Pyrimidine macrocyclic KRAS inhibitor

Abstract

The present invention belongs to the technical field of medicinal chemistry, and particularly relates to a pyrimidine macrocyclic compound. The compound has a good inhibitory effect on KRAS mutations, has a good inhibitory effect on the G12V mutation and other types of mutations of the KRAS gene, can be used as a general KRAS inhibitor, and can be used for the treatment of tumors driven by KRASG12V and other types of gene mutations.

Description

Pyrimidine macrocyclic KRAS inhibitors

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on February 6, 2024, with application number CN202410171828.7 and the invention name “Pyrimido-macrocyclic KRAS inhibitors”, the Chinese patent application filed with the China Patent Office on April 17, 2024, with application number CN202410465574.X and the invention name “Pyrimido-macrocyclic KRAS inhibitors”, the Chinese patent application filed with the China Patent Office on May 27, 2024, with application number CN202410670498.6 and the invention name “Pyrimido-macrocyclic KRAS inhibitors”, and the Chinese patent application filed with the China Patent Office on January 15, 2025, with application number CN202510066649.1 and the invention name “Pyrimido-macrocyclic KRAS inhibitors”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry and specifically relates to a class of pyrimido-macrocyclic compounds. These compounds have potent inhibitory effects on KRAS mutations, particularly the G12V mutation in the Kras gene, as well as other mutations. They can act as pan-KRAS inhibitors and are useful in treating tumors driven by KRASG12V and other gene mutations. Background Art

[0003] The RAS gene is one of the most commonly mutated genes in cancer cells, with RAS gene mutations detected in 30% of tumors. The RAS subfamily includes HRAS, NRAS, and KRAS, of which KRAS mutations are the most common in cancer cells, accounting for approximately 85%. KRAS mutations and / or KRAS wild-type amplification are common in colorectal cancer (approximately 45% in the United States and approximately 49% of cases in China), pancreatic cancer (approximately 90% in the United States and approximately 87% of cases in China), and non-small cell lung cancer (subtype adenocarcinoma: approximately 35% in the United States and approximately 13% of cases in China). KRAS mutations have also been found in some cancers, including gastric cancer, uterine cancer, cervical cancer, bladder cancer, bile duct cancer, diffuse large B-cell lymphoma, multiple myeloma, and cutaneous squamous cell carcinoma. The distribution of KRAS genes varies by tumor type, with G12D (41%), G12C (14%), and G12V (28%) being the most common. G12C is mutated in 13.6% of all lung adenocarcinomas, while G12D and G12V are the two most common mutated genes in colorectal cancer and pancreatic cancer.

[0004] KRAS is a guanine nucleotide-binding protein with GTP hydrolase activity, acting as a molecular switch in a range of intracellular signaling pathways. The balance between GDP exchange and GTP hydrolysis determines the level of KRAS activation in cells. When bound to GDP, KRAS is in an "OFF" state. However, under the action of guanine nucleotide exchange factors (such as SOS1), GTP is exchanged for GDP, and KRAS binds to GTP, shifting KRAS to an "ON" state. In its activated state, KRAS can activate downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways, thereby promoting cell proliferation and survival. In cancer cells, KRAS mutations lead to downregulation of KRAS's intrinsic GTP hydrolase activity. Furthermore, KRAS is "locked" in an activated state by GAP-independent activation of KRAS GTP hydrolase activity, resulting in persistent activation of downstream signaling pathways and the resulting persistent growth of tumor cells.

[0005] The affinity of KRAS for GTP is at the picomolar level, and the concentration of GTP in cells is as high as 0.5 μM, so it is difficult for small molecule inhibitors to effectively compete with the GTP binding pocket. In addition, because the surface of KRAS proteins is relatively smooth, they have a nearly spherical structure, no deep hydrophobic pockets, and no obvious binding sites. Therefore, targeting KRAS has been considered very challenging in the past few decades. In recent years, candidate compounds targeting KRASG12C have been developed one after another. Amgen's Sotorasib (AMG510) was approved by the FDA in May 2021 as the world's first drug targeting KRASG12C. However, there are currently no candidate molecules on the market for other mutations, so developing KRAS inhibitors for other subtypes of mutations as soon as possible and pushing them into the clinical stage has also become a key area of ​​development. Summary of the Invention

[0006] The first aspect of the present invention provides a compound represented by general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:

[0007] in,

[0008] M1 is selected from N or CR 4-1 ;

[0009] M2 is selected from O or CH2;

[0010] M3 is selected from N or CR 4-3 ;

[0011] Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-14 Aryl or 5-12 membered heteroaryl; or Ring A is absent, and L1 is directly connected to R1;

[0012] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-14 Aryl or 5-12 membered heteroaryl;

[0013] L1 is selected from a bond, CO or -(CH2) m -, of which -(CH2) m - optionally substituted with one or more R6;

[0014] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -CONR 1a R 1b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0015] R 1a and R 1b are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl;

[0016] R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0017] Alternatively, two R2 on the same carbon atom link to form C3-8 Cycloalkyl;

[0018] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, optionally further substituted by one or more R 3a replace;

[0019] R 3a Selected from deuterium, halogen, amino, C 1-6 Alkylamino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, The amino group, C 1-6 Alkylamino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, Optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0020] R 3-1 and R 3-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0021] R 4-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0022] R 4-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0023] R 4-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0024] R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0025] R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0026] n is selected from 1, 2 or 3;

[0027] m is selected from 1, 2 or 3;

[0028] x is selected from 0, 1, 2, 3 or 4;

[0029] y is selected from 0, 1, 2, 3 or 4;

[0030] z is selected from 0, 1, 2, 3 or 4.

[0031] In certain embodiments of the present invention, M1 is selected from CR 4-1 ; M2 is selected from O; M3 is selected from N; the definitions of other groups are as defined in any technical solution herein.

[0032] In certain embodiments of the present invention, n is selected from 1; and the definitions of other groups are as defined in any technical solution herein.

[0033] In certain embodiments of the present invention, m is selected from 1; and the definitions of other groups are as defined in any technical solution herein.

[0034] In certain embodiments of the present invention, the ring A is selected from phenyl, 5-6 membered heteroaryl, -phenyl and 5-6 membered heteroaryl, -5-6 membered heteroaryl and phenyl, -5-6 membered heteroaryl and 5-6 membered heteroaryl, -3-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, -C 3-8 Cycloalkenyl 5-6 membered heteroaryl, -C 3-8 Heterocycloalkenylphenyl, C 3-6 cycloalkyl, -5-6 membered heteroaryl and 3-6 membered heterocycloalkenyl, -3-6 membered heterocycloalkyl.

[0035] In certain embodiments of the present invention, the ring A is selected from phenyl, 5-6 membered heteroaryl, -phenyl and 5-6 membered heteroaryl, -5-6 membered heteroaryl and phenyl, -5-6 membered heteroaryl and 5-6 membered heteroaryl, -3-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, -C 3-8 Cycloalkenyl and 5-6 membered heteroaryl, C 3-6 Cycloalkyl, -5-6 membered heteroaryl and 3-6 membered heterocycloalkenyl, -3-6 membered heterocycloalkyl;

[0036] Preferably, ring A is selected from phenyl, More preferably, ring A is selected from phenyl,

[0037] The definitions of other groups are as defined in any technical solution herein.

[0038] In certain embodiments of the present invention, Ring B is selected from 5-6 membered heteroaryl, -phenyl 5-6 membered heteroaryl, -pyrido 5-6 membered heteroaryl, naphthyl;

[0039] Preferably, ring B is selected from

[0040] The definitions of other groups are as defined in any technical solution herein.

[0041] In certain embodiments of the present invention, the compound represented by general formula (I) is further represented by general formula (II),

[0042] wherein ring A is selected from -phenyl and 5-6 membered heteroaryl, -5-6 membered heteroaryl and phenyl, -5-6 membered heteroaryl and 5-6 membered heteroaryl, -3-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, -C 3-8 Cycloalkenyl 5-6 membered heteroaryl, -5-6 membered heteroaryl 3-6 membered heterocycloalkenyl;

[0043] Preferably, ring A is selected from

[0044] The definitions of other groups are as defined in any technical solution herein.

[0045] In certain embodiments of the present invention, ring A is selected from -phenyl and 5-6 membered heteroaryl, preferably The definitions of other groups are as defined in any technical solution herein.

[0046] In certain embodiments of the present invention, ring A is selected from 5-6 membered heteroarylphenyl, preferably The definitions of other groups are as defined in any technical solution herein.

[0047] In certain embodiments of the present invention, ring A is selected from -5-6 membered heteroaryl and 5-6 membered heteroaryl, preferably The definitions of other groups are as defined in any technical solution herein.

[0048] In certain embodiments of the present invention, the compound represented by general formula (II) is further represented by general formula (II-A) or general formula (II-B).

[0049] The definitions of other groups are as defined in any technical solution herein.

[0050] In certain embodiments of the present invention, the compound represented by general formula (I) is further represented by general formula (III),

[0051] wherein R6 is selected from -CH2OCH3, -CH2OH, -CH2OCD3;

[0052] The definitions of other groups are as defined in any technical solution herein.

[0053] In certain embodiments of the present invention, R6 is selected from -CH2OCH3; the definitions of other groups are as defined in any technical solution herein.

[0054] In certain embodiments of the present invention, R6 is selected from -CH2OH; the definitions of other groups are as defined in any technical solution herein.

[0055] In certain embodiments of the present invention, R6 is selected from -CH2OCD3; the definitions of other groups are as defined in any technical solution herein.

[0056] In certain embodiments of the present invention, the compound represented by general formula (III) is further represented by general formula (III-A) or general formula (III-B).

[0057] The definitions of other groups are as defined in any technical solution herein.

[0058] In certain embodiments of the present invention, the compound represented by general formula (I) is further represented by general formula (IV),

[0059] The definitions of other groups are as defined in any technical solution herein.

[0060] In certain embodiments of the present invention, the compound represented by the general formula (IV) is further represented by the general formula (IV-A) or the general formula (IV-B).

[0061] The definitions of other groups are as defined in any technical solution herein.

[0062] In certain embodiments of the present invention, the compound represented by general formula (I) is further represented by general formula (V),

[0063] in,

[0064] Ring A is selected from 5-membered heteroaryl groups, preferably Or ring A is selected from

[0065] R6 is independently selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0066] The definitions of other groups are as defined in any technical solution herein.

[0067] In certain embodiments of the present invention, R6 is independently selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl;

[0068] The definitions of other groups are as defined in any technical solution herein.

[0069] In certain embodiments of the present invention, R6 is independently selected from deuterium, methyl, ethynyl, -CH2OCH3, -CH2OH, -CH2OCD3, -CH2SCH3;

[0070] The definitions of other groups are as defined in any technical solution herein.

[0071] In certain embodiments of the present invention, Ring A is selected from The definitions of other groups are as defined in any technical solution herein.

[0072] In certain embodiments of the present invention, Ring A is selected from The definitions of other groups are as defined in any technical solution herein.

[0073] In certain embodiments of the present invention, Ring A is selected from The definitions of other groups are as defined in any technical solution herein.

[0074] In certain embodiments of the present invention, the compound represented by general formula (V) is further represented by general formula (VA) or general formula (VB).

[0075] The definitions of other groups are as defined in any technical solution herein.

[0076] In certain embodiments of the present invention, the compound represented by general formula (I) is further represented by general formula (VI),

[0077] R3 is selected from

[0078] Preferably, R3 is selected from

[0079] The definitions of other groups are as defined in any technical solution herein.

[0080] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0081] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0082] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0083] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0084] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0085] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0086] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0087] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0088] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0089] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0090] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0091] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0092] In certain embodiments of the present invention, R3 is selected from The definitions of other groups are as defined in any technical solution herein.

[0093] In certain embodiments of the present invention, the compound represented by the general formula (VI) is further represented by the general formula (VI-A) or the general formula (VI-B).

[0094] The definitions of other groups are as defined in any technical solution herein.

[0095] In certain embodiments of the present invention, the compound represented by the general formula (I) is further represented by the general formula (VII-1) or (VII-2).

[0096] M4 is selected from N or CH;

[0097] The definitions of other groups are as defined in any technical solution herein.

[0098] In certain embodiments of the present invention, M4 is selected from N; the definitions of other groups are as defined in any technical solution herein.

[0099] In certain embodiments of the present invention, M4 is selected from CH; the definitions of other groups are as defined in any technical solution herein.

[0100] In certain embodiments of the present invention, the compounds represented by the general formula (VII-1) and (VII-2) are further represented by the general formula (VII-1-A), the general formula (VII-1-B), the general formula (VII-2-A), and the general formula (VII-2-B).

[0101] The definitions of other groups are as defined in any technical solution herein.

[0102] In certain embodiments of the present invention, the compound represented by the general formula (I) is further represented by the general formula (VIII-1), the general formula (VIII-2), the general formula (VIII-3), or the general formula (VIII-4).

[0103] The definitions of other groups are as defined in any technical solution herein.

[0104] In certain embodiments of the present invention, the compound represented by the general formula (VIII-1), the general formula (VIII-2), the general formula (VIII-3), or the general formula (VIII-4) is further represented by the general formula (VIII-1-A), the general formula (VIII-1-B), the general formula (VIII-2-A), the general formula (VIII-2-B), the general formula (VIII-3-A), the general formula (VIII-3-B), the general formula (VIII-4-A), or the general formula (VIII-4-B).

[0105] The definitions of other groups are as defined in any technical solution herein.

[0106] In certain embodiments of the present invention, the compound represented by general formula (I) is represented by general formula (IX),

[0107] x is selected from 0, 1, 2 or 3;

[0108] The definitions of other groups are as defined in any technical solution herein.

[0109] In certain embodiments of the present invention, the compound represented by the general formula (IX) is further represented by the general formula (IX-A) or the general formula (IX-B).

[0110] The definitions of other groups are as defined in any technical solution herein.

[0111] In certain embodiments of the present invention, the compound represented by general formula (I) is further represented by general formula (X),

[0112] Among them, R 4-1 Selected from trifluoromethyl, vinyl, difluoromethyl;

[0113] The definitions of other groups are as defined in any technical solution herein.

[0114] In certain embodiments of the present invention, R 4-1 is selected from trifluoromethyl; the definitions of other groups are as defined in any technical solution herein.

[0115] In certain embodiments of the present invention, R 4-1 The definitions of other groups are as defined in any technical solution herein.

[0116] In certain embodiments of the present invention, R 4-1 is selected from difluoromethyl; the definitions of other groups are as defined in any technical solution herein.

[0117] In certain embodiments of the present invention, the compound represented by the general formula (X) is further represented by the general formula (XA) or the general formula (XB).

[0118] The definitions of other groups are as defined in any technical solution herein.

[0119] In certain embodiments of the present invention, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CONR 1a R 1b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl;

[0120] R 1a and R 1b are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl;

[0121] The definitions of other groups are as defined in any technical solution herein.

[0122] In certain embodiments of the present invention, R1 is independently selected from hydrogen, amino, chloro, methyl, -CONH2, -CON(CH3)2, -CH2OH, fluoro, cyano, -CH2NH2;

[0123] The definitions of other groups are as defined in any technical solution herein.

[0124] In certain embodiments of the present invention, Ring A is absent, -L1-R1 is The definitions of other groups are as defined in any technical solution herein.

[0125] In certain embodiments of the present invention, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl group and the 3-6 membered heterocycloalkyl group are substituted by one or more substituents; the definitions of other groups are as defined in any technical solution herein.

[0126] In certain embodiments of the present invention, R2 is independently selected from hydrogen, deuterium, fluorine, and cyclopropyl; the definitions of other groups are as defined in any technical solution herein.

[0127] In certain embodiments of the present invention, two R2 on the same carbon atom are linked to form a cyclopropyl group; the definitions of other groups are as defined in any technical solution herein.

[0128] In certain embodiments of the present invention, R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, optionally further substituted by one or more R 3a replace;

[0129] R 3a Selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, The amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, Optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0130] The definitions of other groups are as defined in any technical solution herein.

[0131] In certain embodiments of the present invention, R3 is selected from

[0132] The definitions of other groups are as defined in any technical solution herein.

[0133] In certain embodiments of the present invention, R3 is selected from

[0134] The definitions of other groups are as defined in any technical solution herein.

[0135] In certain embodiments of the present invention, R 3-1 and R 3-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl;

[0136] The definitions of other groups are as defined in any technical solution herein.

[0137] In certain embodiments of the present invention, R 3-1 and R 3-2 are each independently selected from hydrogen and deuterium;

[0138] The definitions of other groups are as defined in any technical solution herein.

[0139] In certain embodiments of the present invention, R 4-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl group and the 3-6 membered heterocycloalkyl group are substituted by one or more substituents; the definitions of other groups are as defined in any technical solution herein.

[0140] In certain embodiments of the present invention, R 4-1 Selected from chloro, trifluoromethyl, vinyl, difluoromethyl;

[0141] The definitions of other groups are as defined in any technical solution herein.

[0142] In certain embodiments of the present invention, R 4-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl;

[0143] The definitions of other groups are as defined in any technical solution herein.

[0144] In certain embodiments of the present invention, R 4-2 selected from fluorine;

[0145] The definitions of other groups are as defined in any technical solution herein.

[0146] In certain embodiments of the present invention, R 4-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl;

[0147] The definitions of other groups are as defined in any technical solution herein.

[0148] In certain embodiments of the present invention, R 4-3 selected from cyano;

[0149] The definitions of other groups are as defined in any technical solution herein.

[0150] In certain embodiments of the present invention, R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl;

[0151] The definitions of other groups are as defined in any technical solution herein.

[0152] In certain embodiments of the present invention, R5 is independently selected from hydrogen, amino, trifluoromethyl, methyl, fluoro, hydroxy, ethynyl, cyano;

[0153] The definitions of other groups are as defined in any technical solution herein.

[0154] In certain embodiments of the present invention, R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl;

[0155] The definitions of other groups are as defined in any technical solution herein.

[0156] In certain embodiments of the present invention, R6 is independently selected from hydrogen, deuterium, methyl, ethynyl, -CH2OCH3, -CH2OH, -CH2OCD3, -CH2SCH3;

[0157] The definitions of other groups are as defined in any technical solution herein.

[0158] The first aspect of the present invention also provides the following compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof;

[0159] The definition of the group is as defined in any technical solution herein.

[0160] In one technical solution of formula (I) of the present invention, it is a compound represented by formula (XIII), or a pharmaceutically acceptable salt or stereoisomer thereof:

[0161] Among them, M4, M5, M 6、 M7 are each independently selected from N or CH; R1, R2, R3, R 3-1 、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z have the same definitions as in formula (I) of the present invention or any other technical solution.

[0162] In any technical solution of formula (XIII) of the present invention, x, y, and z are each independently selected from 0, 1, 2, 3, and 4.

[0163] In any technical solution of formula (XIII) of the present invention, R1 is selected from H, OH, CN, deuterium, amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the amino group may be optionally replaced by 1-2 C 1-4 Alkyl substitution.

[0164] In any technical solution of formula (XIII) of the present invention, R1 is selected from CN, NH2, F, methyl, and trifluoromethyl.

[0165] In any technical solution of formula (XIII) of the present invention, R1 is selected from CN and NH2.

[0166] In any technical solution of formula (XIII) of the present invention, R1 is selected from F and NH2.

[0167] In any technical solution of formula (XIII) of the present invention, R1 is selected from NH2.

[0168] In any technical solution of formula (XIII) of the present invention, R2 is selected from H, OH, CN, deuterium, amino, halogen, C 1-4Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0169] In any technical solution of formula (XIII) of the present invention, R2 is selected from H, F, Cl, CN, deuterium, methyl, ethyl, and trifluoromethyl.

[0170] In any technical solution of formula (XIII) of the present invention, R2 is selected from H, F, Cl, CN, methyl, ethyl, and trifluoromethyl.

[0171] In any technical solution of formula (XIII) of the present invention, R2 is selected from H, deuterium, and methyl.

[0172] In any technical solution of formula (XIII) of the present invention, R2 is H, or R2 is deuterium, or R2 is methyl. In any technical solution of formula (XIII) of the present invention, R2 is H.

[0173] In any technical solution of formula (XIII) of the present invention, R 3-1 and R 3-2 are each independently selected from H, deuterium, halogen, amino, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy.

[0174] In any technical solution of formula (XIII) of the present invention, R 3-1 and R 3-2 Each is independently selected from H, D, and F.

[0175] In any technical solution of formula (XIII) of the present invention, R 3-1 and R 3-2 Both are D.

[0176] In any technical solution of formula (XIII) of the present invention, R 3-1 and R 3-2 Both are H.

[0177] In any technical solution of formula (XIII) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a Selected from OH, amino, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, methenyl (CH2=), or the R 3ais selected from OH, amino, F, Cl, methyl, ethyl, 2,2-difluoroethyl, and methylene; or said R 3a is selected from F or methylene.

[0178] In any technical solution of formula (XIII) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a Selected from OH, amino, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, or the R 3a is selected from F, Cl, methyl, 2,2-difluoroethyl; or said R 3a Selected from F, methyl, 2,2-difluoroethyl.

[0179] In any technical solution of formula (XIII) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a Selected from OH, amino, halogen atom, C 1-4 Alkyl, C 1-4 Halogenated alkyl, methylene (CH2=).

[0180] In any technical solution of formula (XIII) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a is selected from OH, amino, F, Cl, methyl, ethyl, and methylene; or said R 3a is selected from F or methylene.

[0181] In any technical solution of formula (XIII) of the present invention, R3 is selected from

[0182] In any technical solution of formula (XIII) of the present invention, R3 is selected from

[0183] In any technical solution of formula (XIII) of the present invention, R3 is selected from

[0184] In any technical solution of formula (XIII) of the present invention, Selected from

[0185] In any technical solution of formula (XIII) of the present invention, Selected from

[0186] In any technical solution of formula (XIII) of the present invention, Selected from

[0187] In any technical solution of formula (XIII) of the present invention, R 4-1 Selected from H, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkynyl.

[0188] In any technical solution of formula (XIII) of the present invention, R 4-1 Selected from CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl.

[0189] In any technical solution of formula (XIII) of the present invention, R 4-1 Selected from H, CN, OH, methyl, ethyl, monofluoromethyl, trifluoromethyl, trichloromethyl, methoxy, ethynyl, propynyl.

[0190] In any technical solution of formula (XIII) of the present invention, R 4-1 Selected from CN, OH, methyl, ethyl, trifluoromethyl, trichloromethyl, methoxy.

[0191] In any technical solution of formula (XIII) of the present invention, R 4-1 It is monofluoromethyl, trifluoromethyl, or ethynyl.

[0192] In any technical solution of formula (XIII) of the present invention, R 4-1 It is trifluoromethyl.

[0193] In any technical solution of formula (XIII) of the present invention, R 4-1 For ethynyl.

[0194] In any technical solution of formula (XIII) of the present invention, R 4-2 Selected from CN, OH, halogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl.

[0195] In any technical solution of formula (XIII) of the present invention, R 4-2 Selected from CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl.

[0196] In any technical solution of formula (XIII) of the present invention, R 4-2 is selected from F or trifluoromethyl.

[0197] In any technical solution of formula (XIII) of the present invention, R 4-2 For F.

[0198] In any technical solution of formula (XIII) of the present invention, R5 is selected from amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0199] In any technical solution of formula (XIII) of the present invention, R5 is selected from amino, F, Cl, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl;

[0200] In any technical solution of formula (XIII) of the present invention, R5 is selected from amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 In any technical solution of formula (XIII) of the present invention, R5 is selected from F, amino, methyl, and trifluoromethyl.

[0201] In any technical solution of formula (XIII) of the present invention, for

[0202] In any technical solution of formula (XIII) of the present invention, for

[0203] In any technical solution of formula (XIII) of the present invention, for

[0204] In any technical solution of formula (XIII) of the present invention, R6 is selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, cyano-C 1-4 Alkyl, halogenated C 3-6 Cycloalkyl-O-alkyl, halogenated 3-6 membered heterocycloalkyl-O-alkyl.

[0205] In any technical solution of formula (XIII) of the present invention, R6 is selected from methyl, -CD3, ethyl, trifluoromethyl, methoxy, methoxymethyl, hydroxymethyl, cyanomethyl, 2,2-difluorocyclobutane-3-yl-O-methyl.

[0206] In any technical solution of formula (XIII) of the present invention, R6 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 In any technical solution of formula (XIII) of the present invention, R6 is selected from methyl, ethyl, trifluoromethyl, methoxy, methoxymethyl, and hydroxymethyl.

[0207] In any technical solution of formula (XIII) of the present invention, R6 is methyl.

[0208] In any technical solution of formula (XIII) of the present invention, R6 is a hydroxymethyl group.

[0209] In any technical solution of formula (XIII) of the present invention, R6 is methoxymethyl.

[0210] In any technical solution of formula (XIII) of the present invention, it is a compound represented by formula (XIIIa) or formula (XIIIb), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof

[0211] In one technical solution of the present invention, the compound represented by formula (I) or formula (XIII), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is a compound represented by formula (XI), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0212] Wherein, M4, M5, M6 are each independently selected from N or CH; R1, R2, R3, R 3-1 、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z have the same definitions as in Formula I of the present invention or any other technical solution.

[0213] In any technical solution of formula (XI) of the present invention, x, y, and z are each independently selected from 0, 1, 2, 3, and 4.

[0214] In any technical solution of formula (XI) of the present invention, R1 is selected from H, OH, CN, deuterium, amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Alkoxy, hydroxy-C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the amino group may be optionally replaced by 1-2 C 1-4 Alkyl substitution.

[0215] In any technical solution of formula (XI) of the present invention, R1 is selected from CN, NH2, F, methyl, and trifluoromethyl.

[0216] In any technical solution of formula (XI) of the present invention, R1 is selected from CN and NH2.

[0217] In any technical solution of formula (XI) of the present invention, R1 is selected from F and NH2. In any technical solution of formula (XI) of the present invention, R1 is selected from NH2.

[0218] In any technical solution of formula (XI) of the present invention, R2 is selected from H, OH, CN, deuterium, amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0219] In any technical solution of formula (XI) of the present invention, R2 is selected from H, F, Cl, CN, deuterium, methyl, ethyl, and trifluoromethyl.

[0220] In any technical solution of formula (XI) of the present invention, R2 is selected from H, F, Cl, CN, methyl, ethyl, and trifluoromethyl.

[0221] In any technical solution of formula (XI) of the present invention, R2 is selected from H, deuterium, and methyl.

[0222] In any technical solution of formula (XI) of the present invention, R2 is H, or R2 is deuterium, or R2 is methyl. In any technical solution of formula (XI) of the present invention, R2 is H.

[0223] In any technical solution of formula (XI) of the present invention, R 3-1 and R 3-2 are each independently selected from H, deuterium, halogen, amino, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy.

[0224] In any technical solution of formula (XI) of the present invention, R 3-1 and R 3-2 Each is independently selected from H, D, and F.

[0225] In any technical solution of formula (XI) of the present invention, R 3-1 and R 3-2 Both are D.

[0226] In any technical solution of formula (XI) of the present invention, R 3-1 and R 3-2 Both are H.

[0227] In any technical solution of formula (XI) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a Selected from OH, amino, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, methenyl (CH2=), or the R 3a is selected from OH, amino, F, Cl, methyl, ethyl, 2,2-difluoroethyl, and methylene; or said R 3a is selected from F or methylene.

[0228] In any technical solution of formula (XI) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a Selected from OH, amino, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, or the R 3a is selected from F, Cl, methyl, 2,2-difluoroethyl; or said R 3a Selected from F, methyl, 2,2-difluoroethyl.

[0229] In any technical solution of formula (XI) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a Selected from OH, amino, halogen atom, C 1-4 Alkyl, C 1-4 Halogenated alkyl, methylene (CH2=).

[0230] In any technical solution of formula (XI) of the present invention, R3 is and optionally one or more R 3a Substitution; said R 3a is selected from OH, amino, F, Cl, methyl, ethyl, and methylene; or said R 3a is selected from F or methylene.

[0231] In any technical solution of formula (XI) of the present invention, R3 is selected from

[0232] In any technical solution of formula (XI) of the present invention, R3 is selected from

[0233] In any technical solution of formula (XI) of the present invention, R3 is selected from

[0234] In any technical solution of formula (XI) of the present invention, Selected from

[0235] In any technical solution of formula (XI) of the present invention, Selected from

[0236] In any technical solution of formula (XI) of the present invention, Selected from

[0237] In any technical solution of formula (XI) of the present invention, R 4-1 Selected from H, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkynyl.

[0238] In any technical solution of formula (XI) of the present invention, R 4-1 Selected from CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl.

[0239] In any technical solution of formula (XI) of the present invention, R 4-1 Selected from H, CN, OH, methyl, ethyl, monofluoromethyl, trifluoromethyl, trichloromethyl, methoxy, ethynyl, propynyl.

[0240] In any technical solution of formula (XI) of the present invention, R 4-1 Selected from CN, OH, methyl, ethyl, trifluoromethyl, trichloromethyl, methoxy.

[0241] In any technical solution of formula (XI) of the present invention, R 4-1 It is monofluoromethyl, trifluoromethyl, or ethynyl.

[0242] In any technical solution of formula (XI) of the present invention, R 4-1 It is trifluoromethyl.

[0243] In any technical solution of formula (XI) of the present invention, R 4-1 For ethynyl.

[0244] In any technical solution of formula (XI) of the present invention, R 4-2 Selected from CN, OH, halogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl.

[0245] In any technical solution of formula (XI) of the present invention, R 4-2 Selected from CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl.

[0246] In any technical solution of formula (XI) of the present invention, R 4-2 is selected from F or trifluoromethyl.

[0247] In any technical solution of formula (XI) of the present invention, R 4-2 For F.

[0248] In any technical solution of formula (XI) of the present invention, R5 is selected from amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0249] In any technical solution of formula (XI) of the present invention, R5 is selected from amino, F, Cl, methyl, ethyl, difluoromethyl, trifluoromethyl, and cyclopropyl.

[0250] In any technical solution of formula (XI) of the present invention, R5 is selected from amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 In any technical solution of formula (XI) of the present invention, R5 is selected from F, amino, methyl, and trifluoromethyl.

[0251] In any technical solution of formula (XI) of the present invention, for

[0252] In any technical solution of formula (XI) of the present invention, for

[0253] In any technical solution of formula (XI) of the present invention, for

[0254] In any technical solution of formula (XI) of the present invention, R6 is selected from C 1-4Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, cyano-C 1-4 Alkyl, halogenated C 3-6 Cycloalkyl-O-alkyl, halogenated 3-6 membered heterocycloalkyl-O-alkyl.

[0255] In any technical solution of formula (XI) of the present invention, R6 is selected from methyl, -CD3, ethyl, trifluoromethyl, methoxy, methoxymethyl, hydroxymethyl, cyanomethyl, 2,2-difluorocyclobutane-3-yl-O-methyl.

[0256] In any technical solution of formula (XI) of the present invention, R6 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 In any technical solution of formula (XI) of the present invention, R6 is selected from methyl, ethyl, trifluoromethyl, methoxy, methoxymethyl, and hydroxymethyl.

[0257] In any technical solution of formula (XI) of the present invention, R6 is methyl.

[0258] In any technical solution of formula (XI) of the present invention, R6 is a hydroxymethyl group.

[0259] In any technical solution of formula (XI) of the present invention, R6 is methoxymethyl.

[0260] In any technical solution of formula (XI) of the present invention, M4, M5 and M6 are all CH.

[0261] In any technical solution of formula (XI) of the present invention, M4 is N, and M5 and M6 are both CH.

[0262] In any technical solution of formula (XI) of the present invention, M5 is N, and M4 and M6 are both CH.

[0263] In any technical solution of formula (XI) of the present invention, M6 is N, and M4 and M5 are both CH.

[0264] In any technical solution of formula (XI) of the present invention, Selected from

[0265] In any technical solution of formula (XI) of the present invention, Selected from

[0266] In any technical solution of formula (XI) of the present invention, M4, M5, and M6 are all CH, R1 is NH2, R2 is H, and R3 is selected from R 4-1 C 1-4 Haloalkyl, preferably trifluoromethyl; R 4-2 Halogen atoms, C 1-4 Haloalkyl, preferably F; R5 is selected from amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, preferably F, Cl, amino, methyl, trifluoromethyl; R6 is selected from C 1-4 Alkyl, C 1-4 The haloalkyl group is preferably a methyl group. x is 1, y is 0, and z is 3.

[0267] In one technical solution of formula (XI) of the present invention, it has a compound of formula (XI-A) or formula (XI-B), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0268] Wherein, M4, M5, M6 are each independently selected from N or CH; R1, R2, R3, R 3-1 、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z are as defined in formula (I), formula (XI) or any other technical solution of the present invention.

[0269] In one technical solution of formula (XI) of the present invention, it has a structure represented by any one of formula (XI-1), formula (XI-2), formula (XI-3), formula (XI-4), and formula (XI-5):

[0270] Wherein, M4, M5, and M6 are each independently selected from N or CH; R1, R3, and R 4-1 、R 4-2 , R6 is as defined in formula (I), formula (XI) or any other technical solution of the present invention, R 5-1 、R 5-2 、R 5-3 Each independently has the same meaning as R5 in formula (I), formula (XI) or any other technical solution of the present invention. In any technical solution of formula (XI-1), formula (XI-2) or formula (XI-3) of the present invention, R 5-3 Preferably trifluoromethyl, trichloromethyl, F, Cl, R 5-3 Preferably F.

[0271] In one technical solution of formula (XI) of the present invention, it is a compound represented by formula (XI-5A) or formula (XI-5B), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0272] Among them, R3, R 4-2 , R6 is as defined in formula (I) or formula (XI) and any technical solution thereof.

[0273] In one technical solution of formula (XI) of the present invention, it is a compound represented by formula (XI-6), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0274] Among them, R 1a 、R 1b independently selected from H, D, CN, halogen atoms, C 1-3 Alkyl, C 1-3 Haloalkyl; R 2a 、R 2b Each independently selected from H, D, C 1-3 Alkyl, C 1-3 haloalkyl; y is independently selected from 0, 1, 2; z is independently selected from 0, 1, 2, 3; M4 is selected from N, CF or CH; R3, R 4-1 、R 4-2 , R5, and R6 have the same meanings as in formula (XI) and any of its embodiments.

[0275] In any technical solution of formula (XI-6) of the present invention, R 1a 、R 1b are independently selected from H, D, CN, F, Cl, methyl, trifluoromethyl, or R 1a 、R 1b are independently selected from H, CN, F, methyl; M4 is N or CH; R 2a 、R 2b Each is independently selected from H, D. R 4-1 is trifluoromethyl, R 4-2 is F; R5 is selected from amino, F, Cl, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl; R6 is selected from methyl; R3 is y is independently selected from 0, 1, and 2; z is independently selected from 0, 1, 2, and 3.

[0276] In a technical solution of formula (I) or formula (XIII) of the present invention, it is a compound represented by formula (XII), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0277] Wherein, M4 is selected from N or CH; R1, R2, R3, R 3-1、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z have the same definitions as in formula (I), formula (XIII), formula (XI) and any technical solution thereof of the present invention.

[0278] In a technical solution of formula (XII) of the present invention, M4 is selected from CH; R1 is selected from H, CN, NH2, F, methyl, trifluoromethyl; R2, R 3-1 、R 3-2 Both H; R 4-1 is trifluoromethyl, R 4-2 is a halogen atom; R5 is selected from amino, F, Cl, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl; R6 is selected from methyl, trifluoromethyl; R3 is selected from x and y are both 0, and z is selected from 0, 1, 2, 3, 4, and 5.

[0279] In a technical solution of formula (XII) of the present invention, M4 is selected from CH; R1, R2, R 3-1 、R 3-2 Both H; R 4-1 is trifluoromethyl, R 4-2 is F; R5 is selected from amino, F, Cl, methyl; R6 is selected from methyl; R3 is selected from x, y, and z have the same definitions as in formula (I), formula (XIII), formula (XII) of the present invention and any technical solution thereof.

[0280] In one technical solution of formula (XII) of the present invention, it is a compound represented by formula (XIIa), or a pharmaceutically acceptable salt or stereoisomer thereof:

[0281] Among them, R 1a 、R 1b independently selected from H, D, CN, halogen atoms, C 1-3 Alkyl, C 1-3 Haloalkyl; R 2a 、R 2b Each independently selected from H, D, C 1-3 Alkyl, C 1-3 haloalkyl; y is independently selected from 0, 1, 2; z is independently selected from 0, 1, 2, 3, 4; M4 is selected from N or CH; R3, R 4-1 、R 4-2 , R5, and R6 have the same meanings as in formula (XI), formula (XI-6), formula (XII) and any of their embodiments.

[0282] In any technical solution of formula (XIIa) of the present invention, R 1a 、R1b are independently selected from H, D, CN, F, Cl, methyl, trifluoromethyl, or R 1a 、R 1b are independently selected from H, CN, F, methyl, or R 1a 、R 1b Both H; R 2a 、R 2b are independently selected from H, D; M4 is N or CH; R 4-1 is trifluoromethyl, R 4-2 is F; R5 is selected from amino, F, Cl, methyl, trifluoromethyl, cyclopropyl; R6 is selected from methyl; R3 is y is independently selected from 0, 1, 2; z is independently selected from 0, 1, 2, 3, 4.

[0283] In any technical solution of formula (XIIa) of the present invention, R 1a 、R 1b 、R 2a 、R 2b All are H; M4 is CH; R 4-1 is trifluoromethyl, R 4-2 is F; R5 is selected from F, Cl, methyl; R6 is selected from methyl; R3 is y is 0; z is independently selected from 0, 1, 2, 3, and 4.

[0284] In one technical solution of formula (XII) or formula (XIIa) of the present invention, it has a compound represented by formula (XIIa-A) or formula (XIIa-B), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0285] In one technical solution of formula (XII) of the present invention, it is a compound represented by formula (XII-1), formula (XII-2), formula (XII-3), formula (XII-4), formula (XII-5), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0286] wherein q is selected from 1, 2, 3, and 4; R3, R 4-1 、R 4-2 , R5, R6, R 3a , z has the same meaning as in formula (I), formula (XIII), or formula (XII) and any technical solution thereof; R 5-2 、R 5-3 、R 5-4 、R 5-5 It has the same meaning as R5 in formula (I), formula (XIII), formula (XI), formula (XII) and any technical solution thereof.

[0287] The first aspect of the present invention also provides the following compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof;

[0288] The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and any pharmaceutically acceptable carrier. In certain embodiments of the present invention, in the pharmaceutical composition, the content of the compound, stereoisomer, or pharmaceutically acceptable salt thereof is selected from 0.1 mg to 1000 mg. In certain embodiments of the present invention, in the pharmaceutical composition, the pharmaceutically acceptable carrier comprises one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0289] The third aspect of the present invention provides the use of the compound described in the first aspect of the present invention, its pharmaceutically acceptable salt or its stereoisomer in the preparation of a medicament for treating diseases associated with KRAS G12V gene mutation and other types of KRAS gene mutation; the diseases are preferably colorectal cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, uterine cancer, cervical cancer, bladder cancer, bile duct cancer, diffuse large B-cell lymphoma, multiple myeloma, and cutaneous squamous cell carcinoma.

[0290] The fourth aspect of the present invention provides the use of the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for treating diseases associated with KRAS G12V gene mutation and other types of KRAS gene mutation; the diseases are preferably colorectal cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, uterine cancer, cervical cancer, bladder cancer, bile duct cancer, diffuse large B-cell lymphoma, multiple myeloma, and cutaneous squamous cell carcinoma.

[0291] The fifth aspect of the present invention provides a method for treating diseases associated with KRAS G12V gene mutation and other types of KRAS gene mutations, the method comprising administering to a patient in need thereof an effective amount of the compound of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition of the second aspect of the present invention.

[0292] In the present invention, the disease associated with KRAS G12V gene mutation may be lung cancer associated with KRAS G12V gene mutation.

[0293] Definition and Explanation

[0294] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0295] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0296] The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes in the disclosed compounds include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically labeled reagent in place of the unlabeled reagent.

[0297] The term "prodrug" refers to certain derivatives of the compounds of the present invention that have little or no pharmacological activity themselves, which have a cleavable group and decompose into the compounds of the present invention through solvent decomposition or under physiological conditions. The types of prodrugs include, but are not limited to, amides, esters, anhydrides, salts, etc. The "ester" refers to a derivative formed with a suitable alcohol when the compound of the present invention contains an acidic group (such as a carboxylic acid); when the compound of the present invention contains a hydroxyl group, it is formed with a suitable acid (including an organic acid or an inorganic acid). The preparation method of prodrugs is well known to those skilled in the art.

[0298] The term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. The term "hydrate" may be used when the solvent is water. The solvent molecules may be present in stoichiometric or non-stoichiometric amounts. Methods for preparing solvates are known in the art.

[0299] The term "nitrogen oxide" or "N-oxide" refers to a derivative formed by further oxidation of the nitrogen atom in a nitrogen-containing group. Common N-oxides include N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. Synthesis methods of N-oxides are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines using peroxyacids such as peracetic acid and m-chloroperbenzoic acid, hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0300] The compounds of the present disclosure and their salts may exist as isotopic derivatives, and the compounds of the present disclosure include various isotopic derivatives and mixtures thereof.

[0301] The compounds of the present disclosure and their salts may exist in the form of solvates, such as hydrates, and the compounds of the present disclosure include various solvates and mixtures thereof.

[0302] The compounds of the present disclosure and their salts may exist in the form of "N-oxides", and the compounds of the present disclosure include various N-oxides and mixtures thereof.

[0303] The compounds described in the present disclosure, and their pharmaceutically acceptable salts, isotopic derivatives, solvates, and N-oxides have the same or similar biological activities and are all included within the scope of the present disclosure.

[0304] The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of the compound of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof, and compositions must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination with or concurrently with the specific compound employed; and similar factors well known in the medical field.

[0305] The absolute stereo configuration of a compound can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction can be used. Alternatively, the absolute configuration of a compound can be confirmed based on the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereo configuration can be determined by comparison with a product with a confirmed absolute configuration. Compounds labeled "absolute configuration unknown / undetermined" herein are typically resolved from racemic compounds into individual isomers by chiral preparative SFC, followed by characterization and testing.

[0306] The term "optionally" means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on chemical feasibility. For example, the term "optionally substituted with one or more R6" means that it may be substituted with one or more R6 or not. When any variable (such as R1) appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, It means that pyridine is replaced by x R1, and each R1 has independent options.

[0307] "Substitution" means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents, for example, It means that x hydrogen atoms on the six-membered heterocyclic ring are replaced by x R1 atoms; when x is 0, all the atoms connected to the six-membered heterocyclic ring are hydrogen atoms.

[0308] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that the substituent R1 can be substituted at any position on pyridine.

[0309] When a substituent is listed without specifying the atom through which it is bonded to a compound included in the general chemical formula but not specifically mentioned, the substituent may be bonded through any atom thereof. For example, pyrimidine as a substituent means that any carbon atom or nitrogen atom on the pyrimidine ring is bonded to the substituted group; when a substituent appears in the structure , it indicates that the atom is a bonding atom, for example It means that the C atom on pyridine is a bonding atom.

[0310] Unless otherwise specified, the term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having the specified number of carbon atoms by removing one hydrogen, including "C 1-6 Alkyl", "C 1-3 Alkyl" etc. For example, "C 1-6The term "alkyl" refers to C1, C2, C3, C4, C5, and C6 alkyl groups, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, and 1,1-dimethylbutyl.

[0311] Unless otherwise specified, the term "deuterated alkyl" refers to a group obtained by replacing one or more hydrogen atoms of an alkyl group with D; 1-4 Examples of deuterated alkyl groups include, but are not limited to, deuterated methyl groups (—CD 3 ).

[0312] Unless otherwise specified, the term "alkenyl" refers to a group derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing a hydrogen atom, including methylene, "C 2-6 Alkenyl", "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 "Alkenyl", specific examples include but are not limited to: CH2=, -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc. The above-mentioned alkenyl refers to an alkylene group that is bonded or linked to the same position of other fragments in the form of a double bond, which can be expressed as CH2=.

[0313] Unless otherwise specified, the term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing a hydrogen atom, including "C 2-6 Alkynyl", "C 2-4 Alkynyl", "C 2-3 Specific examples include, but are not limited to: -C≡CH, -C≡CHCH3, CH≡CHCH2-, CH≡CC≡C-, etc.

[0314] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein attached to another group through an oxygen atom, i.e., "alkyl-O-", including "C 1-6 Alkoxy" (structure is C 1-6 Alkyl-O-), "C 1-3 "alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in the present disclosure is preferably C 1-3 Alkoxy.

[0315] Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

[0316] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom.1-6 Halogenated alkyl, more preferably C 1-3 Examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Alkyl is as defined above.

[0317] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. The "hydroxyalkyl" described in the present disclosure includes "C 1-6 Hydroxyalkyl", "C 1-4 Specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, wait.

[0318] Unless otherwise specified, the term "alkylthio" refers to an -S-alkyl group in which alkyl is as previously defined.

[0319] Unless otherwise specified, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms in an alkoxy group are replaced by halogen. Preferably, the "haloalkoxy" described in the present disclosure is preferably a "haloC 1-6 Alkoxy", "halogenated C 1-3 Alkoxy". Specific examples of the present disclosure include: fluoromethoxy (including monofluoromethoxy, difluoromethoxy, trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkoxy is as defined above.

[0320] Unless otherwise specified, the term “C 1-4 Alkoxy-C 1-4 "Alkyl" refers to C 1-4 One or more hydrogen atoms in the alkyl group are replaced by C 1-4 Alkoxy substituted groups derived from; C 1-4 Alkoxy-C 1-4 Specific examples of "alkyl" include methoxymethyl (CH3O-CH2-), ethoxymethyl (C2H5O-CH2-), and methoxyethyl (CH3O-CH2CH2-).

[0321] Unless otherwise specified, the term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also known as heteroatomic groups), wherein the heteroatoms are generally selected from N, O, and S, and the 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 in the ring is generally defined as the number of ring members, for example, "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms arranged around, 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, where R is a group defined herein.

[0322] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl derived from a cycloalkane by removing a 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 connected by spiro, bridge, condensation, etc. The carbon atoms in the cycloalkyl group can be further oxidized to form C(O). Unless otherwise specified, the "monocyclic cycloalkyl" described herein can be understood as a monocyclic cycloalkyl group. When it is polycyclic, it will be specifically specified as a spiro, condensation or bridged ring group. The cycloalkyl group includes "C 3-12 Cycloalkyl", "C 3-8 Cycloalkyl", "C 3-6 Cycloalkyl", "C 3-5 Preferably, specific examples of the cycloalkyl group include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0323] Unless otherwise specified, the term "heterocycloalkyl" refers to a saturated cyclic group derived from a cycloalkyl group in which one or more ring carbon atoms are replaced by heteroatoms and / or heteroatomic groups. The heteroatoms and / or heteroatomic groups are generally selected from N, O, S, NO, SO, S(O)2, P(O) and NR, wherein the carbon atoms in the heterocyclic ring are optionally oxidized, i.e., forming -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocycloalkyl group includes "3-12 membered heterocycloalkyl", "3-8 membered heterocycloalkyl", "3-6 membered heterocycloalkyl", "3-5 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl". Examples of heterocycloalkyl include, but are not limited to

[0324] Unless otherwise specified, "cycloalkenyl" means that one or more ring bonds in the "cycloalkyl" are double bonds and the cycloalkenyl is not aromatic. The carbon atoms in the cycloalkenyl can be further oxidized, i.e., to form C(O). The cycloalkenyl can be fused to an aryl, heteroaryl, or heterocycloalkenyl, wherein the ring connected to the parent structure is a cycloalkenyl. The cycloalkenyl includes "3-12 membered cycloalkenyl", "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". The definition of "cycloalkyl" is the same as above. Examples of cycloalkenyl include, but are not limited to

[0325] Unless otherwise specified, the term "heterocycloalkenyl" means that one or more ring bonds in the "heterocycloalkyl" are double bonds and are not aromatic. The "heterocycloalkyl" is the same as described above. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocycloalkenyl can be fused to an aryl or heteroaryl group, wherein the ring connected to the parent structure is a heterocycloalkenyl, etc. The heterocycloalkenyl includes "3-12 membered heterocycloalkenyl", "3-8 membered heterocycloalkenyl", "3-6 membered heterocycloalkenyl", "3-5 membered heterocycloalkenyl", "5-6 membered heterocycloalkenyl". Examples of heterocycloalkenyl include but are not limited to

[0326] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic hydrocarbon group, which may be a single ring or multiple rings fused together. A fused ring aryl group refers to a group in which two or more cyclic structures share two adjacent atoms, and the ring directly connected to the parent structure is aromatic (the ring not directly connected to the parent structure is aromatic and does not contain heteroatoms or is non-aromatic). The aryl group may be fused to a heterocycloalkenyl or cycloalkenyl group, wherein the ring connected to the parent structure is an aryl group, etc. Preferably, C 6-14 Aryl, more preferably C 6-10 Aryl; examples of aryl include, but are not limited to, phenyl, naphthyl.

[0327] The "heteroaryl" described in the present invention refers to a monocyclic or polycyclic group with aromatic properties containing one or more heteroatoms in the ring, and the heteroatoms are generally selected from N, O, and S; preferably, the heteroatoms are independently selected from 1-3 N and / or O. In addition, the N atoms and S atoms may be optionally oxidized and the N atoms may be optionally quaternized. The "heteroaryl" includes "monocyclic heteroaryl" and "fused-ring heteroaryl". The fused-ring heteroaryl refers to a group containing one or more heteroatoms formed by two or more cyclic structures sharing two adjacent atoms, and the ring directly connected to the parent structure has aromatic properties (the ring not directly connected to the parent structure is an aromatic ring or a non-aromatic ring); when the ring not directly connected to the parent structure is an aromatic ring, the heteroatom may be located on the ring not directly connected to the parent structure or on the ring directly connected to the parent structure; when the ring not directly connected to the parent structure is a non-aromatic ring, the heteroatom is located on the ring directly connected to the parent structure. The heteroaryl group described in the present invention is preferably a "nitrogen-containing heteroaryl group", preferably a "5-6 membered nitrogen-containing aryl group", and the heteroatom in the "nitrogen-containing heteroaryl group" contains at least one nitrogen atom, for example, only 1, 2 or 3 nitrogen atoms, or, contains one nitrogen atom and other 1 or 2 heteroatoms (such as S and / or O atoms), or, contains 2 nitrogen atoms and other 1 or 2 heteroatoms. The heteroaryl group can be fused to a heterocycloalkenyl group or a cycloalkenyl group, wherein the ring connected to the parent structure is a heteroaryl group. Specific examples of the heteroaryl group include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, wait.

[0328] In various parts of this disclosure, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a 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 the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0329] Combinations of substituents and / or variables described herein are permissible only if these combinations result in stable compounds or useful synthetic intermediates. A stable compound or structure is one that is sufficiently robust to withstand chemical reactions, to be isolated to a useful degree of purity, and to be formulated into an efficacious therapeutic agent.

[0330] In the examples of this invention, the title compound names were derived from the compound structures using ChemDraw. If the compound name and structure are inconsistent, the structure can be determined by integrating relevant information and reaction routes. If other methods are unavailable for confirmation, the given compound structure will prevail.

[0331] The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0332] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0333] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from combination of the specified ingredients in the specified amounts. Those skilled in the art can modify the actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention so as to achieve the desired therapeutic response in an amount effective for a particular patient, composition, and route of administration.

[0334] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, especially mammals.

[0335] The term "effective amount" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, which is a sufficient amount of the compound to treat the disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention.

[0336] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. The compounds of the present invention can be reacted with corresponding acids or bases to obtain their corresponding salts.

[0337] The term "stereoisomer" as used herein refers to isomers resulting from differences in the spatial arrangement of atoms in a molecule. Stereoisomers include atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof, all of which are within the scope of the present invention. The term "enantiomer" refers to stereoisomers that are mirror images of one another. The term "tautomer" refers to a type of functional group isomer that has different hydrogen attachment points due to displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. The term "diastereomer" refers to stereoisomers in which a molecule has two or more chiral centers and is not a mirror image of the other. The term "cis-trans isomer" refers to different spatial configurations in a molecule where double bonds or single bonds of ring carbon atoms cannot rotate freely. The term "atropisomer" refers to stereoisomers that can be separated due to the fact that single bond rotation is hindered or rotates very slowly.

[0338] In the Examples of the present invention, unless otherwise specified, the ratios of eluent components used in column chromatography or column chromatography are by volume. For example, "eluent: tetrahydrofuran / petroleum ether" indicates that the eluent is a mixture of tetrahydrofuran and petroleum ether. Those skilled in the art can determine the appropriate solvent ratio through simple experimentation. Throughout the present invention, the unit M for reagent concentration refers to mol / L; for example, 1 mM refers to 1 mmol / L.

[0339] In the embodiments of the present invention, different stereoisomers of the same compound molecule are distinguished by polarity or retention time (RT) under specific separation conditions. The stereo configuration of a chiral center in the chemical structure can be determined by reference to published literature or by single crystal diffraction. In the embodiments of the present invention, wedge-shaped bonds and bold bonds are not distinguished and have the same meaning.

[0340] In the present invention, the compounds of the present invention and their related chiral intermediate compounds can be prepared with reference to the preparation methods of similar structural compounds described in WO2022035790A or WO2022216762A, and those skilled in the art can make appropriate adjustments to the starting materials and reaction conditions according to the structural characteristics of the target compound. The single stereoisomers of the compounds of the present invention or the single stereoisomers of the related intermediates can also be split with reference to the splitting conditions described in the above-mentioned documents to obtain the corresponding single stereoisomers or hindered isomers. Those skilled in the art can make appropriate adjustments to the splitting conditions according to the structural characteristics of the target compound.

[0341] The chemical abbreviations used in the present invention and the chemical names they refer to are as follows: DETAILED DESCRIPTION

[0342] The present invention 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 only for specific illustration purposes and should not be understood as limiting the present invention in any form. It is clear to those skilled in the art that, unless otherwise specified below, the materials used are well known in the art and can be purchased on the market or obtained by those skilled in the art according to published literature or conventional methods. Unless otherwise stated, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, and the solvent is a dry solvent. Wherein: (i) The temperature is expressed in degrees Celsius (°C), and the operation is carried out at room temperature, which generally refers to 15-35°C, preferably 20-30°C, and more preferably 20-25°C; (ii) The removal of the solvent is carried out by reduced pressure evaporation on a rotary evaporator, and the bath temperature is generally not higher than 60°C; (iii) The reaction process is tracked by thin layer chromatography (TLC); (iv) The final product has a satisfactory hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR) and / or mass spectrometry (MS) data. For example, percentage contents or ratios referred to in this application, unless otherwise specified, refer to mass percentages or mass ratios for solid-liquid mixtures and solid-solid mixtures, and to volume percentages or volume ratios for liquid-liquid mixtures.

[0343] Test equipment:

[0344] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and / or deuterated chloroform (CDCl3) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0345] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu 2030Plus-LCMS2020 mass spectrometer, an Agilent 1260-6125B single quadrupole mass spectrometer, or a Shimadzu LCMS-2020 mass spectrometer. HPLC was performed using a Shimadzu LCMS-2020 or Agilent 1260 high-performance liquid chromatograph.

[0346] Preparative high-performance liquid chromatography was performed using a Shimadzu FRC-40 equipped with LC-20AP and PDA-20A (column: Synergi Max-RP, 150×30 mm, 4 m) or a GILSON Trilution LC (column: SunFire Prep C18, 10 μm, 19×250 mm XBridge Prep C18, 10 μm, 19×250 mm)).

[0347] The model of the microwave synthesizer is Biotage Initiator+.

[0348] Example 1: Preparation of Compound 1

[0349] Step A:

[0350] Starting material 1a (10 g, 79.94 mmol) was dissolved in 1,4-dioxane (100 mL). Triethylamine (24.27 g, 239.8 mmol) was added, followed by N,N-bis(4-methoxybenzyl)amine (24.69 g, 95.93 mmol) at room temperature. The reaction system was stirred at 90°C under nitrogen for 16 hours. After the disappearance of the starting material as monitored by LCMS, the reaction solution was concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-15 / 1-5 / 1) to yield 2-(bis(4-methoxybenzyl)amino)nicotinaldehyde 1b (27.5 g).

[0351] LCMS (ESI) M / Z: 363.4 [M+H] + .

[0352] Step B:

[0353] 1b (27.5 g, 75.88 mmol) was dissolved in tetrahydrofuran (286 mL). Ethynylmagnesium bromide (19.61 g, 151.7 mmol) was added under nitrogen, and the reaction system was stirred at room temperature for 3 hours. After the disappearance of the starting material as monitored by LCMS, the reaction was quenched by the addition of aqueous ammonium chloride (20 mL). The product was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-15 / 1-5 / 1) to afford 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)prop-2-yn-1-ol 1c (28.0 g).

[0354] LCMS (ESI) M / Z: 389.4 [M+H] + .

[0355] Step C:

[0356] 1c (7 g, 18.02 mmol) was dissolved in dichloromethane (370 mL). The reaction system was cooled to -40°C under nitrogen, and thionyl chloride (2.73 g, 22.93 mmol) was added. The mixture was stirred at this temperature for 30 minutes. LCMS monitoring revealed the disappearance of the starting material, and the reaction was quenched with sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 15 / 1) to yield 1.4 g of 3-(1-chloroprop-2-en-1-yl)-N-(4-methoxybenzyl)pyridin-2-amine, compound 1d.

[0357] LCMS (ESI) M / Z: 287.0 [M+H] + .

[0358] Step D:

[0359] 1d (0.7 g, 1.72 mmol) was dissolved in 1,4-dioxane (8 mL), and 4-dimethylaminopyridine (0.021 g, 0.17 mmol) and ethanolamine (3 mL) were added. The reaction was stirred at 80°C for 30 minutes under nitrogen. After the disappearance of the starting material as monitored by LCMS, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1 to 20 / 1) to provide 2-((1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)prop-2-yn-1-yl)amino)ethan-1-ol 1e (1.2 g).

[0360] LCMS (ESI) M / Z: 312.3 [M+H] + .

[0361] Step E:

[0362] 1e (0.30 g, 0.73 mmol) was dissolved in dimethyl sulfoxide (0.9 mL). Sodium bis(trimethylsilyl)amide (0.22 mL, 0.44 mmol, 2 M in tetrahydrofuran) was added at room temperature. After stirring for 40 minutes, a solution of intermediate 1 (59.13 mg, 0.33 mmol, prepared according to WO2022173678A1) in dimethyl sulfoxide (1 mL) was added, and the reaction solution was stirred at 30°C for 2 hours. After the disappearance of the starting material as monitored by LCMS, the reaction solution was quenched with ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to provide 1f (60 mg).

[0363] LCMS (ESI) M / Z: 956.4 [M+H] + .

[0364] Step F:

[0365] 1f (60 mg, 0.063 mmol) was dissolved in chloroform (1 mL), and ethyldiisopropylamine (41 mg, 0.32 mmol) was added. Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (27.26 mg, 0.11 mmol) was added at room temperature. The reaction solution was heated to 70°C and stirred for 1 hour. After the disappearance of the starting material as monitored by LCMS, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain compound 1g (20 mg).

[0366] LCMS (ESI) M / Z: 938.4 [M+H] + .

[0367] Step G:

[0368] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (23.40 mg, 0.15 mmol) was dissolved in tetrahydrofuran (0.5 mL), and sodium hydride (5.88 mg, 0.15 mmol, 60% purity) was added. The reaction mixture was stirred at room temperature for 0.5 hours. Then, a solution of compound 1g (20 mg, 0.021 mmol) in tetrahydrofuran (0.4 mL) was added to the reaction mixture and stirred at 50°C for 1 hour. After the disappearance of the starting material as monitored by LCMS, the reaction mixture was quenched with ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to provide compound 1h (10 mg).

[0369] LCMS (ESI) M / Z: 1061.6 [M+H] + .

[0370] Step H:

[0371] Compound 1h (10 mg, 0.0094 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL) and stirred at room temperature for 3 hours. LCMS monitored the disappearance of the starting material. The reaction solution was diluted with saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin-layer chromatography (eluent: DCM / MeOH = 15 / 1) to afford 2.05 mg of compound 1 in a 26.69% yield.

[0372] LCMS (ESI) M / Z: 701.6 [M+H] + ;

[0373] 1 H NMR (400MHz, CD3OD) δ8.18 (dd, J=4.8Hz, 1.2Hz, 1H), 7.95 (d, J=7.6Hz, 1H), 7.47- 7.34(m,1H),7.11(dd,J=8.0Hz,5.2Hz,1H),6.60(s,1H),6.52(s,1H),5.46-5.29( m,1H),4.62-4.60(m,2H),4.48-4.39(m,2H),4.12-4.10(m,2H),3.76-3.58(m,3H ),3.25-3.23(m,1H),2.57-2.48(m,1H),2.44(d,J=1.6Hz,3H),2.35-1.88(m,5H).

[0374] Example 2: Preparation of Compound 2 and its isomers

[0375] Step A:

[0376] The starting material, 3-acetyl-2-fluoropyridine (1.0 g, 7.19 mmol), was dissolved in 1,4-dioxane (30 mL). Diisopropylethylamine (2.0 g, 15.52 mmol) was added, followed by N,N-bis(4-methoxybenzyl)amine (1.39 g, 10.79 mmol) at room temperature. The reaction system was stirred at 100°C for 12 hours under nitrogen. After the disappearance of the starting material as monitored by LCMS, the reaction was quenched by addition of saturated aqueous ammonium chloride. The reaction was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to afford 2a (1.1 g).

[0377] LCMS (ESI) M / Z: 377.1 [M+H] + .

[0378] Step B:

[0379] 2a (3 g, 7.97 mmol) was dissolved in methanol (10 mL). 3-Aminopropan-1-ol (1.80 g, 23.91 mmol) and acetic acid (0.10 g, 1.75 mmol) were added at room temperature. The reaction solution was heated to 80°C and stirred for 16 h. Sodium cyanoborohydride (2.50 g, 39.85 mmol) was then added and the reaction solution was heated to 90°C and stirred for 6 h. After the disappearance of the starting material as monitored by LCMS, the reaction solution was cooled to room temperature and directly purified by C18 column chromatography to afford 2b (1.5 g).

[0380] LCMS (ESI) M / Z: 436.4 [M+H] + .

[0381] Step C:

[0382] 2b (66.4 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (5 mL). Sodium bis(trimethylsilyl)amide (0.2 mL, 0.4 mmol, 2 M in tetrahydrofuran) was added at room temperature and stirred for 40 minutes. A solution of intermediate 1 (43.5 mg, 0.065 mmol) in dimethyl sulfoxide (2 mL) was then added. The reaction mixture was heated to 65°C and stirred for 10 hours under nitrogen. LCMS monitoring indicated the disappearance of the starting material. The reaction mixture was quenched with ammonium chloride and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1; dichloromethane / methanol = 50 / 1) to afford 2c (118 mg crude product).

[0383] LCMS (ESI) M / Z: 1080.4 [M+H] + .

[0384] Step D:

[0385] Compound 2c (100 mg, 0.093 mmol) was dissolved in chloroform (2 mL), and diisopropylethylamine (254.7 mg, 1.97 mmol) was added. Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (40 mg, 0.158 mmol) was then added at room temperature. The reaction mixture was heated to 70°C and stirred for 1 h under nitrogen. After the disappearance of the starting material as monitored by LCMS, the reaction mixture was quenched with water (10 mL) and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to provide compound 2d (66 mg).

[0386] MS (ESI) M / Z: 1062.4 [M+H] + .

[0387] Step E:

[0388] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (49.5 mg, 0.311 mmol) was dissolved in tetrahydrofuran (1.5 mL). Sodium hydride (12.44 mg, 0.311 mol) was added at room temperature and stirred for 10 minutes. A solution of compound 2d (66 mg, 0.0622 mmol) in tetrahydrofuran (1 mL) was then added. The reaction mixture was heated to 50°C and stirred for 1 hour under nitrogen. After the disappearance of the starting material as monitored by LCMS, the reaction mixture was quenched with ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1 to 20 / 1) to provide compound 2e (59 mg).

[0389] MS (ESI) M / Z: 1185.6 [M+H] + .

[0390] Step F:

[0391] 2e (59 mg, 0.05 mmol) was dissolved in a mixture of trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.5 mL) and stirred at room temperature under nitrogen for 1 h. LCMS monitored the disappearance of the starting material. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to yield two fractions: 2-P1 (1.79 mg, less polar by TLC) and 2-P2 (1.35 mg, more polar by TLC).

[0392] 2-P1:

[0393] MS (ESI) M / Z: 705.3 [M+H] + ;

[0394] 1H NMR(400MHz,CD3OD)δ8.24(t,J=8.0Hz,1H),7.96-7.94(m,1H),7.06-7.02(m,1H),6.62(s,1H) ,6.09-6.02(m,1H),5.62-5.48(m,1H),4.66-4.51(m,3H),4.31-4.27(m,1H),3.92-3.83(m,3H) ,3.80-3.75(m,1H),3.67-3.61(m,1H),3.51-3.43(m,2H),2.62-2.57(m,2H),2.44(s,3H),2.3 6-2.32(m,2H),2.18-2.11(m,1H),1.91-1.88(m,1H),1.77(d,J=7.2Hz,3H),1.62-1.54(m,1H).

[0395] 2-P2:

[0396] MS (ESI) M / Z: 705.4 [M+H] + ;

[0397] 1 H NMR (400MHz, CD3OD) δ8.22-8.18(m,1H),7.96-7.93(m,1H),7.06-7.02(m,1H),6.62(s,1H),6.09-6.02(m ,1H),5.62-5.48(m,1H),4.66-4.51(m,3H),4.33-4.28(m,1H),3.92-3.83(m,3H),3.80-3.75(m,1H),3.67 -3.61(m,1H),3.51-3.43(m,2H),2.62-2.57(m,2H),2.44(s,3H),2.36-2.32(m,2H ),2.18-2.11(m,1H),1.91-1.88(m,1H),1.79(d,J=6.8Hz,3H),1.63-1.57(m,1H).

[0398] Example 3: Preparation of Compound 3

[0399] Compound 3

[0400] Step A:

[0401] Referring to the method of step B of Example 2, compound 3a was prepared using compound 2a and (1-aminocyclopropyl)methanol as raw materials.

[0402] LCMS (ESI) M / Z: 448.5 [M+H] + .

[0403] Step B:

[0404] Referring to the method of step C of Example 2, compound 3b was prepared using compound 3a and intermediate 1 as raw materials.

[0405] LCMS (ESI) M / Z: 1092.5 [M+H] + .

[0406] Step C:

[0407] Compound 3c was prepared by referring to the method of Step D of Example 2 using compound 3b as raw material.

[0408] LCMS (ESI) M / Z: 1076.4 [M+H] + .

[0409] Step D:

[0410] Referring to the method of Step E of Example 2, Compound 3d was prepared using Compound 3c and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol as raw materials.

[0411] LCMS (ESI) M / Z: 599.9 [M / 2+H] + .

[0412] Step E:

[0413] 3d (20 mg, 0.019 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL). The reaction mixture was allowed to react at room temperature for 3 hours. LCMS monitoring revealed the disappearance of the starting material. The reaction mixture was quenched with saturated aqueous NaHCO₃ and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography (dichloromethane / methanol = 15 / 1) to afford compound 3 (1.43 mg).

[0414] LCMS (ESI) M / Z: 717.6 [M+H] + ;

[0415] 1H NMR (400MHz, CD3OD) δ7.95 (d, J = 4.8Hz, 1H), 7.74-7.71 (m, 1H), 6.76-6.74 (m, 1H), 6.60 (s, 1H), 5.82-5.79 (m, 1H), 5.39-5.25 (m, 1H), 4.57-4. 12(m,4H),3.30-3.20(m,3H),3.30-3.05(m,1H),2.44(s,3H),2.25-2. 02(m,6H),1.88(d,J=7.2Hz,3H),0.91-0.88(m,2H),0.85-0.77(m,2H).

[0416] Example 4: Preparation of Compound 4 and Its Isomers

[0417] Step A:

[0418] 3-Bromo-quinolin-2-amine 4a (5 g, 22.41 mmol) was dissolved in toluene (40 mL), and tributyl(1-ethoxyvinyl)stannane (13.76 g, 38.10 mmol) and tetrakistriphenylphosphine (2.07 g, 1.79 mmol) were added. The mixture was heated to 100°C under nitrogen for 4 hours. LCMS monitoring revealed the disappearance of the starting material. The reaction solution was diluted with ethyl acetate, washed with water and then with saturated sodium chloride solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1-1 / 2) to afford compound 4b (4.3 g).

[0419] LCMS (ESI) M / Z: 215.2 [M+H] + .

[0420] Step B:

[0421] Compound 4b (2.56 g, 11.95 mmol) was dissolved in tetrahydrofuran (15 mL), and 6 mol / L aqueous hydrochloric acid (15 mL) was added. The mixture was stirred at room temperature for 0.5 h. LCMS monitoring revealed the disappearance of the starting material. The reaction mixture was filtered and the filter cake was dried to obtain compound 4c (2.1 g).

[0422] LCMS (ESI) M / Z: 187.0 [M+H] + .

[0423] Step C:

[0424] 4c (2 g, 10.74 mmol), 1-(chloromethyl)-4-methoxybenzene (13.46 g, 85.92 mmol), triethylamine (6.52 g, 64.44 mmol), and 4-dimethylaminopyridine (0.13 g, 1.07 mmol) were dissolved in a mixture of dioxane (20 mL) and N,N-dimethylformamide (10 mL). The reaction mixture was heated to 110°C and stirred for 48 hours. LCMS monitoring revealed the disappearance of the starting material. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1; DCM / MeOH = 10 / 1) to afford the crude product. The crude product was then purified from PE / EA = 3 / 1 to afford 4d (2 g).

[0425] LCMS (ESI) M / Z: 427.2 [M+H] + .

[0426] Step D:

[0427] Referring to the method of step B of Example 2, compound 4e was prepared using compound 4d and 2-aminoethan-1-ol as raw materials.

[0428] LCMS (ESI) M / Z: 472.2 [M+H] + .

[0429] Step E:

[0430] Referring to the method of step C of Example 2, compound 4f was prepared using compound 4e and intermediate 1 as raw materials.

[0431] LCMS (ESI) M / Z: 1116.4 [M+H] + .

[0432] Step F:

[0433] Referring to the method of Step D of Example 2, Compound 4g was prepared using Compound 4f as the starting material.

[0434] MS (ESI) M / Z: 1098.5 [M+H] + .

[0435] Step G:

[0436] Referring to the preparation method of Step E of Example 2, Compound 4h was prepared using Compound 4g and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol as raw materials.

[0437] MS (ESI) M / Z: 1121.6 [M+H] + .

[0438] Step H:

[0439] The synthesis method was the same as that in step F of Example 2, and two components were separated and obtained in sequence: 4-P1 (7.2 mg, less polar by TLC) and 4-P2 (5.6 mg, more polar by TLC).

[0440] 4-P1:

[0441] MS (ESI) M / Z: 741.2 [M+H] + ;

[0442] 1 H NMR (400MHz, CD3OD) δ8.24(s,1H),7.79(d,J=8.0Hz,1H),7.57(s,2H),7.32-7.30(m,1H),6.68-6.65(m,1H),6.59(s,1H),5 .43-5.28(m,1H),4.44-4.31(m,4H),3.74-3.30(m,5H),3.13(s,1H),2.43(s,3H),2.39-1.97(m,6H),1.78(d,J=7.2Hz,3H).

[0443] 4-P2:

[0444] MS (ESI) M / Z: 741.2 [M+H] + ;

[0445] 1 H NMR (400MHz, CD3OD) δ8.24(s,1H),7.79(d,J=8.0Hz,1H),7.57(s,2H),7.32-7.30(m,1H),6.68-6.65(m,1H),6.59(s,1H),5 .43-5.28(m,1H),4.44-4.31(m,4H),3.74-3.30(m,5H),3.13(s,1H),2.43(s,3H),2.39-1.97(m,6H),1.78(d,J=7.2Hz,3H).

[0446] Example 5: Preparation of Compound 5 and its isomers

[0447] Step A:

[0448] 2-Bromo-6-fluorobenzonitrile 5a (10 g, 50.0 mmol) was dissolved in n-butanol (100 mL). Hydrazine hydrate (16.0 g, 500 mmol) was added at room temperature. The reaction system was stirred at 110°C for 2 hours under nitrogen. After completion of the reaction, as monitored by LCMS, the mixture was concentrated under vacuum to provide 4-bromo-1H-indazol-3-amine 5b (10 g).

[0449] LCMS (ESI) M / Z: 212.1, 214.1 [M+H] + .

[0450] Step B:

[0451] 5b (1 g, 4.72 mmol) was dissolved in 1,4-dioxane (10 mL). Triethylamine (1.43 g, 14.2 mmol), 4-methoxybenzyl chloride (3.70 g, 23.6 mmol), and 4-dimethylaminopyridine (0.8 g, 0.47 mmol) were added to the mixture at room temperature. The reaction system was stirred at 100°C under nitrogen for 12 hours. After completion of the reaction, as monitored by LCMS, the resulting mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to afford compound 5c (2.45 g).

[0452] LCMS (ESI) M / Z: 572.2, 574.2 [M+H] + .

[0453] Step C:

[0454] 5c (2 g, 3.49 mmol) was dissolved in DMF (20 mL). Tributyl(1-ethoxyvinyl)tin (1.89 g, 5.24 mmol) and tetrakis(triphenylphosphine)palladium (0.40 g, 0.35 mmol) were added to the mixture at 25°C. The reaction system was stirred at 120°C for 12 hours under nitrogen. After completion of the reaction, the reaction solution was purified by C18 column chromatography (ACN:H2O = 0:1 to 9:1) to afford the crude product, which was then purified by silica gel column chromatography (PE:EA = 5:1) to afford compound 5d (0.653 g).

[0455] LCMS (ESI) M / Z: 536.5 [M+H] + .

[0456] Step D:

[0457] 5d (653 mg, 1.22 mmol) was dissolved in a mixture of methanol (7 mL) and acetic acid (0.1 mL). Aminoethanol (223 mg, 3.66 mmol) was added at 25°C. The reaction system was stirred at 110°C under nitrogen for 12 hours. The temperature was then cooled to room temperature, and sodium cyanoborohydride (383 mg, 6.1 mmol) was added to the reaction solution. The mixture was stirred at 100°C for another 12 hours. After completion of the reaction, as monitored by LCMS, the reaction was quenched with water and purified by C18 column chromatography (ACN:H2O = 1:99 to 70:30) to afford the crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford compound 5e (505 mg).

[0458] LCMS (ESI) M / Z: 581.3 [M+H] + ;

[0459] 1 H NMR(400MHz,DMSO-d6)δ7.62(d,J=8.2Hz,1H),7.42(dd,J=14.4,7.6Hz,2H), 7.20-7.02(m,6H),6.87-6.72(m,6H),5.51(s,1H),5.44(s,2H),5.20(s,1H), 4.26-4.05(m,4H),3.70(d,J=1.2Hz,9H),3.61-3.48(m,2H),3.17(d,J=5.2Hz ,1H),2.69-2.60(m,1H),2.41(dt,J=12.2,5.6Hz,1H),1.60(d,J=6.4Hz,3H).

[0460] Step E:

[0461] 5e (0.16 g, 0.28 mmol) was dissolved in dimethyl sulfoxide (5 mL), and a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (0.46 mL, 0.92 mmol, 2 M) was added at room temperature. The reaction solution was stirred at 25°C for 30 minutes under nitrogen protection, and then intermediate 1-R (150 mg, 0.23 mmol, intermediate 1 was obtained by SFC separation (Waters UPCC (CA-119), chromatographic column: )250*4.6mm 5μm; Mobile Phase: A=Supercritical CO2, B=MeOH (0.1% DEA), Gradient Ratio: 60% A) in dimethyl sulfoxide (3mL), and the reaction solution was heated to 70°C under nitrogen and stirred for 4 hours. After completion of the reaction, as monitored by LCMS, saturated aqueous NH4Cl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA=1 / 1 to 1 / 2, then DCM / MeOH=50 / 1) to afford compound 5f (0.3g).

[0462] LCMS (ESI) M / Z: 614.0 [M / 2+H] + .

[0463] Step F:

[0464] Referring to the method of Step D of Example 2, Compound 5g was prepared using Compound 5f as the starting material.

[0465] MS (ESI) M / Z: 605.0 [M / 2+H] + .

[0466] Step G:

[0467] Referring to the preparation method of Step E of Example 2, Compound 5h was prepared using Compound 5g and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol as raw materials.

[0468] MS (ESI) M / Z: 666.4 [M / 2+H] + .

[0469] Step H:

[0470] The synthesis method was the same as that in step F of Example 2, and two components were separated and obtained in sequence: 5-P1 (10.95 mg, less polar by TLC) and 5-P2 (8.42 mg, more polar by TLC).

[0471] 5-P1:MS(ESI)M / Z:730.5[M+H] + ;

[0472] 1H NMR(400MHz, Methanol-d4)δ7.40-7.28(m,2H),7.15(d,J=6.4Hz,1H),6.90(q,J=6 .8Hz,1H),6.58(d,J=1.2Hz,1H),5.29(d,J=54.0Hz,1H),4.33(dt,J=12.0,3.2Hz, 1H),4.29-4.18(m,2H),4.13-4.01(m,1H),3.70(t,J=3.6Hz,2H),3.24-3.15(m,2H ),3.07-2.93(m,1H),2.49-2.41(m,3H),2.36-1.83(m,7H),1.75(d,J=6.8Hz,3H).

[0473] 5-P2: MS (ESI) M / Z: 730.5 [M+H] + ;

[0474] 1 H NMR (400MHz, Methanol-d4) δ7.39-7.29(m,2H),7.14(d,J=6.4Hz,1H),6.90(q,J=6.8Hz,1H),6.57(s,1H),5.29(d,J=53.6Hz,1H),4.38(dd,J=12.0,5. 2Hz,1H),4.31-4.12(m,3H),3.78-3.62(m,2H),3.23-3.15(m,2H),2.98(d, J=5.5Hz,1H),2.47-2.37(m,3H),2.35-1.84(m,7H),1.76(d,J=6.8Hz,3H).

[0475] Example 6: Preparation of Compound 6 and Its Isomers

[0476] Step A:

[0477] Compound 6a (3.5 g, 17.7 mmol) was dissolved in N,N-dimethylformamide (60 mL). Sodium hydride (0.78 g, 19.5 mmol, 60% content) was added in an ice bath under nitrogen. 4-Methoxybenzyl chloride (2.78 g, 17.8 mmol) was added dropwise at 0°C for 1 hour after stirring. The reaction mixture was allowed to react at 25°C under nitrogen for 16 hours. LCMS monitoring indicated the disappearance of the starting material. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution, respectively. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The concentrated residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to afford compound 6b (4.8 g).

[0478] LCMS (ESI) M / Z: 317.0, 319.0 [M+H] + .

[0479] Step B:

[0480] 6b (4.3 g, 13.5 mmol), tributyl(1-ethoxyvinyl)stannane (8.33 g, 23.1 mmol), and tetrakis(triphenylphosphine)palladium (1.25 g, 1.08 mmol) were dissolved in toluene (80 mL) and stirred at 110°C under nitrogen for 16 hours. LCMS monitoring revealed the disappearance of the starting material. The reaction mixture was then filtered, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to afford compound 6c (4.0 g).

[0481] LCMS (ESI) M / Z: 309.2 [M+H] + .

[0482] Step C:

[0483] 6c (4.0 g, 12.9 mmol) was dissolved in a mixture of tetrahydrofuran (16 mL) and concentrated hydrochloric acid (4 mL) and stirred at room temperature under nitrogen for 0.5 hour. LCMS monitoring indicated the disappearance of the starting material. The reaction solution was neutralized with saturated aqueous NaHCO₃ and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to afford compound 6d (4.0 g crude product).

[0484] LCMS (ESI) M / Z: 281.1 [M+H] + .

[0485] Step D:

[0486] 6d (1.2 g, 4.28 mmol), 2-aminoethane-1-ol (0.78 g, 12.8 mmol), and tetraisopropyl titanate (2.53 mL, 8.56 mmol) were dissolved in methanol (10 mL) and microwaved under nitrogen at 100°C for 2 hours. After obtaining the imine, sodium cyanoborohydride (0.81 g, 12.8 mmol) was added under nitrogen and microwaved at 100°C for another 0.5 hour. LCMS monitoring indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and quenched by the addition of NH4Cl solution. The reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford 6e (1.1 g).

[0487] LCMS (ESI) M / Z: 326.2 [M+H] + .

[0488] Step E:

[0489] Referring to the method of step C of Example 2, compound 6f was prepared using compound 6e and intermediate 1 as raw materials.

[0490] LCMS (ESI) M / Z: 970.5 [M+H] + .

[0491] Step F:

[0492] Referring to the method of Step D of Example 2, Compound 6g was prepared using Compound 6f as raw material.

[0493] MS (ESI) M / Z: 952.3 [M+H] + .

[0494] Step G:

[0495] Referring to the preparation method of Step E of Example 2, Compound 6h was prepared using Compound 6g and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol as raw materials.

[0496] MS (ESI) M / Z: 1075.5 [M+H] + .

[0497] Step H:

[0498] Compound 6h (70 mg, 0.083 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL) and stirred at room temperature under nitrogen for 1 h. LCMS monitoring revealed the disappearance of the starting material. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford compound 6i (50 mg crude product).

[0499] MS (ESI) M / Z: 835.4 [M+H] + .

[0500] Step I:

[0501] Compound 6i (50 mg, 0.06 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (1 mL) and stirred at 70°C under nitrogen for 1 h. LCMS monitored the disappearance of the starting material. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford compound 6. Further purification by preparative plate isolation afforded two fractions: 6-P1 (1.45 mg, less polar fraction by TLC) and 6-P2 (1.05 mg, more polar fraction by TLC).

[0502] 6-P1: MS (ESI) M / Z: 715.5 [M+H] + ;

[0503] 1 H NMR (400MHz, CD3OD) δ8.25(d,J=4.8Hz,1H),7.39(d,J=4.4Hz,1H),7.21(d,J=4.8Hz,1H),6.91-6.86(m,1H),6.59(s,1H),6.43(t,J=4.4H z,1H),5.36-5.18(m,1H),4.38-4.05(m,4H),3.79-3.55(m,2H),3.26-2.93(m,5H),2.43(s,3H),2.39-1.87(m,6H),1.78(d,J=7.2Hz,3H).

[0504] 6-P2: MS (ESI) M / Z: 715.5 [M+H] + ;

[0505] 1 H NMR (400MHz, CD3OD) δ8.25(d,J=4.8Hz,1H),7.40(d,J=4.4Hz,1H),7.22(d,J=4.8Hz,1H),6.91-6.86(m,1H),6.59(s,1H),6.44(t,J=4.4H z,1H),5.36-5.18(m,1H),4.37-4.08(m,4H),3.79-3.55(m,2H),3.26-2.93(m,5H),2.43(s,3H),2.39-1.87(m,6H),1.78(d,J=7.2Hz,3H).

[0506] Example 7: Preparation of Compound 7 and Its Isomers

[0507] Step A:

[0508] To a solution of compound 7-1 (400 mg, 2.03 mmol) in tetrahydrofuran (5 mL) at 0°C was added sodium hydride (106 mg, 2.64 mmol, 60% purity). The resulting mixture was stirred at 25°C under nitrogen for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (372 mg, 2.23 mmol) was added, and the reaction solution was stirred at 25°C for 18 h. After completion of the reaction, the diluted reaction solution was quenched with water and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain compound 7-2 (410 mg, 62%).

[0509] LCMS (ESI) M / Z: 329.1 [M+H] + .

[0510] Step B:

[0511] 7-2 (4 g, 12.2 mmol) was dissolved in 1,4-dioxane (40 mL), and tributyl(1-ethoxyvinyl)tin (7.50 g, 20.8 mmol) and tetrakis(triphenylphosphine)palladium (1.13 g, 0.98 mmol) were added at room temperature. The mixture was stirred and heated at 100°C under nitrogen for 4 h. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 7-3 (6 g, 77%).

[0512] Step C:

[0513] Compound 7-3 (2.5 g, 7.85 mmol) was dissolved in tetrahydrofuran (20 mL). Trifluoroacetic acid (10 mL) was added at room temperature, and the resulting mixture was stirred at 25°C for 5 hours. After the reaction, the reaction mixture was concentrated in vacuo, and the residue was purified by C18 column chromatography (acetonitrile:water = 60:40) to afford compound 7-4 (0.5 g, 39%).

[0514] LCMS (ESI) M / Z: 161.1 [M+H] + .

[0515] Step D:

[0516] 7-4 (350 mg, 2.19 mmol) was dissolved in methanol (3.5 mL), and 2-amino-1-ol (401 mg, 6.57 mmol) and tetraisopropoxytitanium (1.25 g, 4.38 mmol) were added at room temperature. The resulting mixture was heated in a microwave oven at 100°C for 2 h. Then, sodium cyanoborohydride (413 mg, 6.57 mmol) was added at 25°C, and the resulting mixture was further reacted in a microwave oven at 100°C for 0.5 h. After completion of the reaction, the reaction solution was quenched with water, filtered, and the filtrate was purified by C18 column chromatography (acetonitrile:water = 3:7) to obtain compound 7-5 (170 mg, 38%).

[0517] LCMS (ESI) M / Z: 206.2 [M+H] + .

[0518] Step E:

[0519] 7-5 (48.0 mg, 0.23 mmol) was dissolved in dimethyl sulfoxide (1 mL), sodium bis(trimethylsilyl)amide (132 mg, 0.72 mmol) was added, and the mixture was stirred at 25°C for 30 minutes under nitrogen protection. Intermediate 1-R (120 mg, 0.18 mmol, intermediate 1 was separated and obtained by the following conditions: instrument: SFC-150 mg / m (waters), column: Daicel OZ (25*250mm, 10μm), temperature: 30°C, mobile phase: CO2 / methanol [0.2% NH3 (7M in methanol)] = 65 / 35, flow rate: 100mL / min, back pressure: 100bar) in dimethyl sulfoxide (1mL), the resulting mixture was stirred at 50°C for 4 hours under nitrogen protection. After completion of the reaction, saturated NH4Cl solution was added to quench the reaction, and the product was extracted three times with ethyl acetate and washed with brine. The organic phase was concentrated and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain compound 7-6 (110mg, 72%).

[0520] LCMS (ESI) M / Z: 850.4 [M+H] + .

[0521] Step F:

[0522] To a solution of 7-6 (120 mg, 0.14 mmol) in chloroform (2.5 mL) were added N,N-diisopropylethylamine (90.5 mg, 0.70 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (60.6 mg, 0.24 mmol), and the mixture was stirred at 70°C under nitrogen for 1 h. After completion of the reaction, the reaction solution was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 7-7 (75 mg, 64%).

[0523] LCMS (ESI) M / Z: 830.2 [MH] -

[0524] Step G:

[0525] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57.3 mg, 0.36 mmol) in tetrahydrofuran (1 mL) was added sodium hydride (14.4 mg, 0.36 mmol, 60% purity). The mixture was stirred at 25°C under nitrogen for 0.5 h. Compound 7-7 (50 mg, 0.060 mmol) was added to the reaction solution, and the resulting mixture was stirred at 25°C under nitrogen for 2 h. After completion of the reaction, the reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford compound 7-8 (45 mg, 55%).

[0526] LCMS (ESI) M / Z: 955.5 [M+H] + .

[0527] Step H:

[0528] 7-8 (40 mg, 0.042 mmol) was dissolved in a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid (10:1) (1 mL) and stirred at 25°C under nitrogen for 0.5 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting residue was purified by prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Mobile phase B gradient (Gradient B): 25%-90%) to afford compounds 7-P1 (5.52 mg) and 7-P2 (5.90 mg), respectively.

[0529] 7-P1: HPLC (Agilent 1260, Sunfire C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 10%-95%), retention time: 7.988 min.

[0530] MS (ESI) M / Z: 715.4 [M+H] + .

[0531] 1 H NMR(400MHz,CD3OD)δ8.12(s,1H),7.80(d,J=8.0Hz,1H),7.52(d,J=7.2Hz,1H),7.27-7 .21(m,1H),6.66(d,J=6.8Hz,1H),6.58(s,1H),5.27(d,J=53.6Hz,1H),4.37-4.29(m,1 H),4.25-4.12(m,2H),4.05-3.93(m,1H),3.75(dd,J=15.2,8.0Hz,1H),3.62-3.52(m,2 H),3.19(d,J=19.2Hz,2H),2.46-2.39(m,3H),2.35-1.89(m,7H),1.83(d,J=6.8Hz,3H).

[0532] 7-P2: HPLC (Agilent 1260, Sunfire C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 10%), retention time: 7-P2 8.217 min.

[0533] MS (ESI) M / Z: 715.4 [M+H] + .

[0534] 1 H NMR (400MHz, CD3OD) δ8.11(s,1H),7.80(d,J=8.0Hz,1H),7.52(d,J=7.2Hz,1H),7.23(t,J=7.6Hz,1H) ,6.70(q,J=6.8Hz,1H),6.58(s,1H),5.41-5.22(m,1H),4.40(dd,J=11.6,5.6Hz,1H),4.27(d,J=10.4H z,1H),4.14(d,J=10.8Hz,1H),4.09-.02(m,1H),3.81(dd,J=16.0,7.6Hz,1H),3.56(dd,J=15.4,6.0Hz ,2H),3.21(d,J=9.2Hz,2H),2.46-2.42(s,3H),2.35-1.92(m,6H),1.84(d,J=6.8Hz,3H),1.78(m,1H).

[0535] Example 8: Preparation of Compound 8

[0536] Step A:

[0537] Methoxy(methyl)amine hydrochloride (2 g, 20.5 mmol), 8-1 (3.78 g, 20.5 mmol), and pyridine (3.31 mL, 41.0 mmol) were dissolved in dichloromethane (50 mL) and reacted at 25°C under nitrogen for 16 hours. LCMS monitoring revealed the disappearance of the starting material. The reaction solution was diluted with ethyl acetate and washed sequentially with water and a saturated aqueous sodium chloride solution. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate: 5 / 1) to obtain compound 8-2 (4.1 g).

[0538] LCMS (ESI) M / Z: 210.2 [M+H] + .

[0539] Step B:

[0540] 2-Fluoropyridine (1.81 g, 18.6 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen, a solution of LDA (18.6 mL, 18.6 mmol) was added dropwise to the reaction mixture at -70°C, maintaining the internal temperature below -60°C. After the addition was complete, the mixture was stirred for 30 minutes. A solution of 8-2 (3 g, 14.3 mmol) in tetrahydrofuran (5 mL) was slowly added. After the addition was complete, the reaction mixture was allowed to react at -70°C for 1 hour under nitrogen. LCMS showed the disappearance of the starting material. The reaction was quenched with water and diluted with ethyl acetate, followed by washing with water and saturated sodium chloride solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate: 4 / 1) to afford 8-3 (2.2 g).

[0541] LCMS (ESI) M / Z: 246.2 [M+H] + .

[0542] Step C:

[0543] Compound 8-3 (1.7 g, 6.93 mmol), bis(4-methoxybenzyl)amine (2.23 g, 8.66 mmol), and triethylamine (1.92 mL, 13.8 mmol) were dissolved in 1,4-dioxane (70 mL) and heated to 110°C under nitrogen for 16 hours. LCMS showed the disappearance of the starting material. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to afford compound 8-4 (2.2 g).

[0544] LCMS (ESI) M / Z: 483.3 [M+H] + .

[0545] Step D:

[0546] Compound 8-4 (1.0 g, 2.07 mmol), 2-aminoethanol (0.38 g, 6.21 mmol), and tetraisopropyl titanate (1.23 mL, 4.14 mmol) were dissolved in methanol (10 mL) and microwave-heated at 100°C for 2 hours. LCMS monitored the disappearance of the starting material. After the reaction mixture returned to room temperature, sodium cyanoborohydride (0.39 g, 6.21 mmol) was added and heated to 100°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford compound 8-5 (0.8 g).

[0547] LCMS (ESI) M / Z: 528.3 [M+H] + .

[0548] Step E:

[0549] 8-5 (121 mg, 0.23 mmol) was dissolved in DMSO (2 mL). A solution of sodium bis(trimethylsilyl)amide (0.46 mL, 0.92 mmol, 2 M) in tetrahydrofuran was added at room temperature under nitrogen. The reaction solution was stirred at room temperature for 40 minutes. A solution of intermediate 1-R (150 mg, 0.23 mmol) in dimethyl sulfoxide (2 mL) was added and the mixture was heated to 65°C under nitrogen for 2 hours. After LCMS showed the disappearance of the starting material, the reaction solution was quenched with aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to dichloromethane / methanol = 50 / 1) to give compound 8-6 (120 mg).

[0550] LCMS (ESI) M / Z: 1172.4 [M+H] + .

[0551] Step F:

[0552] Compound 8-6 (120 mg, 0.10 mmol) was dissolved in chloroform (4 mL), and ethyldiisopropylamine (0.20 mL, 1.23 mmol) was added. Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (43.3 mg, 0.17 mmol) was added at room temperature. The reaction system was heated to 70°C under nitrogen for 1 h. LCMS showed the disappearance of the starting material. The reaction solution was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to afford compound 8-7 (80 mg).

[0553] MS (ESI) M / Z: 1156.5 [M+H] + .

[0554] Step G:

[0555] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (32.9 mg, 0.21 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (8.4 mg, 0.21 mol, 60%) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 10 minutes. A solution of 8-7 (80 mg, 0.07 mmol) in tetrahydrofuran (0.5 mL) was added to the reaction mixture, and the mixture was stirred at 50°C under nitrogen for 1 hour. LCMS showed the disappearance of the starting material. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1 to 20 / 1) to afford 8-8 (50 mg).

[0556] MS (ESI) M / Z: 1277.5 [M+H] + .

[0557] Step H:

[0558] 8-8 (47 mg, 0.04 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.03 mL) and stirred at room temperature under nitrogen for 5 min. LCMS showed the disappearance of the starting material. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford the title compound 8 (5.03 mg) as a mixture of two isomers.

[0559] MS (ESI) M / Z: 707.5 [M+H] + .

[0560] 1H NMR (400MHz, CD3OD) δ7.94(d,J=4.8Hz,1H),7.68(d,J=7.6Hz,1H),6.73(t,J=7.2Hz,1H),6.58(s, 1H), 6.53 (t, J = 6.8Hz, 1H), 5.37-5.28 (m, 1H), 4.64-2.98 (m, 12H), 2.43 (s, 3H), 2.34-1.89 (m, 6H).

[0561] Example 9: Preparation of Compound 9

[0562] Step A:

[0563] 9-1 (1.0 g, 4.48 mmol) was dissolved in tetrahydrofuran, and a solution of 4-methoxybenzyl chloride (2.10 g, 13.4 mmol) in tetrahydrofuran (25 mL) was added. The mixture was stirred at 25°C under nitrogen for 0.5 h. After cooling to 0°C in an ice bath, potassium tert-butyrate (1.01 g, 8.96 mmol) was added, and the reaction mixture was stirred at 30°C for 18 h. LCMS monitoring indicated the disappearance of the starting material. The reaction mixture was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the resulting crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to afford 9-2 (1.7 g, 82% yield).

[0564] LCMS (ESI) M / Z: 463.2 [M+H] + .

[0565] Step B:

[0566] 9-2 (1.0 g, 2.16 mmol), tributyl(1-ethoxyvinyl)tin (3.12 g, 8.64 mmol), and tetrakistriphenylphosphine palladium (374 mg, 0.32 mmol) were dissolved in toluene (20 mL). The reaction mixture was heated to 90°C and stirred for 18 h under nitrogen. After LCMS showed the disappearance of the starting material, the reaction mixture was concentrated, the residue was diluted with water, and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain compound 9-3 (865 mg).

[0567] LCMS (ESI) M / Z: 455.3 [M+H] + .

[0568] Step C:

[0569] Compound 9-3 (900 mg, 1.98 mmol) was dissolved in tetrahydrofuran (10 mL), and aqueous formic acid (10 mL, 3 M) was added. The reaction mixture was heated to 50°C and stirred for 3 h. After LCMS showed the disappearance of the starting material, the reaction mixture was diluted with water (100 mL) and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 9-4 (600 mg).

[0570] LCMS (ESI) M / Z: 427.2 [M+H] + .

[0571] Step D:

[0572] Compound 9-4 (100 mg, 0.23 mmol) was dissolved in methanol (1.2 mL), followed by the addition of ethanolamine (42 mg, 0.69 mmol) and acetic acid (0.14 g, 2.30 mmol). The resulting mixture was heated to 100°C and stirred under nitrogen for 18 h. After LCMS showed the disappearance of the starting material, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to afford compound 9-5 (30 mg).

[0573] MS (ESI) M / Z: 470.2 [M+H] + .

[0574] Step E:

[0575] Compound 9-5 (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (1 mL). Under nitrogen, a solution of lithium aluminum tetrahydride in tetrahydrofuran (0.043 mL, 41.7 mmol, 1 M) was added. The reaction mixture was stirred at room temperature for 18 h. After LCMS showed the disappearance of the starting material, the mixture was quenched with aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography (ACN / H2O) to afford compound 9-6 (15 mg).

[0576] MS (ESI) M / Z: 472.2 [M+H] + .

[0577] Step F:

[0578] Referring to the method of step C of Example 2, compound 9-7 was prepared using compound 9-6 and intermediate 1-R as raw materials.

[0579] MS (ESI) M / Z: 1116.2 [M+H] + .

[0580] Step G:

[0581] Compound 9-7 (40 mg, 0.014 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (7.13 mg, 0.028 mmol) were dissolved in chloroform (2 mL). N,N-diisopropylethylamine (9.05 mg, 0.070 mmol) was added, and the reaction mixture was heated to 70°C and stirred for 1 h under nitrogen. After LCMS showed the disappearance of the starting material, the reaction was quenched with water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE / EA = 4 / 1) to give compound 9-8 (16 mg, crude product).

[0582] LCMS (ESI) M / Z: 1098.5 [M+H] + .

[0583] Step H:

[0584] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (12.7 mg, 0.080 mmol) was dissolved in tetrahydrofuran (0.6 mL) and sodium hydride (3.2 mg, 0.080 mmol, 60% purity) was added. The reaction mixture was stirred at room temperature for 0.5 h under nitrogen, followed by the addition of compound 9-8 (18 mg, 0.016 mmol). The reaction mixture was heated to 60°C and stirred for 3 h. After LCMS showed the disappearance of the starting material, the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to afford compound 9-9 (10 mg).

[0585] LCMS (ESI) M / Z: 1221.8 [M+H] + .

[0586] Step I:

[0587] Compound 9-9 (10 mg, 0.0082 mmol) was dissolved in a mixture of trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.5 mL) and stirred at room temperature under nitrogen for 1 h. After LCMS showed the disappearance of the starting material, the reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford a mixture of two isomers, 9 (2.0 mg).

[0588] MS (ESI) M / Z: 741.1 [M+H] + ;

[0589] 1 H NMR (400MHz, CD3OD) δ8.83 (d, J = 2.0Hz, 1H), 7.97-7.90 (m, 2H), 7.62-7.58 (m, 1H), 7.34-7.31 (m, 1H), 6.69-6.67 (m, 1H), 5.58 (s, 1H), 5.34-5. 30(m,1H),4.47-4.24(m,4H),3.90-3.86(m,2H),3.48-3.42(m,3H),3. 15-3.13(m,1H),2.43(s,3H),2.21-2.02(m,6H),1.95(d,J=7.2Hz,3H).

[0590] Example 10: Preparation of Compound 10 and Its Isomers

[0591] Step A:

[0592] 10-1 (10 g, 64.9 mmol) was dissolved in N,N-dimethylformamide (100 mL). Methyl iodide (37.1 g, 259.5 mmol) and potassium carbonate (22.42 g, 162.2 mmol) were added at room temperature. The reaction system was heated to 50°C in a sealed container under nitrogen and stirred for 16 hours. After the reaction, the reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain 10-2 (6.5 g) and 10-2b (2.3 g).

[0593] LCMS (ESI) M / Z: 183.1 [M+H] + .

[0594] Step B:

[0595] 10-2 (2 g, 10.9 mmol) was dissolved in acetonitrile (30 mL). N-chlorosuccinimide (2.93 g, 21.9 mmol) was added to the mixture at room temperature. The reaction mixture was heated to 95°C and stirred for 16 hours under nitrogen. After the reaction, the mixture was quenched with water and purified by C18 column chromatography (ACN:H2O = 1:99 to 65:35) to obtain product 10-3 (1 g).

[0596] LCMS (ESI) M / Z: 217.0 [M+H] + .

[0597] Step C:

[0598] 10-3 (2 g, 10.9 mmol) and lithium hydroxide (0.53 g, 21.9 mmol) were dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (10 mL) and heated with stirring at 50°C for 2 hours. After the reaction, the reaction solution was adjusted to pH 4 with dilute hydrochloric acid (1 M), extracted three times with ethyl acetate, washed with saturated brine, and the organic phase was concentrated and purified by C18 column chromatography (ACN:H2O=1:99 to 70:30) to obtain compound 10-4 (1.6 g).

[0599] MS (ESI) M / Z: 203.0 [M+H] + .

[0600] Step D:

[0601] 10-4 (860 mg, 4.24 mmol), ammonium chloride (2.3 g, 42.4 mmol), diisopropylethylamine (1.6 g, 12.7 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.2 g, 8.48 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 16 hours. After the reaction, the reaction solution was diluted with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, washed with brine, concentrated, and purified by C18 column chromatography (ACN:H2O = 1:99 to 70:30) to obtain compound 10-5 (500 mg).

[0602] MS (ESI) M / Z: 202.0 [M+H] + .

[0603] Step E:

[0604] Compound 10-5 (240 mg, 1.19 mmol) was dissolved in methanol (2 mL). Ethanolamine (218 mg, 3.57 mmol) and tetraisopropyl titanate (0.7 mL, 2.38 mmol) were added at 25°C. The reaction mixture was heated to 100°C under nitrogen and microwave-heated for 2 hours. The mixture was then cooled to room temperature and sodium cyanoborohydride (224 mg, 3.57 mmol) was added. The reaction mixture was microwave-heated at 100°C for another 0.5 hours. After the reaction was complete, the reaction mixture was quenched with water and purified by C18 column chromatography (ACN:H2O = 1:99-70:30) to afford the crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford compound 10-6 (290 mg).

[0605] MS (ESI) M / Z: 247.1 [M+H] + .

[0606] Step F:

[0607] 10-6 (148 mg, 0.60 mmol) was dissolved in dimethyl sulfoxide (5 mL), and a solution of sodium bis(trimethylsilyl)amine (0.37 mL, 1.80 mmol, 2 M) in tetrahydrofuran was added at room temperature. The mixture was stirred for 30 minutes under nitrogen protection. A solution of intermediate 1-R (200 mg, 0.30 mmol) in dimethyl sulfoxide (3 mL) was added to the reaction solution. The reaction solution was heated to 70 ° C and stirred for 4 hours under nitrogen protection. After the reaction was completed, the mixture was quenched and diluted with saturated aqueous ammonium chloride solution, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine, and the organic phase was concentrated and column chromatography (PE / EA=1 / 1-1 / 2, then DCM / MeOH=50 / 1) was performed to obtain compound 10-7 (80 mg).

[0608] MS (ESI) M / Z: 891.2 [M+H] + .

[0609] Step G:

[0610] 10-7 (80 mg, 0.09 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (46 mg, 0.18 mmol) were dissolved in chloroform (1 mL). Diisopropylethylamine (56 mg, 0.45 mmol) was added, and the reaction mixture was heated to 70°C and stirred for 1 h under nitrogen. After completion of the reaction, the reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to afford compound 10-8 (34 mg).

[0611] MS (ESI) M / Z: 873.2 [M+H] + .

[0612] Step H:

[0613] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (50 mg, 0.31 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (15.0 mg, 0.62 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 0.5 h. Compound 10-8 (34 mg, 0.039 mmol) was dissolved in tetrahydrofuran (1 mL), and the above mixture was added. The reaction mixture was stirred at room temperature under nitrogen for 2 h. After the reaction, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford compound 10-9 (29 mg).

[0614] MS (ESI) M / Z: 996.4 [M+H] + .

[0615] Step I:

[0616] Compound 10-9 was dissolved in a mixture of trifluoromethanesulfonic acid (0.1 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature under nitrogen for 1 hour. After the reaction, the reaction solution was spun off and the residue was purified by reverse preparative chromatography (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 5%-95%) to afford compounds 10-P1 (5.06 mg) and 10-P2 (4.42 mg).

[0617] 10-P1: HPLC (Agilent 1260, Sunfire C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 10%-95%), retention time: 6.931 min.

[0618] MS (ESI) M / Z: 756.1 [M+H] + .

[0619] 1 H NMR (400MHz, Methanol-d4) δ6.62-6.58(m,2H),5.24(d,J=56.0Hz,1H),4.47-4.44(m,1H),4.40-4.36(m,1H),4.31(d,J=12.0Hz,1H),4.23(d,J=8 .0Hz,1H),4.06(s,3H),3.76-3.71(m,2H),3.26-3.19(m,2H),3.03-3.00 (m,1H),2.43(s,3H),2.36-1.95(m,6H),1.88(s,1H),1.68(d,J=4Hz,3H)

[0620] 10-P2: HPLC (Agilent 1260, Sunfire C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 10%-95%), retention time: 7.440 min.

[0621] MS (ESI) M / Z: 756.1 [M+H] + .

[0622] 1 H NMR (400MHz, Methanol-d4) δ6.621-6.57(m,2H),5.30(d,J=54.0Hz,1H),4.52-4.47(m,1H),4.40-4.30(m,2H),,4.21(d,J=10.0Hz,1H),4.05(s, 3H),3.79-3.76(m,1H),3.73-3.71(m,1H),3.23-3.18(m,2H),3.01-3.00 (m,1H),2.43(s,3H),2.35-1.95(m,6H),1.88(s,1H),1.69(d,J=8Hz,3H)

[0623] Example 11: Preparation of Compound 11 and Its Isomers

[0624] Step A:

[0625] Compound 10-2b (2.3 g, 12.6 mmol) was dissolved in acetonitrile (10 mL). N-chlorosuccinimide (13.4 g, 100.9 mmol) was added to the mixture at room temperature. The reaction mixture was heated to 95°C under nitrogen for 16 hours. After the reaction, the mixture was quenched with water and purified by C18 column chromatography (ACN:H2O = 1:99-65:35) to obtain compound 11-1 (2.5 g).

[0626] LCMS (ESI) M / Z: 217.1 [M+H] + .

[0627] Step B:

[0628] Compound 11-1 (2.5 g, 11.5 mmol) and lithium hydroxide (0.55 g, 23.1 mmol) were dissolved in a mixture of tetrahydrofuran (10 mL) and water (10 mL) and heated with stirring at 50°C for 2 hours. After the reaction, the reaction solution was adjusted to pH 4 with dilute hydrochloric acid (1 M), extracted three times with ethyl acetate, and washed with saturated brine. The organic phase was concentrated, and the residue was purified by C18 column chromatography (ACN:H2O=1:99-70:30) to obtain compound 11-2 (1.16 g).

[0629] MS (ESI) M / Z: 203.1 [M+H] + .

[0630] Step C:

[0631] Compound 11-2 (1.16 g, 5.73 mmol), ammonium chloride (3.06 g, 57.3 mmol), diisopropylethylamine (2.22 g, 17.19 mmol), and N,N,N,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (4.36 g, 11.46 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, and purified by C18 column chromatography (ACN:H2O = 1:99-70:30) to obtain compound 11-3 (500 mg).

[0632] MS (ESI) M / Z: 202.1 [M+H] + .

[0633] Step D:

[0634] Compound 11-3 (240 mg, 1.19 mmol) was dissolved in methanol (2 mL). Ethanolamine (218 mg, 3.57 mmol) and tetraisopropyl titanate (0.7 mL, 2.38 mmol) were added at room temperature. The reaction solution was microwave-heated at 100°C under nitrogen for 2 hours. The reaction solution was cooled to room temperature, and sodium cyanoborohydride (224 mg, 3.57 mmol) was added. The reaction solution was microwave-heated at 100°C for another 0.5 hour. After the reaction was completed, the mixture was quenched with water and purified by C18 column chromatography (ACN:H2O = 1:99-70:30) to obtain the crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 11-4 (270 mg).

[0635] MS (ESI) M / Z: 247.2 [M+H] + .

[0636] Step E:

[0637] Referring to the method of Step F of Example 10, compound 11-5 was prepared using compound 11-4 as raw material.

[0638] MS (ESI) M / Z: 891.2 [M+H] + .

[0639] Step F:

[0640] Referring to the method of step G of Example 10, compound 11-6 was prepared using compound 11-5 as raw material.

[0641] MS (ESI) M / Z: 873.2 [M+H] + .

[0642] Step G:

[0643] Referring to the method of Step H in Example 10, compound 11-7 was prepared using compound 11-6 as raw material.

[0644] MS (ESI) M / Z: 996.4 [M+H] + .

[0645] Step H:

[0646] Compounds 11-P1 and 11-P2 were prepared by referring to step I of Example 10 using compound 11-7 as starting material. Prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 25%-90%) was used.

[0647] 11-P1: HPLC (SHIMADZU UHLC-010, RD-C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 5%-95%), retention time: 9.947 min.

[0648] MS (ESI) M / Z: 756.5 [M+H] + .

[0649] 1 H NMR(400MHz, Methanol-d4)δ6.59-6.52(m,2H),5.31(d,J=52.0Hz,1H),4.50-4.48(m,1H),4.36-4.34(m,1H),4.24(s,2H),3 .93(s,3H),3.89-3.83(m,1H),3.28-3.18(m,3H),3.01-3.00(m,1H),2.43(s,3H),2.34-1.94(m,7H),1.86(d,J=7.2Hz,3H).

[0650] 11-P2: HPLC (SHIMADZU UHLC-010, RD-C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 5%-95%), retention time: 10.449 min.

[0651] MS (ESI) M / Z: 756.5 [M+H] + .

[0652] 1H NMR (400MHz, Methanol-d4) δ6.58=6.50(m,2H),5.30(d,J=54.0Hz,1H),4.57-4.52(m,1H),4.40-4.29(m,2H),4.17(d,J=10.0Hz, 1H),3.93(s,3H),3.84-3.83(m,1H),3.24-3.19(m,3H),3.01-3.00(m,1H),2.44(s,3H),2.25-1.95(m,7H),1.85(d,J=6.8Hz,3H).

[0653] Example 12: Preparation of Compound 12 and Its Isomers

[0654] Step A:

[0655] Under nitrogen, 12-1 (1 g, 5.7 mmol), PMBCl (4 g, 25.5 mmol), and DIPEA (3.67 g, 28.5 mmol) were heated to 90°C without solvent and stirred for 6 hours. TLC confirmed the near-complete reaction of the starting materials. Most of the DIPEA was removed by rotary evaporation under reduced pressure, and the product was diluted with water. The product was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 12-2 (2 g, 76% yield).

[0656] MS (ESI) M / Z: 416.2 [M+H] + .

[0657] Steps B & C:

[0658] Compound 12-2 (1.1 g, 2.65 mmol), triphenylphosphine palladium dichloride (186 mg, 0.265 mmol), and 12-3 (1.91 g, 5.3 mmol) were dissolved in DMF (15 mL) at room temperature. The reaction mixture was heated to 90°C and stirred for 16 hours under nitrogen. TLC indicated the reaction was complete. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the residue 12-4. This residue was purified by silica gel column chromatography (petroleum ether / acetone = 5 / 1) to afford compound 12-5 (500 mg, 50% yield).

[0659] MS (ESI) M / Z: 380.3 [M+H] + .

[0660] 1H NMR (400MHz, CDCl3) δ7.70 (s, 1H), 7.24 (s, 4H), 6.79 (d, J = 8.6Hz, 4H), 4.49 (s, 4H), 3.77 (s, 6H), 3.73 (s, 3H), 2.41 (s, 3H).

[0661] Step D:

[0662] Compound 12-5 (230 mg, 0.61 mmol), ethanolamine (111.78 mg, 1.83 mmol), and tetraisopropyl titanate (0.36 mL, 1.22 mmol) were dissolved in methanol (3 mL) and microwave-heated at 100°C for 4 hours. After the starting material was essentially gone by LCMS, the reaction solution was cooled to room temperature and dried by spin drying. The residue was dissolved in tetrahydrofuran (3 mL) and 1 M lithium tetrahydroaluminate (2.16 mL, 2.16 mmol) was added under nitrogen. The mixture was stirred at room temperature for 16 hours. After completion of the reaction as monitored by LCMS, the reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate concentrated under vacuum. The residue was purified by C18 silica gel column chromatography (ACN / H2O) to afford compound 12-6 (80 mg, 35% yield).

[0663] MS (ESI) M / Z: 425.3 [M+H] + .

[0664] Step E:

[0665] Referring to the method of Step F of Example 10, compound 12-7 was prepared using compound 12-6 as raw material.

[0666] MS (ESI) M / Z: 1069.5 [M+H] + .

[0667] Step F:

[0668] Referring to the method of step G of Example 10, compound 12-8 was prepared using compound 12-7 as raw material.

[0669] MS (ESI) M / Z: 873.2 [M+H] + .

[0670] Step G:

[0671] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (45.4 mg, 0.29 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (15.6 mg, 0.29 mmol, 60% purity) was added. The mixture was stirred at room temperature under nitrogen for 0.5 h. Compound 12-8 (60 mg, 0.057 mmol) was added, and the reaction mixture was heated to 60°C for 2 h. LCMS showed the disappearance of the starting material. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under vacuum. The residue was purified by preparative TLC (EA / PE = 3 / 1) to afford compound 12-9 (40 mg, 59% yield).

[0672] LCMS (ESI) M / Z: 1174.3 [M+H] + .

[0673] Step H:

[0674] Compounds 12-P1 and 12-P2 were prepared using compound 12-9 as the starting material, following the procedure of Step 1 in Example 10. Prep-HPLC: Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 25%-90%.

[0675] 12-P1: HPLC: Agilent 1100, XBridge C18 4.6*150mm 5μm, Mobile phase: A: H2O (10mM) NH4HCO3 B: MeCN, Flow rate: 1.0mL / min, 16min, Gradient B: 30%-95%, retention time: 7.568min.

[0676] MS (ESI) M / Z: 694.2 [M+H] + .

[0677] 1H NMR (400MHz, CD3OD) δ7.51(s,1H),6.58(s,1H),6.35-6.33(m,1H),5.34-5.30(m,1H),4.35-4.34(m,1H),4.32-4.23(m ,3H),3.68-3.65(m,5H),3.34-3.31(m,2H),3.30-3.29(m,1H),2.43(s,3H),2.16-1.88(m,7H),1.57(d,J=8.0Hz,3H).

[0678] 12-P2: HPLC: Agilent 1100, XBridge C18 4.6*150mm 5μm, Mobile phase: A: H2O (10mM) NH4HCO3 B: MeCN, Flow rate: 1.0mL / min, 16min, Gradient B: 30%, retention time: 8.919min.

[0679] MS (ESI) M / Z: 694.1 [M+H] + .

[0680] 1 H NMR (400MHz, CD3OD) δ7.51(s,1H),6.58(s,1H),6.35-6.33(m,1H),5.34-5.30(m,1H),4.35-4.34(m,1H),4.32-4.23(m,3H),3.68(s,3 H),3.67-3.66(m,1H),3.57-3.46(m,1H),3.34-3.31(m,2H),3.30-3.29(m,1H),2.43(s,3H),2.16-1.88(m,7H),1.57(d,J=8.0Hz,3H).

[0681] Example 13: Preparation of Compound 13

[0682] Step A:

[0683] Compound 13-2 (16.5 mg, 0.10 mmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydride (4 mg, 0.10 mmol, 60 wt%) was added. The mixture was stirred at room temperature under nitrogen for 0.5 h. Compound 13-1 (20 mg, 0.020 mmol, prepared according to WO2022216762) was dissolved in tetrahydrofuran (1 mL) and added to the above mixture. The reaction mixture was heated at 60°C and stirred for 2 h under nitrogen. After completion of the reaction, water was added to quench the reaction, and the product was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to afford compound 13-3 (15 mg, 66% yield).

[0684] MS (ESI) M / Z: 1177.4 [M+H] + .

[0685] Step B:

[0686] Compound 13-3 (15.0 mg, 0.013 mmol) was dissolved in a mixture of toluene-4-sulfonic acid (0.2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the resulting crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford compound 13 (3.12 mg, 35% yield).

[0687] MS (ESI) M / Z: 697.1 [M+H] + .

[0688] 1H NMR (400MHz, DMSO-d6) δ7.97(dd,J=1.2Hz,4.8Hz,1H),7.63(d,J=7.6Hz,1H),6.80(s,2H),6.68-6.65(m,1H),6.47(s ,1H),6.28-6.26(m,1H),5.75(s,2H),5.57(s,1H),4.45-4.40(m,1H),4.27-4.23(m,2H),4.10(d,J=10.0Hz,1H),3.6 2-3.53(m,2H),3.39-3.35(m,1H),3.13(d,J=9.2Hz,1H),2.95(d,J=15.6Hz,1H),2.55-2.53(m,1H),2.35(d,J=1.6Hz ,3H),2.01-1.98(m,1H),1.76-1.73(m,1H),1.69(s,2H),1.49(d,J=0.8Hz,3H),0.85-0.83(m,1H),0.52-0.43(m,2H).

[0689] Example 14: Preparation of Compound 14

[0690] Step A:

[0691] (1-((Morpholin-4-yl)methyl)cyclopropyl)methanol (32.5 mg, 0.19 mmol) was dissolved in tetrahydrofuran (1 mL). Sodium hydride (7.6 mg, 0.19 mmol, 60% purity) was added at room temperature under nitrogen. The reaction solution was stirred at room temperature for 30 minutes. Compound 13-1 (20 mg, 0.019 mmol) was added, and the reaction solution was stirred at 50°C for 3 hours. After completion of the reaction, the reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 14-1 (20 mg, 88%).

[0692] MS (ESI) M / Z: 1183.7 [M+H] + .

[0693] Step B:

[0694] 14-1 (20 mg, 0.017 mmol) was dissolved in trifluoroacetic acid (1 mL), and 3 drops of a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid (10:1) were added. The mixture was stirred at room temperature under nitrogen for 30 minutes. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse preparative purification (acetonitrile:H2O = 5:95 to 95:5) to afford compound 14 (2.92 mg, 25%).

[0695] MS (ESI) M / Z: 703.5 [M+H] + .

[0696] 1 H NMR (400MHz, Methanol-d4) δ7.96(d,J=4.4Hz,1H),7.75(d,J=7.2Hz,1H),6.78(dd,J=7.6,5.2Hz,1H),6.58(s,1H),6.50(d,J=6.8Hz,1H),4.50-4. 38(m,2H),4.33-4.24(m,1H),3.65(d,J=5.6Hz,6H),3.52(d,J=6.0Hz,1H) ,2.52(s,4H),2.44(s,5H),1.66(d,J=6.8Hz,3H),0.60(d,J=91.6Hz,4H).

[0697] Examples 39 and 40 can be prepared by selecting corresponding raw materials according to Example 14:

[0698] Example 15: Preparation of Compound 15 and Its Isomers

[0699] Step A:

[0700] 15-1 (5.5 g, 20.4 mmol) was dissolved in a mixture of trifluoroacetic acid (20 mL) and trifluoromethanesulfonic acid (0.05 mL). The reaction mixture was heated to 25°C and stirred for 30 min under nitrogen. LCMS showed the disappearance of the starting material. The reaction solution was concentrated, and the resulting mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 15-2 (2.5 g, 72% yield).

[0701] LCMS (ESI) M / Z: 156.2 [M+H] + .

[0702] Step B:

[0703] Compound 15-2 (400 mg, 2.58 mmol) was dissolved in dichloromethane (20 mL), and silver oxide (1195 mg, 5.16 mmol) and trideuteriodine (iodine)methane (3740 mg, 25.8 mmol) were added. The mixture was reacted at room temperature under nitrogen for 18 hours. LCMS showed the disappearance of the starting material. The reaction solution was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to afford compound 15-3 (300 mg, 67% yield).

[0704] LCMS (ESI) M / Z: 173.2 [M+H] + .

[0705] Step C:

[0706] Compound 15-3 (500 mg, 2.90 mmol), bis(4-methoxybenzyl)amine (1492 mg, 5.8 mmol), and triethylamine (0.88 g, 8.7 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 110°C under nitrogen for 16 hours. LCMS showed the disappearance of the starting material. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to afford compound 15-4 (850 mg, 71% yield).

[0707] LCMS (ESI) M / Z: 410.4 [M+H] + .

[0708] Step D:

[0709] Compound 15-4 (200 mg, 0.49 mmol), 2-(tert-butyldimethylsilyloxy)ethylamine (257 mg, 1.47 mmol), and tetraisopropyl titanate (278 mg, 0.98 mmol) were dissolved in methanol (10 mL) and microwave-heated at 100°C for 2 hours. LCMS analysis indicated the reaction was nearly complete. After cooling to room temperature, sodium cyanoborohydride (92.3 mg, 1.47 mmol) was added and the reaction continued at 100°C under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature and quenched with aqueous ammonium chloride. 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. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford compound 15-5 (230 mg, 83% yield).

[0710] LCMS (ESI) M / Z: 569.3 [M+H] + .

[0711] Step E:

[0712] Compound 15-5 (210 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium fluoride (1124 mg, 7.0 mmol) was added. The reaction mixture was heated to 60°C for 18 hours. After LCMS showed the disappearance of the starting material, the reaction mixture was quenched with aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to provide compound 15-6 (140 mg, 83% yield).

[0713] LCMS (ESI) M / Z: 455.2 [M+H] + .

[0714] Step F:

[0715] Compound 15-6 (115 mg, 0.25 mmol) was dissolved in DMSO (2 mL). A solution of sodium bis(trimethylsilyl)amide (0.19 mL, 0.93 mmol, 2 M) in tetrahydrofuran was added at room temperature under nitrogen. The resulting yellow solution was stirred at room temperature for 30 minutes, followed by the addition of a solution of intermediate 1-R (150 mg, 0.23 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was heated to 60°C and stirred for 2 hours under nitrogen. LCMS indicated the disappearance of the starting material. The reaction mixture was quenched with aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to dichloromethane / methanol = 50 / 1) to afford compound 15-7 (200 mg, 81% yield).

[0716] LCMS (ESI) M / Z: 1099.2 [M+H] + .

[0717] Step G:

[0718] Compound 15-7 (200 mg, 0.18 mmol) was dissolved in chloroform (5 mL), and diisopropylethylamine (116 mg, 0.90 mmol) was added, followed by bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (77.9 mg, 0.31 mmol). The reaction mixture was heated to 70°C and stirred for 1 hour under nitrogen. LCMS showed the disappearance of the starting material. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford compound 15-8 (130 mg, 66% yield).

[0719] MS (ESI) M / Z: 1081.2 [M+H] + .

[0720] Step H:

[0721] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (103.4 mg, 0.65 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (15.6 mg, 0.65 mol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of a solution of compound 15-8 (140 mg, 0.13 mmol) in tetrahydrofuran (0.5 mL). The mixture was stirred at 60°C under nitrogen for 1 hour. LCMS showed the disappearance of the starting material. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1 to 20 / 1) to afford compound 15-9 (140 mg, 89% yield).

[0722] MS (ESI) M / Z: 1204.4 [M+H] + .

[0723] Step I:

[0724] Compound 15-9 (100 mg, 0.083 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL) and stirred at room temperature under nitrogen for 30 minutes. LCMS indicated the disappearance of the starting material. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol: 10 / 1) to afford compounds 15-P1 (20.69 mg, 34% yield) and 15-P2 (18.29 mg, 30.43% yield).

[0725] 15-P1: HPLC (Agilent 1100, XBridge C18 5uM 4.6*150MM, Mobile phase: A: H2O(0.03% TFA) B: MeCN(0.03% TFA), Flow rate: 1.0mL / min, 16min, Gradient B: 10%), Retention time: 7.521min.

[0726] MS(ESI) M / Z: 724.1[M+H] + .

[0727] 1 H NMR(400MHz, CD3OD) δ7.95(d, J=1.2Hz, 1H), 7.68(d, J=6.8Hz, 1H), 6.73(t, J=5.2Hz, 1H), 6.59(s, 1H), 6.54 - 6.51(m, 1H), 5.30 - 5.25(m, 1H), 4.54 - 4.41(m, 1H), 4.29 - 4.26(m, 1H), 4.26(s, 2H), 4.20 - 4.15(m, 1H), 4.10 - 4.09(m, 1H), 3.94 - 3.90(m, 1H), 3.84 - 3.80(m, 1H), 3.58 - 3.31(m, 4H), 2.43(s, 3H), 2.34 - 2.20(m, 3H), 2.18 - 1.90(m, 3H).

[0728] 15-P2: HPLC (Agilent 1260, Sunfire C18 4.6*150mm 5μm, Mobile phase: A: H2O(0.03% TFA) B: MeCN(0.03% TFA), Flow rate: 1.0mL / min, 16min, Gradient B: 10%), Retention time: 6.259min.

[0729] MS(ESI) M / Z: 724.1[M+H] + .

[0730] 1H NMR (400MHz, CD3OD) δ7.95(d,J=1.2Hz,1H),7.68(d,J=7.6Hz,1H),6.74-6.71(m,1H),6.58-6.53(m,2H),5.30-5.25(m,1H),4.54-4.41 (m,1H),4.29-4.25(m,2H),4.20-4.15(m,2H),3.97-3.83(m,2H),3.59-3.54(m,1H),3.38-3.25(m,4H),2.30(s,3H),2.24-1.90(m,6H).

[0731] Example 16: Preparation of Compound 16 and Its Isomers

[0732] Step A:

[0733] Compound 16-1 (530 mg, 3.13 mmol), bis(4-methoxybenzyl)amine (1.01 g, 3.91 mmol), and triethylamine (0.87 mL, 6.26 mmol) were dissolved in 1,4-dioxane (8 mL). The reaction mixture was heated to 110°C under nitrogen for 16 hours. After LCMS showed the disappearance of the starting material, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to provide compound 16-2 (1.0 g).

[0734] LCMS (ESI) M / Z: 407.2 [M+H] + ;

[0735] 1 H NMR (400MHz, CDCl3) δ8.33 (dd, J=2.0Hz, J=4.8Hz, 1H), 7.74 (dd, J=2.0Hz, J=7.6Hz, 1H), 7. 01(d,J=8.8Hz,4H),6.82-6.79(m,5H),4.43(s,3H),4.41(s,3H),3.78(s,6H),3.41(s,3H).

[0736] Step B:

[0737] Compound 16-2 (600 mg, 1.48 mmol), ethanolamine (271 mg, 4.44 mmol), and tetraisopropyl titanate (0.88 mL, 2.96 mmol) were dissolved in methanol (6 mL). The reaction mixture was heated to 100°C in a microwave oven under nitrogen for 2 hours. LCMS indicated the disappearance of the starting material. After the reaction mixture returned to room temperature, sodium cyanoborohydride (279 mg, 4.44 mmol) was added. The reaction mixture was microwaved at 100°C under nitrogen for 0.5 h. Additional sodium borohydride (164 mg, 4.44 mmol) was added and the microwave oven reaction continued for 1 h. LCMS indicated the reaction was complete. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford compound 16-3 (270 mg).

[0738] LCMS (ESI) M / Z: 452.3 [M+H] + ;

[0739] 1 H NMR (400MHz, CDCl3) δ8.55-8.54(m,1H),8.40(s,1H),7.99-7.97(m,1H),7.19(dd,J=4.8H z, J=7.6Hz, 1H), 7.08 (d, J=8.4Hz, 4H), 6.78 (d, J=8.4Hz, 4H), 4.79 (dd, J=2.8Hz, J=8.8Hz, 1H),4.17(d,J=12.8Hz,2H),4.02(d,J=13.2Hz,2H),3.76(s,6H),3.51(t,J=4.4Hz,2H),3. 34(t,J=8.0Hz,1H),3.30(s,3H),3.02-2.96(m,2H),2.19-2.14(m,1H),2.03-1.98(m,1H).

[0740] Step D:

[0741] Compound 16-3 (110 mg, 0.25 mmol) was dissolved in DMSO (2 mL). Under nitrogen, a solution of sodium bis(trimethylsilyl)amide (0.46 mL, 0.92 mmol, 2.0 M) in tetrahydrofuran was added at room temperature. After stirring at room temperature for 40 minutes, a solution of intermediate 1-R (150 mg, 0.23 mmol) in dimethyl sulfoxide (2 mL) was added. The reaction mixture was heated to 65°C and stirred for 2 hours under nitrogen. After LCMS showed the disappearance of the starting material, the reaction was quenched with saturated aqueous ammonium chloride. The product was 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 purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to dichloromethane / methanol = 50 / 1) to give compound 16-4 (150 mg).

[0742] LCMS (ESI) M / Z: 1096.4 [M+H] + .

[0743] Step E:

[0744] Compound 16-4 (160 mg, 0.15 mmol) was dissolved in chloroform (4 mL), and diisopropylethylamine (0.31 mL, 1.85 mmol) was added. Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (64.9 mg, 0.26 mmol) was added at room temperature. The reaction solution was heated to 70°C and stirred under nitrogen for 1 hour. After LCMS showed the disappearance of the starting material, water (10 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to provide compound 16-5 (100 mg).

[0745] MS (ESI) M / Z: 1078.5 [M+H] + .

[0746] Step F:

[0747] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (44.4 mg, 0.28 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (11.2 mg, 0.28 mmol) was added at room temperature and stirred for 10 minutes. Compound 16-5 (100 mg, 0.09 mmol) in tetrahydrofuran (0.5 mL) was then added to the reaction system at room temperature. The reaction mixture was heated to 50°C and stirred for 1 hour under nitrogen. After LCMS showed the disappearance of the starting material, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50:1 to 20:1) to provide compound 16-6 (100 mg).

[0748] MS (ESI) M / Z: 1201.6 [M+H] + .

[0749] Step G:

[0750] Compound 16-6 (100 mg, 0.083 mmol) was dissolved in a mixed solution of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 h. LCMS indicated the disappearance of the starting material. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford the crude product. This was then purified by Prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 25%-90%) to afford compounds 16-P1 (10.41 mg) and 16-P2 (10.85 mg).

[0751] 16-P1: HPLC (Agilent 1260, Sunfire C18 4.6*150 mm 5 μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 3%) retention time: 6.632 min.

[0752] MS (ESI) M / Z: 721.6 [M+H] + ;

[0753] 1 H NMR (400MHz, CD3OD) δ7.94(d,J=4.8Hz,1H),7.68(d,J=7.6Hz,1H),6.73(t,J=7.2Hz ,1H),6.58(s,1H),6.53(t,J=6.8Hz,1H),5.37-5.28(m,1H),4.54-4.41(m,1H),4.39 -4.36(m,1H),4.26(s,2H),4.13-4.09(m,1H),3.97-3.93(m,1H),3.84-3.78(m,1H) ,3.62-3.57(m,1H),3.41(s,3H),3.26-2.98(m,4H),2.43(s,3H),2.34-1.89(m,6H).

[0754] 16-P2: HPLC (Agilent 1260, Sunfire C18 4.6*150 mm 5 μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 3%) retention time: 7.022 min.

[0755] MS (ESI) M / Z: 721.6 [M+H] + ;

[0756] 1 H NMR (400MHz, CD3OD) δ7.95(d,J=4.8Hz,1H),7.69(d,J=7.6Hz,1H),6.73(dd,J=7.5,5.1 Hz,1H),6.59(s,1H),6.56f(t,J=6.8Hz,1H),5.37-5.28(m,1H),4.59-4.50(m,1H),4.4 2-4.34(m,1H),4.34-4.19(m,2H),4.17-4.09(m,1H),3.99-3.93(m,1H),3.89-3.78(m, 1H),3.62-3.52(m,1H),3.41(s,3H),3.27-2.96(m,4H),2.44(s,3H),2.40-1.89(m,6H).

[0757] Example 17: Preparation of Compound 17 and Its Isomers

[0758] Step A:

[0759] Compound 17-1 (122 g, 575 mmol) and diisopropylethylamine (149 g, 1.15 mmol) were dissolved in methanol (1.25 L). Methylhydrazine sulfate (41.4 g, 287 mmol) was added, and the reaction mixture was heated to 70°C under nitrogen for 4 h. The reaction mixture was diluted with water and extracted three times with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-3%) to provide compound 17-2 (10 g).

[0760] MS (ESI) M / Z: 223.3 [M+H] + .

[0761] Step B:

[0762] Compound 17-2 (4 g, 18.0 mmol) was dissolved in tetrahydrofuran (40 mL), and a solution of lithium hydroxide hydrate (1.51 g, 36 mmol) in water (20 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (40 mL) was added to dilute the reaction mixture, and the organic phase was washed three times with dichloromethane. The aqueous phase was collected and the pH was adjusted to 5.0 with 3M hydrochloric acid. A large amount of solid precipitated, and the filter cake was collected by filtration and dried to obtain compound 17-3 (3 g).

[0763] MS (ESI) M / Z: 195.2 [M+H] + .

[0764] Step C:

[0765] Compound 17-3 (2.7 g, 13.9 mmol) and triethylamine (3.09 g, 30.6 mmol) were dissolved in anhydrous tert-butanol (40 mL) at room temperature. Diphenylphosphoryl azide (5.74 g, 20.8 mmol) was added, and the resulting mixture was stirred at 100°C under nitrogen for 16 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1) to obtain compound 17-4 (3 g).

[0766] MS (ESI) M / Z: 210.2 [M+H-56] + .

[0767] Step D:

[0768] Compound 17-4 (1.1 g, 4.15 mmol) and ethanolamine (1.01 g, 16.6 mmol) were dissolved in dry tetrahydrofuran (14 mL). One drop of acetic acid was added. The reaction mixture was heated to 100°C under nitrogen and stirred for 16 hours. After the reaction mixture cooled to room temperature, sodium cyanoborocyanide (471 mg, 12.5 mmol) was added portionwise and the reaction continued at room temperature for 3 hours. The reaction mixture was subjected to reverse-phase flash chromatography to obtain a crude product, which was then purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain compound 17-5 (200 mg).

[0769] MS (ESI) M / Z: 311.1 [M+H] + .

[0770] Step E:

[0771] Compound 17-5 (50 mg, 0.16 mmol) was dissolved in dimethyl sulfoxide (1 mL) at room temperature, and a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.32 mL, 0.64 mmol, 2 M) was added. The mixture was stirred at room temperature under nitrogen for 0.5 hours, followed by the addition of a solution of intermediate 1-R (80 mg, 0.12 mmol) in dimethyl sulfoxide (1 mL). The reaction mixture was heated to 60°C and stirred for 1 hour under nitrogen. After LCMS showed the disappearance of the starting material, the reaction solution was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to give compound 17-6 (120 mg).

[0772] MS (ESI) M / Z: 955.3 [M+H] + .

[0773] Step F:

[0774] Compound 17-6 (100 mg, 0.10 mmol) and diisopropylethylamine (64.6 mg, 0.50 mmol) were dissolved in chloroform (2 mL). Bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (43.3 mg, 0.17 mmol) was added. The reaction mixture was heated to 70°C and stirred for 1 hour under nitrogen. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 1 / 3) to give compound 17-7 (60 mg).

[0775] MS (ESI) M / Z: 937.3 [M+H] + .

[0776] Step G:

[0777] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (47.9 mg, 0.30 mol) was dissolved in tetrahydrofuran (0.5 mL) and sodium hydride (12.0 mg, 0.30 mmol, 60% content) was added. The reaction system was stirred at room temperature under nitrogen for 15 minutes. A solution of compound 17-7 (40.3 mg, 0.043 mmol) in tetrahydrofuran (1 mL) was added and stirred at room temperature for 0.5 hours. After LCMS showed the disappearance of the starting material, the reaction was quenched by the addition of cold saturated aqueous NH4Cl solution. The product was 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 filtrate was purified by Prep-TLC (DCM / MeOH = 10 / 1) to afford compound 17-8 (15 mg).

[0778] MS (ESI) M / Z: 1060.5 [M+H] + .

[0779] Step H:

[0780] Compound 17-8 (15 mg, 0.014 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.05 mL) and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and basified to pH ~8.0 with cold saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 25%-90%) to afford two isomers: 17-P1: 2.61 mg, 17-P2: 1.10 mg.

[0781] 17-P1: HPLC (Agilent 1100, XBridge C18 5uM 4.6*150mm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0mL / min, 16min, Gradient B: 10%-95%), retention time: 7.665min.

[0782] MS (ESI) M / Z: 720.1 [M+H] + ；

[0783] 1 H NMR (400MHz, CD3OD) δ6.59 (s, 1H), 6.20 (t, J = 5.6Hz, 1H), 5.37-5.24 (m, 1H), 4.66-4.62 (m, 1H), 4.48-4.44 (m, 1H), 4.37-4.22 (m, 2H), 3.7 4-3.60(m,2H),3.57(s,3H),3.27-3.22(m,2H),3.04-3.01(m,1H),2.63-2.60(m,2H),2.44(s,3H),2.36-2.13(m,5H),2.02-1.86(m,6H).

[0784] 17-P2: HPLC (Agilent 1100, XBridge C18 5uM 4.6*150mm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0mL / min, 16min, Gradient B: 10%-95%), retention time: 8.336min.

[0785] MS (ESI) M / Z: 720.1 [M+H] + ；

[0786] 1 H NMR (400MHz, CD3OD) δ6.58 (s, 1H), 6.21 (t, J = 4.8Hz, 1H), 5.37-5.24 (m, 1 H),4.62-4.59(m,1H),4.51-4.49(m,1H),4.29-4.22(m,2H),3.75-3.61(m ,2H),3.57(s,3H),3.26-3.19(m,2H),3.02-2.99(m,1H),2.63-2.60(m,2 H),2.44(s,3H),2.36-2.10(m,6H),2.00-1.94(m,3H),1.90-1.86(m,2H).

[0787] Example 18: Preparation of Compound 18 and Its Isomers

[0788] Step A:

[0789] (1-(Morpholinomethyl)cyclopropyl)methanol (119 mg, 0.70 mmol) was dissolved in tetrahydrofuran (1.5 mL). Sodium hydride (28 mg, 0.70 mmol, 60% purity) was added at room temperature under nitrogen and stirred for 0.5 hours. Compound 16-5 (150 mg, 0.14 mmol) was added, and the reaction mixture was heated to 50°C and stirred for 3 hours under nitrogen. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford compound 18-1 (130 mg).

[0790] MS (ESI) M / Z: 607.8 [M / 2+H] + .

[0791] Step B:

[0792] Compound 18-1 (120 mg, 0.099 mmol) was dissolved in trifluoroacetic acid (1 mL). 0.2 mL of a 10:1 mixture of trifluoroacetic acid and trifluoromethanesulfonic acid was added three times in a 15°C water bath. The mixture was reacted at room temperature for 0.5 h each time. After the reaction, the reaction solution was poured into an icy sodium bicarbonate aqueous solution, extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00mm 10μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0mL / min, Gradient B: 5%-95%) to obtain two isomers: 18-P1 (14.46mg) and 18-P2 (11.72mg).

[0793] 18-P1: HPLC (Agilent 1260, Sunfire C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 20%-95%) retention time: 4.417 min.

[0794] MS (ESI) M / Z: 733.5 [M+H] + ;

[0795] 1H NMR (400MHz, CD3OD) δ7.95(dd,J=5.2,1.6Hz,1H),7.69(d,J=7.6Hz,1H),6.73(dd,J =7.6,5.2Hz,1H),6.58(s,1H),6.54(t,J=6.4Hz,1H),4.55-4.33(m,4H),4.11(dd,J =10.4,7.2Hz,1H),3.97(dd,J=10.4,5.6Hz,1H),3.80(dd,J=15.6,6.4Hz,1H),3.70 -3.54(m,5H),3.42(s,3H),2.58-2.40(m,9H),0.72-0.69(m,2H),0.49-0.46(m,2H).

[0796] 18-P2: HPLC (Agilent 1260, Sunfire C18 4.6*150mm 5μm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 20%-95%) retention time: 4.881 min.

[0797] MS (ESI) M / Z: 733.5 [M+H] + ;

[0798] 1 H NMR (400MHz, CD3OD) δ7.95(dd,J=5.2,1.6Hz,1H),7.69(d,J=7.6Hz,1H),6.73(dd,J=7.6,5.2Hz ,1H),6.62-6.52(m,2H),4.54(dd,J=12.0,7.2Hz,1H),4.46-4.33(m,3H),4.12(dd,J=10.4,7.2 Hz,1H),3.97(dd,J=10.4,5.6Hz,1H),3.83(dd,J=15.6,6.4Hz,1H),3.64(t,J=4.8Hz,4H),3.57 (dd,J=15.6,6.8Hz,1H),3.44(s,3H),2.58-2.41(m,9H),0.72-0.69(m,2H),0.48-0.46(m,2H).

[0799] Examples 31 to 35 can be prepared by selecting corresponding raw materials with reference to Example 18:

[0800] Example 19: Preparation of Compound 19 and Its Isomers

[0801] Step A:

[0802] Compound 19-1 (290 mg, 0.35 mmol, prepared with reference to WO2022216762), (5-methyl-1H-indazol-4-yl)boric acid (122 mg, 0.69 mmol), tetrakis(triphenylphosphine)palladium (8 mg, 0.07 mmol) and sodium carbonate were dispersed in a mixed solution of 1,4-dioxane and water (10 mL / 5 mL) and heated in a microwave at 120 ° C under nitrogen protection for 1 hour. TLC monitoring showed that the product content no longer increased, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (prep-HPLC: Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00mm 10μm, Mobile phase: A: H2O (10mM NH4HCO3) B: MeCN, Flow rate: 20.0mL / min, Gradient B: 25%-90%) to give two components: 19-2-P1 (15 mg, shorter retention time) and 19-2-P2 (50 mg, longer retention time).

[0803] MS (ESI) M / Z: 887.1 [M+H] + .

[0804] Step B:

[0805] Compound 19-2-P1 (15 mg, 0.017 mmol) was dissolved in a mixed solvent (trifluoromethanesulfonic acid / trifluoroacetic acid / anhydrous dichloromethane = 0.1 / 1.5 / 5, 6.6 mL), and the reaction solution was stirred at room temperature for 0.5 hours. The reaction of the starting material was basically completed as monitored by LCMS. The product was quenched by adding aqueous sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (prep-HPLC: Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00mm10μm, Mobile phase: A: H2O (10mM NH4HCO3) B: MeCN, Flow rate: 20.0mL / min, Gradient B: 25%-90%) to give the target product 19-P1 (2.38mg); 19-2-P1 was replaced with 19-2-P2 and the above operation was repeated to give the target product 19-P2 (6.20mg).

[0806] 19-P1:

[0807] MS (ESI) M / Z: 647.4 [M+H] + .

[0808] 1 H NMR (400MHz, DMSO) δ13.12(s,1H),7.98(d,J=4.3Hz,1H),7.64(d,J=7.4Hz,1H),7.57-7.51(m,2H), 7.36(d,J=8.4Hz,1H),6.67(dd,J=7.3,4.9Hz,1H),6.35(d,J=6.7Hz,1H),5.82(s,2H),5.29(d,J=5 4.6Hz,1H),4.50(s,1H),4.32(s,1H),4.07(d,J=22.8Hz,2H),3.75(d,J=16.8Hz,1H),3.43(s,1H), 3.05(d,J=30.3Hz,3H),2.82(s,1H),2.15(s,3H),2.06(s,3H),1.78(s,3H),1.59(d,J=6.8Hz,3H).

[0809] 19-P2:

[0810] MS (ESI) M / Z: 646.8 [M+H] + .

[0811] 1 H NMR (400MHz, DMSO) δ13.14(s,1H),7.98(d,J=3.7Hz,1H),7.65(d,J=7.1Hz,1H),7.58-7.49(m,2H),7.36( d,J=8.6Hz,1H),6.67(dd,J=7.4,4.9Hz,1H),6.33(d,J=6.9Hz,1H),5.79(s,2H),5.30(d,J=54.3Hz,1H),4 .52(dd,J=12.0,6.5Hz,1H),4.37-4.26(m,1H),4.12(s,2H),3.74(dd,J=15.8,6.8Hz,1H),3.42(dd,J=15. 6,6.0Hz,1H),3.12(s,3H),2.84(s,1H),2.19-1.99(m,6H),1.77(d,J=14.7Hz,3H),1.59(d,J=6.8Hz,3H).

[0812] Example 20: Preparation of Compound 20 and Its Isomers

[0813] Step A:

[0814] Compound 20-1 (37 mg, 0.09 mmol, prepared according to WO2022170999), 20-2 (50 mg, 0.06 mmol, prepared according to WO2022216762), (1,1'-bis(di-tert-butylphosphino)ferrocene)palladium dichloride (3.7 mg, 0.006 mmol), and N,N-diisopropylethylamine (23.2 mg, 0.18 mmol) were dissolved in a mixed solvent (tetrahydrofuran / water = 5 / 1, 2.4 mL) and heated to 70°C under nitrogen with stirring for 2 hours. LCMS confirmed the substantial reaction of the starting materials. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 20-3 (20 mg).

[0815] MS (ESI) M / Z: 1047.3 [M+H] +.

[0816] Step B:

[0817] Compound 20-3 (20 mg, crude product) was dissolved in a mixed solvent of dichloromethane / trifluoroacetic acid = 3 / 1 (2 mL), stirred at room temperature for 1 hour, concentrated under reduced pressure to remove dichloromethane, and then a mixed solvent of trifluoromethanesulfonic acid / trifluoroacetic acid = 1 / 9 (2 mL) was added thereto, and stirring was continued at room temperature for 1 hour. LCMS monitoring showed that the reaction of the raw material was basically complete. The reaction solution was diluted with ice water (20 mL), the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, extracted three times with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (GILSON-281, Column: XBridge C18 250*19.00mm10μm, Mobile phase: A: H2O (10mM NH4HCO3) B: MeCN, Flow rate: 20.0mL / min, Gradient B: 25%-90%) to give two isomers 20-P1: 1.63 mg, 20-P2: 2.6 mg.

[0818] 20-P1: HPLC (Agilent 1260, XBridge BEH-C18 3.5 μm, 4.6 mm * 150 mm, Mobile phase A: H2O (10 mM NH4HCO3), B: MeCN, Flow rate: 2.0 mL / min, Gradient: 10% for 0.5 min, increase to 95% B within 9.0 min, 95% B for 2.0 min, back to 10% B within 1.0 min, then 10% B for 2.5 min), retention time: 8.869 min.

[0819] MS (ESI) m / z: 707.2 [M + H] + .

[0820] 1 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H), 7.97 (dd, J = 4.9, 1.6 Hz, 1H), 7.63 (d, J = 6.5 Hz, 1H), 7.23 - 7.10 (m, 2H), 6.67 (dd, J = 7.4, 4.9 Hz, 1H), 6.25 (q, J = 6.9 Hz, 1H), 5.71 (s, 2H), 5.28 (d, J = 53.7 Hz, 1H), 4.42 (dd, J = 10.6, 6.7 Hz, 1H), 4.3 (dd, J = 12.0, 8.6 Hz, 1H), 4.09 (q, J = 10.4 Hz, 2H), 3.61 (dd, J = 15.2, 6.1 Hz, 1H), 3.41 (d, J = 6.6 Hz, 1H), 3.11 - 3.05 (m, 2H), 3.01 (s, 1H), 2.82 (dd, J = 15.3, 8.8 Hz, 1H), 2.16 - 2.01 (m, 3H), 1.86 - 1.76 (m, 3H), 1.60 (d, J = 6.8 Hz, 3H).

[0821] 20-P2: HPLC (Agilent 1260, 2.0min, back to 10%B within 1.0min, then 10%B for 2.5min), retention time: 9.820min.

[0822] MS (ESI) M / Z: 707.2 [M+H] + .

[0823] 1 HNMR(400MHz,DMSO-d6)δ8.08(s,2H),7.97(d,J=3.6Hz,1H),7.63(d,J=7.5Hz,1H),7.24-7.09(m,2H), 6.67(dd,J=7.4,5.0Hz,1H),6.30-6.21(m,1H),5.71(s,2H),5.29(d,J=59.8Hz,1H),4.42(dd,J=11.0, 6.5Hz,1H),4.35-4.26(m,1H),4.11(s,2H),3.62(dd,J=15.2,6.5Hz,1H),3.41(d,J=6.3Hz,1H),3.06( d,J=33.1Hz,3H),2.84(s,1H),2.19-1.99(m,3H),1.85(dd,J=27.9,13.3Hz,3H),1.60(d,J=6.7Hz,3H).

[0824] Examples 37 and 38 were prepared by adopting the synthesis method of Example 20 and selecting appropriate raw materials:

[0825] Example 21: Preparation of Compound 21 and Its Isomers

[0826] Step A:

[0827] Compound 2a (4.8 g, 12.76 mmol) was dissolved in tetrahydrofuran (40 mL), and tetraethyl titanate (14.54 g, 63.8 mmol) and (R)-2-methylpropane-2-sulfamide (2 g, 16.59 mmol) were added. The mixture was stirred at 90°C under nitrogen for 48 hours. TLC confirmed the substantial reaction of the starting materials. The reaction mixture was cooled to -78°C, and sodium borohydride (1.44 g, 38.29 mmol) was slowly added. The mixture was stirred at -40°C for 4 hours, then slowly warmed to room temperature and stirred overnight. TLC confirmed the substantial reaction of the intermediate. The reaction mixture was quenched with a small amount of water, filtered, and the filtrate extracted with ethyl acetate. The organic phase was washed with saturated brine, filtered, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1.5) to afford compound 21-1 (3.8 g).

[0828] MS (ESI) M / Z: 482.2 [M+H] + .

[0829] Step B:

[0830] Compound 21-1 (6.4 g, 13.31 mmol) was dissolved in methanol (120 mL). Dioxane hydrochloride (13.3 mL, 53.22 mmol, 4 M) was then slowly added and stirred at room temperature for 30 minutes. TLC confirmed the reaction was essentially complete. Saturated sodium bicarbonate solution was added to adjust the pH to 8. The organic solvent was removed by vortexing, and the mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude product 21-2 (4.6 g).

[0831] MS (ESI) M / Z: 378.4 [M+H] + .

[0832] Step C:

[0833] Compound 21-2 (300 mg, 0.796 mmol), ethyl bromoacetate (173 mg, 1.034 mmol), and potassium carbonate (220 mg, 1.592 mmol) were added to acetonitrile (3 mL) and stirred at room temperature for 2 hours. TLC and LCMS confirmed the substantial reaction of the starting materials. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 21-3 (247 mg).

[0834] MS (ESI) M / Z: 464.2 [M+H] + .

[0835] Step D:

[0836] Compound 21-3 (310 mg, 0.669 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). Lithium aluminum hydride (56 mg, 1.337 mmol) was added at 0°C under nitrogen, and the mixture was stirred at low temperature for 1 hour. TLC and LCMS confirmed the substantial reaction of the starting material. Ice 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, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 21-4 (182 mg).

[0837] MS (ESI) M / Z: 424.2 [M+H] + .

[0838] 1 H NMR(400MHz, CDCl3) δ8.39(dd,J=4.7,1.8Hz,1H),7.81(dd,J=7.6,1.6Hz,1H),7.14-7.10(m,4H),7.09(d,J=4.7Hz,1H),6.82-6.76(m,4H),4.54 (q,J=6.6Hz,1H),4.18(d,J=13.4Hz,2H),4.02(d,J=13.4Hz,2H),3.77(s,6H),2.31(d,J=12.5Hz,2H),2.18-2.13(m,2H),1.28(d,J=6.7Hz,3H).

[0839] Step E:

[0840] Compound 21-4 (190 mg, 0.449 mmol), intermediate 1-R (120 mg, 0.180 mmol) and sodium bis(trimethylsilyl)amide (1.4 mL, 1.347 mmol) were added to dimethyl sulfoxide (3 mL), and the mixture was stirred at 60° C. for 16 hours.

[0841] LCMS monitored that the raw material had basically reacted completely. Ice 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, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to give compound 21-5 (150 mg).

[0842] MS (ESI) M / Z: 1068.2 [M+H] + .

[0843] Step F:

[0844] Referring to step F of Example 17, compound 21-6 can be prepared by replacing the raw material compound 17-6 with 21-5.

[0845] MS (ESI) M / Z: 1050.8 [M+H] + .

[0846] Step G:

[0847] Referring to step G of Example 17, compound 21-7 can be prepared by replacing the starting compound 17-7 with 21-6.

[0848] MS (ESI) M / Z: 1173.4 [M+H] + .

[0849] Step H:

[0850] Compound 21-7 (110 mg, 0.094 mmol) was dissolved in a mixed solvent of trifluoromethanesulfonic acid / trifluoroacetic acid (1 / 9, 3 mL) and stirred at room temperature for 1 hour. LCMS analysis indicated that the reaction was essentially complete. The reaction solution was diluted with ice water (30 mL) and the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The product was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by HPLC (GILSON-281, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (10 mM NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 25%-90%) to afford two isomers: 21-P1 (19.95 mg) and 21-P2 (11.72 mg).

[0851] 21-P1: HPLC (Agilent 1260, 2.0min, back to 10%B within 1.0min, then 10%B for 2.5min), retention time: 8.662min.

[0852] MS (ESI) M / Z: 692.8 [M+H]+ .

[0853] 1 HNMR(400 MHz, MeOD-d4) δ 7.95 (dd, J = 5.1, 1.5 Hz, 1H), 7.78 - 7.72 (m, 1H), 6.77 (dd, J = 7.5, 5.1 Hz, 1H), 6.59 (s, 1H), 6.51 (q, J = 6.9 Hz, 1H), 5.30 (d, J = 54.5 Hz, 1H), 4.27 (q, J = 10.4 Hz, 2H), 3.67 (d, J = 15.8 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.27 - 3.12 (m, 3H), 3.05 - 2.97 (m, 1H), 2.43 (d, J = 1.3 Hz, 3H), 2.40 - 2.11 (m, 3H), 2.04 - 1.86 (m, 3H), 1.65 (d, J = 6.9 Hz, 3H).

[0854] 21-P2: HPLC (Agilent 1260, XBridge BEH-C18 3.5 μm, 4.6 mm * 150 mm, Mobile phase A: H2O (10 mM NH4HCO3) B: MeCN, Flow rate: 1.0 mL / min, Gradient: 10% for 0.5 min, increase to 95% B within 9.0 min, 95% B for 2.0 min, back to 10% B within 1.0 min, then 10% B for 2.5 min), retention time: 9.481 min.

[0855] MS (ESI) M / Z: 692.8 [M + H] + .

[0856] 1HNMR(400MHz,MeOD-d4)δ7.95(dd,J=5.1,1.5Hz,1H),7.75(d,J=7.5Hz,1H),6.77(dd,J=7.5,5 .1Hz,1H),6.59(s,1H),6.52(q,J=6.8Hz,1H),5.31(d,J=54.2Hz,1H),4.28(dd,J=33.0,10.4Hz ,2H),3.70(d,J=15.8Hz,1H),3.52-3.43(m,1H),3.27-3.12(m,3H),3.06-2.96(m,1H),2.44(d ,J=1.4Hz,3H),2.41-2.11(m,3H),2.04-1.94(m,2H),1.94-1.82(m,1H),1.66(d,J=6.9Hz,3H).

[0857] Example 22: Preparation of Compound 22 and Its Isomers

[0858] Step A:

[0859] Compound 21-2 (0.7 g, 1.85 mmol) was dissolved in dimethylformamide (5 mL), and 2-hydroxyacetic acid (425 mg, 5.59 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.8 g, 4.73 mmol), and triethylamine (581 mg, 5.75 mmol) were added. The reaction solution was heated to 60°C and stirred overnight. LCMS confirmed the substantial reaction of the starting material. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 22-1 (800 mg).

[0860] MS (ESI) M / Z: 436.0 [M+H] + .

[0861] Step B:

[0862] Compound 22-1 (800 mg, 1.83 mmol) was dissolved in tetrahydrofuran (10 mL). Lithium aluminum deuteride (154 mg, 3.6 mmol) was added under ice-cooling, and the reaction mixture was heated to 80°C and stirred for 2 h. LCMS confirmed the substantial reaction of the starting material. Sodium sulfate decahydrate was added to quench the reaction, and the mixture was filtered. The filter cake was washed with ethyl acetate, and the filtrate was collected and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 22-2 (139 mg).

[0863] MS (ESI) M / Z: 424.4 [M+H] + .

[0864] Step C:

[0865] Referring to step E of Example 21, compound 22-3 was prepared by replacing the starting material 21-4 with 22-2.

[0866] MS (ESI) M / Z: 1070.0 [M+H] + .

[0867] Step D:

[0868] Referring to step F of Example 17, compound 22-4 can be prepared by replacing the starting compound 17-6 with 22-3.

[0869] MS (ESI) M / Z: 1050.3 [M+H] + .

[0870] Step E:

[0871] Referring to step G of Example 17, compound 22-5 can be prepared by replacing the starting compound 17-7 with 22-4.

[0872] MS (ESI) M / Z: 1173.4 [M+H] + .

[0873] Step F:

[0874] Referring to step H of Example 21, two isomers, 22-P1 and 22-P2, were prepared by replacing the starting compound 21-7 with 22-5.

[0875] 22-P1: HPLC (Agilent 1260, 2.0min, back to 10%B within 1.0min, then 10%B for 2.5min), retention time: 8.679min.

[0876] MS(ESI) M / Z: 693.5 [M+H] + ;

[0877] 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 4.8, 1.3 Hz, 1H), 7.63 (dd, J = 7.4, 1.0 Hz, 1H), 6.80 (s, 2H), 6.66 (dd, J = 7.5, 4.9 Hz, 1H), 6.47 (s, 1H), 6.25 (q, J = 6.7 Hz, 1H), 5.76 (s, 2H), 5.37 (d, J = 51.4 Hz, 1H), 4.44 (d, J = 12.2 Hz, 1H), 4.33 - 4.13 (m, 3H), 3.27 - 3.15 (m, 2H), 3.13 - 2.78 (m, 2H), 2.36 (s, 3H), 2.30 - 2.05 (m, 3H), 2.00 - 1.80 (m, 3H), 1.56 (d, J = 6.8 Hz, 3H).

[0878] 22 - P2: HPLC (Agilent 1260, XBridge BEH - C18 3.5 μm, 4.6 mm * 150 mm, Mobile phase A: H2O (10 mM NH4HCO3) B: MeCN, Flow rate: 1.0 mL / min, Gradient: 10% for 0.5 min, increase to 95% B within 9.0 min, 95% B for 2.0 min, back to 10% B within 1.0 min, then 10% B for 2.5 min), retention time: 9.485 min.

[0879] MS(ESI) M / Z: 693.5 [M+H] + ;

[0880] 1H NMR (400MHz, DMSO-d6) δ7.96(d,J=4.8Hz,1H),7.63(d,J=7.6Hz,1H),6.80(s,2H),6.65(dd,J=7.5,4.8Hz,1H ),6.47(s,1H),6.26(t,J=5.5Hz,1H),5.78(d,J=22.6Hz,2H),5.30(d,J=56.0Hz,1H),4.50(d,J=12.2Hz,1H) ,4.30(d,J=12.2Hz,1H),4.09(d,J=53.9Hz,2H),3.14-3.02(m,3H),2.83(dd,J=16.8,6.4Hz,1H),2.36(d,J= 1.3Hz, 3H), 2.07 (ddd, J=22.3, 17.0, 6.6Hz, 3H), 1.80 (ddd, J=20.0, 10.5, 3.3Hz, 3H), 1.58 (d, J=6.9Hz, 3H).

[0881] Example 23: Preparation of Compound 23 and Its Isomers

[0882] Step A:

[0883] Compound 2a (500 mg, 1.33 mmol), ethanolamine (162 mg, 2.66 mmol), and tetraisopropyl titanate (1.89 g, 6.65 mmol) were dissolved in methanol (10 mL). The reaction mixture was heated to 70°C and stirred for 16 hours under nitrogen. LCMS confirmed the substantial reaction of the starting materials. The reaction mixture was cooled to 0°C and sodium borodeuteride (55 mg, 1.33 mmol) was added. The mixture was stirred at room temperature for 2 hours, quenched with water (0.3 mL), and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to afford crude compound 23-1.

[0884] MS (ESI) M / Z: 423.0 [M+H] + .

[0885] Step B:

[0886] Referring to step E of Example 21, compound 23-2 was prepared by replacing the starting material 21-4 with 23-1.

[0887] MS (ESI) M / Z: 1067.8 [M+H] + .

[0888] Step C:

[0889] Referring to step F of Example 17, compound 23-3 can be prepared by replacing the starting compound 17-6 with 23-2.

[0890] MS (ESI) M / Z: 1049.8 [M+H] + .

[0891] Step D:

[0892] Referring to step G of Example 17, compound 23-4 can be prepared by replacing the starting compound 17-7 with 23-3.

[0893] Step E:

[0894] Referring to step H of Example 21, two isomers, 23-P1 and 23-P2, were prepared by replacing the starting compound 21-7 with 23-4.

[0895] 23-P1: HPLC (Agilent 1260, 2.0min, back to 10%B within 1.0min, then 10%B for 2.5min), retention time: 8.716min.

[0896] MS (ESI) M / Z: 691.8 [M+H] + .

[0897] 1HNMR(400 MHz, DMSO-d6) δ 7.97 (dd, J = 4.9, 1.6 Hz, 1H), 7.63 (dd, J = 7.5, 1.6 Hz, 1H), 6.80 (s, 2H), 6.66 (dd, J = 7.5, 4.9 Hz, 1H), 6.47 (s, 1H), 5.72 (d, J = 4.7 Hz, 2H), 5.29 (d, J = 53.6 Hz, 1H), 4.43 (dd, J = 11.3, 6.5 Hz, 1H), 4.25 (dd, J = 10.9, 7.1 Hz, 1H), 4.08 (dd, J = 27.0, 10.3 Hz, 2H), 3.65 (dd, J = 15.2, 7.1 Hz, 1H), 3.41 - 3.35 (m, 1H), 3.18 - 2.99 (m, 3H), 2.88 - 2.78 (m, 1H), 2.36 (d, J = 1.4 Hz, 3H), 2.21 - 1.99 (m, 3H), 1.90 - 1.73 (m, 3H), 1.55 (s, 3H).

[0898] 23 - P2: HPLC (Agilent 1260, XBridge BEH - C18 3.5 μm, 4.6 mm * 150 mm, Mobile phase A: H2O (10 mM NH4HCO3) B: MeCN, Flow rate: 1.0 mL / min, Gradient: 10% for 0.5 min, increase to 95% B within 9.0 min, 95% B for 2.0 min, back to 10% B within 1.0 min, then 10% B for 2.5 min), retention time: 9.526 min.

[0899] MS(ESI) M / Z: 691.8 [M + H] + .

[0900] 1HNMR(400MHz,DMSO-d6)δ7.96(dd,J=4.9,1.6Hz,1H),7.63(dd,J=7.5,1.6Hz,1H),6.81(s,2H),6.65(dd,J=7.5,4 .9Hz,1H),6.47(s,1H),5.81(d,J=4.4Hz,2H),5.29(d,J=54.5Hz,1H),4.57-4.47(m,1H),4.31(dd,J=11.2,6.7Hz, 1H), 4.16 (d, J = 10.3Hz, 1H), 4.00 (d, J = 10.3Hz, 1H), 3.71 (dd, J = 15.3, 6.3Hz, 1H), 3.36 (d, J = 7.1Hz, 1H), 3.09 (dd, J=30.4,18.7Hz,3H),2.87-2.78(m,1H),2.36(d,J=1.4Hz,3H),2.20-1.96(m,3H),1.89-1.71(m,3H),1.58(s,3H).

[0901] Example 24: Preparation of Compound 24

[0902] Step A:

[0903] Under nitrogen, compound 24-1 (100 mg, 0.62 mmol, prepared according to WO2023274383) was dissolved in anhydrous tetrahydrofuran (10 mL). Sodium hydroxide (26.73 mg, 0.668 mmol, 60 wt%) was added under ice-cooling. The reaction solution was stirred for 0.5 hours under ice-cooling. Compound 13-1 (70 mg, 0.0668 mmol) was added to the above solution, and the reaction solution was heated to 65°C and stirred for 1 hour. LCMS confirmed the substantial reaction of the starting material. The reaction solution was cooled to room temperature and quenched with water. The product was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2.5) to afford compound 24-2 (55 mg).

[0904] Step B:

[0905] Referring to step H of Example 21, compound 24 can be prepared by replacing the starting compound 21-7 with 24-2.

[0906] MS (ESI) M / Z: 693.2 [M+H] + .

[0907] 1H NMR(400MHz,MeOD)δ7.95(d,J=4.4Hz,1H),7.75(d,J=7.1Hz,1H),6.84-6.73(m,1H),6.59(s ,1H),6.51(d,J=6.8Hz,1H),5.32(d,J=53.5Hz,1H),4.44(dd,J=12.0,6.0Hz,1H),4.36-4.21 (m,1H),3.68(dd,J=15.7,6.7Hz,1H),3.51(dd,J=15.8,5.6Hz,1H),3.25(s,3H),3.05(s,1H ), 2.43 (s, 3H), 2.21 (dd, J = 32.6, 16.6Hz, 3H), 1.97 (d, J = 39.1Hz, 3H), 1.65 (d, J = 6.8Hz, 3H).

[0908] Example 25: Preparation of Compound 25

[0909] Step A:

[0910] Under nitrogen, compound 25-1 (70 mg, 0.42 mmol, prepared according to WO2023274383) was dissolved in anhydrous tetrahydrofuran (4 mL). Sodium hydroxide (30 mg, 0.76 mmol, 60 wt%) was added under ice-cooling. The reaction solution was stirred for 0.5 hours under ice-cooling conditions. Compound 13-1 (70 mg, 0.0668 mmol) was added to the above solution, and the reaction solution was heated to 65 degrees Celsius and stirred for 2 hours. LCMS monitoring confirmed the substantial reaction of the starting material. The reaction solution was cooled to room temperature and quenched with water. The product was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2.5) to afford compound 25-2 (50 mg).

[0911] Step B:

[0912] Referring to step H of Example 21, compound 25 can be prepared by replacing the raw material compound 21-7 with 25-2.

[0913] MS (ESI) M / Z: 695.2 [M+H] + .

[0914] 1H NMR (400MHz, MeOD) δ7.95 (dd, J=5.1, 1.7Hz, 1H), 7.75 (dt, J=7.4, 1.5Hz, 1H), 6.77 (dd, J=7.5 ,5.1Hz,1H),6.59(t,J=0.9Hz,1H),6.51(q,J=6.9Hz,1H),5.31(d,J=53.6Hz,1H),4.44(dd,J= 12.0,5.6Hz,1H),4.33-4.24(m,1H),3.84-3.61(m,1H),3.56-3.45(m,1H),3.23(d,J=17.9Hz, 2H), 2.43(dt,J=2.6,1.3Hz,3H),2.41-2.08(m,3H),2.07-1.81(m,3H),1.65(d,J=6.9Hz,3H).

[0915] Example 26: Preparation of Compound 26 and Its Isomers

[0916] Step A

[0917] Compound 26-1 (3.0 g, 18.7 mmol) was dissolved in tetrahydrofuran (40 mL). The reaction mixture was cooled to 0°C and sodium hydride (974 mg, 24.3 mmol, 60 wt%) was added under nitrogen. The resulting mixture was stirred at room temperature for 0.5 hours, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (3.44 g, 20.6 mmol) and stirring at room temperature for 18 hours. After the disappearance of the starting material as monitored by LCMS, the reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 5 / 1 to 1 / 1) to afford compound 26-2 (3.1 g).

[0918] LCMS (ESI) M / Z: 291.2 [M+H] + .

[0919] Step B:

[0920] Compound 26-2 (800 mg, 2.75 mmol) was dissolved in methanol (20 mL), and ethanolamine (336 mg, 5.5 mmol) and tetraisopropyl titanate (2.35 g, 8.25 mmol) were added. The reaction solution was heated to 100°C in a microwave oven under nitrogen for 2 h. After cooling to room temperature, sodium cyanoborohydride (864 mg, 13.8 mmol) was added and the reaction was continued at 100°C in a microwave oven for 1 h. After the disappearance of the starting material as monitored by LCMS, the reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE / EA = 5 / 1 to 1 / 1) to obtain compound 26-3 (0.76 g).

[0921] LCMS (ESI) M / Z: 336.1 [M+H] + .

[0922] Step C:

[0923] Referring to step E of Example 21, compound 26-4 was prepared by replacing the starting material 21-4 with 26-3.

[0924] LCMS (ESI) M / Z: 980.4 [M+H] + .

[0925] Step D:

[0926] Referring to step F of Example 17, compound 26-5 can be prepared by replacing the starting compound 17-6 with 26-4.

[0927] LCMS (ESI) M / Z: 962.2 [M+H] + .

[0928] Step E:

[0929] Referring to step G of Example 17, compound 26-6 can be prepared by replacing the starting compound 17-7 with 26-5.

[0930] LCMS (ESI) M / Z: 1085.6 [M+H] + .

[0931] Step F:

[0932] Referring to step H of Example 21, two isomers, 26-P1 and 26-P2, were prepared by replacing the starting compound 21-7 with 26-6.

[0933] 26-P1: HPLC (SHIMADZU UHLC-010, RD-C18 5μm 4.6x150mm, Mobile phase A: 0.03% TFA in H2O B: 0.03% TFA in MeCN, Flow rate: 1.0 mL / min, 16 min, Gradient: 10%B - 95%B), Retention time: 9.104 min.

[0934] LCMS (ESI) M / Z: 715.5 [M+H] + .

[0935] 1 H NMR (400 MHz, CD3OD) δ 8.22 (t, J = 1.2 Hz, 1H), 7.91 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 7.58 (s, 1H), 7.08 (dd, J = 7.6 Hz, 4.4 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.59 (s, 1H), 5.46 - 5.29 (m, 1H), 4.37 - 4.28 (m, 3H), 4.15 - 3.95 (m, 1H), 3.62 - 3.58 (m, 2H), 3.29 - 3.26 (m, 3H), 3.11 - 2.95 (m, 1H), 2.43 (d, J = 1.2 Hz, 3H), 2.41 - 1.81 (m, 6H), 1.73 (d, J = 6.8 Hz, 3H).

[0936] 26-P2: HPLC (SHIMADZU UHLC-010, RD-C18 5μm 4.6x150mm, Mobile phase A: 0.03% TFA in H2O B: 0.03% TFA in MeCN, Flow rate: 1.0 mL / min, 16 min, Gradient: 10%B - 95%B), Retention time: 9.357 min.

[0937] LCMS (ESI) M / Z: 715.5 [M+H] + .

[0938] 1H NMR (400MHz, CD3OD) δ8.21(d,J=4.4Hz,1H),7.84(d,J=8.0Hz,1H),7.57(s,1H ),7.05(dd,J=6.0Hz,0.8Hz,1H),6.93-6.91(m,1H),6.59(s,1H),5.46-5.29(m ,1H),4.40-4.27(m,3H),4.10-4.00(m,1H),3.72-3.54(m,2H),3.30-3.22(m, 3H),3.04-3.02(m,1H),2.43(s,3H),2.41-1.85(m,6H),1.74(d,J=6.4Hz,3H).

[0939] Example 27: Compound 27

[0940] Step A:

[0941] Compound 27-1 (15 g, 68.7 mmol) and ethanolamine (12.6 g, 206 mmol) were dissolved in tetrahydrofuran (150 mL). Acetic acid (0.6 mL) was added, and the mixture was heated to 70°C and stirred under nitrogen for 36 hours. Sodium cyanoborohydride (21.6 g, 343 mmol) was added, and stirring was continued at 70°C for 12 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was purified by C18 column chromatography (acetonitrile:water = 2:8) to obtain compound 27-2 (11 g crude product).

[0942] LCMS (ESI) M / Z: 264.1 [M+H] +

[0943] Step B:

[0944] Compound 27-2 (11 g, crude product) was dissolved in 1,4-dioxane (100 mL), and di-tert-butyl dicarbonate (8.2 g, 37.6 mmol) and triethylamine (6.34 g, 62.7 mmol) were added. The mixture was heated to 80°C and stirred under nitrogen for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by C18 column chromatography (ACN:H2O=3:7) to obtain compound 27-3 (400 mg).

[0945] LCMS (ESI) M / Z: 364.4 [M+H] + .

[0946] Step C:

[0947] Compound 27-3 (0.4 g, 1.10 mmol) was dissolved in tetrahydrofuran (5 mL), and 10% Pd / C (0.04 g) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain compound 27-4 (0.3 g).

[0948] LCMS (ESI) M / Z: 274.2 [M+H] + .

[0949] Step D:

[0950] Compound 27-4 (300 mg, 1.10 mmol) was dissolved in acetonitrile (5 mL), and 1-hydroxybenzotriazole (0.19 g, 1.43 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22 g, 1.43 mmol) were added. The reaction mixture was stirred at room temperature under nitrogen for 2 hours, and then concentrated aqueous ammonia (0.12 g) was added. Stirring was continued at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered and purified on a C18 reverse-phase column to obtain compound 27-5 (90 mg).

[0951] LCMS (ESI) M / Z: 273.1 [M+H] + ;

[0952] 1 H NMR(400MHz,CD3OD)δ4.27-4.09(m,2H),3.27-2.97(m,2H),2.88-2.74(m,1H),2.60- 2.33(m,2H),2.12-1.89(m,2H),1.46(d,J=1.1Hz,9H),1.13(dd,J=26.8,6.2Hz,3H).

[0953] Step E:

[0954] Compound 27-5 (50 mg, 0.18 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 27-6 (30 mg crude product). The crude product was used directly in the next step without further purification.

[0955] LCMS (ESI) M / Z: 173.3 [M+H] + .

[0956] Step F:

[0957] Referring to step E of Example 21, compound 27-7 was prepared by replacing the starting material 21-4 with 27-6.

[0958] LCMS (ESI) M / Z: 817.2 [M+H] + .

[0959] Step G:

[0960] Referring to step F of Example 17, compound 27-8 can be prepared by replacing the starting compound 17-6 with 27-7.

[0961] MS (ESI) M / Z: 799.3 [M+H] + .

[0962] Step H:

[0963] Referring to step G of Example 17, compound 27-9 can be prepared by replacing the starting compound 17-7 with 27-8.

[0964] MS (ESI) M / Z: 922.3 [M+H] + .

[0965] Step I:

[0966] Referring to step H of Example 21, a mixture of two isomers, 27, can be prepared by replacing the starting compound 21-7 with 27-9.

[0967] MS (ESI) M / Z: 682.4 [M+H] + ;

[0968] 1 H NMR (400MHz, CD3OD) δ6.61-6.58(m,1H),5.36-5.22(d,J=56.0Hz,1H),4.65-4.49(m,2H),4.37-4.21(m,2H),3.99(d,J=5.2Hz,2H),3.93(d,J=5.2Hz ,1H),3.24-3.20(m,2H),3.02(s,1H),2.84-2.81(m,2H),2.44(s,3H),2.2 4-2.08(m,3H),1.99(s,4H),1.84(t,J=6.7Hz,3H),1.31(d,J=9.2Hz,2H).

[0969] Example 28: Compound 28 and its isomers

[0970] Step A:

[0971] Compound 28-1 (22 g, 82.7 mmol), iodine (31.5 g, 124.0 mmol), and silver sulfate (20.6 g, 66.2 mmol) were dissolved in ethanol (110 mL) and stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction solution was quenched with sodium thiosulfate solution and extracted three times with ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (PE / EA = 10 / 1-5 / 1) to afford compound 28-2 (29 g, 89.5% yield).

[0972] MS (ESI) M / Z: 392.1 [M+1] + .

[0973] Step B:

[0974] Compound 28-2 (29 g, 74.0 mmol) and pyridine (6.97 g, 88.8 mmol) were dissolved in dichloromethane (120 mL). Acetyl chloride (17.9 mL, 222 mol) was added at 0°C and the temperature was slowly warmed to room temperature. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, concentrated, and purified by column chromatography (PE / EA = 10 / 1) to afford compound 28-3 (16 g, 49.8% yield).

[0975] MS (ESI) M / Z: 456.0 [M+Na] + .

[0976] Step C:

[0977] Compound 28-3 (50 mg, 0.12 mmol) and cuprous iodide (6.86 mg, 0.036 mmol) were dissolved in NMP (1 mL). Methyl fluorosulfonylacetate (46.11 mg, 0.24 mmol) was added, and the reaction mixture was stirred in a sealed glass tube at 80°C for 18 hours. After cooling to room temperature, the reaction mixture was purified by C18 silica gel column chromatography (ACN / H2O + 0.1% FA) to afford compound 28-4 (20 mg, 46.2% yield).

[0978] MS (ESI) M / Z: 373.9 [MH] + .

[0979] Step D:

[0980] Compound 28-4 (40 mg, 0.11 mmol) and lithium hydroxide (7.90 mg, 0.33 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL), and the resulting mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction solution was purified by C18 silica gel column chromatography (ACN / H2O + 0.1% FA) to give compound 28-5 (30 mg, 88.1% yield).

[0981] MS (ESI) M / Z: 360.0 [MH] + .

[0982] Step E:

[0983] Compound 28-5 (30 mg, 0.083 mmol) was dissolved in MeOH (2 mL) and HCl / MeOH (2 mL, 2 M), and the resulting mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction solution was purified by C18 silica gel column chromatography (ACN / H2O + 0.1% FA) to provide compound 28-6 (25 mg, 94.3% yield).

[0984] MS (ESI) M / Z: 317.9 [MH] + .

[0985] Step F:

[0986] Compound 28-6 (300 mg, 0.94 mmol) and ammonium chloride (502 mg, 9.40 mmol) were dissolved in DMF (6 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (536 mg, 1.41 mmol) and diisopropylethylamine (182 mg, 1.41 mmol) were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was directly purified by C18 column chromatography (ACN / H2O + 0.1% FA) to give compound 28-7 (110 mg, 36.8% yield). MS (ESI) M / Z: 317.0 [MH] + .

[0987] Step G:

[0988] Compound 28-7 (260 mg, 0.81 mmol) was dissolved in anhydrous 1,4-dioxane (1 mL), and thiophosgene (377 mg, 3.28 mmol) was added. The resulting mixture was heated at 105°C in a sealed glass tube for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography (ACN / H2O + 0.1% FA) to obtain compound 28-8 (190 mg, 64.1% yield).

[0989] MS (ESI) M / Z: 363.1 [M+H] + .

[0990] Step H:

[0991] 28-9 (463 mg, 1.1 mmol, prepared according to WO2022216762) was dissolved in tetrahydrofuran (8 mL). Sodium bis(trimethylsilyl)amide (2.2 mL, 4.4 mmol, 2 M in tetrahydrofuran) was added at room temperature. After stirring at room temperature for 0.5 hours, a solution of compound 28-8 (400 mg, 1.1 mmol) in tetrahydrofuran (8 mL) was added. The mixture was stirred at room temperature for 1 hour under nitrogen. After completion of the reaction, the reaction solution was poured into an ice-cold ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 28-10 (330 mg, 39.2% yield).

[0992] MS (ESI) M / Z: 764.0 [M+H] + .

[0993] Step I:

[0994] Compound 28-10 (80 mg, 0.10 mmol) was dissolved in chloroform (2 mL), and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (43 mg, 0.17 mmol) and diisopropylethylamine (64 mg, 0.50 mmol) were added. The mixture was heated to 70°C in a sealed glass tube and stirred for 1 hour. The reaction solution was cooled to room temperature, diluted with dichloromethane, washed with water, and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 28-11 (50 mg, 64.0% yield).

[0995] MS (ESI) M / Z: 746.1 [M+H] + .

[0996] Step J:

[0997] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (159 mg, 1.0 mmol) was dissolved in tetrahydrofuran (2.5 mL). Sodium hydride (40 mg, 1.0 mmol, 60 wt%) was added and stirred at room temperature for 0.5 hour. A solution of compound 28-11 (150 mg, 0.20 mmol) in tetrahydrofuran (2.5 mL) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 28-12 (100 mg, 57.3% yield).

[0998] MS (ESI) M / Z: 869.0 [M+H] + .

[0999] Step K:

[1000] Compound 28-12 (25 mg, 0.029 mmol), compound 28-13 (18 mg, 0.058 mmol, synthesized with reference to WO2021118877), potassium phosphate (19 mg, 0.087 mmol), and dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) (6 mg, 0.0087 mmol) were dissolved in a mixture of 1,4-dioxane / water (5 mL, 9:1) and heated to 90°C under nitrogen for 6 h. The resulting mixture was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 28-14 (30 mg, crude product), which was used directly in the next step.

[1001] MS (ESI) M / Z: 1057.0 [M+H] + .

[1002] Step L:

[1003] Compound 28-14 (25 mg, 0.024 mmol) was dissolved in trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL) and stirred at room temperature for 0.5 h. The resulting mixture was diluted with ethyl acetate and washed with cold aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 5%-95%) to afford two individual isomers: 28-P1 and 28-P2.

[1004] 28-P1 (3.06 mg): HPLC (Agilent 1100, XBridge C18 5uM 4.6*150mm, Mobile phase: A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0mL / min, 16min, Gradient B: 10%-95%), retention time: 7.845min.

[1005] MS (ESI) M / Z: 717.0 [M+H] + ;

[1006] 1 H NMR(400MHz,CD3OD)δ7.96(d,J=8.4Hz,1H),7.77(d,J=7.2Hz,1H),7.11-7.07(m ,1H),6.93(t,J=8.8Hz,1H),6.80-6.77(m,1H),6.39-6.34(m,1H),5.37-5.22(m, 1H),4.44-4.39(m,1H),4.33-4.19(m,3H),3.73-3.48(m,3H),3.24-3.19(m,2H) ,3.05-2.99(m,1H),2.38-2.13(m,3H),2.03-1.88(m,3H),1.69(d,J=6.8Hz,3H).

[1007] 28-P2 (3.31 mg): HPLC (Agilent 1100, XBridge C18 5uM 4.6*150mm, Mobile phase: A: H2O (10mM NH4HCO3) B: MeCN, Flow rate: 1.0mL / min, 16min, Gradient B: 40%-95%), retention time: 7.397min.

[1008] MS (ESI) M / Z: 717.0 [M+H] + ;

[1009] 1 H NMR(400MHz,CD3OD)δ7.95(d,J=8.4Hz,1H),7.76(d,J=7.2Hz,1H),7.12-7.09(m,1H) ,6.93(t,J=8.8Hz,1H),6.79-6.76(m,1H),6.41-6.38(m,1H),5.37-5.22(m,1H),4.54 -4.47(m,1H),4.34-4.26(m,3H),3.75-3.69(m,1H),3.62-3.44(m,2H),3.30-3.20(m ,2H),3.04-2.99(m,1H),2.38-2.11(m,3H),2.07-1.87(m,3H),1.71(d,J=6.8Hz,3H).

[1010] The following was prepared using the synthesis method of Example 28 by selecting appropriate raw materials:

[1011] Example 29: Preparation of Compound 29

[1012] Step A:

[1013] Compound 29-1 (5.8 g, 23.01 mmol) was dissolved in acetic acid (50 mL), and N-iodosuccinimide (5.18 g, 23.0 mmol) was added. The reaction mixture was reacted at 30°C for 10 minutes. The reaction mixture was directly purified by C18 column chromatography (ACN / H2O + 0.1% FA) to obtain compound 29-2 (4.5 g, 52% yield).

[1014] MS (ESI) M / Z: 375.8 [MH] + .

[1015] Step B:

[1016] Compound 29-2 (4.1 g, 10.8 mmol), ammonium chloride (5.8 g, 108 mmol), and diisopropylethylamine (4.2 g, 32.5 mmol) were dissolved in DMF (40 mL). N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (8.2 g, 21.7 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was purified by C18 column chromatography (ACN / H2O + 0.1% FA) to obtain compound 29-3 (3.1 g, 76% yield).

[1017] MS (ESI) M / Z: 376.8 [M+H] + .

[1018] Step C:

[1019] Compound 29-3 (3.0 g, 7.96 mmol) was dissolved in dry 1,4-dioxane (48 mL), and thiophosgene (2.75 g, 23.9 mmol) was added. The reaction solution was heated to 100°C for 1 hour. After the reaction, it was slowly cooled to room temperature and poured into cold aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was directly slurried with PE / EA = 3 / 1 (50 mL) to obtain compound 29-4 (3 g, 89% yield).

[1020] MS (ESI) M / Z: 420.9 [M+H] + .

[1021] Step D:

[1022] Compound 29-4 (2.5 g, 5.93 mmol), vinyl pinacol borate (1.09 g, 7.12 mmol), potassium carbonate (1.64 g, 11.8 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (484 mg, 0.59 mmol) were dissolved in a mixture of DMF (100 mL) and water (25 mL). The reaction mixture was heated to 65°C under nitrogen for 6 hours. The reaction mixture was purified by C18 column chromatography (ACN / H2O + 0.1% FA) to give compound 29-5 (1.6 g, 84% yield).

[1023] MS (ESI) M / Z: 321.2 [M+H] + .

[1024] Step E:

[1025] Refer to Example 21 Step E to prepare compound 29-6.

[1026] MS (ESI) M / Z: 722.2 [M+H] + .

[1027] Step F:

[1028] Compound 29-6 (800 mg, 1.11 mmol) was dissolved in chloroform (8 mL), and diisopropylethylamine (717 mg, 5.55 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (480 mg, 1.89 mmol) were added. The resulting mixture was heated to 70°C for 1 h. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to provide compound 29-7 (400 mg, 51% yield).

[1029] MS (ESI) M / Z: 704.2 [M+H] + .

[1030] Step G:

[1031] Referring to step G of Example 17, compound 29-8 was prepared.

[1032] MS (ESI) M / Z: 827.2 [M+H] + .

[1033] Step H:

[1034] Compound 29-8 (90 mg, 0.11 mmol), compound 28-13 (68 mg, 0.22 mmol), dichloro(1,1-bis(di-tert-butyl)ferrocenephosphate)palladium(II) (36 mg, 0.055 mmol), and tripotassium phosphate (70 mg, 0.33 mmol) were dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (0.45 mL). The mixture was heated to 100°C under nitrogen for 2 hours. After cooling to room temperature, the reaction solution was concentrated and directly purified by C18 column chromatography (ACN / H2O + 0.1% FA) to give compound 29-9 (50 mg, 45% yield).

[1035] MS (ESI) M / Z: 1015.4 [M+H] + .

[1036] Step I:

[1037] Compound 29-9 (50 mg, 0.049 mmol) was dissolved in trifluoroacetic acid (2 mL), and a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid (0.4 mL, 10 / 1) was added. The mixture was stirred at room temperature for 25 minutes. The reaction was quenched with an ice-cold aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 5%-95%) to afford a mixture containing two isomers, 29 (9.74 mg, 29% yield).

[1038] MS (ESI) M / Z: 675.1 [M+H] + ;

[1039] 1 H NMR (400MHz, CD3OD) δ7.95(d,J=4.8Hz,1H),7.75(d,J=8.4Hz,1H),7.12-7.08(m,1H),6.94(t,J=8 .8Hz,1H),6.79-6.75(m,1H),6.48-6.44(m,1H),6.42-6.35(m,1H),5.38-5.23(m,1H),5.21-5.16( m,1H),5.05-5.02(m,1H),4.43-4.37(m,1H),4.32-4.19(m,3H),3.70-3.65(m,1H),3.49-3.42(m,1 H),3.30-3.20(m,3H),3.04-2.99(m,1H),2.35-2.14(m,3H),2.04-1.89(m,3H),1.69-1.65(m,3H).

[1040] Example 30: Compound 30 and its isomers

[1041] Step A:

[1042] Compound 29-7 (160 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL). Potassium osmate dihydrate (21 mg, 0.057 mmol), N-methylmorpholine-N-oxide (22 mg, 0.119 mmol), and citric acid (55 mg, 0.29 mmol) were added. After stirring at room temperature for 20 minutes, sodium periodate (203 mg, 0.95 mmol) was added, and the reaction solution was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction solution was directly purified by C18 column chromatography (ACN / H2O + 0.1% FA) to obtain compound 30-1 (70 mg, 43% yield).

[1043] LCMS (ESI) M / Z: 829.2 [M+H] + .

[1044] Step B:

[1045] Compound 30-1 (70 mg, 0.084 mmol) was dissolved in dichloromethane (4 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (371 mg, 1.68 mmol) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was quenched with an aqueous sodium bicarbonate solution mixed with ice water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography (ACN / H2O + 0.1% FA) to obtain compound 30-2 (50 mg, 70% yield).

[1046] MS (ESI) M / Z: 851.2 [M+H] + .

[1047] Step C:

[1048] Referring to step H of Example 29, compound 30-3 was prepared.

[1049] MS (ESI) M / Z: 1039.4 [M+H] + .

[1050] Step D:

[1051] Referring to step L of Example 28, prep-HPLC (Instrument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00mm10μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0mL / min, Gradient B: 5%-95%) was used to obtain compounds 30-P1 and 30-P2.

[1052] 30-P1: HPLC (Sunfire C18 4.6*150mm 5μm, Mobile phase A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 20%-95%), retention time: 5.285 min.

[1053] MS (ESI) M / Z: 699.1 [M+H] + ;

[1054] 1 H NMR (400MHz, CD3OD) δ7.96(d,J=5.2Hz,1H),7.76(d,J=7.6Hz,1H),7.18-7.15(m,1H),6.95( t,J=8.8Hz,1H),6.78(t,J=7.6Hz,1H),6.64(t,J=54.0Hz,1H),6.48-6.43(m,1H),5.36-5.2 3(m,1H),4.44-4.40(m,1H),4.31-4.23(m,3H),3.73-3.67(m,1H),3.53-3.48(m,1H),3.25- 3.17(m,3H),3.01-2.99(m,1H),2.34-2.13(m,3H),2.02-1.88(m,3H),1.67(d,J=6.8Hz,3H).

[1055] 30-P2: HPLC (Sunfire C18 4.6*150mm 5μm, Mobile phase A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 20%-95%), retention time: 5.743 min.

[1056] MS (ESI) M / Z: 699.1 [M+H] + ;

[1057] 1 H NMR (400MHz, CD3OD) δ7.95(d,J=5.2Hz,1H),7.75(d,J=8.0Hz,1H),7.18-7.15(m,1H),6.95( t,J=9.2Hz,1H),6.77(t,J=6.4Hz,1H),6.65(t,J=54.0Hz,1H),6.51-6.46(m,1H),5.36-5.2 3(m,1H),4.51-4.46(m,1H),4.33-4.25(m,3H),3.76-3.70(m,1H),3.52-3.47(m,1H),3.25- 3.18(m,3H),3.02-2.99(m,1H),2.34-2.12(m,3H),2.01-1.89(m,3H),1.69(d,J=6.8Hz,3H).

[1058] Example 44: Compound 44 and its isomers

[1059] Step A:

[1060] Compound 44-1 (1.0 g, 1.66 mmol, synthesized according to WO2022173678) was dissolved in DMF (10 mL) and acetic acid (10 mL). Nis (1.12 g, 4.98 mmol) was added, and the resulting mixture was stirred at room temperature under nitrogen for 0.5 hours. The reaction solution was directly purified by C18 column chromatography using ACN / H2O (0.1% FA) as the eluent to afford compound 44-2 (1 g, 82% yield).

[1061] MS (ESI) M / Z: 728.2 [M+H] + .

[1062] Step B:

[1063] Compound 44-2 (700 mg, 0.96 mmol) was dissolved in dry dichloromethane (14 mL), and pyridine (303 mg, 3.84 mmol) and acetyl chloride (200 mg, 2.55 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain crude compound 44-3 (700 mg).

[1064] MS (ESI) M / Z: 770.1 [M+H]+ .

[1065] Step C:

[1066] Compound 44-3 (900 mg, 1.17 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (674 mg, 3.51 mmol), cuprous iodide (557 mg, 2.92 mmol), and HMPA (1.05 g, 5.85 mmol) were dissolved in dry DMF (15 mL). The reaction mixture was heated to 90°C and stirred for 16 hours under nitrogen. After completion of the reaction, the mixture was diluted with water and quenched with 100 mL of aqueous ammonia. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1 and DCM / MeOH = 25 / 1) to afford compound 44-4 (800 mg) as a crude product.

[1067] MS (ESI) M / Z: 712.0 [M+H] +.

[1068] Step D:

[1069] Compound 44-4 (800 mg, 1.12 mmol) was dissolved in a mixture of methanol (5 mL) and THF (1 mL). Aqueous sodium hydroxide (11.2 mmol, 2.8 mL, 4 M) was added, and the reaction mixture was heated to 80°C and stirred for 2 hours. After completion of the reaction, the product was purified by C18 column chromatography using ACN / H2O (0.1% FA) as the eluent to afford compound 44-5 (250 mg, 34% yield).

[1070] MS (ESI) M / Z: 656.2 [M+H] + .

[1071] Step E:

[1072] Compound 44-5 (250 mg, 0.38 mmol), ammonium chloride (203 mg, 3.8 mmol), and DIEA (294 mg, 2.28 mmol) were dissolved in DMF (3 mL). HATU (288 mg, 0.76 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, the mixture was directly purified by C18 column chromatography using ACN / H2O (0.1% FA) as the eluent to obtain compound 44-6 (240 mg, 96% yield).

[1073] MS (ESI) M / Z: 655.3 [M+H] + .

[1074] Step F:

[1075] Compound 44-6 (4 g, 6.11 mmol) was dissolved in dry dioxane (48 mL), and thiophosgene (2.81 g, 24.44 mmol) was added. The resulting mixture was heated to 85°C and stirred for 2 hours. After the reaction, ethyl acetate (600 mL) was added for dilution and the mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography using ACN / H2O (0.1% FA) as the eluent to afford compound 44-7 (2 g, 47% yield).

[1076] MS (ESI) M / Z: 699.5 [M+H] + .

[1077] Step G:

[1078] Compound 44-8 (297 mg, 0.70 mmol) was dissolved in THF (6 mL), and sodium bis(trimethylsilyl)amide (1.88 mmol, 0.94 mL, 2 M in THF) was added. The resulting mixture was stirred at room temperature for 15 minutes, cooled to 0°C, and a THF solution of compound 44-7 (330 mg, 0.47 mmol) was added, followed by stirring at 0°C for 15 minutes. After completion of the reaction, the mixture was quenched with aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford compound 44-9 (330 mg, 63% yield).

[1079] MS (ESI) M / Z: 1100.3 [M+H] + .

[1080] Step H:

[1081] Compound 44-9 (340 mg, 0.35 mmol) was dissolved in chloroform (8 mL), and DIEA (452 ​​mg, 3.5 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (267 mg, 1.05 mol) were added. The resulting mixture was heated to 70°C and stirred for 1 hour. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 2 / 1) to afford compound 44-10 (150 mg, 41% yield).

[1082] MS (ESI) M / Z: 1082.3 [M+H] + .

[1083] Step I:

[1084] (2R,8S)-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (111 mg, 0.70 mmol) was dissolved in THF (3 mL), and sodium hydride (28 mg, 0.70 mmol, 60 wt%) was added. The resulting mixture was stirred at room temperature for 15 minutes. A solution of compound 44-10 (150 mg, 0.14 mmol) in THF (3 mL) was added at 0°C. The resulting mixture was stirred for another 15 minutes at 0°C, then returned to room temperature and stirred for 1 hour. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to afford compound 44-11 (80 mg, 48% yield).

[1085] MS (ESI) M / Z: 603.6 [M / 2+H] + .

[1086] Step J:

[1087] Compound 44-11 (80 mg, 0.066 mmol) was dissolved in TFA (3 mL), and a mixture of TFA / TfOH (10 / 1) (1.2 mL) was added, followed by stirring at room temperature for 20 minutes. After completion of the reaction, the mixture was quenched with icy sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Instument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 30%-95%) to afford 44-P1 (10.81 mg, 22% yield) and 44-P2 (9.37 mg, 19% yield).

[1088] 44-P1 HPLC (RD C18 4.6*150mm 5μm, Mobile phase A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 10%-90%), retention time: 8.355 min.

[1089] MS (ESI) M / Z: 725.1 [M+H] + ;

[1090] 1 H NMR (400MHz, CD3OD) δ7.96 (dd, J=4.8Hz, 1.2Hz, 1H), 7.75 (d, J=6.4Hz, 1H), 6.79-6.76 (m,1H),6.54(s,1H),6.42-6.40(m,1H),5.37-5.23(m,1H),4.47-4.44(m,1H),4.28-4 .25(m,3H),3.73-3.66(m,1H),3.53-3.48(m,1H),3.27-3.18(m,3H),3.03-2.99(m,1H ),2.42(d,J=1.2Hz,3H),2.38-2.15(m,3H),2.03-1.87(m,3H),1.68(d,J=6.8Hz,3H).

[1091] 44-P2 HPLC (RD C18 4.6*150mm 5μm, Mobile phase A: H2O (0.03% TFA) B: MeCN (0.03% TFA), Flow rate: 1.0 mL / min, 16 min, Gradient B: 10%-90%), retention time: 8.874 min.

[1092] MS (ESI) M / Z: 725.0 [M+H] + ;

[1093] 1 H NMR (400MHz, CD3OD) δ7.95(d,J=5.2Hz,1H),7.75(d,J=7.2Hz,1H),6.77(t,J=6.0H z,1H),6.54(s,1H),6.42-6.40(m,1H),5.37-5.23(m,1H),4.47-4.43(m,1H),4.36 -4.25(m,3H),3.73-3.66(m,1H),3.55-3.49(m,1H),3.27-3.18(m,3H),3.03-2.99 (m,1H),2.42(s,3H),2.36-2.12(m,3H),2.01-1.91(m,3H),1.67(d,J=6.8Hz,3H).

[1094] Examples 45, 46, 49-54 were prepared using the synthesis method of Example 44 by selecting appropriate raw materials:

[1095] Example 47: Compound 47 and its isomers

[1096] Step A:

[1097] Raw material 47-1 (5 g, 10.8 mmol), compound 47-2 (3.05 g, 9.75 mmol), RuPhos Pd G3 (0.910 g, 1.08 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (1.01 g, 2.17 mmol), and potassium carbonate (4.49 g, 32.5 mmol) were mixed in 1,4-dioxane (100 mL) and water (15 mL). The reaction mixture was heated to 80°C and stirred under nitrogen for 12 hours. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was purified on a normal silica gel column (PE:EA = 5:1) to obtain compound 47-3 (3.5 g, 57% yield).

[1098] MS (ESI) M / Z: 568.4 [M+H] + .

[1099] Step B:

[1100] Compound 47-3 (3.00 g, 5.28 mmol) was dissolved in acetic acid (30 mL) and DMF (30 mL), and NIS (1.78 g, 7.92 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified on a normal silica gel column (PE:EA = 5:1) to obtain compound 47-4 (3 g, 82% yield).

[1101] MS (ESI) M / Z: 694.4 [M+H] + .

[1102] Step C:

[1103] Compound 47-4 (2.80 g, 4.04 mmol) and pyridine (3.19 g, 40.4 mmol) were dissolved in DCM (50 mL), and acetyl chloride (1.91 g, 24.2 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a normal silica gel column (PE:EA = 2:1) to obtain compound 47-5 (2.2 g, 70% yield).

[1104] MS (ESI) M / Z: 778.6 [M+H] + .

[1105] Step D:

[1106] Compound 47-5 (2.60 g, 3.34 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.92 g, 10.0 mmol), cuprous iodide (1.59 g, 8.35 mmol), and hexamethylphosphoric triamide (2.99 g, 16.7 mmol) were dissolved in DMF (50 mL). The reaction mixture was heated to 90°C and stirred for 16 hours under nitrogen. The reaction mixture was diluted with water, and ammonia was added to complex the copper ions. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 47-6 (1.4 g, 62% yield).

[1107] MS (ESI) M / Z: 678.5 [M+H] + .

[1108] Step E:

[1109] Compound 47-6 (1.32 g, 1.94 mmol) was dissolved in methanol (12 mL) and tetrahydrofuran (2.5 mL). Aqueous sodium hydroxide (5 mL, 4 M) was added, and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with water and acidified to pH 5.0 by dropwise addition of 1 M HCl. The resulting solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 47-7 (1.3 g, 91% yield).

[1110] MS (ESI) M / Z: 622.4 [M+H] + .

[1111] Step F:

[1112] Compound 47-7 (490 mg, 0.79 mmol), ammonium chloride (634 mg, 11.9 mmol), DIEA (306 mg, 2.37 mmol), and HATU (451 mg, 1.19 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and purified by column chromatography to afford compound 47-8 (400 mg, 82% yield).

[1113] MS (ESI) M / Z: 621.4 [M+H] + .

[1114] Step G:

[1115] Under nitrogen, compound 47-8 (700 mg, 1.13 mmol) was dissolved in 1,4-dioxane (8 mL), and thiophosgene (520 mg, 4.52 mmol) was added. The reaction solution was heated to 80°C in a sealed glass tube and stirred for 2 hours. After the reaction, the reaction solution was diluted with a large amount of ethyl acetate and concentrated under reduced pressure to remove the thiophosgene. The residue was purified by C18 silica gel column chromatography (80% MeCN:20% H2O (0.1% FA)) to provide compound 47-9 (500 mg, 67% yield).

[1116] LCMS (ESI) M / Z: 665.4 [M+H] + .

[1117] Step H:

[1118] Compound 44-8 (160 mg, 0.38 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium bis(trimethylsilyl)amide (0.56 mL, 2 M in THF) was added under nitrogen. After stirring at room temperature for 15 minutes, a mixture of compound 47-9 (250 mg, 0.38 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred at room temperature for 15 minutes under nitrogen. After completion of the reaction, the reaction mixture was poured into ammonium chloride solution for quenching, extracted with ethyl acetate, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 47-10 (350 mg, 87% yield).

[1119] LCMS (ESI) M / Z: 1066.3 [M+H] + .

[1120] Step I:

[1121] Compound 47-10 (375 mg, 0.35 mmol), bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (178 mg, 0.70 mmol), and DIEA (226 mg, 1.75 mmol) were dissolved in chloroform (7 mL). The reaction mixture was heated to 70°C under nitrogen and stirred for 1 hour. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified on a silica gel column (PE:EA = 2:1) to afford compound 47-11 (150 mg, 41% yield).

[1122] LCMS (ESI) M / Z: 1048.1 [M+H] + .

[1123] Step J:

[1124] (2R,8S)-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (191 mg, 1.2 mmol) was dissolved in THF (3 mL), and sodium hydride (48 mg, 1.2 mmol, 60 wt%) was added. The resulting mixture was stirred at room temperature for 15 minutes. A solution of compound 47-11 (150 mg, 0.14 mmol) in THF (3 mL) was added at 0°C, and the mixture was stirred at 0°C for 15 minutes, then returned to room temperature and stirred for 1 hour. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to afford compound 47-12 (120 mg, 86% yield).

[1125] MS (ESI) M / Z: 1171.5 [M+H] + .

[1126] Step K:

[1127] Compound 47-12 (120 mg, 0.10 mmol) was dissolved in trifluoroacetic acid (2 mL), and a mixture of TFA and TfOH (10:1) (0.5 mL) was added. The mixture was stirred at room temperature under nitrogen for 20 minutes. After completion of the reaction, the reaction solution was poured into an ice-cold saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure. 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: MeCN, Flow rate: 20.0 mL / min, Gradient B: 30%-95%) to isolate 47-P1 (11.61 mg, 16% yield) and 47-P2 (7.75 mg, 11% yield).

[1128] 47-P1: HPLC(Waters

[1129] MS (ESI) M / Z: 691.0 [M+H] + .

[1130] 1 H NMR(400MHz,MeOD)δ7.96(dd,J=5.2,1.6Hz,1H),7.76(d,J=7.2Hz,1H),6.77(dd,J=7.6,5.2Hz,1H ),6.59(s,1H),6.40(d,J=6.8Hz,1H),5.30(d,J=53.6Hz,1H),4.46(dd,J=12.0,3.6Hz,1H),4.29(q ,J=10.4Hz,3H),3.70(dd,J=14.4,6.4Hz,1H),3.53(dd,J=15.6,3.6Hz,1H),3.18(t,J=20.4Hz,3H) ,3.02(s,1H),2.31(d,J=16.0Hz,3H),2.27-2.08(m,3H),2.06-1.87(m,3H),1.68(d,J=6.8Hz,3H).

[1131] 47-P2: HPLC (Waters XBridge C18 5μm, 4.6*150mm Column, 25°C, Mobile phase: A: H2O (0.03% TFA in H2O, B: 0.03% TFA in MeCN, Flow rate: 1.0mL / min, 16.0min), retention time: 7.451min.

[1132] MS (ESI) M / Z: 691.0 [M+H] + .

[1133] 1 H NMR(400MHz,MeOD)δ7.96(dd,J=5.2,1.6Hz,1H),7.76(d,J=7.6Hz,1H),6.77(dd,J=7.6,5.2Hz ,1H),6.58(s,1H),6.42(q,J=6.8Hz,1H),5.30(d,J=54.4Hz,1H),4.48(dd,J=11.2,5.2Hz,1H), 4.29(q,J=10.4Hz,3H),3.72(dd,J=14.8,6.4Hz,1H),3.52(dd,J=14.8,4.8Hz,1H),3.18(t,J=2 0.0Hz,3H),3.01(d,J=5.6Hz,1H),2.39-2.10(m,6H),2.01-1.85(m,3H),1.68(d,J=6.8Hz,3H).

[1134] The following was prepared using the synthesis method of Example 47 by selecting appropriate raw materials:

[1135] Example 48: Compound 48 and its isomers

[1136] Step A:

[1137] The raw material 48-1 (940 mg, 2.87 mmol, synthesized with reference to WO2023183585), compound 47-2 (900 mg, 2.87 mmol), RuPhos Pd G3 (240 mg, 0.29 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (267 mg, 0.57 mmol) and potassium carbonate (991 mg, 7.15 mmol) were mixed in 1,4-dioxane (50 mL) and water (10 mL). The reaction solution was heated to 80 ° C and stirred for 3 hours under nitrogen protection. After the reaction was completed, it was diluted with water and extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was purified by normal silica gel column (PE:EA=4:1) to obtain compound 48-2 (750 mg, yield 54%).

[1138] MS (ESI) M / Z: 479.3 [M+H] + .

[1139] Step B:

[1140] Compound 48-2 (500 mg, 1.05 mmol) was dissolved in NMP (5 mL), and N-chlorosuccinimide (140 mg, 1.05 mmol) was added. The mixture was reacted at room temperature under nitrogen for 2 hours. The reaction solution was purified by reverse phase preparative chromatography (mobile phase A: H2O (0.1% FA), mobile phase B: MeCN, flow rate: 20.0 mL / min, gradient B: 5%-95%) to obtain compound 48-3 (220 mg, 41% yield).

[1141] LCMS (ESI) M / Z: 513.2 [M+H] + .

[1142] Step C:

[1143] Compound 48-4 (400 mg, 0.780 mmol) was dissolved in a mixture of THF, MeOH, and water (10 mL / 5 mL / 5 mL). Sodium hydroxide (31.2 mg, 0.780 mmol) was added, and the mixture was reacted at 50°C under nitrogen for 2 hours. The resulting reaction solution was purified by reverse phase preparative chromatography (mobile phase A: H2O (0.1% FA), mobile phase B: MeCN, flow rate: 20.0 mL / min, gradient B: 5%-95%) to afford compound 48-4 (310 mg, 79% yield).

[1144] LCMS (ESI) M / Z: 499.2 [M+H] + .

[1145] Step D:

[1146] Compound 48-4 (350 mg, 0.70 mmol) and ammonium chloride (74.8 mg, 1.40 mmol) were dissolved in DMF (10 mL). N,N-diisopropylethylamine (271 mg, 2.10 mmol) and 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (399 mg, 1.05 mmol) were then added. The mixture was reacted at room temperature under nitrogen for 2 hours. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to afford compound 48-5 (220 mg, 62% yield).

[1147] LCMS (ESI) M / Z: 498.2 [M+H] +.

[1148] Step E:

[1149] Compound 48-5 (50 mg, 0.10 mmol) was dissolved in anhydrous dioxane (0.5 mL), and thiophosgene (45.9 mg, 0.40 mmol) was added. The mixture was heated to 85°C and stirred for 1 hour under nitrogen. After completion of the reaction, the mixture was quenched with icy sodium bicarbonate solution and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to afford compound 48-6 (30 mg, 55% yield).

[1150] LCMS (ESI) M / Z: 542.2 [M+H] + .

[1151] Step F:

[1152] Compound 44-8 (19.3 mg, 0.046 mol) was dissolved in THF (1 mL), and a solution of sodium bis(trimethylsilyl)amide (0.100 mL, 0.184 mmol, 2 M in THF) was added. The mixture was stirred at room temperature under nitrogen for 30 minutes. A solution of compound 48-6 (25.0 mg, 0.046 mmol) in THF (1 mL) was added, and the reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 48-7 (15 mg, 34% yield).

[1153] LCMS (ESI) M / Z: 943.0 [M+H] + .

[1154] Step G:

[1155] Compound 48-7 (20 mg, 0.021 mmol), bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (10.6 mg, 0.04 mmol), and diisopropylethylamine (13.5 mg, 0.11 mmol) were dissolved in chloroform (3 mL). The reaction mixture was heated to 70°C under nitrogen and stirred for 1 hour. After completion of the reaction, the mixture was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified on a silica gel column (PE:EA = 1:1) to afford compound 48-8 (10 mg, 50% yield).

[1156] LCMS (ESI) M / Z: 925.0 [M+H] + .

[1157] Step H:

[1158] (2R,8S)-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (9 mg, 0.05 mmol) was dissolved in THF (1 mL), and sodium hydride (1.5 mg, 0.05 mmol, 60 wt%) was added. The resulting mixture was stirred at room temperature for 15 minutes. A solution of compound 48-8 (10 mg, 0.01 mmol) in THF (1 mL) was added at 0°C, and the mixture was stirred at 0°C for 15 minutes, then returned to room temperature and stirred for 1 hour. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to afford compound 48-9 (5 mg, 44% yield).

[1159] LCMS (ESI) M / Z: 1048.1 [M+H] + .

[1160] Step I:

[1161] Compound 48-9 (20 mg, 0.019 mmol) was dissolved in TFA / TfOH (1 mL / 0.1 mL) and stirred at room temperature under nitrogen for 0.5 h. After completion, the reaction was quenched with cold aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Instument: Waters 2767 / 2545 / 2489, Column: XBridge C18 250*19.00 mm 10 μm, Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 20.0 mL / min, Gradient B: 30%-95%) to afford the axial chiral isomers 48-P1 (2.75 mg, 13% yield) and 48-P2 (1.08 mg, 6% yield).

[1162] 48-P1:

[1163] HPLC (Waters XBridge C18 4.6*150mm 5μm Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 1.0mL / min, 16.0min), retention time: 7.629min.

[1164] LCMS (ESI) M / Z: 708.0 [M+H] + .

[1165] 1 H NMR(400MHz,CD3OD)δ8.28(s,1H),7.95-7.96(m,1H),7.75-7.77(m,1H),6.77-6.78(m,1H),6.48-6.50(m,1H),5.34-5.37(m,1H),4.25-4.30 (m,4H),3.63-3.69(m,2H),3.52-3.62(m,1H),3.12-3.24(m,2H),3.00 -3.02(m,1H),2.17-2.26(m,3H),1.91-2.02(m,3H),1.66-1.68(m,3H).

[1166] 48-P2:

[1167] HPLC (Waters XBridge C18 4.6*150mm 5μm Mobile phase: A: H2O (0.1% NH4HCO3) B: MeCN, Flow rate: 1.0mL / min, 16.0min), RT: 8.373min.

[1168] LCMS (ESI) M / Z: 708.0 [M+H] + .

[1169] 1 H NMR (400MHz, CD3OD) δ8.28(s,1H),7.96(s,1H),7.75-7.77(m,1H),6.77-6.79(m,1H),6.48-6.50(m,1H),5.23-5.34(m,1H),4.32-4.35(m,1H), 4.25-4.30(m,3H),3.54-3.69(m,2H),3.48-3.53(m,1H),3.02-3.19(m,2H), 2.99-3.01(m,1H),2.14-2.25(m,3H),1.91-2.02(m,3H),1.60-1.68(m,3H).

[1170] Example 79: Compound 79 and its isomers

[1171] Step A:

[1172] Starting material 79-1 (10.5 g, 27.42 mmol) was dissolved in N,N-dimethylformamide (105 mL). N-chlorosuccinimide (3.66 g, 27.42 mmol) was added to the solution at room temperature, and the mixture was stirred overnight at room temperature. LCMS confirmed the reaction was complete. An appropriate amount of water was added to the mixture under an ice-water bath, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain 79-2 (6.8 g, 59% yield).

[1173] MS (ESI) M / Z: 417.7 [M+H] + .

[1174] 1H NMR (400MHz, DMSO) δ7.20-7.12(m,4H),6.92-6.83(m,4H),6.65(d,J=0.9Hz,1H),4.62(s,4H),3.72(s,6H),2.23(d,J=0.8Hz,3H).

[1175] Step B:

[1176] 2,2,2-Trichloroethane-1,1-diol (2.23 g, 13.45 mmol) and sodium sulfate (5.1 g, 35.87 mmol) were dissolved in water (14 mL) and heated to 50°C. A solution of 79-3 (1 g, 4.48 mmol) in ethanol (1 mL) was added with stirring, followed by a mixture of concentrated hydrochloric acid (1.7 mL) and water (5.7 mL). Finally, a suspension of hydroxylamine hydrochloride (1.87 g, 26.91 mmol) in water (2.4 mL) was added to the reaction mixture, and the reaction system was stirred at 95°C for 6 hours. After LCMS monitoring showed the disappearance of the starting material, the mixture was cooled to room temperature and filtered. The filter cake was washed with water, and the solid was collected to obtain the crude product. The crude product was slurried with a small amount of a mixed solvent (PE:EA = 10:1) and filtered to obtain the product. This afforded 79-4 (yield 70%).

[1177] MS (ESI) M / Z: 295.1 [M+H] + .

[1178] Step C:

[1179] 79-4 (4.8 g, 17.34 mmol) was dissolved in concentrated sulfuric acid (25 mL, 5V) and stirred at 90°C under nitrogen for 1 hour. After LCMS monitoring indicated the disappearance of the starting material, the reaction solution was cooled to room temperature. With rapid stirring, the reaction solution was added to ice water to precipitate a solid. The filter cake was filtered and washed with ice water to collect the solid to obtain 79-5 (yield 83%).

[1180] MS (ESI) M / Z: 278.2 [M+H] + .

[1181] Step D:

[1182] Step F: Dissolve 79-5 (3.7 g, 13.29 mmol) in an aqueous sodium hydroxide solution (74 mL, 2 M, 20 V). Add 30% aqueous H₂O₂ (4.3 mL) dropwise at 0°C. Stir the reaction at 0°C under nitrogen for 1 hour. LCMS monitoring indicates the disappearance of the starting material. Pour the reaction mixture into 60 mL of ice water. Adjust the pH to 2 with concentrated hydrochloric acid to precipitate a solid, which is then filtered. Wash the filter cake three times with 3 mL of water and dry in an oven at 40°C overnight to obtain 79-6 (84% yield).

[1183] MS (ESI) M / Z: 268.1 [M+H] + .

[1184] Step E:

[1185] 79-6 (2.8 g, 10.4 mmol) and potassium carbonate (2.88 g, 20.86 mmol) were dissolved in DMF (30 mL, 10 V). Methyl iodide (2.2 g, 15.64 mmol) was added dropwise at 0°C and stirred at room temperature for 4 hours. LCMS monitoring indicated the disappearance of the starting material. An appropriate amount of water was added to the reaction solution, and the mixture was extracted three times with a mixture of EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 10) to obtain 79-7 (yield 88%).

[1186] Step F:

[1187] 79-7 (1 g, 3.54 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4-dioxaborolan (1.08 g, 4.25 mmol), potassium acetate (1.04 g, 10.61 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (289 mg, 0.354 mmol) were dissolved in 1,4-dioxane (20 mL, 20 V). The reaction system was stirred at 110°C for 4 hours under nitrogen. After LCMS analysis, the dioxane was removed under pressure, and the resulting mixture was diluted with water. Extraction was performed three times with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by normal phase silica gel column (PE:EA=5:1) to give 79-8 (yield 89%).

[1188] MS (ESI) M / Z: 330.4 [M+H] +.

[1189] Step G:

[1190] 79-2 and 79-8 were selected as raw materials and the synthesis method of Example 47 was used to prepare compound 79-P1 and compound 79-P2.

[1191] Compound 79-P1:

[1192] HPLC(Waters 10%B within 1.0min, then 10%B with 2.5min. Retention time: 8.870min.

[1193] LCMS (ESI) M / Z: 707.3 [M+H] + .

[1194] 1 H NMR (400MHz, DMSO-d6) δ7.98 (dd, J=4.9, 1.7Hz, 1H), 7.63 (dd, J=7.5, 1.8Hz, 1H), 6.66 (dd, J=7.5, 4.9H z,1H),6.43(d,J=1.0Hz,1H),6.13(s,2H),6.13-6.08(m,1H),5.71(s,2H),5.29(d,J=54.2Hz,1H),4.5 0-4.43(m,1H),4.25-4.16(m,2H),4.13(s,1H),3.70-3.61(m,1H),3.49-3.43(m,1H),3.16-2.98(m,3H ),2.83(s,1H),2.24(s,3H),2.15(s,1H),2.12-2.01(m,2H),1.88-1.75(m,3H),1.59(d,J=6.8Hz,3H).

[1195] 79-P2:

[1196] HPLC(Waters 10%B within 1.0min, then 10%B with 2.5min. Retention time: 9.843min.

[1197] MS (ESI) M / Z: 707.2 [M+H] +.

[1198] 1H NMR (400MHz, DMSO-d6) δ7.97 (dd, J=4.9, 1.7Hz, 1H), 7.63 (dd, J=7.4, 1.8Hz, 1H), 6.66 (d d,J=7.5,4.9Hz,1H),6.43(s,1H),6.18-6.10(m,3H),5.82(s,2H),5.33(d,J=54.0Hz,1H) ,4.59-4.53(m,1H),4.31-4.10(m,3H),3.72-3.67(m,1H),3.51-3.41(m,2H),3.15(s,2H ),2.88(s,1H),2.24(s,3H),2.18-2.00(m,3H),1.96-1.77(m,3H),1.61(d,J=6.8Hz,3H).

[1199] Biological activity test

[1200] Experimental Example 1: KRAS-G12V & cRAF Binding Test

[1201] Experimental steps:

[1202] 1. Dilute the compound in DMSO and add it to a 384-well plate;

[1203] 2. Add 2.5 μL of KRAS G12V protein (purchased from ICE) to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 15 minutes;

[1204] 3. Add 2.5 μL of cRAF protein (purchased from Pharmaron) to a 384-well plate and centrifuge at 1000 rpm for 1 minute.

[1205] 4. Add 5 μL of Tb&XL665 detection reagent (purchased from Cisbio) to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes;

[1206] 5. Read the signal ratio (665 / 620nm);

[1207] 6. Data analysis: According to the formula Percent inhibition (% inh) for compound well = 100 * (ave High control - cpd well) / (ave High control - ave Low control), that is, compound inhibition rate (% inh) = 100 × (high control - compound) / (high control - low control), the log value of the sample compound concentration is the horizontal axis (X), and the Percent inhibition (% inh) is the vertical axis (Y). Prism8 software is used according to Y = Bottom + (Top - Bottom) / (1 + 10^((logIC 50 -X)*HillSlope)) analyzes the data and fits the compound IC 50 The specific results are shown in Table 1.

[1208] Experimental Example 2: KRAS G12V / SOS1 / cRAF exchange assay

[1209] Experimental steps:

[1210] 1. Dilute the compound in DMSO and add it to a 384-well plate;

[1211] 2. Add 2.5 μL of KRAS G12V protein (purchased from ICE) to a 384-well plate and incubate at 25°C for 15 minutes;

[1212] 3. Add 2.5 μL of GTP and SOS1 protein to a 384-well plate and incubate at 25°C for 60 minutes.

[1213] 4. Add 5 μL of cRAF protein (purchased from Pharmaron) to the 384-well plate and incubate at 25°C for 60 minutes;

[1214] 5. Add 10 μL of Tb&XL665 detection reagent (purchased from Cisbio) to the 384-well plate and incubate at 25°C for 60 minutes;

[1215] 6. Read the signal ratio (665 / 615nm);

[1216] 7. Data analysis: According to the formula Percent inhibition (% inh) for compound well = 100 * (ave High control - cpd well) / (ave High control - ave Low control), with the log value of the sample compound concentration as the horizontal axis (X) and the Percent inhibition (% inh) as the vertical axis (Y), Prism 8 software was used according to the four-parameter fitting formula Y = Bottom + (Top - Bottom) / (1 + 10^((logIC 50 -X)*HillSlope)) analyzes the data and fits the compound IC 50 The specific results are shown in Table 1.

[1217] Table 1. KRAS G12V / SOS1 / cRAF exchange assay test results of the compounds of the present invention Note: “ / ” means not tested.

[1218] The above results indicate that the compounds of the present invention have a significant inhibitory effect on the functional process of the target mutant protein.

[1219] Experimental Example 3: KRAS(G12V)-GDP / SOS1 / cRAF interaction test

[1220] In this study, the AlphaLISA method was used to determine the inhibitory activity of the compounds of the present invention on KRAS-G12V, and the half-maximal inhibitory concentration (IC50) of the compounds of the present invention on KRAS-G12V activity was obtained. 50 ).

[1221] Experimental Materials:

[1222] KRAS (G12V) GDP-Loaded protein, SOS1 protein, and cRAF protein were purchased from BPS Bioscience, Alpha glutathione donor beads, AlphaLISA Nickel Acceptor beads, and OPTIPLATE-384 were purchased from PerkinElmer, HEPES was purchased from Teknova, and DTT (dithiothreitol), GTP (guanosine triphosphate), MgCl2, Triton X-100, and DMSO (dimethyl sulfoxide) were purchased from Sigma.

[1223] Experimental Buffer:

[1224] Buffer A: 10mM MgCl2, 25mM HEPES pH7.4, 0.01% Triton X-100;

[1225] Buffer B: 10mM MgCl2, 25mM HEPES pH7.4, 0.01% Triton X-100, 1mM DTT.

[1226] Experimental methods:

[1227] 1. Add 5 μL of 2.5 nM KRAS G12V protein diluted in Buffer A to a 384-well plate and centrifuge briefly.

[1228] 2. The compound was diluted with DMSO in a gradient manner and added to a 384-well plate. After instant centrifugation, the plate was shaken at 1000 rpm for 5 minutes, then sealed with aluminum foil and incubated at 25°C for 1 hour.

[1229] 3. Add 5 μL of 2.5 mM GTP and 40 nM SOS1 protein diluted in Buffer B to a 384-well plate. Centrifuge briefly and shake at 1000 rpm for 5 minutes. Seal the plate with aluminum foil and incubate at 25°C for 1 hour.

[1230] 4. Add 5 μL of 5 nM cRAF protein and 80 μg / mL acceptor beads diluted in Buffer B to a 384-well plate. Centrifuge briefly and shake at 1000 rpm for 5 minutes. Seal the plate with aluminum foil and incubate at 25°C for 1 hour.

[1231] 5. Add 5 μL of 80 μg / mL donor beads diluted in Buffer B to a 384-well plate. Centrifuge briefly and shake at 1000 rpm for 5 minutes. Seal the plate with aluminum foil and incubate at 25°C for 1 hour.

[1232] 6. Read the signal using the Envision2105 AlphaLISA program;

[1233] 7. Data Analysis: The wells containing only 0.5% DMSO were designated as High controls, and the wells containing 10 μM positive reference compounds were designated as Low controls. The logarithmic values ​​of the sample compound concentrations were plotted as the horizontal axis (X) and the percent inhibition (%inh) as the vertical axis (Y) using Prism 8 software using the four-parameter fitting formula Y = Bottom + (Top - Bottom) / (1 + 10^((logIC 50 -X)*HillSlope)) analyzes the data and fits the compound IC 50 The specific test results are shown in Table 2.

[1234] Table 2 KRAS (G12V)-GDP / SOS1 / cRAF interaction test results of the compounds of the present invention

[1235] Experimental Example 4: Evaluation of the inhibitory effect of the compounds of the present invention on the proliferation of human colorectal cancer cell line SW480

[1236] In this experiment, the intracellular ATP (adenosine triphosphate) content was determined by chemiluminescence to detect the proliferation inhibitory effect of the compound of the present invention on the human colorectal cancer cell line SW480, and the half-maximal inhibitory concentration (IC) of the compound of the present invention on the inhibition of proliferation of the human colorectal cancer cell line SW480 was obtained. 50 .

[1237] 1. Experimental Materials

[1238] L15 culture medium, fetal bovine serum (FBS), and 100× penicillin / streptomycin mixed solution (Pen / Strep) were purchased from GIBCO. 3D Cell Titer-Glo luminescent cell viability assay reagent was purchased from Promega. Human colorectal cancer cell line SW480 was purchased from ATCC.

[1239] 2. Experimental Methods

[1240] 1) Human colorectal cancer cell line SW480 was cultured in L15 medium containing FBS and penicillin-streptomycin at 37°C, 0 vol% CO2 until the logarithmic phase. Cells were counted using a cell counter and seeded into 96-well low-adhesion culture plates at a density of 1000 cells per well, with 100 μL per well. The plates were incubated overnight in an incubator (37°C, 0 vol% CO2).

[1241] 2) Day 0: Use a D300e (TECAN) micropipette to add 500 nL of serially diluted test compound (9 concentrations, 1:3 dilution ratio) to the cells in the culture plate. The final DMSO concentration is 0.5 vol%. The culture plate is incubated in a cell culture incubator for 7 days (37°C, 0 vol% CO2). For a blank control, add 500 nL of DMSO per well.

[1242] 3) Day 7: Add 100 μL of 3D Cell Titer-Glo reagent to each well, shake at 600 rpm for 5 minutes, and incubate at room temperature in the dark for 25 minutes to stabilize the luminescence signal.

[1243] 4) Luminescent signals were detected using Envision microplate reader (PerkinElmer).

[1244] 5) GraphPad Prism 6 software was used for data analysis and calculation of the IC of the compound. 50 .

[1245] The results of the inhibitory effect of the compounds of the present invention on the proliferation of human colorectal cancer cell line SW480 are shown in Table 3.

[1246] Table 3 Inhibitory effect of the compounds of the present invention on the proliferation of human colorectal cancer cell line SW480

[1247] In summary, the compounds of the embodiments of the present invention have excellent inhibitory effects on KRAS mutations, especially KRAS G12V mutations, and can be used as potential pan-KRAS inhibitors.

[1248] Experimental Example 5: Pharmacokinetic Determination in Balb / C Mice

[1249] Study purpose: Balb / C mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in the plasma of mice after oral administration at a dose of 30 mg / kg.

[1250] 1. Experimental Plan

[1251] 1.1 Experimental animals

[1252] Balb / C mice, female, Shanghai Jihui Laboratory Animal Co., Ltd., license number: SCXK(Shanghai)2022-0009 20220009016269.

[1253] 1.2 Administration:

[1254] IV: 3 Balb / C mice, free access to food; the compound was mixed with the vehicle (10% DMSO + 20% Solutol + 70% Saline) and vortexed to prepare a 0.2 mg / mL clear intravenous injection solution, which was then injected into the tail vein.

[1255] PO: 3 Balb / C mice, fasted overnight the day before administration and fed 4 hours after administration; the compound was mixed with the solvent (10% DMSO + 20% Solutol + 70% Saline) by vortexing to prepare a 3 mg / mL solution, which was administered orally.

[1256] 1.3 Sample collection

[1257] After administration, 0.03 mL of venous blood was collected from mice at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in a K2EDTA tube, and centrifuged at 2000 g for 5 minutes at 2-8°C to separate the plasma, which was then stored at -80°C.

[1258] 1.4 Sample processing

[1259] 1) 10 μL of plasma sample was added to 100 μL of acetonitrile for precipitation, mixed, and centrifuged at 5800 rpm for 10 minutes.

[1260] 2) The supernatant solution after treatment was taken and the concentration of the test compound was analyzed by LC / MS / MS.

[1261] 1.5 Liquid phase analysis

[1262] Liquid chromatography-mass spectrometry instrument: Triple Quad 6500+;

[1263] Chromatographic column: Waters HSS T3 (2.1×50 mm, 1.8 μm);

[1264] Mobile phase: Solution A is H2O-0.025% FA-1mM NH4OAc, and Solution B is MeOH-0.025% FA-1mM NH4OAc;

[1265] Flow rate: 0.6 mL / min;

[1266] Elution time: gradient elution 0-2.5 minutes.

[1267] 2. Experimental Results and Analysis

[1268] The main pharmacokinetic parameters were calculated using WinNonlin 8.0. Detailed results are shown in Table 4.

[1269] Table 4 Pharmacokinetic parameters of some compounds of the present invention in mice after oral administration Note: “ / ” means not tested.

[1270] The experimental results show that the compound of the present invention has good pharmacokinetic properties and bioavailability in mice.

[1271] Experimental Example 6: Caco-2 permeability test

[1272] Experimental purpose: To detect the permeability coefficient of the test substance in the Caco-2 cell model and investigate the possible permeation and absorption.

[1273] 1. Instruments, equipment and materials

[1274] 1) Caco-2 cells were purchased from the American Type Culture Collection (ATCC).

[1275] 2) Hank's balanced salt solution (HBSS) and non-essential amino acids (NEAA) were purchased from Thermo Fisher Scientific; HEPES (4-hydroxyethylpiperazineethanesulfonic acid), penicillin, streptomycin, and trypsin / EDTA were purchased from Solebro; fetal bovine serum (FBS) was purchased from AusGeneX; and high-glucose DMEM medium was purchased from Hyclone.

[1276] 3) HTS-96-well Transwell plates and other sterile consumables were purchased from Corning.

[1277] 4) Millicell resistance measurement system was purchased from Millipore; Vision was purchased from Nexcelom Bioscience; Infinite 200PRO microplate reader was purchased from Tecan; MTS2 / 4 orbital shaker was purchased from IKA Labortechnik.

[1278] 2. Experimental Methods

[1279] 1) Prepare 1 L of HBSS (10 mM HEPES, pH 7.4): Weigh 2.38 g HEPES and 0.35 g sodium bicarbonate, dissolve in 900 mL of water, then add 100 mL of 10× HBSS, stir well, adjust pH to 7.4, and filter.

[1280] 2) Prepare a 1 mM DMSO stock solution of the test substance and dilute it with HBSS (10 mM HEPES, pH 7.4) to a test concentration of 5 μM.

[1281] 3) Prepare 2 mM DMSO stock solutions of control drugs digoxin and metoprolol, and then dilute them accordingly with HBSS (10 mM HEPES, pH 7.4) to a test concentration of 10 μM.

[1282] 4) The cell monolayer was rinsed twice with HBSS (10 mM HEPES, pH 7.4) buffer and incubated at 37°C for 30 minutes.

[1283] 5) Determine the transport rate of the compound from the apical to the basolateral side. Add 125 μL of the dosing solution to each well of the upper chamber (apical side). Then, transfer 50 μL of the sample to 200 μL of acetonitrile containing the internal standard as the 0-minute dosing sample at the apical side of the Transwell plate. Add 235 μL of the receiving solution to each well of the lower chamber (basolateral side).

[1284] 6) Determine the transport rate of the compound from the basolateral to the apical side. Add 75 μL of the receiving solution to each well of the upper chamber (apical side) and 285 μL of the dosing solution to each well of the lower chamber (basolateral side). Then, transfer 50 μL of the sample to 200 μL of acetonitrile containing an internal standard as the 0-minute dosing sample at the basolateral side of the Transwell plate for detection.

[1285] 7) Combine the upper and lower transfer devices and incubate at 37°C for 2 hours.

[1286] 8) Transfer 50 μL of sample from the working solution preparation plate and add it to 200 μL of acetonitrile containing internal standard as the 0-minute dosing sample for detection.

[1287] 9) After incubation, sample 50 μL from each well of the upper and lower chambers of the Transwell plate and transfer to new sample tubes. Add 200 μL of acetonitrile containing the internal standard to each tube, vortex for 10 minutes, and centrifuge at 3220 g for 30 minutes. Aspirate 150 μL of the supernatant, dilute with an equal volume of water, and perform LC-MS / MS analysis. All samples should be prepared in duplicate.

[1288] 3. Data Analysis

[1289] All calculations were performed using Microsoft Excel. The apparent permeability coefficient (Papp, unit: cm / s) of the compound in Caco-2 cells was calculated using the following formula based on the specific concentrations at the receiving and administering sites:

[1290] In the formula: V A is the volume of the solution at the receiving end (0.235 mL from the top to the base, and 0.075 mL from the base to the top), and Area is the area of ​​the Transwell-96 well plate membrane (0.143 cm 2 ); time is the incubation time (unit: s). [drug] acceptor represents the concentration of the solution at the receiving end, [drug]initial,donor represents the concentration of the solution at the administering end;

[1291] The efflux rate ER is calculated using the following formula:

[1292] Where: Papp(BA) is the apparent permeability coefficient from the base end to the tip end; Papp(AB) is the apparent permeability coefficient from the tip end to the base end. Specific experimental results are shown in Table 5.

[1293] Table 5 Permeation and efflux test results of the compounds of the present invention

[1294] The experimental results show that the compound of the present invention has excellent permeability and low efflux effect.

[1295] Example 7: Determination of protein binding rate in plasma of different species

[1296] Objective: To evaluate the protein binding of the test drug in human, monkey, dog, rat and mouse plasma by equilibrium dialysis.

[1297] 1. Experimental Methods

[1298] 1.1 Preparation of compound working solution

[1299] The test substance and control compound ketoconazole were prepared into 1 mM working solution, and the final test concentration was 5 μM.

[1300] 1.2 Preparation of phosphate buffer (pH 7.4)

[1301] Weigh 12.0g NaH2PO4 and 8.77g NaCl and dissolve them in 1L of water to make an alkaline solution. Weigh 14.2g Na2HPO4 and 8.77g NaCl and dissolve them in 1L of water to make an acidic solution. Titrate the alkaline solution with the acidic solution to a pH of 7.4.

[1302] 1.3 Preparation of incubation system

[1303] Take 3 μL of the working solution of the test drug and control drug and add it to 597 μL of pre-incubated plasma. Mix thoroughly. The final organic solvent content of the incubation system is 0.5%. Immediately after mixing, transfer 50 μL of the incubation system to a new 96-well plate as the zero-point sample and treat it in the same manner as the pre-incubated samples.

[1304] 1.4 Dialysis method

[1305] Add 120 μL of the incubation system to each well of the dialysis apparatus and an equal volume of dialysis buffer (PBS) to the other side. Prepare all samples in duplicate. Seal the dialysis plate and equilibrate it in a 37°C, 5% CO2 incubator at 100 rpm for 6 hours. After incubation, remove 50 μL of sample from each end of the dialysis plate for processing.

[1306] 1.5 Treatment of dialysis samples

[1307] Add 50 μL of blank plasma to the buffer sample, and add an equal volume of blank buffer to the plasma sample. Mix well, and then add 400 μL of stop solution (containing internal standard acetonitrile).

[1308] All samples were vortexed for 10 minutes and then centrifuged at 3220 g for 30 minutes to precipitate proteins. 120 μL of supernatant was transferred to a sample injection plate and mixed with 120 μL of pure water for UPLC / MS / MS analysis.

[1309] 2. Data Analysis

[1310] All data calculations were performed using Microsoft Excel software. The drug concentrations in free and plasma samples were determined using the following formula:

[1311] Percentage of free compound %=(peak area ratio at buffer end / peak area ratio at plasma end)×100%. Specific test results are shown in Table 6.

[1312] Table 6 Free compound content of the compounds of the present invention in mouse plasma

[1313] The experimental results show that the compound of the present invention has more free drug in mouse plasma than the comparative compound 1.

[1314] Example 8: Pharmacokinetic determination in SD rats

[1315] Study purpose: SD rats were used as test animals to study the pharmacokinetics of the compound of the present invention in rat plasma.

[1316] 1.1 Experimental animals

[1317] Female SD rats were obtained from Shanghai Jihui Laboratory Animal Co., Ltd. (license number: SCXK(Shanghai)2022-0009 20220009018511).

[1318] 1.2 Administration:

[1319] IV: 3 SD rats, free diet; the compound was mixed with the solvent (10% DMSO + 20% Solutol + 70% Saline) and vortexed to prepare a 0.2 mg / mL clear intravenous injection solution, which was then injected into the tail vein.

[1320] PO: 3 SD rats, fasted overnight the day before administration and fed 4 hours after administration; the compound was mixed with the solvent (10% DMSO + 20% Solutol + 70% Saline) by vortexing to prepare a 3 mg / mL solution, which was administered orally.

[1321] 1.3 Sample collection

[1322] After administration, 0.03 mL of venous blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in a K2EDTA tube, and centrifuged at 2000 g for 5 minutes at 2-8°C to separate the plasma, which was then stored at -80°C.

[1323] 1.4 Sample processing

[1324] 1) 10 μL of plasma sample was added to 100 μL of acetonitrile for precipitation, mixed, and centrifuged at 5800 rpm for 10 minutes.

[1325] 2) The supernatant solution after treatment was taken and the concentration of the test compound was analyzed by LC / MS / MS.

[1326] 1.5 Liquid phase analysis

[1327] Liquid chromatography-mass spectrometry instrument: Triple Quad 5500;

[1328] Chromatographic column: Waters HSS T3 (2.1×50 mm, 1.8 μm);

[1329] Mobile phase: Liquid A is H2O-0.025% FA-1mM NH4OAc, and Liquid B is MeOH-0.025% FA-1mM NH4OAc;

[1330] Flow rate: 0.6 mL / min;

[1331] Elution time: gradient elution 0-2.5 minutes.

[1332] 2. Experimental Results and Analysis

[1333] The main pharmacokinetic parameters were calculated using WinNonlin 8.0. The specific results are shown in Table 7.

[1334] Table 7 Pharmacokinetic parameters of some compounds of the present invention in rats after oral administration Note: “ / ” means not tested.

[1335] The experimental results show that the compound of the present invention has better pharmacokinetic properties and bioavailability than the comparative compound 1.

[1336] Example 9: Pharmacokinetic Determination in Cynomolgus Monkeys

[1337] Study purpose: Cynomolgus monkeys were used as test animals to study the pharmacokinetics of the compound of the present invention in monkey plasma.

[1338] 1.1 Experimental animals

[1339] Cynomolgus macaques, female, Huazheng Laboratory Animal Breeding Centre, license number: SCXK(Yue)2020-0028 44410300000504.

[1340] 1.2 Administration

[1341] IV: Two cynomolgus monkeys were fed ad libitum; the compound was mixed with the vehicle (10% DMSO + 30% PEG400 + 60% water) and vortexed to prepare a 0.5 mg / mL clear intravenous injection solution, which was then administered intravenously.

[1342] 1.3 Sample collection

[1343] After administration, 0.03 mL of venous blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in a K2EDTA tube, and centrifuged at 2000 g for 5 minutes at 2-8°C to separate the plasma, which was then stored at -80°C.

[1344] 1.4 Sample processing

[1345] 1) 10 μL of plasma sample was added to 100 μL of acetonitrile for precipitation, mixed, and centrifuged at 5800 rpm for 10 minutes.

[1346] 2) The supernatant solution after treatment was taken and the concentration of the test compound was analyzed by LC / MS / MS.

[1347] 1.5 Liquid phase analysis

[1348] Liquid chromatography-mass spectrometry instrument: Triple Quad 5500;

[1349] Chromatographic column: Waters HSS T3 (2.1×50 mm, 1.8 μm);

[1350] Mobile phase: Liquid A is H2O-0.025% FA-1mM NH4OAc, and Liquid B is MeOH-0.025% FA-1mM NH4OAc;

[1351] Flow rate: 0.6 mL / min;

[1352] Elution time: gradient elution 0-2.5 minutes.

[1353] 2. Experimental Results and Analysis

[1354] The main pharmacokinetic parameters were calculated using WinNonlin 8.0. Detailed results are shown in Table 8.

[1355] Table 8 Pharmacokinetic results of the compounds of the present invention in cynomolgus monkeys

[1356] The experimental results show that the compound of the present invention has better pharmacokinetic properties than the comparative compound 1.

[1357] Experimental Example 10: Evaluation of the inhibitory effect of the compounds of the present invention on the activity of HRAS or NRAS wild-type proteins

[1358] In this study, the TR-FRET (time-resolved fluorescence resonance energy transfer) method was used to determine the inhibitory activity of the compounds of the present invention on the wild-type HRAS or NRAS proteins, and the half-maximal inhibitory concentration (IC50) of the compounds of the present invention on the activity of the wild-type HRAS or NRAS proteins was obtained. 50 ).

[1359] 1. Experimental Materials

[1360] The experimental reagents are shown in Table 9-1, the experimental consumables are shown in Table 9-2, and the experimental instruments are shown in Table 9-3.

[1361] Table 9-1 Experimental Reagents

[1362] Table 9-2 Experimental consumables

[1363] Table 9-3 Experimental instruments

[1364] 2. Experimental Methods

[1365] 1) Dilute the compound to the specified concentration, using the dilution as the first point, and perform 3-fold dilutions for a total of 10 points;

[1366] 2) Transfer 50 nL of compound to a 384-well plate, with each concentration point containing two replicate wells, and centrifuge the 384-well plate at 1000 rpm;

[1367] 3) Add 2.5 μL of HRAS_GDP / NRAS_GDP to each well and incubate for 15 minutes;

[1368] 4) Add 2.5 μL of GTP and SOS1 to each well and incubate for 1 hour;

[1369] 5) Add 5 μL of cRAF to each well and incubate for 15 minutes;

[1370] 6) Add 10 μL of SA-Tb & GST-XL665 to each well and incubate for 1 hour;

[1371] 7) Read the HTRF 665 / 615 signal, the inhibition rate of each well (%inh) = 100% * (average value of control wells - average value of test compound) / (average value of control wells - average value of blank wells), use four-parameter logistic simulation to fit the curve, and obtain IC 50 value.

[1372] The initial and final concentrations of each reagent are shown in Tables 9-4, 9-5, and 9-6.

[1373] Table 9-4

[1374] Table 9-5

[1375] Table 9-6

[1376] 3. Experimental Results and Analysis

[1377] The experimental results are shown in Table 10.

[1378] Table 10 Effects of the compounds of the present invention on H RAS WT / N RAS WT The inhibitory effect

[1379] The experimental results show that the compounds of the present invention have an effect on H RAS WT / N RAS WT All of them have weaker inhibitory effects and show better selectivity and safety.

[1380] In the experimental examples of the present invention, comparative compound 1 is the target compound obtained in Example 48 of patent document WO2022216762, which can be prepared according to Example 48 of WO2022216762 and has the following chemical structure:

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof: in, M1 is selected from N or CR 4-1 ; M2 is selected from O or CH2; M3 is selected from N or CR 4-3 ; Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-14 Aryl or 5-12 membered heteroaryl; or Ring A is absent, and L1 is directly connected to R1; Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-14 Aryl or 5-12 membered heteroaryl; L1 is selected from a bond, CO or -(CH2) m -, of which -(CH2) m - optionally substituted with one or more R6; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -CONR 1a R 1b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R 1a and R 1b are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; Alternatively, two R2 on the same carbon atom link to form C 3-8 Cycloalkyl; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, optionally further substituted by one or more R 3a replace; R 3a Selected from deuterium, halogen, amino, C 1-6 Alkylamino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, The amino group, C 1-6 Alkylamino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, Optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R 3-1 and R 3-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R 4-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R 4-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R 4-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; n is selected from 1, 2 or 3; m is selected from 1, 2 or 3; x is selected from 0, 1, 2, 3 or 4; y is selected from 0, 1, 2, 3 or 4; z is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The ring A is selected from phenyl, 5-6 membered heteroaryl, -phenyl and 5-6 membered heteroaryl, -5-6 membered heteroaryl and phenyl, -5-6 membered heteroaryl and 5-6 membered heteroaryl, -3-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, -C 3-8 Cycloalkenyl and 5-6 membered heteroaryl, -C 3-8 Heterocycloalkenylphenyl, C 3-6 Cycloalkyl, -5-6 membered heteroaryl and 3-6 membered heterocycloalkenyl, -3-6 membered heterocycloalkyl; Preferably, ring A is selected from phenyl, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Ring B is selected from 5-6 membered heteroaryl, -phenyl 5-6 membered heteroaryl, -pyrido 5-6 membered heteroaryl, naphthyl; Preferably, ring B is selected from 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound is shown in general formula (II), wherein ring A is selected from -phenyl and 5-6 membered heteroaryl, -5-6 membered heteroaryl and phenyl, -5-6 membered heteroaryl and 5-6 membered heteroaryl, -3-6 membered heterocycloalkenyl and 5-6 membered heteroaryl, -C 3-8 Cycloalkenyl 5-6 membered heteroaryl, -5-6 membered heteroaryl 3-6 membered heterocycloalkenyl; Preferably, ring A is selected from 5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (II-A) and general formula (II-B).

6. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (III), Wherein, R6 is selected from -CH2OCH3, -CH2OH, -CH2OCD3.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (III-A) and general formula (III-B).

8. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (IV), 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (IV-A) and general formula (IV-B).

10. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound is shown in general formula (V), Wherein, ring A is selected from 5-membered heteroaryl groups, preferably R6 is independently selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Alkylthio, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; Preferably, R6 is independently selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; More preferably, R6 is independently selected from deuterium, methyl, ethynyl, -CH2OCH3, -CH2OH, -CH2OCD3, -CH2SCH3.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (VA) and general formula (VB), 12. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (VI), R3 is selected from Preferably, R3 is selected from 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (VI-A) and general formula (VI-B), 14. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound is shown in general formula (VII-1) and (VII-2), M4 is selected from N or CH.

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is represented by the general formula (VII-1-A), the general formula (VII-1-B), the general formula (VII-2-A), and the general formula (VII-2-B).

16. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is as shown in the general formula (VIII-1), the general formula (VIII-2), the general formula (VIII-3), and the general formula (VIII-4).

17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is as shown in the general formula (VIII-1-A), the general formula (VIII-1-B), the general formula (VIII-2-A), the general formula (VIII-2-B), the general formula (VIII-3-A), the general formula (VIII-3-B), the general formula (VIII-4-A), and the general formula (VIII-4-B).

18. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in the general formula (IX), x is selected from 0, 1, 2 or 3.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (IX-A) and general formula (IX-B), 20. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in the general formula (X), Among them, R 4-1 Selected from trifluoromethyl, vinyl, difluoromethyl.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound is shown in general formula (XA) and general formula (XB), 22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CONR 1a R 1b , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; R 1a and R 1b are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; Preferably, R1 is independently selected from hydrogen, amino, chlorine, methyl, -CONH2, -CON(CH3)2, -CH2OH, fluorine, cyano, -CH2NH2; or, ring A is absent, -L1-R1 is 23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, R2 is independently selected from hydrogen, deuterium, fluorine, cyclopropyl; Alternatively, two R2 groups on the same carbon atom are linked to form a cyclopropyl group.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-10 membered heterocycloalkyl, optionally further substituted by one or more R 3a replace; R 3a Selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, The amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, Optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-8 substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; Preferably, R3 is selected from More preferably, R3 is selected from 25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 3-1 and R 3-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, R 3-1 and R 3-2 are each independently selected from hydrogen and deuterium.

26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 4-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, R 4-1 Selected from chlorine, trifluoromethyl, vinyl, difluoromethyl.

27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 4-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, R 4-2 Selected from fluorine.

28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 4-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, R 4-3 Selected from cyano.

29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, R5 is independently selected from hydrogen, amino, trifluoromethyl, methyl, fluoro, hydroxy, ethynyl, cyano.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 1-3 Deuterated alkoxy, C 3-6 substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, R6 is independently selected from hydrogen, deuterium, methyl, ethynyl, -CH2OCH3, -CH2OH, -CH2OCD3, -CH2SCH3.

31. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a chemical structure shown in formula (XIII): Wherein, M4, M5, M6, and M7 are each independently selected from N or CH; R1, R2, R3, R 3-1 、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z have the same definitions as in any of the technical solutions in claims 1-3 or 22-30.

32. The compound according to any one of claims 1 to 3 or 31, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a chemical structure shown in formula (XI): Wherein, M4, M5, M6 are each independently selected from N or CH; R1, R2, R3, R 3-1 、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z have the same definitions as in any of the technical solutions in claims 1-3 or 22-30.

33. The compound according to any one of claims 1 to 3 or 31, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a chemical structure shown in formula (XII): Wherein, M4 is selected from N or CH; R1, R2, R3, R 3-1 、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z have the same definitions as in any of the technical solutions in claims 1-3 or 22-30.

34. The compound according to any one of claims 31 to 33, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: x, y, and z are each independently selected from 0, 1, 2, 3, and 4.

35. The compound according to any one of claims 31 to 34, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R1 is selected from H, OH, CN, deuterium, amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the amino group may be optionally replaced by 1-2 C 1-4 Alkyl substituted; preferably, R1 is selected from CN, NH2, F, methyl, trifluoromethyl; more preferably, R1 is selected from NH2.

36. The compound according to any one of claims 31 to 35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R2 is selected from H, OH, CN, deuterium, amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; preferably, R2 is selected from H, OH, F, Cl, CN, methyl, ethyl, trifluoromethyl; more preferably, R2 is H, or R2 is D, or R2 is methyl.

37. The compound according to any one of claims 31 to 36, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 3-1 and R 3-2 are each independently selected from H, deuterium, halogen, amino, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkoxy; preferably, R 3-1 、R 3-2 are each independently selected from H, D, F; more preferably, R 3-1 and R 3-2 Both are H or R 3-1 and R 3-2 Both are D.

38. The compound according to any one of claims 31 to 37, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R3 is and optionally one or more R 3a Substituted; said R 3a Selected from OH, amino, halogen atom, C 1-4 Alkyl, C 1-4 Halogenated alkyl, methylene; or said R 3a is selected from OH, amino, F, Cl, methyl, ethyl, 2,2-difluoroethyl, and methylene; or said R 3a Selected from F or methylene; preferably, R3 is selected from More preferably, R3 is selected from 39. The compound according to any one of claims 31 to 36, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Selected from 40. The compound according to any one of claims 31 to 39, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 4-1 Selected from H, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 2-4 Alkynyl, ethynyl, propynyl; preferably, R 4-1 is selected from H, CN, OH, methyl, ethyl, monofluoromethyl, trifluoromethyl, trichloromethyl, methoxy; more preferably, R 4-1 is trifluoromethyl, or R 4-1 is ethynyl or propynyl.

41. The compound according to any one of claims 31 to 40, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 4-2 Selected from CN, OH, halogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 preferably, R 4-2 is selected from F or trifluoromethyl.

42. The compound according to any one of claims 31 to 41, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R5 is selected from amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; preferably, R5 is selected from F, Cl, amino, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl.

43. The compound according to any one of claims 31 to 41, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: for 44. The compound according to any one of claims 31 to 43, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R6 is selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, cyano-C 1-4 Alkyl, halogenated C 3-6 Cycloalkyl-O-alkyl, halogenated 3-6 membered heterocycloalkyl-O-alkyl; preferably, R6 is selected from methyl, -CD3, ethyl, trifluoromethyl, methoxy, methoxymethyl, hydroxymethyl, cyanomethyl, 2,2-difluorocyclobutane-3-yl-O-methyl; more preferably, R6 is methyl, or R6 is methoxymethyl, or R6 is hydroxymethyl.

45. The compound according to any one of claims 31-32 or 34-44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: M4, M5, and M6 are all CH; or M4 is N, and M5 and M6 are all CH; or M5 is N, and M4 and M6 are all CH; or M6 is N, and M4 and M5 are all CH.

46. The compound according to any one of claims 31-32 or 34-44, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Selected from 47. The compound according to any one of claims 31-32 or 34-46, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: M4, M5, and M6 are all CH, R1 is NH2, R2 is H, and R3 is selected from R 4-1 C 1-4 Haloalkyl, preferably trifluoromethyl; R 4-2 Halogen atoms, C 1-4 Haloalkyl, preferably F; R5 is selected from amino, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, preferably F, Cl, amino, methyl, trifluoromethyl; R6 is selected from C 1-4 Alkyl, C 1-4 A haloalkyl group, preferably a methyl group; x is 1, y is 0, and z is 3.

48. The compound according to any one of claims 31-32 or 34-47, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a structure shown in formula (XI-A) or formula (XI-B): Wherein, M4, M5, M6 are each independently selected from N or CH; R1, R2, R3, R 3-1 、R 3-2 、R 4-1 、R 4-2 , R5, R6, x, y, and z are as defined in any one of claims 31-47.

49. The compound according to any one of claims 31-32 or 34-46, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a structure represented by any one of formula (XI-1), formula (XI-2), formula (XI-3), formula (XI-4), and formula (XI-5): Wherein, M4, M5, and M6 are each independently selected from N or CH; R1, R3, and R 4-1 、R 4-2 , R6 is as defined in any one of claims 31-48, R 5-1 、R 5-2 、R 5-3 Each independently has the same meaning as R5 in any one of claims 31-48.

50. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has the chemical structure shown in Formula (XI-5A) and Formula (XI-5B): Among them, R3, R 4-2 , R6 is as defined in any one of claims 31-48.

51. The compound according to claim 31-32, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a chemical structure shown in formula (XI-6): Among them, R 1a 、R 1b Independently selected from H, D, CN, halogen atoms, C 1-3 Alkyl, C 1-3 Haloalkyl; R 2a 、R 2b Each independently selected from H, D, C 1-3 Alkyl, C 1-3 haloalkyl; y is independently selected from 0, 1, 2; z is independently selected from 0, 1, 2, 3; M4 is selected from N, CF, or CH; R3, R 4-1 、R 4-2 , R5, and R6 have the same meanings as defined in any one of claims 1-3, 24, 26, 27, 29, 30, and 37-44.

52. The compound according to claim 51, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 1a 、R 1b are independently selected from H, D, CN, F, Cl, methyl, trifluoromethyl, or R 1a 、R 1b are independently selected from H, CN, F, methyl; M4 is N or CH; R 2a 、R 2b are each independently selected from H, D; R 4-1 is trifluoromethyl, R 4-2 is F; R5 is selected from amino, F, Cl, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl; R6 is selected from methyl; R3 is y is independently selected from 0, 1, and 2; z is independently selected from 0, 1, 2, and 3.

53. The compound according to claim 31 or 33, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a structure shown in formula (XIIa): Among them, R 1a 、R 1b Independently selected from H, D, CN, halogen atoms, C 1-3 Alkyl, C 1-3 Haloalkyl; R 2a 、R 2b Each independently selected from H, D, C 1-3 Alkyl, C 1-3 haloalkyl; y is independently selected from 0, 1, 2; z is independently selected from 0, 1, 2, 3, 4; M4 is selected from N or CH; R3, R 4-1 、R 4-2 , R5, and R6 have the same meanings as in any one of claims 1-3, 24, 26, 27, 29, 30, and 37-44.

54. The compound according to claim 53, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 1a 、R 1b are independently selected from H, D, CN, F, Cl, methyl, trifluoromethyl, or R 1a 、R 1b are independently selected from H, CN, F, methyl, or R 1a 、R 1b Both H; R 2a 、R 2b are independently selected from H, D; M4 is N or CH; R 4-1 is trifluoromethyl, R 4-2 is F; R5 is selected from amino, F, Cl, methyl, trifluoromethyl, cyclopropyl; R6 is selected from methyl; R3 is y is independently selected from 0, 1, 2; z is independently selected from 0, 1, 2, 3, 4.

55. The compound according to claim 53-54, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is a compound represented by formula (XIIa-A) or formula (XIIa-B), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, R 1a 、R 1b 、R 2a 、R 2b ,y,z,M4,R3,R 4-1 、R 4-2 , R5, R6 are as defined in claim 53 or 54.

56. The compound according to claim 31, 33, 53-54, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is a compound represented by formula (XII-1), formula (XII-2), formula (XII-3), formula (XII-4), or formula (XII-5), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, q is selected from 1, 2, 3, and 4; R3, R 4-1 、R 4-2 , R5, R6, z have the same meanings as in claims 1-3, 37-44; R 5-2 、R 5-3 、R 5-4 、R 5-5 Has the same meaning as R5 in 1-3, 37-44; R 3a has the same meaning as in claim 38.

57. The compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; characterized in that: The compound is selected from the following compounds:

58. A pharmaceutical composition comprising the compound according to any one of claims 1 to 57 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and any pharmaceutically acceptable carrier.

59. Use of the compound according to any one of claims 1 to 57, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for treating diseases associated with KRAS G12V gene mutation and other types of KRAS gene mutations.

60. Use of the pharmaceutical composition according to claim 58 in the preparation of a medicament for treating diseases associated with KRAS G12V gene mutation and other types of KRAS gene mutations.

61. A method for treating diseases associated with KRAS G12V gene mutation and other types of KRAS gene mutations, comprising administering to a patient in need thereof an effective amount of the compound according to any one of claims 1 to 57, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 58.

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