48-7.36(m,5H),7.20(d,J=7.7Hz,1H),7.12-6.96(m,4H),6.27(d,J=9.3Hz,1H),5.33(t,J=4.8Hz,1H),4.49-4 .34(m,4H),4.28-4.14(m,2H),4.13(s,3H),4.06(s,2H),3.67(s,2H),3.29(s,5H),3.00-2.86(m,3H),2.45(s,3H) ,2.45(s,4H),2.16-1.97(m,8H),1.59(d,J=12.4Hz,2H),1.46(s,2H),1.24(s,6H),0.96(s,3H),0.90-0.82(m,1H).

[0703] Example 5 Preparation of Compound H-5

[0704] Step 1: Dissolve benzyl piperazine-1-carboxylate (5.0 g, 22.7 mmol) in DMF (50 mL). Add potassium carbonate (9.4 g, 68.1 mmol) and 2-bromo-1,1-dimethoxyethane (4.6 g, 27.3 mmol) at room temperature. Stir at 80°C for 16 hours. Cool to room temperature, add water (100 mL), and extract with ethyl acetate (100 mL x 3). The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 0-30 vol%) to afford H-5-a (6.1 g, light yellow oil) in an 87.2% yield. MS m / z (ESI): 309.2 [M+H] + .

[0705] Step 2: Dissolve H-5-a (6.1 g, 19.8 mmol) in ethyl acetate (80 mL), add palladium on carbon (10%, 1.8 g), and stir at 35°C for 16 hours. Filter and concentrate the filtrate to obtain H-5-b (3.1 g, pale yellow oil, crude product). MS m / z (ESI): 175.1 [M+H] + .

[0706] Step 3: Dissolve H-5-b (420 mg, 2.4 mmol) and methyl α-(1-methylethyl)-3-[(1,1,2,2,3,3,4,4,4-nonafluorobutyl)sulfonyl]oxy]-5-isoxazoleacetate (731 mg, 1.5 mmol) in DMSO (20 mL). Add DIEA (929 mg, 7.2 mmol). Stir under nitrogen at 105°C for 2 hours. Cool to room temperature, add water (50 mL), and extract with ethyl acetate (50 mL x 3). The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 10-50%) to afford H-5-c (370 mg, light yellow oil) in a 43.4% yield. MS m / z (ESI): 356.0 [M+H] + .

[0707] Step 4: Add H-5-c (370 mg, 1.04 mmol) to THF (5 mL), methanol (5 mL), and water (5 mL) under nitrogen atmosphere. Add LiOH·H2O (171 mg, 4.16 mmol). Reaction at room temperature for 16 hours. Adjust the pH to 6 with 2 mol / L dilute hydrochloric acid. The organic phase is concentrated and purified by silica gel column chromatography (MeOH / DCM = 5-25%) to afford H-5-d (170 mg, light yellow solid) in a 47.9% yield. MS m / z (ESI): 342.0 [M+H] + .

[0708] Step 5: H-5-d (115 mg, 0.34 mmol), intermediate 2 (113 mg, 0.34 mmol), and DIEA (132 mg, 1.02 mmol) were dissolved in DMF (10 mL) under nitrogen atmosphere. HOBt (55 mg, 0.41 mmol) and EDCI (71 mg, 0.37 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (35 mL) was added and the mixture was extracted with ethyl acetate (35 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH / DCM = 0-15%) to afford H-5-e (140 mg, light yellow solid) in a yield of 62.9%. MS m / z (ESI): 654.9 [M+H] + .

[0709] Step 6: Dissolve H-5-e (110 mg, 0.17 mmol) in THF (8 mL) and add dilute hydrochloric acid (1 mol / L, 8 mL). Under nitrogen, react at 62°C for 48 hours. Cool to room temperature, adjust the pH to 9 with saturated sodium bicarbonate solution, add water (10 mL), and extract with ethyl acetate (20 mL x 3). The organic phase is dried over anhydrous sodium sulfate and concentrated to afford H-5-f (61 mg, crude, light yellow solid). Yield: 58.7%. MS m / z (ESI): 609.3 [M+H]. + .

[0710] Step 7: H-5-f (61 mg, 0.10 mmol) and H-18-j (60 mg, 0.11 mmol) were dissolved in methanol (6 mL) and DCM (2 mL). 2 drops of acetic acid were added and the mixture was stirred at room temperature for 1 hour. NaBHCN (19 mg, 0.30 mmol) was added and the mixture was allowed to react at room temperature for 16 hours. The reaction solution was concentrated and purified by pre-HPLC (A: H2O containing 0.1% wt FA; B: MeCN, preparative column: 19 x 150 mm C18 column; gradient: 20%-70% acetonitrile) to obtain H-5 (7 mg) in a 6.2% yield. MS m / z (ESI): 1134.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 8.98-8.97 (m, 1H), 8.41-8.20 (m, 1H), 7.95-7.93 (d, J = 7.2 Hz,1H),7.59(s,1H),7.45-7.31(m,5H),7.26-7.23(t,J=7.6Hz,1H),7.11-7.09(d,J=8.0H z,1H),6.91-6.89(m,2H),6.72(s,1H),6.62-6.59(d,J=8.4Hz,1H),6.30(s,2H),6.15-6.1 3(d,J=6.4Hz,1H),4.91-4.78(m,2H),4.30-4.28(m,3H),3.70-3.69(m,1H),3.58-3.55(m, 2H),3.43-3.42(m,2H),3.14-3.09(m,6H),2.93-2.88(t,J=12.0Hz,2H),2.84-2.80(t,J=6 .8Hz,2H),2.73-2.71(m,2H),2.46-2.44(m,6H),2.41-2.36(m,6H),2.33-2.26(m,4H),2.1 7-2.16(m,2H),2.10-2.06(m,3H),2.03-2.01(m,2H),1.79-1.77(m,3H),1.58(s,1H),1.55 -1.53(m,1H),1.46-1.44(m,2H),1.40-1.34(m,3H),0.96-0.94(m,3H),0.82-0.78(m,3H).

[0711] Example 6 Preparation of Compound H-6

[0712] Step 1: Intermediate d (4.44 g, 11.2 mmol) and 1-tert-butyloxycarbonylpiperazine (4.17 g, 22.4 mmol) were dissolved in 1,4-dioxane (100 mL). Under nitrogen, Xantphos (1.12 g, 1.94 mmol), Cs2CO3 (7.5 g, 13.1 mmol), and Pd2(dba)3 (0.94 g, 1.03 mmol) were reacted at 110°C for 16 hours. After cooling, 100 mL of water was added, and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 0-50%) to afford H-6-a (1.84 g, light yellow solid) in a yield of 32.9%. MS m / z (ESI): 504.0 [M+H] + .

[0713] Step 2: Dissolve H-6-a (1.54 g, 3.06 mmol) in EA (15 mL), add Pd / C (10%, 0.5 g), displace H2, and stir at room temperature for 16 hours. After completion of the reaction, concentrate to obtain H-6-b (1.44 g, crude product, yellow solid). MS m / z (ESI): 372.0 [M+H] + .

[0714] Step 3: 4-Bromo-6-chloropyridazin-3-amine (0.98 g, 4.7 mmol) and DIEA (2.2 g, 17.1 mmol) were added to DMSO (70 mL), followed by H-6-b (1.4 g, 3.76 mmol). The mixture was reacted at 120°C under nitrogen atmosphere for 16 hours. After cooling, 200 mL of water was added, and the aqueous phase was extracted with ethyl acetate (250 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EtOAc / PE = 0-90%) to afford H-6-c (1.5 g, light yellow solid) in an 81% yield. MS m / z (ESI): 498.9 [M+H] + .

[0715] Step 4: Dissolve H-6-c (1.48 g, 3.0 mmol), 2-hydroxyphenylboronic acid (0.734 g, 5.3 mmol), Xantphos G3Pd (0.3284 g, 0.39 mmol), and K2CO3 (7.5 g, 13.1 mmol) in a mixture of 1,4-dioxane (40 mL) and water (8 mL) under nitrogen atmosphere at 90°C for 5 hours. After cooling, water (100 mL) was added, and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 0-15%) to obtain H-6-d (1.3 g, light yellow solid) in an 83% yield. MS m / z (ESI): 557.0 [M+H] + .

[0716] Step 5: Dissolve H-6-d (1.3 g, 2.3 mmol) in DCM (10 mL) under nitrogen atmosphere. Add TFA (4.0 mL) in an ice-water bath and stir at room temperature for 16 hours. After completion of the reaction, wash with saturated NaHCO3 solution and concentrate to obtain H-6-e (1.0 g, crude product, yellow solid). MS m / z (ESI): 457.0 [M+H] + .

[0717] Step 6: Dissolve H-6-e (196 mg, 0.43 mmol) in a mixture of MeOH (10 mL) and DMF (3 mL), add methyl 4-oxobutanoate (0.043 mL, 0.43 mmol), and then add 2 drops of acetic acid. Stir at room temperature under nitrogen for 0.5 h. Add NaBH3CN (136 mg, 2.2 mmol) and stir at room temperature for 16 h. Quench with saturated aqueous NH4Cl (3.0 mL). Add water (30 mL), and extract the aqueous phase with DCM / MeOH (v / v = 10:1, 50 mL x 3). The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 0-15%) to obtain H-6-f (142 mg, light yellow solid) in a 59% yield. MS m / z (ESI): 557.0 [M+H] + .

[0718] Step 7: Dissolve H-6-f (142 mg, 0.26 mmol) in a mixture of methanol (7 mL), water (7 mL), and THF (7 mL). Add LiOH·H2O (53 mg, 1.26 mmol) and stir under nitrogen at room temperature for 16 h. After completion, add 2 mol / L aqueous hydrochloric acid dropwise to adjust the pH to 6-7. Concentrate to remove tetrahydrofuran, add water (30 mL), and extract the aqueous phase with DCM / MeOH (v / v = 10:1, 50 mL x 3). Dry the organic phase over anhydrous sodium sulfate and concentrate to yield H-6-g (89 mg, crude, light yellow solid). MS m / z (ESI): 543.0 [M+H] + .

[0719] Step 8: H-6-g (89 mg, 0.16 mmol) was dissolved in DMF (2 mL), and HOBT (44 mg, 0.33 mmol) and EDCI (276 mg, 1.39 mmol) were added to obtain Solution A. The mixture was protected by nitrogen. Intermediate 7 (146 mg, 0.34 mmol) was dissolved in DMF (2 mL), and DIEA (0.3 mL, 1.8 mmol) was added to obtain Solution B. Solution B was then added to Solution A and the reaction was allowed to proceed at room temperature for 1 h. Water (30 mL) and ethyl acetate (50 mL × 3) were added to extract the aqueous phase. The organic phase was concentrated and purified by pre-HPLC (A: H2O containing 0.1 wt% FA; B: MeCN, preparative column: 19 x 150 mm C18 column; gradient: 20%-70% acetonitrile) to obtain H-6 (26.4 mg) in a yield of 25.17%. MS m / z (ESI): 955.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 14.32 (s, 1H), 8.98 (s, 1H), 8.58-8.55 (t, J = 6.0Hz, 1H ),7.95-7.94(d,J=7.6Hz,1H),7.88-7.86(d,J=9.2Hz,1H),7.59(s,1H),7.44-7.37(m ,4H),7.26-7.22(t,J=8.8Hz,1H),7.11-7.08(d,J=9.2Hz,1H),6.91-6.87(m,2H),6.7 9-6.77(m,2H),6.28(s,2H),5.14-5.13(d,J=3.2Hz,1H),4.57-4.55(d,J=9.6Hz,1H), 4.45-4.41(m,2H),4.36(s,1H),4.24-4.19(m,1H),3.67(s,2H),3.45-3.42(d,J=11. 6Hz,2H),3.08(s,4H),2.92-2.82(m,4H),2.47(s,2H),2.45(s,3H),2.31-2.28(m,3H) ,2.20-2.18(d,J=7.2Hz,1H),2.12-2.07(m,2H),2.06-2.02(t,J=7.6Hz,3H),1.93-1. 88(m,1H),1.71-1.66(m,2H),1.56-1.53(d,J=12.4Hz,2H),1.23(s,2H),0.95(s,9H).

[0720] Example 7 Preparation of Compound H-7

[0721] Step 1: Dissolve intermediate i (320 mg, 0.92 mmol) in 1,2-dichloroethane (10 mL). Add (S)-pyrrolidine-3-carboxylic acid methyl ester (152 mg, 0.92 mmol) and tetraisopropyl titanate (116 mg, 0.41 mmol) at room temperature. Stir at room temperature for 1 hour. Then, add sodium acetate borohydride (975 mg, 4.6 mmol). Place the reaction mixture under a nitrogen atmosphere and stir at 25°C for 16 hours. After completion of the reaction, concentrate the mixture and purify it by silica gel column chromatography to obtain H-7-a (320 mg, colorless oil) in a 79% yield. MS m / z (ESI): 461.2 [M+H] + .

[0722] Steps 2-6: Referring to Steps 2 to 6 of Example 1, H-7 was prepared according to the synthetic route of Example 7, substituting H-7-a for H-1-a. Purification was performed by silica gel column chromatography using a 30:1 ratio of DCM:MeOH. Preparative HPLC purification conditions were: A: H2O containing 0.1 wt% FA; B: MeCN. Preparative column: 19 x 150 mm C18 column; gradient: 20% to 70% acetonitrile. MS m / z (ESI): 912.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.99 (s, 1H), 8.58 (t, J = 5.8Hz, 1H), 7.94 (d, J = 7.2Hz, 1H), 7.60 (s, 1H), 7. 47-7.33(m,8H),7.25(t,J=7.2Hz,1H),6.91(d,J=8.0Hz,2H),6.31(s,2H),5.14(s,1H),4.56(d,J=5.6Hz, 1H),4.48-4.36(m,4H),4.24(d,J=5.6Hz,1H),3.71-3.68(m,1H),3.62-3.59(m,1H),3.46(d,J=8.0Hz,2H ),2.95-2.90(m,4H),2.44(s,3H),2.33-2.27(m,1H),2.19-2.09(m,5H),2.05-2.03(m,1H),1.95-1.88(m, 2H), 1.60 (d, J = 8.4Hz, 2H), 1.24 (s, 4H), 0.95 (s, 9H), 0.86 (t, J = 6.6Hz, 1H).

[0723] Example 8 Preparation of Compound H-8

[0724] Step 1: Dissolve 4-(4-bromophenyl)-4-oxobutanoic acid (10 g, 38.898 mmol) in DCM (18 mL), add tert-butanol (7.12 mL, 77.80 mmol) and DMAP (1.43 g, 11.67 mmol), cool to 0°C in an ice-water bath, add DCC (9.63 g, 46.68 mmol), and stir at room temperature for 18 hours. TLC monitors the reaction for completion. The reaction mixture is adjusted to pH 8 with saturated sodium carbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 0-10%) to afford H-8-a (6.3 g, brown solid). Yield: 51.71%.

[0725] Step 2: Dissolve H-8-a (6.3 g, 20.12 mmol) in DMA (80 mL), add 4-methylthiazole (3.99 g, 40.23 mmol), potassium acetate (3.95 g, 40.23 mmol), and palladium acetate (0.45 g, 2.01 mmol). Heat to 90°C under nitrogen and stir for 6 hours. TLC monitors the reaction for completion. Cool to room temperature, add water, and extract with ethyl acetate. The organic phase is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 0-20%) to afford H-8-b (5.53 g, yellow oil) in a yield of 82.90%.

[0726] Step 3: H-8-b (2.0 g, 6.034 mmol) and ammonium acetate (9.30 g, 120.69 mmol) were dissolved in methanol (35 mL). NaBH3CN (1.52 g, 24.138 mmol) and anhydrous sodium sulfate (2.0 g, 14.08 mmol) were added. The reaction temperature was raised to 50°C for 6 hours. The reaction was monitored for completion by TLC. The reaction temperature was lowered to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM = 0-8%) to give H-8-c (1.33 g, green oil). Yield: 66.29%.

[0727] Step 4: Intermediate 8 (470 mg, 1.423 mmol) was dissolved in DMF (15 mL), and PyBOP (1.11 g, 2.133 mmol), H-8-c (480 mg, 1.444 mmol), and DIEA (0.7 mL, 4.235 mmol) were added. The reaction was stirred at room temperature for 18 hours. TLC confirmed the reaction was complete. The reaction solution was quenched with water (40 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 50-100%) to afford H-8-d (225 mg, yellow solid). Yield: 24.52%.

[0728] Step 5: H-8-d (35 mg, 0.054 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) in an ice-water bath and stirred at room temperature for 3 hours. The reaction was monitored for completion by TLC. Concentration afforded H-8-e (30 mg, yellow oil) in a 93.90% yield, which was used directly in the next step.

[0729] Step 6: Dissolve H-23-e (1.35 g, 2.963 mmol) in DCE (30 mL), add N-tert-butyloxycarbonyl-4-piperidone (2.95 g, 14.806 mmol) and anhydrous sodium sulfate (1.0 g, 7.04 mmol), and heat to 80°C for 4 hours. Cool the temperature to room temperature, add NaBH(OAc)3 (2.5 g, 11.852 mmol), and heat to 80°C for 4 hours. TLC monitors the reaction for completion. The reaction mixture is quenched with water and extracted with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (MeOH / DCM = 0-10%) to afford H-8-f (720 mg, yellow solid) in a yield of 38.04%.

[0730] Step 7: Dissolve H-8-f (720 mg, 1.127 mmol) in ethanol (8 mL) and ethanolic hydrochloric acid solution (2 mol / L, 8 mL) in an ice-water bath and stir at room temperature for 18 hours. Monitor the reaction for completion by TLC. Concentrate, add ethyl acetate, slurry, and filter to obtain H-8-g (560 mg, yellow solid). Yield: 86.39%.

[0731] Step 8: H-8-e (30 mg, 0.051 mmol) was dissolved in DMF (2 mL), and HATU (30 mg, 0.079 mmol) and DIEA (40 mg, 0.309 mmol) were added. The mixture was stirred for 5 minutes, and H-8-g (30 mg, 0.052 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction solution was purified by pre-HPLC (HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: 0.1 wt% FA in water, mobile phase B: ACN) to obtain H-8 (19.64 mg), yield: 33.04%. MS m / z (ESI): 555.4 [M / 2+H]+.1H NMR (400MHz, DMSO-d6): δ (ppm) 14.31 (s, 1H), 8.99 (d, J = 2.6Hz, 1H), 8.51 (dd, J = 30.7, 8.1Hz, 1H), 8.22 (s, 1H), 7.95 (dd, J = 8.3, 1.7Hz, 1H), 7.60 (s ,1H),7.54-7.36(m,4H),7.32-7.15(m,3H),7.11-7.02(m,2H),6.94-6.8 5(m,2H),6.29(s,2H),5.17(s,1H),4.81(s,1H),4.63-4.39(m,3H),4.32( s,1H),3.69-3.54(m,2H),2.90(dt,J=20.2,7.3Hz,8H),2.47(d,J=3.3Hz ,3H),2.24(d,J=10.1Hz,1H),2.19-1.97(m,5H),1.76(ddd,J=22.5,10.7, 4.4Hz,6H),1.59(t,J=9.9Hz,6H),1.43-1.31(m,2H),1.24(s,3H),1.30-1 .17(m,4H),1.00(s,4H),0.98(d,J=3.5Hz,1H),0.91(s,6H),0.73(s,1H).

[0732] Example 9 Preparation of Compound H-9

[0733] Step 1: Intermediate d (5.5 g, 13.809 mmol), methyl 4-piperidinate (3.95 g, 27.617 mmol), cesium carbonate (13.50 g, 41.426 mmol) and BrettPhos Pd G3 (2.51 g, 2.762 mmol) were dissolved in 1,4-dioxane (100 mL), heated to 110 ° C and stirred for 12 hours. The reaction was completed by TLC monitoring. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE=1:10-1:3) to obtain H-9-a (3.5 g, white solid). Yield: 55.03%.

[0734] Step 2: H-9-a (3.5 g, 7.599 mmol) was dissolved in methanol (50 mL), wet palladium carbon (0.08 g, 10% purity) was added, and the reaction was carried out at 50°C under a hydrogen atmosphere overnight. The reaction was monitored by TLC to be complete. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain H-9-b (2.3 g, white solid) with a yield of 92.15%, which was used directly in the next step.

[0735] Step 3: H-9-b (1.8 g, 5.480 mmol), 3-amino-4-bromo-6-chloropyridazine (1.37 g, 6.576 mmol) and potassium carbonate (1.51 g, 10.960 mmol) were dissolved in DMSO (20 mL) and reacted at 100 ° C under a nitrogen atmosphere overnight. The reaction was completed after monitoring by TLC. Water (100 mL) was added and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA=1:1-0:100) to give H-9-c (1.5 g, orange solid). Yield: 60.03%.

[0736] Step 4: H-9-c (1.4 g, 3.070 mmol), o-hydroxyphenylboronic acid (0.65 g, 4.605 mmol), Pd2(dba)3 (0.12 g, 0.154 mmol), Ruphos (0.14 g, 0.307 mmol) and potassium carbonate (1.06 g, 7.676 mmol) were dissolved in 1,4-dioxane (16 mL) and water (4 mL). The reaction was carried out at 100 ° C. under a nitrogen atmosphere overnight. The reaction was completed after monitoring by TLC. The reaction solution was concentrated and purified by column chromatography (PE / EA = 10:1-1:1) to obtain H-9-d (1.0 g, brown solid, yield: 63.41%).

[0737] Step 5: H-9-d (1.0 g, 1.947 mmol) and LiOH·H2O (0.16 g, 3.894 mmol) were dissolved in methanol (16 mL) and water (2 mL). The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC to completion. The product was concentrated to remove most of the methanol and the pH was adjusted to 6-7 with dilute hydrochloric acid (1 mol / L). A solid precipitated and was filtered. The filter cake was dried to obtain H-9-e (0.6 g, brown solid). Yield: 61.68%.

[0738] Step 6: Intermediate 9 (88.92 mg, 0.200 mmol) was dissolved in acetonitrile (2 mL), and H-9-e (100 mg, 0.200 mmol) and N-methylimidazole (82.17 mg, 1.001 mmol) were added. The mixture was stirred for 5 minutes, and TCFH (73.01 mg, 0.260 mmol) was added. The reaction was stirred at room temperature for 3 hours. TLC monitored the reaction completion. The reaction solution was purified by pre-HPLC (HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: aqueous solution containing 0.1 wt% FA, mobile phase B: ACN) to obtain H-9 (25.05 mg), yield: 13.18%. MS m / z (ESI): 463.8 [M / 2+H]. + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.99 (s, 1H), 8.39 (d, J = 7.9Hz, 1H), 8.21 (s, 1H), 7.95 (dd, J = 8.3, 1.7Hz, 1H), 7.82 (d, J = 9.3Hz, 1H), 7.59 (s, 1H),7.48-7.30(m,5H),7.30-7.19(m,1H),7.10(d,J=9.0Hz,1H),6.89(dd,J=7.7,5.7Hz,2H),6.84-6.76(m,2H),6.29(s,2H),4.93(p,J=7. 0Hz,1H),4.55-4.39(m,2H),4.29(s,1H),3.70-3.55(m,4H),3.44(d,J=11.7Hz,2H),2.96-2.80(m,4H),2.63(d,J=10.9Hz,2H),2.46(s,4H) ,2.16-2.02(m,4H),2.05-1.97(m,1H),1.80(ddd,J=13.8,9.2,4.9Hz,2H),1.70-1.52(m,5H),1.39(d,J=6.9Hz,3H),0.95(d,J=7.7Hz,9H).

[0739] Example 10 Preparation of Compound H-10

[0740] Step 1: Intermediate 10 (40 mg, 0.090 mmol) was dissolved in acetonitrile (1 mL) and DMF (1 mL). H-1-e (44.75 mg, 0.090 mmol) and N-methylimidazole (36.77 mg, 0.448 mmol) were added and stirred for 5 minutes. TCFH (30.16 mg, 0.107 mmol) was added and stirred at room temperature for 3 hours. The reaction was monitored for completion by TLC. The reaction solution was purified by pre-HPLC (HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: 0.1 wt% FA in water, mobile phase B: ACN) to obtain H-10 (10 mg) in a yield of 12.03%. MS m / z (ESI): 464.8 [M / 2+H]. + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.32 (s, 1H), 11.10 (s, 1H), 8.50 (t, J = 6.0Hz, 1H ),8.22-8.16(m,1H),7.99-7.84(m,2H),7.62(dd,J=8.5,2.3Hz,1H),7.59(s,1H ),7.25(td,J=7.6,1.5Hz,1H),7.10(d,J=9.0Hz,1H),7.00-6.85(m,2H),6.80(d d,J=6.6,2.4Hz,2H),6.52(d,J=1.2Hz,1H),6.29(s,2H),5.14(d,J=3.4Hz,1H), 4.53(d,J=9.3Hz,1H),4.42-4.33(m,1H),4.35(s,2H),4.09(dd,J=15.3,5.2Hz, 1H),3.65(dt,J=12.9,8.3Hz,4H),3.44(d,J=11.4Hz,2H),2.95-2.80(m,4H),2. 74-2.54(m,1H),2.40(s,1H),2.23(d,J=1.1Hz,3H),2.15-1.94(m,4H),1.94-1. 74(m,2H),1.66(s,2H),1.56(d,J=12.4Hz,2H),1.27-1.22(m,6H),0.96(s,7H).

[0741] Example 11 Preparation of Compound H-11

[0742] Step 1: Intermediate f (1.0 g, 2.51 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (1.0 g, 3.09 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), along with Cs2CO3 (0.87 g, 6.28 mmol) and Pd(dppf)Cl2 (0.204 g, 0.28 mmol) under nitrogen and reacted at 90°C for 6 hours. After cooling, water (100 mL) was added, and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 0-50%) to afford H-11-a (1.14 g, light yellow solid) in an 87.7% yield. MS m / z(ESI):415.1[M-100+H] + .

[0743] Step 2: Dissolve H-11-a (1.14 g, 2.22 mmol) in ethyl acetate (35 mL), add Pd / C (10% purity, 0.44 g), displace the hydrogen atmosphere, and stir at room temperature for 16 hours. After the reaction is complete, filter and concentrate the filtrate to obtain H-11-b (970 mg, crude product, yellow solid). MS m / z (ESI): 385.2 [M+H] + .

[0744] Step 3: 4-Bromo-6-chloropyridazin-3-amine (0.6318 g, 3.03 mmol) and DIEA (2 mL, 12.6 mmol) were added to DMSO (45 mL), followed by H-11-b (0.97 g, 2.52 mmol). The mixture was reacted at 120°C under nitrogen for 16 hours. After cooling, water (100 mL) was added, and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 0-90%) to afford H-11-c (0.75 g, light yellow solid) in a yield of 56.4%. MS m / z (ESI): 512.2 [M+H] + .

[0745] Step 4: Dissolve H-11-c (750 mg, 1.46 mmol), 2-hydroxyphenylboronic acid (243 mg, 1.76 mmol), XPhos G3Pd (140 mg, 0.165 mmol), and K2CO3 (506 mg, 3.67 mmol) in a mixture of 1,4-dioxane (20 mL) and water (4 mL) under nitrogen at 90°C for 5 hours. After cooling, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 0-15%) to obtain H-11-d (820 mg, light yellow solid) in a yield of 98.0%. MS m / z (ESI): 570.2 [M+H] + .

[0746] Step 5: Dissolve H-11-d (820 mg, 1.44 mmol) in DCM (25 mL) under nitrogen protection. Add TFA (5.0 mL) in an ice-water bath and stir at room temperature for 16 hours. After the reaction is complete, wash with saturated NaHCO3 solution and concentrate the organic phase to obtain H-11-e (847 mg, crude product, yellow solid). MS m / z (ESI): 470.2 [M+H] + .

[0747] Step 6: Dissolve H-11-e (410 mg, 0.87 mmol) in a mixture of MeOH (9 mL) and 1,2-dichloroethane (9 mL). Add tert-butyl 4-oxopiperidine-1-carboxylate (1.32 g, 6.6 mmol) and 4 drops of acetic acid. Stir at room temperature under nitrogen for 0.5 hour. Add NaBH3CN (415 mg, 6.6 mmol) and stir at room temperature for 16 hours. Quench with saturated aqueous NH4Cl (3.0 mL). Add water (50 mL) and extract the aqueous phase with a DCM / MeOH (v / v = 10:1) mixture (50 mL x 3). The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 0-15%) to obtain H-11-f (290 mg, light yellow solid) in a yield of 51.1%. MS m / z (ESI): 653.2 [M+H]. + .

[0748] Step 7: Dissolve H-11-f (290 mg, 0.44 mmol) in DCM (10 mL), add TFA (2 mL) under ice-cooling, and stir at room temperature for 2 hours. Concentrate to remove the solvent, add DCM / MeOH (v / v = 10:1) solvent (60 mL), wash with saturated NaHCO3 aqueous solution (50 mL), dry over anhydrous sodium sulfate, and concentrate to give H-11-g (223 mg, light yellow solid). MS m / z (ESI): 553.2 [M+H] + .

[0749] Step 8: Methyl α-(1-methylethyl)-3-[(1,1,2,2,3,3,4,4,4-nonafluorobutyl)sulfonyl]oxy]5-isoxazoleacetate (670 mg, 1.39 mmol) and DIEA (1.10 g, 8.56 mmol) were added to DMSO (15 mL), followed by 4-(dimethoxymethyl)piperidine (680 mg, 4.28 mmol). The mixture was reacted at 105°C under nitrogen for 2 hours. After cooling, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 0-35%) to afford H-11-h (175 mg, colorless oil) in a 37.0% yield. MS m / z (ESI): 341.2 [M+H]. + .

[0750] Step 9: Dissolve H-11-h (174 mg, 0.51 mmol) in a mixture of methanol (4 mL), water (4 mL), and THF (4 mL). Add LiOH·H2O (69 mg, 1.64 mmol) and stir at room temperature under nitrogen for 16 hours. After completion of the reaction, add aqueous hydrochloric acid (2 mol / L) dropwise to adjust the pH to 6-7. Add acetonitrile and concentrate to afford H-11-i (267 mg, white solid, crude product). MS m / z (ESI): 281.2 [M-45].

[0751] Step 10: H-11-i (267 mg, 0.51 mmol), DIEA (329 mg, 2.55 mmol), and intermediate 2 (203 mg, 0.61 mmol) were dissolved in DMF (14 mL). HOBt (138 mg, 1.02 mmol) was added, and EDCI (979 mg, 5.10 mmol) was added portionwise. The mixture was allowed to react at room temperature for 3 hours. Water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (MeOH / DCM = 0-8%) to obtain H-11-j (134 mg, white solid) in a yield of 41.1%. MS m / z (ESI): 640.2 [M+H]+ .

[0752] Step 11: Add H-11-j (134 mg, 0.21 mmol) to THF (6 mL), add dilute aqueous hydrochloric acid (1 mol / L, 6 mL), and react at 64°C under nitrogen for 5 hours. After cooling, adjust the pH to 9 with saturated aqueous NaHCO₃. Extract the aqueous phase with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated to afford H-11-k (104 mg, off-white solid) in an 83.4% yield. MS m / z (ESI): 594.1 [M+H] + .

[0753] Step 12: Dissolve H-11-g (143 mg, 0.26 mmol) and H-11-k (104 mg, 0.18 mmol) in a mixture of MeOH (2 mL) and DCM (3 mL). Add 3 drops of tetraisopropyl titanate, and stir at room temperature under nitrogen for 1 hour. Add NaBH3CN (49 mg, 0.78 mmol) and stir at room temperature for 16 hours. After concentration, purify by column chromatography (MeOH / DCM = 5-35%) and then by pre-HPLC (A: H2O containing 0.1 wt% FA; B: MeCN, preparative column: 19 x 150 mm C18 column, gradient: 20%-70% acetonitrile) to afford H-11 (22 mg), yield: 7.5%. MS m / z (ESI): 1130.3 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 8.98-8.97 (m, 1H), 8.40-8.38 (m, 2H), 7.96-7.94 (d, J = 8.4Hz, 1H), 7.59 (s, 1H), 7.45-7.32 (m, 4H), 7.26-7.21 ( m,1H),7.12-7.10(d,J=7.6Hz,1H),7.05(s,2H),6.95-6.93(d,J=7.6Hz ,1H),6.91-6.87(m,2H),6.30(s,2H),6.11-6.09(m,1H),4.91-4.89(m, 1H),4.41-4.36(m,1H),4.28(s,1H),3.73-3.69(m,1H),3.61-3.54(m,4 H),3.46-3.43(m,4H),2.93-2.84(m,8H),2.71-2.67(m,2H),2.46-2.44 (m,4H),2.23-2.06(m,12H),1.83-1.78(m,3H),1.70-1.56(m,9H),1.45 -1.35(m,6H),1.17-1.07(m,3H),0.95-0.93(m,2H),0.83-0.77(m,3H).

[0754] Example 12 Preparation of Compound H-12

[0755] Step 1: H-2-d (1.0 g, 2.0 mmol) was dissolved in MeOH / THF / H2O (v / v / v = 1 / 1 / 1, 10.5 mL), and LiOH (0.24 g, 10.0 mmol) was added. The mixture was stirred at room temperature (25°C) for 16 hours. After the reaction was complete, water (8 mL) was added to dilute the mixture, and the pH was adjusted to 6 using dilute hydrochloric acid (1 mol / L). The mixture was extracted with ethyl acetate (25 mL × 3), and the organic phase was dried to give H-12-a (0.97 g, yellow solid, crude product). MS m / z (ESI): 487.3 [M+H] + .

[0756] Step 2: H-12-a (48 mg, 0.10 mmol) was dissolved in DMF (3 mL), and H-2-m (98 mg, 0.15 mmol), DIEA (0.05 mL, 0.30 mmol), and HATU (57 mg, 0.15 mmol) were added. The mixture was stirred at room temperature (25°C) for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EA (3 × 50 mL). The collected organic phase was washed with saturated brine (50 mL × 3), dried over Na2SO4, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 50:1-20:1) and pre-HPLC purification (A: H2O containing 0.1 wt% FA; B: MeCN, preparative column: 19 × 150 mm C18 column; gradient: 20% to 70% acetonitrile) to obtain H-12 (22.7 mg), yield: 20%. MS m / z(ESI):1133.5[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.31 (s, 1H), 8.99-8.97 (m, 1H), 8.45-8.38 (m, 1H), 7.94 (d,J=1.4Hz,1H),7.59(s,1H),7.47-7.41(m,2H),7.39-7.32(m,2H),7.26-7.22(m,1H),7 .10(d,J=8.0Hz,1H),6.90-6.87(m,2H),6.71(d,J=2.4Hz,1H),6.60(d,J=2.2Hz,1H),6. 30(s,2H),6.15-6.13(m,1H),5.10-5.09(m,1H),4.92-4.87(m,1H),4.69-4.65(m,1H),4. 28-4.25(m,1H),3.91-3.87(m,1H),3.70-3.65(m,2H),3.57-3.52(m,2H),3.45-3.40(m, 5H),3.13-3.07(m,2H),2.95-2.89(m,4H),2.81(t,J=7.2Hz,2H),2.67-2.62(m,2H),2.45 (s,3H),2.44(s,2H),2.33-2.26(m,5H),2.18-2.13(m,3H),2.09-2.06(m,3H),1.82-1.7 6(m,5H),1.56(d,J=7.2Hz,2H),1.46-1.44(m,2H),0.96-0.93(m,3H),0.85-0.73(m,6H).

[0757] Example 13 Preparation of Compound H-13

[0758] Step 1: Under nitrogen, intermediate d (1.5 g, 3.75 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1.6 g, 5.63 mmol), NaCO (1.2 g, 11.3 mmol), and Pd(dppf)Cl (137 mg, 0.19 mmol) were dissolved in 1,4-dioxane (60 mL) and water (15 mL) and reacted in an oil bath at 110°C for 16 hours. TLC monitored the reaction completion. The concentrated residue was purified by column chromatography (PE / EA = 20:1-5:1) to afford H-13-a (500 mg, white solid) in a 29% yield. MS m / z (ESI): 474.2 [M+H]. + .

[0759] Step 2: H-13-a (100 mg, 0.21 mmol) and wet Pd / C (70 mg, 10% purity) were added to methanol (5 mL) under a hydrogen atmosphere (1 atm) and reacted at room temperature for 16 hours. TLC monitored the reaction for completion. The reaction mixture was filtered and the filtrate was concentrated to afford H-13-b (65 mg, white solid) in a 90% yield. MS m / z (ESI): 342.3 [M+H] + .

[0760] Step 3: Under nitrogen, H-13-b (700 mg, 2.05 mmol), 3-amino-4-bromo-6-chloropyridazine (598 mg, 2.87 mmol), and K2CO3 (850 mg, 6.15 mmol) were dissolved in DMAC (20 mL) and reacted in an oil bath at 110°C for 12 hours. TLC monitored the reaction completion. The reaction solution was extracted with ethyl acetate, washed with a 0.5 mol / L aqueous NaOH solution, and then washed with saturated brine. The organic phases were combined, concentrated, and purified by column chromatography (PE / EA = 10:1 to 1:1) to obtain H-13-c (360 mg, off-white solid) in a 37% yield. MS m / z (ESI): 469.3 [M+H] + .

[0761] Step 4: Under nitrogen, H-13-c (310 mg, 0.66 mmol), o-hydroxyphenylboronic acid (118 mg, 0.86 mmol), K2CO3 (182 mg, 1.32 mmol), Pd2(dba)3 (15 mg, 0.0165 mmol), and Ruphos (31 mg, 0.066 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) and reacted in an oil bath at 95°C for 16 hours. TLC monitored the reaction completion. The concentrated residue was purified by column chromatography (PE / EA = 10:1 to 1:1) to afford H-13-d (240 mg, off-white solid) in a 68% yield. MS m / z (ESI): 527.3 [M+H] + .

[0762] Step 5: H-13-d (240 mg, 0.46 mmol) was dissolved in MeOH / THF / H2O (1 mL / 3 mL / 1 mL). LiOH·H2O (193 mg, 4.6 mmol) was added and the mixture was allowed to react at room temperature for 16 hours. TLC was used to monitor the reaction. Dilute hydrochloric acid solution (1 mol / L) was added to adjust the pH to acidic. Water (10 mL) was then added to precipitate a white solid. The filter cake was collected by filtration and dried to afford H-13-e (180 mg, off-white solid) in a yield of 78%.

[0763] Step 6: Intermediate 7 (43 mg, 0.1 mmol), H-13-e (50 mg, 0.1 mmol), and DIEA (64.6 mg, 0.5 mmol) were dissolved in DMF (2 mL). The mixture was stirred on ice for 10 minutes. HATU (38 mg, 0.1 mmol) and HOAT (14 mg, 0.1 mmol) were added and stirred on ice for 0.5 hours and then at room temperature for 2 hours. The reaction was monitored by LCMS. Upon completion, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mL x 3), and concentrated to obtain the crude product. The crude product was purified by pre-HPLC (HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: aqueous solution containing 0.1 wt% FA, mobile phase B: ACN) to afford H-13 (43 mg) in a yield of 47.25%. MS m / z (ESI): 456.3 [M / 2+H]. + . 1H NMR (400MHz, CDCl3): δ (ppm) 8.70-8.69 (m, 1H), 7.65-7.62 (m, 1H), 7.41-7.35 (m, 5H), 7.33-7.30 (m, 1 H),7.16-7.04(m,3H),6.95-6.91(t,J=8Hz,1H),6.37-6.28(m,1H),5.12(s,2H),4.79-4.75(m,1H),4 .63-4.56(m,3H),4.39-4.34(m,1H),4.20-4.14(m,1H),3.66-3.62(m,1H),3.54-3.50(m,2H),2.98-2 .92(m,4H),2.60-2.53(m,6H),2.18-1.99(m,8H),1.78-1.73(m,5H),1.66-1.51(m,6H),0.98(s,9H).

[0764] Example 14 Preparation of Compound H-14

[0765] Step 1: To a solution of H-23-e (0.30 g, 0.66 mmol) in methanol (5 mL) and DMSO (1 mL) were added methyl 4-oxocyclohexane-1-carboxylate (0.20 g, 1.32 mmol), NaBH3CN (0.20 g, 3.29 mmol), and acetic acid (0.02 g, 0.33 mmol) at room temperature. The reaction mixture was stirred at 75°C for 18 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain H-14-a (0.38 g, yellow solid) in a yield of 96.8%. MS m / z(ESI):596.4[M+H] + .

[0766] Step 2: H-14-a (0.30 g, 0.50 mmol) was dissolved in methanol (5 mL) and water (1 mL) at room temperature, and LiOH·H 2 O (0.06 g, 1.51 mmol), the reaction mixture was stirred at 60°C for 18 hours. After the reaction was complete, the reaction solution was concentrated in vacuo to give H-14-b (0.29 g, white solid, crude product) in a yield of 99.6%. MS m / z (ESI): 582.4 [M+H] + .

[0767] Step 3: To a solution of H-14-b (0.29 g, 0.50 mmol) in dry DMF (5 mL) were added intermediate 7 (0.43 g, 1.01 mmol), DIEA (0.25 mL, 1.51 mmol) and HATU (0.19 g, 0.50 mmol) at room temperature. The reaction mixture was stirred at 25 ° C for 18 hours. After the reaction was complete, the reaction solution was filtered through a filter membrane and the filtrate was purified by pre-HPLC ( Prep C18 OBD™ 10 μm, 19 x 250 mm column (mobile phase: 40%-70% (v / v) CH₃CN and 0.1 wt% NH₄HCO₃ aqueous solution) to yield: H-14-1 (40 mg). Yield: 9.35%. MS m / z (ESI): 994.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.32 (s, 1H), 8.99 (s, 1H), 8.58 (t, J = 6.2Hz, 1H), 7.97-7.91 (m, 1H), 7.74 (d, J = 9.2Hz, 1H), 7.59 (s, 1H), 7.44-7.35(m,4H),7.26-7.21(m,1H),7.17(d,J=7.8Hz,1H),7.06(d,J=10.5Hz,2H),6.90-6.85(m,2H),6.30(s,2H),5.14(d,J=3.5Hz,1H ),4.53-4.38(m,3H),4.34-4.33(m,1H),4.24-4.22(m,1H),3.65-3.62(m,2H),3.45-3.42(m,2H),2.90-2.85(m,6H),2.40(s,3H),2.30- 2.25(m,4H),2.16-2.01(m,5H),1.89-1.88(m,1H),1.84-1.67(m,6H),1.58-1.56(m,4H),1.42-1.17(m,5H),0.93(s,9H).H-14-2(50mg). Yield: 11.5%. MS m / z(ESI):994.5[M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm) 14.30 (s, 1H), 8.96 (s, 1H), 8.56 (t, J = 6.2Hz, 1H), 7.92 (dd, J = 8.3, 1.7Hz, 1H), 7.67 (d, J = 9.1Hz ,1H),7.57(s,1H),7.38(q,J=8.2Hz,4H),7.23-7.15(m,2H),7.08-7.03(m,2H),6.89-6.84(m,2H),6.28(s,2H),5.12(s,1H),4 .52(d,J=9.3Hz,1H),4.44-4.37(m,2H),4.33(s,1H),4.20-4.18(m,1H),3.65-3.63(m,2H),3.42-3.40(m,2H),3.07-3.05(m, 2H),2.90-2.85(m,4H),2.42(s,3H),2.17-1.96(m,7H),1.87-1.84(m,4H),1.80-1.74(m,6H),1.58-1.21(m,8H),0.92(s,9H).

[0768] Example 15 Preparation of Compound H-15

[0769] Step 1: A solution of intermediate i (410 mg, 1.18 mmol) and ethyl piperidine-4-carboxylate (0.36 mL, 2.36 mmol) in methanol (10.0 mL) was added with one drop of acetic acid. The resulting mixture was then stirred at 25°C for 1 hour, and then NaBH3CN (223 mg, 3.54 mmol) was added to the resulting mixture and stirred at 50°C for 3 hours. The mixture was concentrated and diluted with saturated aqueous sodium chloride solution (20 mL), and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography. H-15-a (420 mg, crude product) was obtained. Yield: 72.8%. MS m / z (ESI): 489.6 [M+H] + .

[0770] Step 2: H-15-a (410 mg, 0.84 mmol) was dissolved in methanol (15 mL), and Pd / C (20 mg, 0.84 mmol) was added. The resulting mixture was stirred at 25°C under a H2 atmosphere (1 atm) for 16 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL x 3). The filtrate was concentrated to afford H-15-b (300 mg, 0.82 mmol). Yield: 98.28%. MS m / z (ESI): 357.2 [M+H]+ .

[0771] Step 3: H-15-b (280 mg, 0.79 mmol) was added to a solution in DMSO (10 mL), followed by the addition of 4-bromo-6-chloropyridazin-3-amine (0.17 mL, 1.57 mmol) and DIEA (405 mg, 3.14 mmol), and the resulting mixture was stirred at 120 ° C for 16 hours. The mixture was concentrated and diluted with saturated aqueous sodium chloride solution (20 mL), and extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give H-15-c (150 mg, crude product). Yield: 39.46%. MS m / z (ESI): 484.2 [M+H] + .

[0772] Step 4: To a solution of H-15-c (150 mg, 0.31 mmol) dissolved in 1,4-dioxane / water (v / v = 4:1, 10 mL) was added (2-hydroxyphenyl)boranediol (86 mg, 0.62 mmol), Pd(dppf)Cl2 (22.0 mg, 0.03 mmol), and potassium carbonate (171 mg, 1.24 mmol). The resulting mixture was then stirred at 100 ° C under N2 atmosphere for 16 h. The mixture was concentrated and diluted with saturated aqueous sodium chloride solution (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain H-15-d (40.0 mg, crude product). Yield: 24.4%. MS m / z (ESI): 542.2 [M+H] + .

[0773] Step 5: H-15-d (55.0 mg, 0.10 mmol) was dissolved in methanol / water (v / v = 5:1, 6.00 mL) at room temperature, and LiOH·H 2 O (52.5 mg, 1.25 mmol). The resulting mixture was then stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure to afford H-15-e (50.0 mg) in a yield of 95.8%. MS m / z (ESI): 512.2 [MH] - .

[0774] Step 6: H-15-e (50 mg, 0.10 mmol) and intermediate 7 (41.91 mg, 0.10 mmol) were dissolved in DMF (5 mL), and HATU (87.0 mg, 0.230 mmol) and DIEA (96.0 mg, 0.740 mmol) were added, and the resulting mixture was stirred at 25 ° C for 24 hours. After treatment, the filtrate was purified by pre-HPLC ( A C18 OBD™ 10 μm, 19×250 mm column (mobile phase: 30%-90% (v / v) CH₃CN and 0.1 wt% NH₄HCO₃ aqueous solution) was used to obtain H-15 (25 mg). Yield: 27.7%. MS m / z (ESI): 926.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 14.33 (s, 1H), 8.99 (s, 1H), 8.59 (t, J = 6.0Hz, 1H), 7.95 (d, J = 8.0Hz, 1H), 7.81 (s, 1H), 7. 60(s,1H),7.41(q,J=8.3Hz,4H),7.27-7.15(m,2H),7.15(s,2H),6.92-6.86(m,2H),6.32(s,2H),5.16(d,J=3.0Hz,1H ),4.53(d,J=9.3Hz,1H),4.48-4.39(m,2H),4.35(s,1H),4.24-4.20(m,1H),3.69-3.61(m,2H),3.47-3.40(m,3H),2.9 7-2.79(m,6H),2.45(s,3H),2.21-2.00(m,6H),1.92-1.86(m,2H),1.69-1.51(m,6H),1.41-1.34(m,2H),0.92(s,9H).

[0775] Example 16 Preparation of Compound H-16

[0776] Step 1: H-16-g (3 g, 10.8 mmol), intermediate g (2.4 g, 7.2 mmol), and tri-n-butylphosphine (2.9 g, 14.4 mmol) were dissolved in toluene (45 mL). TMAD (2.5 g, 14.4 mmol) was added under ice-cooling. The reaction mixture was stirred at 100°C for 16 hours, cooled to 25°C, poured into water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, concentrated, and purified by column chromatography to obtain H-16-h (2 g, yellow solid) in a 48% yield. MS m / z (ESI): 589.3 [M+H] + .

[0777] Step 2: H-16-h (2 g, 3.4 mmol) was dissolved in methanol (35 mL), and palladium on carbon (200 mg, 10%) was added at room temperature. The reaction solution was stirred at 25°C under 15 psi of hydrogen for 5 hours, filtered, and the filtrate was concentrated to obtain H-16-i (1.9 g, yellow oil). Yield: 80%. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 7.05 (d, J = 8.8Hz, 1H), 6.56-6.55 (m, 2H), 4.77-4.73 (m, 1H), 4.34-4.29 (m, 1H), 3.68-3.65(m,2H),3.48-3.43(m,1H),2.97-2.87(m,4H),2.76-2.64(m,4H),2.36-2.31(m,4 H),2.00-1.96(m,2H),1.78-1.74(m,2H),1.69-1.62(m,2H),1.39(s,9H),1.34-1.24(m,5H).

[0778] Step 3: Dissolve H-16-i (1.9 g, 2.7 mmol) and 4-bromo-6-chloropyridazin-3-amine (1.38 g, 6.7 mmol) in DMSO (4 mL). Add DIEA (1.3 mL, 8.1 mmol) at room temperature. Stir the reaction mixture at 130°C for 3 hours. Cool the mixture to 25°C, pour it into water, and extract with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain H-16-j (1.3 g, yellow solid). MS m / z (ESI): 584.3 [M+H] + .

[0779] Step 4: H-16-j (1.3 g, 2.2 mmol), (2-hydroxyphenyl)boronic acid (550 mg, 4 mmol), and potassium carbonate (920 mg, 6.6 mmol) were dissolved in dioxane (10 mL) and water (2 mL). BrettPhos Pd G3 (400 mg, 0.4 mmol) was added and the reaction mixture was stirred at 90°C for 5 hours. The reaction mixture was cooled to 25°C and poured into water. The mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford H-16-k (1.3 g, yellow solid) in a 90% yield. MS m / z (ESI): 642.3 [M+H]. + .

[0780] Step 5: Dissolve H-16-k (1.3 g, 2 mmol) in a solution of hydrogen chloride in dioxane (20 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent is then evaporated to give H-16-1 (1 g, yellow solid). Yield: 90%. MS m / z (ESI): 542.3 [M+H] + .

[0781] Step 6: Intermediate b (350 mg, 1.21 mmol) was dissolved in DMF (8 mL). HATU (558 mg, 1.46 mmol) was added at 0°C and stirred for 10 min. Intermediate 2 (484 mg, 1.46 mmol) and DIPEA (0.8 mL 4.8 mmol) were then added in one portion. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried, concentrated, and purified on a silica gel column to obtain H-16-m (400 mg, yellow solid) in a 55% yield. MS m / z (ESI): 601.3 [M+H] + .

[0782] Step 7: H-16-m (250 mg, 0.4 mmol) was dissolved in THF (2 mL), and sulfuric acid solution (1 mol / L, 2 mL) was added at room temperature. The reaction was heated at 50°C for 20 min. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried, and concentrated to give H-16-n (200 mg, yellow solid) with a yield of 87%. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 9.70 (d, J = 11.6Hz, 1H), 8.98 (d, J = 4.8Hz, 1H), 7.48-7.32 (m, 5H ),6.07(d,J=2.8Hz,1H),5.11-5.09(m,1H),5.00-4.86(m,1H),1.47-4.40(m,2H),4.27(brs,1 H),3.76-3.64(m,1H),3.56-3.42(m,2H),2.92-2.86(m,2H),2.45(s,3H),2.33-2.14(m,2H),2 .07-2.02(m,1H),1.82-1.74(m,1H),1.39-1.34(m,3H),0.97-0.95(m,3H),0.84-0.80(m,3H).

[0783] Step 8: H-16-1 (187 mg, 0.34 mmol) and H-16-n (130 mg, 0.23 mmol) were dissolved in DCM (6 mL) and methanol (3 mL). Acetic acid (4 drops) was added at room temperature, followed by stirring for 30 min. NaBHCN (58 mg, 0.92 mmol) was added and stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (DCM:MeOH = 12:1) to afford H-16 (60 mg) in a 25% yield. MS m / z (ESI): 1081.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.28 (s, 1H), 8.99-8.98 (m, 1H), 8.40 (d, J = 8.0Hz, 1H ),7.94(d,J=7.6Hz,1H),7.60(s,1H),7.49-7.41(m,2H),7.37-7.35(m,1H),7.32(d,J =8.0Hz,1H),7.25(t,J=8.8Hz,1H),7.10(d,J=8.4Hz,1H),6.91-6.87(m,2H),6.72(s ,1H),6.61(d,J=8.8Hz,1H),6.30(s,2H),6.08(s,1H),5.11(s,1H),5.02-4.85(m,1H) ,4.79(s,1H),4.45-4.26(m,3H),4.20(s,2H),3.77-3.55(m,2H),3.45-3.42(m,4H), 3.27-3.09(m,2H),2.91(t,J=12.0Hz,2H),2.82(t,J=7.2Hz,2H),2.45(s,3H),2.38-2 .23(m,7H),2.16-1.99(m,8H),1.92-1.73(m,4H),1.56(d,J=12.4Hz,2H),1.46(d,J= 7.2Hz,1H),1.37(t,J=8.0Hz,3H),1.24(s,1H),0.97-0.96(m,3H),0.84-0.75(m,3H).

[0784] Example 17 Preparation of Compound H-17

[0785] Step 1: Under nitrogen protection, PPh3 (1182.67 mg, 4.509 mmol) was added to THF (20 mL) in an ice-water bath, followed by the slow dropwise addition of DIAD (911.76 mg, 4.509 mmol). The mixture was stirred at 0°C for 30 minutes, followed by the slow dropwise addition of a solution of ethyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (641 mg, 3.006 mmol) and 4-(1,3-dioxolan-2-yl)cyclohexane-1-ol (518 mg, 3.008 mmol) in THF (10 mL). After addition, the mixture was slowly returned to room temperature and allowed to react for 48 hours. The reaction was monitored by TLC. The residue was concentrated and purified by column chromatography (EA / PE = 1:9-1:4) to afford H-17-a (534 mg) in a yield of 48.35%.

[0786] Step 2: Dissolve H-17-a (560 mg, 1.524 mmol) in a mixed solvent of water (6 mL) and THF (18 mL). Add hydrochloric acid solution (3 mol / L, 0.508 mL) and heat to 55°C for 5 hours. Monitor the reaction for completion by TLC. Concentrate and add water (20 mL). Adjust the pH to 8 with saturated sodium bicarbonate solution. Extract with ethyl acetate (10 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (EA / PE = 1:9) to afford H-17-b (452 ​​mg, oil) in a yield of 91.71%.

[0787] Step 3: Dissolve intermediate j (755 mg, 3.732 mmol), 3-amino-4-bromo-6-chloropyridazine (855.71 mg, 4.105 mmol), and DIEA (2894.23 mg, 22.392 mmol) in DMSO (40 mL) and heat to 90°C for 16 hours. The reaction was complete by TLC. Water (50 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 1:4 to 1:1) to afford H-17-c (640 mg, yellow solid) in a yield of 51.99%.

[0788] Step 4: Under nitrogen, H-17-c (640 mg, 1.940 mmol), 2-hydroxyphenylboronic acid (347.93 mg, 2.523 mmol), RuPhos (90.53 mg, 0.194 mmol), Pd2(dba)3 (44.41 mg, 0.049 mmol), and K2CO3 (536.22 mg, 3.880 mmol) were dissolved in water (40 mL) and 1,4-dioxane (7.5 mL). The mixture was heated to 100°C and allowed to react overnight. TLC confirmed the reaction was complete. The reaction solution was concentrated and purified by column chromatography (EA / PE = 1:5-2:1) to afford H-17-d (400 mg, yellow solid) in a yield of 53.2%.

[0789] Step 5: Dissolve H-17-d (390 mg, 1.006 mmol), H-17-b (325.48 mg, 1.006 mmol), and acetic acid (241.76 mg, 4.026 mmol) in THF (40 mL) and stir at room temperature for 2 hours. Add NaBH(OAc)3 (10.94 mg, 0.052 mmol) under an ice-water bath and stir at 0°C for 2 hours. Monitor the reaction by TLC for completion. Quench the reaction by adding water (50 mL) and extract with ethyl acetate (20 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 1:4 to 1:1) to afford H-17-e (426 mg, yellow solid) in a yield of 60.91%.

[0790] Step 6: Dissolve H-17-e (390 mg, 0.561 mmol) and NaOH (134.70 mg, 3.367 mmol) in a mixed solvent of THF (10 mL), water (5 mL), and methanol (5 mL). Warm the mixture to 50°C for 2 hours. Monitor the reaction by TLC. Concentrate the mixture, add 50 mL of water, and adjust the pH to 4 with aqueous hydrochloric acid (1 mol / L). Filter the mixture, wash the filter cake with water (20 mL x 2), and dry the solid in vacuo to afford H-17-f (365 mg, white solid) in a yield of 97.53%, which is used directly in the next step.

[0791] Step 7: H-17-f (310 mg, 0.465 mmol), Intermediate 2 (165 mg, 0.466 mmol), DIEA (360.52 mg, 2.789 mmol), and HATU (185.61 mg, 0.488 mmol) were added to DMF (10 mL) and stirred. The mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC. Water (100 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by pre-HPLC (HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: aqueous solution containing 0.1 wt% FA, mobile phase B: ACN) to afford H-17 (230 mg) in a yield of 51.9%. MS m / z (ESI): 483.9 [M / 2+H]. + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.32 (s, 1H), 9.0-8.90 (m, 1H), 8.57-8.45 (m, 1H), 7.94(dd,J=8.3,1.6Hz,1H),7.58(s,1H),7.50-7.36(m,3H),7.33(t,J=7.3Hz,1H) ,7.29-7.20(m,1H),6.92(ddt,J=24.7,7.4,3.7Hz,3H),6.42(d,J=5.1Hz,2H),6.2 5(s,1H),6.13-6.01(m,1H),5.41(s,1H),5.15(s,1H),4.44(t,J=7.8Hz,1H),4.40 -4.22(m,3H),3.82-3.72(m,1H),3.58(s,1H),3.44(s,5H),3.16(s,1H),2.88(t,J =11.9Hz,3H),2.77(d,J=7.1Hz,2H),2.48-2.39(m,5H),2.31-2.15(m,2H),2.05(s ,1H),2.04-1.96(m,3H),1.91(s,1H),1.52(d,J=12.7Hz,3H),1.38-1.21(m,3H),1 .12-0.91(m,3H),0.90-0.77(m,3H),0.67(d,J=6.6Hz,1H),0.58(d,J=6.8Hz,1H).

[0792] Example 18 Preparation of Compound H-18

[0793] Step 1: H-18-d (1.30 g, 4.26 mmol) was dissolved in DCM (10 mL) and triethylamine (1.77 mL, 12.7 mmol) was added. Methanesulfonyl chloride (0.49 mL, 6.39 mmol) was added dropwise at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give H-18-e (1.65 g, colorless oil) in a yield of 99.05%. MS m / z (ESI): 384.5 [M+H] + .

[0794] Step 2: Intermediate h (1.25 g, 4.12 mmol) was dissolved in DMF (15 mL), and H-18-e (1.90 g, 4.95 mmol), cesium carbonate (4.03 g, 12.3 mmol), and potassium iodide (0.46 mL, 4.12 mmol) were added. The resulting mixture was then stirred at 90°C for 18 hours. The mixture was concentrated and diluted with saturated aqueous ammonium chloride (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give H-18-f (1.95 g) in a yield of 80.12%. MS m / z (ESI): 591.4 [M+H] + .

[0795] Step 3: H-18-f (1970 mg, 3.33 mmol) was dissolved in DCM (15 mL), and a 4 mol / L HCl / dioxane solution (20 mL) was added. The resulting mixture was then stirred at 25°C for 2 hours. The filtrate was concentrated under reduced pressure to afford H-18-g (1.60 g, crude product), which was used directly in the next step in a 97.79% yield. MS m / z (ESI): 491.6 [M+H] + .

[0796] Step 4: H-18-g (1.10 g, 2.24 mmol) was dissolved in DMSO (5 mL), and 4-bromo-6-chloropyridazin-3-amine (0.48 mL, 4.48 mmol) and DIEA (1.56 mL, 8.97 mmol) were added. The resulting mixture was then stirred at 120°C for 16 hours. Saturated aqueous ammonium chloride (10.0 mL) was added, the mixture was diluted with water (50.0 mL), and extracted with ethyl acetate (50.0 mL x 2). The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give H-18-h (480 mg) in a yield of 34.63%. MS m / z (ESI): 619.2 [M+H]+ .

[0797] Step 5: H-18-h (650 mg, 1.05 mmol) was dissolved in 1,4-dioxane / water (v / v = 4:1, 15 mL), and {2-[(methoxymethyl)oxy]phenyl}boronic acid (382 mg, 2.10 mmol), Pd(dppf)Cl2 (76.86 mg, 0.11 mmol), and potassium carbonate (581 mg, 4.21 mmol) were added. The resulting mixture was then stirred at 100°C for 16 hours. The reaction mixture was concentrated, diluted with water (40 mL), and extracted with ethyl acetate (40 mL x 2). The organic phase was concentrated and purified by silica gel column chromatography (PE / EA = 1 / 1) to give H-18-i (460 mg) in a yield of 60.77%. MS m / z (ESI): 676.3 [M+H] + .

[0798] Step 6: H-18-i (470 mg, 0.70 mmol) was dissolved in ethyl acetate (15 mL), and palladium on carbon (100 mg, 0.94 mmol) was added to the mixture. The mixture was stirred at 25°C under a hydrogen atmosphere (1 atm) for 5 hours. The mixture was filtered and the filtrate was concentrated to give crude product H-18-j (380 mg) in a yield of 98.00%. MS m / z (ESI): 542.4 [M+H] + .

[0799] Step 7: H-18-j (360 mg, 0.66 mmol) was dissolved in methanol (15 mL). Intermediate c (320.64 mg, 1.33 mmol), NaBH3CN (125.60 mg, 1.99 mmol), and a drop of acetic acid were added to the solution, and the resulting mixture was stirred at 50°C for 2 hours. The mixture was then stirred at 100°C overnight for 15 hours, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give H-18-k (415 mg) in a yield of 81.42%. MS m / z (ESI): 767.5 [M+H] + .

[0800] Step 8: Dissolve H-18-k (385 mg, 0.50 mmol) in methanol / water (v / v = 5:1, 20 mL) and add an aqueous solution of LiOH·H2O (210 mg, 5.02 mmol). The resulting mixture is then stirred at 25°C for 3 h. The reaction solution is spin-dried to afford H-18-1 (370 mg, crude product), which is directly used in the next step. Yield: 97.89%. MS m / z (ESI): 753.8 [M+H]+ .

[0801] Step 9: H-18-1 (60 mg, 0.08 mmol) was dissolved in DMF (3 mL), and HATU (45.42 mg, 0.12 mmol) and DIEA (51.40 mg, 0.40 mmol) were added. After 10 minutes, intermediate 2 (36.98 mg, 0.11 mmol) was added, and the resulting mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated and diluted with saturated aqueous ammonium chloride (20 mL), and extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by pre-HPLC ( Prep C18 OBD™ 10 μm, 19×250 mm colume (eluent: 64% to 74% (v / v) CH₃CN and 0.1 wt% NH₄HCO₃ aqueous solution) to afford H-18 (20 mg) in a 23.53% yield. MS m / z (ESI): 1066.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 14.33 (s, 1H), 8.98 (d, J = 2.8Hz, 1H), 8.38 (dd, J = 43.2 ,7.7Hz,1H),7.96-7.94(m,1H),7.60(s,1H),7.47-7.30(m,4H),7.28-7.21(m,1H),7 .10(d,J=8.2Hz,1H),6.91-6.85(m,2H),6.71(s,1H),6.60(d,J=8.5Hz,1H),6.32(s, 2H),6.09(d,J=4.4Hz,1H),5.12(s,1H),4.96-4.85(m,1H),4.81-4.75(m,1H),4.45- 4.34(m,1H),4.34-4.28(m,2H),4.23-4.16(m,2H),3.77-3.54(m,2H),3.48-3.42(m ,3H),3.31-3.20(m,2H),2.91-2.87(m,2H),2.83-2.80(m,2H),2.77-2.71(m,2H),2. 66-2.59(m,2H),2.46-2.44(m,3H),2.39-2.29(m,4H),2.17-2.05(m,7H),1.80-1.72 (m,3H),1.57-1.54(m,2H),1.44-1.33(m,5H),0.97-0.95(m,3H),0.84-0.74(m,3H).

[0802] Example 19 Preparation of Compound H-19

[0803] Step 1: Dissolve methyl 4-oxocyclohexane-1-carboxylate (344 mg, 0.2 mmol) in methanol (3.5 mL). Add H-23-e (100 mg, 0.22 mmol) and NaBHCN (110.6 mg, 1.76 mmol) sequentially to the reaction mixture. Stir the reaction in a microwave oven at 90°C for 2 hours. Concentrate in vacuo to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM / MeOH = 10:1) to afford H-19-a (87 mg, colorless oil) in a 66% yield. MS m / z (ESI): 596.3 [M+H]. + .

[0804] Step 2: H-19-a (87 mg, 0.146 mmol) was dissolved in ultra-dry methanol (2 mL). Water (2 mL) and THF (2 mL) were then added to the reaction mixture. Finally, LiOH.H2O (63 mg, 1.5 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 8 with 1 mol / L hydrochloric acid. The reaction mixture was extracted with water (20 mL) and ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford H-19-b (80 mg, white solid, crude product) in a 94% yield. The crude product was used directly in the next step. MS m / z (ESI): 582.4 [M+H] + .

[0805] Step 3: H-19-b (60 mg, 0.103 mmol) was dissolved in DMF (9 mL). Intermediate 1 (46.6 mg, 0.103 mmol), DIEA (0.084 mL, 0.515 mmol), and HATU (47.1 mg, 0.124 mmol) were added sequentially to the reaction mixture. The reaction was stirred at room temperature for 1 hour. The reaction mixture was extracted with water and ethyl acetate. Solid precipitated on the wall of the flask. The solid was dissolved in dichloromethane and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC (acetonitrile: water (0.1 wt% NH4HCO3) = 10%-90%) to afford H-19 (15 mg) in a 15% yield. MS m / z (ESI): 980.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 14.32 (s, 1H), 8.99 (s, 1H), 8.31 (s, 1H), 7.95-7.93 (m, 2H), 7.59 (s, 1H), 7.43- 7.36(m,4H),7.26-7.22(m,1H),7.19-7.17(m,1H),7.09-7.08(m,2H),6.90-6.87(m,2H),6.28(s,2H),4.41-4. 30(m,6H),3.66-3.65(m,2H),3.45-3.42(m,2H),2.94-2.85(m,6H),2.45-2.40(m,3H),2.32-2.29(m,2H),2.1 5-1.99(m,8H),1.91-1.87(m,5H),1.75-1.72(m,2H),1.60-1.57(m,4H),1.29-1.23(m,6H),0.89-0.82(m,6H).

[0806] Example 20 Preparation of Compound H-20

[0807] Step 1: Dissolve intermediate g (2.20 g, 7.2 mmol) in THF (100 mL), add PPh3 (3.77 g, 14.4 mmol) and cis-3-(benzyloxy)cyclobutane-1-ol (1.92 g, 10.8 mmol), and then cool to 0°C. Add DEAD (1.25 g, 7.2 mmol), raise the temperature to 60°C, and stir for 16 hours. After completion of the reaction, concentrate and purify by silica gel column chromatography with an eluent (PE:EA = 5:1-1:2) to obtain H-20-a (1.21 g, yellow oil) in a 33.0% yield. MS m / z (ESI): 496.2 [M+H] + .

[0808] Step 2: Dissolve H-20-a (1.21 g, 2.4 mmol) in ethanol, add Pd / C (10%, 1.21 g) and acetic acid (0.4 mL), warm to 50°C, and react overnight under a hydrogen atmosphere (15 psi). After the reaction, filter the mixture, and concentrate the filtrate under vacuum to obtain H-20-b (720 mg, colorless oil, crude product). MS m / z (ESI): 274.1 [M+H] + .

[0809] Step 3: H-20-b (720 mg, 2.4 mmol) was dissolved in DMSO (5 mL). DIPEA (619 mg, 4.8 mmol) and 4-bromo-6-chloropyridazin-3-amine (742 mg, 3.6 mmol) were added at room temperature. The reaction was then heated to 120°C and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography using an eluent (PE:EA = 5:1-1:2) to obtain H-20-c (550 mg, yellow solid) in a 57% yield. MS m / z (ESI): 401.4 [M+H] + .

[0810] Step 4: Dissolve H-20-c (550 mg, 1.4 mmol) in dioxane (15 mL) and add 2-hydroxyphenylboronic acid (386 mg, 2.8 mmol), Pd(PPh3)4 (162 mg, 10 mol%), and K2CO3 (580 mg, 4.2 mmol) at room temperature. The reaction mixture was heated to 100°C and stirred under nitrogen for 12 hours. After completion, the reaction was cooled to room temperature, quenched with water (20 mL), and 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 using PE:EA (5:1 to 1:2) as eluent to afford H-20-d (575 mg, yellow solid) in a 91% yield. MS m / z (ESI): 459.3 [M+H]. + .

[0811] Step 5: H-20-d (515 mg, 1.1 mmol) was dissolved in THF (20 mL), and PPh3 (1.18 g, 4.5 mmol) and 2-iodopyrimidin-5-ol (250 mg, 1.1 mmol) were added. The mixture was then cooled to 0°C, and DEAD (909 mg, 4.5 mmol) was added. The temperature was raised to 60°C and stirred for 16 hours. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography using an eluent (PE:EA = 10:1-3:1) to afford H-20-e (230 mg, yellow oil) in a 31% yield. MS m / z (ESI): 663.2 [M+H] + .

[0812] Step 6: H-20-e (200 mg, 0.3 mmol) was dissolved in DMF (5 mL). Intermediate 15 (139 mg, 0.3 mmol), Pd(dppf)Cl2 (105 mg, 0.15 mmol), CuI (28 mg, 0.15 mmol), and triethylamine (90 mg, 0.9 mmol) were added at room temperature. The mixture was stirred at room temperature for 12 hours under nitrogen. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by Pre-HPLC (A: H2O, 0.1 wt% NH4HCO3; B: MeCN, preparative column: 19 x 150 mm C18 column; gradient: 20% to 70% acetonitrile) to obtain H-20 (2.8 mg), yield 1%. MS m / z (ESI): 999.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.30 (s, 1H), 8.48 (s, 2H), 7.94 (d, J = 8Hz, 1H), 7.77 (t, J = 20Hz, 2H), 7.59 (s, 1H), 7.47-7.41 (m, 2H), 7.2 6-7.20(m,1H),7.12(d,J=8Hz,1H),6.90(d,J=8Hz,2H),6.75(s,1H),6.65(d,J=8Hz,1H),6.28(s,2H),5.34-5.31(t,J=12Hz,1H),5.17( d,J=8Hz,3H),5.12(s,1H),4.95-4.95(m,2H),4.41-4.35(m,1H),4.26(s,1H),3.69(d,J=8Hz,1H),2.93-2.81(m,4H),2.67(s,4H),2.17 -2.07(m,4H),2.03-1.97(m,4H),1.57(d,J=12Hz,2H),1.17-1.41(m,2H),1.06(t,J=12Hz,1H),0.95(t,J=12Hz,3H),0.87-0.79(m,6H).

[0813] Example 21 Preparation of Compound H-21

[0814] Step 1: Intermediate d (1.00 g, 2.51 mmol), methyl azetidine-3-carboxylate hydrochloride (0.43 g, 3.77 mmol), RuPhos Pd G3 (0.42 g, 0.50 mmol), and cesium carbonate (2.45 g, 7.53 mmol) were dissolved in 1,4-dioxane (10 mL) at room temperature. The reaction mixture was stirred at 100°C under nitrogen for 18 hours. After the reaction was complete, the reaction mixture was dried and purified by silica gel column chromatography (EA / PE = 0-50%) to obtain H-21-a (0.47 g, yellow solid). Yield: 43.3%. MS m / z (ESI): 433.2 [M+H] + .

[0815] Step 2: To a solution of H-21-a (0.47 g, 1.09 mmol) in methanol (10 mL) was added palladium on carbon (0.10 g, 10% purity) at room temperature. The reaction was stirred at 25°C under a hydrogen atmosphere (1 atm) for 18 hours. After the reaction was complete, the reaction solution was filtered through celite and the filtrate was concentrated to afford H-21-b (0.32 g, yellow solid). Yield: 98.0%. MS m / z (ESI): 301.4 [M+H] + .

[0816] Step 3: To a solution of H-21-b (0.27 g, 0.90 mmol) in DMSO (6 mL) was added 4-bromo-6-chloropyridazin-3-amine (0.20 g, 0.99 mmol) and DIPEA (0.74 mL, 4.49 mmol) at room temperature. The reaction mixture was stirred at 120°C for 18 hours. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA / PE = 0%-50%) to obtain H-21-c (0.20 g, yellow solid). Yield: 41.6%. MS m / z (ESI): 428.1 [M+H] + .

[0817] Step 4: H-21-c (0.16 g, 0.37 mmol), (2-hydroxyphenyl)boronic acid (0.06 g, 0.45 mmol), Pd(dppf)Cl2 (0.13 g, 0.19 mmol), and potassium carbonate (0.15 g, 1.12 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL) at room temperature. The reaction mixture was stirred at 100°C under nitrogen for 18 hours. After the reaction was complete, the reaction mixture was dried to give a crude product, which was purified by C18 column chromatography (MeCN / 0.1 wt% FA aqueous solution = 0-100%) to give H-21-d (0.02 g, brown solid). Yield: 14.1%. MS m / z (ESI): 472.2 [M+H] + .

[0818] Step 5: To a solution of H-21-d (0.02 g, 0.04 mmol) in DMF (1 mL) were added intermediate 7 (0.03 g, 0.08 mmol), HATU (0.01 g, 0.04 mmol), and DIPEA (0.02 mL, 0.13 mmol) at room temperature. The reaction mixture was stirred at 25°C for 18 hours. After the reaction was complete, the reaction mixture was filtered and analyzed by pre-HPLC ( Purification was performed on a Prep C18 OBD™ 10 μm, 19×250 mm column (mobile phase: 20%-50% (v / v) CH₃CN and 0.1 wt% NH₄HCO₃ aqueous solution) to afford H-21 (8 mg). Yield: 21.3%. MS m / z (ESI): 884.4 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 8.99 (s, 1H), 8.57 (t, J = 6.0Hz, 1H), 8.11 (d, J = 9.2Hz, 1H), 7.94 (d, J = 7.9Hz, 1H), 7.58 (s,1H),7.41(q,J=8.3Hz,4H),7.26-7.22(m,1H),7.06(d,J=8.0Hz,1H),6.93-6.85(m,2H),6.30-6.27(m,3H),5.12(s ,1H),4.58-4.56(m,1H),4.48-4.40(m,2H),4.35(s,1H),4.25-4.19(m,1H),3.99-3.87(m,2H),3.78-3.76(m,1H),3.6 8-3.66(m,3H),3.43(m,2H),2.94-2.78(m,4H),2.45-2.44(m,4H),2.13-1.86(m,7H),1.55-1.52(m,3H),0.95(s,9H).

[0819] Example 22 Preparation of Compound H-22

[0820] Step 1: To a solution of intermediate d (1 g, 2.51 mmol) in 1,4-dioxane (15 mL) were added ethyl piperidine-4-carboxylate (0.47 g, 3.01 mmol), cesium carbonate (2.0 g, 6.14 mmol), and RuPhos PD G3 (0.21 g, 0.25 mmol). The mixture was stirred at 100° C. under a nitrogen atmosphere for 18 hours. The mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA=10:1-1:1) to obtain H-22-a (0.84 g, yellow solid) in a yield of 70.59%. MS m / z (ESI): 475.4 [M+H] + .

[0821] Step 2: To a solution of H-22-a (840 mg, 1.77 mmol) in EA (20 mL) was added palladium on carbon (840 mg, 1.77 mmol, 10% purity). The mixture was stirred at 25°C under a hydrogen atmosphere (1 atm) for 18 hours. After filtration, the filtrate was concentrated to afford H-22-b (470 mg, yellow oil) in a yield of 77.54%. MS m / z (ESI): 343.2 [M+H] + .

[0822] Step 3: To a solution of H-22-b (420 mg, 1.23 mmol) in DMSO (8 mL) were added 4-bromo-6-chloropyridazin-3-amine (256 mg, 1.23 mmol) and DIPEA (476 mg, 3.68 mmol). The mixture was stirred at 120°C under a nitrogen atmosphere for 7 hours. After the reaction, the mixture was poured into water (20 mL) to form a yellow suspension. The filter cake was filtered, washed with water (20 mL x 2), and dried to obtain H-22-c (490 mg, yellow solid) in a yield of 85.01%. MS m / z (ESI): 470.2 [M+H] + .

[0823] Step 4: To a solution of H-22-c (490 mg, 1.04 mmol) in 1,4-dioxane (10 mL) were added (2-hydroxyphenyl)boronic acid (173 mg, 1.25 mmol), potassium carbonate (289 mg, 2.09 mmol), and Pd(dppf)Cl2 (76 mg, 0.10 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. After the reaction, the mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH = 100:1-10:1) to obtain H-22-d (350 mg, yellow solid) in a yield of 60.44%. MS m / z (ESI): 264.8 [M / 2+H] + .

[0824] Step 5: To a solution of H-22-d (300 mg, 0.54 mmol) in MeOH (8 mL) and water (2 mL) was added LiOH·H2O (150 mg, 3.57 mmol), and the mixture was stirred at 25°C under a nitrogen atmosphere for 18 hours. After the reaction, the organic solvent was dried and diluted with water (2 mL), and then the pH was adjusted to 4 with aqueous hydrochloric acid (2 mol / L). A dark red solid was formed, which was filtered, and the filter cake was washed with water (10 mL) and dried to obtain H-22-e (240 mg, dark red solid) in a yield of 84.49%. MS m / z (ESI): 500.4 [M+H] + .

[0825] Step 6: To a solution of H-22-e (140 mg, 0.27 mmol) in DMF (5 mL) at 0°C under nitrogen atmosphere were added intermediate 11 (147 mg, 0.29 mmol), HATU (152 mg, 0.40 mmol) and DIPEA (172 mg, 1.33 mmol), and the mixture was stirred at 25°C under nitrogen atmosphere for 2 hours. After the reaction was completed, the mixture was poured into water (20 mL) to form a gray suspension, which was filtered and the filter cake was washed with water (10 mL) and dried to give a crude product. The crude product was purified by pre-HPLC (( Purification was performed on a Prep C18 OBD™ 10 μm, 19×250 mm column (mobile phase: 30%-60% (v / v) CH₃CN and 0.1 wt% NH₄HCO₃ aqueous solution) to afford H-22 (20 mg) in a 7.91% yield. MS m / z (ESI): 940.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 14.29 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.95 (d, J = 7.6Hz, 1H), 7.89 (d, J = 9.2Hz, 1H), 7.59 (s, 1H),7.53(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),7.24(t,J=7.2Hz,1H),7.15-7.05(m,1H),6.95-6.85(m,2H),6.83-6.75(m,2H),6.29(s, 1H),6.13(s,1H),5.14(s,1H),4.52(t,J=8.0Hz,2H),4.33(s,1H),3.75-3.55(m,4H),3.43(d,J=11.2Hz,3H),2.99-2.71(m,4H),2.72-2. 52(m,3H),2.45(s,3H),2.17-1.97(m,3H),1.91-1.75(m,2H),1.67(s,2H),1.59(s,3H),1.55(d,J=12.4Hz,2H),1.48(s,3H),0.92(s,9H).

[0826] Example 23 Preparation of Compound H-23

[0827] Step 1: Dissolve intermediate d (10.0 g, 25.107 mmol) in 1,4-dioxane (120 mL) and water (30 mL). Add sodium carbonate (6.65 g, 62.767 mmol), Pd(dppf)Cl2 (1.84 g, 2.511 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (8.54 g, 27.617 mmol). Under nitrogen, heat to 100°C for 16 hours. Completion of the reaction is monitored by TLC. The reaction solution is dried and purified by column chromatography (EA / PE = 1:20-1:5) to obtain H-23-a (10.0 g, white solid). Yield: 79.56%.

[0828] Step 2: Dissolve H-23-a (10.0 g, 19.974 mmol) in methanol (100 mL) and add wet palladium on carbon (0.21 g, 10% purity). The mixture was reacted at room temperature under 1 atm of hydrogen for 16 hours. Completion of the reaction was monitored by TLC. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to afford H-23-b (8.0 g, colorless oil, crude product) in a yield of 109.29%, which was used directly in the next reaction.

[0829] Step 3: H-23-b (7.40 g, 19.971 mmol), 3-amino-4-bromo-6-chloropyridazine (6.37 g, 29.956 mmol), and potassium carbonate (8.28 g, 59.913 mmol) were dissolved in DMA (100 mL). The mixture was heated to 110°C under nitrogen for 16 hours. Completion of the reaction was monitored by TLC. Water (500 mL) was added to the reaction solution, which was extracted with ethyl acetate (200 mL x 5). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA / PE = 1:10-2:1) to afford H-23-c (7.3 g, yellow solid). Yield: 73.39%.

[0830] Step 4: Dissolve H-23-c (7.30 g, 14.657 mmol), o-hydroxyphenylboronic acid (3.03 g, 21.985 mmol), potassium carbonate (5.06 g, 36.641 mmol), Pd2(dba)3 (0.34 g, 0.366 mmol), and Ruphos (0.68 g, 1.466 mmol) in 1,4-dioxane (100 mL) and water (25 mL). Heat to 95°C under nitrogen for 16 hours. Completion of the reaction was monitored by TLC. The reaction solution was dried and purified by column chromatography (EA / PE = 1:20-1:2) to afford H-23-d (7.3 g, brown solid) in a yield of 89.68%.

[0831] Step 5: Dissolve H-23-d (7.3 g, 13.136 mmol) in DCM (50 mL) and ethyl acetate hydrochloric acid solution (2 mol / L, 50 mL) in an ice-water bath. Stir overnight at room temperature. Monitor the reaction by TLC. Filter and wash the filter cake with dichloromethane to obtain H-23-e (5.9 g, white solid). Yield: 98.66%.

[0832] Step 6: Dissolve 4-(4-(4-methylthiazol-5-yl)phenyl)-4-oxobutanoic acid (0.55 g, 1.995 mmol) in DMF (10 mL), add DIEA (0.77 g, 5.986 mmol) and HATU (1.14 g, 2.993 mmol), and stir at room temperature for 1 hour. Add H-23-e (1.0 g, 2.915 mmol), and stir at room temperature for 1 hour. The reaction is monitored by TLC for completion. Water (50 mL) is added to the reaction solution, which is extracted with ethyl acetate (50 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 50:1) to afford H-23-f (1.1 g, green solid) in a yield of 77.46%.

[0833] Step 7: Dissolve H-23-f (1.09 g, 1.529 mmol) in methanol (10 mL) and dichloromethane (10 mL), add sodium cyanoborohydride (0.6 g, 9.548 mmol) and ammonium acetate (4.0 g, 51.894 mmol), and heat to 50°C overnight. Completion of the reaction was monitored by TLC. The reaction solution was concentrated and purified by column chromatography to afford H-23-g (0.4 g, green solid) in a yield of 36.70%.

[0834] Step 8: Intermediate 8 (42.07 mg, 0.127 mmol) was dissolved in DMF (1 mL), and DIEA (49.37 mg, 0.382 mmol) and HATU (72.63 mg, 0.191 mmol) were added. The mixture was stirred at room temperature for 1 hour. H-23-g (100 mg, 0.140 mmol) was added and stirred at room temperature for 2 hours. The reaction was monitored for completion by TLC. The reaction solution was purified by pre-HPLC (HPLCONE 10C18A 20 mm x 250 mm, mobile phase A: 0.1 wt% FA in water, mobile phase B: ACN) to obtain H-23 (20 mg) in a yield of 15.38%. MS m / z (ESI): 513.9 [M / 2+H]. + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 14.30 (s, 1H), 8.99 (d, J = 3.1Hz, 1H), 8.51 (dd, J = 23 .7,8.6Hz,1H),7.95(dd,J=8.3,1.7Hz,1H),7.60(s,1H),7.56-7.46(m,2H),7.50-7 .38(m,3H),7.32-7.20(m,2H),7.19(t,J=6.0Hz,2H),7.12-7.04(m,3H),6.89(ddd, J=6.9,6.0,1.4Hz,2H),6.28(s,2H),5.16(s,1H),4.61-4.42(m,3H),4.34(d,J=17. 0Hz,1H),3.68-3.54(m,2H),3.45(d,J=11.6Hz,3H),3.09(t,J=11.9Hz,1H),2.97-2 .83(m,5H),2.77-2.69(m,2H),2.60(t,J=11.2Hz,1H),2.46(dd,J=4.8,1.5Hz,4H), 2.19-1.99(m,5H),1.94(tt,J=14.4,8.8Hz,1H),1.77(d,J=13.0Hz,3H),1.58(d,J= 12.5Hz,3H),1.43(s,3H),1.43-1.30(m,1H),1.30-1.16(m,4H),1.01-0.89(m,4H).

[0835] Example 24 Preparation of Compound H-24

[0836] Step 1: H-23-c (300 mg, 0.59 mmol) was dissolved in dioxane (15 mL) and water (2.5 mL). (2-Hydroxyphenyl)boronic acid (105 mg, 0.76 mmol), potassium carbonate (204 mg, 1.48 mmol), and Brettphos Pd G3 (75 mg, 0.09 mmol) were added sequentially at room temperature. The reaction mixture was stirred at 90°C under nitrogen for 6 hours. The reaction mixture was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain H-23-d (272 mg, pale yellow solid) in an 83% yield. MS m / z (ESI): 556.5 [M+H] + .

[0837] Step 2: Dissolve H-23-d (272 mg, 0.5 mmol) in DCM (17 mL) and add TFA (4.2 mL) at 0°C. Stir the reaction at room temperature for 2 hours. Concentrate the reaction mixture in vacuo to obtain H-23-e (163 mg, brown solid, crude product) in a 72% yield. MS m / z (ESI): 456.2 [M+H] + .

[0838] Step 3: Methyl α-(1-methylethyl)-3-[(1,1,2,2,3,3,4,4,4-nonafluorobutyl)sulfonyl]oxy]5-isoxazoleacetate (127 mg, 0.264 mmol) was dissolved in DMSO (5 mL). H-23-e (100 mg, 0.22 mmol) and DIEA (0.18 mL, 1.1 mmol) were added sequentially at room temperature. The reaction was stirred at 100°C for 4 hours. The reaction solution was extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to afford H-24-a (44 mg, pale yellow solid) in a 31% yield. MS m / z (ESI): 637.4 [M+H]. + .

[0839] Step 4: H-24-a (44 mg, 0.07 mmol) was dissolved in methanol (2 mL), and water (2 mL) and THF (2 mL) were added to the reaction solution. LiOH was added to the reaction solution. . H2O (14.5 mg, 0.35 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 8 with 1 mol / L hydrochloric acid, extracted with water (20 mL) and ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford H-24-b (40 mg, pale yellow solid, crude product) in a 93% yield. MS m / z (ESI): 623.4 [M+H] + .

[0840] Step 5: H-24-b (30 mg, 0.048 mmol) was dissolved in DMF (2 mL). Intermediate 4 (15.3 mg, 0.048 mmol), DIEA (0.04 mL, 0.24 mmol), and HATU (22 mg, 0.058 mmol) were added sequentially to the reaction mixture. The reaction was stirred at room temperature for 1 hour. The reaction mixture was extracted with water (20 mL) and ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (45 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product. The crude product was purified by pre-HPLC (acetonitrile:water (0.1 wt% NH4HCO3) = 10%-90%) to afford H-24 (6.8 mg) in a 15% yield. MS m / z (ESI): 922.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.30 (s, 1H), 8.99-8.96 (m, 1H), 8.45 (s, 1H), 7.95-7.93 (m, 1H), 7.59 (s, 1H), 7.45- 7.32(m,4H),7.24-7.18(m,3H),7.11-7.15(m,3H),6.91-6.87(m,3H),6.28-6.27(m,2H),6.18-6.14(m,1H),4.45(s, 1H),4.38-4.30(m,4H),3.72-3.59(m,4H),3.46-3.40(m,2H),2.94-2.85(m,4H),2.67-2.66(m,1H),2.45-2.41(m,3H) ),2.33-2.26(m,2H),2.15-2.04(m,7H),1.79-1.78(m,2H),1.60-1.57(m,2H),0.98-0.94(m,3H),0.86-0.81(m,3H).

[0841] Example 25 Preparation of Compound H-25

[0842] Step 1: Dissolve 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (1.30 g, 5.39 mmol) in dry DMF (5 mL) at room temperature, add potassium carbonate (1.49 g, 10.8 mmol) and iodoethane (3.88 mL, 48.5 mmol), and react at 60°C for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give H-25-a (1.39 g, white solid). Yield: 95.8%. MS m / z (ESI): 214.1 [M-56+H] + .

[0843] Step 2: Dissolve H-25-a (1.39 g, 5.16 mmol) in DCM (10 mL) at room temperature, add HCl / dioxane solution (4 mol / L, 2 mL), and react at room temperature for 4 hours. Concentrate the reaction mixture to obtain H-25-b (0.76 g, colorless oil). Yield: 87.0%. MS m / z (ESI): 170.1 [M+H] + .

[0844] Step 3: Dissolve intermediate d (1.54 g, 3.86 mmol), H-25-b (0.76 g, 4.52 mmol), RuPhos Pd G3 (0.63 g, 0.75 mmol), and cesium carbonate (3.68 g, 11.3 mmol) in dry 1,4-dioxane (10 mL) at room temperature. The reaction was carried out under nitrogen at 100°C for 18 hours. The reaction solution was concentrated and purified by column chromatography (EA / PE = 0-50%) to obtain H-25-c (0.94 g, yellow solid). Yield: 50.7%. MS m / z (ESI): 487.3 [M+H]. + .

[0845] Step 4: H-25-c (0.94 g, 1.93 mmol) was dissolved in EA (10 mL) at room temperature, and 10% palladium on carbon (100 mg) was added. The reaction mixture was reacted at 60°C under a hydrogen atmosphere (1 atm) for 18 hours. The reaction mixture was filtered through celite, the filter cake was washed with ethyl acetate (10 mL x 3), and the filtrate was concentrated to obtain H-25-d (0.67 g, yellow solid). Yield: 97.8%. MS m / z (ESI): 355.2 [M+H] + .

[0846] Step 5: H-25-d (0.67 g, 1.89 mmol) was dissolved in DMSO (10 mL) at room temperature, and DIPEA (1.57 mL, 9.45 mmol) and 3-amino-4-bromo-6-chloropyridazine (433 mg, 2.08 mmol) were added. The reaction was incubated at 120°C for 18 hours. The reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (MeOH / DCM = 0-5%) to afford H-25-e (0.75 g, brown solid). Yield: 83.0%. MS m / z (ESI): 482.3 [M+H] + .

[0847] Step 6: H-25-e (0.75 g, 1.57 mmol) and (2-hydroxyphenyl)boronic acid (0.26 g, 1.88 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL) at room temperature. Pd(dppf)Cl2 (0.57 mg, 0.78 mmol) and potassium carbonate (0.65 mg, 4.71 mmol) were added. The reaction was stirred at 100°C under nitrogen for 18 hours. The reaction solution was concentrated and purified by column chromatography (MeOH / DCM = 0-5%) to obtain H-25-f (0.25 g, brown solid) in a yield of 29.5%. MS m / z (ESI): 540.4 [M+H] + .

[0848] Step 7: Dissolve H-25-f (0.25 g, 0.46 mmol) in methanol (5 mL) and water (1 mL) at room temperature, add LiOH·H2O (58.3 mg, 1.39 mmol), and react at room temperature for 18 hours. Concentrate the reaction mixture to obtain H-25-g (230 mg, white solid). Yield: 97.04%. MS m / z (ESI): 512.3 [M+H] + .

[0849] Step 8: H-25-g (210 mg, 0.41 mmol) was dissolved in dry DMF (5 mL) at room temperature, and intermediate 7 (212 mg, 0.49 mmol), DIEA (0.20 mL, 1.23 mmol), and HATU (234 mg, 0.62 mmol) were added. The reaction was allowed to proceed at room temperature for 18 hours. The reaction solution was filtered and the filtrate was purified by pre-HPLC ( A Prep C18 OBD™ 10 μm, 19×250 mm column (mobile phase: 48%-78% (v / v) CH₃CN and 0.1 wt% NH₄HCO₃ aqueous solution) was used to obtain H-25 (40.0 mg) in a 9.7% yield. MS m / z (ESI): 924.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 14.32 (s, 1H), 8.99 (s, 1H), 8.57 (t, J = 6.0Hz, 1H), 7.95-7.93 (m, 1H), 7.79 (d, J = 9.3Hz, 1H), 7 .58(s,1H),7.40(d,J=6.7Hz,3H),7.26-7.24(m,1H),7.05(d,J=8.0Hz,1H),6.91-6.87(m,2H),6.27(s,4H),5.14(d,J=3.6Hz ,1H),4.55-4.53(m,1H),4.45-4.34(m,3H),4.24-4.22(m,1H),3.79-3.77(m,2H),3.66-3.64(m,3H),3.43(d,J=11.6Hz,2H), 3.17(t,J=8.1Hz,1H),2.92-2.79(m,6H),2.45(s,3H),2.37-2.26(m,4H),2.11-1.99(m,6H),1.54-1.50(m,2H),0.93(s,9H).

[0850] Example 26 Preparation of Compound H-26

[0851] Step 1: Dissolve intermediate f (1 g, 2.5 mmol) in 1,4-dioxane (30 mL), add (1R,3R)-3-aminocyclobutanecarboxylic acid methyl ester hydrochloride (497 mg, 3.0 mmol), Pd2(dba)3 (229 mg, 0.25 mmol), XPhos (119 mg, 0.25 mmol), and cesium carbonate (2.45 g, 325.82 mmol), and react at 105°C under nitrogen for 15 h. Extract with ethyl acetate (30 mL x 3), was...

Claims

1. A compound represented by formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, A ring is selected from C 4-8 Cycloalkyl, 4- to 8-membered heterocycloalkyl; Y1, Y2, Y3, Y4 are each independently selected from a bond, -CH2-, -CH=CH-, -C(O)-, -NH-, -O-, -S-, -SO- and -SO2-; The C ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, deuterium, hydroxyl, carboxyl, cyano, halogen (preferably fluorine, chlorine or bromine), C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), -NR a0 R b0 、-CONR a1 R b1 、-COC 1-6 Alkyl (preferably -COC 1-3 Alkyl), -C(O)OC 1-6 Alkyl (preferably -C(O)OC 1-3 Alkyl), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 Alkyl), C 2-4 Alkenyl, C 2-4 Alkynyl, -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), -SO2C 1-6 Alkyl (preferably -SO2C 1-3 Alkyl), -S(O)C 1-6 Alkyl (preferably -S(O)C 1-3 Alkyl), C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 3-6 Cycloalkyloxy, 3 to 6 membered heterocycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, -COC 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OCOC 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -SC 1-6 Alkyl, -SO2C 1-6 Alkyl, -S(O)C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 3-6 Cycloalkyloxy and 3- to 6-membered heterocycloalkyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, amino, carboxyl; R a0 , R b0 are each independently selected from deuterium, hydrogen, C 1-6 Alkyl (preferably C 1-3 Alkyl), -COC 1-6 Alkyl (preferably -COC 1-3 Alkyl), -COOC 1-6 Alkyl (preferably -COOC 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); R a1 , R b1 are each independently selected from deuterium, hydrogen, C 1-6 Alkyl (preferably C 1-3 Alkyl), -COC 1-6 Alkyl (preferably -COC 1-3 alkyl); Each occurrence of n1, n2, n3, n4, and n5 is independently 0, 1, 2, 3, or 4; L is a linking group; ULM is a linker to the E3 ligase.

2. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Ring C is a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an isothiazolyl group, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, a 1,3,4-oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring or a tetrazine ring; Preferably, the C ring is a benzene ring, a pyridine ring or a pyrimidine ring.

3. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (II) has the structure represented by formula (II-A): Wherein, Y5, Y6, and Y7 are each independently selected from CH and N; R1, R2, R3, R4, R5, n1, n2, n3, n4, n5, Y1, Y2, Y3, Y4, L, ULM as described in claim 1; Preferably, Y5, Y6, and Y7 are each independently CH; Preferably, Y5 is N, and Y6 and Y7 are each independently CH; Preferably, Y6 is N, and Y5 and Y7 are each independently CH; Preferably, Y7 is N, and Y5 and Y6 are each independently CH; Preferably, Y5 and Y7 are each independently N, and Y6 is CH.

4. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (II) has the structure represented by formula (II-B): Among them, Y8, Y9, Y 10 are each independently selected from CH and N; R1, R2, R3, R4, R5, n1, n2, n3, n4, n5, Y1, Y2, Y3, Y4, L, ULM as described in claim 1; Preferably, Y8, Y9, Y 10 Each independently is CH; Preferably, Y8 is N, Y9, Y 10 Each independently is CH; Preferably, Y9 is N, Y8, Y 10 Each independently is CH; Preferably, Y 10 is N, Y8 and Y9 are each independently CH; Preferably, Y8, Y 10 Each is independently N, and Y9 is CH.

5. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Y1 is -CH2-, -O-, -SO2-, -CH=CH-, -NH- or -C(O)-; preferably, Y1 is -CH2-; Y2 is a bond, -CH2-, -NH-, -C(O)- or -O-; preferably, Y2 is -CH2- or -NH-; Y3 is a bond or -NH-; preferably, Y3 is a bond; Y4 is a bond; Preferably, Y1 is -CH=CH-, and Y2, Y3, and Y4 are each independently a bond; Preferably, Y1 and Y2 are each independently -CH2-, and Y3 and Y4 are each independently a bond; Preferably, Y1 is -CH2-, Y2 is -NH-, and Y3 and Y4 are each independently a bond; Preferably, Y1 is -C(O)-, Y2 is -NH-, and Y3 and Y4 are each independently a bond; Preferably, Y1 is -CH2-, Y2 is -O-, and Y3 and Y4 are each independently a bond; Preferably, Y1 is -SO2-, Y2 is -NH-, and Y3 and Y4 are each independently a bond; Preferably, Y1 is -O-, Y2 is -C(O)-, Y3 is -NH-, and Y4 is a bond; Preferably, Y1 is -NH, Y2 is -C(O)-, and Y3 and Y4 are each independently a bond; Preferably, Y1 is -NH-, Y2 is -CH2-, and Y3 and Y4 are each independently a bond.

6. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Ring A is a 4- to 8-membered nitrogen-containing heterocycloalkyl group; Preferably, ring A is a 4- to 6-membered nitrogen-containing heterocycloalkyl ring; Preferably, ring A is a piperidine ring, a piperazine ring, a tetrahydropyrrole ring, a 1,4-dihydropyridine ring, a tetrahydropyrazine ring, an azetidine ring or a tetrahydropyridine ring; Preferably, ring A is a piperidine ring; Preferably, Ring A is an azetidine ring.

7. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Select from the following structures: Preferably, the structure Select from the following structures:

8. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R1, R2, R3, R4, R5 are each independently hydrogen, deuterium, hydroxyl, halogen (preferably fluorine, chlorine), carboxyl, amino, hydroxymethyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, cyclopropyl, difluoromethyl, monofluoromethyl, vinyl, ethynyl, cyano, -SCH3, -COCH3, -COCH2CH3, -COOCH3, -COOCH2CH3, -OCOCH3, -OCOCH2CH3, -NHCH3, -N(CH3)2, -NHCONH2, -NHCOCH2CH3 or -NHCOCH3; Preferably, R1 is deuterium, fluorine, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, monofluoromethoxy or -OCOCH3; Preferably, R1 is hydroxyl; Preferably, R1 is fluorine or hydroxyl; Preferably, R2 is deuterium, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3 or -NHCONH2; Preferably, R2 is -NH2; 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: Preferably, the structure Selected from the following structures or isomers thereof:

9. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R4 is hydrogen, deuterium, 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 or halogen; Preferably, R4 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, monofluoropropoxy, difluoropropoxy, trifluoropropoxy, -COCH3, -COOCH3, fluorine or chlorine; Preferably, R4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, -C(O)CH3 or fluorine.

10. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Select from the following structures: Preferably, the structure Select from the following structures:

11. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (II) is a compound of formula (III) having the structure: Among them, R3, R4, R5, n3, n4, n5, Y1, Y2, Y3, Y4, L, ULM are as described in claim 1.

12. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Ring A is a piperidine ring, a tetrahydropyrrole ring or an azetidine ring; preferably, ring A is an azetidine ring; The C ring is a benzene ring or a pyridine ring; preferably, the C ring is a benzene ring; Y1 is -CH2-, -O-, -SO2-, -CH=CH-, -NH- or -C(O)-; preferably, Y1 is -CH2-; Y2 is a bond, -CH2-, -NH-, -C(O)- or -O-; preferably, Y2 is -CH2- or -NH-; Y3 is a bond, -NH-; preferably, Y3 is a bond; Y4 is a bond; n3 is 0; n4 is 0, 1 or 2, R4 is C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy or -C(O)C 1-6 Alkyl; preferably, R4 is methyl, ethyl, n-propyl, isopropyl or -C(O)CH3; n5 is 0; L. ULM as described in claim 1.

13. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (II) is the structure represented by the compound represented by formula (IV): Among them, (R4) n4 represents n4 R4, n4 is 1 or 2, each R4 is the same or different, and each independently represents hydrogen, deuterium, fluorine, chlorine or C 1-3 Alkyl; L, ULM as described in claim 1; Preferably, the compound represented by formula (II) is selected from the following structures: wherein n4 is 1 or 2, each R4 is the same or different and is independently hydrogen, deuterium, fluorine, chlorine or C 1-3 Alkyl; L, ULM as described in claim 1; Preferably, the compound represented by formula (II) is selected from the following structures: Wherein, L and ULM are as described in claim 1.

14. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound represented by formula (II) has a structure represented by formula (V): Wherein, R1, n1, R4, n4, Y1, Y2, Y3, Y4, L, ULM are as described in claim 1; Preferably, the compound represented by formula (II) is selected from the following structures: Among them, R1, n1, R4, n4, Y1, Y2, Y3, Y4, L, and ULM are as described in claim 1.

15. The compound of formula (II) 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, -(L1) m1 -(X1) p1 -(L2) m2 -(X2) p2 -(L3) m3 -(X3) p3 -(L4) m4 -(X4) p4 -, (L-1) Wherein, m1, m2, m3, m4, p1, p2, p3, p4 are each independently 0, 1 or 2; L1, L2, L3, L4 are each independently selected from C 3-15 Cycloalkyl ring (preferably C 3-10 A cycloalkyl ring, more preferably C 3-7 Cycloalkyl ring, more preferably C 3-6 cycloalkyl ring), 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), a 5- to 6-membered heteroaryl ring, a C 6-10 Aromatic ring (preferably a benzene ring); wherein the C 3-15 Cycloalkyl ring, 3- to 15-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring, C 6-10 The aromatic ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxyl, carboxyl, oxo, -NR a2 R b2 , 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), -SC 1-10 Alkyl (preferably -SC 1-8 Alkyl, more preferably -SC 1-6 Alkyl, more preferably -SC 1-3 Alkyl), -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), 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), -CO2C 1-10 Alkyl (preferably -CO2C 1-8 Alkyl, more preferably -CO2C 1-6 Alkyl, more preferably -CO2C 1-3 Alkyl), C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl or C 6-10 Aryl (preferably phenyl); X1, X2, X3, and X4 are each independently selected from a bond, C 2-4 Alkynylidene, C 2-4 Alkenylene, 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(O)-, -O-, -N(R L1 )-, -S-, -S(O)-, -SO2-, -P(O)-, -P(O)O-, -C(O)O-, -OC(O)-, -N(R L1 )C(O)-、-C(O)N(R L1 )-、-N(R L1 )C(O)N(R L1 )-、-N(R L1 )S(O)- and -N(R L1 )SO2-; wherein the C 2-4 Alkynylidene, C 2-4 Alkenylene, C 1-10 Alkylene, C 1-10 The alkyleneoxy radicals are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, C 3-6 Cycloalkyl (preferably cyclopropyl cyclohexyl), 3- to 6-membered heterocycloalkyl, hydroxy, carboxyl, -NR a2 R b2 , C 1-6 Alkyl (preferably C 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), -SOC 1-6 Alkyl (preferably -SOC 1-3 Alkyl), -SO2C 1-6 Alkyl (preferably -SO2C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably halogenated C 1-3 Alkoxy), -COC 1-6 Alkyl (preferably -COC 1-3 Alkyl), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 Alkyl), -CO2C 1-6 Alkyl (preferably -CO2C 1-3 alkyl), 5- to 6-membered heteroaryl or C 6-10 Aryl (preferably phenyl); R L1 Each occurrence is independently hydrogen, deuterium, 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 3-6 Cycloalkyl ring, 3- to 6-membered heterocycloalkyl ring; R a2 , R b2 Each independently represents hydrogen, deuterium, C 1-6 Alkyl (preferably C 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), -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl); or R a2 , R b2 and the N atom connected thereto together form a 3- to 10-membered heterocycloalkyl group (preferably a 3- to 8-membered heterocycloalkyl group, more preferably a 3- to 6-membered heterocycloalkyl group); the 3- to 10-membered heterocycloalkyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, -NH2, 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 (preferably halogenated C 1-3 Alkoxy), -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), -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 Alkyl), -NHC 1-6 Alkyl (preferably -NHC 1-3 Alkyl), -N(C 1-6 Alkyl)2 (preferably -N(C 1-3 Alkyl)2), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 1-3 Alkyl), cyano substituted C 1-6 Alkyl (preferably cyano-substituted C 1-3 Alkyl), -CONHC 1-6 Alkyl, -CON(C 1-6 alkyl)2 and -CONH2.

16. The compound of formula (II) according to claim 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: X1, X2, X3, and X4 are each independently selected from a bond, C 2-4 Alkynylidene, C 2-4 Alkenylene, C 1-6 Alkylene, C 1-6 Alkyleneoxy, -C(O)-, -O-, -NH-, -N(CH3)-, -N(C2H5)-, -N(CH2CH2Cl)-, -N(CH2CH2F)-, -S-, -S(O)-, -SO2-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)- and -NHSO2-; wherein the C 2-4 Alkynylidene, C 2-4 Alkenylene, C 1-6 Alkylene, C 1-6 The alkyleneoxy radicals are each independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, hydroxyl, carboxyl, -NH2, -NHCOCH3, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, -SC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -COC 1-3 Alkyl, -CO2C 1-3 Alkyl, 5- to 6-membered heteroaryl or phenyl; Preferably, X1, X2, X3, X4 are each independently selected from a bond, vinylene, propenylene, butenylene, ethynylene, propynylene, butynylene, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2O-, -(CH2)2O-, -(CH2)3O-, -C(O)-, -C(O)NH-, -O-, -NH-, -N(CH3)- and -S-; Preferably, X1, X2, X3, X4 are each independently selected from a bond, -NH-, -O-, -C(O)-, -(CH2)4-, -(CH2)3-, -(CH2)2-, -CH2- and -C(O)NH-; Preferably, X1, X2, X3, X4 are each independently selected from a bond, -C(O)-, -O-, -CH2- and -CH2CH2-.

17. The compound of formula (II) according to claim 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: L1, L2, L3, L4 are each independently selected from a piperidine ring, a hydroxy-substituted piperidine ring, a piperazine ring, an azetidine ring, a tetrahydropyrrole ring, a 3,8-diazabicyclo[3.2.1]octanyl ring, a pyrimidine ring, a pyridine ring, a benzene ring, a pyrazine ring, a cyclohexane ring, a cyclobutane ring, a cyclopentane ring, a cyclopropane ring, a 2-azaspiro[3.3]heptane ring, a spiro[3.3]heptane ring, a 2,6-diazaspiro[3.3]heptane ring ring, octahydropyrrolo[3,4-c]pyrrole ring, octahydrocyclopenta[c]pyrrole ring, 1,2,3,6-tetrahydropyridine ring, 2,5-diazabicyclo[2.2.1]heptyl ring, 3-azabicyclo[3.1.0]hexyl ring, bicyclopentyl ring, 2,8-diazaspiro[4.5]decane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane and 3,9-diazaspiro[5.5]undecane; Preferably, L1, L2, L3, L4 are each independently a cyclobutane ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, 2-azaspiro[3.3]heptane, 2,8-diazaspiro[4.5]decane, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane or 3,9-diazaspiro[5.5]undecane; Preferably, L1, L2, L3, and L4 are each independently a cyclobutane ring, a piperidine ring, a piperazine ring, or 2-azaspiro[3.3]heptane.

18. The compound of formula (II) according to claim 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: L1, L2, L3, L4 are each independently selected from Preferably, L1, L2, L3, L4 are each independently selected from Preferably, L1, L2, L3, L4 are each independently selected from Preferably, L1, L2, L3, L4 are each independently selected from 19. The compound of formula (II) according to claim 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: L is selected from the following structures or isomers thereof: Preferably, L is selected from the following structures or isomers thereof:

20. The compound of formula (II) according to claim 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: L is selected from the following structures or isomers thereof: Preferably, L is selected from the following structures or isomers thereof: Among them, X 10 is the connection key between L and POI, X 20 It is the connection key between L and ULM.

21. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: ULM is a VHL (von Hippel-Lindau) linker.

22. The compound of formula (II) according to claim 21, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: ULM is a structure represented by formula (V-1) or an isomer thereof: in, U1 is -CONR U7 C(R U5 R U6 )-, -CONHO-, -CONH-, or a substituted or unsubstituted 5- or 6-membered heteroaryl ring; R U5 , R U6 are each independently selected from X, hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), amino, cyano, carboxyl, hydroxyl, -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), -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), or R U5 , R U6 Together with the carbon atom it is connected to form C 3-7 Cycloalkyl ring, 3 to 7 membered heterocycloalkyl ring; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 The cycloalkyl ring and the 3- to 7-membered heterocycloalkyl ring are each independently unsubstituted or substituted by 1, 2, or 3 substituents selected from the group consisting of halogen (preferably fluorine, chlorine, or bromine), hydroxyl, cyano, carboxyl, amino, C 1-6 Alkyl-substituted amino, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; 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; D ring is C 6-10 Aromatic ring (preferably benzene ring), 5- to 6-membered heteroaryl ring (preferably pyridine ring, pyrimidine ring, pyrazine ring), C 3-10 Cycloalkyl ring, 3- to 10-membered heterocycloalkyl ring; (R U1 ) r1 represents r1 R U1 , r1 is 0, 1, 2 or 3, each R U1 are the same or different and are each independently deuterium, halogen (preferably fluorine or chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, -NR a3 R b3 、-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONR a4 R b4 、-SOC 1-6 Alkyl, -SO2C 1-6 Alkyl or -SC 1-6 alkyl; (R U2 ) r2 Represents r2 R U2 , r2 is 0, 1, 2 or 3, each R U2 are the same or different and are each independently X, hydrogen, deuterium, halogen (preferably fluorine or 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 a5 R b5 、-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 alkyl Base, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SC 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 5- to 6-membered heteroaryl, C 6-10 Aryl, C 3-10 Cycloalkyl, 3 to 10 membered heterocycloalkyl; wherein the C 2-4 Alkenyl, C 2-4 Alkynyl, 5- to 6-membered heteroaryl, C 6-10 Aryl, C 3-10 The cycloalkyl and 3- to 10-membered heterocycloalkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONH2, -NHCONH2, -CONHC 1-6 Alkyl, -NHCONHC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl and -SC 1-6 alkyl; W1 is selected from the following structures: X, -NHCO-X, -NHCOCH3, R W1 , R W2 are each independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl and halogenated C 1-6 Alkoxy; R U3 , R U4 are each independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, -NR a3 R b3 、-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONR a4 R b4 、-SOC 1-6 Alkyl, -SO2C 1-6 Alkyl and -SC 1-6 Alkyl; or R U3 , R U4 Together with the carbon atom to which it is attached, it forms C 3-7 Cycloalkyl ring, 3 to 7 membered heterocycloalkyl ring; wherein said C 3-7 The cycloalkyl ring and the 3- to 7-membered heterocycloalkyl ring are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-6 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, carboxyl substituted C 1-6 Alkyl, amino substituted C 1-6 Alkyl, -NR a3 R b3 、-COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONR a4 R b4 、-SOC 1-6 Alkyl, -SO2C 1-6 Alkyl and -SC 1-6 alkyl; R a3 , R b3 Each independently represents hydrogen, deuterium, C 1-6 Alkyl (preferably C 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), -CONHC 1-6 Alkyl (preferably -CONHC 1-3 alkyl), -CONH2; or R a3 , R b3 Together with the N atom, it forms a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring); the 3- to 10-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, -NH2, 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 (preferably halogenated C 1-3 Alkoxy), -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), -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 Alkyl), -NHC 1-6 Alkyl (preferably -NHC 1-3 Alkyl), -N(C 1-6 Alkyl)2 (preferably -N(C 1-3 Alkyl)2), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 1-3 Alkyl), cyano substituted C 1-6 Alkyl (preferably cyano-substituted C 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); R a4 , R b4 Each independently represents hydrogen, deuterium, C 1-6 Alkyl (preferably C 1-3 alkyl); or R a4 , R b4 Together with the N atom, it forms a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring); the 3- to 10-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the following: hydrogen, hydroxyl, cyano, halogen, -NH2, 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 (preferably halogenated C 1-3 Alkoxy), -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), -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 Alkyl), -NHC 1-6 Alkyl (preferably -NHC 1-3 Alkyl), -N(C 1-6 Alkyl)2 (preferably -N(C 1-3 Alkyl)2), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C 1-3 Alkyl), cyano substituted C 1-6 Alkyl (preferably cyano-substituted C 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); R a5 , R b5 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), -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 C 6-10 Aryl; wherein the 5- to 6-membered heteroaryl, the C 6-10 Each aryl group is independently unsubstituted or substituted with 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), -CONHC 1-6 Alkyl (preferably -CONHC 1-3 Alkyl), -CON(C 1-6 Alkyl)2 (preferably -CON(C 1-3 Alkyl)2), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 alkyl); X is the connecting key between ULM and L, and U1, R U2 , any structure of W1 contains X.

23. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: U1 is -CONHC(R U5 R U6 )-.

24. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: ULM is a structure represented by formula (V-3) or an isomer thereof: Among them, D ring, R U1 , R U2 , R U3 , R U4 , R U5 , R U6 , r2, W1 as described in claim 22.

25. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: W1 is selected from the following structures: X, -NHCO-X, -NHCOCH3, Preferably, W1 is -NHCO-X; Preferably, W1 is Preferably, W1 is selected from the following structures:

26. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U1 Hydroxyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkyl, -SC 1-3 Alkyl or -OCOC 1-3 alkyl; Preferably, R U1 is hydroxy, -OCH3, -SCH3, -OCF3, -CH3, -CF3 or -OCOCH3; Preferably, R U1 It is hydroxyl.

27. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U2 Selected from the following structures: cyano, nitro, -NR a5 R b5 , Among them, R Ua , R Ub , R Uc , R Ud , R Ue , R Uf Each independently selected from deuterium, halogen (preferably fluorine, chlorine, bromine), amino, amino-substituted C 1-3 Alkyl, C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkyl, -SC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 alkyl; t1, t2, t3, t4, t5, t6 are each independently 0, 1 or 2; R a5 , R b5 As claimed in claim 22; Preferably, R U2 For-NR a5 R b5 , where R a5 , R b5 is a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is thiazole, imidazole, pyrazole, oxazole, pyridine or pyrimidine; the 5- to 6-membered heteroaryl 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 or -OCOC 1-3 alkyl; Preferably, R U2 NHR a5 , where R a5 is a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is thiazole, imidazole, pyrazole, oxazole, pyridine or pyrimidine; the 5- to 6-membered heteroaryl 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 or -OCOC 1-3 alkyl.

28. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U2 Selected from the following structures: cyano, 29. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: r2 is 1, R U2 for Preferably, r2 is 1, R U2 For cyano, Preferably, r2 is 1, R U2 for 30. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: r2 is 2, R U2 X and Wherein, X is the connecting bond between ULM and L.

31. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U3 , R U4 are each independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, -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, -SC 1-6 Alkyl; or R U3 , R U4 Together with the carbon atom to which it is attached, it forms a saturated C 3-7 Cycloalkyl ring, saturated 3- to 7-membered heterocycloalkyl ring; Preferably, R U3 , R U4 are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino substituted C 1-6 Alkyl, -NHCOC 1-3 Alkyl, -COC 1-3 Alkyl, -COOC 1-3 Alkyl, -OCOC 1-3 Alkyl, -CONHC 1-3 Alkyl, -NHCONHC 1-3 Alkyl, -SOC 1-3 Alkyl, -SO2C 1-3 Alkyl or -SC 1-6 Alkyl; or R U3 , R U4 Together with the carbon atom to which it is attached, it forms a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring; Preferably, R U3 , R U4 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 Alkyl, 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 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; Preferably, R U3 , R U4 are each independently selected from hydrogen, C 1-3 Alkyl, halogenated C 1-3 alkyl; Preferably, R U3 , R U4 Each is independently hydrogen, -CH3, -CF3, -CHF2, -CH2F, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCF3, -OCHF2, -OCH2F, -OCH(CH3)2, -OC(CH3)3, fluoroisopropyl or fluorotert-butyl; 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, -CH2CH3 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 are each independently hydrogen, -C(CH3)3 or -CH(CH3)2; 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 -CH2CH3; Preferably, R U3 , R U4 Each is independently hydrogen or -C(CH3)3.

32. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The D ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a cycloalkyl ring, a piperidine ring, a piperazine ring, a pyrrole ring or 2,3-dihydro-1H-indene; Preferably, the D ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or 2,3-dihydro-1H-indene; Preferably, the D ring is a benzene ring, a pyridine ring or 2,3-dihydro-1H-indene.

33. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U5 , R U6 are each independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), amino, cyano, carboxyl, hydroxyl, -NHCOC 1-6 Alkyl, -COC 1-6 Alkyl, -COOC 1-6 Alkyl, -OCOC 1-6 Alkyl, -CONH2, -NHCONH2, -CONHC 1-6 Alkyl, -NHCONHC 1-6 Alkyl, -SOC 1-6 Alkyl, -SO2C 1-6 Alkyl, -SC 1-6 Alkyl, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), or R U5 , R U6 Together with the carbon atom it is connected to form C 3-7 Cycloalkyl ring, 3 to 7 membered heterocycloalkyl ring; the C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 3-7 The cycloalkyl ring and the 3- to 7-membered heterocycloalkyl ring are each independently unsubstituted or substituted by 1, 2, or 3 substituents selected from the group consisting of halogen (preferably fluorine, chlorine, or bromine), hydroxyl, cyano, carboxyl, amino, C 1-3 Alkyl-substituted amino, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy; Preferably, R U5 , R U6 are each independently X, hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, carboxyl, hydroxyl, 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, carboxyl substituted C 1-6 Alkyl, -NH2, amino substituted C 1-6 Alkyl, -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 or -SC 1-6 Alkyl, wherein X is the bond connecting ULM and L; Preferably, R U5 , R U6 are independently hydrogen, deuterium, halogen, hydroxyl, carboxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy; Preferably, R U5 , R U6 are independently hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; Preferably, R U5 , R U6 Each is independently hydrogen, -OCH3, -SCH3, -OCH2F, -OCHF2, -OCF3, -CH3, -CH2CH3, -CF3, -CHF2 or -CH2F; Preferably, R U5 , R U6 Each is independently hydrogen, -OCH3, -SCH3, -OCF3, -CF3, -CHF2, -CH2F, -OCHF2, -OCH2F or -CH3; Preferably, R U5 , R U6 are each independently hydrogen, -CH3 or -CH2CH3; Preferably, R U5 , R U6 Each is independently hydrogen or -CH3.

34. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R U7 is hydrogen, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl; Preferably, R U7 For hydrogen.

35. The compound of formula (II) according to claim 22, 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 4- to 6-membered heterocycloalkyl ring or a 5- to 6-membered heteroaryl 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 or a pyrimidine 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.

36. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Selected from the following structures or isomers thereof: Where X is the bond connecting ULM and L; Preferably, the structure Selected from the following structures or isomers thereof: Wherein, X is the connecting bond between ULM and L.

37. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: structure Selected from the following structures or isomers thereof: Wherein, X is the connecting bond between ULM and L.

38. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The ULM is selected from the following structures or isomers thereof: Wherein, X is the connecting bond between ULM and L; Preferably, the ULM is selected from the following structures or isomers thereof: Wherein, X is the connecting bond between ULM and L; Preferably, the ULM is selected from the following structures or isomers thereof: Wherein, X is the connecting bond between ULM and L.

39. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (II) is selected from the following compounds or their stereoisomers:

40. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (II) is selected from the following compounds or their stereoisomers:

41. A pharmaceutical composition comprising: (1) The compound of formula (II) according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and (2) a pharmaceutically acceptable carrier.

42. Use of the compound of formula (II) according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 41 in the preparation of a medicament for treating diseases associated with BRM (SMARCA2 gene editing) activity.

43. The use according to claim 42, wherein: The disease associated with BRM (SMARCA2 gene editing) activity is cancer.

44. A compound of formula (N-1), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in, The NA ring is a 4- to 8-membered heterocycloalkyl ring (preferably a 4- to 6-membered heterocycloalkyl ring); Z1, Z2, Z3, and Z4 are each independently a bond, -CH2-, -CH=CH-, -C(O)-, -NH-, -O-, -S-, -SO-, or -SO2-; The NC ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring; (R n1 ) q1 Indicates that the hydrogen on the NA ring is replaced by q1 R n1 Substitution, q1 is 0, 1, 2, 3 or 4, each R n1 are the same or different, each independently selected from hydrogen, an amino protecting group (preferably -Boc, -Cbz, -Fomc), -C(O)C 1-6 Alkyl and oxo; (R n2 ) q2 Indicates that the hydrogen on the NB ring is replaced by q2 R n2 substituted, q2 is 0, 1, 2, 3 or 4, each R n2 are the same or different and are each independently selected from halogen (preferably fluorine, chlorine or bromine), oxo, hydroxyl, carboxyl, amino, C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 1-6 Alkyl (preferably C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably halogenated C 1-3 Alkoxy), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), -C(O)C 1-6 Alkyl (preferably -C(O)C 1-3 Alkyl), -C(O)OC 1-6 Alkyl (preferably -C(O)OC 1-3 Alkyl), -OC(O)C 1-6 Alkyl (preferably -OC(O)C 1-3 Alkyl), C 3-6 Cycloalkyls, -OMs, -OTs, and amino protecting groups; (R n3 ) q3 It means that the hydrogen on the NC ring is replaced by q3 R n3 substituted, q3 is 0, 1, 2, 3 or 4, each R n3 are the same or different and are each independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, carboxyl, amino, carboxyl, C 1-6 Aldehyde group (preferably C 1-3 Aldehyde), C 2-4 Ketone, C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 1-6 Alkyl (preferably C 1-3 Alkyl), -COC 1-6 Alkyl (preferably -COC 1-3 Alkyl), -OCOC 1-6 Alkyl (preferably -OCOC 1-3 Alkyl), -COOC 1-6 Alkyl (preferably -COOC 1-3 alkyl), -CONH2, -SO2NH2, -NHCOC 1-6 Alkyl (preferably -NHCOC 1-3 alkyl), 4,4,5,5-tetramethyl-1,3,2-dioxaboryl and -SO2C 1-6 Alkyl (preferably -SO2C 1-3 alkyl); wherein the C 1-6 Alkyl, C 1-6 Alkoxy, -COC 1-6 Alkyl, -OCOC 1-6 Alkyl, -COOC 1-6 Alkyl, -NHCOC 1-6 Alkyl, -SO2C 1-6 Each alkyl group is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen (preferably fluorine, chlorine, bromine), cyano or carboxyl.

45. The compound of formula (N-1) according to claim 44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The NA ring is a 4- to 8-membered heterocycloalkyl ring (preferably a 4- to 6-membered heterocycloalkyl ring); Z1, Z2, Z3, and Z4 are each independently a bond, -CH2-, -CH=CH-, -C(O)-, -NH-, -O-, -S-, -SO-, or -SO2-; (R n2 ) q2 Indicates that the hydrogen on the NB ring is replaced by q2 R n2 substituted, q2 is 0, 1, 2, 3 or 4, each R n2 The same or different, each independently C 1-6 Alkyl (preferably C 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl (preferably -C(O)C 1-3 Alkyl), -OC(O)C 1-6 Alkyl(-OC(O)C 1-3 alkyl), 2-(trimethylsilyl)ethoxymethyl, -Boc, -Cbz, -Fomc, oxo, -OH, -OMs or -OTs; The NC ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring; (R n1 ) q1 Indicates that the hydrogen on the NA ring is replaced by q1 R n1 Substitution, q1 is 0, 1, 2, 3 or 4, each R n1 are the same or different, and are each independently hydrogen, an amino protecting group (preferably -Boc, -Cbz, -Fomc), -C(O)C 1-3 Alkyl or oxo; (R n3 ) q3 It means that the hydrogen on the NC ring is replaced by q3 R n3 substituted, q3 is 0, 1, 2, 3 or 4, each R n3 are the same or different and are each independently halogen, hydroxyl, amino, cyano, C 1-6 Alkoxy (preferably C 1-3 Alkoxy), hydroxy substituted C 1-6 Alkyl (preferably hydroxy substituted C1-3 alkyl), amino substituted C 1-6 Alkyl (preferably amino substituted C 1-3 Alkyl), cyano substituted C 1-6 Alkyl (preferably cyano-substituted C 1-3 Alkyl), C 1-6 Aldehyde group (preferably C 1-3 aldehyde group).

46. ​​The compound of formula (N-1) according to claim 44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (N-1) is a structure represented by formula (M-1) or an isomer thereof: Among them, (R m1 ) s1 Indicates s1 R m1 , s1 is 0, 1, 2, 3 or 4, each R m1 are the same or different and are each independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, carboxyl, amino, C 1-3 Aldehyde, C 2-4 Ketone, C 1-3 Alkoxy, C 1-3 Alkyl, -COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -CONH2, -SO2NH2, -NHCOC 1-3 Alkyl, 4,4,5,5-tetramethyl-1,3,2-dioxaboryl and -SO2C 1-3 Alkyl; wherein the C 1-3 Alkyl, C 1-3 Alkoxy, COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2C 1-3 The alkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen (preferably fluorine, chlorine, bromine), cyano or carboxyl; (R m2 ) s2 Indicates s2 R m2 , s2 is 0, 1, 2, 3 or 4, each R m2 are the same or different and are independently selected from halogen, oxo, hydroxyl, carboxyl, amino, C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkoxy and halogenated C 1-3 alkyl; R m3 is selected from hydrogen and an amino protecting group; Indicates a single bond or a double bond.

47. The compound of formula (N-1) according to claim 44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (N-1) is a structure represented by formula (M-2) or an isomer thereof: wherein Z5 and Z6 are each independently -CH-, -CH2-, -NH-, -N-, -O-, -C(O)-, -C(O)O- or -SO2-; Z7, Z8, Z9, Z 10 each independently is -CH- or -N-; (R m1 ) s1 Indicates that the hydrogen on the F ring is replaced by s1 R m1 Substitution, s1 is 0, 1, 2, 3 or 4, each R m1 are the same or different and are each independently selected from halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, carboxyl, amino, C 1-3 Aldehyde, C 2-4 Ketone, C 1-3 Alkoxy, C 1-3 Alkyl, -COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -CONH2, -SO2NH2, -NHCOC 1-3 Alkyl, 4,4,5,5-tetramethyl-1,3,2-dioxaboryl and -SO2C 1-3 Alkyl; wherein the C 1-3 Alkyl, C 1-3 Alkoxy, COC 1-3 Alkyl, -OCOC 1-3 Alkyl, -COOC 1-3 Alkyl, -NHCOC 1-3 Alkyl, -SO2C 1-3 The alkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, amino, halogen (preferably fluorine, chlorine, bromine), cyano or carboxyl; (R m2 ) s2 Indicates that the hydrogen on the E ring is replaced by s2 R m2 Substitution, s2 is 0, 1, 2, 3 or 4, each R m2 are the same or different and are independently selected from halogen, oxo, hydroxyl, carboxyl, amino, C 1-3 Alkoxy, C 1-3 Alkyl, halogenated C 1-3 Alkoxy and halogenated C 1-3 alkyl; R m3 is selected from hydrogen and an amino protecting group; Indicates a single bond or a double bond.

48. The compound of formula (N-1) according to claim 44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound of formula (N-1) is selected from the compounds shown below or their stereoisomers: Preferably, the compound of formula (N-1) is selected from the compounds shown below or their stereoisomers:

49. Use of a compound of formula (N-1), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of claims 1 to 40; Preferably, the compound of formula (N-1) is a structure represented by formula (M-1) or an isomer thereof; Preferably, the compound of formula (N-1) is a structure represented by formula (M-2) or an isomer thereof.

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