Polycyclic compound and application thereof

Abstract

The present disclosure provides a class of compounds represented by formula (I '), or tautomers, stereoisomers or pharmaceutically acceptable salts thereof. The compound disclosed by the invention has a relatively strong agonistic effect on GLP-1R, can be used for treating diseases such as diabetes mellitus, metabolism-related fatty liver diseases, Alzheimer's disease and the like or has an effect of reducing weight. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202310900145.6 filed with the State Intellectual Property Office of China on July 21, 2023, Chinese Patent Application No. 202311081129.5 filed with the State Intellectual Property Office of China on August 25, 2023, and Chinese Patent Application No. 202410698010.0 filed with the State Intellectual Property Office of China on May 31, 2024, and the contents disclosed in the above applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to the field of medical technology, and in particular, to a class of novel compounds that are GLP-1R agonists and their use in treating and preventing diseases, disorders and conditions mediated by GLP-1R. Background Art

[0004] Overweight and obesity have become a global health problem. Now about 50% of type 2 diabetes, 30% of ischemic cardiovascular and cerebrovascular diseases and 10%-40% of cancers are caused by obesity or overweight.

[0005] Type 2 diabetes is the most common form of diabetes, accounting for over 90% of all diabetics. The pathogenesis of type 2 diabetes remains unclear, but it is currently believed to be linked to unhealthy lifestyles, genetic factors, environmental factors, and the toxic effects of lipotoxicity and glucotoxicity on pancreatic beta cells. Diabetes can lead to various complications, including atherosclerosis, retinopathy and neuritis, renal insufficiency and proteinuria, myocarditis, heart failure, and urinary tract infections.

[0006] GLP-1 (glucagon-like peptide-1) is primarily secreted by L cells. Its receptor, GLP-1R (full name: glucagon-like peptide-1 receptor), is primarily distributed in the pancreas, gastrointestinal tract, central nervous system, and cardiovascular system. The GLP-1R belongs to the glucagon receptor subfamily of the G protein-coupled receptor cluster B. Its characteristic structure consists of a seven-transmembrane core domain, an extracellular N-terminal domain, and an intracellular C-terminal domain, connected by three intracellular loops and three extracellular loops on either side of the membrane. It typically binds to peptide ligands via a two-domain model: the C-terminus of the ligand first binds to the extracellular domain of the GLP-1R, altering its conformation and exposing the binding site of the core domain. The N-terminus of the ligand then binds to the core domain of the GLP-1R, activating the GLP-1R. Generally speaking, the GLP-1R extracellular domain primarily recognizes specific ligands, while the core domain plays an important role in signal transduction.

[0007] In pancreatic islet cells, the primary function of GLP-1 is to promote the proliferation of pancreatic beta cells, stimulate the synthesis and release of insulin, and inhibit the synthesis and release of glucagon. In tissues such as the gastrointestinal tract, GLP-1 can inhibit gastric secretion and gastrointestinal motility, delay gastric emptying, increase satiety, and reduce food intake. In neural tissue, GLP-1 can protect nerve cells, combat loss of appetite, and enhance memory. In cardiovascular health, GLP-1 can improve cardiovascular function and reduce inflammation. In the liver, GLP-1 can increase insulin sensitivity and reduce gluconeogenesis. Therefore, GLP-1R receptor agonism can achieve weight loss effects through multiple biological mechanisms.

[0008] Defective insulin signaling is reportedly associated with the pathogenesis of AD (Alzheimer's disease). GLP-1 can counteract the significant increase in TLR-4 expression in glial cells induced by LPS (lipopolysaccharide) and reduce the expression of p-p38, p-JNK, and p-AKT, suggesting that GLP-1 suppresses inflammatory responses by inhibiting the MAPKs signaling pathway. Furthermore, studies have shown that in AD, when glucose metabolism is impaired and mitochondrial function is impaired, the shuttling of lactate during glial glycolysis becomes increasingly important for neuronal survival, serving as an energy substitute. GLP-1 can partially restore glycolytic function in astrocytes and increase lactate flux, which helps alleviate the neuronal energy crisis. The neuroprotective mechanism of GLP-1 is closely related to its promotion of aerobic glycolysis, alleviation of oxidative phosphorylation activation, and activation of the PI3K / Akt pathway. Therefore, GLP-1 agonists are a promising strategy for the prevention and treatment of AD.

[0009] Metabolic associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), has seen a significant increase in the incidence of MAFLD, with a prevalence as high as 40%. It has now surpassed viral liver diseases as the most common liver disease worldwide, increasing the urgency of further basic and clinical research. MAFLD is divided into two major categories: non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis (NASH). With an oversupply of metabolic substrates, excess fat accumulates in hepatocytes, accompanied by the gradual production of potentially toxic lipid species and, in MAFLD, a progressive increase in de novo lipogenesis (DNL). NASH, characterized by cell damage and inflammatory cell infiltration, is considered a more aggressive form of MAFLD and can progress to cirrhosis and hepatocellular carcinoma, with limited treatment options. Studies have shown that obesity and type 2 diabetes are two major risk factors for NASH, and individuals with a history of NASH are significantly more likely to develop liver and cardiovascular disease. Furthermore, insulin resistance in the liver and adipose tissue is considered a key driver of NASH morbidity and mortality. GLP-1 analogs can improve glycemic control, reduce weight, and activate liver enzymes in patients with T2DM. Liraglutide has been reported to reduce steatosis in vitro by directly targeting human hepatocytes, lowering DNL levels and increasing fatty acid oxidation. Literature shows that steatosis and hepatocyte swelling improve in most patients after liraglutide treatment, suggesting that liraglutide has the potential to reduce lipotoxicity by improving insulin sensitivity in adipose tissue. Only a small percentage of NASH patients experience progression after liraglutide treatment. Furthermore, semaglutide can reduce alanine aminotransferase and inflammatory markers, with significant reductions in inflammatory biomarkers after treatment. Given the lack of GLP-1R expression in the liver, the potential mechanism of action of GLP-1R agonists in NASH may involve indirect benefits on weight and reductions in metabolic dysfunction, lipotoxicity, and inflammation. Summary of the Invention

[0010] In one aspect, the present application provides a compound represented by formula (I'), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which has the following structure:

[0011]

[0012] in,

[0013] Ring A is independently selected from 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0014] Ring B is independently selected from C 3-10 Carbocyclic group, 3-12 membered heterocyclic group, C6-14 Aryl, 5-12 membered heteroaryl;

[0015] Ring C is independently selected from C 3-12 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0016] Ring D is independently selected from 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0017] R a Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR a1 、-S(O)R a1 、-SO2(R a1 ),-C(O)R a1 、-C(O)OR a1 、-OC(O)R a1 、-N(R a1 )(R a2 )、-C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 )、-S(O)N(R a1 )(R a2 )、-SO2N(R a1 )(R a2 )、-N(R a1 )S(O)(R a2 )、-N(R a1 )SO2(R a2 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R a3 replaced by;

[0018] R a1 、R a2Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0019] R a3 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R a4 、-OR a4 、-SR a4 、-S(O)R a4 、-SO2(R a4 ),-C(O)R a4 、-C(O)OR a4 、-OC(O)R a4 、-N(R a4 )(R a5 )、-C(O)N(R a4 )(R a5 )、-N(R a4 )C(O)(R a5 )、-S(O)N(R a4 )(R a5 )、-SO2N(R a4 )(R a5 )、-N(R a4 )S(O)(R a5 )、-N(R a4 )SO2(R a5 );

[0020] R a4 、R a5 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Substituted by a cycloalkyl group, a 3-7 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0021] or two R a Together with the atoms to which they are attached, they form deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 one or more optionally substituted 3-10 membered heterocyclic groups or 5-12 membered heteroaryl groups among aryl groups and 5-12 membered heteroaryl groups;

[0022] R b Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R b1 replaced by;

[0023] or two R b Together with the atoms to which they are attached, they form deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14one or more optionally substituted 3-10 membered heterocyclic groups or 5-12 membered heteroaryl groups among aryl groups and 5-12 membered heteroaryl groups;

[0024] R b1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R b2 、-OR b2 、-SR b2 、-S(O)R b2 、-SO2(R b2 ),-C(O)R b2 、-C(O)OR b2 、-OC(O)R b2 、-N(R b2 )(R b3 )、-C(O)N(R b2 )(R b3 )、-N(R b2 )C(O)(R b3 )、-S(O)N(R b2 )(R b3 )、-SO2N(R b2 )(R b3 )、-N(R b2 )S(O)(R b3 )、-N(R b2 )SO2(R b3 );

[0025] R b2 、R b3 Each occurrence is independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0026] R c Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R c1 replaced by;

[0027] or two R c Together with the atoms to which they are attached, they form deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 one or more optionally substituted 3-10 membered heterocyclic groups or 5-12 membered heteroaryl groups among aryl groups and 5-12 membered heteroaryl groups;

[0028] R c1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R c2 、-OR c2 、-SR c2 、-S(O)R c2 、-SO2(R c2 ),-C(O)R c2 、-C(O)OR c2 、-OC(O)R c2 、-N(R c2 )(R c3 )、-C(O)N(R c2 )(R c3 )、-N(R c2 )C(O)(R c3 )、-S(O)N(R c2 )(R c3 )、-SO2N(R c2 )(R c3 )、-N(R c2 )S(O)(R c3 )、-N(R c2 )SO2(R c3 );

[0029] R c2 、R c3 Each occurrence is independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0030] R d 、R e Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced by;

[0031] or R d and R e Together with the carbon atoms to which they are attached, they form deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 one or more optionally substituted 3-10 membered heterocyclic groups or 5-12 membered heteroaryl groups among aryl groups and 5-12 membered heteroaryl groups;

[0032] R d1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR d2 、-SR d2 、-S(O)R d2 、-SO2(R d2 ),-C(O)R d2 、-C(O)OR d2 、-OC(O)R d2 、-N(R d2 )(R d3 )、-C(O)N(R d2 )(R d3 )、-N(Rd2 )C(O)(R d3 )、-S(O)N(R d2 )(R d3 )、-SO2N(R d2 )(R d3 )、-N(R d2 )S(O)(R d3 )、-N(R d2 )SO2(R d3 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0033] R d2 、R d3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0034] R f Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR f4 、-SR f4 、-S(O)R f4 、-SO2(R f4 ),-C(O)R f4 、-C(O)OR f4 、-OC(O)R f4 、-N(R f4 )(R f5 )、-C(O)N(R f4 )(R f5 )、-N(R f4 )C(O)(R f5 )、-S(O)N(R f4 )(R f5 )、-SO2N(R f4 )(R f5 )、-N(R f4 )S(O)(R f5 )、-N(R f4 )SO2(R f5 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, optionally substituted with one or more R f1 replaced by;

[0035] or two R f Together with the atoms to which they are attached, they form deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14one or more optionally substituted 3-10 membered heterocyclic groups or 5-12 membered heteroaryl groups among aryl groups and 5-12 membered heteroaryl groups;

[0036] R f1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R f2 、-OR f2 、-SR f2 、-S(O)R f2 、-SO2(R f2 ),-C(O)R f2 、-C(O)OR f2 、-OC(O)R f2 、-N(R f2 )(R f3 )、-C(O)N(R f2 )(R f3 )、-N(R f2 )C(O)(R f3 )、-S(O)N(R f2 )(R f3 )、-SO2N(R f2 )(R f3 )、-N(R f2 )S(O)(R f3 )、-N(R f2 )SO2(R f3 );

[0037] R f2 、R f3 Each occurrence is independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; or when R f2 and R f3 When connected to the same nitrogen atom, R f2 and R f3 Together with the nitrogen atoms to which they are attached, they form deuterated, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 one or more optionally substituted 3-10 membered heterocyclic groups or 5-12 membered heteroaryl groups among aryl groups and 5-12 membered heteroaryl groups;

[0038] R f4 、R f5 Each occurrence is independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; or when R f4 and R f5 When connected to the same nitrogen atom, R f4 and R f5 Together with the nitrogen atoms to which they are attached, they form deuterated, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 one or more optionally substituted 3-10 membered heterocyclic groups or 5-12 membered heteroaryl groups among aryl groups and 5-12 membered heteroaryl groups;

[0039] R g Each occurrence is independently selected from -R g1 、-OR g1 、-SR g1 、-S(O)R g1 、-SO2(R g1 ),-C(O)R g1 、-C(O)OR g1 、-OC(O)R g1 、-N(R g1 )(R g2 )、-C(O)N(R g1 )(R g2 )、-C(O)N(R g1 )SO2N(Rg1 )(R g2 )、-C(O)N(R g1 )SO2R g2 、-P(O)(R g1 )R g2 、-N(R g1 )C(O)(R g2 )、-S(O)N(R g1 )(R g2 )、-SO2N(R g1 )(R g2 )、-N(R g1 )S(O)(R g2 )、-N(R g1 )SO2(R g2 );

[0040] R g1 、R g2 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl, one or more optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0041] L1 is independently selected from a bond, -C(R L1 )2-、-O-、-C(R L1 )2O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L1 )C(O)-、-C(O)N(R L1 )-or-N(R L1 )-;R L1 are independently selected from hydrogen, deuterium, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10One or more arbitrarily substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group;

[0042] L2 is independently selected from a bond, -C(R L2 )2-、-O-、-C(R L1 )2O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L2 )C(O)-、-C(O)N(R L2 )-or-N(R L2 )-;R L2 are independently selected from hydrogen, deuterium, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 One or more arbitrarily substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group;

[0043] L3 is independently selected from a bond, -C(R L3 )2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L3 )C(O)-、-C(O)N(R L3 )-or-N(R L3 )-;R L3 are independently selected from hydrogen, deuterium, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Alkenyl, C 3-6 Alkynyl, C 3-10 One or more arbitrarily substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Alkenyl, C 3-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group;

[0044] L4 is independently selected from a bond, -C(R L4 )2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L4 )C(O)-、-C(O)N(R L4 )-、-N(R L4 )-、-CH=CH-、-C(R L4 )=C-、-CH=C(R L4 )-;R L4 are independently selected from hydrogen, deuterium, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0045] m, n, o, and p are each independently 0, 1, 2, or 3;

[0046] Unless otherwise specified, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0047] In some embodiments, in Formula (I'):

[0048] Ring A is independently selected from phenyl, 5-6 membered heteroaryl;

[0049] Ring B is independently selected from 8-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl;

[0050] Ring C is independently selected from piperidinyl, piperazinyl, C 8-10 Bicyclic carbocyclic group, 8-10 membered bicyclic heterocyclic group, 8-10 membered bicyclic heteroaryl;

[0051] Independently selected from

[0052] R aEach occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group are optionally substituted by one or more R a3 replaced by;

[0053] R a1 、R a2 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0054] R a3 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R a4 ;

[0055] R a4 independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, amino, nitro, mercapto, and cyano;

[0056] R b Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6Alkoxy; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R b1 replaced by;

[0057] R b1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R b2 ;

[0058] R b2 are independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 One or more optionally substituted C 1-6 Alkyl, C 1-6 alkoxy;

[0059] R c Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R c1 replaced by;

[0060] or two R c Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group which is arbitrarily substituted by one or more of deuterium, halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, methoxy, and ethoxy;

[0061] R c1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or C substituted with one or more of halogen, hydroxy, amino, cyano 1-4 alkyl;

[0062] R d 、R e One of them is selected from hydrogen, deuterium, and the other is selected from optionally substituted C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced by;

[0063] R d1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R d2 )(R d3 )、-N(R d2)C(O)(R d3 ), C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 substituted by an alkoxy substituent;

[0064] R d2 、R d3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more radicals selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0065] R f Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR f4 、-C(O)N(R f4 )(R f5 )、-N(R f4 )C(O)(R f5 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R f1 replaced by;

[0066] R f1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -R f2 ;

[0067] R f2 are independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6One or more substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0068] R f4 、R f5 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0069] R g Each occurrence is independently selected from -C(O)OR g1 ; R g1 is hydrogen;

[0070] L1 is independently selected from a bond, -C(R L1 )2-、-O- or -C(R L1 )2O-;R L1 independently selected from hydrogen, deuterium, or C substituted by one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, and cyano 1-6 alkyl;

[0071] L2 is independently selected from a bond, -C(R L2 )2-、-O- or -C(R L1 )2O-;R L2 are independently selected from hydrogen, deuterium, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 One or more optionally substituted C 1-6 alkyl;

[0072] L3 is independently selected from a bond, -C(R L3 )2-, -O-, -S-, -C(O)-, -C(O)O- or -OC(O)-; R L3 are independently selected from hydrogen, deuterium, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 One or more optionally substituted C 1-6 alkyl;

[0073] L4 is a bond; m, n, o, and p are each independently 0, 1, 2, or 3;

[0074] Unless otherwise specified, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0075] In some embodiments, Ring A is independently selected from 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.

[0076] In some embodiments, ring A is independently selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, wherein the heteroatom in the heteroaryl is selected from N or S, and the number of heteroatoms is 1 or 2.

[0077] In some embodiments, Ring A is independently selected from phenyl, pyridinyl.

[0078] In some embodiments, Ring A is independently selected from phenyl.

[0079] In some embodiments, Independently selected from

[0080] In some embodiments, Independently selected from Preferred

[0081] In some embodiments, R a independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 ), C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic group are optionally substituted by one or more R a3 The heteroatom in the 3-6 membered heterocyclic group is O or N, and the number of heteroatoms is 1 or 2.

[0082] In some embodiments, R a independently selected from halogen, hydroxy, amino, cyano, -C(O)N(C 1-4 Alkyl)2, -C(O)NH(C 1-4 alkyl), -C(O)NH2, C 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered heterocyclic group are optionally substituted by one or more R a3 The heteroatom in the 3-6 membered heterocyclic group is O or N, and the number of heteroatoms is 1 or 2.

[0083] In some embodiments, R aindependently selected from halogen, hydroxy, amino, cyano, -C(O)NH2, -C(O)N(CH3)2, -C(O)NH(CH3), methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy; said methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy are optionally replaced by one or more R a3 replaced.

[0084] In some embodiments, R a independently selected from halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Alkoxy, 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 The alkoxy group and the 4-6 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen; the heteroatom in the 4-6 membered heterocyclic group is O, and the number of heteroatoms is 1.

[0085] In some embodiments, R a independently selected from halogen, cyano, -C(O)NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 3-6 membered heterocyclic group, wherein the heteroatom in the 3-6 membered heterocyclic group is O, and the number of heteroatoms is 1.

[0086] In some embodiments, R a independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, 3-6 membered heterocyclic group, wherein the heteroatom in the 3-6 membered heterocyclic group is O, and the number of heteroatoms is 1.

[0087] In some embodiments, R a independently selected from halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, oxetanyl.

[0088] In some embodiments, R a independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, oxetanyl.

[0089] In some embodiments, R a independently selected from halogen, cyano, C 1-2 Alkyl, C 1-2 Halogenated alkyl (preferably C 1-2 Fluorinated alkyl), C 1-2 Alkoxy, C 1-2 Halogenated alkoxy (preferably C 1-2 fluoroalkoxy), oxetane.

[0090] In some embodiments, R a independently selected from halogen, cyano, -C(O)NH2, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, oxetanyl.

[0091] In some embodiments, R a are independently selected from fluorine, chlorine, bromine, cyano, -C(O)NH2, -CF3, -OCHF2, -OCF3, methyl, ethyl, methoxy, ethoxy,

[0092] In some embodiments, R a independently selected from fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, -OCF3, methyl, methoxy and

[0093] In some embodiments, R a independently selected from fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, methyl, methoxy and

[0094] In some embodiments, R a are independently selected from fluorine, chlorine, cyano, -CF3, -OCHF2, -OCF3, methyl, methoxy,

[0095] In some embodiments, R a are independently selected from fluorine, chlorine, bromine, cyano, -C(O)NH2, -CF3, -OCHF2, methyl, ethyl, methoxy, ethoxy,

[0096] In some embodiments, R a Independently selected from halogen, cyano, -C(O)NH2.

[0097] In some embodiments, R a Independently selected from fluoro, chloro, and cyano.

[0098] In some embodiments, R a1 、Ra2 are independently selected from hydrogen, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, and amino.

[0099] In some embodiments, R a1 、R a2 are each independently selected from hydrogen.

[0100] In some embodiments, R a3 In some embodiments, R a3 In some embodiments, R a3 are independently selected from fluorine.

[0101] In some embodiments, R a4 、R a5 are independently selected from hydrogen, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more substituents selected from halogen.

[0102] In some embodiments, R a4 、R a5 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

[0103] In some embodiments, m is independently selected from 1, 2. In some embodiments, m is 2.

[0104] In some embodiments, Ring A is a benzene ring, m is 2, one R a Located in the para position of the junction between ring A and L1, another R a Located adjacent to the junction between ring A and L1.

[0105] In some embodiments, Independently selected from

[0106]

[0107] In some embodiments, Independently selected from

[0108]

[0109] In some embodiments, L1 is independently selected from a bond, -C(R L1 )2O-;R L1 It is selected from hydrogen, or methyl or ethyl optionally substituted by one or more of fluorine, chlorine, bromine, hydroxyl, amino and cyano.

[0110] In some embodiments, L1 is independently selected from a bond, -CH2O-.

[0111] In some embodiments, L1 is independently selected from a bond, -CH2O-; wherein the CH2 group is connected to the A end of the ring and the O group is connected to the B end of the ring.

[0112] In some embodiments, L1 is independently selected from a bond.

[0113] In some embodiments, L1 is independently selected from -CH2O-.

[0114] In some embodiments, L1 is independently selected from -CH2O-; wherein the CH2 group is connected to the A end of the ring and the O group is connected to the B end of the ring.

[0115] In some embodiments, L1 is independently selected from -CH2O-; wherein the CH2 group is connected to the B end of the ring and the O group is connected to the A end of the ring.

[0116] In some embodiments, Ring B is independently selected from 4-6 membered heterocycloalkyl, 8-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl.

[0117] In some embodiments, Ring B is independently selected from a 9-10 membered bicyclic heterocyclyl, a 5-6 membered monocyclic heteroaryl; the heteroatoms in the 9-10 membered bicyclic heterocyclyl, the 5-6 membered monocyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0118] In some embodiments, Ring B is independently selected from a 9-membered bicyclic heterocyclic group and a 5-6-membered monocyclic heteroaryl; the heteroatoms in the 9-membered bicyclic heterocyclic group and the 5-6-membered monocyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0119] In some embodiments, ring B is independently selected from 5-6 membered monocyclic heteroaryl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, and 6-membered / 6-membered heterocyclyl, and the heteroatoms in the 5-6 membered monocyclic heteroaryl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, and 6-membered / 6-membered heterocyclyl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0120] In some embodiments, ring B is independently selected from 5-6 membered monocyclic heteroaryl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, wherein the heteroatom in the 5-6 membered monocyclic heteroaryl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl is selected from N or O, and the number of heteroatoms is 1 or 2.

[0121] In some embodiments, Ring B is independently selected from phenyl, pyridyl, pyrimidinyl, and a 9-10 membered bicyclic heterocyclic group, wherein the heteroatom in the 9-10 membered bicyclic heterocyclic group is O and the number of heteroatoms is 2.

[0122] In some embodiments, Ring B is independently selected from phenyl, 6-membered heteroaryl, the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1 or 2.

[0123] In some embodiments, Ring B is independently selected from phenyl, pyridyl, pyrimidinyl, and a 9-membered bicyclic heterocyclic group, wherein the heteroatom in the 9-membered bicyclic heterocyclic group is O and the number of heteroatoms is 2.

[0124] In some embodiments, Ring B is independently selected from phenyl, pyridinyl, pyrimidinyl,

[0125] In some embodiments, Ring B is independently selected from phenyl, pyridinyl, pyrimidinyl,

[0126] In some embodiments, Ring B is independently selected from phenyl, pyridinyl, pyrimidinyl.

[0127] In some embodiments, Ring B is independently selected from pyridinyl, pyrimidinyl. In some embodiments, Ring B is selected from pyridinyl.

[0128] In some embodiments, Ring B is independently selected from the following groups:

[0129] The “*” end is connected to L1, and the “**” end is connected to L2.

[0130] In some embodiments, Ring B is independently selected from the following groups: The “*” end is connected to L1, and the “**” end is connected to L2.

[0131] In some embodiments, Ring B is independently selected from the following groups: The “*” end is connected to L1, and the “**” end is connected to L2.

[0132] In some embodiments, Ring B is independently selected from the following groups: The “*” end is connected to L1, and the “**” end is connected to L2.

[0133] In some embodiments, Ring B is independently selected from the following groups: The “*” end is connected to L1, and the “**” end is connected to L2.

[0134] In some embodiments, Ring B is independently selected from The “*” end is connected to L1, and the “**” end is connected to L2.

[0135] In some embodiments, R b are independently selected from halogen, hydroxy, amino, cyano, or optionally substituted C 1-4 Alkyl, C 1-4 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R b1 replaced.

[0136] In some embodiments, R b independently selected from halogen, C 1-3 Alkyl, C 1-3 more preferably halogen, C 1-3 alkyl.

[0137] In some embodiments, R b Independently selected from C 1-3 Alkyl; more preferably methyl.

[0138] In some embodiments, R b Independently selected from halogen, methyl; preferably halogen.

[0139] In some embodiments, R b Independently selected from fluorine, chlorine, bromine, methyl, -CF3.

[0140] In some embodiments, R b Independently selected from fluorine, chlorine, bromine, methyl; more preferably fluorine, chlorine, bromine; more preferably fluorine.

[0141] In some embodiments, R b1 are independently selected from halogen (eg, fluorine, chlorine, bromine).

[0142] In some embodiments, n is independently selected from 0, 1, 2; preferably 0, 1; more preferably 0.

[0143] In some embodiments, n is 1, R b Selected from halogen, C 1-3 Alkyl, C 1-3 haloalkyl; or, n is 1, R b Selected from halogen, C 1-3 Alkyl; or, n is 1, R b is selected from fluorine, chlorine, bromine, methyl, -CF3; or, n is 1, R b In some embodiments, n is 1, R b For fluorine.

[0144] In some embodiments, Selected from

[0145]

[0146] The “*” end is connected to L1, and the “**” end is connected to L2.

[0147] In some embodiments, Selected from

[0148] Or Or Or The “*” end is connected to L1, and the “**” end is connected to L2.

[0149] In some embodiments, L2 is a bond.

[0150] In some embodiments, Ring C is independently selected from C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl.

[0151] In some embodiments, Ring C is independently selected from C 8-10 In some embodiments, ring C is independently selected from C9 bicyclic carbocyclyl.

[0152] In some embodiments, ring C is independently selected from 5-10 membered heterocyclyl. In some embodiments, ring C is independently selected from 8-10 membered bicyclic heterocyclyl.

[0153] In some embodiments, ring C is independently selected from piperidinyl, piperazinyl, and 9-membered bicyclic heterocyclic group; the heteroatom in the 9-membered bicyclic heterocyclic group is O, and the number of heteroatoms is 1 or 2.

[0154] In some embodiments, ring C is independently selected from a 9-membered bicyclic heterocyclic group; the heteroatom in the 9-membered bicyclic heterocyclic group is selected from O, and the number of heteroatoms is 1 or 2.

[0155] In some embodiments, ring C is independently selected from 8-10 membered bicyclic heteroaryl. In some embodiments, ring C is independently selected from 9 membered bicyclic heteroaryl; wherein the heteroatom in the 9 membered bicyclic heteroaryl is N, and the number of heteroatoms is 1 or 2.

[0156] In some embodiments, Ring C is independently selected from C 8-10Bicyclic carbocyclyl, 5-6 membered heterocycloalkyl, 8-10 membered bicyclic heterocyclyl, 8-10 membered bicyclic heteroaryl. In some embodiments, Ring C is independently selected from piperidinyl, piperazinyl, C9 bicyclic carbocyclyl, 9 membered bicyclic heterocyclyl, 10 membered bicyclic heterocyclyl, 9 membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclyl, 9 membered bicyclic heterocyclyl, 10 membered bicyclic heterocyclyl, 9 membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0157] In some embodiments, Ring C is independently selected from piperidinyl, piperazinyl.

[0158] In some embodiments, ring C is independently selected from C9 bicyclic carbocyclyl, 9-membered bicyclic heterocyclyl, 10-membered bicyclic heterocyclyl, and 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclyl, 9-membered bicyclic heterocyclyl, 10-membered bicyclic heterocyclyl, and 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0159] In some embodiments, ring C is independently selected from a C9 bicyclic carbocyclyl, a 9-membered bicyclic heterocyclyl, or a 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclyl, the 9-membered bicyclic heterocyclyl, or the 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0160] In some embodiments, Ring C is independently selected from piperidinyl, piperazinyl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, 6-membered / 6-membered heterocyclyl, 5-membered / 6-membered carbocyclyl, 6-membered / 5-membered carbocyclyl, 6-membered / 6-membered carbocyclyl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, and 6-membered / 6-membered fused heteroaryl.

[0161] In some embodiments, Ring C is independently selected from 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, 6-membered / 6-membered heterocyclyl, 5-membered / 6-membered carbocyclyl, 6-membered / 5-membered carbocyclyl, 6-membered / 6-membered carbocyclyl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, and 6-membered / 6-membered fused heteroaryl.

[0162] In some embodiments, ring C is independently selected from piperidinyl, piperazinyl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, and 6-membered / 6-membered heterocyclyl; the heteroatoms in the 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, and 6-membered / 6-membered heterocyclyl are selected from O, and the number of heteroatoms is 1 or 2.

[0163] In some embodiments, ring C is independently selected from 5-membered / 6-membered heterocyclyl and 6-membered / 5-membered heterocyclyl; the heteroatom in the 5-membered / 6-membered heterocyclyl and 6-membered / 5-membered heterocyclyl is selected from O, and the number of heteroatoms is 1 or 2.

[0164] In some embodiments, Ring C is independently selected from:

[0165]

[0166] In some embodiments, Ring C is independently selected from:

[0167] In some embodiments, Ring C is independently selected from:

[0168] In some embodiments, Ring C is independently selected from the following groups:

[0169] The "+" end is connected to L2, and the "++" end is connected to L3.

[0170] In some embodiments, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3.

[0171] In some embodiments, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3.

[0172] In some embodiments, Ring C is independently selected from the following groups: The "+" end is connected to L2, and the "++" end is connected to L3.

[0173] In some embodiments, Ring C is independently selected from The "+" end is connected to L2, and the "++" end is connected to L3.

[0174] In some embodiments, Ring C is When R c is selected from hydroxy, oxo, halogen (preferably fluorine), and o is 1.

[0175] In some embodiments, Ring C is When R c Methyl, o is 0 or 1, wherein the "+" end is the end connected to L2, and the "++" end is the end connected to L3.

[0176] In some embodiments, ring C is piperidinyl or piperazinyl. In some embodiments, ring C is

[0177] In some embodiments, R c are independently selected from halogen, hydroxy, amino, cyano, oxo, or optionally substituted C 1-6Alkyl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R c1 Replaced by; R c1 Independently selected from halogen, hydroxy, amino, cyano.

[0178] In some embodiments, R c independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-4 alkyl.

[0179] In some embodiments, R c Independently selected from halogen, hydroxy, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

[0180] In some embodiments, R c Independently selected from halogen, hydroxy, oxo, C 1-3 alkyl.

[0181] In some embodiments, R c Independently selected from fluorine, chlorine, hydroxy, oxo, methyl, ethyl, -CF3.

[0182] In some embodiments, R c Independently selected from fluoro, chloro, hydroxy, oxo, methyl, ethyl.

[0183] In some embodiments, R c Independently selected from fluoro, chloro, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl.

[0184] In some embodiments, R c Independently selected from fluorine, chlorine, oxo, methyl, -OH, -CF3.

[0185] In some embodiments, R c Independently selected from fluoro, chloro, methyl.

[0186] In some embodiments, R c Independently selected from halogen; preferably fluorine, chlorine; more preferably fluorine.

[0187] In some embodiments, R c1 are independently selected from halogen (eg, fluorine, chlorine, bromine).

[0188] In some embodiments, o is independently selected from 0, 1, 2; preferably 0, 1; more preferably 0.

[0189] In some embodiments, Selected from

[0190] Or The "+" end is connected to L2, and the "++" end is connected to L3.

[0191] In some embodiments, Selected from

[0192] Or Or The "+" end is connected to L2, and the "++" end is connected to L3.

[0193] In some embodiments, L3 is independently selected from -C(R L3 )2-、-C(O)-;R L3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and n-butyl.

[0194] In some embodiments, L3 is independently selected from -CH2-, -C(O)-, -CH(CH3)-; preferably -CH2-, -CH(CH3)-; more preferably -CH2-.

[0195] In some embodiments, Ring D is independently selected from Preferred The “#” end is connected to L3, and the “##” end is connected to L4.

[0196] In some embodiments, Independently selected from Preferred The “#” end is the end connected to L3.

[0197] In some embodiments, Independently selected from

[0198] In some embodiments, Independently selected from

[0199]

[0200] In some embodiments, Independently selected from

[0201] In some embodiments, Independently selected from

[0202]

[0203]

[0204] or,

[0205] In some embodiments, R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced.

[0206] In some embodiments, R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, 5-6 membered heteroaryl, the heteroatom in the heterocyclic group is selected from O, the number of heteroatoms is 1, the heteroatom in the heteroaryl is selected from N, the number of heteroatoms is 1 or 2; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced.

[0207] In some embodiments, R d 、R e are independently selected from hydrogen, or optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced.

[0208] In some embodiments, R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced.

[0209] In some embodiments, R d 、R e are independently selected from hydrogen, or optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced.

[0210] In some embodiments, R d 、R e are independently selected from hydrogen, or optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced.

[0211] In some embodiments, R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 independently selected from -C(O)N(R d2 )(R d3 )、-N(R d2 )C(O)(R d3 ), or C substituted by one or more of fluorine, chlorine, hydroxyl, amino, and cyano 1-6 Alkyl; R d2 、R d3 Each occurrence is independently selected from hydrogen, C 1-3 alkyl.

[0212] In some embodiments, R e is hydrogen, R d Selected from optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 Independently selected from -N(C 1-2 alkyl)C(O)(C 1-2 alkyl), or C substituted by one or more of fluorine, chlorine, and cyano 1-3 alkyl.

[0213] In some embodiments, R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 independently selected from -C(O)N(R d2 )(R d3 )、-N(R d2 )C(O)(R d3 ), or methyl, ethyl, n-propyl, isopropyl, or n-butyl substituted by one or more of fluorine, chlorine, and cyano; R d2 、R d3 Each occurrence is independently selected from hydrogen, methyl, ethyl.

[0214] In some embodiments, Independently selected from

[0215] In some embodiments, Independently selected from

[0216] In some embodiments, Independently selected from

[0217] In some embodiments, Independently selected from In some embodiments, Independently selected from Preferred More preferred More preferred More preferred In some embodiments, for

[0218] In some embodiments, R d1 independently selected from C substituted by one or more of halogen, hydroxy, amino, and cyano 1-6 alkyl.

[0219] In some embodiments, R d1 independently selected from -C(O)N(R d2 )(R d3 )、-N(R d2 )C(O)(R d3 ), or C substituted by one or more of fluorine, chlorine, and cyano 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl).

[0220] In some embodiments, R d1 independently selected from C substituted by one or more of fluorine, chlorine, and cyano 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl).

[0221] In some embodiments, R d1 Independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, -CH2CN, -CH2CH2CN, -N(CH3)C(O)CH3, -NHC(O)CH3, -C(O)N(CH3)2, -C(O)NHCH3, -C(O)NH2.

[0222] In some embodiments, R d1Independently selected from fluorine, chlorine, bromine, hydroxy, amino, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, -CH2CN, -CH2CH2CN.

[0223] In some embodiments, R d1 Independently selected from monofluoromethyl, -CH2CN, -N(CH3)C(O)CH3.

[0224] In some embodiments, R d1 Independently selected from monofluoromethyl, -CH2CN, methyl, ethyl.

[0225] In some embodiments, R d1 Independently selected from monofluoromethyl, -CH2CN.

[0226] In some embodiments, R d1 Independently selected from -CH2F, -CH2CN, -N(CH3)C(O)CH3, -CH2CH3.

[0227] In some embodiments, R d2 、R d3 are independently selected from hydrogen and methyl.

[0228] In some embodiments, R f are independently selected from halogen, hydroxy, amino, cyano, -OR f4 、-C(O)N(R f4 )(R f5 )、-N(R f4 )C(O)(R f5 ), C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more R f1 replaced.

[0229] In some embodiments, R f are independently selected from halogen, hydroxy, amino, cyano, -OR f4 、-C(O)N(R f4 )(R f5 )、-N(R f4 )C(O)(R f5 ), C 1-4 Alkyl, C 1-4 Alkoxy; the C 1-4 Alkyl, C 1-4 The alkoxy group is optionally substituted with one or more R f1 replaced.

[0230] In some embodiments, R f are independently selected from halogen, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl.

[0231] In some embodiments, R f are independently selected from halogen, hydroxy, amino, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy, -C 1-2 Alkoxy-phenyl; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from fluorine and chlorine.

[0232] In some embodiments, R f independently selected from halogen, C 1-3 Alkoxy; the C 1-3 The alkoxy group is optionally substituted with one or more fluorine groups.

[0233] In some embodiments, R f independently selected from halogen, C 1-2 Alkoxy; the C 1-2 The alkoxy group is optionally substituted with one or more fluorine groups.

[0234] In some embodiments, R f Independently selected from fluorine, chlorine, hydroxyl, amino, -O-cyclopropane, -C(O)NHCH3, -NHC(O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF2.

[0235] In some embodiments, R f independently selected from chloro, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl.

[0236] In some embodiments, R f Independently selected from hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl.

[0237] In some embodiments, R f Independently selected from fluorine, hydroxy, amino, -O-cyclopropane, -NHC(O)CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF2.

[0238] In some embodiments, R f Independently selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more R f1 replaced.

[0239] In some embodiments, R f independently selected from halogen, hydroxy, amino, cyano, or C substituted by one or more of halogen, hydroxy, amino, cyano 1-4 alkyl.

[0240] In some embodiments, R f Independently selected from halogen; preferably fluorine, chlorine; preferably fluorine.

[0241] In some embodiments, R f are independently selected from halogen, hydroxy, amino, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OC 1-3Alkyl-phenyl.

[0242] In some embodiments, R f independently selected from fluorine, chlorine, bromine, hydroxyl, amino, -O(C 3-4 Cycloalkyl), -NHC(O)(C 1-3 Alkyl), C 1-4 Alkoxy, C 1-3 Haloalkoxy, -OC 1-3 Alkyl-phenyl.

[0243] In some embodiments, R f independently selected from halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy.

[0244] In some embodiments, R f independently selected from fluorine, chlorine, bromine, C 1-4 Alkoxy, C 1-3 Halogenated alkoxy.

[0245] In some embodiments, R f Independently selected from fluorine, chlorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CF3, -OCH2CHF2.

[0246] In some embodiments, R f Independently selected from fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CHF2.

[0247] In some embodiments, R f It is -OCH3.

[0248] In some embodiments, R f1 are independently selected from halogen, hydroxy, amino, cyano, -R f2 ; R f2 、R f3 are independently selected from hydrogen, or C substituted by one or more of halogen, hydroxyl, amino, and cyano 1-4 Alkyl, phenyl.

[0249] In some embodiments, R f1 In some embodiments, R f1 is halogen; preferably fluorine.

[0250] In some embodiments, R f4 、R f5 are independently selected from hydrogen, C 1-3 Alkyl, C 3-6Cycloalkyl.

[0251] In some embodiments, R f4 、R f5 Each is independently selected from hydrogen, methyl, and cyclopropane.

[0252] In some embodiments, p is independently selected from 0, 1, 2; preferably 0, 1; preferably 1.

[0253] In some embodiments, p is 1.

[0254] In some embodiments, L4 is independently selected from a bond, -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NH-, -CH=CH-.

[0255] In some embodiments, L4 is a bond.

[0256] In some embodiments, R g is -COOH.

[0257] In some embodiments, Independently selected from L4 is a bond; R g is -COOH; p is 0 or 1; R f Selected from halogen, hydroxy, amino, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 Alkoxy is optionally substituted by one or more substituents selected from fluorine, chlorine, phenyl; or R f R is independently selected from fluorine, hydroxyl, amino, -O-cyclopropane, -NHC(O)CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF2; or, f Selected from halogen, C 1-3 Alkoxy; the C 1-3 Alkoxy is optionally substituted with one or more fluorine; or, R f Independently selected from fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CHF2.

[0258] In some embodiments, m, n, and o are each independently 0, 1, or 2; and p is 1.

[0259] In some embodiments, m is 1 or 2, n, o, and p are all 0; in some embodiments, m is 1 or 2, n and o are all 0, and p is 1; in some embodiments, m is 2, n is 0 or 1, o is 1, and p is 1.

[0260] In some embodiments, Ring A is phenyl, m is 2, and both R a They are located at the ortho and para positions of the connection site between ring A and L1 respectively.

[0261] In some embodiments, Ring A is phenyl, m is 2, and both R a Located at the ortho and para positions of the connection site between ring A and L1, R a independently selected from halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, oxetanyl.

[0262] In some embodiments, Ring A is phenyl, m is 2, and both R a Located at the ortho and para positions of the connection site between ring A and L1, R a independently selected from fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, -OCF3, methyl, methoxy and

[0263] In some embodiments, Ring A is pyridyl, m is 1, and R a Located opposite to the junction between ring A and L1.

[0264] In some embodiments, Ring A is pyridyl, m is 1, and R a Located in the para position of the connection site between ring A and L1, R a independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 In some embodiments, Ring A is pyridyl, m is 1, and R a Located in the para position of the connection site between ring A and L1, R a Independently selected from chloro, cyano, -CF3, -OCH3.

[0265] In some embodiments, for L1 is the key; for The "*" end is connected to L1, and the "**" end is connected to L2; for Wherein the "+" end is connected to the end of L2, and the "++" end is connected to the end of L3; L3 is independently selected from -CH2-, -CH(CH3)-; for for R f For hydroxyl, amino, -O(C 3-4 Cycloalkyl), C 1-3 Alkoxy, -OCH2-phenyl; the C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from fluorine and chlorine; p is 1.

[0266] In some embodiments, Ring A is phenyl or pyridinyl; R a Halogen, cyano, C 1-2 Alkyl, C 1-3 Halogenated alkyl (preferably C 1-2 Fluorinated alkyl), C 1-3 Alkoxy, C 1-3 Halogenated alkoxy (preferably C 1-2 fluoroalkoxy), oxetane; for The "*" end is connected to L1, and the "**" end is connected to L2; for The "+" end is connected to L2, and the "++" end is connected to L3; L2 is a bond; L3 is -CH2-, -CH(CH3-); for for R f For hydroxyl, amino, -O(C 3-4 Cycloalkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkoxy, C 1-3 Haloalkoxy, -OC 1-2 Alkyl-phenyl; p is 1; when for When L1 is -CH2O-, the CH2 group is connected to the end of ring A, and the O group is connected to the end of ring B; when for When , L1 is the key.

[0267] In some embodiments, Ring A is phenyl; Ring B is phenyl, pyridinyl, or pyrimidinyl; Ring C is The "+" end is connected to L2, and the "++" end is connected to L3; R a is halogen (preferably fluorine, chlorine), cyano, C 1-2Alkyl, C 1-2 Halogenated alkyl (preferably C 1-2 Fluorinated alkyl), C 1-2 Alkoxy, C 1-2 Halogenated alkoxy (preferably C 1-2 Fluoroalkoxy), oxetane; R b is halogen (preferably fluorine); R c For fluorine; for for R f is hydrogen, halogen (preferably fluorine), C 1-3 Alkoxy (preferably -OCH3), C 1-3 Halogenated alkoxy (preferably -OCH2CHF2); m is 2, n is 0 or 1, o is 1, and p is 0 or 1; L1 is -CH2O-, wherein the CH2 group is connected to the A end of the ring and the O group is connected to the B end of the ring; L2 is a bond; L3 is -CH2-.

[0268] In some embodiments, for for The "*" end is connected to L1, and the "**" end is connected to L2; for The "+" end is connected to L2, and the "++" end is connected to L3; for for R f For -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CHF2(R f Preferably -OCH3); p is 1; L1 is -CH2O-, wherein the CH2 group is connected to the A end of the ring and the O group is connected to the B end of the ring; L2 is a bond; L3 is -CH2-.

[0269] In some embodiments, Ring A is independently selected from phenyl and pyridyl; Ring B is independently selected from 9-membered bicyclic heterocyclic group and 5-6-membered monocyclic heteroaryl; Ring C is independently selected from C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl, piperidinyl and piperazinyl;

[0270] Independently selected from X1 is CH or N;

[0271] R a independently selected from halogen, hydroxy, amino, cyano, -C(O)N(C 1-4 Alkyl)2, -C(O)NH(C1-4 alkyl), -C(O)NH2, C 1-4 Alkyl, C 1-4 Alkoxy, 4-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 The alkoxy group and the 4-6 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, and amino; the heteroatom in the 4-6 membered heterocyclic group is O, and the number of heteroatoms is 1;

[0272] R b Independently selected from C 1-4 alkyl;

[0273] R c independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 alkyl halide;

[0274] R f are independently selected from halogen, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl;

[0275] L1 is independently selected from a bond, -CH2O-; L2 is independently selected from a bond, -CH2-; L3 is independently selected from -CH2-, -C(O)-, -CH(C 1-4 alkyl)-; L4 is independently selected from a bond;

[0276] m, n, o, and p are each independently 0, 1, 2, or 3;

[0277] The compound is not:

[0278]

[0279] In some embodiments, Ring A is independently selected from phenyl, 5-6 membered heteroaryl;

[0280] Ring B is independently selected from a 9-membered bicyclic heterocyclic group and a 5-6-membered monocyclic heteroaryl group; the heteroatom in the 9-membered bicyclic heterocyclic group and the 5-6-membered monocyclic heteroaryl group is selected from N or O, and the number of heteroatoms is 1 or 2;

[0281] Ring C is independently selected from a C9 bicyclic carbocyclic group, a 9-membered bicyclic heterocyclic group, or a 9-membered bicyclic heteroaryl group; the heteroatoms in the C9 bicyclic carbocyclic group, the 9-membered bicyclic heterocyclic group, or the 9-membered bicyclic heteroaryl group are selected from N or O, and the number of heteroatoms is 1 or 2;

[0282] Ring D is independently selected from The "#" end is connected to L3, and the "##" end is connected to L4;

[0283] R a Independently selected from fluorine, chlorine, cyano, -C(O)NH2, -C(O)N(CH3)2, -C(O)NH(CH3), methyl, ethyl, methoxy, ethoxy;

[0284] R b independently selected from methyl;

[0285] R c independently selected from fluoro, chloro, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0286] R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 independently selected from C substituted by one or more of fluorine, chlorine, hydroxyl, amino, and cyano 1-4 alkyl;

[0287] R f are independently selected from fluorine, chlorine; R g independently selected from -COOH;

[0288] L1 is independently selected from a bond, -CH2O-; L2 is independently selected from a bond; L3 is independently selected from -CH2-, -C(O)-, -CH(CH3)-; L4 is independently selected from a bond;

[0289] m, n, o, and p are each independently 0, 1, or 2.

[0290] In some embodiments, Ring A is independently selected from phenyl and pyridyl; Ring B is independently selected from pyridyl; Ring C is independently selected from C9 bicyclic carbocyclyl, 9-membered bicyclic heterocyclyl, 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclyl, 9-membered bicyclic heterocyclyl, and 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2;

[0291] Ring D is independently selected from The "#" end is connected to L3, and the "##" end is connected to L4;

[0292] R a Independently selected from fluorine, chlorine, cyano, -C(O)NH2, -C(O)N(CH3)2, -C(O)NH(CH3), methyl, ethyl, methoxy, ethoxy;

[0293] R b independently selected from methyl;

[0294] R c independently selected from fluoro, chloro, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0295] R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 independently selected from C substituted by one or more of fluorine, chlorine, hydroxyl, amino, and cyano 1-4 alkyl;

[0296] R f are independently selected from fluorine, chlorine; R g independently selected from -COOH;

[0297] L1 is independently selected from a bond, -CH2O-; L2 is independently selected from a bond; L3 is independently selected from -CH2-, -C(O)-, -CH(CH3)-; L4 is independently selected from a bond;

[0298] m, n, o, and p are each independently 0, 1, or 2.

[0299] In some embodiments, ring A is independently selected from phenyl, 5-6 membered heteroaryl; ring B is independently selected from 9 membered bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl; ring C is independently selected from 9 membered bicyclic heterocyclyl;

[0300] Ring D is independently selected from The "#" end is connected to L3, and the "##" end is connected to L4;

[0301] R a independently selected from halogen, hydroxy, amino, cyano, -C(O)N(C 1-4 Alkyl)2, -C(O)NH(C 1-4 alkyl), -C(O)NH2, C 1-4 Alkyl, C 1-4Alkoxy; the C 1-4 Alkyl, C 1-4 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, and amino;

[0302] R b Independently selected from C 1-6 alkyl;

[0303] R c independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 alkyl halide;

[0304] R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 independently selected from C substituted by one or more of halogen, hydroxy, amino, and cyano 1-6 alkyl;

[0305] R f are independently selected from halogen; R g Selected from -COOH;

[0306] L1 is independently selected from a bond, -CH2O-; L2 is independently selected from a bond, -CH2-; L3 is independently selected from -CH2-, -C(O)-, -CH(C 1-4 alkyl)-; L4 is independently selected from a bond;

[0307] m, n, o, and p are each independently 0, 1, or 2.

[0308] In some embodiments, Ring A is independently selected from phenyl, 5-6 membered heteroaryl; Ring B is independently selected from 9 membered bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl; Ring C is independently selected from C9 bicyclic carbocyclyl, 9 membered bicyclic heterocyclyl, 10 membered bicyclic heterocyclyl, 9 membered bicyclic heteroaryl, piperidinyl, piperazinyl;

[0309] Independently selected from X1 is CH or N;

[0310] R a independently selected from halogen, hydroxy, amino, cyano, -C(O)N(C 1-4 Alkyl)2, -C(O)NH(C 1-4 alkyl), -C(O)NH2, C 1-4 Alkyl, C1-4 Alkoxy, 4-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 The alkoxy group and the 4-6 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, and amino; the heteroatom in the 4-6 membered heterocyclic group is O, and the number of heteroatoms is 1;

[0311] R b Independently selected from C 1-4 alkyl;

[0312] R c independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 alkyl halide;

[0313] R f independently selected from fluorine, chlorine, bromine, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl;

[0314] L1 is independently selected from a bond, -CH2O-; L2 is independently selected from a bond, -CH2-; L3 is independently selected from -CH2-, -C(O)-, -CH(C 1-4 alkyl)-; L4 is independently selected from a bond;

[0315] m, n, and o are each independently 0, 1, or 2; p is 1;

[0316] The compound is not:

[0317] In some embodiments, ring A is independently selected from phenyl, 5-6 membered heteroaryl; ring B is independently selected from 9 membered bicyclic heterocyclyl, 5-6 membered monocyclic heteroaryl; ring C is independently selected from piperidinyl, piperazinyl;

[0318] Independently selected from X1 is CH or N;

[0319] R a independently selected from halogen, hydroxy, amino, cyano, -C(O)N(C 1-3 Alkyl)2, -C(O)NH(C 1-3 alkyl), -C(O)NH2, C1-3 Alkyl, C 1-3 Alkoxy, 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 The alkoxy group and the 4-6 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, and amino; the heteroatom in the 4-6 membered heterocyclic group is O, and the number of heteroatoms is 1;

[0320] R b Independently selected from C 1-3 alkyl;

[0321] R c independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-4 Alkyl, C 1-3 alkyl halide;

[0322] R f independently selected from fluorine, chlorine, bromine, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl;

[0323] L1 is independently selected from a bond, -CH2O-; L2 is independently selected from a bond, -CH2-; L3 is independently selected from -CH2-, -C(O)-, -CH(C 1-3 alkyl)-; L4 is independently selected from a bond;

[0324] m, n, and o are each independently 0, 1, or 2; p is 1;

[0325] The compound is not:

[0326] On the other hand, the present application provides a compound represented by formula (II) or formula (III), or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof:

[0327]

[0328] Among them, ring A, ring B, ring C, L1, L3, R a 、R b 、R c 、R d 、R e 、R f, m, n, o, and p are defined as those for the compound represented by formula (I') of the present application.

[0329] In some embodiments, Ring A is independently selected from phenyl, pyridinyl;

[0330] Ring B is independently selected from a 9-membered bicyclic heterocyclic group, a 10-membered bicyclic heterocyclic group, and a pyridyl group; the heteroatom of the 9-membered bicyclic heterocyclic group and the 10-membered bicyclic heterocyclic group is O, and the number of heteroatoms is 1 or 2;

[0331] Ring C is independently selected from piperidinyl and piperazinyl.

[0332] In some embodiments, Ring A is independently selected from phenyl, pyridinyl;

[0333] Ring B is independently selected from a 9-membered bicyclic heterocyclic group, a pyridyl group, a phenyl group, and a pyrimidinyl group; the heteroatom of the 9-membered bicyclic heterocyclic group is O, and the number of heteroatoms is 1 or 2;

[0334] Ring C is independently selected from a C9 bicyclic carbocyclic group, a 9-membered bicyclic heterocyclic group, a 10-membered bicyclic heterocyclic group, and a 9-membered bicyclic heteroaryl group; the heteroatoms in the C9 bicyclic carbocyclic group, the 9-membered bicyclic heterocyclic group, the 10-membered bicyclic heterocyclic group, and the 9-membered bicyclic heteroaryl group are selected from N or O, and the number of heteroatoms is 1 or 2.

[0335] In some embodiments, Ring A is independently selected from phenyl, pyridinyl;

[0336] Ring B is independently selected from a 9-membered bicyclic heterocyclic group, a 10-membered bicyclic heterocyclic group, and a pyridyl group; the heteroatom of the 9-membered bicyclic heterocyclic group and the 10-membered bicyclic heterocyclic group is O, and the number of heteroatoms is 1 or 2;

[0337] Ring C is independently selected from a C9 bicyclic carbocyclic group, a 9-membered bicyclic heterocyclic group, a 10-membered bicyclic heterocyclic group, and a 9-membered bicyclic heteroaryl group; the heteroatoms in the C9 bicyclic carbocyclic group, the 9-membered bicyclic heterocyclic group, the 10-membered bicyclic heterocyclic group, and the 9-membered bicyclic heteroaryl group are selected from N or O, and the number of heteroatoms is 1 or 2.

[0338] In some embodiments, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3.

[0339] In some embodiments, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3.

[0340] In some embodiments, Ring A is independently selected from phenyl, pyridinyl; Ring B is independently selected from The “*” end is connected to L1, and the “**” end is connected to L2.

[0341] In some embodiments, Ring A is independently selected from phenyl, pyridinyl;

[0342] Ring B is independently selected from The “*” end is connected to L1, and the “**” end is connected to L2.

[0343] In some embodiments, Ring A is independently selected from phenyl.

[0344] In another aspect, the present application provides a compound represented by formula (II-1) or formula (III-1), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof:

[0345]

[0346] Among them, ring B, ring C, L1, L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined as those for the compounds represented by formula (I'), formula (II) or formula (III) of the present application.

[0347] In another aspect, the present application provides a compound represented by formula (II-2), formula (II-3), formula (III-2) or formula (III-3), or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof:

[0348]

[0349] Among them, ring C, L1, L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1) or formula (III-1) of the present application.

[0350] In some embodiments, Ring C is independently selected from piperidinyl, piperazinyl.

[0351] In some embodiments, ring C is independently selected from C9 bicyclic carbocyclyl, 9-membered bicyclic heterocyclyl, 10-membered bicyclic heterocyclyl, and 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclyl, 9-membered bicyclic heterocyclyl, 10-membered bicyclic heterocyclyl, and 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0352] In some embodiments, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3.

[0353] In some embodiments, Ring C is independently selected from: Or The "+" end is connected to L2, and the "++" end is connected to L3.

[0354] In some embodiments, Selected from Or The "+" end is connected to L2, and the "++" end is connected to L3.

[0355] In another aspect, the present application provides a compound represented by formula (IV), or its tautomers, stereoisomers or pharmaceutically acceptable salts:

[0356]

[0357] Wherein, X1 is CH or N;

[0358] Ring A, Ring B, Ring C, L1, L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2) or formula (III-3) in this application.

[0359] In some embodiments, Ring A is independently selected from phenyl, pyridinyl;

[0360] Ring B is independently selected from The “*” end is connected to L1, and the “**” end is connected to L2.

[0361] In some embodiments, R f independently selected from chloro, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl.

[0362] In some embodiments, Ring A is phenyl or pyridinyl.

[0363] In some embodiments, Ring B is independently selected from a 9-membered bicyclic heterocyclic group, a pyridyl group, a phenyl group, or a pyrimidinyl group; the heteroatom of the 9-membered bicyclic heterocyclic group is O, and the number of heteroatoms is 2. In some embodiments, Ring C is independently selected from a C9 bicyclic carbocyclic group, a 9-membered bicyclic heterocyclic group, a 10-membered bicyclic heterocyclic group, or a 9-membered bicyclic heteroaryl group; the heteroatom of the 9-membered bicyclic heterocyclic group, the 10-membered bicyclic heterocyclic group, or the 9-membered bicyclic heteroaryl group is selected from N or O, and the number of heteroatoms is 1 or 2.

[0364] In some embodiments, Ring C is independently selected from piperidinyl, piperazinyl.

[0365] In some embodiments, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3.

[0366] In some embodiments, Ring C is independently selected from: Or The "+" end is connected to L2, and the "++" end is connected to L3.

[0367] In some embodiments, R f Independently selected from hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl.

[0368] In some embodiments, R fIndependently selected from hydroxy, amino, -O-cyclopropane, -C(O)NHCH3, -NHC(O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF2.

[0369] In some embodiments, R f independently selected from halogen, hydroxy, amino, cyano, or C substituted by one or more of halogen, hydroxy, amino, cyano 1-3 alkyl.

[0370] In some embodiments, R f are independently selected from halogen (more preferably fluorine, chlorine).

[0371] In some embodiments, R f are independently selected from halogen, hydroxy, amino, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OC 1-3 Alkyl-phenyl.

[0372] In some embodiments, R f independently selected from fluorine, chlorine, bromine, hydroxyl, amino, -O(C 3-4 Cycloalkyl), -NHC(O)(C 1-3 Alkyl), C 1-4 Alkoxy, C 1-3 Haloalkoxy, -OC 1-3 Alkyl-phenyl.

[0373] In some embodiments, R f Independently selected from fluorine, chlorine, hydroxyl, amino, -O-cyclopropane, -C(O)NHCH3, -NHC(O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF2.

[0374] In some embodiments, R f independently selected from halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy.

[0375] In some embodiments, R findependently selected from fluorine, chlorine, bromine, C 1-4 Alkoxy, C 1-3 Halogenated alkoxy.

[0376] In some embodiments, R f Independently selected from fluorine, chlorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CF3, -OCH2CHF2.

[0377] In some embodiments, p is 0. In some embodiments, p is 1.

[0378] In some embodiments, X1 is CH. In some embodiments, p is 0 or 1, and ring C is independently selected from The "+" end is connected to L2, and the "++" end is connected to L3.

[0379] In some embodiments, p is 1, and ring C is independently selected from a C9 bicyclic carbocyclic group, a 9-membered bicyclic heterocyclic group, a 10-membered bicyclic heterocyclic group, and a 9-membered bicyclic heteroaryl group; the heteroatoms in the 9-membered bicyclic heterocyclic group, the 10-membered bicyclic heterocyclic group, and the 9-membered bicyclic heteroaryl group are selected from N or O, and the number of heteroatoms is 1 or 2.

[0380] In some embodiments, p is 1, Ring C is piperidine or piperazine, and the compound is not

[0381] In some embodiments, p is 1, for Ring C is selected from piperidinyl, piperazinyl, C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2; or Ring C is selected from piperidinyl, piperazinyl, The "+" end is connected to L2, and the "++" end is connected to L3.

[0382] In some embodiments, p is 0, for Ring C is selected from C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2; or Ring C is selected from The "+" end is connected to L2, and the "++" end is connected to L3.

[0383] In another aspect, the present application provides a compound represented by formula (IV-1), or its tautomers, stereoisomers or pharmaceutically acceptable salts:

[0384]

[0385] Wherein, X1 is CH or N; X2 is CH or N;

[0386] Ring B, Ring C, L1, L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3) or formula (IV) in this application.

[0387] In some embodiments, X1 is CH. In some embodiments, X2 is CH.

[0388] In some embodiments, p is 0. In some embodiments, p is 1.

[0389] In another aspect, the present application provides a compound represented by formula (IV-2), (IV-2-1), (IV-2-2), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof:

[0390]

[0391] wherein X1 is CH or N; X2 is CH or N; X3 is CH or N; X4 is N;

[0392] Ring B, L1, L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3), formula (IV) or formula (IV-1) in this application.

[0393] In another aspect, the present application provides a compound represented by formula (IV-3), or its tautomers, stereoisomers or pharmaceutically acceptable salts:

[0394]

[0395] Wherein, X1 is CH or N; X2 is CH or N;

[0396] Ring B, L1, L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3), formula (IV), formula (IV-1) or formula (IV-2) in this application.

[0397] In another aspect, the present application provides a compound represented by formula (IV-4), formula (IV-5), or formula (IV-6), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof:

[0398]

[0399] Wherein, X1 is CH or N; X2 is CH or N;

[0400] Ring C, L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3), formula (IV), formula (IV-1), formula (IV-2) or formula (IV-3) in this application.

[0401] In some embodiments, p is 0. In some embodiments, p is 1.

[0402] In some embodiments of formula (IV-4), p is 0, and ring C is selected from C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2; or ring C is selected from The "+" end is connected to L2, and the "++" end is connected to L3.

[0403] In some embodiments of formula (IV-4), p is 1, and ring C is selected from a C9 bicyclic carbocyclic group, a 9-membered bicyclic heterocyclic group, a 10-membered bicyclic heterocyclic group, and a 9-membered bicyclic heteroaryl group; the heteroatoms in the C9 bicyclic carbocyclic group, the 9-membered bicyclic heterocyclic group, the 10-membered bicyclic heterocyclic group, and the 9-membered bicyclic heteroaryl group are selected from N or O, and the number of heteroatoms is 1 or 2.

[0404] In some embodiments, X1 is CH.

[0405] In some embodiments, X2 is CH.

[0406] In some embodiments, X2 is CH, and m is 2. In some embodiments, X2 is N, and m is 1.

[0407] In some embodiments, n is 0. In some embodiments, n is 1.

[0408] In some embodiments, o is 0. In some embodiments, o is 1.

[0409] In another aspect, the present application provides a compound represented by Formula (IV-7), Formula (IV-8), Formula (IV-9), Formula (IV-10), Formula (IV-11), Formula (IV-12), Formula (IV-13), Formula (IV-14), Formula (IV-15), Formula (IV-16), or Formula (IV-17), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof:

[0410]

[0411]

[0412] wherein X1 is CH or N; X2 is CH or N; X3 is CH or N; X4 is N;

[0413] L3, R a 、R b 、R c 、R d 、R e 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (II-2), formula (II-3), formula (III-1), formula (III-2), formula (III-3), formula (IV), formula (IV-1), formula (IV-2), formula (IV-3), formula (IV-4), formula (IV-5) or formula (IV-6) in this application.

[0414] In some embodiments, X1 and X2 are both CN.

[0415] In some embodiments, X3 is CH, X4 is N, and o is 0; or, X3 and X4 are both N, R c is methyl, and o is 0. In some embodiments, R a independently selected from halogen, hydroxy, amino, cyano, -C(O)N(C 1-3 Alkyl)2, -C(O)NH(C 1-3 alkyl), -C(O)NH2, C 1-3 Alkyl, C 1-3 Alkoxy, 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 The alkoxy group and the 4-6 membered heterocyclic group are optionally substituted by one or more substituents selected from halogen, hydroxyl, and amino; the heteroatom in the 4-6 membered heterocyclic group is O, and the number of heteroatoms is 1;

[0416] R b independently selected from methyl;

[0417] R c independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-3 Alkyl, C 1-3 alkyl halide;

[0418] R d 、R e One of them is selected from hydrogen, and the other is selected from optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 independently selected from -C(O)N(R d2 )(R d3 )、-N(R d2 )C(O)(R d3 ), or methyl, ethyl, n-propyl, isopropyl, or n-butyl substituted by one or more of fluorine, chlorine, and cyano; R d2 、R d3 Each occurrence is independently selected from hydrogen, methyl, ethyl;

[0419] R f independently selected from fluorine, chlorine, bromine, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl;

[0420] L1 is independently selected from a bond, -CH2O-; L3 is independently selected from -CH2-, -C(O)-, -CH(C 1-3 alkyl)-.

[0421] In some embodiments, R a are independently selected from fluorine, chlorine, bromine, cyano, -C(O)NH2, -CF3, -OCHF2, methyl, ethyl, methoxy, ethoxy,

[0422] R b independently selected from methyl;

[0423] R c independently selected from fluoro, chloro, oxo, methyl, ethyl;

[0424] Independently selected from

[0425] R f Independently selected from fluorine, chlorine, hydroxyl, amino, -O-cyclopropane, -C(O)NHCH3, -NHC(O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF2;

[0426] L1 is independently selected from a bond, -CH2O-; L3 is independently selected from -CH2-, -C(O)-, -CH(CH3)-.

[0427] In some embodiments, R f independently selected from halogen, hydroxy, amino, cyano, or C substituted by one or more of halogen, hydroxy, amino, cyano 1-3 alkyl.

[0428] In some embodiments, R f are independently selected from halogen (more preferably fluorine, chlorine).

[0429] In some embodiments, p in Formula (IV-7) and Formula (IV-8) is 0. In some embodiments, p in Formula (IV-7) and Formula (IV-8) is 1, R f are independently selected from halogen, hydroxy, amino, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from fluorine, chlorine, and phenyl; or, R f Independently selected from fluorine, hydroxy, amino, -O-cyclopropane, -NHC(O)CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF.

[0430] In another aspect, the present application provides a compound represented by formula (V), or its tautomers, stereoisomers or pharmaceutically acceptable salts:

[0431]

[0432] Wherein, X1 is CH or N; Ring B, Ring C, L1, L3, R a 、R b 、R c 、R d 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), and formula (IV-1) in this application.

[0433] In another aspect, the present application provides a compound represented by formula (V-1), or its tautomers, stereoisomers or pharmaceutically acceptable salts:

[0434]

[0435] Wherein, X1 is CH or N; Ring A, Ring B, L1, L3, R a 、R b 、R c 、R d 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), and formula (IV-1) in this application.

[0436] In some embodiments, ring A is independently selected from phenyl, 5-6 membered heteroaryl, the heteroatom in the heteroaryl is selected from N, and the number of heteroatoms is 1 or 2.

[0437] In some embodiments, Ring A is independently selected from phenyl, pyridyl, preferably phenyl.

[0438] In some embodiments, Ring B is independently selected from phenyl, 6-membered heteroaryl, the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1 or 2.

[0439] In some embodiments, Ring B is independently selected from phenyl, pyridinyl, pyrimidinyl; preferably pyridinyl, pyrimidinyl.

[0440] In some embodiments, Ring B is independently selected from the following groups: Preferred The “*” end is connected to L1, and the “**” end is connected to L2.

[0441] In some embodiments, R a independently selected from halogen, cyano, -C(O)NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 3-6 membered heterocyclic group, wherein the heteroatom in the 3-6 membered heterocyclic group is O, and the number of heteroatoms is 1.

[0442] In some embodiments, R a independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, oxetanyl.

[0443] In some embodiments, R a are independently selected from fluorine, chlorine, cyano, -CF3, -OCHF2, -OCF3, methyl, methoxy,

[0444] In some embodiments, R b Independently selected from halogen; preferably fluorine, chlorine, bromine; preferably fluorine.

[0445] In some embodiments, R c Independently selected from halogen; preferably fluorine, chlorine, bromine; preferably fluorine.

[0446] In some embodiments, R d Selected from optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 Replaced by; R d1 independently selected from C substituted by one or more of fluorine, chlorine, and cyano 1-3 alkyl.

[0447] In some embodiments, Independently selected from Preferred More preferred

[0448] In some embodiments, R f independently selected from halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy.

[0449] In some embodiments, R f independently selected from fluorine, chlorine, bromine, C 1-4 Alkoxy, C 1-3 Halogenated alkoxy.

[0450] In some embodiments, R f Independently selected from fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CHF2.

[0451] In some embodiments, L1 is independently selected from a bond, -CH2O-; preferably -CH2O-; more preferably -CH2O-, wherein the CH2 group is connected to the A end of the ring and the O group is connected to the B end of the ring.

[0452] In some embodiments, L3 is independently selected from -CH2-, -C(O)-, -CH(CH3)-; preferably -CH2-, -CH(CH3)-; more preferably -CH2-.

[0453] In some embodiments, m is 2.

[0454] In some embodiments, n is independently selected from 0, 1; preferably 0.

[0455] In some embodiments, o is independently selected from 0, 1; preferably 0.

[0456] In some embodiments, p is independently selected from 0, 1; preferably 1.

[0457] In some embodiments, X1 is CH.

[0458] In another aspect, the present application provides a compound represented by formula (V-2), or its tautomers, stereoisomers or pharmaceutically acceptable salts:

[0459]

[0460] Wherein, X1 is CH or N; Ring B, L1, L3, R a 、R b 、R c 、R d 、R f, m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), and formula (V-1) in this application.

[0461] In another aspect, the present application provides a compound represented by formula (V-3), or its tautomers, stereoisomers or pharmaceutically acceptable salts:

[0462]

[0463] Among them, ring B, L1, L3, R a 、R b 、R c 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), and formula (V-1) in this application.

[0464] In another aspect, the present application provides a compound represented by formula (V-4), formula (V-5), formula (V-6), formula (V-7), or formula (V-8), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof:

[0465]

[0466]

[0467] Wherein, X1 is CH or N; Ring C, R a 、R b 、R c 、R d 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), and formula (V-1) in this application.

[0468] In another aspect, the present application provides a compound represented by Formula (V-9), Formula (V-10), Formula (V-11), Formula (V-12), Formula (V-13), Formula (V-14), Formula (V-15), Formula (V-16), or Formula (V-17), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof:

[0469]

[0470] Wherein, X1 is CH or N; R a 、R b 、Rc 、R d 、R f , m, n, o, and p are defined the same as those for the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), and formula (V-1) in this application.

[0471] In some embodiments, m is 2, and both R a Located at the ortho and para positions of the connection site between ring A and L1, R a independently selected from halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, oxetane; or R a independently selected from fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, -OCF3, methyl, methoxy and

[0472] In some embodiments, n is 0. In some embodiments, n is 1, R b independently selected from halogen, C 1-3 Alkyl, C 1-3 haloalkyl; or, R b Independently selected from fluorine, chlorine, bromine, -CF3.

[0473] In some embodiments, n is 0. In some embodiments, n is 1, R b are independently selected from halogen; or, R b are independently selected from fluorine, chlorine, bromine; or, R b For fluorine.

[0474] In some embodiments, o is 0. In some embodiments, o is 1, R c independently selected from halogen, or independently selected from fluorine or chlorine.

[0475] In some embodiments, L3 is independently selected from -CH2-, -C(O)-, -CH(CH3)-; or L3 is -CH2-.

[0476] In some embodiments, Independently selected from

[0477] In some embodiments, Independently In some embodiments, Independently

[0478] In some embodiments, X1 is CH. In some embodiments, X1 is N.

[0479] In some embodiments, p is 0.

[0480] In some embodiments, p is 1, R f are independently selected from halogen, hydroxy, amino, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl), -NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3 Alkoxy is optionally substituted with one or more substituents selected from fluorine; or, R f independently selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from fluorine and chlorine; or, R f Independently selected from fluorine, hydroxy, amino, -O-cyclopropane, -NHC(O)CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, -OCH2CHF2.

[0481] In some embodiments, p is 1, R f independently selected from halogen, C 1-3 Alkoxy, the C 1-3 Alkoxy is optionally substituted with one or more substituents selected from fluorine; or, R f Independently selected from C 1-3 Alkoxy; or, R f Independently selected from fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CHF2.

[0482] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present application.

[0483] Preferably, the compound provided herein or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494] The present application also aims to provide a method for preparing the compound represented by formula (I') or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof.

[0495] The method can be prepared, for example, using the method shown in the following scheme.

[0496]

[0497] The carboxyl group of intermediate 1.1 reacts with the two amino groups of compound 1.2 to produce intermediate 1.3. There are two methods to convert intermediate 1.3 into the target product.

[0498] Method 1: The halogen of intermediate 1.1 is converted to boronic acid or boronic ester, which then undergoes Suzuki coupling reaction with compound 1.5 to produce intermediate 1.6, which is then subjected to esterification to obtain the target compound.

[0499] Method 2: The halogen of compound 1.5 is converted to a substituted tin fragment 1.7, which then undergoes a Stille coupling reaction with intermediate 1.3 to give intermediate 1.6, which is finally converted to the target compound.

[0500] Method 3: Intermediate 1.8 reacts with intermediate 1.9 to form intermediate 1.10, and then the ester group is hydrolyzed under alkaline conditions to obtain the target compound 1.11.

[0501]

[0502] Note: The partial protection and deprotection reaction steps involved in this step have been omitted.

[0503] Among them, ring F is a monocyclic aromatic group or a monocyclic heteroaromatic group, preferably a phenyl group or a 5-6 membered heteroaromatic group, more preferably a phenyl group or a pyridyl group; ring A, ring B, ring C, ring D, L1, L2, L3, L4, Ra 、R b 、R c 、R d 、R e 、R f 、R g , m, n, o, p, etc. are as defined in the compounds of the present application.

[0504] On the other hand, the present application also provides a pharmaceutical composition comprising the compound described in the present application or its tautomer, stereoisomer or pharmaceutically acceptable salt.

[0505] Furthermore, the pharmaceutical composition described in the present application comprises the compound described in the present application or its tautomer, stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.

[0506] The administration of the present invention compound or its tautomer, stereoisomer or pharmaceutically acceptable salt can be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration of a drug of similar use. The pharmaceutical composition of the present application can be prepared by combining the present invention compound with a suitable pharmaceutically acceptable excipient. The pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations. Generally, the above-mentioned pharmaceutical composition can be prepared by conventional preparation methods using conventional excipients in the field of pharmaceutical preparations.

[0507] On the other hand, the present application also provides the use of the compound described in the present application or its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application in the preparation of a drug for preventing and / or treating diseases, disorders and conditions by stimulating the cascade signal mediated by GLP-1R.

[0508] Furthermore, the use provided in the present application, wherein the diseases, disorders and conditions are GLP-1R related, including diabetes, obesity, overweight, metabolic-related fatty liver disease, Alzheimer's disease, etc.

[0509] On the other hand, the present application also provides the use of the compound described in the present application or its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application in the preparation of drugs for diabetes, weight loss, metabolic-related fatty liver disease, Alzheimer's disease, etc.

[0510] On the other hand, the present application provides a method for preventing and / or treating diseases, disorders and conditions by stimulating the GLP-1R-mediated cascade signal, which comprises administering the compound described herein or its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application to an individual in need; the diseases, disorders and conditions are GLP-1R-related, including diabetes, obesity, overweight, metabolic-related fatty liver disease, Alzheimer's disease, etc.

[0511] In another aspect, the present application provides the compounds described herein or their tautomers, stereoisomers or pharmaceutically acceptable salts or the pharmaceutical compositions of the present application for preventing and / or treating diseases, disorders and conditions by stimulating the cascade signal mediated by GLP-1R; the diseases, disorders and conditions are GLP-1R-related, including diabetes, obesity, overweight, metabolic-related fatty liver disease, Alzheimer's disease, etc.

[0512] In another aspect, the present application provides the use of the compound described herein or its tautomer, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application for preventing and / or treating diseases, disorders and conditions by stimulating the cascade signal mediated by GLP-1R; the diseases, disorders and conditions are GLP-1R-related, including diabetes, obesity, overweight, metabolic-related fatty liver disease, Alzheimer's disease, etc.

[0513] Furthermore, the present application provides a use or method, wherein the compound described in the present application or its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application is used in combination with another, two or more compounds having the same or similar indications.

[0514] The present application also provides a pharmaceutical composition comprising the compound of the present application or its tautomers, stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the present application and another, two or more compounds having the same or similar indications.

[0515] definition

[0516] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0517] When any variable (such as R a ) occurs more than once in the composition or structure of a compound, its definition is independent on each occurrence. Thus, for example, if a group, a site or an atom is represented by two R a is replaced, then each Ra There are independent options.

[0518] The term "plurality" refers to 2-10, for example 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 2, 3, 4, 5, 6, 7, 8; preferably 2, 3, 4, 5, 6; more preferably 2, 3.

[0519] “R b are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl", should be understood as "R b independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 1-6 Alkylamino, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic group, optionally substituted C 6-14 Other similar expressions in this application should be understood in the same manner as above.

[0520] The terms "optional," "optionally," "optionally," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0521] The term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond (ie, =0).

[0522] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 Alkyl), such as "C 1-6"Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0523] Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 alkenyl), further preferably containing 2 to 8 carbon atoms (C 2-8 alkenyl), more preferably containing 2 to 6 carbon atoms (ie, C 2-6 alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl), 2-4 carbon atoms (ie C 2-4 alkenyl), 2-3 carbon atoms (ie C 2-3 alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example, "C 2-6 The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl.

[0524] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl), more preferably containing 2-6 carbon atoms (ie, C 2-6 Alkynyl), 2-5 carbon atoms (ie C 2-5 Alkynyl), 2-4 carbon atoms (ie C 2-4 Alkynyl), 2-3 carbon atoms (ie C 2-3 alkynyl), 2 carbon atoms (i.e., C2 alkynyl), for example, "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.

[0525] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0526] Unless otherwise specified, the term "alkylamino" refers to -NR'R", R' and R" are the same or different and may be H or an alkyl group as defined above, wherein the alkyl group is as defined above, i.e., contains 1-20 carbon atoms, preferably, contains 1-10 carbon atoms, more preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, -NH(CH3), -N(CH3)(CH3), -N(CH2CH3)(CH3), -N(CH2CH3)[CH(CH3)2], etc.

[0527] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0528] Unless otherwise specified, the term "carbocyclyl" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon radical ("C 3-14 In some embodiments, the carbocyclyl group has 3-12 ring carbon atoms ("C 3-12 carbocyclyl”), or 4-12 ring carbon atoms (“C 4-12 carbocyclyl”), or 3 to 10 ring carbon atoms (“C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl”), or 5 to 7 ring carbon atoms (“C 5-7 Carbocyclyl”). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydrogen-

[0529] 1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As illustrated in the above examples, in certain embodiments, the carbocyclyl group is a monocyclic ("monocyclic carbocyclyl") or a fused (and carbocyclyl), bridged (bridged cyclyl) or spiro-fused (spirocyclyl) ring system, such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused by one or more aryl groups, wherein the point of attachment is on the carbocyclyl or aryl ring, and in such cases, the number of atoms of the carbocyclyl ring system is the number of carbons in the carbocyclyl system after fusion. In certain embodiments, each example of a carbocyclyl group is independently optionally substituted, for example, unsubstituted (a "unsubstituted carbocyclyl") or substituted by one or more substituents (a "substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0530] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-7 carbon atoms (C 3-7Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0531] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, containing 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, the heterocyclyl contains 3 to 12 ring atoms (3-12 membered heterocyclyl), more preferably 3 to 10 ring atoms (3-10 membered heterocyclyl), or 3 to 8 ring atoms (3-8 membered heterocyclyl), or 3 to 6 ring atoms (3-6 membered heterocyclyl), or 4 to 6 ring atoms (4-6 membered heterocyclyl), or 5 to 6 ring atoms (5-6 membered heterocyclyl). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include cyclic, spirocyclic and bridged heterocyclic groups. "Heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused (cyclic heterocyclic group), bridged ("heterobridged heterocyclic group" or "bridged heterocyclic group") or spiro ("heterospirocyclic group", "spiroheterocyclic group" or "spirocyclic heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, or cycloalkyl ring, as defined above, is fused to one or more heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, cycloalkyl ring, aryl ring, or heteroaryl ring, and in such cases, the number of members of the heterocyclyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridine, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one.

[0532] Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexane, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazacyclohexane. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxanyl, and thianyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxacyclooctanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0533] Unless otherwise specified, the term "paracyclic" refers to a non-aromatic, saturated or partially unsaturated ring system formed by two or more cyclic structures sharing two adjacent atoms, including paracarbocyclyl and paraheterocyclyl. The term "non-aromatic" means that the entire ring system is non-aromatic.

[0534] The carbocyclyl group may contain 5-14 ring atoms, preferably 6-12 ring atoms, more preferably 7-10 ring atoms. The carbocyclyl group includes a bicyclic, tricyclic, tetracyclic or polycyclic carbocyclyl group, preferably a bicyclic, tricyclic or tetracyclic carbocyclyl group, more preferably a bicyclic or tricyclic carbocyclyl group. Illustrative examples of carbocyclyl groups include (but are not limited to) wait.

[0535] The heterocyclic group may contain 5-14 ring atoms, preferably 6-12 ring atoms, more preferably 7-10 ring atoms, including 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2, or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O, and S. The heterocyclic group includes a bicyclic, tricyclic, tetracyclic, or polycyclic heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic heterocyclic group, more preferably a bicyclic or tricyclic heterocyclic group. Illustrative examples of heterocyclic groups include (but are not limited to) Illustrative examples of bicyclic heterocyclic groups or bicyclic heterocyclic groups include, but are not limited to: wait.

[0536] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0537] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing 5-14 members, or preferably 5-10 members, or preferably 5-8 members, and more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms being preferably 1, 2 or 3. Polycyclic heteroaryl is a fused heteroaryl. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0538] Unless otherwise specified, the term "fused heteroaryl" refers to an aromatic ring system formed by two or more cyclic structures sharing two adjacent atoms. Each ring in the fused heteroaryl is an unsaturated aromatic ring, which may contain 5-20 ring atoms, preferably 6-14 ring atoms, more preferably 7-10 ring atoms, including 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2 or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O and S. Fused heteroaryl includes bicyclic, tricyclic, tetracyclic or polycyclic fused heteroaryl, preferably bicyclic, tricyclic or tetracyclic fused heteroaryl, more preferably bicyclic or tricyclic fused heteroaryl. Illustrative examples of fused heteroaryl include (but are not limited to) wait.

[0539] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. Such salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting a free base or free acid with a suitable reagent.

[0540] Unless otherwise specified, the compounds of the present application also include their "isotopic derivatives". The term "isotopic derivative" means that the compounds of the present application may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number is different from the atomic weight or mass number of the largest atom found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O. 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H) substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0541] Unless otherwise specified, the compounds of the present application also include their "solvates" or "solvates". The terms "solvate" and "solvate" mean the physical association of the compounds of the present application with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" covers solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art. The term "hydrate" refers to a substance formed by water molecules being bound to cations or anions in a compound by coordinate bonds or covalent bonds, or by water ions that are not directly bound to cations or anions but are present in a certain proportion at a defined position in the solid crystal lattice.

[0542] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where the term "E" represents higher-order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents higher-order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rules). The compounds of the present application may also exist as a mixture of "E" and "Z" isomers.

[0543] Unless otherwise specified, the term "tautomer" refers to structural isomers of different energies that are interconvertible through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons.

[0544] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0545] Unless otherwise specified, the compounds of the present application also include their "prodrugs". The term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are generally useful and can improve certain, undesirable physical or biological properties. Physical properties are usually related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which themselves may be related to physicochemical properties. For example, they can be bioavailable by oral administration, while the parent drug cannot. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited to this, can be any compound of the present application, which is administered as an ester ("prodrug") to facilitate transmission across the cell membrane, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to a carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.

[0546] Unless otherwise specified, the term "treat," "treatment," "treatment," or "treating" encompasses any treatment of a disease, disorder, or condition in a patient, including: (a) inhibiting the symptoms of the disease, disorder, or condition, i.e., arresting its development; or (b) relieving the symptoms of the disease, disorder, or condition, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating the disease, disorder, or condition or one or more symptoms associated with the disease.

[0547] Abbreviations used in the Preparation Examples, Examples, and elsewhere herein are:

[0548] AIBN: azobisisobutyronitrile; DCM: dichloromethane; DIAD: diisopropyl azodicarboxylate; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; EA: ethyl acetate; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; LDA: lithium diisopropylamide; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; NMI: N-methylimidazole ; NMP: N-methylpyrrolidone; Pd(dppf)Cl2: 1,1-bis(diphenylphosphino)diphenylferric palladium(II) dichloride; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; THF: tetrahydrofuran; BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)phosphine; DMA: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0549] The beneficial effects of this application are:

[0550] The present application designs a class of compounds with novel structures. Enzymatic tests show that the compounds of the present application have a strong agonist effect on GLP-1R, providing a new direction for the treatment of diseases such as diabetes, metabolic-related fatty liver disease, Alzheimer's disease, and weight loss. In vivo tests show that the compounds of the present application have good pharmacokinetic properties. hERG tests show that the compounds of the present application have a low risk of cardiotoxicity and good safety. The feeding inhibition rate shows that the compounds of the present application have a good feeding inhibition effect, and the weight loss efficacy study on mice shows that the compounds of the present application have a weight loss effect. In addition, the present application studies a specific synthesis method, which has a simple process, convenient operation, and is conducive to large-scale industrial production and application. DETAILED DESCRIPTION

[0551] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present application method. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0552] The following are examples of the preparation of exemplary compounds of the present application.

[0553] Synthesis of 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetic acid (Intermediate 1.1-A)

[0554]

[0555] Step 1: Synthesis of ethyl 7-bromobenzo[d][1,3]dioxolane-4-carboxylate

[0556] Ethyl 4-bromo-2,3-dihydroxybenzoate (2 g, 7.66 mmol) was dissolved in DMF (20 mL), and cesium carbonate (5.5 g, 16.86 mmol) was added. The mixture was stirred at 20°C for 1 hour. CH2I2 (328.45 mg, 1.24 mmol) was then added, and the mixture was stirred at 70°C for 12 hours. After the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain ethyl 7-bromobenzo[d][1,3]dioxolane-4-carboxylate (1.05 g). ESI-MS (m / z): 273.2 [M+H]. + .

[0557] Step 2: Synthesis of (7-bromobenzo[d][1,3]dioxolan-4-yl)methanol

[0558] The product from the previous step (1.05 g, 1.94 mmol) was added to THF (11 mL), cooled to 0°C, and LiAlH4 (175.12 mg, 2.33 mmol) was added portionwise. The mixture was stirred at 0°C for 1 hour. After the reaction, water was added to quench the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product (7-bromobenzo[d][1,3]dioxolan-4-yl)methanol (1.05 g). ESI-MS (m / z): 231.2 [M+H] + .

[0559] Step 3: Synthesis of 4-bromo-7-(chloromethyl)benzo[d][1,3]dioxolane

[0560] The product from the previous step (1.05 g, 4.54 mmol) was dissolved in DCM (10 mL), and SOCl2 (2.70 g, 22.72 mmol) was added. The mixture was stirred at 20°C for 2 hours. TLC indicated that the reaction was complete, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to give 4-bromo-7-(chloromethyl)benzo[d][1,3]dioxolane (830 mg). ESI-MS (m / z): 249.0 [M+H] + .

[0561] Step 4: Synthesis of 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetonitrile

[0562] The product from the previous step (830 mg, 3.33 mmol) was added to DMF (8.3 mL), followed by the addition of NaCN (1.63 g, 33.3 mmol). The mixture was stirred at 90°C for 5 h. After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to give 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetonitrile (570 mg). ESI-MS (m / z): 240.1 [M+H] + .

[0563] Step 5: Synthesis of 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetic acid

[0564] The product from the previous step (570 mg, 2.37 mmol) was added to EtOH (5.7 mL), and then KOH (483.6 mg, 8.62 mmol) was dissolved in H2O (5.7 mL). The mixture was stirred at 80°C for 5 h. After the reaction, water was added to the reaction solution, and then extracted with chloroform. The aqueous phase was adjusted to pH 5 with 1M hydrochloric acid, then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetic acid (500 mg). ESI-MS (m / z): 257.0 [MH] - .

[0565] Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetic acid (Intermediate 1.1-B)

[0566]

[0567] Step 1: Synthesis of methyl 3-(allyloxy)-4-bromobenzoate

[0568] Methyl 4-bromo-3-hydroxybenzoate (30 g, 129.84 mmol) was dissolved in DMF (300 mL), and then K2CO3 (26.93 g, 194.81 mmol) was added. The mixture was stirred at 60°C for 3 hours. After the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude methyl 3-(allyloxy)-4-bromobenzoate (31 g). ESI-MS (m / z): 271.1 [M+H] + .

[0569] Step 2: Synthesis of methyl 2-allyl-4-bromo-3-hydroxybenzoate

[0570] The product from the previous step (10 g, 7.37 mmol) was added to NMP (58 mL). The mixture was stirred and reacted at 200°C under microwave for 5 hours. After the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:20) to obtain methyl 2-allyl-4-bromo-3-hydroxybenzoate (6.4 g). ESI-MS (m / z): 271.1 [M+H] + .

[0571] Step 3: Synthesis of methyl 2-hydroxy-7-bromo-2,3-dihydrobenzofuran-4-carboxylate

[0572] The product from the previous step (4.7 g, 18.44 mmol) was dissolved in THF (90 mL) and H2O (90 mL), and OsO4 (3.34 g, 13.15 mmol) and NaIO4 (7.89 g, 36.89 mmol) were added. The mixture was stirred at 20°C for 6 hours. After the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain methyl 2-hydroxy-7-bromo-2,3-dihydrobenzofuran-4-carboxylate (4.2 g). ESI-MS (m / z): 273.1 [M+H] + .

[0573] Step 4: Synthesis of methyl 4-bromo-3-hydroxy-2-(2-hydroxyethyl)benzoate

[0574] The product from the previous step (4.2 g, 14.65 mmol) was added to THF (56 mL) and MeOH (56 mL), followed by the addition of NaBH4 (554.16 mg, 14.65 mmol). The mixture was stirred at 0°C for 1 h. After the reaction, water was added to the reaction solution, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude methyl 4-bromo-3-hydroxy-2-(2-hydroxyethyl)benzoate (3.5 g). ESI-MS (m / z): 275.0 [M+H] + .

[0575] Step 5: Synthesis of methyl 7-bromo-2,3-dihydrobenzofuran-4-carboxylate

[0576] The product from the previous step (3.5 g, 12.00 mmol) was dissolved in THF (103 mL), and PPh3 (3.78 g, 14.41 mmol) and DIAD (2.91 g, 14.40 mmol) were added. The mixture was stirred at 50°C for 5 hours. After TLC detected that the reaction of the raw material was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain methyl 7-bromo-2,3-dihydrobenzofuran-4-carboxylate (2.5 g). ESI-MS (m / z): 257.2 [M+H] + .

[0577] Step 6: Synthesis of (7-bromo-2,3-dihydrobenzofuran-4-yl)methanol

[0578] The product from the previous step (2.5 g, 9.72 mmol) was added to THF (38 mL), cooled to 0°C, and LiAlH4 (443 mg, 11.67 mmol) was added portionwise. The mixture was stirred at 0°C for 1 hour. After the reaction, water was added to quench the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product (7-bromo-2,3-dihydrobenzofuran-4-yl)methanol (1.9 g). ESI-MS (m / z): 229.0 [M+H] + .

[0579] Step 7: Synthesis of 7-bromo-4-(chloromethyl)-2,3-dihydrobenzofuran

[0580] The product from the previous step (1.9 g, 8.16 mmol) was dissolved in dichloromethane (18.7 mL), and SOCl2 (4.86 g, 40.82 mmol) was added. The mixture was stirred at 20°C for 2 hours. TLC indicated that the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to give 7-bromo-4-(chloromethyl)-2,3-dihydrobenzofuran (1.6 g). ESI-MS (m / z): 247.1 [M+H]. + .

[0581] Step 8: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile

[0582] The product from the previous step (2.0 g, 8.07 mmol) was added to DMF (16 mL), followed by the addition of NaCN (3.17 g, 80.7 mmol). The mixture was stirred at 90°C for 4 h. After the reaction, water was added to the reaction solution, which was then extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to afford 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile (1 g). ESI-MS (m / z): 238.1 [M+H] + .

[0583] Step 9: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetic acid

[0584] The product from the previous step (1 g, 4.20 mmol) was dissolved in EtOH (10 mL) and H2O (10 mL), and KOH (855 mg, 15.25 mmol) was added. The mixture was stirred at 80°C for 3 hours. After the reaction, the reaction solution was quenched with water, extracted with chloroform, adjusted to pH 5 with 1M HCl, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetic acid (900 mg). ESI-MS (m / z): 255.1 [MH] - .

[0585] Synthesis of 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetic acid (Intermediate 1.1-C)

[0586]

[0587] Step 1: Synthesis of tert-butyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate

[0588] 4-Bromo-2-fluoro-benzoic acid tert-butyl ester (20 g, 72.7 mmol) was added to THF (400 mL) and the nitrogen atmosphere was replaced. The temperature in the bottle was lowered to -78°C using a dry ice acetone bath. LDA (1.5 M, 48.46 mL) was slowly added dropwise to the mixture using a constant pressure dropping funnel. The addition was completed over 60 minutes. The reaction solution was stirred at -78°C for 4 hours. The solution turned yellow. Ethylene oxide was added to the reaction solution, and the reaction solution was stirred at -78°C for 6 hours. After the reaction was completed, it was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, washed with brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain tert-butyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate (3 g). ESI-MS (m / z): 299.2 [M+H]. + .

[0589] Step 2: Synthesis of methyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate

[0590] The product from the previous step (2.3 g, 7.69 mmol) was dissolved in a methanol solution of hydrochloric acid (46 mL), and the mixture was stirred at 20°C for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain methyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate (1.7 g). ESI-MS (m / z): 257.2 [M+H] + .

[0591] Step 3: Synthesis of (4-bromo-2,3-dihydrobenzofuran-7-yl)methanol

[0592] The product from the previous step (1.7 g, 6.61 mmol) was added to THF (17 mL), and then lithium aluminum tetrahydride (301 mg, 7.94 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 h. After the reaction was complete, water was added to quench the reaction solution, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (4-bromo-2,3-dihydrobenzofuran-7-yl)methanol (1.4 g). ESI-MS (m / z): 229.1 [M+H] + .

[0593] Step 4: Synthesis of 4-bromo-7-(chloromethyl)-2,3-dihydrobenzofuran

[0594] The product from the previous step (1.4 g, 6.11 mmol) was added to DCM (14 mL), cooled to 0°C, and then SOCl2 (3.64 g, 30.56 mmol) was added. The mixture was stirred at 0°C for 2 h. TLC indicated that the reaction of the starting material was complete. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain 4-bromo-7-(chloromethyl)-2,3-dihydrobenzofuran (1.3 g). ESI-MS (m / z): 247.2 [M+H] + .

[0595] Step 5: Synthesis of 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetonitrile

[0596] The product from the previous step (1.3 g, 5.25 mmol) was added to DMF (13 mL), followed by the addition of NaCN (2.57 g, 52.52 mmol). The mixture was stirred at 90°C for 4 h. After completion of the reaction, the reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetonitrile (1 g). ESI-MS (m / z): 238.0 [M+H] + .

[0597] Step 6: Synthesis of 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetic acid

[0598] The product from the previous step (800 mg, 3.36 mmol) was dissolved in EtOH (8 mL), followed by the addition of KOH (684 mg, 12.20 mmol), and the mixture was stirred at 80°C for 3 hours. TLC confirmed the complete reaction of the starting material. Water was added to the reaction solution, extracted with chloroform, adjusted to pH 5 with 1M HCl, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetic acid (760 mg). ESI-MS (m / z): 255.1 [MH] - .

[0599] Synthesis of 2-(7-bromo-1H-indol-4-yl)acetic acid (Intermediate 1.1-D)

[0600]

[0601] Step 1: Synthesis of 7-bromo-4-methyl-1-p-toluenesulfonyl-1H-indole

[0602] 7-Bromo-4-methyl-1H-indole (1.4 g, 6.7 mmol) and N,N-dimethylformamide (20 mL) were added to a 100 mL flask. Sodium hydride (536 mg, 13.4 mmol) was added portionwise at 0°C and stirred for 10 minutes. p-Toluenesulfonyl chloride (1.91 g, 10 mmol) was added and the mixture was slowly warmed to room temperature while continuing to stir. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The mixture was dried and concentrated. The crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 7-bromo-4-methyl-1-p-toluenesulfonyl-1H-indole (2 g). ESI-MS (m / z): 364.0 [M+H]. + .

[0603] Step 2: Synthesis of 7-bromo-4-(bromomethyl)-1-toluenesulfonyl-1H-indole

[0604] 7-Bromo-4-methyl-1-toluenesulfonyl-1H-indole (2 g, 5.51 mmol), NBS (1.17 g, 6.61 mmol), AIBN (181 mg, 1.1 mmol), and carbon tetrachloride (30 mL) were added to a 100 mL flask and heated to 80°C with stirring for reaction. After the reaction, the solvent was concentrated, and the crude product was separated by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 7-bromo-4-(bromomethyl)-1-toluenesulfonyl-1H-indole (1.6 g). ESI-MS (m / z): 441.9 [M+H] + .

[0605] Step 3: Synthesis of 2-(7-bromo-1-toluenesulfonyl-1H-indol-4-yl)acetonitrile

[0606] 7-Bromo-4-(bromomethyl)-1-toluenesulfonyl-1H-indole (1.6 g, 3.62 mmol), trimethylsilyl cyanide (538 mg, 5.44 mmol), potassium carbonate (1.5 g, 11.2 mmol), and acetonitrile (50 mL) were added to a 100 mL flask and heated to 80°C with stirring. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate. After drying and concentration, the crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 2-(7-bromo-1-toluenesulfonyl-1H-indol-4-yl)acetonitrile (1.2 g). ESI-MS (m / z): 389.0 [M+H] + .

[0607] Step 4: Synthesis of 2-(7-bromo-1H-indol-4-yl)acetonitrile

[0608] 2-(7-Bromo-1-toluenesulfonyl-1H-indol-4-yl)acetonitrile (1.4 g, 3.61 mmol) and methanol (40 mL) were added to a 100 mL flask. Sodium hydroxide (1.44 g, 36.1 mmol) was added and the mixture was heated to 65°C and stirred. After the reaction, the mixture was concentrated and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain 2-(7-bromo-1H-indol-4-yl)acetonitrile (500 mg). ESI-MS (m / z): 235.0 [M+H] + .

[0609] Step 5: Synthesis of 2-(7-bromo-1H-indol-4-yl)acetic acid

[0610] 2-(7-Bromo-1H-indol-4-yl)acetonitrile (200 mg, 0.85 mmol), potassium hydroxide (476 mg, 8.5 mmol), ethanol (5 mL), and water (10 mL) were added to a 25 mL round-bottom flask and heated to 100°C with stirring. After the reaction, the reaction solution was concentrated and the pH was adjusted to 3 with acetic acid. It was then further concentrated. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to give 2-(7-bromo-1H-indol-4-yl)acetic acid (180 mg). ESI-MS (m / z): 254.0 [M+H]. + .

[0611] Synthesis of 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid (Intermediate 1.1-E)

[0612]

[0613] Step 1: 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetonitrile

[0614] 2-(7-Bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile (500 mg, 2.11 mmol) and N,N-dimethylformamide (10 mL) were added to a 100 mL flask, followed by the addition of N-chlorosuccinimide (337 mg, 2.5 mmol), and the reaction was stirred at 60°C. After the reaction, the temperature was lowered and the mixture was added to ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetonitrile (480 mg).

[0615] Step 2: 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid

[0616] 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetonitrile (480 mg, 1.77 mmol) and ethanol (20 mL) were added to a 100 mL flask, followed by the addition of potassium hydroxide (992 mg, 17.7 mmol) and water (25 mL). The mixture was stirred at 100°C. After the reaction, the temperature was lowered and the solution was acidified with 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin-layer chromatography (methanol:dichloromethane = 1:15) to obtain 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid (480 mg). ESI-MS (m / z): 289.0 [MH] - .

[0617] Synthesis of 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid (Intermediate 1.1-F)

[0618]

[0619] Step 1: 2-(4-bromo-2-fluoro-5-methoxyphenyl)acetic acid

[0620] 2-(4-Bromo-5-methoxyphenyl)acetic acid (4.5 g, 24.43 mmol) was dissolved in acetonitrile (120 mL), and Br2 (3.51 g, 21.99 mmol, 1.13 mL) was added at 0°C. The reaction solution was stirred at 20°C. After the reaction, water was added to the reaction solution, and acetic acid was added to adjust the pH to about 5. The solution was then extracted with ethyl acetate. The organic phase was washed with NaCl solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 2-(4-bromo-2-fluoro-5-methoxyphenyl)acetic acid (8.6 g). ESI-MS (m / z): 261.0 [MH] - .

[0621] Step 2: Methyl 2-(4-bromo-2-fluoro-5-methoxyphenyl)acetate

[0622] The product from the previous step (7.9 g, 17.72 mmol) was dissolved in DMF (80 mL), and K2CO3 (4.9 g, 35.44 mmol) and MeI (3.77 g, 26.58 mmol) were added. The reaction solution was stirred at 20°C. After the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with a semi-saturated NaCl solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain methyl 2-(4-bromo-2-fluoro-5-methoxyphenyl)acetate (4.2 g). ESI-MS (m / z): 277.0 [M+H] + .

[0623] Step 3: Methyl 2-(4-bromo-2-fluoro-5-hydroxyphenyl)acetate

[0624] The product from the previous step (4.2 g, 15.16 mmol) was dissolved in dichloromethane (72 mL), and then BBr3 (11.39 g, 45.47 mmol) was added. The reaction solution was stirred at 0°C. After the reaction was completed, the reaction solution was quenched with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give methyl 2-(4-bromo-2-fluoro-5-hydroxyphenyl)acetate (4 g). ESI-MS (m / z): 263.0 [M+H] + .

[0625] Step 4: Methyl 2-(5-allyloxy-4-bromo-2-fluorophenyl)acetate

[0626] The product from the previous step (4 g, 15.21 mmol) and allyl bromide (2.76 g, 22.81 mmol) were dissolved in DMF (40 mL), followed by the addition of potassium carbonate (3.15 g, 22.81 mmol). The reaction mixture was stirred at 60°C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with a semi-saturated NaCl solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product. Purification by column chromatography (ethyl acetate:petroleum ether = 1:2) afforded methyl 2-(5-allyloxy-4-bromo-2-fluorophenyl)acetate (3.7 g). ESI-MS (m / z): 303.1 [M+H] + .

[0627] Step 5: Methyl 2-(2-allyl-4-bromo-6-fluoro-3-hydroxyphenyl)acetate

[0628] The product from the previous step (3.7 g, 12.21 mmol) was dissolved in NMP (15 mL) and microwave-treated at 200°C for 4 hours. After the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with a semi-saturated NaCl solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product. Purification by column chromatography (ethyl acetate:petroleum ether = 1:3) afforded methyl 2-(2-allyl-4-bromo-6-fluoro-3-hydroxyphenyl)acetate (2.45 g). ESI-MS (m / z): 303.1 [M+H] + .

[0629] Step 6: Methyl 2-(7-bromo-5-fluoro-2-hydroxy-2,3-dihydrobenzofuran-4-yl)acetate

[0630] The product from the previous step (2.35 g, 7.75 mmol) was dissolved in THF (40 mL) and H₂O (40 mL). NaIO₄ (3.32 g, 15.51 mmol) and OsO₄ (1.41 g, 5.53 mmol) were added, and the reaction mixture was stirred at 20°C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with NaCl solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product. Purification by column chromatography (ethyl acetate:petroleum ether = 1:2) afforded methyl 2-(7-bromo-5-fluoro-2-hydroxy-2,3-dihydrobenzofuran-4-yl)acetate (1.3 g). ESI-MS (m / z): 305.1 [M+H] + .

[0631] Step 7: Methyl 2-(4-bromo-6-fluoro-3-hydroxy-2-(2-hydroxyethyl)phenyl)acetate

[0632] The product from the previous step (1.2 g, 3.93 mmol) was dissolved in THF (15 mL) and MeOH (15 mL), and NaBH4 (148.80 mg, 3.93 mmol) was added. The reaction solution was stirred at 0°C. After the reaction was completed, the reaction solution was quenched with NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with semi-saturated NaCl, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give crude methyl 2-(4-bromo-6-fluoro-3-hydroxy-2-(2-hydroxyethyl)phenyl)acetate (1.1 g). ESI-MS (m / z): 307.1 [M+H] + .

[0633] Step 8: Methyl 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetate

[0634] The product from the previous step (1.1 g, 3.58 mmol) was dissolved in THF (22 mL). PPh3 (1.13 g, 4.3 mmol) and DIAD (1.9 M, 2.26 mL) were added at 20°C, and the reaction mixture was stirred at 50°C. LCMS detected the desired product. The reaction mixture was quenched with H2O and extracted with ethyl acetate. The organic phase was washed with semi-saturated NaCl (20 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. Purification by column chromatography (PE:EA = 2:1) afforded methyl 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetate (834 mg). ESI-MS (m / z): 289.1 [M+H]. + .

[0635] Step 9: 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid

[0636] The product from the previous step (200 mg, 0.7 mmol) was dissolved in MeOH (2 mL), THF (2 mL), and H2O (2 mL). LiOH (66 mg, 2.7 mmol) was added, and the mixture was stirred at 20°C for reaction. After the reaction, the reaction solution was concentrated under reduced pressure, adjusted to acidity with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to give 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid (120 mg). ESI-MS (m / z): 273.1 [MH] - .

[0637] Synthesis of 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)acetic acid (Intermediate 1.1-G)

[0638]

[0639] Referring to the synthetic method of intermediate 1.1-A, the target compound 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)acetic acid was obtained using 4-bromo-2,3-dihydroxybenzoic acid ethyl ester and 1,2-dibromoethane as raw materials. ESI-MS (m / z): 271.0 [MH] - .

[0640] Synthesis of 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate 1.1-H)

[0641]

[0642] Step 1: (E)-4-(2-ethoxyvinyl)-7-methoxy-2,3-dihydro-1H-inden-1-one

[0643] 4-Bromo-7-methoxy-1-indanone (5 g, 20.74 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (4.5 g, 22.85 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (1.5 g, 2.05 mmol) and cesium carbonate (20 g, 60.79 mmol) were added to dioxane (50 mL) and water (10 mL). Under argon protection, the mixture was heated to 100°C and stirred for reaction. After the reaction, saturated brine was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain (E)-4-(2-ethoxyvinyl)-7-methoxy-2,3-dihydro-1H-inden-1-one (4.6 g). ESI-MS (m / z): 233.1 [M+H] + .

[0644] Step 2: 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetaldehyde

[0645] The product from the previous step (4.6 g, 19.82 mmol) was dissolved in anhydrous formic acid (40 mL) and stirred at room temperature. After the reaction, the crude product of 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetaldehyde was obtained by distillation under reduced pressure.

[0646] Step 3: 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid

[0647] The product from the previous step was dissolved in a mixed solution of dimethyl sulfoxide (25 mL) and tetrahydrofuran (25 mL). Separately, sodium chlorite (9 g, 99.51 mmol) and sodium dihydrogen phosphate (16.6 g, 138.36 mmol) were dissolved in water (25 mL) and added dropwise to the above reaction solution under an ice-water bath. The reaction solution was stirred under an ice-water bath for 30 minutes, then returned to room temperature and continued to stir. After the reaction was completed, saturated brine was added, and 1N hydrochloric acid was added dropwise to adjust the pH to 2-3. The product was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid.

[0648] Step 4: Ethyl 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate

[0649] The product from the previous step was dissolved in anhydrous N,N-dimethylformamide (30 mL), and potassium carbonate (5.5 g, 39.57 mmol) and iodoethane (3.7 g, 23.72 mmol) were added, and the reaction was stirred at room temperature. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product. After purification by column chromatography (ethyl acetate: petroleum ether = 1:10), ethyl 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate (4.1 g) was obtained. ESI-MS (m / z): 249.1 [M+H] + .

[0650] Step 5: Ethyl 2-(7-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate

[0651] The product from the previous step was dissolved in dichloromethane (10 mL), and boron tribromide (1 g, 3.99 mmol) was then added dropwise under an ice-water bath. The reaction solution was stirred under ice-water bath. After completion of the reaction, anhydrous ethanol was added to quench the reaction. Saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain crude ethyl 2-(7-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetate.

[0652] Step 6: Ethyl 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetate

[0653] The product from the previous step was dissolved in dichloromethane (20 mL), and then diisopropylethylamine (331 mg, 2.57 mmol) was added, followed by dropwise addition of trifluoromethanesulfonic anhydride (360 mg, 1.28 mmol), and the reaction was stirred at room temperature. After completion of the reaction, saturated brine was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product. After purification by column chromatography (ethyl acetate: petroleum ether = 1:8), ethyl 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetate (190 mg) was obtained. ESI-MS (m / z): 367.0 [M+H] + .

[0654] Step 7: 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetic acid

[0655] The product from the previous step (110 mg, 0.31 mmol) was dissolved in dioxane (8 mL), and then water (1.5 mL) and lithium hydroxide (24 mg, 1.00 mmol) were added. The reaction was stirred at room temperature. After the reaction, the pH of the reaction solution was adjusted to about 2 with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to give 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetic acid (75 mg). ESI-MS (m / z): 337.0 [MH] - .

[0656] Synthesis of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (Intermediate 1.2-A)

[0657]

[0658] Step 1: Synthesis of methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate

[0659] Methyl 3-fluoro-4-nitrobenzoate (10 g, 50.20 mmol), (S)-oxetane-2-methylamine (5.25 g, 60.20 mmol), DIPEA (12.90 g, 100.4 mmol), and DMF (50 mL) were added to a 200 mL round-bottom flask and heated to 70°C with stirring for 3 h. After the reaction was completed, the mixture was cooled to room temperature, extracted with water and ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the desired product, methyl (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate (13.1 g). ESI-MS (m / z): 267.1 [M+H]. + .

[0660] Step 2: Synthesis of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate

[0661] The product from the previous step, (S)-methyl 4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate (5 g, 18.79 mmol), iron powder (5.24 g, 93.98 mmol), ammonium chloride (9.96 g, 187.9 mmol), ethanol (50 mL), and water (10 mL) were added to a 100 mL round-bottom flask and reacted at room temperature for 3 h. After the reaction, the mixture was filtered, the ethanol was removed by vortexing, and the mixture was extracted with water and ethyl acetate. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered and dried to obtain the target product, methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate (3.6 g). ESI-MS (m / z): 237.1 [M+H] + .

[0662] Synthesis of (S)-methyl 4-amino-5-fluoro-3-((oxetan-2-ylmethyl)amino)benzoate (Intermediate 1.2-B)

[0663]

[0664] Referring to the synthesis method of intermediate 1.1-A, methyl 3,5-difluoro-4-nitrobenzoate was used as the synthetic raw material to obtain compound (S)-4-amino-5-fluoro-3-((oxetane-2-ylmethyl)amino)benzoate (3.8 g). ESI-MS (m / z): 255.1 [M+H] + .

[0665] Synthesis of methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (Intermediate 1.2-C)

[0666]

[0667] Referring to the method for synthesizing (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (1.2-A), methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (520 mg) was synthesized using 2-(1-(aminomethyl)cyclopropyl)acetonitrile as the starting material. ESI-MS (m / z): 260.2 [M+H] + .

[0668] Synthesis of methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (Intermediate 1.2-D)

[0669]

[0670] Referring to the method for synthesizing (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (1.2-C), methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1543 mg) was synthesized using (1-(fluoromethyl)cyclopropyl)methanamine as the starting material. ESI-MS (m / z): 253.1 [M+H] + .

[0671] The synthesis of (1-(fluoromethyl)cyclopropyl)methylamine is as follows:

[0672]

[0673] Step 1: Ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate

[0674] Ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (3 g, 26.3 mmol) and dichloromethane (50 mL) were added to a 100 mL flask and cooled to -78°C. Diethylaminosulfur trifluoride (5.1 g, 31.1 mmol) was then added, and the reaction mixture was stirred at room temperature. After the reaction, the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate (4.7 g, crude product).

[0675] Step 2: (1-(Fluoromethyl)cyclopropyl)methanol

[0676] The product from the previous step (4.7 g, crude) and tetrahydrofuran (30 mL) were added to a 250 mL flask. Lithium aluminum hydride (1.5 g, 39.45 mmol) was added portionwise under an ice bath and stirred at room temperature. After completion of the reaction, the reaction solution was slowly added dropwise to water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield (1-(fluoromethyl)cyclopropyl)methanol (4.0 g, crude).

[0677] Step 3: (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate

[0678] (1-(Fluoromethyl)cyclopropyl)methanol (4.0 g, crude product) and dichloromethane (50 mL) were added to a 250 mL flask, followed by the addition of triethylamine (11.6 g, 0.11 mol) and methylsulfonyl chloride (5.3 g, 46.1 mmol), and the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield (1-(fluoromethyl)cyclopropyl)methyl methanesulfonate (6 g, crude product).

[0679] Step 4: (1-(Fluoromethyl)cyclopropyl)methanamine

[0680] (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate (6 g, crude product) and methanol (50 mL) were added to a 250 mL flask. A 7 M ammonia / methanol solution (10 mL) was added and the mixture was stirred at room temperature. After the reaction, the mixture was concentrated to obtain (1-(fluoromethyl)cyclopropyl)methylamine (4 g). ESI-MS (m / z): 104.1 [M+H] + .

[0681] Synthesis of methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate (Intermediate 1.2-E)

[0682]

[0683] Referring to the method for synthesizing methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (1.2-C), methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate (640 mg) was synthesized using methyl 6-chloro-5-nitropyridine carboxylate as the starting material. ESI-MS (m / z): 261.1 [M+H] + .

[0684] (S)-4-Amino-3-methoxy-5-((oxetan-2-yl-methyl)amino)benzoic acid methyl ester (Intermediate 1.2-F)

[0685]

[0686] Step 1: (S)-methyl 3-fluoro-4-nitro-5-((oxetan-2-yl-methyl)amino)benzoate

[0687] 3,5-Difluoro-4-nitro-benzoic acid methyl ester (1.9 g, 8.75 mmol) was added to DMF (20 mL), and K2CO3 (3.63 g, 26.25 mmol) and (S)-oxetane-2-ylmethylamine (915 mg, 10.50 mmol) were added to the reaction solution in sequence. The reaction solution was stirred at 20°C for 2 hours. After the reaction, the reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoic acid methyl ester (2.8 g). ESI-MS (m / z): 285.1 [M+H]. + .

[0688] Step 2: (S)-methyl 3-methoxy-4-nitro-5-((oxetan-2-yl-methyl)amino)benzoate

[0689] The product from the previous step (1.2 g, 4.22 mmol) was dissolved in MeOH (24 mL), and sodium methoxide (1.52 g, 8.44 mmol, 30% content) was added to the reaction mixture. The mixture was stirred at 20°C for 36 h. After the reaction, saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain methyl (S)-3-methoxy-4-nitro-5-((oxetan-2-yl-methyl)amino)benzoate (850 mg). ESI-MS (m / z): 297.1 [M+H]. + .

[0690] Step 3: (S)-methyl 4-amino-3-methoxy-5-((oxetan-2-yl-methyl)amino)benzoate

[0691] The product from the previous step (650 mg, 2.19 mmol) was dissolved in EtOH (13 mL) and H₂O (2.6 mL). NH₄Cl (587 mg, 10.97 mmol) and iron powder (368 mg, 6.59 mmol) were then added to the reaction mixture, and the reaction was stirred at 80°C for 1 h. After the reaction, the iron powder was filtered off, and the filtrate was concentrated under reduced pressure. The filtrate was then dissolved in dichloromethane and filtered, and then concentrated under reduced pressure to give (S)-methyl 4-amino-3-methoxy-5-((oxetane-2-yl-methyl)amino)benzoate (650 mg). ESI-MS (m / z): 267.0 [M+H]. + .

[0692] Intermediates 1.2-G to 1.2-J were synthesized by referring to the synthesis methods of other intermediates:

[0693]

[0694]

[0695] Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane (Intermediate 1.5-A)

[0696]

[0697] 3-Bromocatechol (5 g, 26.45 mmol) was added to toluene (100 mL), followed by the addition of 4'-chloro-2'-fluoroacetophenone (5.02 g, 29.10 mmol) and p-toluenesulfonic acid monohydrate (5.03 g, 26.45 mmol). The mixture was stirred at 140°C for 60 h. The mixture was concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to afford 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane (600 mg). ESI-MS (m / z): 343.1 [M+H] + .

[0698] Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (Intermediate 1.5-B)

[0699]

[0700] 2-Fluoro-4-chlorobenzyl alcohol (3.2 g, 20 mmol) and N,N-dimethylformamide (50 mL) were added to a 100 mL round-bottom flask. Sodium hydride (1.2 g, 30 mmol) was added portionwise under ice-cooling. The reaction mixture was stirred for 20 minutes under ice-cooling, followed by the addition of 2-bromo-6-fluoropyridine (3.5 g, 20 mmol). The mixture was then warmed to room temperature and stirred. After completion of the reaction, the reaction mixture was added to ice-water (250 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate:n-hexane = 1:100) to afford 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (5 g, 79% yield). ESI-MS (m / z): 316.0 [M+H] + .

[0701] Intermediates 1.5-C to 1.5-AH were synthesized by referring to the synthesis method of the above intermediates:

[0702]

[0703]

[0704]

[0705]

[0706]

[0707] Synthesis of 3-fluoro-4-(((6-(tri-n-butyltin)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.7-A)

[0708]

[0709] 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (1 g, 3.81 mmol) was added to 1,4-dioxane (10 mL), followed by hexa-n-butylditin (2.65 g, 4.57 mmol), Pd(PPh3)4 (220 mg, 0.19 mmol), tricyclohexylphosphine (128 mg, 0.46 mmol), and LiCl (968 mg, 22.84 mmol). The mixture was heated to 120°C and stirred for 12 h. After the reaction, water was added to quench the reaction solution, and then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to give 3-fluoro-4-(((6-(tri-n-butyltin)pyridin-2-yl)oxy)methyl)benzonitrile (700 mg), ESI-MS (m / z): 519.2 [M+H] + .

[0710] Synthesis of tri-n-butyl(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)tin (Intermediate 1.7-B)

[0711]

[0712] Tri-n-butyl(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)tin (320 mg) was prepared from 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane (1.5-A) according to the synthetic method of compound 1.7-A. ESI-MS (m / z): 555.1 [M+H] + .

[0713] 3-Fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-A)

[0714]

[0715] Step 1: tert-Butyl 4-methoxycarbonyl-4-(6-chloropyridin-2-yl)piperidine-1-carboxylate

[0716] Methyl N-Boc-4-piperidinylcarboxylate (10.00 g, 41.10 mmol) was added to tetrahydrofuran (50 mL) and cooled to -60°C. A solution of LDA (62 mL, 1 M) in tetrahydrofuran was added dropwise to the reaction mixture using a constant pressure dropping funnel. After the addition, stirring was continued at -60°C for 1 hour. 2,6-Dichloropyridine (6.38 g, 43.20 mmol) was then added. The reaction mixture was then heated to 0°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was slowly poured into an ice-cold saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (8.00 g). ESI-MS (m / z): 355.2 [M+H]. + .

[0717] Step 2: tert-Butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate

[0718] The product from the previous step (8.00 g, 22.55 mmol) was dissolved in methanol (100 mL). Solid NaOH (1.80 g, 45.09 mmol) was dissolved in water (11 mL) and added dropwise to the reaction solution. The reaction solution was heated to 50°C and stirred at this temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure to remove most of the methanol. The reaction solution was then diluted with water. Diluted hydrochloric acid was slowly added with stirring to adjust the pH to approximately 5. A large amount of solid precipitated. Stirring was continued for 40 minutes and then filtered to obtain the crude product (6.00 g). ESI-MS (m / z): 339.1 [MH] - .

[0719] Step 3: tert-Butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate

[0720] The product from the previous step (1.00 g) was added to 1,4-dioxane (10 mL) and stirred at 110°C for 16 h. After the reaction was complete, the temperature was lowered and the mixture was used directly in the next step.

[0721] Step 4: tert-Butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate

[0722] 4-Cyano-2-fluorobenzyl alcohol (443 mg, 2.93 mmol) was added directly to the reaction mixture from the previous step, followed by the addition of BINAP (204 mg, 0.328 mmol) and cesium carbonate (2.01 g, 6.16 mmol). The atmosphere was replaced with nitrogen, and Pd2(dba)3 (161 mg, 0.176 mmol) was added. The temperature was then raised to 105°C and the reaction was continued under nitrogen for 16 h. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to afford tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (550 mg). ESI-MS (m / z): 412.2 [M+H]. + .

[0723] Step 5: 3-Fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile

[0724] The product from the previous step (550 mg, 1.33 mmol) was added to a solution of hydrogen chloride in ethyl acetate (10 mL) and reacted at 20°C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (410 mg, HCl salt). ESI-MS (m / z): 312.2 [M+H] + .

[0725] 5-Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (Intermediate 1.8-B)

[0726]

[0727] Step 1: (((((3-Bromo-1,2-phenylene)bis(oxy))bis(methylene))bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilyl)

[0728] 3-Bromobenzene-1,2-diphenol (8.5 g, 44.9 mmol) and dichloromethane (170 mL) were added to a 500 mL round-bottom flask, followed by diisopropylethylamine (14.5 g, 112.4 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (18.7 g, 112.4 mmol). The reaction mixture was stirred at room temperature. After the reaction was completed, water was added to dilute the mixture and the layers were separated. The aqueous phase was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (((((3-bromo-1,2-phenylene)bis(oxy))bis(methylene))bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilane) (23 g).

[0729] Step 2: tert-Butyl 4-(2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate

[0730] The product from the previous step (23 g, 51.1 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (18.9 g, 61.4 mmol), and dioxane (200 mL) were added to a 500 mL round-bottom flask. Sodium carbonate (16.2 g, 153.5 mmol), Pd(dppf)Cl2 (2.2 g, 3.1 mmol), and water (50 mL) were then added. The mixture was heated to 85°C and stirred under a nitrogen atmosphere. After the reaction was completed, the temperature was lowered and water was added. The mixture was extracted with ethyl acetate and concentrated. The crude product was separated and purified by column chromatography to give tert-butyl 4-(2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (15 g). ESI-MS (m / z): 552.3 [M+H] + .

[0731] Step 3: tert-Butyl 4-(2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)piperidine-1-carboxylate

[0732] The product from the previous step (15 g, 27.1 mmol) and methanol (200 mL) were added to a 500 mL round-bottom flask, and Pd / C (3.5 g) was added. The mixture was stirred at 40°C under a hydrogen atmosphere. After the reaction, the temperature was lowered, the mixture was filtered, and the mixture was concentrated. The crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain tert-butyl 4-(2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)piperidine-1-carboxylate (12.8 g). ESI-MS (m / z): 554.3 [M+H] + .

[0733] Step 4: 3-(Piperidin-4-yl)phenyl-1,2-diol

[0734] The product from the previous step (12 g, 21.6 mmol) and a methanol solution of hydrogen chloride (100 mL) were added to a 250 mL round-bottom flask and stirred at room temperature. After the reaction, the mixture was concentrated to give 3-(piperidin-4-yl)phenyl-1,2-diphenol (5 g). ESI-MS (m / z): 194.1 [M+H] + .

[0735] Step 5: tert-Butyl 4-(2,3-dihydroxyphenyl)piperidine-1-carboxylate

[0736] The product from the previous step (5 g, 21.7 mmol) and methanol (60 mL) were added to a 250 mL round-bottom flask. Sodium carbonate (6.9 g, 65.3 mmol) and di-tert-butyl carbonate (4.9 g, 22.8 mmol) were then added and stirred at room temperature. After the reaction, the mixture was concentrated, and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain tert-butyl 4-(2,3-dihydroxyphenyl)piperidine-1-carboxylate (4.5 g). ESI-MS (m / z): 294.2 [M+H] + .

[0737] Step 6: tert-Butyl 4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidine-1-carboxylate

[0738] The product from the previous step (300 mg, 1.0 mmol), 5-chloro-2-ethynylpyridine (281.3 mg, 2.0 mmol), and toluene (10 mL) were added to a 100 mL round-bottom flask. Saturated aqueous sodium bicarbonate (1 mL) and triruthenium dodecacarbonyl (58.8 mg, 92.0 μmol) were added. The mixture was stirred at 120°C under a nitrogen atmosphere. After completion of the reaction, the temperature was lowered and the mixture was concentrated. The crude product was isolated and purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain tert-butyl 4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidine-1-carboxylate (90 mg). ESI-MS (m / z): 431.2 [M+H] + .

[0739] Step 7: 5-Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine

[0740] The product from the previous step (70 mg, 162.4 μmol) and dichloromethane (5 mL) were added to a 100 mL round-bottom flask, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature. After the reaction, the mixture was concentrated to yield 5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine (60 mg). ESI-MS (m / z): 331.1 [M+H] + .

[0741] 4-(3-(4-Chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine (Intermediate 1.8-C)

[0742]

[0743] Step 1: 2-(4-chloro-2-fluorophenyl)oxirane

[0744] Trimethylsulfide iodide (48.91 g, 239.66 mmol) was added to DMSO (120 mL) and THF (120 mL), and then potassium tert-butoxide (26.89 g, 239.66 mmol) and 4-chloro-2-fluorobenzaldehyde (19 g, 119.83 mmol) were added to the reaction solution in sequence. The reaction solution was stirred at 20 ° C for 12 hours, and then water (100 mL) and ethyl acetate were added to the reaction solution. The layers were separated, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(4-chloro-2-fluorophenyl) oxirane.

[0745] Step 2: 2-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethan-1-ol

[0746] The product from the previous step (11.90 g, 47.02 mmol) was dissolved in H2O (69 mL) and DMA (34.5 mL). NaOH (1.34 g, 33.58 mmol) and 2,6-dibromophenol (11.58 g, 67.17 mmol) were then added. The mixture was stirred at 130°C for 12 h. After the reaction, water (100 mL) and ethyl acetate were added to the reaction solution. The layers were separated, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to give 2-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethan-1-ol (3.2 g). ESI-MS (m / z): 422.9 [M+H] + .

[0747] Step 3: 5-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane

[0748] The product from the previous step (3 g, 7.06 mmol) was dissolved in toluene (45 mL), followed by the addition of S-binaphthol (809 mg, 2.82 mmol), CuI (269 mg, 1413 μmol), and Cs2CO3 (4.61 g, 14.13 mmol). The mixture was heated to 110°C and stirred for 48 h. After completion of the reaction, the mixture was filtered and the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to afford 5-bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane (2.2 g). ESI-MS (m / z): 343.0 [M+H] + .

[0749] Step 4: tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0750] The product from the previous step (2.2 g, 6.42 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.2 g, 6.42 mmol), 1,4-dioxane (60 mL), H2O (12 mL), Na2CO3 (1.36 g, 12.83 mmol) and Pd(PPh3)4 (730 mg, 640.92 μmol) were added to a round-bottom flask, and the reaction solution was stirred at 90 °C for 4 h. After the reaction, water and ethyl acetate were added to the reaction solution, the layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.8 g). ESI-MS (m / z): 446.2 [M+H] + .

[0751] Step 5: 4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-1,2,3,6-tetrahydropyridine

[0752] The product from the previous step (800 mg, 1.79 mmol) was dissolved in dichloromethane (8 mL), followed by the addition of a 4M hydrochloric acid solution in 1,4-dioxane (8 mL). The reaction mixture was stirred at 20°C for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure to yield 4-(2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1,2,3,6-tetrahydropyridine (700 mg, HCl salt). ESI-MS (m / z): 446.2 [M+H] + , 1H NMR (400MHz, CDCl3) δ9.96 (br s, 2H), 7.47 (t, J = 8.0Hz, 1H), 7.28 (br s,1H),7.14(dd,J=1.6,10.0Hz,1H),6.94-6.84(m,2H),6.83-6.77(m,1H),5.84(br s,1H),5.41(dd,J=1.9,8.2Hz,1H),4.44(dd,J=2.2,11.3Hz,1H),3.97(dd,J=8.3,11.3Hz,1H),3.85(br s,2H),3.38(br s,2H),3.01-2.88(m,1H),2.86-2.73(m,1H).

[0753] Step 6: 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine

[0754] The product from the previous step (380 mg, 0.99 mmol) and isopropanol (30 mL) were added to a 100 mL round-bottom flask, followed by the addition of Pd / C (380 mg). The mixture was stirred at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and the reaction solution was dried to obtain 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine (405 mg). ESI-MS (m / z): 348.1 [M+H] + .

[0755] 2-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Intermediate 1.8-D)

[0756]

[0757] Referring to the synthesis of 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-A), compound 2-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (330 mg) was obtained. ESI-MS (m / z): 367.1 [M+H] + .

[0758] 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidine (Intermediate 1.8-E)

[0759]

[0760] Referring to the synthesis of 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-A), the compound 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperidine (350 mg) was obtained. ESI-MS (m / z): 295.1 [M+H] + .

[0761] 4-Fluoro-3-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-F)

[0762]

[0763] Referring to the synthesis of 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-A), 4-fluoro-3-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (300 mg) was obtained. ESI-MS (m / z): 312.1 [M+H] + .

[0764] 3-Fluoro-4-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-G)

[0765]

[0766] Step 1: tert-Butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazine-1-carboxylate

[0767] 4-(((6-Bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (300 mg, 0.97 mmol), tert-butyl 2-methylpiperazine-1-carboxylate (391 mg, 1.95 mmol), Pd2(dba)3 (60 mg, 0.10 mmol), BINAP (122 mg, 0.19 mmol) and cesium carbonate (955 mg, 1.95 mmol) were added to a 100 mL flask, anhydrous dioxane (15 mL) was added, and the reaction was heated to 100 ° C and stirred for 4 hours. After the reaction, the temperature was lowered, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether=1:10) to give tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-methylpiperazine-1-carboxylate (83 mg). ESI-MS (m / z): 427.2 [M+H] + .

[0768] Step 2: 3-Fluoro-4-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile

[0769] The product from the previous step (83 mg, 0.36 mmol) and dichloromethane (4 mL) were added to a 25 mL flask, followed by the addition of trifluoroacetic acid (2 mL). The reaction solution was stirred at room temperature for 1 hour. After the reaction, the solution was concentrated, sodium bicarbonate aqueous solution was added, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-fluoro-4-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile (63 mg). ESI-MS (m / z): 327.1 [M+H] + .

[0770] Synthesis of 3-fluoro-4-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile (1.8-H)

[0771]

[0772] Step 1: tert-Butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylate

[0773] 4-(((6-Bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (200 mg, 0.65 mmol), tert-butyl piperazine-1-carboxylate (243 mg, 1.32 mmol), Pd2(dba)3 (119 mg, 0.13 mmol), cesium carbonate (636 mg, 1.95 mmol) and BINAP (162 mg, 0.26 mmol) were added to a 100 mL flask, followed by addition of dioxane (15 mL), and the reaction solution was stirred in a nitrogen atmosphere at 100 ° C. After the reaction, the temperature was lowered, water was added to the flask, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated, and the crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether=1:10) to obtain tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylate (150 mg). ESI-MS (m / z): 413.2 [M+H] + .

[0774] Step 2: 3-Fluoro-4-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile

[0775] The product from the previous step (150 mg, 0.36 mmol) and dichloromethane (10 mL) were added to a 100 mL flask, and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and dissolved in ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-fluoro-4-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile (120 mg). ESI-MS (m / z): 313.1 [M+H] + .

[0776] (S)-1-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-methylpiperazine (Intermediate 1.8-1)

[0777]

[0778] Referring to the synthesis method of intermediate 1.8-A, (S)-1-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-methylpiperazine (520 mg) was obtained using 4-chloro-2-fluorobenzyl alcohol and tert-butyl S-2-methylpiperazine-1-carboxylate as starting materials. ESI-MS (m / z): 336.1 [M+H] + .

[0779] (S)-3-Fluoro-4-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-J)

[0780]

[0781] Referring to the synthesis method of intermediate 1.8-G, (S)-3-fluoro-4-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)benzonitrile (480 mg) was obtained using 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile and tert-butyl S-2-methylpiperazine-1-carboxylate as raw materials. ESI-MS (m / z): 327.1 [M+H] + .

[0782] 2-((2-Fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Intermediate 1.8-K)

[0783]

[0784] Step 1: ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane

[0785] 4-Bromo-2-fluorobenzyl alcohol (5.00 g, 24.39 mmol), imidazole (3.32 g, 48.78 mmol), and acetonitrile (50 mL) were added to a reaction flask, followed by tert-butyldimethylsilyl chloride (5.51 g, 36.59 mmol). The reaction was allowed to react at room temperature for 5 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (7.0 g).

[0786] Step 2: 3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)oxetane-3-ol

[0787] The product from the previous step (6.2 g, 19.50 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a reaction flask. n-Butyl lithium (2.5 M in THF, 8.6 mL, 21.45 mmol) was added dropwise at -78 ° C under nitrogen protection. The reaction was allowed to react at this temperature for half an hour. 3-Oxetanone (1.48 g, 20.48 mmol) was then added, and the reaction was allowed to react at room temperature for 2.5 hours. The reaction was monitored by TLC. The reaction was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)oxetane-3-ol (2.6 g).

[0788] Step 3: O-(3-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)oxetan-3-yl)S-methylcarbodisulfide

[0789] The product from the previous step (2.6 g, 8.33 mmol) and anhydrous tetrahydrofuran (30 mL) were added to a reaction flask. 60% sodium hydride (0.67 g, 16.66 mmol) was added at 0°C, and the mixture was allowed to react at room temperature for 2 hours. Carbon disulfide (0.95 g, 12.50 mmol) and iodomethane (1.77 g, 12.50 mmol) were then added at 0°C, and the reaction continued for half an hour. The reaction was monitored by TLC, quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude O-(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenyl)oxetan-3-yl)S-methyl carbodisulfide, which was then directly reacted in the next step without purification.

[0790] Step 4: tert-Butyl((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)dimethylsilane

[0791] The product from the previous step and toluene (20 mL) were added to a reaction flask, followed by tri-n-butyltin hydride (4.85 g, 16.66 mmol) and azobisisobutyronitrile (0.14 g, 0.83 mmol). The system was reacted at 125°C for half an hour. After completion of the reaction, the reaction solution was concentrated by TLC, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to provide tert-butyl((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)dimethylsilane (1.84 g).

[0792] Step 5: (2-Fluoro-4-(oxetan-3-yl)phenyl)methanol

[0793] The product from the previous step (1.84 g, 6.22 mmol) and tetrahydrofuran (20 mL) were added to a reaction flask, followed by triethylamine trihydrofluoride (2.0 g, 12.44 mmol). The system was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to provide (2-fluoro-4-(oxetan-3-yl)phenyl)methanol (1.0 g).

[0794] Step 6: tert-Butyl 4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate

[0795] (2-Fluoro-4-(oxetane-3-yl)phenyl)methanol (0.26 g, 1.43 mmol), tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0.46 g, 1.57 mmol), tris(dibenzylideneacetone)dipalladium (0.13 g, 0.14 mmol), cesium carbonate (0.93 g, 2.86 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.14 g, 0.29 mmol) and dioxane (15 mL) were added to a reaction flask, and the system was reacted at 100 ° C for 5 hours under nitrogen protection. The reaction was monitored by LCMS, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give tert-butyl 4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (0.3 g). ESI-MS (m / z): 443.21 [M+H] + .

[0796] Step 7: 2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine

[0797] Tert-butyl 4-(6-((2-fluoro-4-(oxetane-3-yl)benzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (0.30 g, 0.68 mmol) and dichloromethane (10 mL) were added to a reaction flask, followed by trifluoroacetic acid (1 mL), and the system was reacted at room temperature for 1 hour. LCMS monitored the completion of the reaction, and the solvent was evaporated under reduced pressure. A small amount of water was added to the residue, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The product was extracted with dichloromethane, and the combined organic phases were concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give 2-((2-fluoro-4-(oxetane-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (0.15 g). ESI-MS (m / z): 343.22 [M+H]. + .

[0798] Intermediates 1.8-L to 1.8-AA were synthesized by referring to the synthesis method of the above intermediates:

[0799]

[0800]

[0801]

[0802] (S)-methyl 2-(chloromethyl)-4-methoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 1.9-A)

[0803]

[0804] Step 1: (S)-methyl 3-fluoro-4-nitro-5-((oxetan-2-yl-methyl)amino)benzoate

[0805] 3,5-Difluoro-4-nitro-benzoic acid methyl ester (1.9 g, 8.75 mmol) was added to DMF (20 mL), and K2CO3 (3.63 g, 26.25 mmol) and (S)-oxetane-2-ylmethylamine (915 mg, 10.50 mmol) were added to the reaction solution in sequence. The reaction solution was stirred at 20°C for 2 hours. After the reaction, the reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoic acid methyl ester (2.8 g). ESI-MS (m / z): 285.1 [M+H]. + .

[0806] Step 2: (S)-methyl 3-methoxy-4-nitro-5-((oxetan-2-yl-methyl)amino)benzoate

[0807] The product from the previous step (1.2 g, 4.22 mmol) was dissolved in MeOH (24 mL), and sodium methoxide (1.52 g, 8.44 mmol, 30% content) was added to the reaction mixture. The mixture was stirred at 20°C for 36 h. After the reaction, saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain methyl (S)-3-methoxy-4-nitro-5-((oxetan-2-yl-methyl)amino)benzoate (850 mg). ESI-MS (m / z): 297.1 [M+H]. + .

[0808] Step 3: (S)-methyl 4-amino-3-methoxy-5-((oxetan-2-yl-methyl)amino)benzoate

[0809] The product from the previous step (650 mg, 2.19 mmol) was dissolved in EtOH (13 mL) and H₂O (2.6 mL). NH₄Cl (587 mg, 10.97 mmol) and iron powder (368 mg, 6.59 mmol) were then added to the reaction mixture, and the reaction was stirred at 80°C for 1 h. After the reaction, the iron powder was filtered off, and the filtrate was concentrated under reduced pressure. The filtrate was then dissolved in dichloromethane and filtered, and then concentrated under reduced pressure to give (S)-methyl 4-amino-3-methoxy-5-((oxetane-2-yl-methyl)amino)benzoate (650 mg). ESI-MS (m / z): 267.0 [M+H]. + .

[0810] Step 4: (S)-methyl 2-(chloromethyl)-4-methoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0811] The product from the previous step (850 mg, 3.19 mmol) and 2-chloro-1,1,1-trimethoxyethane (592 mg, 3.83 mmol) were dissolved in MeCN (17 mL). The mixture was stirred at room temperature for 20 minutes, followed by the addition of p-toluenesulfonic acid monohydrate (61 mg, 319.20 μmol). The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to yield (S)-methyl 2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (601 mg). ESI-MS (m / z): 325.0 [M+H]. + , 1HNMR (400MHz, CDCl3) δ = 7.76 (s, 1H), 7.42 (s, 1H), 5.22 (td, J = 4.9, 7.2Hz, 1H), 5.10-4.99 (m, 2H), 4.65-4 .50(m,3H),4.31(td,J=6.0,9.2Hz,1H),4.09(s,3H),3.96(s,3H),2.80-2.69(m,1H),2.45-2.36(m,1H).

[0812] Synthesis of (S)-2-(chloromethyl)-4-isopropoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid isopropyl ester (Intermediate 1.9-B)

[0813]

[0814] Step 1: (S)-methyl 3-fluoro-4-nitro-5-(oxetan-2-ylmethyl)amino)benzoate

[0815] Methyl 3,5-difluoro-4-nitrobenzoate (1.00 g, 4.61 mmol), (S)-oxetane-2-ylmethylamine (0.48 g, 5.53 mmol), potassium carbonate (1.27 g, 9.22 mmol), and acetonitrile (15 mL) were added to a reaction flask and reacted at 60°C for 2 h. After completion of the reaction, the mixture was cooled and concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain methyl (S)-3-fluoro-4-nitro-5-(oxetane-2-ylmethyl)amino)benzoate (770 mg). ESI-MS (m / z): 285.18 [M+H] + .

[0816] Step 2: (S)-isopropyl 3-isopropoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate

[0817] The product from the previous step (700 mg, 2.46 mmol), cesium carbonate (1.6 g, 4.92 mmol), and isopropanol (15 mL) were added to a reaction flask and reacted at room temperature for 20 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain (S)-3-isopropoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoic acid isopropyl ester (400 mg). ESI-MS (m / z): 353.27 [M+H] + .

[0818] Step 3: (S)-isopropyl 4-amino-3-isopropoxy-5-((oxetan-2-ylmethyl)amino)benzoate

[0819] The product from the previous step (400 mg, 1.14 mmol), iron powder (319 mg, 5.70 mmol), ammonium chloride (302 mg, 5.70 mmol), ethanol (15 mL), and water (3 mL) were added to a reaction flask and reacted at 80°C for 1 h. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to give (S)-isopropyl 4-amino-3-isopropoxy-5-((oxetan-2-ylmethyl)amino)benzoate (320 mg). ESI-MS (m / z): 323.31 [M+H] + .

[0820] Step 4: (S)-2-(chloromethyl)-4-isopropoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid isopropyl ester. The product from the previous step (320 mg, 0.99 mmol), 2-chloro-1,1,1-trimethoxyethane (184 mg, 1.19 mmol), p-toluenesulfonic acid (19 mg, 0.10 mmol), and acetonitrile (15 mL) were added to a reaction flask and reacted at 50°C for 2 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to give (S)-2-(chloromethyl)-4-isopropoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid isopropyl ester (260 mg). ESI-MS (m / z): 381.21 [M+H]. + .

[0821] (S)-methyl 2-(chloromethyl)-4-difluoromethoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 1.9-C)

[0822]

[0823] Step 1: Methyl 3-fluoro-5-methoxy-4-nitrobenzoate

[0824] Methyl 3,5-difluoro-4-nitrobenzoate (4.5 g, 20.73 mmol) was dissolved in methanol (90 mL), and a methanol solution containing sodium methoxide (3.92 g, 21.76 mmol) was added dropwise to the reaction solution. The reaction solution was reacted at 65°C for 2.5 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain methyl 3-fluoro-5-methoxy-4-nitrobenzoate (4.5 g). ESI-MS (m / z): 230.0 [M+H] + .

[0825] Step 2: Methyl 3-fluoro-5-hydroxy-4-nitrobenzoate

[0826] The product from the previous step (4.9 g, 21.30 mmol) was dissolved in dichloromethane (50 mL), and boron tribromide (5.33 g, 21.30 mmol) was added dropwise to the reaction solution under an ice-water bath. The mixture was stirred at room temperature overnight. After the reaction, water was added and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. 3-fluoro-5-hydroxy-4-nitrobenzoic acid methyl ester (2.5 g) was separated by column chromatography (ethyl acetate: petroleum ether = 1:3). ESI-MS (m / z): 216.0 [M+H] + .

[0827] Step 3: Methyl 3-difluoromethoxy-5-fluoro-4-nitrobenzoate

[0828] The product from the previous step (2.0 g, 9.3 mmol) and sodium difluorochloroacetate were dissolved in DMF (70 mL) and water (70 mL). Cesium carbonate (6.06 g, 18.59 mmol) was then added and stirred at 100°C for 4 hours. After the reaction, the reaction solution was filtered and lyophilized to obtain methyl 3-difluoromethoxy-5-fluoro-4-nitrobenzoate (2.0 g). ESI-MS (m / z): 252.0 [M+H] + .

[0829] Step 4: (S)-methyl 3-difluoromethoxy-4-nitro-5-(oxetan-2-ylmethyl)amino)benzoate

[0830] The product from the previous step (1.5 g, 5.66 mmol) was dissolved in DMF (20 mL), followed by the addition of potassium carbonate (2.35 g, 16.97 mmol) and (S)-oxetane-2-ylmethylamine (0.74 g, 8.49 mmol). The reaction was stirred at room temperature overnight. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (ethyl acetate:petroleum ether = 1:3) was performed to obtain (S)-3-difluoromethoxy-4-nitro-5-(oxetane-2-ylmethyl)amino)benzoic acid methyl ester (1.6 g). ESI-MS (m / z): 333.1 [M+H] + .

[0831] Step 5: (S)-methyl 4-amino-3-difluoromethoxy-5-(oxetan-2-ylmethyl)amino)benzoate

[0832] The product from the previous step (1.6 g, 4.82 mmol) was dissolved in ethanol (16 mL) and water (4 mL), and then ammonium chloride (1.29 g, 24.08 mmol) and iron powder (0.87 g, 14.45 mmol) were added. The mixture was stirred at 100°C for 2 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (ethyl acetate:petroleum ether = 1:3) was performed to obtain (S)-methyl 4-amino-3-difluoromethoxy-5-(oxetan-2-ylmethyl)amino)benzoate (1.4 g). ESI-MS (m / z): 303.1 [M+H] + .

[0833] Step 6: (S)-methyl 2-(chloromethyl)-4-difluoromethoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0834] The product from the previous step (500 mg, 1.65 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 2-chloro-1,1,1-trimethoxyethane (640 mg, 4.13 mmol) and a catalytic amount of p-toluenesulfonic acid. The mixture was stirred at 60°C for 4 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Thin-layer chromatography (ethyl acetate:petroleum ether = 1:3) was used to isolate (S)-methyl 2-(chloromethyl)-4-difluoromethoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (460 mg). ESI-MS (m / z): 361.1 [M+H]. + , 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.99 (d, J = 1.4Hz, 1H), 7.75 (s, 1H), 7.54-7.32 (m, 1H), 5.24-5.12 (m, 1H), 5.04 (s, 2H),4.69-4.59(m,2H),4.58-4.50(m,1H),4.39-4.34(m,1H),3.97(s,3H),2.82-2.71m,1H),2.50-2.36(m,1H).

[0835] (S)-2-(Chloromethyl)-7-methoxy-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (Intermediate 1.9-D)

[0836]

[0837] Step 1: 2-Chloro-4-methoxy-6-methyl-3-nitropyridine

[0838] 2,4-Dichloro-6-methyl-3-nitropyridine (3 g, 14.5 mmol) and anhydrous methanol (25 mL) were added to a 100 mL round-bottom flask. Sodium methoxide (1.17 g, 21.7 mmol) was then added and stirred at 60°C for 1.5 hours. After the reaction, the mixture was concentrated to yield 2-chloro-4-methoxy-6-methyl-3-nitropyridine (2.7 g). ESI-MS (m / z): 203.1 [M+H] + .

[0839] Step 2: 6-Chloro-4-methoxy-5-nitropyridine carboxylic acid

[0840] The product from the previous step (2.7 g, 13.4 mmol) and concentrated sulfuric acid (25 mL) were added to a 100 mL round-bottom flask, and chromium oxide (2.67 g, 26.7 mmol) was added. The mixture was stirred at 60°C for 3 hours. After the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and concentrated to obtain 6-chloro-4-methoxy-5-nitropyridinecarboxylic acid (ESI-MS (m / z): 233.3 [M+H] + ), and proceed directly to the next step reaction.

[0841] Step 3: Methyl 6-chloro-4-methoxy-5-nitropyridine

[0842] The product from the previous step (2.6 g, 11.2 mmol) and anhydrous methanol (25 mL) were added to a 100 mL round-bottom flask. Thionyl chloride (2 g, 16.8 mmol) was added, and the reaction mixture was heated to 60°C with stirring for 2 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate and added with saturated aqueous sodium bicarbonate. The organic phase was concentrated, and the crude product was isolated and purified by column chromatography (ethyl acetate:petroleum ether = 1:20) to obtain methyl 6-chloro-4-methoxy-5-nitropyridinecarboxylate (2.5 g). ESI-MS (m / z): 247.3 [M+H] + .

[0843] Step 4: (S)-methyl 4-methoxy-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate

[0844] The product from the previous step (2.5 g, 10.1 mmol), (S)-oxetane-2-methylamine (1.32 g, 15.2 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (628 mg, 1.01 mmol), tris(dibenzylideneacetone)dipalladium (916 mg, 1.01 mmol), and dioxane (30 mL) were added to a 100 mL round-bottom flask. The reaction mixture was stirred at 90°C under nitrogen for 5 hours. After the reaction, the solvent was removed under reduced pressure, and the crude product was isolated and purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain (S)-4-methoxy-5-nitro-6-((oxetane-2-ylmethyl)amino)picolinic acid methyl ester (1.3 g). ESI-MS (m / z): 298.3 [M+H] + .

[0845] Step 5: (S)-methyl 5-amino-4-methoxy-6-((oxetan-2-ylmethyl)amino)picolinate

[0846] The product from the previous step (1.3 g, 4.3 mmol), iron powder (613 mg, 10.9 mmol), aqueous ammonium chloride solution (924 mg, 21.5 mmol), and ethanol (30 mL) were added to a 100 mL round-bottom flask and stirred at 80°C for 3 hours. After the reaction, the solvent was removed under reduced pressure, and the crude product was isolated and purified by column chromatography (methanol:dichloromethane = 1:20) to obtain (S)-methyl 5-amino-4-methoxy-6-((oxetan-2-ylmethyl)amino)picolinate (800 mg). ESI-MS (m / z): 268.3 [M+H] + .

[0847] Step 6: (S)-methyl 5-(2-chloroacetylamino)-4-methoxy-6-((oxetan-2-ylmethyl)amino)picolinate

[0848] The product from the previous step (800 mg, 3.0 mmol), triethylamine (605 mg, 6.0 mmol), and dichloromethane (20 mL) were added to a 50 mL round-bottom flask. Chloroacetyl chloride (504 mg, 4.5 mmol) was added dropwise at 0°C and stirred at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure, and the crude product was isolated and purified by column chromatography (methanol:dichloromethane = 1:30) to obtain (S)-methyl 5-(2-chloroacetylamino)-4-methoxy-6-((oxetan-2-ylmethyl)amino)picolinate (800 mg). ESI-MS (m / z): 344.3 [M+H]. + .

[0849] Step 7: (S)-methyl 2-(chloromethyl)-7-methoxy-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0850] The product from the previous step (800 mg, 2.33 mmol), acetic acid (0.5 mL), and tetrahydrofuran (20 mL) were added to a 50 mL round-bottom flask and stirred at 80°C for 2 hours. After the reaction, the solvent was removed under reduced pressure, and the crude product was isolated and purified by column chromatography (methanol:dichloromethane = 1:30) to obtain (S)-2-(chloromethyl)-7-methoxy-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (600 mg). ESI-MS (m / z): 326.3 [M+H] + .

[0851] (S)-methyl 2-(chloromethyl)-1-((oxetan-2-yl)methyl)-4-(trifluoromethoxy)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 1.9-E)

[0852]

[0853] Step 1: Methyl 4-amino-3-chloro-5-(trifluoromethoxy)benzoate

[0854] Methyl 4-amino-3-(trifluoromethoxy)benzoate (10 g, 42.5 mmol), NCS (6.3 g, 46.8 mmol), acetonitrile (100 mL), and DMA (10 mL) were added to a 250 mL round-bottom flask and stirred at 60°C. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain methyl 4-amino-3-chloro-5-(trifluoromethoxy)benzoate (11.5 g). ESI-MS (m / z): 270.0 [M+H] + .

[0855] Step 2: Methyl 3-chloro-4-nitro-5-(trifluoromethoxy)benzoate

[0856] Sodium perborate tetrahydrate (39.4 g, 49.2 mmol) and trifluoroacetic acid (45 mL) were added to a 250 mL round-bottom flask and stirred at 55°C. The product from the previous step (11.5 g, 42.7 mmol) pre-dissolved in trifluoroacetic acid (45 mL) was then added dropwise and stirred at 60°C. After the reaction, water was added and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain methyl 3-chloro-4-nitro-5-(trifluoromethoxy)benzoate (9 g). ESI-MS (m / z): 299.9 [M+H] + .

[0857] Step 3: (S)-methyl 4-nitro-3-((oxetan-2-ylmethyl)amino)-5-(trifluoromethoxy)benzoate

[0858] The product from the previous step (9 g, 30.1 mmol), (S)-oxetane-2-ylmethylamine (2.9 g, 33.0 mmol), cesium carbonate (19.6 g, 60.2 mmol), Pd2(dba)3 (2.8 g, 3.00 mmol), Xantphos (3.5 g, 6.00 mmol), and dioxane (100 mL) were added to a 250 mL round-bottom flask and stirred at 100°C. After completion of the reaction, the mixture was filtered and concentrated, and separated by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain (S)-methyl 4-nitro-3-((oxetane-2-ylmethyl)amino)-5-(trifluoromethoxy)benzoate (2.9 g). ESI-MS (m / z): 351.1 [M+H] + .

[0859] Step 4: (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)-5-(trifluoromethoxy)benzoate

[0860] The product from the previous step (2.9 g, 8.4 mmol), ammonium chloride (2.2 g, 41.9 mmol), iron powder (1.4 g, 25.1 mmol), anhydrous ethanol (30 mL), and water (6 mL) were added to a 100 mL round-bottom flask and stirred at 80°C. After completion of the reaction, the mixture was filtered, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated to give (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)-5-(trifluoromethoxy)benzoate (2.6 g). ESI-MS (m / z): 321.1 [M+H] + .

[0861] Step 5: (S)-methyl 2-(chloromethyl)-1-((oxetan-2-yl)methyl)-4-(trifluoromethoxy)-1H-benzo[d]imidazole-6-carboxylate

[0862] Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)-5-(trifluoromethoxy)benzoate (2.6 g, 7.8 mmol), 2-chloro-1,1,1-trimethoxyethane (6 g, 39 mmol), and anhydrous ethanol (25 mL) were added to a 100 mL round-bottom flask and stirred at 90°C. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain methyl (S)-2-(chloromethyl)-1-((oxetan-2-ylmethyl)methyl)-4-(trifluoromethoxy)-1H-benzo[d]imidazole-6-carboxylate (2.3 g). ESI-MS (m / z): 380.1 [M+H]. + .

[0863] (S)-methyl 4-(benzyloxy)-2-(chloromethyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 1.9-F)

[0864]

[0865] Step 1: Methyl 3-fluoro-5-methoxy-4-nitrobenzoate

[0866] Methyl 3,5-difluoro-4-nitrobenzoate (1.00 g, 4.61 mmol) and methanol (20 mL) were added to a reaction flask, followed by a 5 M sodium methoxide methanol solution (0.967 mL, 4.84 mmol) and stirred at room temperature. After the reaction, the reaction solution was concentrated and then purified by column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain methyl 3-fluoro-5-methoxy-4-nitrobenzoate (900 mg). ESI-MS (m / z): 230.18 [M+H] + .

[0867] Step 2: Methyl 3-fluoro-5-hydroxy-4-nitrobenzoate

[0868] The product from the previous step (0.90 g, 3.93 mmol) and dichloromethane (15 mL) were added to a reaction flask. Boron tribromide (1.48 g, 5.90 mmol) was added dropwise under an ice bath. The ice bath was removed and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain methyl 3-fluoro-5-hydroxy-4-nitrobenzoate (0.74 g). ESI-MS (m / z): 214.17 [MH] -.

[0869] Step 3: Methyl 3-(benzyloxy)-5-fluoro-4-nitrobenzoate

[0870] The product from the previous step (0.64 g, 2.98 mmol), benzyl bromide (0.61 g, 3.58 mmol), potassium carbonate (0.82 g, 5.96 mmol), potassium iodide (0.49 g, 2.98 mmol), and acetonitrile (15 mL) were added to a reaction flask and reacted at room temperature for 12 h. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain methyl 3-(benzyloxy)-5-fluoro-4-nitrobenzoate (0.82 g). ESI-MS (m / z): 306.18 [M+H] + .

[0871] Step 4: (S)-methyl 3-(benzyloxy)-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate

[0872] The product from the previous step (0.82 g, 2.68 mmol), (S)-oxetane-2-ylmethylamine (0.35 g, 4.02 mmol), potassium carbonate (1.10 g, 8.04 mmol), and acetonitrile (15 mL) were added to a reaction flask and reacted at 60°C for 2 h. After completion of the reaction, the mixture was cooled and concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain (S)-methyl 3-(benzyloxy)-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate (0.80 g). ESI-MS (m / z): 373.32 [M+H] + .

[0873] Step 5: (S)-methyl 4-amino-3-(benzyloxy)-5-((oxetan-2-ylmethyl)amino)benzoate

[0874] The product from the previous step (0.80 g, 2.15 mmol), iron powder (0.6 g, 10.75 mmol), ammonium chloride (0.57 g, 10.75 mmol), ethanol (15 mL) and water (3 mL) were added to a reaction flask and reacted at 80°C for 1 h. After the reaction, the mixture was filtered and the solvent was evaporated under reduced pressure. The filtrate was purified by column chromatography (methanol:dichloromethane=1:30) to give (S)-methyl 4-amino-3-(benzyloxy)-5-((oxetan-2-ylmethyl)amino)benzoate (0.62 g). ESI-MS (m / z): 343.31 [M+H] + .

[0875] Step 6: (S)-methyl 4-(benzyloxy)-2-(chloromethyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0876] The product from the previous step (0.62 g, 1.81 mmol), 2-chloro-1,1,1-trimethoxyethane (0.42 g, 2.72 mmol), p-toluenesulfonic acid (0.03 g, 0.18 mmol), and tetrahydrofuran (15 mL) were added to a reaction flask and reacted at 50°C for 2 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to give (S)-methyl 4-(benzyloxy)-2-(chloromethyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (0.63 g). ESI-MS (m / z): 401.10 [M+H]. + .

[0877] (S)-4-Bromo-2-chloromethyl-1-((oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid methyl ester (1.9-G)

[0878]

[0879] Step 1: (S)-methyl 3-bromo-4-nitro-5-(oxetan-2-ylmethylamino)benzoate

[0880] Methyl 3-bromo-5-fluoro-4-nitrobenzoate (1.0 g, 3.6 mmol), (S)-oxetane-2-ylmethylamine (0.37 g, 4.32 mmol), potassium carbonate (0.99 g, 7.2 mmol), and acetonitrile (15 mL) were added to a 100 mL flask and stirred at 80°C. After completion of the reaction, the mixture was cooled and concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain methyl (S)-3-bromo-4-nitro-5-(oxetane-2-ylmethylamino)benzoate (950 mg). ESI-MS (m / z): 345.0 [M+H] + .

[0881] Step 2: (S)-methyl 4-amino-3-bromo-5-(oxetan-2-ylmethyl)amino)benzoate

[0882] The product from the previous step (950 mg, 2.76 mmol) and ethyl acetate (20 mL) were added to a 100 mL flask, followed by palladium on carbon (250 mg). Triethylsilane was added with stirring and the reaction was allowed to stir at room temperature. After completion of the reaction, the filtrate was filtered and concentrated. Purification by column chromatography (methanol:dichloromethane = 1:30) afforded methyl (S)-4-amino-3-bromo-5-(oxetan-2-ylmethyl)amino)benzoate (600 mg). ESI-MS (m / z): 314.0 [M+H] + .

[0883] Step 3: (S)-4-bromo-2-chloromethyl-1-((oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid methyl ester The product from the previous step (600 mg, 1.91 mmol), 2-chloro-1,1,1-trimethoxyethane (353 mg, 0.12 mmol), p-toluenesulfonic acid (4 mg, 0.01 mmol), and acetonitrile (25 mL) were added to a round-bottom flask and stirred at 60°C. After completion of the reaction, the mixture was cooled and concentrated, and then purified by thin-layer chromatography (ethyl acetate:petroleum ether = 1:5) to obtain (S)-4-bromo-2-chloromethyl-1-((oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid methyl ester (450 mg). ESI-MS (m / z): 373.0 [M+H]. + .

[0884] Intermediates 1.9-H to 1.9-O were synthesized by referring to the synthesis method of the above intermediates:

[0885]

[0886]

[0887] Example 1: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 1)

[0888]

[0889] Step 1: Synthesis of (S)-methyl 2-((7-bromobenzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0890] Intermediate 1.1-A (500 mg, 1.93 mmol) and Intermediate 1.2-A (547 mg, 2.31 mmol) were added to acetonitrile (10 mL). TCFH (649 mg, 2.31 mmol) and NMI (554 mg, 6.75 mmol, 485 μL) were then added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 h. After completion of the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 1:5). The purified intermediate was then added to glacial acetic acid (10 mL), heated to 50°C, and stirred for 3 h. After the reaction, water was added to the reaction solution, which was then extracted with ethyl acetate, washed with NaHCO3 solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (S)-2-((7-bromobenzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (430 mg). ESI-MS (m / z): 459.1 [M+H] + .

[0891] Step 2: Synthesis of (S)-methyl 2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylate

[0892] The product from the previous step (119 mg, 259.05 μmol) and intermediate 1.7-A (200 mg, 386.65 μmol) were added to 1,4-dioxane (4 mL), and then LiCl (87 mg, 2.06 mmol, 42 μL) and Pd(PPh3)4 (4.5 mg, 3.87 μmol) were added to the mixture. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (methanol:dichloromethane = 1:15) to give (S)-methyl 2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg). ESI-MS (m / z): 607.2 [M+H]. + .

[0893] Step 3: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0894] The product from the previous step (130 mg, 214.31 μmol) was added to THF (0.2 mL) and isopropanol (0.2 mL). Then, LiOH (20.5 mg, 854.60 μmol dissolved in H2O (0.2 mL)) was added to the reaction solution at 0°C, and the mixture was slowly heated to room temperature and stirred for 4 h. After the reaction, water was added to the reaction solution, followed by extraction with chloroform. The aqueous phase was adjusted to pH 5 with 1 M acetic acid, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (methanol:dichloromethane=1:15) to give (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid (8.2 mg). ESI-MS (m / z): 593.1 [M+H]. + , 1 H NMR (400MHz, CDCl3) δ=8.25-8.18(m,1H),8.12-8.04(m,1H),7.93-7.84(m,1H),7.71-7. 62(m,4H),7.44(dd,J=0.9,7.8Hz,1H),7.38(dd,J=1.2,9.3Hz,1H),7.02-6.91(m,1H),6 .77(dd,J=2.0,6.9Hz,1H),6.11(s,2H),5.59(s,2H),5.11(dq,J=3.0,6.9Hz,1H),4.67- 4.61(m,1H),4.60-4.46(m,3H),4.46-4.39(m,2H),2.78-2.66(m,1H),2.43-2.34(m,1H).

[0895] Example 2: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 2)

[0896]

[0897] Step 1: Synthesis of (S)-methyl 2-((7-bromo-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0898] Intermediate 1.1-B (760 mg, 2.96 mmol) was added to acetonitrile (15.2 mL), followed by Intermediate 1.2-A (838.16 mg, 3.55 mmol), TCFH (995.37 mg, 3.55 mmol), and NMI (849.49 mg, 10.35 mmol). The reaction mixture was stirred at 20°C for 2.5 hours. After completion of the reaction, 20 mL of water was added to quench the reaction mixture and filtered. The filter cake was dissolved in acetic acid (17 mL), and the mixture was stirred at 50°C for 3 hours. After the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (S)-2-((7-bromo-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (760 mg). ESI-MS (m / z): 457.1 [M+H] + .

[0899] Step 2: Synthesis of (S)-methyl 2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0900] The product from the previous step (118.5 mg, 0.26 mmol) was added to 1,4-dioxane (4 mL), followed by intermediate 1.7-A (200 mg, 0.39 mmol), LiCl (87.4 mg, 2.06 mmol) and Pd(PPh3)4 (4.5 mg, 0.00387 mmol), heated to 100°C and stirred for 16 h. After the reaction, water was added to quench the reaction solution, and then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to give (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (54 mg), ESI-MS (m / z): 605.1 [M+H] + .

[0901] Step 3: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 2)

[0902] The product from the previous step (54 mg, 0.09 mmol) was dissolved in isopropanol (0.5 mL), THF (0.5 mL) and H2O (0.5 mL), and LiOH (8.6 mg, 0.36 mmol) was added. The reaction solution was stirred at 20°C for 12 hours. After the reaction, water was added to the reaction solution, followed by extraction with methyl tert-butyl ether. The aqueous phase was adjusted to pH 5 with acetic acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=1:5) to give two components, one of which was (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (6.4 mg), ESI-MS (m / z): 589.1 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ = 8.22 (s, 1H), 7.92-7.88 (m, 1H), 7.86 (d, J = 8.1Hz, 1H), 7.82-7 .76(m,3H),7.76-7.68(m,2H),7.61(d,J=8.4Hz,1H),6.85-6.77(m,2H),5.57(s,2H),4 .98(dq,J=2.3,7.1Hz,1H),4.70-4.59(m,3H),4.54(d,J=2.5Hz,1H),4.50-4.45(m,1H) ,4.41-4.31(m,3H),3.16(dt,J=3.4,8.6Hz,2H),2.68-2.65(m,1H),2.35-2.30(m,1H).

[0903] Example 3: Synthesis of (S)-2-((7-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 3)

[0904]

[0905] The synthesis method was the same as compound 2. Finally, another fraction was collected to obtain (S)-2-((7-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (1 mg). ESI-MS (m / z): 607.1 [MH] - , 1 H NMR (400MHz, DMSO-d6) δ = 8.22 (s, 1H), 8.02 (br s,1H),7.92(d,J=8.1Hz,1H),7.81-7.79(m,1H),7.79-7.76(m,2H),7.72-7.66(m,2H),7.66-7.58(m,2H),7.49(br s,1H),6.83-6.78(m,2H),5.54(s,2H),5.02-4.94(m,1H),4.70-4.62(m,3H),4.54(d,J=2.5Hz,1H),4.51-4.47 (m,1H),4.41-4.37(m,2H),4.35(dd,J=3.0,5.9Hz,1H),3.16(dt,J=3.2,8.7Hz,3H),2.69-2.64(m,1H),2.33(br dd,J=1.9,3.6Hz,1H).

[0906] Example 4: Synthesis of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 4)

[0907]

[0908] Step 1: Synthesis of (S)-methyl 2-((4-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0909] 1.1-C (760 mg, 2.96 mmol) was added to acetonitrile (15.2 mL), followed by 1.2-A (698.47 mg, 3.55 mmol), TCFH (995.37 mg, 3.55 mmol), and NMI (849.49 mg, 10.35 mmol). The reaction mixture was stirred at 20°C for 2.5 hours. After completion of the reaction, 20 mL of water was added to quench the reaction mixture, filtered, and the filter cake was dissolved in acetic acid (20 mL). The mixture was stirred at 50°C for 3 hours. After the reaction, water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (S)-2-((4-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (880 mg). ESI-MS (m / z): 457.1 [M+H] + .

[0910] Step 2: Synthesis of (S)-methyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0911] The product from the previous step (119 mg, 0.26 mmol) was added to 1,4-dioxane (4 mL), followed by the addition of intermediate 1.7-A (200 mg, 0.39 mmol), LiCl (87 mg, 2.05 mmol) and Pd(PPh3)4 (4.5 mg, 3.87 μmol), and the mixture was stirred at 100 °C for 16 h. After the reaction, water was added to the reaction solution, and then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to give (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (90 mg), ESI-MS (m / z): 605.1 [M+H] + .

[0912] Step 3: Synthesis of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 4)

[0913] The product from the previous step (80 mg, 0.13 mmol) was added to isopropanol (0.8 mL), THF (0.8 mL) and H2O (0.8 mL), and LiOH (12.7 mg, 0.53 mmol) was added. The reaction solution was stirred at 20°C for 12 hours. After the reaction, 5 mL of water was added to the reaction solution, and the mixture was extracted with methyl tert-butyl ether. The aqueous phase was adjusted to pH 5 with acetic acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (methanol:dichloromethane=1:15) to give two components, one of which was (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (24.5 mg), ESI-MS (m / z): 589.1 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.91 (d, J = 10.3Hz, 1H), 7.84 (t, J = 7.9Hz, 1H), 7.78 (d, J = 8.5Hz, 1H), 7.72 (d, J = 3.9Hz, 2H), 7.59 (br d,J=8.4Hz,1H),7.44(d,J=7.5Hz,1H),7.28(d,J=8.0Hz,1H),7.05(d,J=8.0 Hz,1H),6.89(d,J=8.1Hz,1H),5.55(s,2H),4.95(dq,J=2.8,7.2Hz,1H),4.7 0-4.61(m,1H),4.59-4.52(m,3H),4.52-4.42(m,2H),4.39-4.32(m,2H),4.2 8-4.22(m,1H),3.49(t,J=8.7Hz,2H),2.66-2.60(m,1H),2.38-2.33(m,1H).

[0914] Example 5: Synthesis of (S)-2-((4-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 5)

[0915]

[0916] The synthesis method was the same as compound 4. Finally, another fraction was collected to obtain (S)-2-((4-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (2.6 mg). ESI-MS (m / z): 607.1 [MH] - , 1 H NMR (400MHz, DMSO-d6) δ = 8.19 (s, 1H), 8.04 (s, 1H), 7.85-7.80 (m, 1H), 7.80-7.77 (m, 1H), 7.74-7.68 (m, 2H), 7. 64-7.59(m,1H),7.58-7.54(m,1H),7.52-7.49(m,1H),7.43(d,J=7.4Hz,1H),7.30(d,J=8.1Hz,1H),7.05(d,J= 8.0Hz,1H),6.87(d,J=8.1Hz,1H),5.51(s,2H),4.99-4.91(m,1H),4.69-4.60(m,1H),4.59-4.53(m,2H),4.53- 4.43(m,2H),4.39-4.32(m,2H),4.28-4.21(m,1H),3.52(t,J=8.6Hz,2H),2.69-2.64(m,1H),2.34-2.31(m,1H).

[0917] Example 6: Synthesis of 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 6)

[0918]

[0919] Step 1: Synthesis of methyl 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0920] Take (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (34 mg, 0.058 mmol), iodomethane (17 mg, 0.12 mmol), potassium carbonate (17 mg, 0.12 mmol) and DMF (1 mL), stir at room temperature for half an hour, add iodomethane (17 mg, 0.12 mmol) and sodium hydride (5 mg, 0.12 mmol), and continue stirring at room temperature. After the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (methanol:dichloromethane = 1:30) to give methyl 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (23 mg). ESI-MS (m / z): 619.5 [M+H]. + .

[0921] Step 2: Synthesis of 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0922] Methyl 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (23 mg, 0.037 mmol), lithium hydroxide (5 mg, 0.19 mmol), isopropanol (0.5 mL), tetrahydrofuran (0.5 mL) and water (0.5 mL) were added to a 25 mL round-bottom flask and stirred at 50°C. After the reaction, the pH was adjusted to 6 with acetic acid, and the mixture was concentrated. The mixture was separated by thin-layer chromatography (methanol:dichloromethane = 1:15) to give 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (13 mg). ESI-MS (m / z): 605.2 [M+H]. + , 1H NMR (600MHz, CDCl3) δ8.15–8.02(m,2H),7.97–7.77(m,3H),7.70–7.59(m,2H),7.47–7.33(m,2H),6.77–6.64(m,2H),5.64–5.54(m,2H),4.94–4. 83(m,1H),4.74–4.58(m,3H),4.57–4.49(m,1H),4.36–4.25(m,1H),4.2 0–4.08(m,2H),3.06–2.85(m,2H),2.72–2.51(m,2H),1.91–1.84(m,3H).

[0923] Example 7: Synthesis of (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 7)

[0924]

[0925] Step 1: Synthesis of (S)-methyl 2-((7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0926] (S)-2-((7-bromo-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (300 mg, 0.65 mmol) was dissolved in DMF (6 mL), and then NCS (70 mg, 0.52 mmol) was added. The mixture was stirred at 60°C for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (methanol:dichloromethane = 1:50) to give (S)-2-((7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (138 mg). ESI-MS (m / z): 491.1 [M+H]. + .

[0927] Step 2: Synthesis of (S)-methyl 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0928] The product from the previous step (100 mg, 0.20 mmol) was added to 1,4-dioxane (2 mL), followed by 1.7-A (105 mg, 0.20 mmol), Pd(PPh3)4 (7.0 mg, 0.06 mmol), and LiCl (46 mg, 1.08 mmol). The reaction mixture was heated to 100°C and stirred for 48 h. After the reaction, water was added to the reaction solution, and then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (150 mg). ESI-MS (m / z): 639.2 [M+H]. + .

[0929] Step 3: Synthesis of (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0930] The product from the previous step (7 mg, 0.10 mmol) was added to isopropanol (0.7 mL), THF (0.7 mL) and H2O (0.7 mL), and LiOH (10.5 mg, 0.43 mmol) was added. The reaction solution was stirred at 20°C for 12 h. After the reaction, water was added to the reaction solution, and the mixture was extracted with methyl tert-butyl ether. The aqueous phase was adjusted to pH 5 with acetic acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (methanol:dichloromethane=1:15) to give (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (5.34 mg). ESI-MS (m / z): 623.1 [MH] - , 1H NMR(400MHz,DMSO-d6)δ=12.75(br s,1H),8.24(d,J=1.0Hz,1H),7.92(d,J=10.4Hz,1H),7.86-7.81(m,2H),7.81-7.70(m,4H),7.55 (d,J=8.4Hz,1H),6.92-6.89(m,1H),5.59(s,2H),5.17-5.04(m,1H),4.81-4.73(m,1H),4.70(br t,J=8.7Hz,2H),4.52-4.45(m,2H),4.37(td,J=6.1,9.1Hz,1H),3.79-3.61(m,2H) ,3.13(dt,J=3.6,8.2Hz,2H),2.73(ddd,J=3.0,5.8,8.3Hz,1H),2.44-2.36(m,1H).

[0931] Example 8: Synthesis of 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 8)

[0932]

[0933] Step 1: Synthesis of methyl 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0934] Intermediate 1.7-B (320 mg, 577.9 μmol) was dissolved in 1,4-dioxane (3.2 mL), and then intermediate (S)-2-((7-bromobenzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (132 mg, 288.95 μmol), LiCl (131 mg, 3.08 mmol) and Pd(PPh3)4 (33.4 mg, 28.90 μmol) were added. The reaction was stirred at 120°C for 16 h. After the reaction, the reaction solution was filtered, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (methanol:dichloromethane=1:30) to give methyl 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (140 mg). ESI-MS (m / z): 641.1 [M+H]. + .

[0935] Step 2: Synthesis of 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0936] The product from the previous step (120 mg, 187.18 μmol) was added to THF (0.12 mL), isopropanol (0.12 mL) and H2O (0.12 mL), and then LiOH (18 mg, 748.73 μmol) was added. The reaction solution was stirred at 20°C for 16 h. After the reaction, the reaction solution was diluted with water, extracted with methyl tert-butyl ether, adjusted to pH 5 with acetic acid, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (methanol: dichloromethane = 1:15) to give 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (36.3 mg), ESI-MS (m / z): 625.1 [MH] - , 1H NMR (400MHz, DMSO-d6) δ = 12.76 (br s, 1H), 8.24 (s, 1H), 7.83-7.77 (m, 1H), 7.69 (t, J = 8.4Hz, 1H), 7.63 (d, J = 8.4Hz, 1H), 7.56 (br d,J=12.2Hz,1H),7.39-7.34(m,1H),7.26(d,J=7.8Hz,1H),7.07(dd,J=2.0,7.1Hz,1H),6.94-6.86(m,2H), 6.76(d,J=8.1Hz,1H),5.03-4.93(m,1H),4.70-4.44(m,5H),4.40-4.32(m,3H),3.22-3.12(m,2H),2.67(br t,J=8.6Hz,1H),2.42-2.34(m,1H),2.02(s,3H).

[0937] Example 9: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 9)

[0938]

[0939] Step 1: Synthesis of (S)-methyl 2-((7-bromo-1H-indol-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0940] 2-(7-Bromo-1H-indol-4-yl)acetic acid (1.1-D) (250 mg, 1 mmol) and N,N-dimethylformamide (25 mL) were added to a 100 mL flask. HATU (57 mg, 1.5 mmol) and triethylamine (305 mg, 3 mmol) were then added. Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (305 mg, 1.3 mmol) was then added with stirring and the mixture was allowed to react at room temperature. After completion of the reaction, the reaction solution was added to water and extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:10). The purified intermediate (300 mg) and glacial acetic acid (5 mL) were added to a 100 mL flask and heated to 120°C with stirring. After the reaction, the reaction solution was added to water and extracted with ethyl acetate, washed with aqueous sodium bicarbonate solution, and concentrated. The crude product was separated and purified by column chromatography (methanol:dichloromethane = 1:50) to give (S)-2-((7-bromo-1H-indol-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (220 mg). ESI-MS (m / z): 454.1 [M+H] + .

[0941] Step 2: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[0942] (S)-2-((7-Bromo-1H-indol-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (220 mg, 0.49 mmol), bispinacol boronate (247 mg, 0.97 mmol), Pd(dppf)Cl2 (71 mg, 0.097 mmol), potassium acetate (95 mg, 0.97 mmol) and dioxane (10 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at 100° C. under a nitrogen atmosphere. After completion of the reaction, the mixture was concentrated and the crude product was purified by column chromatography (methanol:dichloromethane=1:30) to give (S)-1-(oxetan-2-ylmethyl)-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (180 mg). ESI-MS (m / z): 502.2 [M+H] + .

[0943] Step 3: Synthesis of (S)-methyl 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0944] (S)-1-(oxetan-2-ylmethyl)-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.16 mmol), 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (50 mg, 0.16 mmol), Pd(dppf)Cl2 (23 mg, 0.032 mmol), potassium carbonate (66 mg, 0.48 mmol), dioxane (5 mL) and water (2 mL) were added to a 100 mL flask. The mixture was stirred at 80°C under a nitrogen atmosphere. After the reaction, the reaction solution was added to water, followed by extraction with ethyl acetate, drying, and concentration. The crude product was purified by thin plate chromatography (methanol: dichloromethane = 1:30) to give (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1H-indol-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (20 mg). ESI-MS (m / z): 611.2 [M+H]. + .

[0945] Step 4: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0946] (S)-methyl 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1H-indol-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.082 mmol), sodium hydroxide (33 mg, 0.82 mmol), methanol (4 mL), tetrahydrofuran (4 mL) and water (2 mL) were added to a 25 mL flask. The reaction was stirred at room temperature. After completion of the reaction, the organic solvent was removed by concentration, glacial acetic acid was added to adjust the pH to 3 and the mixture was concentrated. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to give (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (21 mg). ESI-MS (m / z): 597.2 [M+H] + , 1 H NMR (600MHz, CDCl3) δ10.46(s,1H),8.12(s,1H),8.05(d,J=6.5Hz,1H),7.86(d,J=7.1Hz,1H) ,7.76-7.68(m,1H),7.61-7.54(m,2H),7.50–7.42(m,1H),7.21-7.14(m,3H),6.95(d,J=6.6Hz ,1H),6.80(d,J=7.2Hz,1H),6.66(s,1H),5.56(s,2H),4.99–4.90(m,1H),4.86-4.79(m,2H),4 .61–4.53(m,1H),4.41–4.33(m,1H),3.95-3.87(m,2H),2.51-2.48(m,1H),2.15-2.11(m,1H).

[0947] Example 10: Synthesis of 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1H-indol-4-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 10)

[0948]

[0949] Referring to the synthesis method of compound 8, 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1H-indol-4-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (3 mg) was obtained. ESI-MS (m / z): 624.2 [M+H] + , 1 H NMR (600MHz, DMSO) δ12.75(s,1H),10.86(s,1H),8.20(s,1H),7.79(d,J=8.5Hz,1H),7.63(d,J=8 .4Hz,1H),7.52-7.47(m,2H),7.31-7.30(m,2H),7.13(d,J=7.2Hz,1H),7.06-7.05(m,1H),7.02-6 .99(m,2H),6.93(d,J=7.4Hz,1H),6.63(s,1H),4.82-4.77(m,1H),4.69-4.60(m,3H),4.50-4.48 (m,1H),4.44-4.42(m,1H),4.35-4.32(m,1H),2.43-2.40(m,1H),2.29-2.23(m,1H),2.05(s,3H).

[0950] Example 11: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-methyl-1H-indol-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 11)

[0951]

[0952] Step 1: Synthesis of (S)-methyl 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-methyl-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0953] (S)-methyl 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.11 mmol) and N,N-dimethylformamide (5 mL) were added to a 100 mL flask, followed by cesium carbonate (375 mg, 1.15 mmol) and iodomethane (163 mg, 1.15 mmol). The mixture was stirred at room temperature. After the reaction, the mixture was added to water and extracted with ethyl acetate. The mixture was dried and concentrated. The crude product was purified by column chromatography (methanol:dichloromethane = 1:30) to give (S)-methyl 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-methyl-1H-indol-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg). ESI-MS (m / z): 625.2 [M+H]. + .

[0954] Step 2: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-methyl-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0955] (S)-methyl 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-methyl-1H-indol-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.096 mmol), sodium hydroxide (40 mg, 1 mmol), methanol (4 mL), tetrahydrofuran (4 mL), and water (2 mL) were added to a 100 mL flask. The reaction was stirred at 50°C. After completion of the reaction, the organic solvent was removed under reduced pressure, and the pH was adjusted to 3 with acetic acid. The mixture was further concentrated, and the crude product was purified by column chromatography (methanol:dichloromethane=1:15) to give (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-methyl-1H-indol-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg). ESI-MS (m / z): 611.2 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ12.69(s,1H),8.20(s,1H),7.85(t,J=7.8Hz,1H),7.78(d,J=8.4Hz,1H),7.62( d,J=8.4Hz,1H),7.56(t,J=7.9Hz,1H),7.45(d,J=9.7Hz,1H),7.34-7.25(m,2H),7.20(d,J=7.2Hz,1H) ,7.01(d,J=7.3Hz,1H),6.92(d,J=6.2Hz,2H),6.63(s,1H),5.36(s,2H),4.90-4.85(m,1H),4.70-4.66 (m,2H),4.63-4.59(m,1H),4.50-4.45(m,2H),4.38-4.34(m,1H),2.62-2.56(m,1H),2.32-2.27(m,1H).

[0956] Example 12: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 12)

[0957]

[0958] Referring to the synthesis of compound 7, 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid (1.1-F) and (1.2-A) were used as raw materials to obtain (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg). ESI-MS (m / z): 618.2 [M+H] + , 1H NMR(600MHz,DMSO-d6)δ8.22(s,1H),7.83-7.79(m,2H),7.78-7.73(m,2H),7.60-7.58(m,1H),7 .56(d,J=8.4Hz,1H),7.48(dd,J=9.9,1.7Hz,1H),7.31(dd,J=8.2,1.5Hz,1H),6.86-6.80(m,1H ),5.51(s,2H),5.09-5.05(m,1H),4.76-4.72(m,1H),4.68(t,J=8.8Hz,2H),4.62-4.59(m,1H), 4.52-4.45(m,2H),4.39-4.33(m,2H),3.15-3.10(m,2H),2.72-2.69(m,1H),2.41-2.35(m,1H).

[0959] Example 13: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 13)

[0960]

[0961] Referring to the synthesis method of compound 12, 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid (1.1-F) and intermediate 1.2-B were used as raw materials to obtain (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg). ESI-MS (m / z): 627.2 [M+H] + , 1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),8.12(s,1H),7.91(d,J=9.9Hz,1H),7.84-7.81(m,2H) ,7.76-7.70(m,2H),7.68(d,J=11.6Hz,1H),7.49(d,J=11.3Hz,1H),6.89-6.87(m,1H),5.60 (s,2H),5.08-5.04(m,1H),4.79-4.75(m,1H),4.69(t,J=9.0Hz,2H),4.65-4.62(m,1H),4.5 1-4.47(m,2H),4.41-4.33(m,2H),3.16-3.09(m,2H),2.73-2.68(m,1H),2.40-2.34(m,1H).

[0962] Example 14: Synthesis of 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 14)

[0963]

[0964] Referring to the synthesis method of compound 12, 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid (1.1-F) and intermediate 1.2-D were used as raw materials to obtain 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (32 mg). ESI-MS (m / z): 634.2 [M+H] + , 1 H NMR (600MHz, CDCl3) δ8.20(s,1H),8.01(d,J=8.2Hz,1H),7.83(d,J=11.4Hz,1H ),7.79-7.75(m,2H),7.61-7.59(m,1H),7.47-7.44(m,1H),7.13-7.12(m,2H), 6.70(d,J=8.1Hz,1H),5.50(s,2H),4.67(t,J=8.4Hz,2H),4.47-4.35(m,4H),4 .18-4.13(m,1H),4.10-4.05(m,1H),3.20(t,J=8.5Hz,2H),0.83-0.77(m,4H).

[0965] Example 15: Synthesis of 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 15)

[0966]

[0967] Step 1: Synthesis of methyl 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0968] Methyl 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 14, 60 mg, 0.093 mmol) and N,N-dimethylformamide (5 mL) were added to a 100 mL flask, and iodomethane (66 mg, 0.46 mmol) and cesium carbonate (91 mg, 0.28 mmol) were added and stirred at room temperature. After the reaction, the reaction solution was added to water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by thin plate chromatography (methanol: dichloromethane = 1:50) to give methyl 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg). ESI-MS (m / z): 662.2 [M+H]. + .

[0969] Step 2: Synthesis of 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0970] Methyl 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, 0.045 mmol) and tetrahydrofuran (4 mL) were added to a 25 mL flask, followed by methanol (4 mL), sodium hydroxide (18 mg, 0.45 mmol) and water (4 mL), and the reaction was stirred at 50°C. After the reaction, the temperature was lowered and 0.1 mL of glacial acetic acid was added. The mixture was stirred at room temperature for 10 minutes and then concentrated. The crude product was separated and purified by thin-layer chromatography (methanol:dichloromethane = 1:30) to give 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (21 mg). ESI-MS (m / z): 648.1 [M+H]. + , 1 H NMR (600MHz, CDCl3) δ8.45 (s, 1H), 8.11 (d, J = 6.0Hz, 1H), 7.94-7.90 (m, 3H), 7.68-7.66 (m, 1H), 7.47-7.43 (m, 1H), 7.14-7.11 (m, 2H), 6.78 ( d,J=8.1Hz,1H),5.50(s,2H),4.90(br,2H),4.79-4.76(m,2H),4.09(d,J=47.8Hz,2H),3.46-3.43(m,2H),0.88-0.84(m,2H),0.70(br,2H).

[0971] Example 16: Synthesis of 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 16)

[0972]

[0973] Step 1: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propionitrile

[0974] 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile (300 mg, 1.27 mmol) and tetrahydrofuran (10 mL) were added to a 100 mL flask. Methyl iodide (899 mg, 6.33 mmol) and cesium carbonate (2.1 g, 6.33 mmol) were added and stirred at room temperature. After the reaction, the mixture was added to water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin-layer chromatography (ethyl acetate:petroleum ether = 1:15) to obtain 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propionitrile (200 mg).

[0975] Step 2: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propanoic acid

[0976] 2-(7-Bromo-2,3-dihydrobenzofuran-4-yl)propionitrile (200 mg, 0.8 mmol) and ethanol (5 mL) were added to a 100 mL flask, potassium hydroxide (446 mg, 8 mmol) and water (10 mL) were added, and the mixture was stirred at 100°C. After the reaction was completed, the temperature was lowered and the mixture was adjusted to acidity with 1N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin plate chromatography (ethyl acetate: petroleum ether = 1:10) to obtain 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propanoic acid (180 mg).

[0977] Step 3: Synthesis of methyl 2-(1-(7-bromo-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0978] 2-(7-Bromo-2,3-dihydrobenzofuran-4-yl)propanoic acid (180 mg, 0.67 mmol) and N,N-dimethylformamide (10 mL) were added to a 100 mL flask. HATU (382 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) were added and stirred at room temperature for 10 minutes. Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.2-D, 203 mg, 0.8 mmol) was added and allowed to react at room temperature. After the reaction, the mixture was added to water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. This crude product and glacial acetic acid (10 mL) were added to a 100 mL flask and heated to 120°C with stirring. After the reaction, the temperature was lowered and the mixture was added to ethyl acetate. The mixture was then washed with water and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin plate chromatography (methanol:dichloromethane = 1:50) to give methyl 2-(1-(7-bromo-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (240 mg). ESI-MS (m / z): 487.1 [M+H] + .

[0979] Step 4: Synthesis of methyl 1-((1-(fluoromethyl)cyclopropyl)methyl)-2-(1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1H-benzo[d]imidazole-6-carboxylate

[0980] Methyl 2-(1-(7-bromo-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (240 mg, 0.49 mmol), pinacol diboron (752 mg, 2.96 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol), potassium acetate (115 mg, 1.47 mmol) and dioxane (10 mL) were added to a 100 mL flask, and the mixture was stirred in a nitrogen atmosphere at 100 ° C. After completion of the reaction, the reaction mixture was cooled and concentrated, and the crude product was separated and purified by column chromatography (methanol:dichloromethane = 1:30) to obtain methyl 1-((1-(fluoromethyl)cyclopropyl)methyl)-2-(1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1H-benzo[d]imidazole-6-carboxylate (170 mg). ESI-MS (m / z): 535.3 [M+H] + .

[0981] Step 5: Synthesis of methyl 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0982] Methyl 1-((1-(fluoromethyl)cyclopropyl)methyl)-2-(1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.13 mmol), 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (41 mg, 0.13 mmol), Pd(dppf)Cl2 (19 mg, 0.026 mmol), potassium carbonate (54 mg, 0.39 mmol), dioxane (8 mL) and water (4 mL) were added to a 100 mL flask and the mixture was stirred under a nitrogen atmosphere at 80°C. After the reaction, the temperature was lowered and the mixture was added to water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin plate chromatography (methanol:dichloromethane = 1:50) to give methyl 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (65 mg). ESI-MS (m / z): 644.2 [M+H]. + .

[0983] Step 6: Synthesis of 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0984] Methyl 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (65 mg, 0.1 mmol) and tetrahydrofuran (4 mL) were added to a 100 mL flask. Methanol (4 mL), sodium hydroxide (40 mg, 1 mmol) and water (4 mL) were added, and the reaction was heated to 50°C with stirring. After the reaction, the temperature was lowered, glacial acetic acid (0.1 mL) was added, and the mixture was stirred at room temperature for 10 minutes, then concentrated. The crude product was separated and purified by thin-layer chromatography (methanol:dichloromethane = 1:30) to give 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg). ESI-MS (m / z): 630.2 [M+H]. + , 1 H NMR (600MHz, DMSO-d6) δ12.65(s,1H),8.19(s,1H),7.89(d,J=8.2Hz,1H),7.83(d,J=8.4Hz,1H),7.77-7. 73(m,3H),7.57-7.54(m,1H),7.46(d,J=9.9Hz,1H),7.28(d,J=8.1Hz,1H),6.76(d,J=7.4Hz,1H),6.65(d, J=8.3Hz,1H),5.43(s,2H),4.71-4.67(m,2H),4.57-4.53(m,1H),4.30(d,J=15.4Hz,1H),4.22(d,J=15.4H z,1H),4.18-4.03(m,2H),3.29-3.25(m,1H),3.20-3.16(m,1H),1.73(d,J=6.6Hz,3H),0.69-0.59(m,4H).

[0985] Example 17: Synthesis of 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 17)

[0986]

[0987] Referring to the synthesis method of compound 16, 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (21 mg) was synthesized using 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile as the starting material. ESI-MS (m / z): 621.2 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ12.76(s,1H),8.19(d,J=1.2Hz,1H),7.88(d,J=9.0Hz,1H),7.83-7.82(m,2H),7.79-7. 73(m,3H),7.72-7.67(m,2H),6.81(dd,J=7.9,0.7Hz,1H),6.64(d,J=8.3Hz,1H),5.53(s,2H),4.70-4.67(m,2H) ,4.55(q,J=6.9Hz,1H),4.30(d,J=15.4Hz,1H),4.22(d,J=15.4Hz,1H),4.18(d,J=10.2Hz,0.5H),4.12-4.08(m ,1H),4.04(d,J=10.2Hz,0.5H),3.28-3.24(m,1H),3.19-3.15(m,1H),1.73(d,J=7.2Hz,3H),0.69-0.59(m,4H).

[0988] Example 18: Synthesis of 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 18)

[0989]

[0990] Referring to the synthesis method of compound 14, 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid (1.1-E) and 1.2-C were used as raw materials to obtain 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg). ESI-MS (m / z): 648.2 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ12.78 (s, 1H), 8.26 (d, J = 1.2Hz, 1H), 7.92-7.89 (m, 1H), 7.85-7. 82(m,2H),7.81-7.89(m,1H),7.77(dd,J=8.4,1.5Hz,1H),7.72-7.70(m,2H),7.56(d,J=8 .4Hz,1H),6.90(dd,J=8.1Hz,0.6Hz,1H),5.59(s,2H),4.73(t,J=8.8Hz,2H),4.59(s,2H ), 4.43 (s, 2H), 3.22 (t, J = 8.8Hz, 2H), 2.69 (s, 2H), 0.78-0.77 (m, 2H), 0.75-0.73 (m, 2H).

[0991] Example 19: Synthesis of 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 19)

[0992]

[0993] Referring to the synthesis method of compound 14, 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid (1.1-E) and (1.2-E) were used as raw materials to obtain 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (42 mg). ESI-MS (m / z): 649.2 [M+H] + , 1 H NMR(600MHz,DMSO-d6)δ12.97(s,1H),8.04(d,J=8.2Hz,1H),7.95(d,J=8.2Hz,1H) ,7.91(d,J=9.4Hz,1H),7.85-7.83(m,2H),7.80(d,J=7.1Hz,1H),7.74-7.70(m,2H ),6.92-6.89(m,1H),5.59(s,2H),4.74(t,J=8.8Hz,2H),4.55(s,2H),4.50(s,2H) ,3.24(t,J=8.8Hz,2H),2.80(s,2H),1.10(t,J=5.3Hz,2H),0.72(t,J=5.4Hz,2H).

[0994] Example 20: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-inden-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 20)

[0995]

[0996] Referring to the synthetic method of compound 14, 2-(7-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid and intermediate 1.2-A were used as raw materials to obtain (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-inden-4-yl)methyl)-1-(oxetane-2-ylmethyl)-

[0997] 1H-Benzo[d]imidazole-6-carboxylic acid (42 mg), ESI-MS (m / z): 610.2 [MH] - ,H NMR (600MHz, CDCl3) δ8.11–8.05(m,2H),7.88(d,J=8.5Hz,1H),7.59(t,J=7.8Hz,1H),7.52(d,J=7.7Hz,1H),7.45–7.40 (m,2H),7.19(d,J=7.4Hz,1H),7.11(dd,J=8.2,2.3Hz,1H),7.09–7.05(m,1H),6.75(d,J=8.2Hz,1H),5.35(s,2H),5.21–

[0998] 5.14(m,1H),4.74–4.60(m,3H),4.43–4.35(m,2H),4.31(d,J=15.3Hz,1H),3.14–3.09(m,2H),2.74–

[0999] 2.72(m,2H),2.44–2.34(m,2H).

[1000] Example 21: (S)-4-Acetylamino-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid (Compound 21)

[1001]

[1002] Step 1: (S)-methyl 4-bromo-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylate

[1003] (S)-methyl 4-bromo-2-chloromethyl-1-((oxetane-2-yl)methyl)-1H-benzimidazole-6-carboxylate (1.9-G, 170 mg, 0.45 mmol), 4-fluoro-3-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 1.8-F, 58 mg, 0.50 mmol), potassium carbonate (600 mg, 1.80 mmol), potassium iodide (5 mg) and DMF (15 mL) were added to a 100 mL round-bottom flask and the reaction was stirred at room temperature. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and separated by thin plate chromatography (methanol:dichloromethane=1:30) to give (S)-4-bromo-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-2-ylmethyl-1H-benzimidazole-6-carboxylic acid methyl ester (150 mg). ESI-MS (m / z): 648.2 [M+H]. + .

[1004] Step 2: (S)-methyl 2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-(diphenylmethylene)amino)-1-(((S)-oxetan-2-yl)methyl)-2-ylmethyl-1H-benzimidazole-6-carboxylate

[1005] The product from the previous step (150 mg, 0.23 mmol), dibenzhydryl imine (50.3 mg, 0.28 mmol), bis(dibenzylideneacetone) palladium (42 mg, 0.20 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.40 mmol) and cesium carbonate (60 mg, 0.46 mmol) were added to a 100 mL flask, and then toluene (20 mL) was added and the reaction was heated to 130 °C with stirring. After the reaction, the temperature was lowered, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (methanol:dichloromethane = 1:30) to give (S)-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-(diphenylmethylene)amino)-1-(((S)-oxetane-2-yl)methyl)-2-ylmethyl-1H-benzimidazole-6-carboxylic acid methyl ester (120 mg). ESI-MS (m / z): 749.3 [M+H]. + .

[1006] Step 3: (S)-methyl 4-amino-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl))-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylate

[1007] The product from the previous step (120 mg, 0.16 mmol) was added to a 100 mL flask, followed by tetrahydrofuran (10 mL) and water (10 mL). Citric acid (200 mg) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to alkaline with aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (methanol:dichloromethane = 1:15) was performed to obtain (S)-methyl 4-amino-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylate (62 mg). ESI-MS (m / z): 585.2 [M+H]. + .

[1008] Step 4: (S)-methyl 4-acetamido-2((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylate

[1009] The product from the previous step (62 mg, 0.11 mmol) was added to a 100 mL round-bottom flask, followed by dichloromethane (30 mL), acetyl chloride (10 mg, 0.13 mmol), and triethylamine (23 mg, 0.22 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and then purified by column chromatography (methanol:dichloromethane = 1:20) to obtain (S)-methyl 4-acetylamino-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylate (26 mg). ESI-MS (m / z): 627.1 [M+H]. + .

[1010] Step 5: (S)-4-Acetylamino-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid

[1011] The product from the previous step (26 mg, 0.04 mmol) was added to a 100 mL round-bottom flask, followed by the addition of lithium hydroxide (5 mg, 0.20 mmol), isopropyl alcohol (1.5 mL), tetrahydrofuran (1.5 mL), and water (1.5 mL). The mixture was stirred at room temperature. After completion of the reaction, the pH was adjusted to 8 with dilute hydrochloric acid, the mixture was concentrated, and the mixture was separated by thin-layer chromatography (methanol:dichloromethane = 1:15) to afford (S)-4-acetamido-2-((4-(6-((5-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid (8 mg). ESI-MS (m / z): 613.1 [M+H]. + .

[1012] Example 22: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 22)

[1013]

[1014] Step 1: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[1015] 5-Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B, 22 mg, 0.067 mmol), (S)-methyl 2-(chloromethyl)-4-methoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (1.9-A, 24 mg, 0.074 mmol), potassium carbonate (27 mg, 0.2 mmol), potassium iodide (11 mg, 0.067 mmol) and N,N-dimethylformamide (5 mL) were added to a 100 mL round-bottom flask and stirred at room temperature for reaction. After the reaction, water was added and the mixture was extracted with ethyl acetate. The mixture was dried and concentrated. The crude product was separated and purified by thin plate chromatography (methanol: dichloromethane = 1:20) to give methyl 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (35 mg). ESI-MS (m / z): 619.2 [M+H]. + .

[1016] Step 2: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1017] The product from the previous step (35 mg, 0.056 mmol), sodium hydroxide (32 mg, 0.81 mmol), methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL) were added to a 25 mL round-bottom flask and heated to 50°C with stirring. After the reaction, the temperature was lowered and acetic acid was added to adjust the pH to acidic. The mixture was concentrated, and the crude product was isolated and purified by thin-layer chromatography (methanol:dichloromethane = 1:15) to give 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (26 mg). ESI-MS (m / z): 605.2 [M+H]. + , 1H NMR (600MHz, DMSO-d6) δ7.23-7.21(m,2H),7.09-7.06(m,2H),6.87-6.85(m,4H),4.15(t,J=7.1Hz,1.5H), 4.09(t,J=7.0Hz,0.5H),3.72(s,3H),3.71(s,3H),3.70-3.68(m,3H),3.66-3.63(m,1H),3.54-3.48(m,2H ),3.41-3.38(m,1H),3.16-3.12(m,0.5H),3.04-2.96(m,2.5H),2.94-2.88(m,0.5H),2.81-2.76(m,1.5H) ,2.73-2.70(m,0.5H),2.58-2.53(m,0.5H),2.45-2.39(m,1H),2.35-2.29(m,1.5H),2.20-2.16(m,0.5H).

[1018] Example 23: Synthesis of 2-((1R)-1-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)ethyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 23A) and 2-((1S)-1-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)ethyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 23B)

[1019]

[1020] Step 1: Ethyl 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)propanoate

[1021] 5-Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B, 77 mg, 232.0 μmol) and acetonitrile (2 mL) were added to a 25 mL round-bottom flask. Potassium carbonate (128 mg, 928 μmol) and ethyl 2-bromopropionate (46 mg, 255 μmol) were then added and stirred at room temperature. After completion of the reaction, the mixture was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:1) to afford ethyl 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)propanoate (95 mg). ESI-MS (m / z): 431.2 [M+H] + .

[1022] Step 2: 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)propanoic acid

[1023] The product from the previous step (95 mg, 220.9 μmol), methanol (2 mL), and tetrahydrofuran (0.5 mL) were added to a 25 mL round-bottom flask, followed by the addition of sodium hydroxide (35 mg, 88.2 μmol). The reaction mixture was stirred at room temperature. After the reaction, water was added, and the pH was adjusted with hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried in a rotary evaporation chamber to obtain 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)propanoic acid (89 mg). ESI-MS (m / z): 403.2 [M+H] + .

[1024] Step 3: 2-(1-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)ethyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[1025] The product from the previous step (89 mg, 220.9 μmol), methyl (R)-4-amino-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate methanol (71 mg, 265.1 μmol), (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (126 mg, 331.4 μmol), and N,N-dimethylformamide (2 mL) were added to a 25 mL round-bottom flask. N,N-diisopropylethylamine (85 mg, 663.1 μmol) was then added dropwise. The reaction mixture was stirred at room temperature. After the reaction, water was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 118 mg of the intermediate. This intermediate was then dissolved in acetic acid (8 mL) and stirred at 120°C. After the reaction, the mixture was dried and purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give methyl 2-(1-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)ethyl)-4-methoxy-1-(((R)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (119 mg). ESI-MS (m / z): 633.2 [M+H] + .

[1026] Step 4: 2-(1-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)ethyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1027] The product from the previous step (119 mg, 187.9 μmol), methanol (2 mL), tetrahydrofuran (2 mL), water (1 mL), and lithium hydroxide (32 mg, 751.8 μmol) were added to a 25 mL round-bottom flask, and the reaction solution was stirred at room temperature. After the reaction, water was added to the reaction solution, the pH was adjusted with acetic acid, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. Two main components were separated by thin-layer chromatography (methanol: dichloromethane = 1:20), one of which was compound 2-((1R)-1-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)ethyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg), ESI-MS (m / z): 619.2 [M+H] + , 1H NMR(600MHz, CDCl3)δ8.60(s,1H),7.76–7.58(m,3H),7.26(s,1H),6.78(t,J=7.6Hz,1H),6.71(m,2H),5.23-5 .15(m,1H),5.03-5.02(m,1H),4.88-4.82(m,1H),4.65-4.59(m,2H),4.34(dd,J=14.7,6.5Hz,1H),4.03(s,3H ),3.52-3.38(m,2H),3.10-3.25(m,1H),2.81–2.74(m,2H),2.68-2.60(m,1H),2.57–2.49(m,1H),2.24–2.15( m,1H),2.08–2.04(m,1H),2.02(d,J=9.4Hz,3H),1.99-1.96(m,1H),1.94–1.87(m,1H),1.73(d,J=6.4Hz,3H).

[1028] Finally, another component obtained by separation and purification was 2-((1S)-1-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)ethyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (19 mg). ESI-MS (m / z): 619.2 [M+H] + , 1 H NMR(600MHz, CDCl3)δ8.60(d,J=7.8Hz,1H),7.69-7.59(m,3H),7.32(s,1H),6.75(t,J=7.5Hz,1H),6.7 1(d,J=7.6Hz,1H),6.68(d,J=7.6Hz,1H),5.27-5.24(m,1H),5.11-5.05(m,1H),4.87-4.81(m,1H),4.5 3-4.48(m,1H),4.43-4.37(m,1H),4.08-4.05(m,4H),3.47-3.37(m,1H),3.06-2.96(m,1H),2.83-2.76 (m,1H),2.66-2.61(m,1H),2.58-2.53(m,1H),2.28-2.22(m,1H),2.16-2.11(m,1H),2.06-1.99(m,4H).

[1029] Example 24: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-isopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 24)

[1030]

[1031] Referring to the synthesis method of compound 22, 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-isopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (40 mg) was obtained using (S)-2-(chloromethyl)-4-isopropoxy-1-((oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid isopropyl ester (1.9-B) and 5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B). ESI-MS (m / z): 633.17 [M+H]. + , 1 H NMR (600MHz, DMSO-d6) δ12.75(s,1H),8.73-8.72(m,1H),8.00(d,J=6.0Hz,1H),7.86(s,1H),7.62-7.60(m ,1H),7.24(s,1H),6.82-6.75(m,3H),5.09-5.08(m,1H),5.03-4.99(m,1H),4.75-4.71(m,1H),4.61-4.59( m,1H),4.48-4.35(m,2H),3.93-3.91(m,1H),3.75-3.73(m,1H),3.01-2.99(m,1H),2.84-2.82(m,1H),2.72 -2.63(m,2H),3.47-3.39(m,1H),2.23-2.16(m,2H),2.01(s,3H),1.77-1.72(m,4H),1.35(d,J=6.0Hz,6H).

[1032] Example 25: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid (Compound 25)

[1033]

[1034] Referring to the synthesis method of compound 22, (S)-2-(chloromethyl)-4-difluoromethoxy-1-((oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1.9-C) and 5-chloro-2-(2-methyl-4-piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B) were used as raw materials to obtain 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzimidazole-6-carboxylic acid (35 mg). ESI-MS (m / z): 641.2 [M+H]. + , 1 H NMR (600MHz, CDCl3) δ8.62(t,J=6Hz,1H),7.74(s,1H),7.69-7.60(m,3H),7.30(t,1H),6.80(t,J=6.0Hz,1H),6.74(t,J=6.0Hz,2H),5.13-5.12(dd ,1H),4.62-4.58(m,4H),4.41-4.39(m,1H),4.36-4.33(m,4H),3.54-3.4 8(m,3H),2.88(s,1H),2.73-2.61(m,3H),2.41-2.38(m,1H),2.05(s,3H).

[1035] Example 26: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-7-methoxy-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 26)

[1036]

[1037] Referring to the synthetic method of compound 22, (S)-2-(chloromethyl)-7-methoxy-3-((oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.9-D) and 5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B) were used as raw materials to obtain 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-7-methoxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (750 mg), ESI-MS (m / z): 606.3 [M+H] + .

[1038] Example 27: Synthesis of 2-(((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-4-(trifluoromethoxy)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 7) (Compound 27)

[1039]

[1040] Referring to the synthesis method of compound 22, (S)-2-(chloromethyl)-1-((oxetane-2-yl)methyl)-4-(trifluoromethoxy)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1.9-E) and 5-chloro-2-(2-methyl 4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B) were used as raw materials to obtain To 2-(((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethoxy)-1H-benzo[d]imidazole-6-carboxylic acid (44 mg), ESI-MS (m / z): 659.2 [M+H] + , 1H NMR (600MHz, CDCl3) δ8.67–8.54(m,1H),8.47(s,1H),7.92(s,1H),7.65(d,J=8.3Hz,1H) ,7.61–7.50(m,1H),6.83–6.75(m,1H),6.73–6.68(m,2H),5.20(d,J=6.7Hz,1H),5.09(s, 1H),4.82(d,J=13.4Hz,1H),4.69–4.60(m,1H),4.45(s,1H),4.34–4.09(m,2H),3.33–3.0 4(m,2H),2.90–2.72(m,2H),2.58–2.38(m,3H),2.03(d,J=2.0Hz,3H),1.99–1.80(m,4H).

[1041] Example 28: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-benzyloxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 28)

[1042]

[1043] Referring to the synthesis method of compound 22, 5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B) and (S)-4-(benzyloxy)-2-(chloromethyl)-1-((oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1.9-F) were used as raw materials. The two-step reaction gave 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-benzyloxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (24 mg). ESI-MS (m / z): 681.2 [M+H] + .

[1044] Example 29: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-hydroxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 29)

[1045]

[1046] Step 1: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[1047] Methyl 4-(benzyloxy)-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.09 mmol) and dichloromethane (10 mL) were added to a reaction flask, followed by palladium on carbon (10 mg), and the reaction was carried out at room temperature under a hydrogen atmosphere for 12 h. After the reaction, the mixture was filtered and concentrated, and purified by thin layer plate separation (methanol: dichloromethane = 1:20) to give 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-hydroxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (30 mg). ESI-MS (m / z): 605.11 [M+H] + .

[1048] Step 2: 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1049] Methyl 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-hydroxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, 0.05 mmol), sodium hydroxide (10 mg, 0.25 mmol), methanol (2 mL) and water (2 mL) were added to a reaction flask and reacted at room temperature for 4 h. After the reaction, the pH was adjusted to 6 with glacial acetic acid, and the mixture was concentrated. The mixture was separated and purified by thin layer chromatography (methanol: dichloromethane = 1:10) to obtain 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-hydroxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 mg). ESI-MS (m / z): 591.10 [M+H]. + , 1H NMR(600MHz, CDCl3)δ8.62(s,1H),7.82(s,1H),7.69-7.67(m,2H),7.60-7.59(m, 1H),6.81-6.78(m,1H),6.73-6.72(m,2H),5.26-5.27(m,1H),4.85-4.84(m,1H),4 .75-4.74(m,1H),4.66-4.64(m,1H),4.45-4.44(m,1H),4.16-4.13(m,2H),3.10-3 .09(m,2H),2.81-2.79(m,2H),2.53-2.41(m,3H),2.06(s,3H),2.01-1.90(m,4H).

[1050] Example 30: 4-amino-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 30)

[1051]

[1052] Step 1: 4-Bromo-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[1053] (S)-methyl 4-bromo-2-chloromethyl-1-((oxetane-2-yl)methyl)-1H-benzimidazole-6-carboxylate (1.9-G, 170 mg, 0.45 mmol), 5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)pyridine (1.8-B, 165 mg, 0.50 mmol), potassium carbonate (600 mg, 1.80 mmol), potassium iodide (5 mg) and DMF (15 mL) were added to a round-bottom flask and the reaction was stirred at room temperature. After the reaction, water was added to the reaction solution and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated. The mixture was separated by thin plate chromatography (methanol:dichloromethane=1:30) to give methyl 4-bromo-2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (130 mg). ESI-MS (m / z): 667.1 [M+H].+ .

[1054] Step 2: Methyl 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidin-1-yl)methyl)-4-((diphenylmethylene)amino)-4-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[1055] The product from the previous step (130 mg, 0.20 mmol), dibenzhydryl imine (50.3 m...

Claims

1. A compound represented by formula (I') or its tautomer, stereoisomer or pharmaceutically acceptable salt, which has the following structure: in, Ring A is independently selected from phenyl, 5-6 membered heteroaryl; Ring B is independently selected from 8-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl; Ring C is independently selected from piperidinyl, piperazinyl, C 8-10 Bicyclic carbocyclic group, 8-10 membered bicyclic heterocyclic group, 8-10 membered bicyclic heteroaryl; Independently selected from R a Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group optionally with one or more R a3 replaced by; R a1 , R a2 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituted by a cycloalkyl group or a 3-6-membered heterocyclic group; R a3 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, thiol, cyano, oxo, -R a4 ; R a4 independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen, hydroxy, amino, nitro, mercapto, cyano; R b Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, thiol, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R b1 replaced by; R b1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, thiol, cyano, oxo, -R b2 ; R b2 are independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 One or more arbitrarily substituted C 1-6 Alkyl, C 1-6 Alkoxy; R c Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, oxo, or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R c1 replaced by; or two R c Together with the atoms to which they are attached, they form a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group arbitrarily substituted by one or more of deuterium, halogen, hydroxyl, amino, cyano, oxo, methyl, ethyl, methoxy, and ethoxy; R c1 Each occurrence is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, or C substituted with one or more of halogen, hydroxyl, amino, cyano 1-4 alkyl; R d , R e One of them is selected from hydrogen, deuterium, and the other is selected from optionally substituted C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R d1 replaced by; R d1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R d2 )(R d3 )、-N(R d2 )C(O)(R d3 ), C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 substituted by an alkoxy substituent; R d2 , R d3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R f Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, thiol, cyano, oxo, -OR f4 、-C(O)N(R f4 )(R f5 )、-N(R f4 )C(O)(R f5 ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, optionally substituted with one or more R f1 replaced by; R f1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -R f2 ; R f2 are independently selected from hydrogen, deuterium, or halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 One or more of cycloalkyl, 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group optionally substituted with C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; R f4 , R f5 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; R g Each occurrence is independently selected from -C(O)OR g1 ; R g1 is hydrogen; L1 is independently selected from a bond, -C(R L1 )2-, -O- or -C(R L1 )2O-;R L1 independently selected from hydrogen, deuterium, or C substituted by one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, and cyano 1-6 alkyl; L2 is independently selected from a bond, -C(R L2 )2-, -O- or -C(R L1 )2O-;R L2 are independently selected from hydrogen, deuterium, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 One or more arbitrarily substituted C 1-6 alkyl; L3 is independently selected from a bond, -C(R L3 )2-, -O-, -S-, -C(O)-, -C(O)O- or -OC(O)-; R L3 are independently selected from hydrogen, deuterium, or deuterated, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 One or more arbitrarily substituted C 1-6 alkyl; L4 is a bond; m, n, o, and p are each independently 0, 1, 2, or 3; Unless otherwise specified, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

2. The compound according to claim 1 or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Ring A is independently selected from phenyl and pyridyl; Alternatively, Ring A is independently selected from phenyl; or, Independently selected from and / or R a are independently selected from halogen, hydroxy, amino, cyano, -C(O)N(C 1-4 Alkyl)2, -C(O)NH(C 1-4 alkyl), -C(O)NH2, C 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered heterocyclic group; the C 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered heterocyclic group are optionally substituted with one or more R a3 The heteroatom in the 3-6 membered heterocyclic group is O or N, and the number of heteroatoms is 1 or 2; Or, R a are independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 A halogenated alkoxy group or a 3-6-membered heterocyclic group, wherein the heteroatom in the 3-6-membered heterocyclic group is O and the number of heteroatoms is 1; Or, R a are independently selected from halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, oxetane; Or, R a are independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, oxetane; Or, R a are independently selected from halogen, cyano, -C(O)NH2, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, oxetane; Or, R a are independently selected from fluorine, chlorine, bromine, cyano, -C(O)NH2, -CF3, -OCHF2, -OCF3, methyl, ethyl, methoxy, ethoxy, Or, R a are independently selected from fluorine, chlorine, cyano, -CF3, -OCHF2, -OCF3, methyl, methoxy, Or, R a independently selected from fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, -OCF3, methyl, methoxy and Or, R a independently selected from fluorine, chlorine, cyano; Or, R a1 , R a2 are each independently selected from hydrogen; Or, R a3 independently selected from halogen; Or, R a3 independently selected from fluorine and chlorine; Or, R a4 , R a5 are independently selected from hydrogen, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more substituents selected from halogen; Or, R a4 , R a5 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl; Or, m is independently selected from 1, 2; Or, m is 2; or, Independently selected from 3. The compound according to claim 1 or 2, or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: L1 is independently selected from a bond, -CH2O-; Alternatively, L1 is independently selected from -CH2O-; wherein the CH2 group is connected to the A end of the ring, and the O group is connected to the B end of the ring; and / or L2 is independently selected from a bond; and / or L3 is independently selected from -CH2-, -C(O)-, -CH(CH3)-; Preferably, L3 is independently selected from -CH2-, -CH(CH3)-; Preferably, L3 is independently selected from -CH2-.

4. The compound according to any one of claims 1 to 3, or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Ring B is independently selected from phenyl, pyridyl, pyrimidinyl, and 9-10 membered bicyclic heterocyclic group, wherein the heteroatom in the 9-10 membered bicyclic heterocyclic group is O, and the number of heteroatoms is 2; Alternatively, Ring B is independently selected from phenyl and 6-membered heteroaryl, the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1 or 2; Alternatively, Ring B is independently selected from phenyl, pyridyl, pyrimidinyl, and a 9-membered bicyclic heterocyclic group, wherein the heteroatom in the 9-membered bicyclic heterocyclic group is O, and the number of heteroatoms is 2; Alternatively, ring B is independently selected from phenyl, pyridyl, pyrimidinyl, Alternatively, Ring B is independently selected from the following groups: The "*" end is connected to L1, and the "**" end is connected to L2; Alternatively, Ring B is independently selected from the following groups: The "*" end is connected to L1, and the "**" end is connected to L2; Alternatively, Ring B is independently selected from the following groups: The "*" end is connected to L1, and the "**" end is connected to L2; Alternatively, Ring B is independently selected from The "*" end is connected to L1, and the "**" end is connected to L2; and / or R b independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl; Or, R b Independently selected from fluorine, chlorine, bromine, methyl, -CF3; Or, R b Independently selected from halogen, methyl; Or, R b independently selected from methyl; Or, R b independently selected from halogen; Or, R b independently selected from fluorine, chlorine, and bromine; Or, R b independently selected from fluorine; Or, R b independently selected from methyl; Or, R b1 independently selected from halogen (e.g., fluorine, chlorine, bromine); Alternatively, n is independently selected from 0, 1; Or, n is 0; or, Selected from The "*" end is connected to L1, and the "**" end is connected to L2.

5. The compound according to any one of claims 1 to 4, or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: C is independently selected from piperidinyl, piperazinyl, C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl; the heteroatoms in the C9 bicyclic carbocyclic group, 9-membered bicyclic heterocyclic group, 10-membered bicyclic heterocyclic group, 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2; C is independently selected from a C9 bicyclic carbocyclic group, a 9-membered bicyclic heterocyclic group, and a 9-membered bicyclic heteroaryl group; the heteroatoms in the C9 bicyclic carbocyclic group, the 9-membered bicyclic heterocyclic group, and the 9-membered bicyclic heteroaryl group are selected from N or O, and the number of heteroatoms is 1 or 2; Alternatively, ring C is independently selected from a 9-membered bicyclic heterocyclic group; the heteroatom in the 9-membered bicyclic heterocyclic group is selected from O, and the number of heteroatoms is 1 or 2; Alternatively, Ring C is independently selected from piperidinyl, piperazinyl; Alternatively, Ring C is independently selected from piperidinyl, piperazinyl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, 6-membered / 6-membered heterocyclyl, 5-membered / 6-membered carbocyclyl, 6-membered / 5-membered carbocyclyl, 6-membered / 6-membered carbocyclyl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, 6-membered / 6-membered fused heteroaryl; Alternatively, Ring C is independently selected from a 5-membered / 6-membered heterocyclic group, a 6-membered / 5-membered heterocyclic group; the heteroatom in the 5-membered / 6-membered heterocyclic group, the 6-membered / 5-membered heterocyclic group is selected from O, and the number of heteroatoms is 1 or 2; Alternatively, Ring C is independently selected from: Alternatively, Ring C is independently selected from: Alternatively, Ring C is independently selected from: Alternatively, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3; Alternatively, Ring C is independently selected from: The "+" end is connected to L2, and the "++" end is connected to L3; Alternatively, Ring C is independently selected from: in The "+" end is connected to L2, and the "++" end is connected to L3; Alternatively, Ring C is independently selected from The "+" end is connected to L2, and the "++" end is connected to L3; and / or R c are independently selected from halogen, hydroxy, amino, cyano, oxo, or optionally substituted C 1-6 Alkyl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R c1 Replaced by; R c1 Independently selected from halogen, hydroxy, amino, cyano; Or, R c are independently selected from halogen, hydroxy, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl; Preferably, or, R c are independently selected from halogen, hydroxy, oxo, C 1-3 Alkyl; or, R c Independently selected from fluorine, chlorine, hydroxyl, oxo, methyl, ethyl, -CF3; Or, R c independently selected from fluorine, chlorine, methyl; Or, R c independently selected from halogen; Or, R c independently selected from fluorine and chlorine; Or, R c independently selected from fluorine; Or, R c1 independently selected from halogen (e.g., fluorine, chlorine, bromine); Or, o is independently selected from 0, 1; Or, o is 0; or, Selected from 6. The compound according to any one of claims 1 to 5, or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: for and / or R d , R e are independently selected from hydrogen, or optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R d1 replaced by; Or, R d , R e are independently selected from hydrogen, or optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R d1 replaced by; Or, R e is hydrogen, R d Selected from optionally substituted The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R d1 Replaced by; R d1 Independently selected from -N(C 1-2 alkyl)C(O)(C 1-2 alkyl), or C substituted by one or more of fluorine, chlorine, and cyano 1-3 alkyl; or, Independently selected from or, Independently selected from or, Independently selected from or, Independently selected from or, Independently selected from or, for Or, R d1 are independently selected from -C(O)N(R d2 )(R d3 )、-N(R d2 )C(O)(R d3 ), or C substituted by one or more of fluorine, chlorine, and cyano 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl); Or, R d1 independently selected from C substituted by one or more of fluorine, chlorine, and cyano 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl); Or, R d1 independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, -CH2CN, -CH2CH2CN, -N(CH3)C(O)CH3, -NHC(O)CH3, -C(O)N(CH3)2, -C(O)NHCH3, -C(O)NH2; Or, R d1 Independently selected from monofluoromethyl, -CH2CN, methyl, ethyl; Or, R d2 , R d3 are independently selected from hydrogen and methyl; and / or R f are independently selected from halogen, hydroxy, amino, cyano, -OR f4 、-C(O)N(R f4 )(R f5 )、-N(R f4 )C(O)(R f5 ), C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more R f1 replaced by; Or, R f are independently selected from halogen, hydroxy, amino, cyano, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 alkyl),- NHC(O)(C 1-3 Alkyl), C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from fluorine, chlorine, and phenyl; Or, R f independently selected from fluorine, chlorine, hydroxyl, amino, -O-cyclopropane, -C(O)NHCH3, -NHC(O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, - OCH2CF3, -OCH2CHF2; Or, R f independently selected from halogen, hydroxyl, amino, cyano, or C substituted by one or more of halogen, hydroxyl, amino, cyano 1-4 alkyl; Or, R f independently selected from halogen; Or, R f independently selected from fluorine and chlorine; Or, R f are independently selected from halogen, hydroxy, amino, -O(C 3-6 Cycloalkyl), -C(O)NH(C 1-3 Alkyl), -NHC(O)(C 1-3 Alkyl), C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OC 1-3 Alkyl-phenyl; Or, R f independently selected from fluorine, chlorine, bromine, C 1-4 Alkoxy, C 1-3 Haloalkoxy; Or, R f Independently selected from fluorine, chlorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CF3, -OCH2CHF2; Or, R f1 are independently selected from halogen, hydroxy, amino, cyano, -R f2 ; R f2 , R f3 are independently selected from hydrogen, or C substituted by one or more of halogen, hydroxyl, amino, cyano 1-4 Alkyl, phenyl; Or, R f1 Independently selected from fluorine, chlorine, methyl, phenyl; Or, R f4 , R f5 are independently selected from hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl; Or, R f4 , R f5 Each is independently selected from hydrogen, methyl, and cyclopropane; Alternatively, p is independently selected from 0, 1; Or, p is 1; Or, p is 0; or, Independently selected from or, Independently selected from:

7. The compound according to any one of claims 1 to 6, or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: It has formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-1), formula (III-2), formula (III-3), formula (IV), formula (IV-1), formula (IV-2), formula (IV-2-1), formula (IV-2-2), formula (IV-3), formula (IV-4), formula (IV-5), formula (IV-6), formula (IV-7), formula (IV-8), formula (IV-9), formula (IV-10), formula (IV-11), formula (I Formula (V-12), Formula (IV-13), Formula (IV-14), (IV-15), Formula (IV-16), Formula (IV-17), Formula (V), Formula (V-1), Formula (V-2), Formula (V-3), Formula (V-4), Formula (V-5), Formula (V-6), Formula (V-7), Formula (V-8), Formula (V-9), Formula (V-10), Formula (V-11), Formula (V-12), Formula (V-13), Formula (V-14), Formula (V-15), Formula (V-16), and Structures represented by Formula (V-17):

8. The compound according to claim 1 or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof; optionally, further comprising another, two or more compounds having the same or similar indications.

10. Use of the compound according to any one of claims 1 to 8 or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating diseases, disorders and conditions by stimulating the cascade signal mediated by GLP-1R; preferably, the diseases, disorders and conditions are GLP-1R related, including diabetes, obesity, overweight, metabolic-related fatty liver disease, and Alzheimer's disease.

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