Macrocyclic compound, preparation method therefor and use thereof

Abstract

The present disclosure belongs to the technical field of medicinal chemistry, and specifically provides a macrocyclic compound, a preparation method therefor and the use thereof. The compound has a good tumor inhibition effect.

Description

Macrocyclic compounds, their preparation methods and uses

[0001] This application claims priority to Chinese patent application 2025103792195, filed on March 27, 2025; Chinese patent application 2025105190551, filed on April 23, 2025; Chinese patent application 2025107721131, filed on June 10, 2025; Chinese patent application 2025109921734, filed on July 17, 2025; and Chinese patent application 2025109921734, filed on August 15, 2025. Priority claims are made to Chinese Patent Application No. 2025111497783, Chinese Patent Application No. 2025113585774 (filed September 22, 2025), Chinese Patent Application No. 2025118978479 (filed December 15, 2025), PCT Application No. PCT / CN2026 / 073673 (filed January 20, 2026), and Chinese Patent Application No. 2026103544310 (filed March 20, 2026). The full text of the aforementioned patent applications is incorporated herein by reference. Technical Field

[0002] This disclosure belongs to the field of medicinal chemistry, specifically providing a class of cyclic compounds or their pharmaceutically acceptable salts, and a method for their preparation. These compounds exhibit good tumor-suppressive effects. Background Technology

[0003] RAS is one of the most well-known proto-oncogenes. Approximately 30% of human cancers contain mutations in the three most prominent members: KRAS, HRAS, and NRAS, making them the most prevalent carcinogenic drivers. KRAS mutations are generally associated with poor prognosis, particularly in colorectal cancer, pancreatic cancer, and lung cancer. As the most frequently mutated RAS subtype, KRAS has been extensively studied in recent years. Among the most common KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc.), G12C, G12D, and G12V account for more than half of all KRAS-driven cancers, including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (LUAD). Notably, KRAS wild-type amplification is also found in approximately 7% of KRAS-altered cancers (ovarian cancer, esophageal and gastric cancer, and uterine cancer), ranking among the top.

[0004] All RAS proteins belong to the family of small GTPases that hydrolyze GTP to GDP. Structurally, KRAS consists of an effector-binding lobe, followed by an allosteric lobe and a C-terminal region responsible for membrane anchoring. The effector lobe includes a p-loop, switch I, and switch II regions. The switch I / II loop plays a crucial role in downstream KRAS signaling by mediating protein-protein interactions with effector proteins, including RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) pathway.

[0005] KRAS proteins switch between inactive and active forms by binding to GTP and GDP, respectively. Under physiological conditions, this switching between the two states is regulated by guanine nucleotide exchange factors (GEFs), such as Son of Sevenless Homolog 1 (SOS1) or GTPase activating proteins (GAPs), which are involved in catalyzing the exchange of GDP for GTP, enhancing intrinsic GTPase activity, or accelerating ras-mediated GTP hydrolysis. Upon extracellular stimulation, inactive RAS-gdp is converted to active RAS-gtp, which directly binds to the RAF RAS-binding domain (RAF RBD), recruiting the RAF kinase family from the cytoplasm to the membrane, where they dimerize and become active. Activated RAFs then undergo a series of phosphorylation reactions with their downstream mitogen-activated protein kinases (MEK) and extracellular signal-regulated kinases (ERK), propagating growth signals. Among the RAF protein kinase family (the three known isoforms ARAF, BRAF, and CRAF / RAF1), BRAF is the most frequently mutated and remains the most potent activator of MEK. Although individual RAS and RAF family members exhibit different binding preferences, all RAFs possess a conserved RBD for positive MAPK signaling and are frequently used to characterize KRAS inhibition (e.g., KRAS-braf RBD). For KRAS, mutations at positions 12, 13, 61, and 146 lead to the conversion of KRAS to its active form by disrupting nucleotide hydrolysis or activating nucleotide exchange, resulting in hyperactivation of the MAPK pathway and consequently tumorigenesis.

[0006] Despite its recognized importance in malignant tumors, persistent efforts have failed to develop approved treatments for KRAS-mutant cancers until recently, when the first selective drug, AMG510, was rapidly approved as a second-line treatment for KRAS G12C-driven non-small cell lung cancer (NSCLC). However, clinically acquired resistance to KRAS G12C inhibitors has become severe with disease progression, occurring approximately 6 months after treatment. All mutations cluster together to reactivate RAS-mapk signaling, with secondary RAS mutations observed in oncogenic hotspots (e.g., G12 / G13 / Q61) and switch II pockets (e.g., H95, R68, and Y96); furthermore, over 85% of cancers driven by KRAS mutations or wild-type amplification still lack new drugs. In conclusion, the numerous escape mechanisms and diverse oncogenic alleles underscore the urgent need for additional RAS therapies. Therefore, we have invented oral compounds that target and inhibit RAS alleles for the treatment of RAS mutation-driven cancers. Summary of the Invention

[0007] This disclosure provides compounds as shown in Formula I, pharmaceutically acceptable salts thereof, or stereoisomers thereof:

[0008] in,

[0009] Ring B is selected from One end marked with * is connected to R 17 The carbon atoms are connected;

[0010] R1, R2, R 3、 R 18 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R2, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R1, R 18 The atoms to which it is attached cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R2 and R 18Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene or C 2-4 alkenyl groups; or R3 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene or C 2-4 Alkenyl group; or R1, R3 and the atoms they are attached to, and the atoms they are attached to, cyclize together to form a 4-7 membered cycloalkyl or a 4-7 membered heterocycloalkyl group; wherein the NH2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, and alkenyl group are optionally substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl or NH2-C 1-4 alkyl;

[0011] X1 is selected from chemical bonds, CHR X1-1 O, NR X1-2 and carbonyl (C=O); the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl and NH2-C 1-4 alkyl;

[0012] X2 is selected from N and C-R9;

[0013] X3 is selected from N and CR. 12 ;

[0014] R4 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl and C 1-6 Alkyl groups; the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkyl groups are optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl or NH2-C1-4 alkyl;

[0015] R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-9 membered cycloalkyl, or 3-9 membered heterocycloalkyl; or R7, R8, and atoms therebetween cyclized to form 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl; or R8, R 15 Directly connected together to form C 2-6 Alkylene, 2-6 heteroalkylene or C 2-6 alkenyl; the alkyl, cycloalkyl, heterocycloalkyl, alkylene, heteroalkylene, and alkenyl groups are optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl;

[0016] L is selected from chemical bonds, O, NH, C 1-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; the alkylene group, alkenyl group, and alkyne group are optionally surrounded by one or more C atoms. 1-4 Alkyl substitution;

[0017] R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl and (C 1-4 Alkyl)2N-C(O)-; the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, =C(R) 10a (R) 10b ), =NR 10c C 2-4 alkynyl group, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, C 1-4 Halogenated alkyl-S(O)2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl-substituted 3-6 membered heterocycloalkyl; wherein R 10-1 R 10-2 R 10a R 10b R 10c Each element is independently selected from H, CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl and C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene or C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 The heteroalkylene group is optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl;

[0018] or Selected from

[0019] The ring C is selected from 6-8-membered heterocyclic alkyl groups and 5-6-membered heteroaryl groups, wherein the 6-8-membered heterocyclic alkyl group and the 5-6-membered heteroaryl group contain 1-2 heteroatoms selected from N, O, and S and optionally are C-shaped. 1-4 Alkyl, deuterated, or oxosubstituted; R 20 Selected from C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered deuterated cycloalkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkoxy-C(O)-, C 1-4 Alkyl-NH-C(O)-, C 1-4 Alkyl-S(O)2-, (C 1-4 Alkyl)2N-S(O)2- and CN; said alkyl, cycloalkyl, heterocycloalkyl is optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, methanyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, cyano-C 1- 4-alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-oxy or C 1-4 Alkyl-S(O)2-;

[0020] R 13 R 14 R 15 R 16 R 17 Each of the following is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O- and 3-6 membered heterocycloalkyl-O-; or R 14 R 15The atoms connected thereto co-cyclize to form a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl or NH2-C 1-4 Alkyl; or R 16 R 17 And the atoms between them are cyclized together to form a 5-6 membered heteroaryl or a 6 membered aryl; and the 5-6 membered heteroaryl or the 6 membered aryl is optionally surrounded by one or more R 19 Instead, the R 19 Selected from H, CN, OH, NH2, oxo, methanyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl;

[0021] X8 and X9 are each independently selected from -C-, CH and -N-;

[0022] n is selected from 0, 1, and 2;

[0023] each It can be used to represent a single bond or a double bond independently.

[0024] This disclosure provides compounds as shown in Formula I, their pharmaceutically acceptable salts, and stereoisomers:

[0025] in,

[0026] Ring B is selected from One end marked with * is connected to R 17 The carbon atoms are connected;

[0027] R1, R2, R 3、 R 18 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R2, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R1, R 18 The atoms to which it is attached cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R2 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene, C 2-4 alkenyl groups; or R3 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene, C 2-4 Alkenyl group; or R1, R3 and the atoms they are attached to, and the atoms they are attached to, cyclize together to form a 4-7 membered cycloalkyl group or a 4-7 membered heterocycloalkyl group; wherein, the NH2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, and alkenyl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0028] X1 is selected from chemical bonds, CHR X1-1 O, NR X1-2 Carbonyl group (C=O); the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0029] X2 is selected from N or C-R9;

[0030] X3 is selected from N or CR 12 ;

[0031] R4 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkyl groups; the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkyl groups may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl.

[0032] R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-9 membered cycloalkyl, 3-9 membered heterocycloalkyl; or R7, R8 and the atoms they are attached to can cyclize to form 5-9 membered cycloalkyl, 5-9 membered heterocycloalkyl; or R8, R 15 Directly connected together to form C 2-6 Alkylene, 2-6 heteroalkylene, C 2-6 alkenyl; the alkyl, cycloalkyl, heterocycloalkyl, alkylene, heteroalkylene, and alkenyl groups may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0033] L is selected from chemical bonds, O, NH, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group;

[0034] R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, =C(R) 10a (R) 10b ), =NR 10c C 2-4 alkynyl group, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, C 1- 4-Haloalkyl-S(O)2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted with 3-6 membered heterocycloalkyl; said R 10-1 R 10-2 R 10a R 10b R 10c Each element is independently selected from H, CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene, C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 Heteroalkylene, C1-4 The denenyl group may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1- 4-Hydroalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0035] or Selected from

[0036] The ring C is selected from 6-8-membered heterocyclic alkyl groups and 5-6-membered heteroaryl groups, wherein the 6-8-membered heterocyclic alkyl group and the 5-6-membered heteroaryl group contain 1-2 heteroatoms selected from N, O, and S and optionally are C-shaped. 1-4 Alkyl, deuterium, and oxo-substituted; R 20 Selected from C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered deuterated cycloalkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkoxy-C(O)-, C 1-4 Alkyl-NH-C(O)-, The alkyl, cycloalkyl, and heterocycloalkyl groups may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, methanyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, NH-C 1-4 Alkyl, cyano-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0037] R 13 R 14 R 15 R 16 R 17 Each of the following is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-; or R 14 R 15 The atoms connected thereto co-cyclize into 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl; or R 16 R 17 The atoms directly or indirectly adjacent to it are cyclized together to form 5-6-membered heteroaryl or 6-membered aryl; and the 5-6-membered heteroaryl or 6-membered aryl can be further cyclized by one or more R atoms. 19 Instead, the R 19 Selected from H, CN, OH, NH2, oxo, methanyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0038] X8 and X9 are each independently selected from -C-, CH, or -N-;

[0039] n is selected from 0, 1, and 2.

[0040] This disclosure provides compounds as shown in Formula I, their pharmaceutically acceptable salts, and stereoisomers:

[0041] Among them, R1, R2, R 3、 R 18 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R2, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R1, R 18 The atoms to which it is attached cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R2 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene, C 2-4 alkenyl groups; or R3 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene, C 2-4 Alkenyl group; or R1, R3 and the atoms they are attached to, and the atoms they are attached to, cyclize together to form a 4-7 membered cycloalkyl group or a 4-7 membered heterocycloalkyl group; wherein, the NH2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, and alkenyl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0042] X1 is selected from chemical bonds, CHR X1-1 O, NR X1-2 Carbonyl group (C=O); the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0043] X2 is selected from N or C-R9;

[0044] X3 is selected from N or CR 12 ;

[0045] R4 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 1-6 Alkyl groups; the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkyl groups may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl.

[0046] R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-9 membered cycloalkyl, 3-9 membered heterocycloalkyl; or R7, R8 and the atoms they are attached to can cyclize to form 5-9 membered cycloalkyl, 5-9 membered heterocycloalkyl; or R8, R 15 Directly connected together to form C 2-6 Alkylene, 2-6 heteroalkylene, C 2-6 alkenyl; the alkyl, cycloalkyl, heterocycloalkyl, alkylene, heteroalkylene, and alkenyl groups may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0047] L is selected from chemical bonds, O, NH, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group;

[0048] R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, =C(R) 10a (R) 10b ), =NR 10c C 2-4 alkynyl group, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, C 1- 4-Haloalkyl-S(O)2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted with 3-6 membered heterocycloalkyl; said R 10-1 R 10-2 R 10a R 10b R 10c Each element is independently selected from H, CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene, C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4The denenyl group may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1- 4-Hydroalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0049] or Selected from

[0050] The ring C is selected from 6-8-membered heterocyclic alkyl groups and 5-6-membered heteroaryl groups, wherein the 6-8-membered heterocyclic alkyl group and the 5-6-membered heteroaryl group contain 1-2 heteroatoms selected from N, O, and S and optionally are C-shaped. 1-4 Alkyl, deuterium, and oxo-substituted; R 20 Selected from C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered deuterated cycloalkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkoxy-C(O)-, C 1-4 Alkyl-NH-C(O)-, The alkyl, cycloalkyl, and heterocycloalkyl groups may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, methanyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, NH-C 1-4 Alkyl, cyano-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0051] R 13 R 14 R 15 R 16 R 17 Each of the following is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-; or R 14 R 15 The atoms connected thereto co-cyclize into 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl; or R 16 R 17 The atoms directly or indirectly adjacent to it are cyclized together to form 5-6-membered heteroaryl or 6-membered aryl; and the 5-6-membered heteroaryl or 6-membered aryl can be further cyclized by one or more R atoms. 19 Instead, the R 19 Selected from H, CN, OH, NH2, oxo, methanyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0052] X8 and X9 are each independently selected from -C-, CH, or -N-;

[0053] n is selected from 0, 1, and 2.

[0054] This disclosure provides compounds as shown in Formula I, their pharmaceutically acceptable salts, and stereoisomers:

[0055] Among them, R1, R2, R 3、 R 18 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R2, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R1, R 18 The atoms to which it is attached cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R2 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene, C 2-4 alkenyl groups; or R3 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene, C 2-4 Alkenyl group; or R1, R3 and the atoms they are attached to, and the atoms they are attached to, cyclize together to form a 4-7 membered cycloalkyl group or a 4-7 membered heterocycloalkyl group; wherein, the NH2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, and alkenyl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0056] X1 is selected from chemical bonds, CHR X1-1 O, NR X1-2 Carbonyl group (C=O); the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0057] X2 is selected from N or C-R9;

[0058] X3 is selected from N or CR 12 ;

[0059] R4 is selected from 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, and 5-10-membered heteroaryl groups; the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl.

[0060] R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-9 membered cycloalkyl, 3-9 membered heterocycloalkyl; or R7, R8 and the atoms they are attached to can cyclize to form 5-9 membered cycloalkyl, 5-9 membered heterocycloalkyl; or R8, R 15 Directly connected together to form C 2-6 Alkylene, 2-6 heteroalkylene, C 2-6 alkenyl; the alkyl, cycloalkyl, heterocycloalkyl, alkylene, heteroalkylene, and alkenyl groups may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0061] L is selected from chemical bonds, O, NH, C 1-4 Alkylene, C2-4 imidene group, C 2-4 Ethyne group;

[0062] R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, =C(R) 10a (R) 10b ), =NR 10c C 2-4 alkynyl group, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, C 1- 4-Haloalkyl-S(O)2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; the R 10-1 R 10-2 R 10a R 10b R 10c Each element is independently selected from H, CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene, C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 The denenyl group may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0063] R 13 R 14 R 15 R 16 R 17 Each of the following is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-; or R 14 R 15 The atoms connected thereto co-cyclize into 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl; or R 16 R 17 The atoms directly or indirectly adjacent to it are cyclized together to form 5-6-membered heteroaryl or 6-membered aryl; and the 5-6-membered heteroaryl or 6-membered aryl can be further cyclized by one or more R atoms. 19 Instead, the R 19 Selected from H, CN, OH, NH2, oxo, methanyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0064] X8 and X9 are each independently selected from -C-, CH, or -N-;

[0065] n is selected from 0, 1, and 2.

[0066] This disclosure provides compounds as shown in Formula I, their pharmaceutically acceptable salts, and stereoisomers:

[0067] Among them, R1, R2, and R3 are independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C, respectively. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R2, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R1, R3 and the atoms they are attached to, and the atoms attached to R2 cyclize together to form 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the NH2, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0068] X1 is selected from chemical bonds, CHR X1-1 O, NR X1-2 Carbonyl group (C=O); the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0069] X2 is selected from N or C-R9;

[0070] X3 is selected from N or CR 12 ;

[0071] R4 is selected from 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, and 5-10-membered heteroaryl groups; the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl.

[0072] R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-9 membered cycloalkyl, 3-9 membered heterocycloalkyl; or R7, R8 and the atoms attached to them can be cyclized to form 5-9 membered cycloalkyl, 5-9 membered heterocycloalkyl; the alkyl, cycloalkyl, and heterocycloalkyl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0073] L is selected from chemical bonds, O, NH, -C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group;

[0074] R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, =C(R) 10a (R) 10b ), =NR 10c C 2-4 alkynyl group, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, C 1- 4-Haloalkyl-S(O)2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; the R 10-1 R 10-2 R 10a R 10b R 10c Each element is independently selected from H, CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene, C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 The denenyl group may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0075] R 13 R 14 R 15 R 16 R 17 Each of the following is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-; or R 14 R 15 The atoms connected thereto co-cyclize into 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl; or R 16 R 17 The smallest ring formed by the common cyclization of atoms directly or indirectly adjacent to it is a 5-6 membered heteroaryl or a 6 membered aryl;

[0076] X8 and X9 are each independently selected from -C-, CH, or -N-;

[0077] n is selected from 0, 1, and 2.

[0078] This disclosure provides compounds as shown in Formula I, their pharmaceutically acceptable salts, and stereoisomers:

[0079] Among them, R1, R2, and R3 are independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C, respectively. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R2, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R1, R3 and the atoms they are attached to, and the atoms attached to R2 cyclize together to form 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the NH2, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0080] X1 is selected from chemical bonds, CHR X1-1 O, NR X1-2 Carbonyl group (C=O); the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0081] X2 is selected from N or C-R9;

[0082] X3 is selected from N or CR 12 ;

[0083] R4 is selected from 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, and 5-10-membered heteroaryl groups; the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl.

[0084] R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R7, R8 and the atoms attached to them can be cyclized to form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl; the alkyl, cycloalkyl, and heterocycloalkyl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0085] L is selected from chemical bonds, O, NH, -C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group;

[0086] R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, =C(R) 10a (R) 10b ), =NR10c C 2-4 alkynyl group, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, C 1- 4-Haloalkyl-S(O)2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; the R 10-1 R 10-2 R 10a R 10b R 10c Each element is independently selected from H, CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene, C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 The denenyl group may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0087] R 13 R 14 R 15 R 16 R 17 Each of the following is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-; or R 14 R 15 The atoms connected thereto co-cyclize into 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl; or R 16 R 17 The smallest ring formed by the common cyclization of atoms directly or indirectly adjacent to it is a 5-6 membered heteroaryl or a 6 membered aryl;

[0088] X8 and X9 are each independently selected from -C-, CH, or -N-;

[0089] n is selected from 0, 1, and 2.

[0090] In one embodiment of this disclosure, the heteroatoms in the heterocyclic alkyl, heteroaryl, and heteroalkylene groups are independently selected from N, O, or S, and the number of heteroatoms is independently 1, 2, or 3.

[0091] In one technical solution disclosed herein, ring B is selected from... One end marked with * is connected to R 17 The carbon atoms are connected;

[0092] R1, R2, R 3、 R 18 Selected independently from H and C respectively 1-4 Alkyl; or, R1 and R2 are H, and R3 and R 18 Interconnected together to form C 1-4 Alkylene; or, R2, R 18 H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups;

[0093] X1 is NH;

[0094] X2 is CH;

[0095] X3 is N;

[0096] R4 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and C 1-6 Alkyl; the cycloalkyl, heterocycloalkyl and alkyl groups are optionally substituted with one or more of the following groups: halogen or C 1- 4-alkyl;

[0097] R5 and R6 are H;

[0098] X8 and X9 are each independently selected from C and N;

[0099] When n is 1, R7 is H and R8 is C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or 3-9 membered cycloalkyl, or, R7, R8 and the atoms between them co-cyclized to form 5-9 membered heterocyclic alkyl; R 16 R 17 and the atoms between them co-cyclize a 6-membered aryl group; the 6-membered aryl group is optionally substituted with a halogen;

[0100] When n is 0, R 16 and R 17 H is H, and C is R8. 1-4 Halogenated alkyl groups;

[0101] R 11 For H;

[0102] L is selected from chemical bonds and C. 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution;

[0103] R 10 Selected from 3-10 membered heterocyclic alkyl groups, 5-10 membered heteroaryl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 Alkyl; the heteroaryl group is optionally substituted with the following groups: 3-6 membered heterocyclic alkyl groups substituted with 3-6 membered heterocyclic alkyl groups;

[0104] or for

[0105] The ring C is a 6-8 membered heterocyclic alkyl group, wherein the 6-8 membered heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O, and S; R20 C 1-4 Alkyl; the alkyl group may optionally be substituted with the following groups: 3-6 membered cycloalkyl-oxy;

[0106] R 13 R 14 R 15 Each was independently selected from H and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Deuterated alkoxy group.

[0107] In one of the technical solutions disclosed herein, R1, R2, R 3、 R 18 Selected independently from H and C respectively 1-4 Alkyl; or, R1 and R2 are H, and R3 and R 18 Interconnected together to form C 1- 4 alkylene groups; or, R2, R 18 H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups.

[0108] In one technical solution disclosed herein, X1 is NH.

[0109] In one technical solution disclosed herein, X2 is CH.

[0110] In one of the technical solutions disclosed herein, X3 is N.

[0111] In one embodiment of this disclosure, R4 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and C. 1-6 Alkyl; the cycloalkyl, heterocycloalkyl and alkyl groups are optionally substituted with one or more of the following groups: halogen or C 1-4 alkyl.

[0112] In one technical solution disclosed herein, R5 and R6 are H.

[0113] In one technical solution disclosed herein, X8 and X9 are each independently selected from C and N;

[0114] When n is 1, R7 is H and R8 is C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or 3-9 membered cycloalkyl, or, R7, R8 and the atoms between them co-cyclized to form 5-9 membered heterocyclic alkyl; R 16 R 17 And the co-cyclization of 6-membered aryl groups between them;

[0115] When n is 0, R16 and R 17 H is H, and C is R8. 1-4 Halogenated alkyl groups.

[0116] In one of the technical solutions disclosed herein, R 11 For H.

[0117] In one of the technical solutions disclosed herein, L is selected from chemical bonds and C. 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution.

[0118] In one of the technical solutions disclosed herein, R 10 Selected from 3-10 membered heterocyclic alkyl groups, 5-10 membered heteroaryl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 Alkyl; the heteroaryl group is optionally substituted with the following groups: 3-6-membered heterocyclic alkyl groups substituted with 3-6-membered heterocyclic alkyl groups.

[0119] In one of the technical solutions disclosed herein, for

[0120] The ring C is a 6-8 membered heterocyclic alkyl group, wherein the 6-8 membered heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O, and S; R 20 C 1-4 Alkyl group; the alkyl group may optionally be substituted with the following groups: 3-6 membered cycloalkyl-oxy group.

[0121] In one of the technical solutions disclosed herein, R 13 R 14 R 15 Each was independently selected from H and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Deuterated alkoxy group.

[0122] In one of the technical solutions disclosed herein, R1, R2, R 3、 R 18 Selected independently from H and C respectively 1-4 Alkyl; or, R2, R 18H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups.

[0123] In one of the technical solutions disclosed herein, L is selected from chemical bonds and C. 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution;

[0124] R 10 Selected from 3-10 membered heterocyclic alkyl groups, 5-10 membered heteroaryl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 Alkyl; the heteroaryl group is optionally substituted with the following groups: 3-6 membered heterocyclic alkyl groups substituted with 3-6 membered heterocyclic alkyl groups;

[0125] or for

[0126] The ring C is a 6-8 membered heterocyclic alkyl group, wherein the 6-8 membered heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O, and S; R 20 C 1-4 alkyl.

[0127] In one technical solution disclosed herein, when L is C 2-4 When it is an ynylene group, the ynylene group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution;

[0128] R 10 Selected from 3-10 membered heterocyclic alkyl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 alkyl;

[0129] When L is a chemical bond, R 10It is a 5-10 membered heteroaryl group; the heteroaryl group is optionally substituted with the following groups: 3-6 membered heterocyclic alkyl groups substituted with 3-6 membered heterocyclic alkyl groups.

[0130] In one of the technical solutions disclosed herein, R 13 R 14 R 15 Each was independently selected from H and C. 1-4 Alkoxy and C 1-4 Deuterated alkoxy group.

[0131] In one of the technical solutions disclosed herein, R1 and R2 are H, and R3 and R 18 Interconnected together to form C 1-4 Alkylene; or, R2, R 18 H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups.

[0132] In one of the technical solutions disclosed herein, R2, R 18 H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups.

[0133] In one embodiment of this disclosure, R4 is selected from 3-6 membered heterocyclic alkyl groups and C groups substituted with one or more halogens. 1-6 alkyl.

[0134] In one embodiment of this disclosure, R4 is selected from 3-6 membered heterocyclic alkyl groups.

[0135] In one embodiment of this disclosure, n is 1, and R7, R8, and the atoms therebetween co-cyclize to form a 5-9 membered heterocyclic alkyl group; R 16 R 17 And the atoms between them co-cyclize a 6-membered aryl group.

[0136] In one of the technical solutions disclosed herein, n is 0, and R8 is C. 1-4 Halogenated alkyl groups.

[0137] In one of the technical solutions disclosed herein, X9 represents N and X8 represents C.

[0138] In one of the technical solutions disclosed herein, X9 represents N, X8 represents C, and R8 represents C. 1-4 Halogenated alkyl groups.

[0139] In one of the technical solutions disclosed herein, X9 is N, X8 is C, n is 0, and R8 is C. 1-4 Halogenated alkyl groups.

[0140] In one of the technical solutions disclosed herein, X9 is N, X8 is C, n is 0, and R8 is C.1-4 Haloalkyl, R 16 and R 17 For H.

[0141] In one of the technical solutions disclosed herein, R8 is C 1-4 Haloalkyl, C 1-4 Alkoxy or 3-9 membered cycloalkyl.

[0142] In one of the technical solutions disclosed herein, R8 is C 1-4 Alkoxy or 3-9 membered cycloalkyl.

[0143] In one of the technical solutions disclosed herein, L represents C. 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution.

[0144] In one of the technical solutions disclosed herein, L represents C. 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution; R 10 Selected from 3-10 membered heterocyclic alkyl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 alkyl.

[0145] In one of the technical solutions disclosed herein, L represents a chemical bond, and R... 10 It is a 5-10 membered heteroaryl group; the heteroaryl group is substituted with the following groups: 3-6 membered heterocyclic alkyl groups substituted with 3-6 membered heterocyclic alkyl groups.

[0146] In one of the technical solutions disclosed herein, L represents a chemical bond, and R... 10 It is an 8-10 membered heterocyclic alkyl group.

[0147] In one of the technical solutions disclosed herein, for In one technical solution disclosed herein, ring B is selected from... One end marked with * is connected to R 17 The carbon atoms are connected;

[0148] R1, R2, R 3、 R 18 Selected independently from H and C respectively 1-4 alkyl;

[0149] X1 is NH;

[0150] X2 is CH;

[0151] X3 is N;

[0152] R4 is selected from 3-6 membered cycloalkyl groups; the cycloalkyl group is optionally substituted with the following groups: C 1-4 alkyl;

[0153] R5 and R6 are H;

[0154] X9 is N, X8 is C;

[0155] When n is 0, R 16 and R 17 H is H, and C is R8. 1-4 Halogenated alkyl groups;

[0156] R 11 For H;

[0157] L is selected from C 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution;

[0158] R 10 Selected from 3-10 membered heterocyclic alkyl groups; wherein the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 alkyl;

[0159] R 13 R 14 R 15 Each was independently selected from H and C. 1-4 Alkyl and C 1-4 Alkyl group.

[0160] In one of the technical solutions disclosed herein, R1, R2, R 3、 R 18 In, the C 1-4 The alkyl group is independently methyl or ethyl, preferably methyl.

[0161] In one technical solution disclosed herein, when R1 and R2 are H, R3 and R 18 Interconnected together to form C 1-4 When alkylene, the C 1-4The alkylene group is methylene or ethylene, preferably methylene.

[0162] In one technical solution disclosed herein, when R2, R 18 When H, R1, R3, and the atoms they are attached to, as well as the atoms attached to R2, are cyclized together to form a 4-7 membered cycloalkyl group, the 4-7 membered cycloalkyl group is cyclobutyl or cyclopentyl, preferably cyclobutyl.

[0163] In one embodiment of this disclosure, in R4, the 3-6 membered cycloalkyl group is cyclopropyl or cyclobutyl, for example, cyclopropyl.

[0164] In one technical solution of this disclosure, in R4, the 3-6 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group with one heteroatom (O), for example...

[0165] In one technical solution disclosed herein, in R4, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or... For example

[0166] In one embodiment of this disclosure, in R4, when the cycloalkyl group is replaced by a halogen, the halogen is fluorine or chlorine, preferably fluorine.

[0167] In one technical solution of this disclosure, in R4, when the cycloalkyl group is C 1-4 When alkyl is substituted, the C 1-4 The alkyl group is methyl or ethyl, preferably methyl.

[0168] In one technical solution disclosed herein, when n is 1, R7 is H, and R8 is C 1-4 In the case of alkyl groups, in R8, the C 1-4 The alkyl group is methyl or ethyl, preferably ethyl.

[0169] In one technical solution disclosed herein, when n is 1, R7 is H, and R8 is C 1-4 In the case of haloalkylation, in R8, the C 1-4 Haloalkyl is C replaced by F. 1-4 Alkyl groups, such as -CH2CF3.

[0170] In one technical solution disclosed herein, when n is 1, R7 is H, and R8 is C 1-4 In the case of alkoxy, in R8, the C 1-4 The alkoxy group is methoxy, ethoxy, n-propoxy, or isopropoxy, for example, methoxy or isopropoxy.

[0171] In one technical solution disclosed herein, when n is 1, R7 is H, and R8 is a 3-9 membered cycloalkyl group, the 3-9 membered cycloalkyl group in R8 is a 3-6 membered cycloalkyl group, such as cyclopropyl.

[0172] In one technical solution of this disclosure, when n is 1, R7, R8 and the atoms therebetween cyclize to form a 5-9 membered heterocyclic alkyl group, the 5-9 membered heterocyclic alkyl group is a 5-9 membered heterocyclic alkyl group with N as the heteroatom and 1 heteroatom, for example a 6 membered heterocyclic alkyl group with N as the heteroatom and 1 heteroatom.

[0173] In one technical solution disclosed herein, when n is 1, R7 is H, and R8 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or 3-9 membered cycloalkyl, or, R7, R8 and the atoms between them co-cyclized to form 5-9 membered heterocyclic alkyl; R 16 R 17 And the atoms between them co-cyclize a 6-membered aryl group; when the 6-membered aryl group is substituted with a halogen, the halogen is fluorine or chlorine, for example fluorine.

[0174] In one of the technical solutions disclosed herein, when n is 0, R 16 and R 17 H is H, and C is R8. 1-4 When alkyl haloides are used, the C 1-4 Haloalkyl is C replaced by F. 1-4 Alkyl groups, such as -CH2CF3 or -CH(CH3)(CF3).

[0175] In one technical solution disclosed herein, the chemical bond in L is a connecting single bond.

[0176] In one technical solution disclosed herein, in L, the C 2-4 The ethynyl group is either ethynyl or propynyl, preferably propynyl.

[0177] In one technical solution of this disclosure, in L, when the acetylenic group is C 1-4 When alkyl is substituted, the C 1-4 The alkyl group is methyl or ethyl, preferably methyl.

[0178] In one of the technical solutions disclosed herein, R 10 In this context, the 3-10 membered heterocyclic alkyl group is a 6-8 membered monocyclic or bicyclic (e.g., fused, bridged, or spirocyclic) heterocyclic alkyl group with one or two heteroatoms selected from N, O, and S.

[0179] In one of the technical solutions disclosed herein, R10 In this context, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group whose heteroatoms are selected from N and O, and whose number of heteroatoms is 1, 2, or 3, for example...

[0180] In one of the technical solutions disclosed herein, R 10 In, the (C) 1-4 C in alkyl)2N-C(O)- 1-4 The alkyl group is methyl or ethyl, preferably methyl.

[0181] In one of the technical solutions disclosed herein, R 10 In this context, when the heterocyclic alkyl group is substituted with a halogen, the halogen is either fluorine or chlorine, preferably fluorine.

[0182] In one of the technical solutions disclosed herein, R 10 In the process, when the heterocyclic alkyl group is C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1- 4-alkyl or -S(O)2-C 1-4 When alkyl is substituted, the C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl groups and -S(O)2-C 1-4 C in alkyl 1-4 The alkyl group is independently methyl or ethyl, preferably methyl.

[0183] In one of the technical solutions disclosed herein, R 10 In the process, when the heterocyclic alkyl group is C 1-4 Alkoxy-C 1-4 When alkyl is substituted, the C 1-4 The alkoxy group is either methoxy or ethoxy, for example, methoxy.

[0184] In one of the technical solutions disclosed herein, R 10 In the context of a heteroaryl group being replaced by a 3-6 membered heterocyclic alkyl group, the 3-6 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group with one heteroatom selected from N and O, for example...

[0185] In one technical solution of this disclosure, in ring C, the 6-8 membered heterocyclic alkyl group is a 7 membered heterocyclic alkyl group with heteroatoms selected from O and N and the number of heteroatoms being 2.

[0186] In one of the technical solutions disclosed herein, R 20 In, the C 1-4 The alkyl group is methyl or ethyl, for example, ethyl.

[0187] In one of the technical solutions disclosed herein, R 20 In this context, when the alkyl group is substituted with a 3-6 membered cycloalkyl-oxy group, the 3-6 membered cycloalkyl group is a cyclopropyl group.

[0188] In one of the technical solutions disclosed herein, R 13 R 14 R 15 In, the C 1-4 The alkyl group is methyl or ethyl, for example, methyl.

[0189] In one of the technical solutions disclosed herein, R 13 R 14 R 15 In, the C 1-4 Haloalkyl is C replaced by F. 1-4 Alkyl groups, such as trifluoromethyl.

[0190] In one of the technical solutions disclosed herein, R 13 R 14 R 15 In, the C 1-4 The alkoxy group is either methoxy or ethoxy, for example, methoxy.

[0191] In one of the technical solutions disclosed herein, R 13 R 14 R 15 In, the C 1-4 The deuterated alkoxy group is a methoxy or ethoxy group that has been substituted with deuterium, for example...

[0192] In one embodiment of this disclosure, each chiral center of the compound exists independently in an R configuration and / or an S configuration.

[0193] In one embodiment of this disclosure, the compound is further shown in Formula IA:

[0194] In one embodiment of this disclosure, the compound is further represented as shown in formulas IB, IC, ID, IE, IF, or IG:

[0195] In one technical solution of this disclosure, the compound represented by Formula I, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by Formula Ic, its pharmaceutically acceptable salt, and its stereoisomer:

[0196] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 R 18 R 19 X1, X2, X3, X8, X9, and L have the same meaning as any of the technical solutions in this disclosure I.

[0197] In one technical solution of this disclosure, the compound represented by Formula I, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by Formula Ic-1, its pharmaceutically acceptable salt, and its stereoisomer:

[0198] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 R 18 R 19 X1, X2, X3, X8, X9, and L have the same meaning as any of the technical solutions in this disclosure I.

[0199] In one technical solution of this disclosure, the compound represented by Formula I, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by Formula Ia, its pharmaceutically acceptable salt, and its stereoisomer:

[0200] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 X1, X2, X3, X8, X9, and L have the same meaning as any of the technical solutions in this disclosure I.

[0201] In one technical solution of this disclosure, the compound represented by formula Ia, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by formula Ia-1, its pharmaceutically acceptable salt, and its stereoisomer:

[0202] Among them, R1, R2, and R3 are independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C, respectively. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R2|, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl; or R1, R3 and the atoms they are attached to, and the atoms attached to R2 cyclize together to form 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the NH2, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0203] X1 is selected from chemical bonds, CHR X1-1 O, NR X1-2 Carbonyl group (C=O); the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0204] X2 is selected from N or C-R9;

[0205] X3 is selected from N or CR 12 ;

[0206] R4 is selected from 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, and 5-10-membered heteroaryl groups; the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl.

[0207] R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R7, R8 and the atoms attached to them can be cyclized to form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl; the cycloalkyl and heterocycloalkyl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl;

[0208] L is selected from chemical bonds, O, NH, -C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group;

[0209] R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; the R 10-1 R 10-2 Selected independently from H and C respectively 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene, C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 The denenyl group may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0210] R 13 R 14 R 15 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-; or R 14 R 15 The atoms connected thereto co-cyclize into 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups may optionally be substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 alkyl.

[0211] In one embodiment of this disclosure, the compound represented by formula Ia, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by formula Ia-2, its pharmaceutically acceptable salt, and its stereoisomer:

[0212] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 X1, X2, X3, and L have the same meaning as in any of the technical solutions disclosed herein.

[0213] In one technical solution of this disclosure, the compound represented by formula Ia-2, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by formula Ia-2a, its pharmaceutically acceptable salt, and its stereoisomer:

[0214] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 X1, X2, X3, and L have the same meaning as in any of the technical solutions disclosed herein.

[0215] In one embodiment of this disclosure, the compound represented by formula Ia, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compounds represented by formula Ia-3, their pharmaceutically acceptable salts, and stereoisomers.

[0216] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 R 18 R 19 X1, X2, X3, X8, X9, and L have the same meaning as in any of the technical solutions disclosed herein.

[0217] In one technical solution of this disclosure, the compound represented by Formula I, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by Formula Ib, its pharmaceutically acceptable salt, and its stereoisomer:

[0218] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 R 16 X1, X2, X3, X8, X9, and L have the same meaning as any of the technical solutions in this disclosure I.

[0219] In one technical solution of this disclosure, the compound represented by formula Ib, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by formula Ib-1, its pharmaceutically acceptable salt, and its stereoisomer:

[0220] Among them, R1, R2, R3, R4, R5, R6, R8, R 10 R 11 R 13 R 14 R 15 R 16 X1, X2, X3, and L have the same meaning as in any of the technical solutions disclosed herein.

[0221] In one embodiment of this disclosure, the compound represented by formula Ib, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by formula Ib-2, its pharmaceutically acceptable salt, and its stereoisomer:

[0222] Among them, R1, R2, R3, R4, R5, R6, R8, R 10 R 11 R 13 R 14 R 15 R 16 X1, X2, X3, and L have the same meaning as in any of the technical solutions in Formula I and Formula Ia of this disclosure. In any technical solution of this disclosure, R1, R2, and R3 are all H.

[0223] In one embodiment of this disclosure, the compound represented by formula Ib-2, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by formula Ib-2a, its pharmaceutically acceptable salt, and its stereoisomer:

[0224] Among them, R1, R2, R3, R4, R5, R6, R8, R 10 R 11 R 13 R 14 R 15 R 16 X1, X2, X3, and L have the same meaning as in any of the technical solutions disclosed herein.

[0225] In any of the technical solutions disclosed herein, R1, R2, and R3 are all H.

[0226] In one technical solution of this disclosure, the compound represented by Formula I, its pharmaceutically acceptable salt, and its stereoisomer are selected from the compound represented by Formula Id, its pharmaceutically acceptable salt, and its stereoisomer:

[0227] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 R 18 R 19 X1, X2, X3, X8, X9, and L have the same meaning in any technical solution of this disclosure I; X 10 X 11 X 12 Each is independently selected from O, NH, and C. 1-4 Alkylene, 2-6 heteroalkylene, C 2-4 Alkenyl; the alkyl, heteroalkylene, or alkenyl group may optionally be substituted by one or more groups selected from: CN, OH, NH2, oxo, methanyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0228] In any of the technical solutions disclosed herein, fragments Selected from or X4 is selected from O, NH, and -(CH2). m - or a combination of segments, where m is selected from 1, 2, 3, or 4.

[0229] In any of the technical solutions disclosed herein, fragments Selected from X4 is selected from O, NH, and -(CH2). m - or a combination of segments, where m is selected from 1, 2, 3, or 4.

[0230] In any of the technical solutions disclosed herein, fragments Selected from

[0231] In any of the technical solutions disclosed herein, fragments Selected from X4 is selected from O, NH, and -(CH2). m - or a combination of segments, where m is selected from 1, 2, 3, or 4.

[0232] In any of the technical solutions disclosed herein, fragments Selected from

[0233] In any of the technical solutions disclosed herein, fragments Selected from

[0234] In any of the technical solutions disclosed herein, fragments Selected from Preferred selection

[0235] In any of the technical solutions disclosed herein, R4 is selected from Preferred selection

[0236] In any of the technical solutions disclosed herein, R5 is H.

[0237] In any of the technical solutions disclosed herein, ring B is (* indicates the site where R5 is attached to the carbon atom).

[0238] In any of the technical solutions disclosed herein, fragments Selected from (For example )and

[0239] In any of the technical solutions disclosed herein, Selected from the following groups: (* indicates a site connected to the ring containing X8).

[0240] In any of the technical solutions disclosed herein Selected from Preferred selection

[0241] In any of the technical solutions disclosed herein, fragments Selected from Preferred selection

[0242] In any of the technical solutions disclosed herein, R4 is selected from Preferred selection

[0243] In any of the technical solutions disclosed herein, fragments Selected from

[0244] In any of the technical solutions disclosed herein, Selected from the following groups: (* indicates a site connected to the ring containing X8).

[0245] In any of the technical solutions disclosed herein, Selected from the following groups: (* indicates a site connected to the ring containing X8).

[0246] In any of the technical solutions disclosed herein Selected from Preferred selection

[0247] In any of the technical solutions disclosed herein, X1 is NH.

[0248] In any of the technical solutions disclosed herein, X2 is CH, N, or CF.

[0249] In any of the technical solutions disclosed herein, X3 is N.

[0250] In any of the technical solutions disclosed herein, X2 is CH and X3 is N.

[0251] In any of the technical solutions disclosed herein, X2 is N and X3 is N.

[0252] In any of the technical solutions disclosed herein, X2 is N and X3 is CH.

[0253] In any of the technical solutions disclosed herein, X2 is CF and X3 is N.

[0254] In any of the technical solutions disclosed herein, R4 is cyclopropyl and may optionally be substituted by one or more of the following groups: methyl, ethyl, methoxy, ethoxy, trifluoromethyl.

[0255] In any of the technical solutions disclosed herein, R4 is oxetane and may optionally be substituted by one or more of the following groups: methyl, ethyl, methoxy, ethoxy, trifluoromethyl.

[0256] In any of the technical solutions disclosed herein, R4 is 3-oxabicyclo[3.1.0]hexane, and may optionally be substituted by one or more of the following groups: methyl, ethyl, methoxy, ethoxy, trifluoromethyl.

[0257] In any of the technical solutions disclosed herein, R4 is C 1-6 Alkyl groups, and optionally substituted with halogens; preferably, optionally substituted with F.

[0258] In any of the technical solutions disclosed herein, R4 is or

[0259] In any of the technical solutions disclosed herein, R4 is or

[0260] In any of the technical solutions disclosed herein, R4 is

[0261] In any of the technical solutions disclosed herein, R5 is independently selected from H,

[0262] In any of the technical solutions disclosed herein, R6 is selected from H, F, and Cl.

[0263] In any of the technical solutions disclosed herein, R5 and R6 are independently selected from H, F, and Cl, respectively.

[0264] In any of the technical solutions disclosed herein, R5 and R6 are both H.

[0265] In any of the technical solutions disclosed herein, R7 and R8 are connected to each other to form the following structures: -CH2-CH2-X5-*, -X5-CH2-CH2-*, -CH2-X5-CH2-*; wherein X5 is selected from chemical bonds, O, and -(CH2). n - NH, where the asterisk * marks the end and the R7 end, and n is selected from 1, 2, or 3;

[0266] In any of the technical solutions disclosed herein, R7 and R8 can be connected to each other to form the following structure: The terminal marked with an asterisk (*) is the R7 terminal;

[0267] In any of the technical solutions disclosed herein, R7 and R8 can be connected to each other to form the following structure: The terminal marked with an asterisk (*) is the R7 terminal;

[0268] In any of the technical solutions disclosed herein, R7 and R8 are connected to each other to form the following structure:

[0269] In any of the technical solutions disclosed herein, R7 and R8 are connected to each other to form the following structure: The asterisk (*) indicates the R7 terminal.

[0270] In any of the technical solutions disclosed herein, R7 and R8 are connected to each other to form the following structure: The asterisk (*) indicates the R7 terminal.

[0271] In any of the technical solutions disclosed herein, R7 is H, and R8 is selected from CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, wherein C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl may optionally be substituted with one or more of the following groups: CN, OH.

[0272] In any of the technical solutions disclosed herein, R7 is H, and R8 is selected from Cl, CN, methyl, ethyl, methoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, difluoromethoxy, vinyl, ethynyl,

[0273] In any of the technical solutions disclosed herein, R7 is H, and R8 is selected from Cl, CN, methyl, ethyl, methoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, difluoromethoxy, vinyl, ethynyl,

[0274] In any of the technical solutions disclosed herein, R7 is H, and R8 is selected from Cl, CN, methyl, ethyl, methoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, difluoromethoxy, ethynyl, etc.

[0275] In any of the technical solutions disclosed herein, R7 is H and R8 is C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0276] In any of the technical solutions disclosed herein, R7 is H, and R8 is selected from methyl, ethyl, methoxy, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0277] In any of the technical solutions disclosed herein, R7 is H and R8 is C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups.

[0278] In any of the technical solutions disclosed herein, R7 is H and R8 is ethyl.

[0279] In any of the technical solutions disclosed herein, R7 is H, and R8 is trifluoromethyl or 2,2,2-trifluoroethyl.

[0280] In any of the technical solutions disclosed herein, R7 is H and R8 is 2,2,2-trifluoroethyl.

[0281] In any of the technical solutions disclosed herein, R7 is H and R8 is methoxy.

[0282] In any of the technical solutions disclosed herein, R7 is H, and R8 is selected from (S)--trifluoroisopropyl and (R)--trifluoroisopropyl.

[0283] In any of the technical solutions disclosed herein, X2 is CH; R 11 For H.

[0284] In any of the technical solutions disclosed herein, X2 represents CF, and R represents R. 11 For H.

[0285] In any of the technical solutions disclosed herein, X2 is CH, R 11 For F;

[0286] In any of the technical solutions disclosed herein, X2 is CH, R 11 C 1-4 Alkyl, C 1-4 Halogenated alkyl groups.

[0287] In any of the technical solutions disclosed herein, L represents a chemical bond, an acetylene group, or a propyne group.

[0288] In any of the technical solutions disclosed herein, L represents a chemical bond.

[0289] In any of the technical solutions disclosed herein, L represents an acetylene group.

[0290] In any of the technical solutions disclosed herein, L is a propynyl group, and the propynyl group is optionally converted by one or more C... 1-4 Alkyl substitution.

[0291] In any of the technical solutions disclosed herein, L represents The asterisk (*) and R 10 connect.

[0292] In any of the technical solutions disclosed herein, L represents The asterisk (*) and R 10 connect.

[0293] In any of the technical solutions disclosed herein, R 10 for Among them, R 10-3 R 10-4 R 10-5 R 10-6 Each is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; or R 10-3 R 10-4 R 10-5 R 10-6 Any two can be connected to form C 1-4 Alkylene, C 1-4 Heteroalkyl; or when L is a chemical bond, R 10-4 With R 11 Can be connected to form C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 sub-enyl, C 1-4 Heteroalkenyl; the C 1-4 Alkylene, C 1-4 Heteroalkyl, C 1-4 sub-enyl, C 1-4 The heterobenzene group may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1- 4-alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; p and q are each independently selected from 0, 1, 2, and 3; X6 is selected from O and CHR. 10-7 NR 10-8 -S(=O)2-, -S(=O)-; X7 is selected from N or CH; the R 10-7 R10-8 Each is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl, N(C) 1-4 Alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; preferably, the R 10-7 R 10- 8 are each independently selected from H, CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH-C 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, and 3-6 membered heterocycloalkyl groups. In R 10 In one technical solution, R 10-3 R 10-4 R 10-5 R 10-6 Each is independently selected from H, oxo, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0294] In R 10 In one technical solution, R 10-4 With R 10-6 Connect into C 1-4 Alkylene, C 1-4 Heteroalkyl; or when p is not 0, adjacent R 10-3 Between, R 10-4 With adjacent R 10- The three are connected to form C 1-4 Alkylene or C 1-4 Heteroalkyl groups; or, when q is not 0, adjacent R 10-5 Between, R 10-6 With adjacent R 10-5 All of them can be connected to form C 1-4 Alkylene or C 1-4 Heteroalkylene; or when both p and q are not 0, R 10-3 With R 10-5 They can be connected to form C 1-4 Alkylene or C 1-4 Heteroalkyl; the C 1-4 Alkylene, C 1-4The heteroalkyl group may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0295] In R 10 In one technical solution, p and q are both 1, and R 10-3 With R 10-4 Between, R 10-4 With R 10-6 Between, R 10-6 With R 10-5 Between, R 10-5 With R 10-3 All of them can be connected to form C 1-4 Alkylene or C 1-4 Heteroalkyl; the C 1-4 Alkylene, C 1-4 The heteroalkyl group may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl.

[0296] In R 10 In one technical solution, p and q are both 1, and R 10-4 With R 10-6 They connect to form ethylene.

[0297] In R 10 In one technical solution, p and q are both 1, and R 10-3 With R 10-5 They connect to form ethylene.

[0298] In R 10 In one technical solution, p and q are both 1, and R 10-3 With R 10-6 They can form methylene or ethylene groups.

[0299] In R 10 In one technical solution, p and q are both 1, and R 10-4 With R10-5 They can form methylene or ethylene groups.

[0300] In R 10 In one technical solution, p and q are both 1, and R 10-3 With R 10-4 They can form methylene or ethylene groups.

[0301] In R 10 In one technical solution, p and q are both 1, and R 10-5 With R 10-6 They can form methylene or ethylene groups.

[0302] In any of the technical solutions disclosed herein, R 10a R 10b Each is independently selected from H and F.

[0303] In any of the technical solutions disclosed herein, R 10a R 10b Both are H or both are F.

[0304] In any of the technical solutions disclosed herein, R 10 Selected from the following groups:

[0305] In any of the technical solutions disclosed herein, R 10 Selected from the following groups:

[0306] In any of the technical solutions disclosed herein, R 10 Selected from the following groups:

[0307] In any of the technical solutions disclosed herein, R 10 Selected from the following groups:

[0308] In any of the technical solutions disclosed herein, R 10 Selected from the following groups:

[0309] In any of the technical solutions disclosed herein, R 10 Selected from -N(R) 10-1 (R) 10-2 ); R 10-1 R 10-2 Each of the following is independently selected from H, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, and methoxyethyl.

[0310] In any of the technical solutions disclosed herein, R 10 for

[0311] In any of the technical solutions disclosed herein, R 10 for

[0312] In any of the technical solutions disclosed herein, R 10 for

[0313] In any of the technical solutions disclosed herein, R 10 for

[0314] In any of the technical solutions disclosed herein, R 10 for

[0315] In any of the technical solutions disclosed herein, R 10 for

[0316] In any of the technical solutions disclosed herein, R 11 Selected from H, halogen, methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, vinyl, ethynyl.

[0317] In any of the technical solutions disclosed herein, R 11 Selected from H, halogen, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy.

[0318] In any of the technical solutions disclosed herein, R 11 Selected from H, F, and methyl.

[0319] In any of the technical solutions disclosed herein, R 13 R 14 R 15 Each is independently selected from H, F, methyl, ethyl, vinyl, ethynyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, trideuteroxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl.

[0320] In any of the technical solutions disclosed herein, R 13 R 14 R 15 Each is independently selected from H, F, methyl, ethyl, vinyl, ethynyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl,

[0321] In any of the technical solutions disclosed herein, R 13 For H, R 14 R 15 Each is independently selected from H, F, methyl, ethyl, ethynyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl.

[0322] In any of the technical solutions disclosed herein, R 13 H, methoxy, R 14 R 15 The atoms connected thereto are cyclized together to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl may optionally be substituted by one or more of the following groups: oxo or methyl.

[0323] In any of the technical solutions disclosed herein, R 13 H, methoxy, R 14 R 15 The atoms connected to it co-cyclize into the following groups, which may optionally be substituted by one or more oxo or methyl groups:

[0324] In any of the technical solutions disclosed herein, Selected from the following groups:

[0325] In any of the technical solutions disclosed herein, Selected from the following groups:

[0326] In any of the technical solutions disclosed herein, L represents a chemical bond, and R... 10 for R 10-4 With R 11 Forming -CH2-O-*, -CH2-O-CH2-*, =CH–*, -CH2–NH-CH2-*, -CH2–NH-CH2-*, -CH2-CH2-O-*, -CH2-NH-*, -CH2-CH2-NH-*, =N-*, and optionally further substituented by one or more of the following groups: CN, OH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, or substituted with one or more of the following groups: CN, OH, oxo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy; wherein the asterisk (*) indicates the R group. 11 end.

[0327] In any of the technical solutions disclosed herein, L represents a chemical bond, and R... 10 for R 10-4 With R 11 Forms -CH2-O-*, -CH2-O-CH2-*, =CH–*, -CH2–N(CH3)-*, -CH2–N(CH3)-CH2-*, -CH2–NH-CH2-*, -CH2–NH-CH2-*, -CH2-CH2-O-*, =C(CH3)–*, -CH2-NH-*, -CH2-CH2-NH-*, =N-*, -C(=O)-NH-*, -C(=O)-N(CH3)-*, -CH2-CH2-N(CH3)-*; where the asterisk * is R. 11 end.

[0328] In any of the technical solutions disclosed herein, Selected from the following groups:

[0329] In any of the technical solutions disclosed herein, Selected from the following groups: The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3.

[0330] In any of the technical solutions disclosed herein, Selected from the following groups: The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3.

[0331] In any of the technical solutions disclosed herein, Selected from the following groups: The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3.

[0332] In any of the technical solutions disclosed herein, Selected from the following groups: The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3.

[0333] In any of the technical solutions disclosed herein, Selected from the following groups: The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3.

[0334] In any of the technical solutions disclosed herein, Selected from the following groups: The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3.

[0335] In any of the technical solutions disclosed herein, the compound of formula I is selected from those having the structures shown in formulas I-1, I-2, I-3, I-4, I-5, and I-6:

[0336] Among them, R1, R2, R3, R4, R5, R6, R 10 R 11 R 13 R 14 R 15 X1, X2, X3, X4, and X5 have the same meaning as in any of the technical solutions disclosed herein.

[0337] In any of the technical solutions disclosed herein, the compound of formula I is selected from those having the structures shown in formulas I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, and I-30.

[0338] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11 R 13 R 14 R 15 R 16 R 18 R 19 X1, X2, X3, X8, X9, and L have the same meaning as in any of the technical solutions disclosed herein.

[0339] In any of the technical solutions disclosed herein, the compound represented by Formula I is selected from any of the following compounds:

[0340] In any embodiment of this disclosure, the compound is any of the following compounds:

[0341] compound A stereoisomer of [a substance] has a retention time of 9.3 min under the following conditions: high performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: phase A is 10 mmol / L ammonium bicarbonate aqueous solution, and phase B is acetonitrile; flow rate is 1.0 mL / min.

[0342] compound A stereoisomer of [a substance] has a retention time of 9.2 min under the following conditions: high performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: phase A is 10 mmol / L ammonium bicarbonate aqueous solution, and phase B is acetonitrile; flow rate is 1.0 mL / min.

[0343] compound A stereoisomer of [a substance] has a retention time of 9.2 min under the following conditions: High-performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, column temperature 25 °C; mobile phase: phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; flow rate: 1.0 mL / min.

[0344] compound A stereoisomer of [a substance] has a retention time of 9.6 min under the following conditions: high performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: phase A is 10 mmol / L ammonium bicarbonate aqueous solution, and phase B is acetonitrile; flow rate is 1.0 mL / min.

[0345] compound A stereoisomer of [a substance] has a retention time of 7.6 min under the following conditions: High-performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, column temperature 25 °C; mobile phase: Phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and Phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; flow rate: 1.0 mL / min.

[0346] compound A stereoisomer of [the substance] has a retention time of 9.6 min under the following conditions: chromatographic column: Waters 3767 Pursuit XRs 10C18 high-performance liquid chromatography column, 19 × 250 mm, 10 μm; mobile phase: phase A is 0.03% trifluoroacetic acid aqueous solution; phase B is 0.03% trifluoroacetic acid acetonitrile solution; flow rate: 20 mL / min; gradient elution: 32%–45%;

[0347] compound A stereoisomer of [a substance] has a retention time of 8.0 min under the following conditions: High-performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: Phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and Phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; flow rate: 1.0 mL / min.

[0348] compound A stereoisomer of [a substance] has a retention time of 7.5 min under the following conditions: High-performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, column temperature 25 °C; mobile phase: Phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and Phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; flow rate: 1.0 mL / min.

[0349] compound A stereoisomer of [a substance] has a retention time of 8.0 min under the following conditions: high performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: phase A is 10 mmol / L ammonium bicarbonate aqueous solution, and phase B is acetonitrile; flow rate: 1.5 mL / min.

[0350] compound A stereoisomer of [a substance] has a retention time of 11.0 min under the following conditions: High-performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: Phase A is an aqueous solution containing 0.05% trifluoroacetic acid, and Phase B is an acetonitrile solution containing 0.05% trifluoroacetic acid; A:B ratio is 80:20; flow rate: 1.0 mL / min.

[0351] compound A stereoisomer of [a substance] has a retention time of 9.4 min under the following conditions: high-performance liquid chromatography (HPLC) using a SunFire C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; A:B ratio is 80:20; flow rate: 1.0 mL / min.

[0352] compound A stereoisomer of [a substance] has a retention time of 9.0 min under the following conditions: High-performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, column temperature 25 °C; mobile phase: Phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and Phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; flow rate: 1.0 mL / min.

[0353] compound A stereoisomer of [a substance] has a retention time of 10.0 min under the following conditions: high-performance liquid chromatography (HPLC) using a SunFire C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; A:B ratio is 80:20, and flow rate is 1.0 mL / min.

[0354] compound A stereoisomer of [a substance] has a retention time of 9.2 min under the following conditions: high-performance liquid chromatography (HPLC) using a SunFire C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; A:B ratio is 90:10; flow rate: 1.0 mL / min.

[0355] compound A stereoisomer of [a substance] has a retention time of 10.6 min under the following conditions: High-performance liquid chromatography (HPLC) using a Waters XBridge C18 column, 5 μm, 4.6 × 150 mm, at a column temperature of 25 °C; mobile phase: Phase A is an aqueous solution of 0.1% ammonium bicarbonate, and Phase B is an acetonitrile solution of 0.1% ammonium bicarbonate; 0-13 min: A:B = 90:10; 13-16 min: A:B = 5:95; flow rate: 1.0 mL / min.

[0356] compound A stereoisomer of [a substance] has a retention time of 8.2 min under the following conditions: High-performance liquid chromatography (HPLC) using a SunFire C18 column, 5 μm, 4.6 × 150 mm, column temperature 25 °C; mobile phase: Phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and Phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; 0-13 min: A:B = 50:50; 13-16 min: A:B = 5:95; flow rate: 1.0 mL / min.

[0357] Or, compounds A stereoisomer of [a substance] has a retention time of 7.4 min under the following conditions: high performance liquid chromatography using a SunFire C18 column, 5 μm, 4.6 × 150 mm, column temperature 25 °C; mobile phase: phase A is an aqueous solution containing 0.03% trifluoroacetic acid, and phase B is an acetonitrile solution containing 0.03% trifluoroacetic acid; flow rate: 1.0 mL / min.

[0358] A second aspect of this disclosure provides a pharmaceutical composition comprising the compound described in the first aspect of this disclosure, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and any pharmaceutically acceptable carrier; wherein the content of the compound, stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from 0.1 mg to 1000 mg, or 1000 to 2000 mg, preferably 10 to 100 mg, 100 to 200 mg, 200 to 500 mg, or 500 to 1000 mg; wherein the pharmaceutically acceptable carrier may include one or more of fillers, disintegrants, binders, flow aids, and lubricants.

[0359] This disclosure provides, in a third aspect, the use of the compounds described in the first aspect of this disclosure, pharmaceutically acceptable salts thereof, or stereoisomers thereof, in the preparation of a medicament for treating diseases associated with RAS gene mutations.

[0360] This disclosure provides, in its fourth aspect, the use of the pharmaceutical composition described in the second aspect of this disclosure in the preparation of a medicament for treating diseases associated with RAS gene mutations.

[0361] The fifth aspect of this disclosure provides a method for treating diseases associated with RAS gene mutations, the method comprising administering to a patient in need an effective amount of the compound described in the first aspect of this disclosure, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition described in the second aspect of this disclosure.

[0362] In this disclosure, the diseases associated with RAS gene mutations may include lung cancer, colorectal cancer (CRC), pancreatic cancer, ovarian cancer, esophageal and gastric cancer, and uterine cancer associated with RAS gene mutations.

[0363] Definitions and Explanations

[0364] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0365] In this disclosure, This indicates that the position can be either a single bond or a double bond, and its further specific designation can be determined based on the specific valence of the atoms at both ends.

[0366] In this disclosure, if a variable is a chemical bond, it can be understood as the variable not existing, and two variables that were originally indirectly connected through this variable will be directly connected. For example, for R... 10 -L-Ar, when L is a chemical bond, is equivalent to R. 10 –Ar.

[0367] In this disclosure, if two adjacent substituents or segments are cyclized into a new ring, when the resulting ring is a cycloalkyl or heterocycloalkyl ring, it means that the unsaturated bonds on the common edges of the resulting new ring and other rings are not included in the new ring; when the resulting ring is an aryl or heteroaryl ring, it means that the unsaturated bonds on the common edges of the resulting ring and other rings are included in the new ring.

[0368] In this disclosure, the term "oxo" refers to the =O structure being attached as a substituent to other structures.

[0369] In this disclosure, the term "thiolated" refers to the =S structure being attached as a substituent to other structures.

[0370] In this disclosure, the term "alkylthio" means alkyl-S-, referring to a group obtained by substituting a thiol group (-SH) with an alkyl group. 1-4 Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and n-butylthio.

[0371] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0372] The term "effective dose" refers to a sufficient amount of the disclosed compound, its pharmaceutically acceptable salt, or its stereoisomer to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder. However, it should be understood that the total daily dosage of the disclosed compound, its stereoisomer, its pharmaceutically acceptable salt, and the composition thereof must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific therapeutically effective dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0373] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SFC) can be used, or the absolute configuration of the compound can be confirmed by examining the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereoconfiguration can be determined by comparing it with a product whose absolute configuration is known. Compounds marked as "absolute configuration unknown / undetermined" in this article are typically racemic compounds resolved into single isomers via chiral preparative SFC, followed by characterization and testing.

[0374] The term “optionally” means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical feasibility. For example, the term “optionally substituted by one or more Rs” means that it may or may not be substituted by one or more Rs.

[0375] When any variable (e.g., R1) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, it means that pyridine is replaced by x R1s, and each R1 has an independent option.

[0376] When a substituent is chemically bonded to a ring, it can bond with any atom on that ring. For example, structural units. This indicates that the substituent R1 can be substituted at any position on the pyridine.

[0377] When the listed substituents do not specify which atom they are attached to in a compound included but not specifically mentioned in the general chemical formula, such substituents can be bonded to any of their atoms. For example, pyrimidine as a substituent means that any carbon or nitrogen atom on the pyrimidine ring is attached to the substituted group; when the structure contains... When, it indicates that the atom is a bonding atom, for example This indicates that the C atom at the 3-position of pyridine is a bonded atom.

[0378] In this disclosure, a substituent further replaced by one or more substituents is referred to as a complex substituent. Although the substituted substituent is described as a "base" when describing a complex group, those skilled in the art should understand that the substituted group is replaced by one or more substituents to become a subunit, secondary base, or a substituent in a higher compound; for example, the term "hydroxyl-C..." 1-4 Alkyl should be understood as a C-shaped hydroxyl-substituted alkyl group. 1-4 Alkyl, although C 1-4 Alkyl groups are still referred to as alkyl groups, but they become methylene or methine due to the substitution of hydroxyl groups.

[0379] Unless otherwise specified, the term "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus a hydrogen-derived group. For example, "C 1-4 "Alkyl" refers to an alkyl group comprising 1 to 4 carbon atoms. 1-4 Specific examples of "alkyl" include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.

[0380] Unless otherwise specified, the term "heteroalkyl" refers to a group formed by replacing one or more C atoms in an alkyl backbone with one or more atoms selected from O, S, and N.

[0381] Unless otherwise specified, the term "alkylene" refers to a substituent derived from an alkane by the loss of two hydrogen atoms. 1-4 Examples of alkylene groups include, but are limited to: methylene (-CH2-), ethylene (-CH2-CH2-), and n-propylene (-CH2-CH2-CH2-).

[0382] Unless otherwise specified, the term "heteroalkylene" refers to a group formed by replacing one or more C atoms in the alkylene backbone with one or more atoms selected from O, S, and N.

[0383] Unless otherwise specified, the term "alkenyl" refers to a group derived from a straight-chain or branched olefin (containing at least one carbon-carbon double bond) by removing one hydrogen atom, including methanyl, "C" and "H" groups. 2-6 "alkenyl", "C" 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", C 2-4 Specific examples of alkenyl groups include, but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc. The methanyl group refers to an alkylene group bonded to the same atom in the form of a double bond, which can be represented as CH2=.

[0384] Unless otherwise specified, the term "alkenyl" refers to a substituent formed when an alkene loses two hydrogen atoms. 1-4 Examples of alkenyl groups include, but are not limited to: vinylidene (-CH=CH-) and propenylidene (-CH=CH-CH2-).

[0385] Unless otherwise specified, the term "subheptyl" refers to a substituent formed when an alkene loses three hydrogen atoms. 1-4 Examples of alkenyl groups include, but are not limited to: vinylene (=CH-CH-) and methemethylene (=CH-).

[0386] Unless otherwise specified, the term "heteroalkenyl" refers to a group formed by replacing one or more C atoms in the alkenyl backbone with one or more atoms selected from O, S, and N.

[0387] Unless otherwise specified, the term "hetereneyl" refers to a group formed by replacing one or more C atoms in the hetereneyl backbone with one or more atoms selected from O, S, and N.

[0388] Unless otherwise specified, the term "alkynyl" refers to a group derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing one hydrogen atom, including "C". 2-6 "Alkyne", "C" 2- 4-Alynyl group, C 2-3 "Alkyne", C 1-4 Specific examples of alkynyl groups include, but are not limited to: ethynyl (-C≡CH) and propynyl (-C≡CHCH). 3) Butynyl (CH3-CH2-C≡C-), etc.

[0389] Unless otherwise specified, the term "ethynyl" refers to a substituent formed by the loss of two hydrogen atoms from an ethynyl group. 1-4 Examples of ynylene groups include, but are not limited to: ynylene (-C≡C-), ynylene (-C≡C-CH2-), and ynylene diynylene (-C≡CC≡C-).

[0390] Unless otherwise specified, the term "hetero-ynyl" refers to a group formed by replacing one or more C atoms in the ynyl backbone with one or more atoms selected from O, S, and N.

[0391] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-3 Alkoxy, C 1-4Specific examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, etc.; preferably, the "alkoxy group" described in this disclosure is preferably C. 1-3 Alkyl group.

[0392] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0393] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C is preferred. 1-6 Halogenated alkyl, more preferably C 1-3 Alkyl halogens. Examples of alkyl halogens include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl groups are as defined above.

[0394] Unless otherwise specified, the term "hydroxy-alkyl" refers to a substituent derived from an alkyl group in which one or more H atoms are replaced by a hydroxyl group. The term "hydroxyalkyl" as used in this disclosure includes "hydroxy-C..." 1-6 "hydroxyalkyl", "hydroxy-C" 1-4 Alkyl group; hydroxyl group - C 1-4 Specific examples of alkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -CH2CH2CH2OH.

[0395] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-3 Alkyl groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkyl groups are as defined above.

[0396] Unless otherwise specified, the term "alkoxyalkyl" refers to a substituent derived from one or more H atoms in an alkyl group by further substitution with an alkoxy group, such as -CH2-OCH3.

[0397] Unless otherwise specified, the term "hetero" refers to substituted or unsubstituted heteroatoms and their oxidized forms (also called heteroatomic groups), which are generally selected from N, O, and S, and whose oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein). The number of atoms on the ring is usually defined as the ring number. For example, "3-6 membered heterocyclic alkyl" refers to a ring consisting of 3-6 atoms arranged in a ring, each ring optionally containing 1 to 3 heteroatoms, i.e., N, O, CO, S, NO, SO, S(O)2, or NR, each ring optionally substituted by an R group, R being a group defined herein.

[0398] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing one hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures linked by spiro, bridging, fused, or other means. The carbon atom in the cycloalkyl group can be further oxidized, i.e., forming C(O). Unless otherwise specified, "membered cycloalkyl" as used herein includes both monocyclic cycloalkyl and polycyclic cycloalkyl such as spiro, fused, or bridged cycloalkyl groups. The cycloalkyl group includes "3- to 10-membered cycloalkyl", "5- to 10-membered cycloalkyl", "5- to 12-membered cycloalkyl", "3- to 8-membered cycloalkyl", "4- to 8-membered cycloalkyl", "3- to 6-membered cycloalkyl", and "3- to 5-membered cycloalkyl". Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0399] Unless otherwise specified, the term "cycloalkyl-oxy" refers to a group having a "cycloalkyl-O-" structure, the definition of which is as described above. For example,

[0400] Unless otherwise specified, the term "deuterated cycloalkyl" refers to a cycloalkyl group in which one or more hydrogen atoms are substituted with deuterium, as defined above.

[0401] Unless otherwise specified, the term "deuterated alkoxy" refers to an alkoxy group in which one or more hydrogen atoms are substituted by deuterium, as defined above. For example, -O-CD3.

[0402] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated cyclic group derived from which one or more cyclic carbon atoms in a cycloalkyl group are replaced by heteroatoms and / or heteroatom groups. The heteroatoms and / or heteroatom groups are generally selected from N, O, S, NO, SO, S(O)₂, P(O), and NR, wherein the carbon atoms in the heterocycle are optionally oxidized to form -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. Heterocyclic alkyl groups include "3-12-membered heterocyclic alkyl", "3-8-membered heterocyclic alkyl", "3-6-membered heterocyclic alkyl", "3-5-membered heterocyclic alkyl", "4-6-membered heterocyclic alkyl", and "5-6-membered heterocyclic alkyl". Examples of 3-6-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, N-heterocyclic butyl, morpholino, and N-heterocyclic pentane.

[0403] Unless otherwise specified, the term "aryl" refers to an unsaturated, aromatic cyclic hydrocarbon group, which may be monocyclic or polycyclic, but with at least one aromatic ring. The aryl group may be fused to a heterocyclic alkenyl or cycloalkenyl group. 6-10 Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0404] The term "heteroaryl" as used in this disclosure refers to a monocyclic or polycyclic hydrocarbon group that is aromatic and contains 1-3 heteroatoms. In polycyclic heteroaryl groups, at least one ring is an aromatic heterocycle. The heteroatoms are generally selected from N, O, and S. Specific examples of heteroaryl groups include, but are not limited to: furanyl, thiopheneyl, pyrroleyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazoleyl, pyrazolyl, and pyrimidinyl.

[0405] Linking substituents are described in various parts of this disclosure. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0406] The combinations of substituents and / or variables described in this disclosure are permitted only when these combinations produce stable compounds or usable synthetic intermediates. A stable compound or stable structure is a compound that is sufficiently stable to withstand chemical reactions, be isolated with useful purity, and be formulated into an effective therapeutic agent.

[0407] The preparation methods of some compounds in this disclosure reference the preparation methods of the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants.

[0408] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0409] As used in this disclosure, the term "composition" means a product comprising specified amounts of each of the specified ingredients, and any product derived directly or indirectly from a combination of specified amounts of the specified ingredients. Those skilled in the art can vary the actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure so that the resulting amount of active compound is effectively targeted at a specific patient, composition, and route of administration to achieve the desired therapeutic response.

[0410] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering bioactive pharmaceutical agents to animals, particularly mammals.

[0411] The term "effective amount" refers to a compound of the present disclosure or a pharmaceutically acceptable salt thereof in sufficient quantity to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder.

[0412] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of reliable medical judgment, is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. The compounds disclosed herein can be reacted with their respective acids or bases to obtain their corresponding salts.

[0413] The term "stereoisomer" as used in this disclosure refers to isomers resulting from different spatial arrangements of atoms in a molecule. Stereoisomers include hindered rotation isomers, cis-trans isomers, enantiomers, diastereomers, tautomers, racemic mixtures thereof, and other mixtures, all of which fall within the scope of this disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to a functional group isomer that has different hydrogen bonding sites through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. The term "diastereomer" refers to stereoisomers in which the molecule has two or more chiral centers and the molecules are not mirror images of each other. The term "cis-trans isomer" refers to different spatial configurations in which double bonds or single bonds of cyclic carbon atoms in a molecule cannot rotate freely. The term "hindered rotation isomer" refers to a stereoisomer that can be separated due to hindered or very slow rotation of single bonds.

[0414] In this disclosure, the compound structure is represented by solid line bonds. When, it indicates that it is located above the plane, for example

[0415] The structural portions representing deuterated seven-membered heterocycles and solid bonds in pyridine are located above the plane.

[0416] In this disclosure, unless otherwise specified, the component ratios of the eluent used in column chromatography or column chromatography are volume ratios. For example, "eluent: tetrahydrofuran / petroleum ether" indicates that the eluent is composed of a mixture of tetrahydrofuran and petroleum ether solvents. Those skilled in the art can determine a suitable solvent ratio through simple experimentation. In this invention, the reagent concentration unit M refers to mol / L; for example, 1 mM refers to 1 mmol / L.

[0417] In this disclosure, the compounds disclosed herein and their related intermediates can be prepared by referring to the preparation methods of similar compounds described in WO2024169914A1 or WO2024060966A1. Those skilled in the art can also make appropriate adjustments to the starting materials and reaction conditions according to the structural characteristics of the target compound. Detailed Implementation

[0418] The present disclosure is further described in detail below through specific preparation examples and biological experiments. However, it should be understood that these examples and biological experiments are for illustrative purposes only and should not be construed as limiting the present disclosure in any way. Those skilled in the art will understand that, unless otherwise specified below, the materials used are well-known in the art and can be obtained commercially or by those skilled in the art based on published literature or conventional methods. Wherein: (i) temperature is expressed in degrees Celsius (°C), and the operation is carried out at room temperature, generally 15-35°C, preferably 20-30°C, more preferably 20-25°C; (ii) solvent removal is performed using a rotary evaporator under reduced pressure, with the bath temperature generally not exceeding 60°C; (iii) the reaction process is monitored by thin-layer chromatography (TLC); (iv) the final product has a satisfactory proton nuclear magnetic resonance spectrum (NMR spectrum). 1 H-NMR and / or mass spectrometry (MS) data.

[0419] in, That is R3 is... PG is a protecting group; R1, R2, R3, R8, R10, R11, R12, R13, X3, and X4 have the meanings described in any of the foregoing items of this disclosure.

[0420] Example 1: Preparation of Compound 1

[0421] Step A:

[0422] Compound 1a (3 g, 4.6 mmol, preparation method see WO2024060966) was dissolved in dioxane (27 mL) and water (2.7 mL). Then, 1b (1.6 g, 4.6 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (0.3 g, 0.46 mmol), and potassium phosphate (2.4 g, 11.5 mmol) were added sequentially. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated. The crude product was purified by normal-phase column chromatography to obtain compound 1c (yield 57.2%).

[0423] LCMS(ESI)M / Z:802.3[M+H] + .

[0424] Step B:

[0425] Compound 1c (700 mg, 0.87 mmol) was dissolved in tetrahydrofuran (1.5 mL) and water (1.5 mL), and lithium hydroxide (100 mg, 4.4 mmol) was added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the pH was adjusted to 6 with 1 M dilute hydrochloric acid. The reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse column chromatography (0.1% FA) to give compound 1d (yield 71%).

[0426] LCMS(ESI) M / Z: 746.2 [M+H] + .

[0427] Step C:

[0428] Compound 1d (440 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (9 mL), and 1e trifluoroacetate (151 mg, 0.56 mmol, preparation method see WO2024067857), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (425.9 mg, 1.12 mmol) and N,N-diisopropylethylamine (506.6 mg, 3.9 mmol) were added. The mixture was stirred at room temperature for 16 h. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase column chromatography to give compound 1f (yield 84%).

[0429] LCMS(ESI)M / Z:884.4[M+H] + .

[0430] Step D:

[0431] Compound 1f (410 mg, 0.46 mmol) was dissolved in tetrahydrofuran (12.3 mL), and a solution of lithium hydroxide (110 mg, 4.6 mmol) in water (6.15 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The pH was adjusted to 6 with 1 M dilute hydrochloric acid, and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 g of compound (94% yield).

[0432] LCMS(ESI)M / Z:870.3[M+H] + .

[0433] Step E:

[0434] 1 g (360 mg, 0.41 mmol) of compound was dissolved in N,N-dimethylformamide (360 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.57 g, 8.2 mmol), 1-hydroxybenzotriazole (1.11 g, 8.2 mmol), 4-dimethylaminopyridine (250 mg, 2.1 mmol), and N,N-diisopropylethylamine (1.06 g, 8.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase column chromatography to give compound 1 h (yield 41%).

[0435] LCMS(ESI)M / Z:852.4[M+H] + .

[0436] Step F:

[0437] Compound 1h (120 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (2.4 mL), and cesium carbonate (91.2 mg, 0.28 mmol) was added with stirring. A solution of iodoethane (32.8 mg, 0.21 mmol) in N,N-dimethylformamide (2.4 mL) was added dropwise to the reaction mixture at room temperature. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1i (yield 89%).

[0438] LCMS(ESI)M / Z:880.3[M+H] + .

[0439] Step G:

[0440] Compound 1i (110 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with water, extracted three times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 1j (yield 94%).

[0441] LCMS(ESI)M / Z:780.3[M+H] + .

[0442] Step H:

[0443] Compound 1j (100 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (29.7 mg, 0.26 mmol), (2-oxime-cyanoethyl acetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (111.4 mg, 0.26 mmol) and N,N-diisopropylethylamine (50.4 mg, 0.39 mmol) were added under ice bath conditions. The reaction mixture was stirred in an ice-water bath for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Prep-HPLC (Instument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00mm 10μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: ACN, Flow rate: 20.0mL / min, Gradient B: 30%-95%) to obtain two axial chiral isomers. One isomer was designated as 1-P1 (yield 25.3%), and the other isomer was designated as 1-P2 (yield 16.9%).

[0444] 1-P1:

[0445] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 10mmol / L NH4HCO3 in H2O, B: ACN, Flow rate: 1.0mL / min, 16.0min), RT: 8.707min.

[0446] MS(ESI)M / Z:876.2[M+H] + .

[0447] 1H NMR(400MHz,DMSO-d6)δ8.81(d,1H),8.47-8.38(m,2H),8.00(d,1H),7.83(s,1H),7.74(d,1H),7.55(d,1H),5.89(d,1H),5.31(t,1H),4.73(d,1H),4.51-4.45(m,1H),3.97-3.78(m,3H),3.70-3.59(m,7H),3.53-3.50(m,1H),3.27-3.23(m,1H),3.17-3.11(m,1H),3.10(s,3H),3.03(d,1H),2.77-2.74(m,4H),2.67-2.65(m,1H),2.36-2.32(m,2H),2.18-2.13(t,1H),1.87-1.82(m,2H),1.64-1.60(t,1H),1.29-1.14(m,7H),1.14-1.03(m,9H),0.92(s,3H),0.48(s,3H).

[0448] 1-P2:

[0449] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:10mmol / L NH4HCO3 in H2O,B:ACN,Flow rate:1.0mL / min,16.0min),RT:9.278min.

[0450] MS(ESI)M / Z:876.1[M+H] + .

[0451] 1H NMR(400MHz,DMSO-d6)δ8.80(d,1H),8.44-8.38(m,2H),7.86(d,1H),7.83(s,1H),7.75(d,1H),7.58(d,1H),5.94(d,1H),5. 37(t,1H),4.66(d,1H),4.51-4.45(m,1H),4.35-4.22(m,2H),4.11-4.01(m,1H),3.71-3.60(m,6H),3.60-3.50(m,2H),3.25- 3.20(m,4H),3.17-3.10(m,1H),2.93(d,1H),2.78-2.71(m,4H),2.68-2.60(m,1H),2.47-2.40(m,1H),2.35-2.31(m,1H),2.1 5(t,1H),1.87-1.81(m,2H),1.57(t,1H),1.36(d,3H),1.27-1.13(m,4H),1.11-1.03(m,6H),0.92-0.83(m,6H),0.33(s,3H).

[0452] Example 2: Preparation of Compound 2

[0453] Step A:

[0454] 2a-1 (10.0 g, 46.3 mmol) and ethynyltrimethylsilane (36.4 g, 370 mmol) were dissolved in a mixed solvent of DMF (50 mL) and triethylamine (15 mL). Cuprous iodide (0.88 g, 4.63 mmol) and bis(triphenylphosphine)palladium chloride (3.25 g, 4.63 mmol) were added, and the mixture was heated to 110 °C under a nitrogen atmosphere and kept in a sealed container for 48 hours. After the reaction was detected by LCMS, the reaction solution was cooled to room temperature. The reaction solution was diluted with water, extracted three times with ethyl acetate (100 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to column chromatography (eluent: EA / PE) to give compound 2a-2 (10.5 g, 97% yield).

[0455] LCMS(ESI)M / Z:234.3[M+H] + .

[0456] Step B:

[0457] 2a-2 (8.00 g, 34.3 mmol) was dissolved in methanol (80 mL), and potassium fluoride (3.98 g, 68.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the starting material had disappeared. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain compound 2a (3.4 g).

[0458] LCMS(ESI) M / Z: 162.3 [M+H] + .

[0459] Step C:

[0460] Compounds 2a (11.5 g, 71.0 mmol) and 2b (24 g, 71.01 mmol) were dissolved in DMF (240 mL), and cuprous iodide (0.68 g, 3.55 mmol), palladium bis(triphenylphosphine)chloride (2.49 g, 3.55 mmol), and triethylamine (35.9 g, 355 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (300 mL), filtered through diatomaceous earth, and the mother liquor was washed with water (300 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give compound 2c (23 g).

[0461] MS(ESI)M / Z:373.0[M+1] + .

[0462] Step D:

[0463] Compound 2c (23.0 g, 62.0 mmol) was dissolved in DMF (300 mL), and palladium chloride (1.10 g, 6.20 mmol) was added. The mixture was heated to 90 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with ethyl acetate (500 mL), filtered through diatomaceous earth, and the mother liquor was washed with water (300 mL) and saturated brine (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain compound 2d (14.5 g).

[0464] MS(ESI)M / Z:373.0[M+1] + .

[0465] Step E:

[0466] Phosphorus oxychloride (14.5 g, 94.25 mmol) was slowly added dropwise to DMF (175 mL) at 0°C. After the mixture reacted at 0°C for 0.5 h, compound 2d (7.0 g, 18.9 mmol) was slowly added. After the addition was complete, the temperature was raised to 45°C and stirred for 1 h. After the reaction was complete, the mixture was slowly poured into a saturated sodium bicarbonate ice-water solution. After the pH was adjusted to weakly alkaline, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give compound 2e (6.0 g).

[0467] MS(ESI)M / Z:399.0[M+H] + .

[0468] Step F:

[0469] Methyl 2-methylpropionate (11.5 g, 113 mmol) was dissolved in THF (60 mL), and LDA (56 mL, 112.7 mmol, 2 M in THF) was added dropwise at -70 °C. The resulting mixture was stirred at -70 °C for 0.5 h, and then a THF solution of compound 2e (7.5 g, 18.8 mmol) in 40 mL was added. The reaction mixture was brought back to room temperature and stirred for another 1 h. After the reaction was completed, ammonium chloride solution was slowly added dropwise to quench the reaction. The reaction mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 2f (9 g).

[0470] MS(ESI)M / Z:502.6[M+H] + .

[0471] Step G:

[0472] Compound 2f (9.0 g, 17.9 mmol) and triethylsilane (8.42 g, 72.4 mmol) were dissolved in DCM (90 mL). Trifluoroacetic acid (41.3 g, 362 mmol) was slowly added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the pH of the reaction mixture was adjusted to weakly alkaline at 0 °C. The mixture was extracted twice with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give compound 2 g (6 g).

[0473] MS(ESI)M / Z:485.1[M+H] + .

[0474] Step H:

[0475] 2 g (4.0 g, 8.24 mmol) of compound and pinacol diboronate (3.14 g, 12.4 mmol) were dissolved in ultra-dry tetrahydrofuran (80 mL), followed by the addition of 4,4'-di-tert-butyl-2,2'-dipyridine (0.33 g, 1.24 mmol) and 1,5-cyclooctadiene iridium chloride dimer (0.17 g, 0.25 mmol). The reaction mixture was stirred at 70 °C for 16 hours under argon protection. After the reaction was completed, the reaction mixture was concentrated to obtain crude product 2 h (4.36 g).

[0476] LCMS(ESI)M / Z:529.0[M+H] + .

[0477] Step I:

[0478] Compound 2h (4.36 g, 8.24 mmol) was dissolved in THF (55 mL). Chloramine T (11.3 g, 49.4 mmol) was added in portions at 0 °C, followed by an aqueous solution of sodium iodide (7.41 g, 49.4 mmol) (22 mL). The reaction mixture was stirred overnight at 50 °C under argon protection. After the reaction was complete, the reaction mixture was diluted with ethyl acetate. The organic phase was washed with an aqueous solution of sodium sulfite, then with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by normal-phase column chromatography to give compound 2i (1.7 g).

[0479] LCMS(ESI) M / Z: 610.9 [M+H] + .

[0480] Step J:

[0481] Compound 2i (1.25 g, 2.09 mmol), cuprous iodide (39.8 mg, 0.21 mmol), and palladium bis(triphenylphosphine)chloride (146 mg, 0.21 mmol), along with 4-(propyn-1-yl)-1,4-oxazacycloheptane (831 mg, 2.09 mmol, 35% purity), were dissolved in DMF (20 mL). Triethylamine (1.06 g, 10.5 mmol) was added, and the reaction mixture was stirred at 70 °C for 15 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by normal-phase column chromatography to obtain compound 2j (800 mg).

[0482] LCMS(ESI)M / Z:622.2[M+H] + .

[0483] Step K:

[0484] Compound 2j (1.5 g, 2.41 mmol) was dissolved in ultra-dry tetrahydrofuran (30 mL), cooled to 0 °C, and then diisobutylaluminum hydrogenation (9.64 mmol, 9.64 mL, 1 M in toluene) was slowly added dropwise under nitrogen protection and stirred for 20 minutes. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by normal-phase column chromatography to obtain axially chiral A and axially chiral B.

[0485] LCMS(ESI)M / Z:594.0[M+H] + .

[0486] Step L:

[0487] Compound 2l (3 g, 8.21 mmol), pinacol diborate (2.50 g, 9.85 mmol), potassium acetate (2.41 g, 24.6 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (300 mg, 0.41 mmol) were dissolved in ultra-dry toluene (35 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours under argon protection. The reaction mixture was used directly in the next step.

[0488] Compound 2k-A or 2k-B (460 mg, 0.77 mmol), the reaction solution from the previous step, tripotassium phosphate (0.82 g, 3.85 mmol), and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium (50.2 mg, 0.077 mmol) were dissolved in a mixed solution of toluene (26 mL), 1,4-dioxane (13 mL), and water (13 mL). The reaction solution was heated to 80 °C and stirred for 1 hour under argon protection. After the reaction was complete, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by normal-phase column chromatography (DCM / MeOH = 60 / 1-30 / 1) to give the corresponding axially chiral compound 2m-A or 2m-B.

[0489] LCMS(ESI)M / Z:800.1[M+H] + .

[0490] Step M:

[0491] Compound 2m-A or 2m-B (1100 mg, 1.37 mmol) was dissolved in tetrahydrofuran (40 mL), and 20 mL of lithium hydroxide (68.9 mg, 2.88 mmol) aqueous solution was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was diluted with water, the pH was adjusted to 5.0 with 1 M dilute hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 2n-A or 2n-B (1 g).

[0492] LCMS(ESI) M / Z: 786.2 [M+H] + .

[0493] Step N:

[0494] 2n-A or 2n-B (1.0 g, 1.27 mmol) and (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride (458 mg, 2.54 mmol) were dissolved in DMF (20 mL), and ethyl diisopropylamine (1.64 g, 12.7 mmol) and HATU (966 mg, 2.54 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 h. After the reaction was complete, the reaction mixture was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by normal-phase column chromatography to obtain 2o-A or 2o-B (1.1 g).

[0495] LCMS(ESI)M / Z:912.2[M+H] + .

[0496] Step O:

[0497] Compound 2o-A or 2o-B (1.1 g, 1.21 mmol) was dissolved in THF (34 mL), and 17 mL of an aqueous solution of lithium hydroxide (57.9 mg, 2.42 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the pH was adjusted to 5.0 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 2p-A or 2p-B.

[0498] LCMS(ESI)M / Z:898.2[M+H] + .

[0499] Step P:

[0500] 2p-A or 2p-B (500 mg, 0.56 mmol) was dissolved in anhydrous acetonitrile (500 mL), and DIEA (1.45 g, 11.2 mmol), EDCI (2.15 g, 11.2 mmol), HOBT (1.51 g, 11.2 mmol), and 4-dimethylaminopyridine (342 mg, 2.80 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness at low temperature, diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was purified by normal-phase column chromatography to give compound 2q-A or 2q-B (140 mg).

[0501] LCMS(ESI)M / Z:880.2[M+H] + .

[0502] Step Q:

[0503] 2q-A or 2q-B (90 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed three times with sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2r-A or 2r-B.

[0504] LCMS(ESI)M / Z:781.2[M+H] + .

[0505] Step R:

[0506] 2r-A or 2r-B (42 mg, 0.054 mmol) and Int 1 (12.3 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1 mL), and ethyl diisopropylamine (69.8 mg, 0.54 mmol) and HATU (41.1 mg, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Prep-HPLC (Instument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00mm 10μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: ACN, Flow rate: 20.0mL / min, Gradient B: 30%-95%) to obtain 2-A or 2-B.

[0507] 2-A:

[0508] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:10mmol / L NH4HCO3 in H2O,B:ACN,Flow rate:1.0ml / min,16min),RT:9.167min.

[0509] MS(ESI)M / Z:876.1[M+H] + .

[0510] 1 H NMR(400MHz,CD3OD-d4)δ8.73(d,1H),8.38(s,1H),7.79(d,1H),7.48(s,1H),7.41(s,1H),5.77(d,1H),4.50-4.41(m,2H),4.24-4.17(m,2H),3.88-3.74(m,6H),3.70(s,2H),3.61-3.55(m,1H),3.42-3.38(m,1H),3.35(s,3H),3.27-3.23(m,1H),3.13-2.96(m,3H),2.91-2.88(m,4H),2.80-2.76(m,1H),2.54(d,1H),2.32-2.27(m,1H),2.22-2.15(m,2H),2.00-1.91(m,3H),1.79-1.70(m,1H),1.64-1.53(m,1H),1.45(d,3H),1.41-1.28(m,2H),1.15-1.11(m,7H),0.95(s,3H),0.53(s,3H).

[0511] 2-B:

[0512] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:10mmol / L NH4HCO3 in H2O,B:ACN,Flow rate:1.0ml / min,16min),RT:8.213min.

[0513] MS(ESI)M / Z:876.2[M+H] + .

[0514] 1H NMR(400MHz,CD3OD-d4)δ8.75(d,1H),8.39(s,1H),7.95(d,1H),7.50(s,1H),7.42(s,1H),5.66(d,1H ),4.78(d,1H),4.43(d,1H),4.30(dd,2H),3.94(dd,1H),3.78(ddt,6H),3.69(d,3H),3.62-3.55(m,1 H),3.42(d,1H),3.24(dd,3H),3.04(s,2H),2.92-2.86(m,4H),2.76(t,1H),2.28(t,3H),2.12(s,1H) ,1.97(dt,3H),1.83(d,1H),1.61(d,1H),1.44-1.32(m,2H),1.15(dd,10H),1.01(s,3H),0.56(s,3H).

[0515] Example 3: Preparation of Compound 3

[0516] Step A:

[0517] Compound 3a (1 g, 1.38 mmol, preparation method see WO2024169914) was dissolved in a mixed solution of toluene (15 mL), 1,4-dioxane (5 mL), and water (5 mL). Then, compound 2l (1260.26 mg, 2.64 mmol), tripotassium phosphate (732.33 mg, 3.45 mmol), and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (179.88 mg, 0.28 mmol) were added. The reaction mixture was heated to 70 °C and stirred for 16 h under argon protection. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with 50 mL of water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE) to obtain compound 3b (675 mg).

[0518] LCMS(ESI)M / Z:881.2[M+H] + .

[0519] Step B:

[0520] Compound 3b (675 mg, 0.69 mmol) was dissolved in 1,2-dichloroethane (14 mL), and trimethyltin hydroxide (623.83 mg, 3.45 mmol) was added. The mixture was stirred at 60 °C for 16 h under nitrogen protection. LC-MS detected the disappearance of the starting material. The reaction solution was diluted with water, extracted three times by DC, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 5%-10%) to give compound 3c (580 mg).

[0521] LCMS(ESI)M / Z:867.4[M+H] + .

[0522] Step C:

[0523] Compound 3c (580 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (4 mL), and 1e (181.03 mg, 0.67 mmol), ethyl diisopropylamine (173.18 mg, 1.34 mmol), and HATU (305.70 mg, 0.80 mmol) were added. The mixture was stirred at room temperature for 0.5 h. The reaction was monitored by LCMS until completion. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA / PE) to obtain compound 3d (640 mg).

[0524] LCMS(ESI)M / Z:1005.2[M+H]+.

[0525] Step D:

[0526] Compound 3d (640 mg, 0.64 mmol) was dissolved in 1,2-dichloroethane (13 mL), followed by the addition of trimethyltin hydroxide (578.62 mg, 3.2 mmol). The reaction was carried out at 60 °C for 16 h under an argon atmosphere. LC-MS detected the disappearance of the starting material. The reaction solution was diluted with water, extracted three times with dichloromethane, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (MeOH / DCM = 5%–10%) to give compound 3e (630 mg).

[0527] LCMS(ESI)M / Z:991.5[M+H] + .

[0528] Step E:

[0529] Compound 3e (580 mg, 0.59 mmol) was dissolved in acetonitrile (290 mL). 1-hydroxybenzotriazole (1594.42 mg, 11.80 mmol), 4-dimethylaminopyridine (360.40 mg, 2.95 mmol), ethyl diisopropylamine (1.95 mL, 11.80 mmol), and EDCI (2262.06 mg, 11.80 mmol) were added under ice bath conditions. The reaction mixture was reacted at room temperature for 24 h under an argon atmosphere. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 3f (280 mg).

[0530] LCMS(ESI)M / Z:487.4[M / 2+H] + .

[0531] Step F:

[0532] Compound 3f (320 mg, 0.33 mmol) and paraformaldehyde (139.37 mg, 1.16 mmol) were dissolved in anhydrous methanol (5 mL), and palladium hydroxide (203.62 mg, 0.14 mmol) was added. The mixture was purged with hydrogen three times, and the reaction was stirred at 35 °C for 16 h. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and diluted with ethyl acetate (30 mL). The organic phase was washed three times with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (MeOH / DCM = 5%-10%) to give compound 3 g (100 mg).

[0533] LCMS(ESI)M / Z:853.5[M+H] + .

[0534] Step G:

[0535] 3 g (80 mg, 0.094 mmol) of the compound was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL, 6.73 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, adjusted to pH 9 with sodium bicarbonate solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and used directly in the next step.

[0536] LCMS(ESI)M / Z:753.1[M+H] + .

[0537] Step H:

[0538] Compound 3 (28.25 mg, 0.25 mmol), Int 1 (0.054 mL, 0.090 mmol), and ethyl diisopropylamine (0.074 mL, 0.45 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the addition of propylphosphonic anhydride (0.053 mL, 0.090 mmol). The mixture was stirred at room temperature for 15 minutes. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to prep-HPLC (Waters 3767 Column: SunFire Prep C18, 19*250 mm, 10 μm; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 23-38%; retention time: 10.48-11.43 min of 16 min) to give compound 3 (23.25 mg).

[0539] HPLC (Waters 3767 Column: SunFire Prep C18, 19*250mm, 10um; Mobile Phase A: 0.03% TFA in H2O, B: 0.03% TFA in ACN; flow rate: 20ml / min; gradient: 23-38%; Retention Time: 10.48-11.43min of 16min), RT: 9.586min.

[0540] MS(ESI)M / Z:849.5[M+H] + .

[0541] 1H NMR (400MHz, MeOD-d4) δ8.39(d,J=2.8Hz,1H),8.26(s,1H),7.48(s,1H),7.38(s,1H),7.26(d,J=2.8Hz,1H),5.57(s,1H) ,4.65(dd,J=10.2,4.5Hz,2H),4.38(q,J=6.1Hz,1H),4.20(s,1H),3.73(d,J=11.0Hz,1H),3.67–3.57(m,2H),3.45–3.33 (m,6H),3.26(d,J=8.0Hz,1H),3.14–2.83(m,4H),2.67(d,J=13.0Hz,6H),2.59–2.53(m,1H),2.46–2.38(m,4H),2.28(d, J=5.0Hz,1H),2.23–2.15(m,2H),1.54(s,1H),1.45–1.36(m,5H),1.14(dd,J=13.2,6.0Hz,8H),0.92(s,3H),0.53(s,3H).

[0542] Example 4: Preparation of Compound 4

[0543] Step A:

[0544] Compound 4a (51 g, 250 mmol) was dissolved in DMSO (600 mL), and benzyl-1-piperazine carbonate (57.8 g, 263 mmol) and potassium carbonate (69.1 g, 500 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and the mother liquor was washed with water (800 mL) and saturated brine (600 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was pulped with PE / EA to obtain compound 4b (90 g).

[0545] MS(ESI)M / Z:406.0[M+1] + .

[0546] Step B:

[0547] Compound 4b (90 g, 223 mmol) was dissolved in DMF (900 mL), and cesium fluoride (33.8 g, 223 mmol) was added at 0°C. Then, (trifluoromethyl)trimethylsilane (158.3 g, 1113 mmol) was slowly added dropwise, and the reaction was continued at 0°C for 2 h. After the reaction was complete, the reaction was quenched with ice water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA) to give compound 4c (50 g).

[0548] MS(ESI)M / Z:474.1[M+H] + .

[0549] Step C:

[0550] Compound 4d (25 g, 52.7 mmol) was dissolved in DMF (250 mL), and sodium hydride (4.22 g, 105 mmol) was slowly added at 0 °C. The mixture was heated to 40 °C and reacted for 1 h. Iodimethane (11.2 g, 79.1 mmol) was slowly added dropwise at 0 °C, and the reaction was continued at room temperature for 1 h. After the reaction was completed, excess sodium hydride was quenched, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA) to give compound 4d (15.0 g).

[0551] MS(ESI)M / Z:490.0[M+1] + .

[0552] Step D:

[0553] Using compound 4d, the above four isomers can be prepared and isolated according to the method of Example 3, namely: 4A-P1, 4A-P2, 4B-P1, and 4B-P2.

[0554] 4A-P1:

[0555] HPLC(Waters

[0556] MS(ESI)M / Z:891.1[M+H] + .

[0557] 1H NMR(400MHz,CD3OD-d4)δ8.46(d,1H),8.41(s,1H),7.47-7.41(m,3H),5.95-5.93(m,1H),4.73-4.68(m,1H),4.43-4.40(m,1H),4.13-3.97(m,4H),3.81(s,2H),3.66-3.62(m,3H),3.39-3.32(m,4H),3.30-3.22(m,4H),3.14-3.08(m,6H),2.99-2.92(m,1H),2.88-2.74(m,2H),2.31-2.24(m,3H),2.21-2.03(m,1H),1.93-1.87(m,1H),1.72-1.57(m,2H),1.39-1.27(m,2H),1.13-1.10(m,6H),0.86(s,3H),0.69(s,3H).

[0558] 4A-P2:

[0559] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.03%TFA in H2O,B:0.03%TFA in ACN,Flow rate:1.0ml / min,16min),RT:9.539min.

[0560] MS(ESI)M / Z:891.1[M+H] + .

[0561] 1H NMR(400MHz,CD3OD-d4)δ8.53-8.50(m,1H),8.41(s,1H),7.64-7.63(m,1H),7.52-7.50(m,1H),7.44-7.43(m,1H),5.69-5.65(m,1H),4.55-4.47(m,1H),4.47-4.38(m,1H),4.33-4.25(m,1H),4.17-3.92(m,3H),3.79-3.64(m,5H),3.50-3.42(m,2H),3.26-3.13(m,4H),3.07-2.99(m,8H),2.81-2.74(m,1H),2.36-2.06(m,5H),2.00-1.80(m,2H),1.66-1.55(m,1H),1.42-1.28(m,2H),1.23-1.08(m,7H),1.02-1.01(m,3H),0.60-0.56(m,3H).

[0562] 4B-P1:

[0563] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.03%TFA in H2O,B:0.03%TFA in ACN,Flow rate:1.0mL / min,16.0min),RT:8.949min.

[0564] MS(ESI)M / Z:891.1[M+H] + .

[0565] 1 H NMR(400MHz,MeOD)δ8.44(s,2H),7.45(s,2H),7.39(s,1H),6.17(s,1H),4.69(d,1H),4.38(d,1H),3.93(d,2H),3.81-3.62(m,3H),3.50-3.36(m,8H),3.12-3.01(m,3H),2.83-2.70(m,5H),2.65-2.60(m,1H),2.52-2.40(m,3H),2.25-2.11(m,2H),1.79(d,2H),1.54-1.42(m,2H),1.36-1.27(m,2H),1.14-1.06(m,8H),0.84(s,3H),0.67(s,3H).

[0566] 4B-P2:

[0567] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0mL / min, 16.0min), RT: 9.218min.

[0568] MS(ESI)M / Z:891.1[M+H] + .

[0569] 1 H NMR(400MHz,MeOD)δ8.44(s,1H),8.40(s,1H),7.50(s,2H),7.42(s,1H),5.66(d,1H),4.63-4.57(m,1H),4.46 -4.40(m,1H),4.33-4.24(m,1H),4.05-3.98(m,1H),3.70(dd,2H),3.61-3.57(m,1H),3.53(s,3H),3.49-3.37 (m,6H),3.26-3.23(m,1H),3.00-3.03(m,1H),2.79-2.61(m,5H),2.44-2.36(m,3H),2.32-2.25(m,3H),2.07- 1.93(m,2H),1.87-1.80(m,1H),1.64-1.57(m,1H),1.42-1.31(m,2H),1.15(dd,8H),1.01(s,3H),0.52(s,3H).

[0570] Example 5: Preparation of Compound 5

[0571] By replacing (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride with intermediate 1e (see WO2024067857 for preparation method), compounds 5-P1 and 5-P2 can be prepared according to the preparation method of Example 2.

[0572] 5-P1:

[0573] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 10mmol / L NH4HCO3 in H2O, B: ACN, Flow rate: 1.0mL / min, 16.0min), RT: 8.624min.

[0574] MS(ESI)M / Z:888.5[M+H] + .

[0575] 1 H NMR(400MHz,MeOD-d4)δ8.75(d,1H),8.27(s,1H),7.97(d,1H),7.51(s,1H),7.42(s,1H),5.90(d,1H),5.41(d,1H),4.78(d,1H),4.67(d,1H),4.30(d,1H),3.96(s,1H),3.83-3.76(m,4H),3.70(s,2H),3.69-3.56(m,3H),3.37(t,2H),3.23(dd,2H),3.04(s,2H),2.91-2.87(m,4H),2.77(d,1H),2.63(s,1H),2.51-2.43(m,1H),2.33(d,2H),2.21-2.06(m,3H),2.00-1.94(m,2H),1.69(t,1H),1.48-1.35(m,2H),1.15(dd,10H),1.00(s,3H),0.54(s,3H).

[0576] 5-P2:

[0577] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:10mmol / L NH4HCO3 in H2O,B:ACN,Flow rate:1.0mL / min,16.0min),RT:9.609min.

[0578] MS(ESI)M / Z:888.5[M+H]+.

[0579] 1H NMR(400MHz,MeOD-d4)δ8.73(d,1H),8.27(s,1H),7.81(d,1H),7.50(s,1H),7.40(s,1H),5.57(s,1H),4.68-4.61(m,2H),4.52-4.4 5(m,1H),4.22-4.16(m,1H),3.82-3.75(m,4H),3.73-3.63(m,3H),3.67-3.55(m,2H),3.42-3.37(m,1H),3.34-3.30(m,2H),3.26-3 .20(m,1H),3.14-2.95(m,4H),2.92-2.86(m,4H),2.72-2.66(m,1H),2.61-2.54(m,2H),2.48-2.42(m,1H),2.32-2.25(m,1H),2.23 -2.15(m,2H),2.00-1.93(m,2H),1.58-1.50(m,1H),1.46(d,3H),1.42-1.27(m,2H),1.18-1.09(dd,7H),0.92(s,3H),0.53(s,3H).

[0580] Example 6: Preparation of Compound 6

[0581] Step A:

[0582] 6a (25 g, 117.87 mmol) was dissolved in isopropanol (300 mL), sodium bicarbonate (19.80 g, 235.74 mmol) was added, and ethyl bromopyruvate (36.78 g, 141.44 mmol) was added while stirring. If the reaction solution solidified, more isopropanol (200 mL) was added, and the mixture was heated to 90 °C and reacted for 16 h. The reaction solution was filtered, the filtrate was diluted with water (1 L), and extracted three times with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with 100 mL of n-hexane:ethyl acetate (20:1) to give compound 6b (18 g).

[0583] MS(ESI)M / Z:328.0[M+H] +

[0584] Step B:

[0585] Compound 6b (20 g, 61.31 mmol) and ethylene glycol monomethyl ether (190 mL) were added to a dry, sealed tube. Magnesium dichloride (17.51 ​​g, 183.93 mmol) was slowly added, and the reaction mixture was heated to 130 °C for 36 h. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was eluted by silica gel column chromatography (ethyl acetate / n-hexane = 3 / 1) to give compound 6c (11.5 g).

[0586] MS(ESI)M / Z:339.9[M+H] + .

[0587] Step C:

[0588] Compound 6c (19 g, 56.18 mmol) was dissolved in tetrahydrofuran (190 mL) under nitrogen protection. Lithium aluminum hydride (6.40 g, 168.54 mmol) was slowly added in an ice bath, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, tetrahydrofuran was added for dilution, and the reaction was quenched by slowly adding sodium sulfate decahydrate in an ice bath. After stirring at room temperature for 1 h, the mixture was filtered, and the filtrate was concentrated to give compound 6d (10.4 g).

[0589] MS(ESI)M / Z:268.0[M+H] + .

[0590] Step D:

[0591] Compound 6d (10.4 g, 39.08 mmol) was dissolved in dichloromethane (300 mL), and manganese dioxide (37.75 g, 390.80 mmol) was added. The reaction mixture was heated to 35 °C and reacted for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated and eluted by silica gel column chromatography (ethyl acetate / dichloromethane = 1 / 6). The filtrate was then slurried with 100 mL of n-hexane / ethyl acetate (4 / 1) to obtain compound 6e (6 g).

[0592] MS(ESI)M / Z:265.9[M+H] + .

[0593] Step E:

[0594] Methyl isobutyrate (7.19 g, 70.44 mmol) was dissolved in tetrahydrofuran (80 mL) and cooled to -70 °C. Diisopropylaminolithium (2 M in THF, 70.44 mmol) was slowly added dropwise under an argon atmosphere. After stirring for 0.5 hours, 6e (3.1 g, 11.74 mmol) dissolved in tetrahydrofuran (62 mL) was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was naturally raised to 0 °C, then heated to 30 °C and reacted for 1 hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal silica gel column chromatography (ethyl acetate / n-hexane = 1 / 1) to give compound 6f (3.75 g).

[0595] 1 H NMR(400MHz, CDCl3)δ7.61(d,1H),7.04(s,1H),7.01(d,1H),5.19(d,1H),4.11(t ,2H),3.74(s,3H),3.0-2.80(m,3H),2.32-2.20(m,2H),1.27(s,3H),1.18(s,3H).

[0596] Step F:

[0597] Compound 6f (1.6 g, 4.37 mmol) was dissolved in dichloromethane (32 mL), and triethylsilane (4.07 g, 34.96 mmol) was added under ice bath cooling, followed by trifluoroacetic acid (19.93 g, 174.8 mmol). The reaction was maintained at 0 °C for 10 minutes. After the reaction was complete, the mixture was diluted with dichloromethane (30 mL), the reaction solution was concentrated, and the residue was dissolved in ethyl acetate. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal-phase silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1) to give compound 6g (1.2 g).

[0598] MS(ESI)M / Z:350.2[M+H] + .

[0599] Step G:

[0600] Compound 6 g (10.2 g, 29.12 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and lithium borohydride (7.61 g, 349.44 mmol) was added in portions under ice bath conditions. The reaction mixture was reacted at room temperature for 2 days. The reaction was quenched with cold saturated ammonium chloride aqueous solution, stirred at room temperature until no more bubbles were produced, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by normal silica gel column chromatography (ethyl acetate / n-hexane = 1 / 5) to give compound 6h (7.3 g).

[0601] LCMS(ESI)M / Z:322.1[M+H] + .

[0602] Step H:

[0603] Compound 6h (10.7 g, 33.21 mmol) was dissolved in anhydrous dichloromethane (58 mL), and pyridine (7.88 g, 99.63 mmol) was added. Acetyl chloride (3.91 g, 49.81 mmol) was slowly added dropwise to the reaction solution under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (50 mL), and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal silica gel column chromatography (ethyl acetate / n-hexane = 1 / 5) to give compound 6i (9.1 g).

[0604] LCMS(ESI) M / Z: 364.0 [M+H] +

[0605] Step I:

[0606] Compound 6i (5.00 g, 13.73 mmol), pinacol diborate (3.84 g, 15.10 mmol), and potassium acetate (3.37 g, 34.33 mmol) were dissolved in anhydrous dioxane (100 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichlorochloride (1.00 g, 1.37 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 16 h under argon protection. LC-MS monitoring showed the disappearance of the starting material. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified by normal silica gel column chromatography (ethyl acetate / n-hexane = 1 / 9) to give compound 6j (3.7 g).

[0607] LCMS(ESI)M / Z:411.9[M+H] + .

[0608] Step J:

[0609] Compound 6j (7.3 g, 17.75 mmol) was dissolved in a mixed solution of toluene (70 mL), dioxane (20 mL), and water (20 mL). 2 L (7.78 g, 21.3 mmol), potassium phosphate (9.42 g, 44.38 mmol), and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium (1.16 g, 1.78 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours under argon protection. LC-MS showed complete reaction. The reaction mixture was filtered through diatomaceous earth, diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then subjected to column chromatography (ethyl acetate / petroleum ether = 0%–40%) to give compound 6k (5.85 g).

[0610] LCMS(ESI)M / Z:570.6[M+H] + .

[0611] Step K:

[0612] Compound 6k (5.3 g, 9.30 mmol) was dissolved in tetrahydrofuran (100 mL), and silver trifluoromethanesulfonate (2.63 g, 10.23 mmol) was added under ice bath cooling. Then, a THF (50 mL) solution of iodine (2.36 g, 9.3 mmol) was added dropwise, and the reaction was carried out at 0 °C for 0.5 h. The reaction solution was quenched with water, filtered through diatomaceous earth, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and subjected to column chromatography (ethyl acetate / petroleum ether = 0%–30%) to give compound 6l (4.5 g).

[0613] LCMS(ESI) M / Z: 696.0 [M+H] + .

[0614] Step L:

[0615] Compound 6l (4600 mg, 6.61 mmol) was dissolved in a mixed solution of tetrahydrofuran (100 mL) and water (100 mL), and lithium hydroxide monohydrate (1.386 g, 33.05 mmol) was added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, 1 M dilute hydrochloric acid was added dropwise to pH 6. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give compound 6m (4100 mg).

[0616] LCMS(ESI)M / Z:640.1[M+H] + .

[0617] Step M:

[0618] Compound 6m (4.1 g, 6.41 mmol) was dissolved in N,N-dimethylformamide (80 mL), and (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride (1389.33 mg, 7.69 mmol), ethyl diisopropylamine (1656.86 mg, 12.82 mmol), and HATU (2924.73 mg, 7.69 mmol) were added. The mixture was stirred at room temperature for half an hour. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (EA / PE = 80%-100%) to give compound 6n (3.7 g).

[0619] LCMS(ESI) M / Z: 765.8 [M+H] + .

[0620] Step N:

[0621] Compound 6n (3 g, 3.92 mmol) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (6 mL), and lithium hydroxide monohydrate (493.45 mg, 11.76 mmol) was added. The mixture was stirred in an ice bath for 2 hours. After the reaction was complete, 1 M dilute hydrochloric acid was added dropwise to pH 6. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6o (2.7 g).

[0622] LCMS(ESI)M / Z:752.1[M+H] + .

[0623] Step O:

[0624] Compound 6o (1.0 g, 1.33 mmol) was dissolved in anhydrous acetonitrile (500 mL), followed by the addition of ethyl diisopropylamine (4.41 mL, 26.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.10 g, 26.6 mmol), 1-hydroxybenzotriazole (3.59 g, 26.6 mmol), and 4-dimethylaminopyridine (0.81 g, 6.65 mmol). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 5 / 2) to give compound 6p (500 mg).

[0625] LCMS(ESI)M / Z:734.1[M+H] + .

[0626] Step P:

[0627] Compound 6S-1 (500 mg, 1.46 mmol) was dissolved in toluene (5 mL), and (1S,6S)-1,6-dihydro-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (340.94 mg, 1.61 mmol), cesium carbonate (1427.09 mg, 4.38 mmol), palladium acetate (32.78 mg, 0.15 mmol), and 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (181.82 mg, 0.29 mmol) were added sequentially. The reaction solution was heated to 95 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (methanol / dichloromethane = 10%) to give compound 6S-2 (500 mg).

[0628] LCMS(ESI)M / Z:328.0[M+H-boc] + .

[0629] Step Q:

[0630] Compound 6S-2 (500 mg, 1.17 mmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (6907.63 mg, 60.58 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was extracted three times with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give compound 6S-3 (320 mg).

[0631] LCMS(ESI) M / Z: 328.0 [M+H] + .

[0632] Step R:

[0633] Compound 6S-3 (380 mg, 1.16 mmol) was dissolved in methanol (10 mL), and paraformaldehyde (235.37 mg, 2.9 mmol) and sodium cyanoborohydride (182.24 mg, 2.9 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and column chromatography (methanol / dichloromethane = 0%–10%) was performed to give compound 6S (340 mg).

[0634] LCMS(ESI)M / Z:340.0[M+H] + .

[0635] Step S:

[0636] Compound 6p (300 mg, 0.41 mmol) and compound 6s (115.69 mg, 0.34 mmol) were dissolved in a mixed solution of 1,4-dioxane (2 mL), water (2 mL), and toluene (6 mL). Dichloro[1,1-bis(di-tert-butylphosphine)ferrocene]palladium (53.44 mg, 0.082 mmol) and tripotassium phosphate (217.58 mg, 1.02 mmol) were added, and the mixture was heated to 85 °C for 3 hours under an argon atmosphere. After the reaction was complete, the mixture was directly concentrated and subjected to stirred column chromatography (methanol / dichloromethane = 10%) to give compound 6q (150 mg).

[0637] LCMS(ESI)M / Z:867.2[M+H] + .

[0638] Step T:

[0639] Compound 6q (180 mg, 0.21 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (20.19 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 6r (125 mg).

[0640] LCMS(ESI) M / Z: 767.6 [M+H] + .

[0641] Step U:

[0642] Compound 6r (120 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (3 mL), and Int 1 (36.52 mg, 0.32 mmol), ethyl diisopropylamine (206.78 mg, 1.6 mmol) and HATU (121.67 mg, 0.32 mmol) were added. The mixture was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse-phase prep-HPLC (waters 3767 Column: SunFire Prep C18, 19*250mm, 10um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min; gradient: 39-48%; retention time: 7.87-9.12, 9.35-10.87min) to obtain compounds 6-P1 (17.7mg) and 6-P2 (51.37mg).

[0643] 6-P1:

[0644] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.03%TFA in H2O,B:0.03%TFA in ACN,Flow rate:1.0ml / min,16min),RT:7.319min.

[0645] MS(ESI)M / Z:863.2.

[0646] 1 H NMR(400MHz,CD3OD-d4)δ8.41(s,1H),8.28(s,1H),7.82(s,1H),7.51(s,1H),7.45(s,1H),5.67(d,1H),4.44-4.41(m,2H),4.29(dd,1H),4.13(d,1H),4.03-3.99(m,1H),3.87-3.82(m,1H),3.77-3.62(m,3H),3.48-3.41(m,8H),3.27-3.05(m,1H),3.05(s,2H),2.90(s,3H),2.79-2.74(m,1H),2.62(d,1H),2.51-2.43(m,1H),2.29-2.25(m,5H),2.13-2.08(m,1H),1.98-1.93(m,1H),1.88-1.79(m,1H),1.63-1.59(m,1H),1.42-1.33(m,3H),1.17-1.10(m,10H),1.04(m,3H),0.56(s,3H).

[0647] 6-P2:

[0648] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.03%TFA in H2O,B:0.03%TFA in ACN,Flow rate:1.0ml / min,16min),RT:7.633min.

[0649] MS(ESI)M / Z:863.1.

[0650] 1H NMR(400MHz,CD3OD-d4)δ8.39-8.36(m,2H),7.49(s,1H),7.45-7.42(m,2H),5.78(d,1H),4.48-4.41(m,2H),4.23-4 .13(m,3H),3.79-3.70(m,3H),3.63-3.59(m,1H),3.41-3.38(m,7H),3.30-3.25(m,1H),3.12-3.05(m,2H),3.01-2.9 6(m,1H),2.89(s,3H),2.76-2.73(m,1H),2.62-2.58(m,2H),2.40-2.30(m,2H),2.20-2.14(m,4H),1.93-1.91(m,1H) ,1.76-1.60(m,1H),1.58-1.54(m,1H),1.43(d,3H),1.41-1.28(m,2H),1.16-1.11(m,8H),0.96(s,3H),0.55(s,3H).

[0651] Example 7: Preparation of Compound 7

[0652] Compounds 7-P1 and 7-P2 can be prepared by using suitable raw materials, following the synthesis method of Example 6.

[0653] 7-P1:

[0654] HPLC (Waters 3767 Column: Pursuit XRs 10C18, 19*250mm, 10um; Mobile Phase A: 0.03% TFA in H2O, B: 0.03% TFA in ACN; flow rate: 20ml / min; gradient: 32-45%; 16min), RT: 9.258min.

[0655] MS(ESI)M / Z:863.2[M+H] + .

[0656] 1H NMR(400MHz,MeOD-d4)δ8.40(s,1H),8.31(s,1H),7.61(d,1H),7.50(s,1H),7.43(s,1H),5.67(d,1H),4.43(d,1H),4.36–4.26(m,2H),4.09(d,1H),3.97(t,1H),3.75(dt,3H),3.63–3.48(m,2H),3.44–3.33(m,6H),3.25(dd,3H),3.05(s,2H),2.90(s,3H),2.76(dd,1H),2.60(d,1H),2.42(s,1H),2.20(ddd,6H),1.90(dd,2H),1.61(dd,1H),1.44–1.30(m,2H),1.17(t,4H),1.12(dd,6H),1.03(s,3H),0.56(s,3H).

[0657] 7-P2:

[0658] HPLC(Waters 3767 Column:Pursuit XRs 10C18,19*250mm,10um;Mobile Phase A:0.03% TFA in H2O,B:0.03% TFA in ACN;flow rate:20ml / min;gradient:32-45%;16min),RT:9.564min.

[0659] MS(ESI)M / Z:863.2[M+H] + .

[0660] 1H NMR(400MHz,MeOD-d4)δ8.37(d,2H),7.49(s,1H),7.42(s,1H),7.37(d,1H),5.78(d,1H),4.48–4.3 9(m,2H),4.25–4.10(m,3H),3.84–3.69(m,3H),3.57(dd,2H),3.39(d,5H),3.28–3.17(m,2H),3.16– 2.93(m,4H),2.90(s,3H),2.76(dd,1H),2.59(d,2H),2.48–2.26(m,2H),2.16(d,4H),1.93(d,1H),1 .75(d,1H),1.59(dt,1H),1.43(d,3H),1.35(ddd,2H),1.16–1.10(m,7H),0.95(s,3H),0.54(s,3H).

[0661] Example 8: Preparation of Compound 8

[0662] Compounds 8-P1 and 8-P2 can be prepared by using suitable raw materials, following the synthesis method of Example 6.

[0663] 8-P1:

[0664] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0ml / min, 16min), RT: 7.773min.

[0665] MS(ESI)M / Z:863.4[M+H] + .

[0666] 1H NMR(400MHz,MeOD-d4)δ8.42(d,1H),8.40(s,1H),7.82(d,1H),7.51(s,1H),7.44(s,1H),5.67(d,1H),4.68(s,2H),4.43(d,1H),4.37(q,1H),4.29(dd,1H),4.02(dd,1H),3.76(d,1H),3.68(d,2H),3.51(d,2H),3.45–3.34(m,5H),3.28–3.19(m,3H),3.05(d,2H),2.86(s,3H),2.76(dd,1H),2.36–2.24(m,5H),2.11(t,3H),1.96(d,1H),1.83(d,1H),1.61(dt,1H),1.37(ddd,2H),1.19–1.14(m,7H),1.13(d,3H),1.04(s,3H),0.59(s,3H).

[0667] 8-P2:

[0668] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.03%TFA in H2O,B:0.03%TFA in ACN,Flow rate:1.0ml / min,16min),RT:8.049min.

[0669] MS(ESI)M / Z:863.4[M+H] + .

[0670] 1H NMR(400MHz,MeOD-d4)δ8.43(d,1H),8.39(s,1H),7.59(d,1H),7.50(s,1H),7.43(s,1H),5.78(d,1H),4.69(d,2 H),4.48(q,1H),4.42(d,1H),4.21(dd,2H),3.76(t,2H),3.67(t,1H),3.54–3.41(m,3H),3.39(s,3H),3.25(dd, 3H),3.11(dd,2H),3.00(d,1H),2.84(s,3H),2.76(dd,1H),2.63(d,1H),2.30(d,3H),2.22–2.07(m,4H),1.93(d ,1H),1.75(dd,1H),1.59(dt,1H),1.47(d,3H),1.41–1.31(m,2H),1.17–1.10(m,7H),0.97(s,3H),0.58(s,3H).

[0671] Example 9: Preparation of Compound 9

[0672] Compounds 9-P1 and 9-P2 can be prepared by using suitable raw materials, following the synthesis method described in Example 6.

[0673] 9-P1:

[0674] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0ml / min, 16min), RT: 7.208min.

[0675] MS(ESI)M / Z:863.5[M+H] + .

[0676] 1H NMR(400MHz,MeOD-d4)δ8.49-8.24(m,2H),7.79-7.70(m,1H),7.54-7.48(m,1H),7.45-7.39(m,1H),5.77-5.59(m,1H),4.71-4.61(m,2H),4.51-4.38(m,1H),4.38-4.24(m,2H),4.05-3.94(m,1H),3.80-3.73(m,1H),3.69-3.52(m,2H),3.49-3.46(m,2H),3.45-3.39(m,2H),3.37(s,3H),3.27-3.25(m,1H),3.24-3.18(m,1H),3.15-3.12(m,1H),3.08-3.02(m,2H),2.87(s,3H),2.80-2.71(m,1H),2.38-2.22(m,5H),2.19-2.02(m,3H),1.99-1.89(m,1H),1.871.78(m,1H),1.67-1.56(m,1H),1.42-1.34(m,2H),1.20-1.15(m,7H),1.14-1.10(m,3H),1.04(s,3H),0.59(s,3H).

[0677] 9-P2:

[0678] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.03%TFA in H2O,B:0.03%TFA in ACN,Flow rate:1.0ml / min,16min),RT:7.549min.

[0679] MS(ESI)M / Z:863.5[M+H] + .

[0680] 1H NMR(400MHz,MeOD-d4)δ8.45-8.34(m,2H),7.49(s,1H),7.45-7.36(m,2H),5.83-5.74(m,1H),4.70-4.60(m,2H),4.48-4.35(m,2H),4.26- 4.15(m,2H),3.79-3.70(m,2H),3.69-3.62(m,1H),3.53-3.44(m,2H) ,3.43-3.40(m,1H),3.36-3.29(m,4H),3.28-3.22(m,2H),3.14-3.04 (m,2H),3.03-2.94(m,1H),2.85(s,3H),2.81-2.71(m,1H),2.64-2.56(m,1H),2.37-2.26(m,3H),2.22-2.12(m,2H),2.09-2.03(m,2H),1. 99-1.89(m,1H),1.81-1.69(m,1H),1.65-1.55(m,1H),1.47-1.44(m, 3H),1.40-1.32(m,2H),1.16-1.11(m,7H),0.96(s,3H),0.56(s,3H).

[0681] Example 10: Preparation of Compound 10

[0682] Step A:

[0683] Compound 10a (8 g, 24.68 mmol, preparation method see WO202260583) and triethylsilane (5.74 g, 49.36 mmol) were dissolved in trifluoroacetic acid (400 mL), and the mixture was heated to 60 °C and stirred for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (EA / PE = 80%-100%) to obtain compound 10b (6.4 g).

[0684] MS(ESI)M / Z:326.0[M+H] +

[0685] Step B:

[0686] Compound 10b (2.5 g, 7.66 mmol) was dissolved in methanol (50 mL). A solution of sodium tungstate (0.45 g, 1.53 mmol) in water (25 mL) was added dropwise to the reaction solution, followed by the addition of hydrogen peroxide (2.35 mL). The reaction solution was stirred at room temperature for 0.5 h, then dimethyl sulfate (1.93 g, 15.32 mmol) and potassium acetate (4.23 g, 30.64 mmol) were added. The reaction was stirred at room temperature under a nitrogen atmosphere for 2 h. After the reaction was completed, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA:PE = 80%-100%) to obtain compound 10c (1.12 g).

[0687] Step C:

[0688] Compound 10c (4.5 g, 12.70 mmol) and silver trifluoromethanesulfonate (3.5 g, 13.97 mmol) were dissolved in tetrahydrofuran (45 mL). Iodine (3.26 g, 12.70 mmol) was added in portions under ice bath conditions, and the mixture was stirred at room temperature for 2 h under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 80%-100%) to give compound 10d (4.5 g).

[0689] MS(ESI)M / Z:480.0[M+H] + .

[0690] Step D:

[0691] Compound 10d (4.5 g, 9.37 mmol), 10m (4.38 g, 9.37 mmol, preparation method see WO202467857), and potassium acetate (3237 mg, 23.4 mmol) were dissolved in toluene (30 mL). [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (342 mg, 0.47 mmol) was added. The reaction mixture was heated to 75 °C and stirred for 16 h under argon protection. After the reaction was complete, the reaction mixture was concentrated and purified by silica gel column chromatography (EA / PE (0.1% TEA) = 80%-100%) to obtain compound 10e (1.1 g).

[0692] MS(ESI)M / Z:707.2[M+H] + .

[0693] Step E:

[0694] Compound 10f (1.1 g) can be prepared by referring to step L of Example 2.

[0695] MS(ESI)M / Z:913.4[M+H]+.

[0696] Step F:

[0697] Compound 10f (1.1 g, 1.2 mmol) was dissolved in a mixed solution of tetrahydrofuran (11 mL), methanol (5.5 mL), and water (11 mL). Lithium hydroxide (290 mg, 12 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the pH was adjusted to 6 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse column chromatography to give compound 10 g (1.0 g).

[0698] LCMS(ESI)M / Z:857.3[M+H] + .

[0699] Step G:

[0700] 10 g (1.0 g, 1.17 mmol) of compound was dissolved in N,N-dimethylformamide (10 mL), and 1e (180 mg, 1.17 mmol), ethyl diisopropylamine (454 mg, 3.51 mmol), and HATU (668 mg, 1.75 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 10 h (1.0 g).

[0701] LCMS(ESI)M / Z:995.5[M+H] +

[0702] Step H:

[0703] Compound 10h (1.0 g, 1 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (10 mL), and lithium hydroxide (240 mg, 10 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the pH was adjusted to 6 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse column chromatography to give compound 10i (850 mg).

[0704] LCMS(ESI)M / Z:981.4[M+H] + .

[0705] Step I:

[0706] Compound 10i (425 mg, 0.43 mmol) was dissolved in acetonitrile (425 mL). 1-Hydroxybenzotriazole (1162 mg, 8.6 mmol), 4-dimethylaminopyridine (263 mg, 2.15 mmol), ethyl diisopropylamine (1.42 mL, 8.6 mmol), and EDCI (1649 mg, 8.6 mmol) were added under ice bath conditions. The reaction was carried out at room temperature for 16 h under an argon atmosphere. After the reaction was complete, the reaction solution was concentrated to dryness. The residue was dissolved in ethyl acetate. The organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 10j (270 mg).

[0707] LCMS(ESI)M / Z:963.4[M+H]+.

[0708] Step J:

[0709] Compound 10j (540 mg, 0.56 mmol) and paraformaldehyde (169 mg, 5.6 mmol) were dissolved in anhydrous methanol (6 mL), and palladium hydroxide (79 mg, 0.56 mmol) was added. The reaction mixture was heated to 35 °C at 15 psi hydrogen atmosphere and reacted for 16 h. After the reaction was completed, the reaction solution was filtered with diatomaceous earth, the filtrate was concentrated, diluted with water and ethyl acetate, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (MeOH / DCM = 5%-10%) to give compound 10k (380 mg).

[0710] LCMS(ESI) M / Z: 843.4, [M+H] + .

[0711] Step K:

[0712] Compound 10k (380 mg, 0.45 mmol) was dissolved in dichloromethane (4.5 mL), and trifluoroacetic acid (1.5 mL, 20.19 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was adjusted to pH 9 with sodium bicarbonate aqueous solution, extracted three times with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10l (300 mg).

[0713] LCMS(ESI) M / Z: 743.4, [M+H] + .

[0714] Step L:

[0715] Compound 10 (300 mg, 0.4 mmol) and Int 1 (46 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (3 mL), and HATU (229 mg, 0.6 mmol) and ethyl diisopropylamine (0.2 mL, 1.2 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to prep-HPLC (Waters 3767 / Qda, Column: XBridge C18, 19*250 mm, 10 μm; Mobile Phase A: 10 mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 48-48%; retention time: 8.2-9 min of 16 min) to give compound 10 (23.25 mg).

[0716] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0ml / min, 16min), RT: 8.845min.

[0717] MS(ESI)M / Z:839.9.

[0718] 1H NMR(400MHz,DMSO-d6)δ8.50-8.36(m,3H),7.91-7.84(m,1H),7.82-7.74(m,1H),7.56-7.26(m,2H),6.00-5.81(m,1H),5.41-5.21 (m,1H),4.74-4.65(m,1H),4.58-4.41(m,1H),4.04-3.89(m,1H),3.87-3.65(m,3H),3.64-3.48(m,2H),3.29-3.20(m,5H),3.19-3 .09(m,2H),3.07-3.01(m,3H),2.72-2.61(m,2H),2.46-2.38(m,4H),2.37-2.28(m,2H),2.24-2.18(m,3H),2.18-2.08(m,1H),1.6 5-1.56(m,1H),1.33-1.27(m,1H),1.27-1.20(m,3H),1.19-1.14(m,2H),1.12-1.03(m,6H),0.95-0.80(m,3H),0.63-0.39(m,3H).

[0719] Example 11: Preparation of Compound 11

[0720] Step A:

[0721] Compound 11a (25.0 g, 127.5 mmol) was dissolved in DMF (400 mL), and trifluoroacetic anhydride (40.2 g, 191.3 mmol) was slowly added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution under ice-water bath conditions. The mixture was washed three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to dryness to obtain compound 11b (35 g).

[0722] LCMS(ESI) M / Z: 294.0 [M+H] + .

[0723] Step B:

[0724] Compound 11b (20.0 g, 68.5 mmol) was dissolved in THF (160 mL), and sodium borohydride (7.77 g, 205.4 mmol) was added in portions at 0 °C, followed by slow dropwise addition of boron trifluoride diethyl ether (19.4 g, 137 mmol). The mixture was stirred at room temperature for 1 hour under nitrogen protection, then heated to 40 °C and stirred for 16 hours. After the reaction was complete, the reaction was quenched by slowly pouring in an ice-water sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 1) to give compound 11c (11 g).

[0725] LCMS(ESI) M / Z: 278.0 [M+H] + .

[0726] Step C:

[0727] Compound 11c (12.6 g, 45.3 mmol) was dissolved in tetrahydrofuran (130 mL), and elemental iodine (11.5 g, 45.3 mmol) was added at 0 °C, followed by silver trifluoromethanesulfonate (10.6 g, 41.4 mmol). The reaction was carried out at 0 °C for 10 minutes, then restored to room temperature for 20 minutes. The reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was washed with saturated sodium thiosulfate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give compound 11d (14 g).

[0728] LCMS(ESI)M / Z:404.0[M+H] + .

[0729] Step D:

[0730] Compounds 11p (4.0 g, 10.0 mmol, preparation method see WO202467857), 11d (4.05 g, 10.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (0.37 g, 0.50 mmol), and potassium carbonate (4.15 g, 30.1 mmol) were dissolved in a mixture of toluene (80 mL) and water (16 mL). The mixture was heated to 70 °C and stirred for 6 hours under argon protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to obtain compound 11e (4.5 g).

[0731] LCMS(ESI) M / Z: 632.8 [M+H] +

[0732] Step E:

[0733] Compound 11e (7.5 g, 11.9 mmol) and cesium carbonate (11.6 g, 35.6 mmol) were dissolved in DMF (75 mL), and tert-butyl(3-iodo-2,2-dimethylpropoxy)dimethylsilane (11.7 g, 35.6 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give compound 11f (6 g).

[0734] LCMS(ESI)M / Z:832.9[M+H] + .

[0735] Step F:

[0736] Compound 11f (7.3 g, 8.78 mmol) was dissolved in THF (58 mL), and tetrabutylammonium fluoride (17.6 mmol, 17.6 mL, 1 M in THF) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, the solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to give compound 11 g (4.9 g).

[0737] LCMS(ESI)M / Z:718.9[M+H] + .

[0738] Step G:

[0739] Compound 11 g (1.5 g, 2.09 mmol), potassium acetate (0.62 g, 6.27 mmol), pinacol diboronate (1.06 g, 4.18 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (0.15 g, 0.21 mmol) were dissolved in toluene (20 mL). The mixture was heated to 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with ethyl acetate, filtered through diatomaceous earth, concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to obtain compound 11 h (1.58 g).

[0740] LCMS(ESI)M / Z:765.1[M+H] + .

[0741] Step H:

[0742] Compound 11h (1.5 g, 1.96 mmol), compound 2l (0.75 g, 2.06 mmol), potassium phosphate (1.25 g, 5.88 mmol), and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium (63.9 mg, 0.098 mmol) were dissolved in a mixed solution of toluene (30 mL), 1,4-dioxane (10 mL), and water (10 mL). The mixture was heated to 80 °C and stirred for 2 hours under argon protection. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain compound 11i (1.6 g).

[0743] LCMS(ESI) M / Z: 923.0 [M+H] + .

[0744] Step I:

[0745] Compound 11i (1.5 g, 1.63 mmol) was dissolved in tetrahydrofuran (30 mL), and an aqueous solution of lithium hydroxide (78.1 mg, 3.26 mmol) (15 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the pH was adjusted to 5 with 0.5 M dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11j (1.4 g).

[0746] LCMS(ESI)M / Z:909.0[M+H] + .

[0747] Step J:

[0748] Compound 11j (700 mg, 0.77 mmol) and compound 1e (229 mg, 0.85 mmol) were dissolved in DMF (14 mL), ethyl diisopropylamine (697 mg, 5.39 mmol) was added, and finally HATU (439 mg, 1.16 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with water, saturated ammonium chloride solution, and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain compound 11k (750 mg).

[0749] LCMS(ESI) M / Z: 1047.1 [M+H] + .

[0750] Step K:

[0751] Compound 11k (640 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), and an aqueous solution of lithium hydroxide (29.2 mg, 1.22 mmol) (5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with water, and the pH was adjusted to 5 with 0.5 M dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11l (600 mg).

[0752] LCMS(ESI)M / Z:1033.1[M+H] + .

[0753] Step L:

[0754] Compound 11l (400 mg, 0.39 mmol) was dissolved in acetonitrile (400 mL), and ethyl diisopropylamine (1.01 g, 7.80 mmol), EDCI (1.50 g, 7.80 mmol), 1-hydroxybenzotriazole (1.05 g, 7.80 mmol), and 4-dimethylaminopyridine (238 mg, 1.95 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated to dryness. The crude product was dissolved in ethyl acetate, and the organic phase was washed with water, saturated ammonium chloride solution, and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (DCM / MeOH = 60 / 1) to give compound 11m (260 mg).

[0755] LCMS(ESI) M / Z: 1015.0 [M+H] + .

[0756] Step M:

[0757] Compound 11m (450 mg, 0.44 mmol) and paraformaldehyde (132 mg, 4.4 mmol) were dissolved in methanol (45 mL), and palladium hydroxide on carbon (272 mg, 0.97 mmol, 50% wt) was added. The mixture was stirred at room temperature for 6 h under a hydrogen atmosphere. After the reaction was completed, the reaction solution was diluted with dichloromethane, filtered through diatomaceous earth, and the filtrate was concentrated and purified by normal column chromatography (DCM / MeOH = 30 / 1) to obtain compound 11n (300 mg).

[0758] LCMS(ESI)M / Z:895.9[M+H] + .

[0759] Step N:

[0760] Compound 11n (150 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the solution was diluted with dichloromethane, the organic phase was concentrated, the crude product was dissolved in ethyl acetate, the organic phase was washed with saturated sodium bicarbonate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 11o (130 mg).

[0761] LCMS(ESI)M / Z:795.4[M+H] + .

[0762] Step O:

[0763] Compound 11o (120 mg, 0.15 mmol) and Int 1 (34.2 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (194 mg, 1.50 mmol) and HATU (114 mg, 0.30 mmol) were added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC (Waters 3767 Column: SunFire Prep C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 in H2O, B: ACN; flow rate: 20ml / min; gradient: 57-80%; retention time: 8.82-10.57min of 16min) to obtain compounds 11-P1 (13.47mg) and 11-P2 (20.81mg).

[0764] 11-P1:

[0765] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 10mmol / L NH4HCO3 in H2O, B: ACN, Flow rate: 1.5mL / min, 5.0min), RT: 8.006min.

[0766] MS(ESI)M / Z:891.4[M+H] + .

[0767] 1H NMR(400MHz,DMSO-d6)δ8.47-8.41(m,2H),8.28(s,1H),7.93(s,1H),7.71(s,2H),7.23(s,1H),5.96-5.93(m,1H),5.31-5.29(m,1H),4.69-4.65(m,1H),4.46-4.29(m,3H),3.90-3.80(m,3H),3.59-3.47(m,2H),3.25-3.17(m,7H),3.15-3.12(m,3H),2.62-2.61(m,1H),2.46-2.44(m,5H),2.17-2.15(m,4H),1.56-1.53(m,1H),1.37-1.35(m,4H),1.23-1.13(m,4H),1.06-1.01(m,4H),0.75(s,3H),0.45(s,3H).

[0768] 11-P2:

[0769] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:10mmol / L NH4HCO3 in H2O,B:ACN,Flow rate:1.5mL / min,5.0min),RT:8.190min.

[0770] MS(ESI)M / Z:891.4[M+H] + .

[0771] 1 H NMR(400MHz,DMSO-d6)δ8.48(d,1H),8.42(d,1H),8.33(s,1H),7.94(s,1H),7.70(s,2H),7.33(d,1H),5.94(d,1H),5.30(t,1H),4.70(d,1H),4.46-4.38(m,2H),3.92(d,1H),3.64-3.61(m,2H),3.54-3.44(m,3H),3.29-3.13(m,7H),3.11(s,3H),2.64-2.61(m,1H),2.47-2.42(m,5H),2.22(s,3H),2.19-2.14(m,1H),1.63-1.59(m,1H),1.29-1.23(m,1H),1.18-1.04(m,11H),0.82(s,3H),0.49(s,3H).

[0772] The following compounds were prepared according to Examples 1-11:

[0773] Example 26: Preparation of Compound 26

[0774] Step A:

[0775] Compound 11d (24 g, 59.41 mmol) and compound 26a (17.98 g, 68.32 mmol, preparation method according to WO2021257736) were dissolved in water (120 mL) and toluene (500 mL), followed by the addition of potassium carbonate (20.53 g, 148.52 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (4.35 g, 5.94 mmol). The reaction mixture was reacted at 80 °C for 16 hours under an argon atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, diluted with water and ethyl acetate, extracted with ethyl acetate (200 mL x 3), the combined organic phases were washed with brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered to concentrate the organic phase, and purified by normal phase (ethyl acetate / petroleum ether, ethyl acetate ratio 50%) to obtain 26b (14.4 g).

[0776] LCMS(ESI)M / Z:413.0[M+H] + .

[0777] Step B:

[0778] Compound 26b (28.5 g, 68.97 mmol) and cesium carbonate (67.42 g, 206.91 mmol) were dissolved in N,N-dimethylformamide (280 mL), and tert-butyl(3-iodo-2,2-dimethylpropoxy)dimethylsilane (84.91 g, 206.91 mmol) were added. The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (200 mL x 3). The mixture was washed with saturated brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified in normal phase (ethyl acetate / petroleum ether, ethyl acetate ratio 25%) to give compound 26c (30 g).

[0779] LCMS(ESI)M / Z:613.2.[M+H] +

[0780] Step C:

[0781] Compound 26c (15 g, 24.24 mmol) and pinacol diboronate (9.31 g, 36.67 mmol) were dissolved in ultra-dry tetrahydrofuran (300 mL). 4,4'-di-tert-butyl-2,2'-bipyridine (984.36 mg, 3.67 mmol) and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (492.69 mg, 0.73 mmol) were added. The reaction mixture was heated to 75 °C for 16 h under argon protection. The reaction mixture was directly evaporated to dryness to obtain crude product 26d.

[0782] Step D:

[0783] Compound 26d (19 g, 25.69 mmol) was dissolved in acetonitrile (200 mL), and hydrogen peroxide (6.56 mL, 64.23 mmol, 30% purity) was added at 0 °C. The mixture was then heated to room temperature and reacted for 1 h. The reaction solution was quenched with a saturated sodium thiosulfate aqueous solution, the organic phase was concentrated, extracted with ethyl acetate (200 mL x 3), washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (n-hexane / ethyl acetate, ethyl acetate ratio 25%) to give compound 26e (11 g).

[0784] LCMS(ESI)M / Z:629.3[M+H]+.

[0785] Step E:

[0786] Compound 26e (22.5 g, 35.74 mmol) was dissolved in tetrahydrofuran (220 mL), and tetrabutylammonium fluoride (285.92 mmol, 285 mL, 1 M in THF) was added. The reaction mixture was heated to 50 °C and reacted for 3 h. After the reaction was complete, ethyl acetate (50 mL) was added to dilute the reaction mixture, and the organic phase was washed three times with water (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to normal-phase column chromatography: hexane / ethyl acetate, 68% ethyl acetate, gave 26f (9.6 g, low polarity); dichloromethane / methanol, 6% methanol, gave another configuration (2.6 g, high polarity).

[0787] 26f:

[0788] LCMS(ESI)M / Z:517.2[M+H] +

[0789] 1H NMR(400MHz,MeOD)δ8.32(d,1H),7.94(d,1H),7.56(d,1H),7.28(dd,2H),4.22(d,1H),3.76-3.66(m,1H),3.65 -3.54(m,2H),3.35(s,1H),3.23(d,1H),3.20-3.14(m,1H),3.12(d,1H),2.83(s,3H),1.45(d,3H),0.70(d,6H).

[0790] Step F:

[0791] 26g (12g) of compound can be prepared by referring to step L of Example 2.

[0792] LCMS(ESI)M / Z:721.7[M+H] + .

[0793] Step G:

[0794] 26 g (11 g, 15.26 mmol) of the compound was dissolved in a mixed solvent of tetrahydrofuran (350 mL) and water (150 mL), and lithium hydroxide monohydrate (3.76 g, 91.56 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The pH of the reaction solution was adjusted to 5 with 1 M dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 26 h (12 g).

[0795] LCMS(ESI)M / Z:707.4.[M+H] + .

[0796] Step H:

[0797] Compounds 26h (11 g, 15.56 mmol) and 1e (5.47 g, 20.23 mmol) were dissolved in N,N-dimethylformamide (220 mL), and N,N-diisopropylethylamine (14.08 g, 108.92 mmol) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (7.10 g, 18.67 mmol) were added, respectively. The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water, extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 26i (11.4 g).

[0798] MS(ESI)M / Z:845.4[M+H] +

[0799] Step I:

[0800] Compound 26i (11.4 g, 67.45 mmol) was dissolved in a mixed solution of tetrahydrofuran (340 mL) and water (170 mL). Lithium hydroxide monohydrate (2.77 g, 1.05 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction solution was adjusted to pH 5 with 1 M dilute hydrochloric acid, extracted with ethyl acetate (200 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and then subjected to silica gel column chromatography (dichloromethane / ethyl acetate, 60% ethyl acetate) to give compound 26j (9 g).

[0801] LCMS(ESI)M / Z:831.7.[M+H] + .

[0802] Step J:

[0803] 26kJ (8.5 g, 10.23 mmol) was dissolved in dichloromethane (260 mL) under an argon atmosphere. N-phenylbis(trifluoromethanesulfonyl)imide (5.85 g, 16.37 mmol) and N,N-diisopropylethylamine (13.2 g, 102.30 mmol) were added separately, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 50 mL of dichloromethane, and the organic phase was washed with 0.5 M hydrochloric acid, saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to normal-phase column chromatography (dichloromethane / ethyl acetate, 70% ethyl acetate) to give compound 26k (6.14 g).

[0804] LCMS(ESI)M / Z:963.1[M+H] +

[0805] Step K:

[0806] 26kJ (1.4 g, 1.45 mmol) was dissolved in acetonitrile (1000 mL), and N,N-diisopropylethylamine (3.75 g, 29 mmol), 4-dimethylaminopyridine (885.73 mg, 7.25 mmol), 1-hydroxybenzotriazole (3.92 g, 29 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (5.56 g, 29 mmol) were added sequentially. The mixture was stirred overnight at room temperature under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction solution was concentrated at low temperature, diluted with ethyl acetate, and the organic phase was washed with water, washed with saturated ammonium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate, 40% ethyl acetate) to give compound 26l.

[0807] LCMS(ESI)M / Z:945.1[M+H] +

[0808] Step L:

[0809] 26 μL (1.7 g, 1.80 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added under ice bath conditions. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, concentrated at low temperature, and the residue was diluted with ethyl acetate. The pH was adjusted to approximately 8 with sodium bicarbonate aqueous solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 26 μL.

[0810] LCMS(ESI)M / Z:845.1[M+H] + .

[0811] Step M:

[0812] 26m (1.5 g, 1.78 mmol) was dissolved in N,N-dimethylformamide (20 mL), and ethyl diisopropylamine (2.30 g, 17.8 mmol), (1R,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (0.41 g, 3.56 mmol), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (1.35 g, 3.56 mmol) were added separately. The mixture was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by normal-phase silica gel column chromatography (n-hexane / ethyl acetate = 2 / 3) to give compound 26n (1.6 g).

[0813] LCMS(ESI) M / Z: 941.6 [M+H] + .

[0814] Step N:

[0815] Compounds 26n (70 mg), 26o (25 mg), bis(triphenylphosphine)palladium(II) chloride (8 mg), and cuprous iodide (4 mg) were dissolved in acetonitrile (10 mL), followed by the addition of lithium chloride (12 mg) and ethyl diisopropylamine (0.05 mL). The reaction mixture was heated to 85 °C for 16 hours under nitrogen protection. LCMS showed the reaction was complete. The reaction was quenched with water, and the reaction solution was extracted three times with ethyl acetate. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to column chromatography (methanol / dichloromethane = 0% to 5%) to obtain the crude product. Compound 26 was prepared by prep-HPLC (Waters 3767 / Qda, Column: XBridge C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20ml / min; gradient: 60-60%; retention time: 7.3-8.2min of 16min).

[0816] HPLC (SunFire C18 5um 4.6x150mm 30C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, A40B60, Flow rate: 1.0mL / min, 16.0min), RT: 6.125min.

[0817] MS(ESI)M / Z: 964.7 [M+H] + .

[0818] 1 H NMR(400MHz,MeOD)δ8.80(s,1H),8.34(s,1H),7.86(s,1H),7.68(dd,3H),5.87(d,1H),4.60(d,2H),4.19-3.58(m,8H),3.41(d,4H) ,3.16(s,9H),2.90-2.60(m,2H),2.42(s,1H),2.25-2.17(m,1H),1.50(d,4H),1.38(d,3H),1.13(d,7H),0.86(s,3H),0.50(s,3H).

[0819] Example 27: Preparation of Compound 27

[0820] Step A:

[0821] Compounds 26n (40 mg), 27a (0.4 mg), bis(triphenylphosphine)palladium chloride (5 mg), and cuprous iodide (2 mg) were dissolved in acetonitrile (10 mL), and lithium chloride (5 mg) and ethyl diisopropylamine (22 mg) were added. The reaction solution was reacted at 85 °C for 16 h under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by prep-HPLC (Waters 3767 / Qda Column: Agilent Pursuit C18, 21.2*250 mm, 10 μm; Mobile Phase A: 0.05% TFA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 33-40%; retention time: 8.0-9.5 min of 16 min) to obtain compound 27.

[0822] HPLC (Sunfire C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, A80B20, Flow rate: 1.0ml / min, 15min), RT: 7.665min.

[0823] MS(ESI)M / Z: 916.8 [M+H] + .

[0824] 1 H NMR(400MHz,CD3OD)δ8.80(s,1H),8.33(s,1H),7.85(s,1H),7.68(m,3H),5.48(s,1H),4.59(d,3H),3.70(m,11H ),3.41(m,6H),2.60(m,8H),2.26-2.13(m,1H),1.50(s,3H),1.38(d,2H),1.12(m,7H),0.85(s,3H),0.50(s,3H).

[0825] Example 28: Preparation of Compound 28

[0826] Step A:

[0827] Compounds 26n (30 mg), 28a (12 mg), bis(triphenylphosphine)palladium chloride (3 mg), and cuprous iodide (2 mg) were dissolved in acetonitrile (10 mL), and lithium chloride (5 mg) and ethyl diisopropylamine (22 mg) were added. The reaction solution was reacted at 85 °C for 16 h under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by prep-HPLC (Waters 3767 / Qda, Column: XBridge C18, 19*250 mm, 10 μm; Mobile Phase A: 10 mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 58-58%; retention time: 7.1-8.1 min of 16 min) to obtain compound 28.

[0828] Waters Sunfire C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, A80B20, Flow rate: 1.0mL / min, 16.0min), RT: 8.044min.

[0829] MS(ESI)M / Z:970.0[M+H] + .

[0830] 1 H NMR(400MHz,MeOD)δ8.81(s,1H),8.33(s,1H),7.84(s,1H),7.68(dd,3H),5. 72(d,1H),4.57(d,3H),3.83(s,3H),3.67(s,3H),3.58(s,3H),3.51-3.32(m, 4H),3.03(d,2H),2.66(t,3H),2.43(s,2H),2.22(t,1H),1.99(d,2H),1.65(t ,3H),1.50(d,3H),1.45-1.20(m,3H),1.12(d,8H),0.77(d,3H),0.48(s,3H).

[0831] Example 29: Preparation of compound 29

[0832] Step A:

[0833] Compounds 26n (42 mg), 29a (18 mg), bis(triphenylphosphine)palladium chloride (5 mg), and cuprous iodide (2 mg) were dissolved in acetonitrile (10 mL), and lithium chloride (7 mg) and ethyl diisopropylamine (22 mg) were added. The reaction solution was reacted at 75 °C for 16 h under nitrogen protection. LCMS showed that the reaction was complete. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by prep-HPLC (Waters 3767 / Qda, Column: XBridge C18, 19*250 mm, 10 μm; Mobile Phase A: 10 mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20 mL / min; gradient: 58-58%; retention time: 7.1-8.1 min of 16 min) to obtain compound 29.

[0834] HPLC (SunFire C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, A80B20, Flow rate: 1.0ml / min, 15min), RT: 9.574min.

[0835] MS(ESI)M / Z:929.1[M+H] + .

[0836] 1 H NMR(400MHz,CD3OD-d4)δ8.80(s,1H),8.34(s,1H),7.85(brs,1H),7.71-7.68(m,3H),5.90(brs,1H),5.43(brs,1H),4.68-4.60(m,3H),3.88-3.60( m,8H),3.47-3.39(m,2H),2.74-2.44(m,11H),2.30(s,3H),2.27-2.19(m, 1H),1.51-1.29(m,7H),1.18-1.05(m,8H),0.88(brs,3H),0.54(brs,3H).

[0837] Example 30: Preparation of compound 30

[0838] Compound 30 can be prepared according to Example 29.

[0839] HPLC (SunFire C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, A80B20, Flow rate: 1.0ml / min, 15min), RT: 9.643min.

[0840] MS(ESI)M / Z:930.1[M+H] + .

[0841] 1 H NMR(400MHz,CD3OD-d4)δ8.79(s,1H),8.33(s,1H),7.85(brs,1H),7.71-7.64(m, 3H),4.69-4.48(m,3H),3.87-3.75(m,6H),3.71(s,3H),3.42-3.32(m,4H),3.30-3 .29(m,1H),2.91-2.88(m,5H),2.74-2.52(brs,1H),2.44-2.36(m,2H),2.24-2.1 8(m,1H),2.00-1.93(m,2H),1.50-1.28(m,7H),1.15-1.11(m,8H),0.88(brs,7H).

[0842] The following compounds were prepared according to Examples 1-30:

[0843] Example 36: Preparation of compounds 36A and 36B

[0844] Step A:

[0845] At 0°C, trifluoroacetic anhydride (73.60 g, 350.42 mmol) was added in portions to a solution of 36a (50 g, 233.61 mmol) in N,N-dimethylformamide (375 mL). The resulting mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with 1.2 L of ethyl acetate, and the mixture was slowly poured into a saturated sodium bicarbonate solution while stirring continuously until no more bubbles were generated. The organic phase was separated, dried, and concentrated. The crude product was purified by a normal column chromatography (hexane / ethyl acetate = 5 / 1), followed by slurrying with a hexane / ethyl acetate ratio of 1 / 20 to obtain compound 36b (52 g).

[0846] 1H NMR (400MHz, DMSO-d6) δ12.99-12.63(m,1H),8.70-8.37(m,1H),8.06-7.76(m,2H).

[0847] Step B:

[0848] Compound 36b (52 g, 167.72 mmol) was dissolved in tetrahydrofuran (350 mL) at 0 °C. Sodium borohydride (19.03 g, 503.16 mmol) was added in portions, followed by the slow dropwise addition of boron trifluoride diethyl ether (47.61 g, 335.44 mmol), releasing a large amount of gas. The temperature was controlled below 5 °C throughout the addition process. After the addition was complete, the mixture was left at room temperature for 1 hour, and then heated to 45 °C overnight. After the reaction was complete, the mixture was slowly poured into an ice-water solution of sodium bicarbonate and stirred for 20 minutes until no more bubbles were generated. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (n-hexane / ethyl acetate = 9 / 1) to obtain the crude product. The crude product was then slurried with n-hexane to obtain compound 36c (38 g).

[0849] 1 H NMR (400MHz, DMSO-d6) δ11.48-11.16(m,1H),7.72-7.62(m,1H),7.60-7.53(m,1H),7.51-7.41(m,1H),3.91-3.47(m,2H).

[0850] Step C:

[0851] Compound 36c (19 g, 64.18 mmol) was dissolved in tetrahydrofuran (200 mL), and iodine (16.29 g, 64.18 mmol) was added in portions at 0 °C. Silver trifluoromethanesulfonate (18.14 g, 70.60 mmol) was added, and the reaction was carried out at 0 °C for 40 minutes. The reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was washed with sodium sulfite solution. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 93 / 7) to give compound 36d (22 g).

[0852] 1 H NMR (400MHz, CDCl3) δ8.31-8.17(m,1H),7.50(d,1H),7.29(d,1H),3.44(q,2H).

[0853] Step D:

[0854] Compounds 36d (20.7 g, 49.06 mmol) and 26a (17.98 g, 68.32 mmol) were dissolved in water (80 mL) and toluene (320 mL), followed by the addition of potassium carbonate (20.34 g, 147.18 mmol) and Pd(dppf)Cl2 (3.59 g, 4.91 mmol). The reaction mixture was reacted at 80 °C for 16 h under an argon atmosphere. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, the residue was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give compound 36e (14 g).

[0855] LCMS(ESI)M / Z:431.0[M+H] + .

[0856] Step E:

[0857] Compound 36e (14 g, 32.47 mmol) was dissolved in N,N-dimethylformamide (140 mL), followed by the sequential addition of tert-butyl(3-iodo-2,2-dimethylpropoxy)dimethylsilane (31.98 g, 97.41 mmol), sodium iodide (14.60 g, 97.41 mmol), and cesium carbonate (31.74 g, 97.41 mmol). The mixture was reacted at 100 °C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, washed with water, and the organic phase was washed with saturated brine. The organic phase was dried and concentrated, and the crude product was purified by normal-phase column chromatography to obtain compound 36f (8 g).

[0858] LCMS(ESI)M / Z:631.1[M+H] + .

[0859] Step F:

[0860] Compound 36f (1.8 g, 4.01 mmol) and pinacol diborate (3.02 g, 11.88 mmol) were dissolved in ultra-dry tetrahydrofuran (100 mL). 4,4'-di-tert-butyl-2,2'-bipyridine (0.32 g, 1.19 mmol) and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (265.99 mg, 0.40 mmol) were added. The reaction mixture was heated to 75 °C for 16 hours under an argon atmosphere. The reaction mixture was filtered and evaporated to dryness to obtain crude compound 36 g, which was used directly in the next step.

[0861] LCMS(ESI)M / Z:759.1[M+H] + .

[0862] Step G:

[0863] 36 g (5 g, 6.60 mmol) of compound was dissolved in acetonitrile (50 mL), and hydrogen peroxide (1.87 g, 16.5 mmol) was added under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated sodium thiosulfate aqueous solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give compound 36h (4.2 g).

[0864] LCMS(ESI)M / Z:647.3.[M+H] + .

[0865] Step H:

[0866] Compound 36h (4.2 g, 5.32 mmol) was dissolved in tetrahydrofuran (50 mL), and tetrabutylammonium fluoride (50 mL, 1 M in THF) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was complete, ethyl acetate was added for dilution, and the organic phase was washed with water. The organic phase was dried over saturated brine and anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal-phase column chromatography (n-hexane / ethyl acetate = 20 / 80) to give compound 36i-A (1.6 g, low polar fraction); and purified by (n-hexane / ethyl acetate = 0 / 100) to give compound 36i-B (1.14 g, high polar fraction).

[0867] 36i-A:LCMS(ESI)M / Z:533.2[M+H] + .

[0868] 36i-B:LCMS(ESI)M / Z:533.3[M+H] + .

[0869] Compounds 36A and 36B can be prepared using 36i-A and 36i-B as raw materials, respectively, according to Example 26.

[0870] 36A:

[0871] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0ml / min, 1.0mL / min, 0-13min: A60B40, 13-16.0min: A5B95), RT: 6.681min.

[0872] MS(ESI)M / Z:934.5.

[0873] 1H NMR(400MHz,CD3OD-d4)δ8.82-8.80(m,1H),8.46(s,1H),7.93-7.70(m,2H),7.47-7.42(m, 1H),6.25-5.47(m,1H),4.84-4.46(m,3H),3.92-3.72(m,8H),3.64-3.54(m,3H),3.47-3.3 1(m,4H),3.29-3.16(m,2H),2.68-2.65(m,5H),2.49-2.37(m,2H),2.25-2.16(m,1H),1.51 -1.47(m,3H),1.38-1.28(m,2H),1.12-1.04(m,8H),0.87-0.67(m,3H),0.64-0.45(m,3H).

[0874] 36B:

[0875] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0ml / min, 0-13min: A60B40, 13-16.0min: A5B95), RT: 6.619min.

[0876] MS(ESI)M / Z:934.4.

[0877] 1 H NMR(400MHz,CD3OD-d4)δ8.84-8.79(m,1H),8.52-8.44(m,1H),8.00-7.93(m,1H),7.82-7.77(m,1H),7.49 -7.41(m,1H),5.99-5.92(m,1H),5.50-5.41(m,1H),4.74-4.55(m,3H),3.89-3.77(m,2H),3.78-3.64(m,6H ),3.63-3.50(m,3H),3.50-3.32(m,3H),3.29-3.20(m,2H),2.78-2.57(m,6H),2.51-2.42(m,1H),2.28-2. 19(m,1H),1.71-1.61(m,1H),1.52-1.33(m,2H),1.22-1.10(m,10H),0.89-0.81(m,3H),0.59-0.50(m,3H).

[0878] Example 37: Preparation of compound 37

[0879] Step A:

[0880] At 0 °C, under an argon atmosphere, a solution of sodium tert-butoxide (27.75 g, 288.78 mmol) in tetrahydrofuran (250 mL) was successively added to a solution of compound 37a (52 g, 240.65 mmol) and a solution of deuterated iodomethane (41.86 g, 288.78 mmol) in tetrahydrofuran (250 mL). The reaction was carried out in an ice-water bath for 16 hours. After the reaction was completed, the solution was quenched with 7.5% w / w ammonia solution (200 mL), the reaction mixture was extracted with methyl tert-butyl ether, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (n-hexane / 16% ethyl acetate) to give compound 37b (52 g).

[0881] LCMS(ESI)M / Z:221.0[M+H] +

[0882] Step B:

[0883] Compound 37b (53 g, 241.91 mmol), pinacol diboronate (67.57 g, 266.10 mmol), potassium acetate (47.48 g, 483.82 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (8.85 g, 12.10 mmol) were dissolved in 1,4-dioxane (530 mL). The reaction mixture was heated to 110°C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 37c, which was used directly in the next step.

[0884] LCMS(ESI) M / Z: 267.0 [M+H] +

[0885] Step C:

[0886] Compound 11d (30 g, 74.26 mmol) and compound 37c (37.65 g, 89.11 mmol) were dissolved in a mixed solution of water (125 mL) and toluene (500 mL). Potassium carbonate (25.66 g, 185.65 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (1.63 g, 2.23 mmol) were added. The reaction solution was heated to 80°C under an argon atmosphere and reacted for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The organic phase of the filtrate was concentrated and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The residue was purified by silica gel column chromatography to obtain compound 37d (21 g).

[0887] LCMS(ESI) M / Z: 416.0 [M+H] +

[0888] Step D:

[0889] Compound 37d (25 g, 60.06 mmol) was dissolved in N,N-dimethylformamide (250 mL), and cesium carbonate (58.71 g, 180.18 mmol) and tert-butyl(3-iodo-2,2-dimethylpropoxy)dimethylsilane (73.94 g, 180.18 mmol) were added. The reaction mixture was heated to 100 °C and reacted for 16 hours. After the reaction was completed, the solution was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain compound 37e (25 g).

[0890] LCMS(ESI)M / Z:618.1[M+H] + .

[0891] Step E:

[0892] Compound 37e (7.5 g, 12.16 mmol) and pinacol diborate (4.63 g, 18.24 mmol) were dissolved in tetrahydrofuran (140 mL). 4,4'-di-tert-butyl-2,2'-bipyridine (0.49 g, 1.82 mmol) and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (0.41 g, 0.61 mmol) were added. The reaction mixture was heated to 80°C under argon protection and reacted for 16 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain crude product 37f.

[0893] LCMS(ESI)M / Z:744.3[M+H] +

[0894] Step F:

[0895] Compound 37f (12.5 g, 16.83 mmol) was dissolved in acetonitrile (125 mL), and hydrogen peroxide (4.77 g, 42.07 mmol, Purity 30%) was added at 0°C. The reaction was then allowed to return to room temperature for 1 hour. The reaction solution was quenched with a saturated sodium thiosulfate aqueous solution, most of the organic solvent was concentrated, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (n-hexane / 25% ethyl acetate) to give compound 37 g (20 g).

[0896] LCMS(ESI) M / Z: 633.9 [M+H] +

[0897] Step G:

[0898] 37 g (7.5 g, 11.86 mmol) of the compound was dissolved in tetrabutylammonium fluoride (75 mL, 1 M in THF) in tetrahydrofuran solution. The mixture was heated to 40°C and reacted for 3 hours. The reaction solution was diluted with ethyl acetate, and the organic phase was washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / 68% ethyl acetate) to give a small polar fraction 37 h (2.3 g); and purified by silica gel column chromatography (dichloromethane / 6% methanol) to give another highly polar fraction (800 mg).

[0899] Small polar component 37h:

[0900] LCMS(ESI)M / Z:519.9.[M+H] + .

[0901] 1 H NMR(400MHz,MeOD)δ8.31(d,1H),7.94(d,1H),7.56(d,1H),7.27(dd,2H),4.22(d,1H) ,3.74-3.67(m,1H),3.60(s,2H),3.23(d,1H),3.12(d,2H),1.44(d,3H),0.70(d,6H).

[0902] Highly polar components:

[0903] LCMS(ESI)M / Z:519.9.[M+H] + .

[0904] 1 H NMR(400MHz,MeOD)δ8.29(d,1H),7.97(d,1H),7.54(d,1H),7.31-7.23(m,2H),4.30(d,1H),3.83( d,1H),3.72(d,1H),3.60-3.45(m,1H),3.24(d,1H),3.21-3.06(m,2H),1.13(d,3H),0.69(s,6H).

[0905] Compound 37 can be prepared using 37h as the raw material, referring to Example 26.

[0906] MS(ESI)M / Z:919.7[M+H] + .

[0907] 1H NMR(400MHz,MeOD-d4)δ8.95-8.68(m,1H),8.34(s,1H),7.90(s,1H),7.85-7.7 8(m,3H),5.80(d,1H),4.60(d,2H),4.06-3.65(m,6H),3.61(d,3H),3.49-3.33 (m,2H),3.30-3.12(m,5H),2.86-2.57(m,5H),2.43(s,2H),2.25-2.12(m,1H), 1.48(t,3H),1.35(dd,2H),1.20-1.00(m,7H),0.93-0.65(m,3H),0.56(d,3H).

[0908] Example 38: Preparation of compounds 38-P1 and 38-P2

[0909] Step A:

[0910] Compound 38a (2.8 g, 8.13 mmol) was dissolved in tetrahydrofuran (20 mL). Bis(trimethylsilyl)aminolithium (11.0 g, 66.0 mmol) was slowly added dropwise at -78 °C with stirring for 1.5 hours. Iodomethane (2.88 g, 20.3 mmol) was then added, and stirring continued for 1 hour. The temperature was slowly raised to 0 °C with stirring for 1 hour, and then stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain compound 38b (1.7 g).

[0911] LCMS(ESI)M / Z:159.0[M-200+H] + .

[0912] Step B:

[0913] Compound 38b (1.0 g, 2.79 mmol) was dissolved in 15 mL of dichloromethane solution, and 12 mL of trifluoroacetic acid was added at room temperature with stirring for 3 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane and concentrated directly to dryness to obtain crude product 38c.

[0914] LCMS(ESI) M / Z: 159.1 [M+H] + .

[0915] Compounds 38-P1 and 38-P2 can be prepared using 38c as a raw material, referring to Example 26.

[0916] 38-P1:

[0917] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.1% NH4HCO3 in H2O,B:0.1% NH4HCO3 in ACN,Flow rate:1.0mL / min,0-13min:A90B10,13-16min:A5B95),RT:10.579min.

[0918] MS(ESI)M / Z:972.0[M+H] + .

[0919] 1 H NMR(400MHz,MeOD)δ8.84(s,1H),8.38(s,1H),7.94(s,1H),7.69(s,2H),7.62(s,1H),6.23(s,1H),5.03(s,1H),4.57(s,1H),4.41(d,2H),3.95(s,2H),3.68(d,3H),3.58(d,2H),3.04(d,3H),2.84(s,3H),2.67(t,3H),2.00(d,4H),1.83-1.72(m,5H),1.70-1.61(m,3H),1.49(d,3H),1.40-1.30(m,3H),1.08(d,3H),1.04-1.00(m,4H),0.82(s,3H),0.61(s,3H).

[0920] 38-P2:

[0921] HPLC(Waters XBridge C18 5μm,4.6*150mm Column,25C,Mobile phase:A:0.1% NH4HCO3 in H2O,B:0.1% NH4HCO3 in ACN,Flow rate:1.0mL / min,0-13min:A90B10,13-16min:A5B95),RT:10.902min.

[0922] MS(ESI)M / Z:972.0[M+H] + .

[0923] 1H NMR(400MHz,MeOD-d4)δ8.80(s,1H),8.48(s,1H),7.93(d,1H),7.65(d,3H),6 .01(s,1H),4.47(d,2H),4.24(s,2H),3.68(d,3H),3.58(s,3H),3.47(d,2H), 3.25-3.12(m,2H),3.03(d,3H),2.94-2.81(m,1H),2.67(t,3H),2.00(d,4H), 1.82(s,4H),1.65(t,3H),1.51(d,3H),1.27(s,2H),1.07(s,7H),0.64(s,7H).

[0924] Example 39: Preparation of compound 39

[0925] Step A:

[0926] Compound 26n (120 mg, 0.13 mmol), 1-(prop-2-yn-1-yl)piperidin-4-onitrile (38.53 mg, 0.26 mmol) were dissolved in acetonitrile (5 mL), followed by the addition of bis(triphenylphosphine)palladium dichloride (13.69 mg, 0.019 mmol), cuprous iodide (5.69 mg, 0.030 mmol), lithium chloride (22.04 mg, 0.52 mmol), and ethyl diisopropylamine (0.086 mL, 0.52 mmol). The reaction mixture was heated to 85 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, water was added to quench the reaction. The reaction solution was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain the crude product. Subsequently, compound 39 (41.53 mg) was prepared by prep-HPLC (Waters 3767 / Qda, Column: XBridge C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20ml / min; gradient: 60-65%; Retention Time: 9.3-10.2min of 16min).

[0927] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0mL / min, 0-13min: A70B30, 13-16min: A5B95) RT: 8.285min.

[0928] MS(ESI)M / Z: 939.8 [M+H] + .

[0929] 1 H NMR(400MHz,MeOD)δ8.80(s,1H),8.33(s,1H),7.84(s,1H),7.68(dd,3H),5.88 (d,1H),4.62(s,3H),3.72(s,4H),3.62(s,3H),3.44(dd,2H),3.30(d,4H),2.85 (s,4H),2.60(s,3H),2.42(s,2H),2.25-2.18(m,1H),2.01(dd,2H),1.91-1.82 (m,2H),1.50(d,3H),1.44-1.34(m,2H),1.12(d,7H),0.77(d,3H),0.48(s,3H).

[0930] Example 40: Preparation of Compound 40

[0931] Step A:

[0932] Compound 40 can be prepared according to Example 39.

[0933] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0mL / min, 0-13min: A70B30, 13-16min: A5B95), RT: 8.131min.

[0934] MS(ESI)M / Z:940.9.

[0935] 1H NMR(400MHz,CD3OD-d4)δ8.86(s,1H),8.33(s,1H),8.01-7.90(m,1H),7.71-7.63(m,3H ),6.31-5.43(m,1H),4.70-4.54(m,3H),4.12(s,2H),3.93-3.66(m,5H),3.51-3.49(m,5 H),3.42-3.36(m,2H),3.24-3.23(m,5H),2.91-2.39(m,5H),2.24-2.19(m,1H),1.51-1 .49(m,3H),1.43-1.33(m,2H),1.15-1.11(m,8H),0.89-0.78(m,3H),0.52-0.43(m,3H).

[0936] Example 41: Preparation of compound 41

[0937] Step A:

[0938] Compound 26n (100 mg, 0.11 mmol) and compound 41a (30 mg, 0.22 mmol) were dissolved in acetonitrile (10 mL), and palladium dichloride bis(triphenylphosphine) (15 mg, 0.022 mmol), cuprous iodide (6.3 mg, 0.033 mmol), N,N-diisopropylethylamine (57 mg, 0.44 mmol) and lithium chloride (19 mg, 0.44 mmol) were added. The reaction solution was heated to 85 degrees Celsius under a nitrogen atmosphere for 3 hours. After the reaction was completed, ethyl acetate was added for dilution, and the organic phase was washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the crude product. The crude product was then prepared by reversed-phase prep-HPLC (waters 3767 / Qda, Column: Pursuit C18, 21.2*250mm, 10um; Mobile Phase A: 10.05% NH4HCO3 / H2O, B: ACN; flow rate: 20ml / min; gradient: 42-52%; Retention Time: 7.3 of 16min) to obtain compound 41 (33.58mg).

[0939] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0mL / min, 0-13min: A90B10, 13-16.0min: A5B95) RT: 10.452min.

[0940] MS(ESI)M / Z: 928.7 [M+H] + .

[0941] 1 H NMR(400MHz,CD3OD-d4)δ8.79(s,1H),8.33(s,1H),7.89-7.82(m,1H),7.71-7.64(m,3H),6.2 9-5.39(m,1H),4.61-4.45(m,4H),4.02-4.00(m,2H),3.78-3.65(m,8H),3.47-3.30(m,4H),2. 93-2.76(m,4H),2.46-2.34(m,3H),2.23-2.19(m,1H),1.98-1.96(m,1H),1.78-1.74(m,1H),1 .50-1.40(m,3H),1.38-1.36(m,2H),1.28-1.11(m,8H),0.86-0.76(m,3H),0.75-0.48(m,3H).

[0942] Example 42: Preparation of compound 42

[0943] Step A:

[0944] Compound 26n (120 mg, 0.13 mmol) and compound 42a (38.53 mg, 0.26 mmol) were dissolved in acetonitrile (5 mL), followed by the addition of bis(triphenylphosphine)phosphine dichloride palladium chloride (13.69 mg, 0.019 mmol), cuprous iodide (5.69 mg, 0.030 mmol), lithium chloride (22.04 mg, 0.52 mmol), and N,N-ethyldiisopropylamine (0.086 mL, 0.52 mmol). The reaction mixture was heated to 85 °C for 3 hours under nitrogen protection. After the reaction was completed, water was added to quench the reaction, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain the crude product. Subsequently, prep-HPLC (Waters 3767 / Qda, Column: XBridge C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20ml / min; gradient: 60-60%; retention time: 7.2-8.1min of 16min) was performed to obtain compound 42 (40.97mg).

[0945] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0mL / min, 16.0min) RT: 8.285min.

[0946] MS(ESI)M / Z: 928.9 [M+H] + .

[0947] 1 H NMR(400MHz,MeOD-d4)δ8.80(s,1H),8.34(s,1H),7.85(s,1H),7.69(t,3H),5. 49(s,1H),4.62(s,2H),4.45(s,2H),4.02(d,2H),3.78(s,3H),3.76-3.59(m,5H ),3.43(d,6H),2.92(d,2H),2.78(d,2H),2.42(s,2H),2.21(t,1H),1.97(d,1H) ,1.77(d,1H),1.49(s,3H),1.38(d,2H),1.12(d,7H),0.84(s,3H),0.48(s,3H).

[0948] Example 43: Preparation of compounds 43A and 43B

[0949] Step A:

[0950] Compound 43a (16.2 g, 73.2 mmol, preparation method according to WO201824602) was dissolved in DMF (250 mL), and N-bromosuccinimide (12.5 g, 70.3 mmol) was added under ice bath cooling. The reaction solution was stirred under ice-water bath for 1 hour. After the reaction was completed, the solution was diluted with ethyl acetate, the organic phase was washed three times with water, and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 43b.

[0951] LCMS(ESI)M / Z:343.0[M+H+ACN] + .

[0952] Step B:

[0953] Compound 43b (5.00 g, 16.7 mmol) was dissolved in a mixed solution of toluene (75 mL) and water (15 mL). Compound 26a (8.77 g, 33.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (1.22 g, 1.67 mmol), and potassium carbonate (6.91 g, 50.0 mmol) were added. The reaction mixture was heated to 100 °C for 16 hours under argon protection. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 43c (5 g).

[0954] LCMS(ESI)M / Z:357.2[M+H] + .

[0955] Step C:

[0956] Compound 43c (5.00 g, 14.0 mmol) was dissolved in DMF (50 mL), and cesium carbonate (1.76 g, 5.4 mmol) and tert-butyl(3-iodo-2,2-dimethylpropoxy)dimethylsilane (17.3 g, 42.1 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 48 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, the organic phase was washed three times with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 43d (3.2 g).

[0957] LCMS(ESI)M / Z:557.6[M+H] + .

[0958] Step D:

[0959] Compound 43d (3.2 g, 5.75 mmol) was dissolved in ethanol (40 mL), and a solution of lithium hydroxide (1.38 g, 57.5 mmol) in water (20 mL) was added. The reaction mixture was heated to 100 °C and reacted for 20 hours. After the reaction was completed, the pH was adjusted to 4 with 1 M hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 43e (2.1 g).

[0960] LCMS(ESI)M / Z:415.1[M+H] + .

[0961] Step E:

[0962] Compound 43e (3.50 g, 8.45 mmol) was dissolved in DMSO (35 mL), and lithium chloride (3.58 g, 84.5 mmol) was added. The reaction solution was heated to 180 °C and reacted for 2 hours. After the reaction was completed, ethyl acetate was added for dilution, the organic phase was washed three times with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 43f (2.4 g).

[0963] LCMS(ESI)M / Z:371.3[M+H] + .

[0964] Step F:

[0965] Compound 43f (3.00 g, 8.10 mmol) was dissolved in DMF (60 mL), and N-bromosuccinimide (1.25 g, 6.88 mmol) was added under ice bath conditions. The reaction mixture was reacted at 0 °C for 10 min under an argon atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate, washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to give compound 43 g (3 g).

[0966] LCMS(ESI)M / Z:449.3[M+H] + .

[0967] Step G:

[0968] 43 g (3.00 g, 6.68 mmol) of compound and pinacol diborate (3.39 g, 13.4 mmol) were dissolved in tetrahydrofuran (60 mL). 4,4'-di-tert-butyl-2,2'-bipyridine (0.36 g, 1.34 mmol) and bis(1,5-cyclooctadiene)iridium(I) chloride dimer (179 mg, 0.27 mmol) were added. The reaction mixture was heated to 80 °C for 16 hours under argon protection. After the reaction was complete, the solution was directly concentrated to obtain the crude product (43 h).

[0969] LCMS(ESI)M / Z:493.2[M+H] + .

[0970] Step H:

[0971] Compound 43h (3.29 g, 6.67 mmol) was dissolved in acetonitrile (15 mL), and hydrogen peroxide (2.27 g, 20.0 mmol, 30%) was added under ice bath conditions. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with saturated sodium sulfite solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 43i (4.3 g, 70% purity, 97% yield) as a yellow solid.

[0972] LCMS(ESI)M / Z:465.2[M+H] + .

[0973] Step I:

[0974] Compound 43i (4.3 g, 6.47 mmol, 70%) was dissolved in DCM (120 mL), and N,N-diisopropylethylamine (8.36 g, 64.7 mmol) was added. Finally, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl)methanesulfonamide (3.70 g, 10.35 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the organic phase was washed with 0.3 M hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the small polar isomer 43j-A (1.5 g); elution with (petroleum ether / ethyl acetate = 2 / 1) gave the large polar isomer 43j-B (1.5 g).

[0975] LCMS(ESI)M / Z:598.7[M+H] + .

[0976] Step J:

[0977] Compound 43j-A (380 mg, 0.64 mmol) and compound 26o (222 mg, 1.28 mmol) were dissolved in acetonitrile (16 mL). Palladium dichloride (67.4 mg, 0.096 mmol), cuprous iodide (28.0 mg, 0.15 mmol), lithium chloride (136 mg, 3.2 mmol), and N,N-diisopropylethylamine (413 mg, 3.2 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 1 hour under argon protection. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to give compound 43k (400 mg).

[0978] LCMS(ESI)M / Z:621.8[M+H] + .

[0979] Step K:

[0980] Compound 43k (400 mg, 0.64 mmol), compound 43l (423 mg, 0.77 mmol, preparation method referred to WO2025045233), tripotassium phosphate (407 mg, 1.92 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (41.7 mg, 0.064 mmol) were dissolved in a mixed solution of toluene (10 mL) and water (2 mL). The reaction solution was heated to 85 °C and stirred for 2 hours under argon protection. After the reaction was completed, the solution was diluted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 25 / 1) to obtain compound 43m (350 mg).

[0981] LCMS(ESI) M / Z: 964.0 [M+H] + .

[0982] Step L:

[0983] Compound 43m (600 mg, 0.62 mmol) was dissolved in tetrahydrofuran (21 mL), and a solution of lithium hydroxide (37.1 mg, 1.55 mmol) in water (10.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the solution was diluted with water, the pH was adjusted to 5 with 0.5 M dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 43n.

[0984] LCMS(ESI)M / Z:950.0[M+H] + .

[0985] Step M:

[0986] Compound 43n (600 mg, 0.63 mmol) was dissolved in acetonitrile (600 mL), and N,N-diisopropylethylamine (1.63 g, 12.6 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.42 g, 12.6 mmol), 1-hydroxybenzotriazole (1.70 g, 12.6 mmol), and 4-dimethylaminopyridine (385 mg, 3.15 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours under argon protection. The reaction mixture was concentrated to dryness at room temperature, and the crude product was dissolved in ethyl acetate. The organic phase was washed with saturated ammonium chloride aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 25 / 1) to give compound 43o (360 mg).

[0987] LCMS(ESI)M / Z:932.0[M+H] + .

[0988] Step N:

[0989] Compound 43o (120 mg, 0.13 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added under ice bath cooling. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was diluted with dichloromethane, concentrated at low temperature, and the crude product was dissolved in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate aqueous solution, followed by washing with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 43p.

[0990] LCMS(ESI)M / Z:832.3[M+H] + .

[0991] Step O:

[0992] Compound 43p (107 mg, 0.13 mmol), (1S,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (29.7 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (168 mg, 1.3 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (98.9 mg, 0.26 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC (Waters 3767 Column: SunFire Prep C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 in H2O, B: ACN; flow rate: 20ml / min; gradient: 57-80%; retention time: 8.82-10.57min of 16min) to obtain compound 43A (58mg).

[0993] 43A:

[0994] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1mL / min, 0-13min: A50B50, 13-16.0min: A5B95), RT: 8.204min.

[0995] MS(ESI)M / Z: 928.7 [M+H] + .

[0996] 1H NMR(400MHz,CD3OD-d4)δ8.73(s,1H),7.81-7.48(m,2H),7.19(s,1H),6.98(d,1H),6.71 (s,1H),6.20-5.60(m,1H),4.36-4.34(m,2H),3.99-3.98(m,2H),3.78(s,2H),3.63-3.3 6(m,3H),3.33(s,3H),3.18-3.15(m,10H),3.00-2.85(m,2H),2.69-2.67(m,1H),2.11-1 .88(m,2H),1.75-1.70(m,4H),1.54-1.50(m,2H),1.20-1.09(m,8H),0.75-0.47(m,6H).

[0997] Compound 43B can be prepared using the highly polar isomer 43j-B, referring to Example 43A.

[0998] 43B:

[0999] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1mL / min, 0-13min: A50B50, 13-16.0min: A5B95), RT: 7.687min.

[1000] MS(ESI)M / Z: 928.7 [M+H] + .

[1001] 1H NMR(400MHz,MeOD)δ8.73(d,1H),7.79(d,1H),7.48(d,1H),7.20(s,1H),6.99(d,1H),6.76(s,1H),5 .56(d,1H),4.38(t,2H),3.97(dd,2H),3.81(d,1H),3.78(s,2H),3.66(d,1H),3.56-3.47(m,1H),3.3 7(s,3H),3.34(d,1H),3.25(d,1H),3.15(d,9H),3.08-2.99(m,1H),2.73(dd,1H),2.13(d,1H),1.90 (d,1H),1.75(d,1H),1.53(dt,1H),1.43-1.31(m,2H),1.20-1.09(m,10H),0.77(s,3H),0.50(s,3H).

[1002] Example 44: Preparation of compound 44

[1003] Synthesis of intermediate 44b

[1004] Step 1:

[1005] Compound 2l (74.0 g, 202 mmol) and ethynyltrimethylsilane (59.7 g, 608 mmol) were dissolved in a mixed solution of N,N-dimethylformamide (1480 mL) and triethylamine (280 mL, 2.03 mol). Cuprous iodide (3.86 g, 20.3 mmol) and triphenylphosphine palladium dichloride (14.2 g, 20.3 mmol) were added. The reaction mixture was heated to 70°C for 1.5 hours under argon protection. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 44b-1 (69 g).

[1006] MS(ESI)M / Z:383.1[M+H] + .

[1007] Step 2:

[1008] Compound 44b-1 (61.3 g, 160 mmol) was dissolved in methanol (613 mL), and potassium fluoride (18.6 g, 320 mmol) was added. The reaction was carried out at room temperature for 0.5 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 70:30) to give compound 44b-2 (39.7 g).

[1009] MS(ESI)M / Z:311.1[M+H] + .

[1010] Step 3:

[1011] Cuprous chloride (1.32 g, 13.3 mmol), sodium tert-butoxide (2.55 g, 26.6 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (6.99 g, 12.1 mmol) were dissolved in tetrahydrofuran (234 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for half an hour. A tetrahydrofuran solution of pinacol diborate (49.1 g, 193 mmol) (234 mL) was added, and the mixture was stirred for ten minutes. Then, a methanol solution of compound 44b-2 (37.5 g, 121 mmol) (6.8 mL) was added, and the reaction was continued for 2 hours. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 60:40) to give compound 44b (52.1 g).

[1012] MS(ESI)M / Z:439.3[M+H] + .

[1013] Synthesis of Compound 44

[1014] Step A:

[1015] Compound 43j-A (32 g, 53.6 mmol) and 4-(prop-2-yn-1-yl)morpholine (13.4 g, 107 mmol) were dissolved in acetonitrile (20 mL). Palladium dichloride (5.64 g, 8.04 mmol), cuprous iodide (2.35 g, 12.3 mmol), lithium chloride (11.4 g, 268 mmol), and N,N-diisopropylethylamine (34.6 g, 268 mmol) were added. The reaction mixture was heated to 85°C and stirred for 1 hour under argon protection. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to give compound 44a (320 mg).

[1016] LCMS(ESI)M / Z:571.9[M+H] + .

[1017] Step B:

[1018] Compounds 44a (12 g, 20.9 mmol), 44b (11.2 g, 23.1 mmol, preparation method according to WO2025045233), dichloro[1,1-bis(di-tert-butylphosphine)ferrocene-palladium (1.37 g, 2.10 mmol), and tripotassium phosphate (13.4 g, 62.9 mmol) were dissolved in a mixed solvent of toluene (80 mL) and water (20 mL). The reaction solution was heated to 85°C for 3 hours under an argon atmosphere. After the reaction was completed, the reaction was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 5% methanol) to give compound 44c (14.4 g).

[1019] MS(ESI)M / Z:804.4[M+H] +

[1020] Step C:

[1021] Compound 44c (30 g, 37.3 mmol) was dissolved in a mixed solvent of tetrahydrofuran (300 mL) and water (150 mL). Lithium hydroxide (2.68 g, 112 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was diluted with water, washed twice with methyl tert-butyl ether, and the aqueous phase was adjusted to pH 4 with 1 M hydrochloric acid. The aqueous phase was then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 44d (26.2 g).

[1022] MS(ESI)M / Z:790.1[M+H] +

[1023] Step D:

[1024] Compound 44d (25 g, 31.7 mmol) and (S)-hexahydropyridazine-3-carboxylic acid methyl ester hydrochloride (11.4 g, 63.3 mmol) were dissolved in N,N-dimethylformamide (250 mL). N,N-diisopropylethylamine (20.5 g, 158 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (24.1 g, 63.3 mmol) were added under ice bath conditions. The reaction mixture was reacted at room temperature for 1 hour under argon protection. After the reaction was complete, the reaction mixture was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol, 3% methanol) to give compound 44e (16.4 g).

[1025] MS(ESI)M / Z: 916.4 [M+H] +

[1026] Step E:

[1027] Compound 44e (310 mg, 0.34 mmol) was dissolved in tetrahydrofuran (11.2 mL), and a solution of lithium hydroxide (20.4 mg, 0.85 mmol) in water (5.6 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the solution was diluted with water, and the pH was adjusted to 5 with 0.5 M dilute hydrochloric acid. The reaction mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 44f (300 mg).

[1028] LCMS(ESI)M / Z:902.0[M+H] + .

[1029] Step F:

[1030] Compound 44f (300 mg, 0.33 mmol) was dissolved in acetonitrile (300 mL), and N,N-diisopropylethylamine (853 mg, 6.6 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.27 g, 6.60 mmol), 1-hydroxybenzotriazole (892 mg, 6.60 mmol), and 4-dimethylaminopyridine (202 mg, 1.65 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours under an argon atmosphere. The reaction mixture was concentrated, and the crude product was dissolved in ethyl acetate. The organic phase was washed with saturated ammonium chloride aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (DCM / MeOH = 25 / 1) to give compound 44 g (180 mg).

[1031] LCMS(ESI)M / Z:884.7[M+H] + .

[1032] Step G:

[1033] 44 g (170 mg, 0.19 mmol) of the compound was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the solution was diluted with dichloromethane, concentrated, and dissolved in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate aqueous solution, followed by washing with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product over 44 h.

[1034] LCMS(ESI)M / Z:783.9[M+H] + .

[1035] Step H:

[1036] Compound 44h (150 mg, 0.19 mmol), (1S,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (43.4 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (245 mg, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (144 mg, 0.38 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction system was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by prep-HPLC (Waters 3767 Column: SunFire Prep C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 in H2O, B: ACN; flow rate: 20ml / min; gradient: 57-80%; retention time: 8.82-10.57min of 16min) to obtain compound 44 (60mg).

[1037] HPLC (SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1mL / min, 0-13min: A97B3, 13-16.0min: A5B95), RT: 8.995min.

[1038] MS(ESI)M / Z:880.4[M+H] + .

[1039] 1 H NMR(400MHz,CD3OD-d4)δ8.74(s,1H),7.80-7.58(m,2H),7.19(s,1H),6.98(d,1H),6.71(s ,1H),6.20-5.60(m,1H),4.77-4.75(m,1H),4.36-4.34(m,2H),3.99-3.98(m,2H),3.89-3. 73(m,4H),3.64-3.47(m,4H),3.45-3.36(m,2H),3.34-3.33(m,3H),3.14-2.95(m,2H),2.6 9-2.65(m,5H),1.93-1.88(m,2H),1.76-1.66(m,6H),1.20-1.09(m,8H),0.77-0.56(m,6H).

[1040] Example 45: Preparation of compound 45

[1041] Step A:

[1042] Compound 10b (2 g, 6.13 mmol) was dissolved in methanol (60 mL), and sodium tungstate aqueous solution (792 mg, 2.70 mmol in 8 mL water) was added under ice bath cooling, followed by 30% wt hydrogen peroxide (6.26 mL, 61.3 mmol). The mixture was stirred at room temperature for 15 minutes. After the reaction was monitored by TLC, saturated sodium thiosulfate aqueous solution was added to quench the reaction. The reaction solution was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 45a, which was directly added to the next step.

[1043] Step B:

[1044] Compound 45a (2.09 g, 6.13 mmol) was dissolved in tetrahydrofuran (72 mL), and 2-iodopropane (5.21 g, 30.7 mmol), sodium hydroxide aqueous solution (2 M, 72 mL), and methyltrioctylammonium chloride (252 mg, 0.61 mmol) were added. The reaction mixture was stirred at room temperature for 3 h under nitrogen protection. After the reaction was completed, ethyl acetate was added for dilution, the organic phase was washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 7.7%) to give compound 45b (1.2 g).

[1045] LCMS(ESI)M / Z:383.0[M+H] + .

[1046] Step C:

[1047] Compound 45b (4.99 g, 13.0 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0 °C in an ice bath, and iodine (3.31 g, 13.0 mmol) and silver trifluoromethanesulfonate (3.69 g, 14.3 mmol) were added under nitrogen protection. The reaction mixture was reacted at 0 °C for 30 minutes. After the reaction was complete, ethyl acetate was added for dilution, and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated sodium sulfite, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to give compound 45c (5.5 g).

[1048] LCMS(ESI)M / Z:508.8[M+H] + .

[1049] Step D:

[1050] Compound 45c (0.6 g, 1.18 mmol) was dissolved in toluene (5 mL), and the toluene reaction solution used to prepare 45d (653 mg, 1.77 mmol, derived from (S)-5-(benzyloxy)-3-bromo-2-(1-methoxyethyl)pyridine according to conventional borate ester preparation methods) was added. Potassium carbonate (408 mg, 2.95 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (76.9 mg, 0.12 mmol), and water (1.4 mL) were also added. The mixture was heated to 80 °C and stirred for 16 h under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound 45e (177 mg).

[1051] LCMS(ESI) M / Z: 625.0 [M+H] + .

[1052] Step E:

[1053] Compound 45f (875 mg) can be prepared by referring to step L of Example 2.

[1054] LCMS(ESI)M / Z:829.2[M+H] + .

[1055] Step F:

[1056] Compound 45f (1.2 g, 1.45 mmol) was dissolved in anhydrous methanol (12 mL), and palladium on carbon (605 mg, 5.68 mmol) and palladium hydroxide on carbon (605 mg, 4.31 mmol) were added. The reaction mixture was heated to 40 °C and stirred for 12 h under a hydrogen balloon atmosphere. After the reaction was completed, dichloromethane was added for dilution, the mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 4) to give compound 45 g (660 mg).

[1057] LCMS(ESI)M / Z:739.1[M+H] + .

[1058] Step G:

[1059] 45 g (330 mg, 0.45 mmol) of compound bis(trifluoromethanesulfonyl)aniline (241 mg, 0.68 mmol) was dissolved in dichloromethane (3.3 mL), and triethylamine (91 mg, 0.9 mmol) and 4-dimethylaminopyridine (5.5 mg, 0.045 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was diluted with dichloromethane, and the organic phase was washed with saturated ammonium chloride aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound 45h (330 mg).

[1060] LCMS(ESI)M / Z:871.0[M+H] + .

[1061] Step H:

[1062] Compound 45h (260 mg, 0.30 mmol), bis(triphenylphosphine)palladium dichloride (31.6 mg, 0.045 mmol), compound 27a (150 mg, 1.20 mmol), cuprous iodide (13.1 mg, 0.069 mmol), N,N-diisopropylethylamine (155 mg, 1.20 mmol), and lithium chloride (50.9 mg, 1.20 mmol) were dissolved in anhydrous acetonitrile (6.5 mL). The reaction mixture was heated to 85 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 25 / 1) to give compound 45i (252 mg).

[1063] LCMS(ESI)M / Z:846.5[M+H]+.

[1064] Step I:

[1065] Compound 45i (440 mg, 0.52 mmol) was dissolved in a mixture of tetrahydrofuran (1.3 mL) and methanol (1.3 mL). Lithium hydroxide aqueous solution (106 mg, 2.58 mmol, 1.3 mL) was added under ice-water bath conditions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 4–5 with 1 M dilute hydrochloric acid. The reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 45i (410 mg).

[1066] LCMS(ESI)M / Z:790.4[M+H]+.

[1067] Step J:

[1068] Compound 45j (404 mg, 0.51 mmol) and compound 1e (179 mg, 0.66 mmol, TFA salt) were dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (461 mg, 3.57 mmol) was added, followed by 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (388 mg, 1.02 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed successively with saturated ammonium chloride water and saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 25 / 1) to obtain compound 45k (270 mg).

[1069] LCMS(ESI) M / Z: 928.6 [M+H] + .

[1070] Step K:

[1071] Compound 45k (300 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5.5 mL), and an aqueous solution of lithium hydroxide (19.2 mg, 0.80 mmol in 5.5 mL water) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with water, and the pH was adjusted to approximately 5 with 0.5 M dilute hydrochloric acid. The reaction mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 45l (295 mg).

[1072] LCMS(ESI)M / Z:914.7[M+H] + .

[1073] Step L:

[1074] Compound 45l (260 mg, 0.28 mmol) was dissolved in acetonitrile (260 mL), and ethyl diisopropylamine (724 mg, 5.60 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.07 g, 5.60 mmol), and 1-hydroxybenzotriazole (757 mg, 5.60 mmol) were added. 4-Dimethylaminopyridine (171 mg, 1.40 mmol) was also added. The reaction mixture was stirred at room temperature for 6 hours under argon protection. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 25 / 1) to obtain compound 45m (125 mg).

[1075] LCMS(ESI)M / Z:896.8[M+H] + .

[1076] Step M:

[1077] Compound 45m (160 mg, 0.18 mmol) was dissolved in dichloromethane (4.5 mL), and trifluoroacetic acid (1.5 mL) was added under ice bath cooling. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was diluted with dichloromethane, washed twice with saturated sodium bicarbonate aqueous solution, and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 45n (140 mg).

[1078] LCMS(ESI) M / Z: 796.5 [M+H] + .

[1079] Step N:

[1080] Compound 45n (130 mg, 0.16 mmol), (1S,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (36.5 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (3 mL), and ethyl diisopropylamine (207 mg, 1.6 mmol) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (122 mg, 0.32 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC (Waters 3767 Column: SunFire Prep C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 in H2O, B: ACN; flow rate: 20ml / min; gradient: 57-80%; retention time: 8.82-10.57min of 16min) to obtain compound 45 (64.6mg).

[1081] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1mL / min, 15min), RT: 7.663min.

[1082] MS(ESI)M / Z:892.8[M+H] +

[1083] 1 H NMR(400MHz,MeOD)δ8.77(s,1H),8.45(s,1H),8.07(s,1H),7.73(d,1H),7.75(s,1H),7.48 (d,1H),5.90(d,1H),5.74(d,1H),4.85-4.65(m,2H),4.17-4.13(m,2H),3.75-3.60(m,8H) ,3.63-3.60(m,1H),3.30-3.16(m,4H),2.76-2.58(m,6H),2.48-2.35(m,2H),2.22-2.17(m ,1H),1.66-1.61(m,1H),1.45-1.30(m,6H),1.23-1.08(m,12H),0.99(s,3H),0.66(s,3H).

[1084] The following compounds were prepared according to the above examples:

[1085] Example 47: Preparation of Compound 47

[1086] Step A:

[1087] Compound 43f (3.60 g, 9.72 mmol) and pinacol diboronate (4.94 g, 19.4 mmol) were dissolved in tetrahydrofuran (72 mL). 4,4'-di-tert-butyl-2,2'-bipyridine (0.52 g, 1.94 mmol) and 1,5-octadiene iridium chloride dimer (261 mg, 0.39 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 hours under argon protection. After the reaction was complete, the reaction mixture was directly concentrated to obtain crude product 47a (3.6 g).

[1088] LCMS(ESI)M / Z:415.4[M+H] + .

[1089] Step B:

[1090] Compound 47a (3.60 g, 8.69 mmol) was dissolved in acetonitrile (18 mL), cooled to 0°C in an ice bath, and hydrogen peroxide (2.95 g, 26.1 mmol, 30% purity) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with saturated sodium sulfite aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 47b (3.3 g).

[1091] LCMS(ESI)M / Z:387.3[M+H] + .

[1092] Step C:

[1093] Compound 47b (3.3 g, 5.98 mmol) was dissolved in DCM (75 mL), and N,N-diisopropylethylamine (7.73 g, 59.8 mmol) and N,N-bis(trifluoromethanesulfonyl)aniline (3.42 g, 9.57 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was washed three times with 0.3 M hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the small polar isomer 47c-A (1.6 g); (petroleum ether / ethyl acetate = 2 / 1) to give the large polar isomer 47c-B (1.2 g).

[1094] LCMS(ESI)M / Z:519.4[M+H] + .

[1095] Step D:

[1096] Compound 47c-A (250 mg, 0.48 mmol), methylpiperazine (480 mg, 4.8 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl), palladium (200 mg, 0.24 mmol), and cesium carbonate (469 mg, 1.44 mmol) were dissolved in toluene (5 mL). The reaction mixture was heated to 90 °C for 3 hours under argon protection. After the reaction was completed, the reaction was quenched with water. The reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 47d (100 mg).

[1097] LCMS(ESI) M / Z: 469.3 [M+H] + .

[1098] Step E:

[1099] Compound 47d (360 mg, 0.77 mmol) was dissolved in N,N-dimethylformamide (9 mL), and N-bromosuccinimide (130 mg, 0.73 mmol) was added under ice bath cooling. The reaction mixture was stirred at 0 °C for 0.5 hours. After the reaction was completed, the reaction mixture was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 47e (320 mg).

[1100] LCMS(ESI) M / Z: 549.0 [M+H] + .

[1101] Step F:

[1102] Compound 47e (350 mg, 0.64 mmol), 47l (561 mg, 1.28 mmol, prepared according to WO2025045233), tripotassium phosphate (407 mg, 1.92 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (41.7 mg, 0.064 mmol) were dissolved in a mixture of toluene (8 mL) and water (1.5 mL). The reaction mixture was heated to 85 °C and stirred for 2 hours under argon protection. After the reaction was completed, the reaction was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 12 / 1) to obtain compound 47f (390 mg).

[1103] LCMS(ESI)M / Z:779.0[M+H] + .

[1104] Step G:

[1105] Compound 47f (550 mg, 0.71 mmol) was dissolved in tetrahydrofuran (24 mL), and a solution of lithium hydroxide (42.5 mg, 1.77 mmol) in water (12 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the solution was diluted with water, the pH was adjusted to 5 with 0.5 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 47 g (540 mg).

[1106] LCMS(ESI)M / Z:765.1[M+H] + .

[1107] Step H:

[1108] Compound 47 g (590 mg, 0.77 mmol) and compound 1e (228 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (10 mL), ethyl diisopropylamine (696 mg, 5.39 mmol) was added, followed by N,N,N,N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (585 mg, 1.54 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed successively with saturated ammonium chloride aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 12 / 1) to obtain compound 47h (680 mg).

[1109] LCMS(ESI)M / Z:903.7[M+H]+ .

[1110] Step I:

[1111] Compound 47i (650 mg, 0.72 mmol) was dissolved in tetrahydrofuran (12 mL), and a solution of lithium hydroxide (43.1 mg, 1.80 mmol) in water (12 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the solution was diluted with water, and the pH was adjusted to 5 with 0.5 M dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 47i (639 mg).

[1112] LCMS(ESI)M / Z:889.1[M+H] + .

[1113] Step J:

[1114] Compound 47i (630 mg, 0.71 mmol) was dissolved in acetonitrile (630 mL), and ethyl diisopropylamine (1.84 g, 14.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.72 g, 14.2 mmol), 1-hydroxybenzotriazole (1.92 g, 14.2 mmol), and 4-dimethylaminopyridine (434 mg, 3.55 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours under argon protection. After the reaction was completed, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic phase was washed successively with saturated ammonium chloride aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to silica gel column chromatography (DCM / MeOH = 15 / 1) to obtain compound 47j (440 mg).

[1115] LCMS(ESI)M / Z:871.1[M+H] + .

[1116] Step K:

[1117] Compound 47j (100 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.5 mL) was added under ice bath cooling. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated at low temperature. The residue was dissolved in ethyl acetate, washed twice with saturated sodium bicarbonate aqueous solution, and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 47k (88 mg).

[1118] LCMS(ESI)M / Z:771.0[M+H] + .

[1119] Step L:

[1120] Compound 47k (88 mg, 0.11 mmol) and (1S,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (25.1 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (3 mL), and ethyl diisopropylamine (142 mg, 1.1 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (83.6 mg, 0.22 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC (Waters 3767 Column: SunFire Prep C18, 19*250mm, 10um; Mobile Phase A: 10mmol / L NH4HCO3 in H2O, B: ACN; flow rate: 20ml / min; gradient: 57-80%; retention time: 8.82-10.57min of 16min) to obtain compound 47 (35mg).

[1121] HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1mL / min, 16min), RT: 8.279min.

[1122] MS(ESI)M / Z:867.1[M+H] + .

[1123] 1 H NMR(400MHz,DMSO-d6)δ8.47-8.39(m,2H),7.41-7.37(m,1H),7.32(s,1H),7.09-6.98(m ,2H),6.68-6.65(m,1H),6.07-5.99(m,1H),5.93-5.91(m,0.5H),5.31-5.29(m,0.5H),4. 33-4.13(m,3H),4.03-3.62(m,3H),3.56-3.39(m,2H),3.24(s,6H),3.17-3.03(m,2H),2 .66-2.62(m,2H),2.45(s,4H),2.33-2.12(m,5H),1.52-0.96(m,14H),0.85-0.35(m,7H).

[1124] Example 49: Preparation of Compound 49

[1125] Referring to Example 44, compound 49 can be prepared using appropriate raw materials.

[1126] HPLC (SunFire C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.1% NH3.H2O in H2O, B: 0.1% NH3.H2O in ACN, Flow rate:1mL / min,0-13min:A60B40,13-16.0min:A5B95),RT:10.351min.

[1127] MS(ESI)M / Z:892.4[M+H] + .

[1128] 1 H NMR(400MHz,MeOD)δ8.72(d,1H),7.88-7.65(m,1H),7.51(dd,1H),7.21(s,1H),6.99(d, 1H),6.69(s,1H),6.29-5.97(m,1H),5.44(s,1H),4.56(s,2H),4.46-4.21(m,2H),4.01(d ,2H),3.78-3.71(m,4H),3.60(s,3H),3.38(dd,3H),3.05(d,2H),2.84(s,2H),2.74-2.6 1(m,5H),2.38(d,2H),2.17(t,1H),1.57(d,2H),1.41(d,4H),1.11(d,8H),0.58(dd,6H).

[1129] Example 50: Preparation of Compound 50

[1130] Step A:

[1131] Compound 43j-A (500 mg, 0.84 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of 1-(propan-2-yn-1-yl)piperidin-4-onitrile (249 mg, 1.68 mmol), cuprous iodide (37 mg, 0.19 mmol), palladium dichloride (88 mg, 0.13 mmol), triethylamine (542 mg, 4.2 mmol), and lithium chloride (178 mg, 4.2 mmol). The reaction mixture was heated to 85 °C and stirred for 2 h under argon protection. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 80%-100%) to obtain compound 50a (380 mg).

[1132] LCMS(ESI)M / Z:595.0[M+Na] + .

[1133] Step B:

[1134] Compound 50a (350 mg, 0.59 mmol) was dissolved in toluene (5 mL) and water (1 mL), followed by the addition of 43L (357 mg, 0.65 mmol), potassium phosphate (375 mg, 1.77 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (38 mg, 0.059 mmol). The reaction mixture was heated to 85 °C and stirred for 4 h under argon protection. After the reaction was completed, the reaction was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (EA / PE = 80%-100%) to obtain compound 50b (400 mg).

[1135] LCMS(ESI)M / Z:939.8[M+H] + .

[1136] Step C:

[1137] Compound 50b (400 mg, 0.43 mmol) was dissolved in tetrahydrofuran (4 mL) and water (4 mL), and lithium hydroxide (31 mg, 1.29 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the pH was adjusted to 6 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse column chromatography (0.1% FA) to give compound 50c (330 mg).

[1138] LCMS(ESI) M / Z: 925.5 [M+H] + .

[1139] Step D:

[1140] Compound 50c (330 mg, 0.36 mmol) was dissolved in acetonitrile (330 mL). Under ice bath cooling, 1-hydroxybenzotriazole (973 mg, 7.2 mmol), 4-dimethylaminopyridine (220 mg, 1.8 mmol), ethyl diisopropylamine (1.19 mL, 7.2 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1380 mg, 7.2 mmol) were added. The reaction mixture was reacted at room temperature under an argon atmosphere for 16 h. After the reaction was complete, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 80%-100%) to give compound 50d (140 mg).

[1141] LCMS(ESI) M / Z: 907.6 [M+H] + .

[1142] Step E:

[1143] Compound 50d (140 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL, 13.46 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated at low temperature. The residue was dissolved in ethyl acetate, and the organic phase was washed with sodium bicarbonate aqueous solution, followed by washing with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 50e (90 mg).

[1144] LCMS(ESI)M / Z:807.5[M+H] + .

[1145] Step F:

[1146] Compound 50e (90 mg, 0.11 mmol), (2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (14 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (63 mg, 0.17 mmol) and ethyl diisopropylamine (0.055 mL, 0.22 mmol) were added under nitrogen protection. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC (Waters 3767QDA Column: Agilent C18, 21.2*150mm, 4um; Mobile Phase A: 10mmol / LNH4HCO3 / H2O, B: ACN; flow rate: 20ml / min; gradient: 52-57%; retention time: 9.32min of 17min) to obtain compound 50 (57mg).

[1147] SunFire C18 5um 4.6x150mm 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0mL / min, 0-13min: A70B30, 13-16.0min: A5B95) RT: 8.012min.

[1148] MS(ESI)M / Z:903.7[M+H] + .

[1149] 1H NMR(400MHz,MeOD)δ8.82-8.65(m,1H),7.95-7.67(m,1H),7.65-7.41(m,1H),7.20(s,1H),7.05-6.93(m,1H),6.71(s,1H ),4.83-4.68(m,1H),4.51-4.21(m,2H),4.11-3.80(m,2H),3.72-3.45(m,4H),3.44-3.31(m,4H),3.30-3.14(m,5H),2.96 -2.77(m,5H),2.73-2.55(m,3H),2.08-1.96(m,2H),1.93-1.86(m,2H),1.82-1.69(m,1H),1. 61-1.41(m,4H),1.41-1.27(m,2H),1.17-1.04(m,7H),0.81-0.69(m,1H),0.65-0.44(m,4H).

[1150] Example 51: Preparation of compound 51

[1151] Step A:

[1152] Compound 43j-A (400 mg, 0.67 mmol), cuprous iodide (29.35 mg, 0.15 mmol), bis(triphenylphosphine)palladium chloride (70.54 mg, 0.10 mmol), 4-(hydroxymethyl)-1-(prop-2-yn-1-yl)piperidin-4-onitrile (238.83 mg, 1.34 mmol), ethyl diisopropylamine (432.95 mg, 3.35 mmol), and lithium chloride (142.01 mg, 3.35 mol) were dissolved in acetonitrile (16 mL). The reaction mixture was heated to 85°C and reacted for 1 hour under an argon atmosphere. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0%–15%) to give compound 51a (380 mg).

[1153] LCMS(ESI)M / Z:627.1[M+H] + .

[1154] Step B:

[1155] Compound 51a (370 mg, 0.59 mmol), compound 43l (357.26 mg, 0.65 mmol), tripotassium phosphate (375.72 mg, 1.77 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (38.45 mg, 0.059 mmol) were dissolved in a mixture of toluene (5 mL) and water (1 mL). The reaction mixture was heated to 85°C and stirred for 2 hours under an argon atmosphere. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-15%) to give compound 51b (350 mg).

[1156] LCMS(ESI) M / Z: 969.5 [M+H] + .

[1157] Step C:

[1158] Compound 51b (356 mg, 0.37 mmol) was dissolved in tetrahydrofuran (12 mL), and lithium hydroxide aqueous solution (6 mL, 22.15 mmol, 3.5 mg / mL) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH was adjusted to 6 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 51c (220 mg).

[1159] LCMS(ESI)M / Z:955.5[M+H] + .

[1160] Step D:

[1161] Compound 51c (220 mg, 0.23 mmol) was dissolved in acetonitrile (220 mL). Under ice bath cooling, 1-hydroxybenzotriazole (621 mg, 4.6 mmol), 4-dimethylaminopyridine (140 mg, 1.2 mmol), ethyl diisopropylamine (0.76 mL, 4.6 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (881 mg, 4.6 mmol) were added. The reaction mixture was reacted at room temperature for 3 h under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 80%-100%) to give compound 51d (120 mg).

[1162] LCMS(ESI) M / Z: 937.7 [M+H] + .

[1163] Step E:

[1164] Compound 51d (120 mg, 0.13 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1.2 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated at low temperature. The residue was dissolved in ethyl acetate, and the organic phase was washed with sodium bicarbonate aqueous solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 51e (90 mg).

[1165] LCMS(ESI)M / Z:837.7[M+H] + .

[1166] Step F:

[1167] Compound 51e (90 mg, 0.11 mmol), (2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (25.11 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (3 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (84 mg, 0.22 mmol) and ethyl diisopropylamine (0.18 mL, 1.12 mmol) were added under nitrogen protection. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC (Waters 3767QDA). Column: Agilent C18, 21.2*150mm, 4um; Mobile Phase A: 10mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20ml / min; gradient: 52-57%; Retention Time: 9.32min of 17min) to obtain compound 51 (35mg).

[1168] HPLC (SunFire C18 5μm, 4.6*150mm Column, 25C, Mobile phase: A: 0.03% TFA in H2O, B: 0.03% TFA in ACN, Flow rate: 1.0ml / min, 0-13min: A70B30, 13-16.0min: A5B95), RT: 7.629min.

[1169] MS(ESI)M / Z: 933.7 [M+H] +

[1170] 1H NMR(400MHz,MeOD)δ8.75(s,1H),7.71(d,2H),7.19(s,1H),6.98(d,1H),6.71(s,1H),5.89(d,1H),4.58(s,2H),4.34(s,2H),3.89(s ,2H),3.63(d,5H),3.40(d,4H),3.13(s,2H),3.03(d,2H),2.71(dd,5H),2.00(d,2H),1.91-1.23(m,11H),1.10(s,7H),0.65(d,6H).

[1171] Example 52: Preparation of compound 52

[1172] Step A:

[1173] Compound 43j-A (400 mg, 0.67 mmol), cuprous iodide (29.35 mg, 0.15 mmol), bis(triphenylphosphine)palladium chloride (70.54 mg, 0.10 mmol), 4-(hydroxymethyl)-1-(prop-2-yn-1-yl)piperidin-4-onitrile (257.63 mg, 1.34 mmol), ethyl diisopropylamine (432.95 mg, 3.35 mmol), and lithium chloride (142.01 mg, 3.35 mol) were dissolved in acetonitrile (16 mL). The reaction mixture was heated to 85°C and reacted for 1 hour under an argon atmosphere. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0%–15%) to give compound 52a (480 mg).

[1174] LCMS(ESI) M / Z: 638.9 [M+H] + .

[1175] Step B:

[1176] Compound 52a (550 mg, 0.86 mmol), compound 43l (568 mg, 1.03 mmol), tripotassium phosphate (547 mg, 2.58 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (56 mg, 0.086 mmol) were dissolved in a mixed solution of toluene (6 mL) and water (1.2 mL). The reaction mixture was heated to 85°C and stirred for 2 hours under an argon atmosphere. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-15%) to give compound 52b (310 mg).

[1177] LCMS(ESI)M / Z:983.4[M+H] + .

[1178] Step C:

[1179] Compound 52b (350 mg, 0.36 mmol) was dissolved in tetrahydrofuran (12 mL), and lithium hydroxide aqueous solution (6 mL, 22.15 mmol, 3.5 mg / mL) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH was adjusted to 6 with 1 M dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 52c (320 mg).

[1180] LCMS(ESI)M / Z:969.2[M+H] + .

[1181] Step D:

[1182] Compound 52c (270 mg, 0.28 mmol) was dissolved in acetonitrile (270 mL). Under ice bath cooling, 1-hydroxybenzotriazole (757 mg, 5.6 mmol), 4-dimethylaminopyridine (171 mg, 0.17 mmol), ethyl diisopropylamine (0.93 mL, 5.6 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1076 mg, 5.6 mmol) were added. The reaction mixture was reacted at room temperature for 3 h under an argon atmosphere. After the reaction was complete, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (MeOH / DCM = 0%–9%) to give compound 52d (177 mg).

[1183] LCMS(ESI)M / Z:951.7[M+H] + .

[1184] Step E:

[1185] Compound 52d (210 mg, 0.22 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated at low temperature. The residue was dissolved in ethyl acetate, and the organic phase was washed with sodium bicarbonate aqueous solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 52e (180 mg).

[1186] LCMS(ESI)M / Z:851.2[M+H] + .

[1187] Step F:

[1188] Compound 52e (150 mg, 0.18 mmol), (2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (41 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (137 mg, 0.36 mmol) and ethyl diisopropylamine (0.3 mL, 1.8 mmol) were added under nitrogen protection. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC (Waters 3767QDA). Column: Agilent C18, 21.2*150mm, 4um; Mobile Phase A: 10mmol / L NH4HCO3 / H2O, B: ACN; flow rate: 20ml / min; gradient: 52-57%; Retention Time: 9.32min of 17min) to obtain compound 52 (65mg).

[1189] HPLC(Waters

[1190] MS(ESI)M / Z:947.9[M+H] + .

[1191] 1H NMR(400MHz,MeOD)δ8.74(s,1H),7.71(d,2H),7.19(d,1H),6.98(d,1H),6.71(s,1H),5. 90(d,2H),4.88(dd,1H),4.86(s,2H),4.84(s,1H),4.35(s,2H),3.94(d,2H),3.66(s,2H) ,3.50(d,1H),3.44(s,2H),3.41(s,3H),3.37(d,1H),3.30-3.20(m,4H),3.01(d,2H),2.8 5(s,1H),2.66(t,3H),2.02(d,2H),1.68(td,3H),1.44(d,6H),1.10(s,7H),0.65(d,6H).

[1192] Example 53: Preparation of compound 53

[1193] Step A:

[1194] Compounds 43j-A (270 mg, 0.45 mmol), 53a (146.01 mg, 0.90 mmol), bis(triphenylphosphine)palladium dichloride (47.38 mg, 0.068 mmol), cuprous iodide (19.71 mg, 0.10 mmol), and lithium chloride (95.38 mg, 2.25 mmol) were dissolved in acetonitrile (6 mL). Ethyl diisopropylamine (290.79 mg, 2.25 mmol) was added, and the reaction mixture was heated to 85 °C for 1 h under argon protection. After the reaction was completed, 50 mL of water was added to quench the reaction. The reaction mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 50-100%) to give compound 53b (270 mg).

[1195] LCMS(ESI)M / Z:611.2[M+H] + .

[1196] Step B:

[1197] Compounds 53b (270 mg, 0.44 mmol), 53c (212.16 mg, 0.48 mmol, prepared according to WO2025045233), tripotassium phosphate (280.20 mg, 1.32 mmol), and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium (28.68 mg, 0.044 mmol) were dissolved in toluene (3 mL) and water (0.5 mL). The reaction mixture was heated to 85°C under an argon atmosphere for 4 hours. After the reaction was complete,...

Claims

1. The compound represented by Formula I, its pharmaceutically acceptable salt, or its stereoisomer: in, Ring B is selected from One end marked with * is connected to R 17 The carbon atoms are connected; R1, R2, R 3、 R 18 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl; or R1, R2 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R2, R3 and the atoms they are attached to cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R1, R 18 The atoms to which it is attached cyclize together to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl; or R2 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene or C 2-4 alkenyl groups; or R3 and R 18 Interconnected together to form C 1-4 Alkylene, C 2-4 Heteroalkylene or C 2-4 Alkenyl group; or R1, R3 and the atoms they are attached to, and the atoms they are attached to, cyclize together to form a 4-7 membered cycloalkyl or a 4-7 membered heterocycloalkyl group; wherein the NH2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, and alkenyl group are optionally substituted by one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl or NH2-C 1-4 alkyl; X1 is selected from chemical bonds, -CHR X1-1 -、-O-、-NR X1-2 -and-C(O)-; the R X1-1 R X1-2 Each element is independently selected from H, CN, OH, NH2, oxo, methanyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl and NH2-C 1-4 alkyl; X2 is selected from N and C-R9; X3 is selected from N and CR. 12 ; R4 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl and C 1-6 Alkyl groups; the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkyl groups are optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl or NH2-C 1-4 alkyl; R5, R6, R7, R8, R9, R 11 R 12 Each element is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxyalkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl-C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-9 membered cycloalkyl, or 3-9 membered heterocycloalkyl; or R7, R8, and atoms therebetween cyclized to form 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl; or R8, R 15 Directly connected together to form C 2-6 Alkylene, 2-6 heteroalkylene or C 2-6 alkenyl; the alkyl, cycloalkyl, heterocycloalkyl, alkylene, heteroalkylene, and alkenyl groups are optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; L is selected from chemical bonds, O, NH, C 1-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; the alkylene group, alkenyl group, and alkyne group are optionally surrounded by one or more C atoms. 1-4 Alkyl substitution; R 10 Selected from -N(R) 10-1 (R) 10-2 ), 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl and (C 1-4 Alkyl)2N-C(O)-; the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 alkenyl, =C(R) 10a (R) 10b ), =NR 10c C 2-4 alkynyl group, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, C 1-4 Halogenated alkyl-S(O)2-C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl-substituted 3-6 membered heterocycloalkyl; wherein R 10-1 R 10-2 R 10a R 10b R 10c Each element is independently selected from H, CN, OH, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl and C 1-4 Haloalkoxy-C 1-4 Alkyl group; and when L is a chemical bond, the R 10 One of the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups in the group is related to R. 11 The adjacent substituent can react with R 11 Connection forms C 1-4 Alkylene or C 1-4 Heteroalkylene; the C 1-4 Alkylene, C 1-4 The heteroalkylene group is optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; or Selected from The ring C is selected from 6-8-membered heterocyclic alkyl groups and 5-6-membered heteroaryl groups, wherein the 6-8-membered heterocyclic alkyl group and the 5-6-membered heteroaryl group contain 1-2 heteroatoms selected from N, O, and S and optionally are C-shaped. 1-4 Alkyl, deuterated, or oxosubstituted; R 20 Selected from C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered deuterated cycloalkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkoxy-C(O)-, C 1-4 Alkyl-NH-C(O)-, C 1-4 Alkyl-S(O)2-, (C 1-4 Alkyl)2N-S(O)2- and CN; said alkyl, cycloalkyl, heterocycloalkyl is optionally substituted with one or more of the following groups: CN, OH, NH2, oxo, thio, halogen, methanyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, cyano-C 1- 4-alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-oxy or C 1-4 Alkyl-S(O)2-; R 13 R 14 R 15 R 16 R 17 Each of the following is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O- and 3-6 membered heterocycloalkyl-O-; or R 14 R 15 The atoms connected thereto co-cyclize to form a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted by one or more of the following groups: CN, OH, NH2, oxo, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl or NH2-C 1-4 Alkyl; or R 16 R 17 And the atoms between them are cyclized together to form a 5-6 membered heteroaryl or a 6 membered aryl; and the 5-6 membered heteroaryl or the 6 membered aryl is optionally surrounded by one or more R 19 Instead, the R 19 Selected from H, CN, OH, NH2, oxo, methanyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; X8 and X9 are each independently selected from -C-, -CH-, and -N-; n is selected from 0, 1, and 2; each It can be used to represent a single bond or a double bond independently.

2. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound satisfies one or more of the following conditions: (1) R1, R2, R 3、 R 18 Selected independently from H and C respectively 1-4 Alkyl; or, R1 and R2 are H, and R3 and R 18 Interconnected together to form C 1-4 Alkylene; or, R2, R 18 H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups; (2) X1 is NH; (3) X2 is CH; (4) X3 is N; (5) R4 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl and C 1-6 Alkyl; the cycloalkyl, heterocycloalkyl and alkyl groups are optionally substituted with one or more of the following groups: halogen or C 1-4 alkyl; (6) R5 and R6 are H; (7) X8 and X9 are each independently selected from C and N; (8) When n is 1, R7 is H and R8 is C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or 3-9 membered cycloalkyl, or, R7, R8 and the atoms between them co-cyclized to form 5-9 membered heterocyclic alkyl; R 16 R 17 And the co-cyclization of 6-membered aryl groups between them; When n is 0, R 16 and R 17 H is H, and C is R8. 1-4 Halogenated alkyl groups; (9)R 11 For H; (10) L is selected from chemical bonds and C 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution; (11)R 10 Selected from 3-10 membered heterocyclic alkyl groups, 5-10 membered heteroaryl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 Alkyl; the heteroaryl group is optionally substituted with the following groups: 3-6 membered heterocyclic alkyl groups substituted with 3-6 membered heterocyclic alkyl groups; Preferably, when L is C 2-4 When it is an ynylene group, the ynylene group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution; R 10 Selected from 3-10 membered heterocyclic alkyl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 alkyl; Alternatively, when L is a chemical bond, R 10 It is a 5-10 membered heteroaryl group; the heteroaryl group is optionally substituted with the following groups: 3-6 membered heterocyclic alkyl groups substituted with 3-6 membered heterocyclic alkyl groups; (12) for The ring C is a 6-8 membered heterocyclic alkyl group, wherein the 6-8 membered heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O, and S; R 20 C 1-4 Alkyl; the alkyl group may optionally be substituted with the following groups: 3-6 membered cycloalkyl-oxy; (13)R 13 R 14 R 15 Each was independently selected from H and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Deuterated alkoxy groups; Each chiral center of the compound described in (14) exists independently in the form of an R configuration and / or an S configuration.

3. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound satisfies one or more of the following conditions: (1) R1 and R2 are H, R3 and R 18 Interconnected together to form C 1-4 Alkylene; or, R2, R 18 H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups; Preferably, R2, R 18 H, R1, R3 and the atoms they are attached to, as well as the atoms attached to R2, cyclize together to form 4-7 membered cycloalkyl groups; (2) R4 is selected from 3-6 membered heterocyclic alkyl groups and C substituted with one or more halogens. 1-6 alkyl; Preferably, R4 is selected from 3-6 membered heterocyclic alkyl groups; (3) When n is 1, R7, R8, and the atoms between them co-cyclize to form 5-9 membered heterocyclic alkyl groups; R 16 R 17 And the co-cyclization of 6-membered aryl groups between them; Alternatively, n is 0, and R8 is C. 1-4 Halogenated alkyl groups; (4) X9 is N, X8 is C; Preferably, X9 is N, X8 is C, and R8 is C. 1-4 Halogenated alkyl groups; More preferably, X9 is N, X8 is C, n is 0, and R8 is C. 1-4 Halogenated alkyl groups; For example, X9 is N, X8 is C, n is 0, and R8 is C. 1-4 Haloalkyl, R 16 and R 17 For H; (5) R8 is C 1-4 Haloalkyl, C 1-4 alkoxy or 3-9 membered cycloalkyl; Preferably, R8 is C 1-4 alkoxy or 3-9 membered cycloalkyl; (6) L is C 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution; Preferably, L is C 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution; R 10 Selected from 3-10 membered heterocyclic alkyl groups and (C 1-4 Alkyl)2N-C(O)-; the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 alkyl; Alternatively, L represents a chemical bond, and R... 10 It is a 5-10 membered heteroaryl group; the heteroaryl group is substituted with the following groups: 3-6 membered heterocyclic alkyl groups substituted with 3-6 membered heterocyclic alkyl groups; Alternatively, L represents a chemical bond, and R... 10 It is an 8-10 membered heterocyclic alkyl group; and (7) for 4. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, Ring B is selected from One end marked with * is connected to R 17 The carbon atoms are connected; R1, R2, R 3、 R 18 Selected independently from H and C respectively 1-4 alkyl; X1 is NH; X2 is CH; X3 is N; R4 is selected from 3-6 membered cycloalkyl groups; the cycloalkyl group is optionally substituted with the following groups: C 1-4 alkyl; R5 and R6 are H; X9 is N, X8 is C; When n is 0, R 16 and R 17 H is H, and C is R8. 1-4 Halogenated alkyl groups; R 11 For H; L is selected from C 2-4 alkyne group; the alkyne group is optionally surrounded by one or more C atoms. 1-4 Alkyl substitution; R 10 Selected from 3-10 membered heterocyclic alkyl groups; wherein the heterocyclic alkyl group is optionally substituted with one or more of the following groups: CN, OH, oxo, halogen, C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 alkyl; R 13 R 14 R 15 Each was independently selected from H and C. 1-4 Alkyl and C 1-4 Alkyl group.

5. The compound according to claim 2, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound satisfies one or more of the following conditions: (1) R1, R2, R 3、 R 18 In, the C 1-4 The alkyl group is independently methyl or ethyl, preferably methyl; (2) When R1 and R2 are H, R3 and R 18 Interconnected together to form C 1-4 When alkylene, the C 1-4 The alkylene group is methylene or ethylene, preferably methylene; (3) When R2, R 18 When H, R1, R3, and the atoms they are attached to, as well as the atoms attached to R2, are cyclized together to form a 4-7 membered cycloalkyl group, the 4-7 membered cycloalkyl group is cyclobutyl or cyclopentyl, preferably cyclobutyl; (4) In R4, the 3-6 membered cycloalkyl group is cyclopropyl or cyclobutyl, for example, cyclopropyl; (5) In R4, the 3-6 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group with one heteroatom (O), for example... (6) In R4, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, or... For example (7) In R4, when the cycloalkyl group is replaced by a halogen, the halogen is fluorine or chlorine, preferably fluorine; (8) In R4, when the cycloalkyl group is C 1-4 When alkyl is substituted, the C 1-4 The alkyl group is methyl or ethyl, preferably methyl; (9) When n is 1, R7 is H and R8 is C 1-4 In the case of alkyl groups, in R8, the C 1-4 The alkyl group is methyl or ethyl, preferably ethyl; (10) When n is 1, R7 is H and R8 is C. 1-4 In the case of haloalkylation, in R8, the C 1-4 Haloalkyl is C replaced by F. 1-4 Alkyl groups, such as -CH2CF3; (11) When n is 1, R7 is H and R8 is C 1-4 In the case of alkoxy, in R8, the C 1-4 The alkoxy group is methoxy, ethoxy, n-propoxy, or isopropoxy, for example, methoxy or isopropoxy; (12) When n is 1, R7 is H, and R8 is a 3-9 membered cycloalkyl group, the 3-9 membered cycloalkyl group in R8 is a 3-6 membered cycloalkyl group, such as cyclopropyl; (13) When n is 1, R7, R8 and the atoms between them cyclize together to form a 5-9 membered heterocyclic alkyl group, the 5-9 membered heterocyclic alkyl group is a 5-9 membered heterocyclic alkyl group with N heteroatom and 1 heteroatom, for example a 6 membered heterocyclic alkyl group with N heteroatom and 1 heteroatom; (14) When n is 1, R7 is H and R8 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or 3-9 membered cycloalkyl, or, R7, R8 and the atoms between them co-cyclized to form 5-9 membered heterocyclic alkyl; R 16 R 17 And the atoms between them co-cyclize a 6-membered aryl group; when the 6-membered aryl group is substituted with a halogen, the halogen is fluorine or chlorine, for example fluorine; (15) When n is 0, R 16 and R 17 H is H, and C is R8. 1-4 When alkyl haloides are used, the C 1-4 Haloalkyl is C replaced by F. 1-4 Alkyl groups, such as -CH2CF3 or -CH(CH3)(CF3); (16)L, the chemical bond is a connecting single bond; (17)L, the C 2-4 The ethynyl group is either ethynyl or propynyl, preferably propynyl; (18)L, when the alkyne group is C 1-4 When alkyl is substituted, the C 1-4 The alkyl group is methyl or ethyl, preferably methyl; (19)R 10 In this context, the 3-10 membered heterocyclic alkyl group is a 6-8 membered monocyclic or bicyclic alkyl group with one or two heteroatoms selected from N, O, and S, such as fused ring, bridged ring, or spirocyclic heterocyclic alkyl groups. (20)R 10 In this context, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group whose heteroatoms are selected from N and O, and whose number of heteroatoms is 1, 2, or 3, for example... (21)R 10 In, the (C) 1-4 C in alkyl)2N-C(O)- 1-4 The alkyl group is methyl or ethyl, preferably methyl; (22)R 10 In this context, when the heterocyclic alkyl group is substituted with a halogen, the halogen is either fluorine or chlorine, preferably fluorine; (23)R 10 In the process, when the heterocyclic alkyl group is C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl or -S(O)2-C 1-4 When alkyl is substituted, the C 1-4 Alkyl, CN-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, NH2-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl groups and -S(O)2-C 1-4 C in alkyl 1-4 The alkyl group is independently methyl or ethyl, preferably methyl; (24)R 10 In the process, when the heterocyclic alkyl group is C 1-4 Alkoxy-C 1-4 When alkyl is substituted, the C 1-4 The alkoxy group is either methoxy or ethoxy, for example, methoxy. (25)R 10 In the context of a heteroaryl group being replaced by a 3-6 membered heterocyclic alkyl group, the 3-6 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group with one heteroatom selected from N and O, for example... (26) In ring C, the 6-8 membered heterocyclic alkyl group is a 7 membered heterocyclic alkyl group whose heteroatoms are selected from O and N and whose number of heteroatoms is 2; (27)R 20 In, the C 1-4 The alkyl group is methyl or ethyl, for example, ethyl; (28)R 20 In this context, when the alkyl group is substituted by a 3-6 membered cycloalkyl-oxy group, the 3-6 membered cycloalkyl group is a cyclopropyl group; (29)R 13 R 14 R 15 In, the C 1-4 The alkyl group is methyl or ethyl, for example, methyl; (30)R 13 R 14 R 15 In, the C 1-4 Haloalkyl is C replaced by F. 1-4 Alkyl groups, such as trifluoromethyl groups; (31)R 13 R 14 R 15 In, the C 1-4 The alkoxy group is either methoxy or ethoxy, for example, methoxy. and (32)R 13 R 14 R 15 In, the C 1-4 The deuterated alkoxy group is a methoxy or ethoxy group that has been substituted with deuterium, for example...

6. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound is represented by any of the following general formulas:

7. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound is represented by any of the following general formulas: Among them, X 10 X 11 X 12 Each is independently selected from O, NH, and C. 1-4 Alkylene, 2-6 heteroalkylene and C 2-4 Alkenyl; the alkyl, heteroalkylene, or alkenyl group is optionally substituted by one or more groups selected from: CN, OH, NH2, oxo, methanyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; 8. The compound according to any one of claims 1-7, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound satisfies one or more of the following conditions: (1) X1 is NH; (2) X2 is CH and X3 is N, or X2 is N and X3 is N, or X2 is N and X3 is CH, or X2 is CF and X3 is N; (3) R4 is cyclopropyl, 3-oxabicyclo[3.1.0]hexane or oxacyclobutane, and the cyclopropyl, 3-oxabicyclo[3.1.0]hexane or oxacyclobutane is optionally substituted by one or more of the following groups: methyl, ethyl, methoxy, ethoxy or trifluoromethyl; Alternatively, R4 is C. 1-6 Alkyl groups, and optionally substituted with halogens; (4) R5 and R6 are independently selected from H, F, and Cl, respectively; (5) R7 and R8 are linked together to form the following structures: -CH2-CH2-X5-*, -X5-CH2-CH2-*, or -CH2-X5-CH2-*; where X5 is selected from chemical bonds, O, and -(CH2). n - NH, where the asterisk * marks the end and the R7 end, and n is selected from 1 and 2; Alternatively, R7 can be H, and R8 can be CN, OH, halogen, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxyalkyl, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkyne group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, wherein C 1-4 Alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl may optionally be substituted with one or more of the following groups: CN, OH; (6) L is a chemical bond, an ethynyl group, or a propynyl group, or L is Or L is The asterisk (*) and R 10 connect; (7)R 10 for Among them, R 10-3 R 10-4 R 10-5 R 10-6 Each is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1- 4-Hydroalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; or R 10-3 R 10-4 R 10-5 R 10-6 Connect any two to form C 1-4 Alkylene, C 1-4 Heteroalkyl; or when L is a chemical bond, R 10-4 With R 11 Connection forms C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 secondary alkenyl or C 1-4 Heteroalkenyl; the C 1-4 Alkylene, C 1-4 Heteroalkyl, C 1-4 sub-enyl, C 1-4 The heteroene group may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; p and q are each independently selected from 0, 1, 2, and 3; X6 is selected from O, CHR 10-7 NR 10-8 -S(=O)2- and -S(=O)-; X7 is selected from N and CH; the R 10-7 R 10-8 Each is independently selected from H, CN, OH, NH2, oxo, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1- 4-alkylthio, hydroxyl-C 1-4 Alkyl, NH-C 1-4 Alkyl, N(C) 1-4 Alkyl groups, 2-3-6 membered cycloalkyl groups, and 3-6 membered heterocycloalkyl groups; Preferably, R 10-3 R 10-4 R 10-5 R 10-6 Each is independently selected from H, oxo, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; (8)R 10a R 10b Each is independently selected from H, F; or R 10a R 10b Both are H, or R 10a R 10b All are F; (9)R 11 Selected from H, F, methyl, ethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, vinyl and ethynyl; (10)R 13 R 14 R 15 Each is independently selected from H, F, methyl, ethyl, vinyl, ethynyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, trideuteroxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl. Or, R 13 H, methoxy, R 14 R 15 The atoms connected thereto are cyclized together to form 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl may optionally be substituted by one or more of the following groups: oxo or methyl.

9. The compound according to any one of claims 1-7, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound satisfies one or more of the following conditions: (1) Fragment Selected from Excerpt Selected from X4 is selected from O, NH, and -(CH2). m - and any combination of the two mentioned above, where m is selected from 1, 2, 3, and 4; (2) R4 is C 1-6 Alkyl groups, and optionally substituted with F; (3) Both R5 and R6 are H; (4) R7 and R8 can be connected to each other to form the following structure: The terminal marked with an asterisk (*) is the R7 terminal; Alternatively, R7 is H, and R8 is selected from Cl, CN, methyl, ethyl, methoxy, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, difluoromethoxy, vinyl, ethynyl. (S)-trifluoroisopropyl and (R)-trifluoroisopropyl; (5) X2 is CH, R 11 For H; or X2 is CF, R 11 For H; or X2 for CH, R 11 For F; or X2 for CH, R 11 C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; (6)R 10 for Among them, R 10-4 With R 10-6 Connect into C 1-4 Alkylene or C 1-4 Heteroalkyl; or when p is not 0, adjacent R 10-3 Between, R 10- 4 and adjacent R 10-3 The connection between them forms C 1-4 Alkylene or C 1-4 Heteroalkyl groups; or, when q is not 0, adjacent R 10-5 Between, R 10-6 With adjacent R 10-5 The connection between them forms C 1-4 Alkylene or C 1-4 Heteroalkylene; or when both p and q are not 0, R 10-3 With R 10-5 The connection between them forms C 1-4 Alkylene or C 1-4 Heteroalkyl; the C 1-4 Alkylene, C 1-4 The heteroalkyl group may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl; (7)R 11 Selected from H, F and methyl; and (8)R 13 For H or methoxy, R 14 R 15 The atoms connected to it co-cyclize into the following groups, which are optionally substituted by one or more oxo or methyl groups:

10. The compound according to any one of claims 1-7, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound satisfies one or more of the following conditions: (1) Fragment Selected from Excerpt Selected from (2) R4 is (3)R 10 for Where p and q are both 1, R 10-3 With R 10-4 Between, R 10-4 With R 10-6 Between, R 10-6 With R 10-5 Between, or R 10-5 With R 10-3 The connection between them forms C 1-4 Alkylene or C 1-4 Heteroalkyl; the C 1-4 Alkylene, C 1-4 The heteroalkyl group may optionally be substituted with one or more of the following groups: CN, OH, NH2, oxo, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkyl, NH2-C 1-4 Alkyl, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; Preferably, p and q are both 1, and: (a) R 10-4 With R 10-6 The two are linked to form an ethylene group, or (b)R 10-3 With R 10-5 The two are linked to form an ethylene, or (c)R 10- 3 and R 10-6 Methylene or ethylene forms between them, or (d)R 10-4 With R 10-5 The formation of methylene or ethylene, or (e)R 10-3 With R 10-4 Methylene or ethylene forms between them, or (f)R 10-5 With R 10-6 Methylene or ethylene forms between them; Or, R 10 Selected from the following groups: Or, R 10 Selected from the following groups: or R 10 for or R 10 for Or R 10 for or R 10 for Or R 10 for and (4) Selected from the following groups:

11. The compound according to any one of claims 1-7, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, Excerpt Satisfy any of the following definitions: (1) L is a chemical bond, R 10 for R 10-4 With R 11 Forming -CH2-O-*, -CH2-O-CH2-*, =CH–*, -CH2–NH-CH2-*, -CH2–NH-CH2-*, -CH2-CH2-O-*, -CH2-NH-*, -CH2-CH2-NH-*, or =N-*, and optionally further substituented by one or more of the following groups: CN, OH, oxo, C 1- 4-alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is a haloalkoxy group, or optionally substituted with one or more of the following groups: CN, OH, oxo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or trifluoromethoxy; wherein the asterisk (*) indicates the R group. 11 end; (2) L is a chemical bond, R 10 for R 10-4 With R 11 Forms -CH2-O-*, -CH2-O-CH2-*, =CH–*, -CH2–N(CH3)-*, -CH2–N(CH3)-CH2-*, -CH2–NH-CH2-*, -CH2–NH-CH2-*, -CH2-CH2-O-*, =C(CH3)–*, -CH2-NH-*, -CH2-CH2-NH-*, =N-*, -C(=O)-NH-*, -C(=O)-N(CH3)-*, or -CH2-CH2-N(CH3)-*; where the asterisk * is R. 11 End; (3) Selected from the following groups: The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3; Or (4) for The asterisk (*) is adjacent to X2, and the other connection point is adjacent to X3.

12. The compound according to any one of claims 1-11, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound satisfies one or more of the following conditions: (1) Fragment Selected from Preferred selection (2) R4 is selected from Preferred selection (3) R5 is H; (4) Ring B is (5) fragment Selected from For example (6) Selected from the following groups: (7) Selected from Preferred selection 13. The compound according to any one of claims 1-12, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, Compounds of Formula I are selected from those having the structures shown in Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, and Formula I-6: Alternatively, the compound of formula I is selected from those having the structures shown in formulas I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, and I-30:

14. The compound according to claim 1, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that, The compound is selected from any of the following compounds:

15. A pharmaceutical composition comprising the compound of any one of claims 1-14, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and any pharmaceutically acceptable carrier; wherein the content of the compound, the pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from 0.1 mg to 1000 mg or 1000 to 2000 mg, preferably 10 to 100 mg, 100 to 200 mg, 200 to 500 mg, or 500 to 1000 mg; wherein the pharmaceutically acceptable carrier may include one or more of fillers, disintegrants, binders, flow aids, and lubricants.

16. The use of the compound of any one of claims 1-14, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition of claim 15 in the preparation of a medicament for treating diseases associated with RAS gene mutations, wherein the RAS gene mutation-related diseases are lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, esophageal or gastric cancer, or uterine cancer associated with RAS gene mutations.

17. A method for treating diseases associated with RAS gene mutations, the method comprising administering to a patient in need an effective amount of the compound of any one of claims 1-14, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition of claim 15, wherein the disease associated with RAS gene mutations is lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, esophageal or gastric cancer or uterine cancer associated with RAS gene mutations.

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