Polycyclic compounds and their uses

Abstract

The present invention provides a compound represented by formula (I'), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof. The compound represented by formula (I') has a strong agonist effect on GLP-1R and can treat diseases such as diabetes, metabolic fatty liver disease, and Alzheimer's disease, or has a weight-reducing effect. [Formula 1] JPEG2026529536000229.jpg35151

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and rights to China Patent Application No. 202310900145.6 filed with the China National Intellectual Property Administration on 21 July 2023, China Patent Application No. 202311081129.5 filed with the China National Intellectual Property Administration on 25 August 2023, and China Patent Application No. 202410698010.0 filed with the China National Intellectual Property Administration on 31 May 2024, the contents disclosed in the above applications being incorporated herein by reference in their entirety.

[0002] This application relates to the pharmaceutical technology field, specifically to a novel compound as a GLP-1R agonist, and to its use in the treatment and prevention of diseases, disorders, and conditions mediated by GLP-1R. [Background technology]

[0003] Overweight and obesity are global health problems, with obesity or overweight accounting for approximately 50% of type 2 diabetes, 30% of ischemic cardiovascular disease, and 10-40% of cancers. China already has the world's largest overweight and obese population, and there is a huge unmet clinical need for obesity treatment.

[0004] Type 2 diabetes is the most common type of diabetes, accounting for over 90% of diabetes cases. While the mechanisms of type 2 diabetes development are not yet fully understood, it is currently believed to involve unhealthy lifestyle habits, genetic factors, environmental factors, and toxic effects on pancreatic β-cells due to lipid toxicity and glucotoxicity. Diabetes can lead to various complications, including arteriosclerosis, retinopathy and neuritis, renal dysfunction and proteinuria, myocarditis, heart failure, and urinary tract infections.

[0005] GLP-1 (glucagon-like peptide-1) is mainly secreted from L cells and acts on its receptor, GLP-1R (glucagon-like peptide-1 receptor), and is mainly distributed in the pancreas, gastrointestinal tract, central nervous system, and cardiovascular system. GLP-1R is classified as a glucagon receptor subfamily belonging to the G protein-coupled receptor B cluster, and its characteristic feature is that it consists of seven transmembrane core domains, an extracellular N-terminal domain, and an intracellular C-terminal domain, which are connected by three intracellular loops and three extracellular loops located on opposite sides of the membrane. Normally, it binds to peptide ligands via a two-domain model, that is, the C-terminus of the ligand first binds to the extracellular domain of GLP-1R, changing the spatial structure of GLP-1R and exposing the binding site of the core domain, and then the N-terminus of the ligand binds to the core domain of GLP-1R and activates GLP-1R. Generally, the primary role of the extracellular domain of GLP-1R is the recognition of specific ligands, while the core domain plays a crucial role in signal transduction-specific transmission.

[0006] In pancreatic islet cells, the main actions of GLP-1 are to promote the proliferation of pancreatic β-cells, stimulate insulin synthesis and secretion, and suppress glucagon synthesis and secretion. In tissues such as the gastrointestinal tract, GLP-1 suppresses gastric juice secretion and gastrointestinal peristalsis, delays gastric emptying, increases satiety, and reduces food intake. In nervous tissue, GLP-1 can protect nerve cells, resist appetite, and enhance memory. In the cardiovascular system, GLP-1 improves cardiovascular function and reduces inflammation. In the liver, GLP-1 increases insulin sensitivity and decreases gluconeogenesis. Therefore, GLP-1R receptor agonists exert weight-reducing effects through multiple biological mechanisms.

[0007] Reports indicate that impaired insulin signaling is involved in the pathogenesis of Alzheimer's disease (AD). GLP-1 counteracts the marked increase in TLR-4 expression in glial cells induced by LPS (lipopolysaccharide) and reduces the expression of p-p38, p-JNK, and p-AKT, suggesting that GLP-1 suppresses inflammatory responses by inhibiting the MAPKs signaling pathway. Furthermore, one study showed that in AD, when glucose metabolism and mitochondrial dysfunction occur, the lactate shuttle in glial cell glycolysis becomes increasingly important for neuronal survival and plays an energy substitution role. GLP-1 partially restores glycolytic function in astrocytes and increases lactate flux, thereby mitigating the neuronal energy crisis. The neuroprotective mechanisms of GLP-1 are closely related to the promotion of aerobic glycolysis, mitigation of oxidative phosphorylation, and activation of the PI3K / Akt pathway. Therefore, GLP-1 agonists are a promising strategy in the prevention and treatment of AD.

[0008] Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), has seen a significant increase in incidence, reaching a prevalence of 40%. Currently, it surpasses viral liver disease in popularity and is the most common liver disease worldwide, highlighting the urgent need for basic and clinical research. MAFLD is classified into two categories: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). In MAFLD, an oversupply of metabolic substrates leads to the accumulation of excess fat in liver cells, gradually generating potentially toxic lipids, and progressively increasing neoadipogenesis (DNL). NASH, characterized by cell damage and inflammatory cell infiltration, is considered a more invasive form of MAFLD, potentially progressing to cirrhosis and hepatocellular carcinoma, and treatment options are limited. Studies have shown that obesity and type 2 diabetes are two major risk factors for NASH, and individuals with a history of NASH have a significantly increased risk of developing liver and cardiovascular disease. Furthermore, insulin resistance in the liver and adipose tissue is considered a major driver of NASH morbidity and mortality, and GLP-1 analogs lead to improved glycemic control, weight loss, and liver enzyme activation in T2DM patients. Liraglutide has been reported to reduce steatosis by directly acting on human hepatocytes in vitro, lowering DNL levels and increasing fatty acid oxidation. According to the literature, steatosis and hepatocyte swelling improved in the majority of patients after liraglutide treatment, suggesting that liraglutide may improve insulin sensitivity in adipose tissue and reduce lipotoxicity. Only a small percentage of NASH patients progressed after liraglutide treatment. In addition, semaglutide lowered levels of alanine transaminase and inflammatory markers, and levels of inflammatory biomarkers decreased significantly after treatment. Given the lack of GLP-1R expression in the liver, the potential mechanisms of action of GLP-1R agonists in NASH may be related to indirect beneficial effects on weight loss, reduction of metabolic dysfunction, lipid toxicity, and suppression of inflammation. [Overview of the project]

[0009] According to one aspect, the present invention provides a compound represented by formula (I') having the following structure, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

Chemical Formula

[0010] In some embodiments, in formula (I'), Ring A was independently selected from the group consisting of phenyl and 5-6 membered heteroaryls. Ring B is independently selected from the group consisting of 8-10 membered bicyclic heterocyclyls, phenyls, 5-6 membered monocyclic heteroaryls, and 8-10 membered bicyclic heteroaryls. Ring C is C 8-10 Independently selected from the group consisting of bicyclic condensed carbon rings, 8-10 membered bicyclic condensed heterocyclyls, and 8-10 membered bicyclic heteroaryls, [ka] R a Each instance of appearance is associated with deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -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 A cycloalkyl group is independently selected from the group consisting of 3-6 member heterocyclines, and the aforementioned C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A cycloalkyl or 3- to 6-membered heterocycline contains one or more R a3 It is optionally replaced by, R a1 , R a2 Each instance of appearance is hydrogen, deuterium, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A C is independently selected from the group consisting of cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyls, 3-6 membered heterocyclyls, phenyls, or 5-6 membered heteroaryls are halogens, hydroxy, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 It is optionally substituted with one or more substituents selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines. R a3 Each instance of appearance contains deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -R. a4 Independently selected from the group consisting of, R a4 is hydrogen, deuterium, C 1-6 Alkyl, and C 1-6 Independently selected from the group consisting of alkoxys, the above C 1-6 Alkyl, or C 1-6The alkoxy is optionally substituted with one or more substituents selected from the group consisting of halogens, hydroxyl, amino, nitro, mercapto, and cyano. R b Each instance of C is substituted with deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, or optionally substituted. 1-6 Alkyl, and C 1-6 Independently selected from the group consisting of alkoxys, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R b1 This means that it has been replaced by R b1 Each instance of appearance contains deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -R. b2 Independently selected from the group consisting of, R b2 These include hydrogen, deuterium, as well as halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 C is optionally substituted with one or more alkoxys. 1-6 Alkyl and C 1-6 Independently selected from the group consisting of alkoxys, R c Each instance of this element is a C atom that is optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, or other elements. 1-6 Alkyl and C 1-6 Independently selected from the group consisting of alkoxys, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R c1 This means that it has been replaced by Alternatively, two R's cTogether with the atoms to which they are bonded, they form 3- to 6-membered heterocyclines or 5- to 6-membered heteroaryls which are optionally substituted with one or more of the following: deuterium, halogen, hydroxyl, amino, cyano, oxo, methyl, ethyl, methoxy, and ethoxy. R c1 Each instance of C is optionally substituted with one or more of the following: deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and halogen, hydroxyl, amino, and cyano. 1-4 Independently selected from the group consisting of alkyls, R d and R e One of the atoms is selected from hydrogen or deuterium, and the other is optionally substituted with C 3-6 Selected from the group consisting of cycloalkyls, 3-6 membered heterocyclyls, and 5-6 membered heteroaryls, the term "optionally substituted" means that the hydrogen atoms in the substituted group are unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means that it has been replaced by R d1 Each instance of appearance is associated with deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -C(O)N(R). d2 )(R d3 ), -N(R d2 )C(O)(R d3 ), C 1-6 Alkyl, and C 1-6 Independently selected from the group consisting of alkoxys, the above C 1-6 Alkyl, C 1-6 Alkoxy compounds include deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys. R d2 and R d3 Each instance of appearance is hydrogen, deuterium, and C, respectively. 1-6 Alkyl, and C1-6 Independently selected from the group consisting of alkoxys, the above C 1-6 Alkyl, C 1-6 Alkoxy compounds include halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, and C 1-6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys. R f Each instance of appearance is associated with deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -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 A C is independently selected from the group consisting of cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl may be one or more R f1 It is optionally replaced by, R f1 Each instance of this compound contains deuterium, halogen, hydroxyl, amino, cyano, and -R. f2 Independently selected from the group consisting of, R f2 These include hydrogen, deuterium, as well as halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 C is optionally substituted with one or more of the following: cycloalkyl, 3-6 member heterocyclyl, phenyl, or 5-6 member heteroaryl. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6Independently selected from the group consisting of cycloalkyls, 3-6 membered heterocyclines, phenyls, and 5-6 membered heteroaryls, R f4 and R f5 Each instance of appearance is hydrogen, deuterium, and C, respectively. 1-6 Alkyl, C 3-6 Independently selected from the group consisting of cycloalkyls, 3-6 membered heterocyclines, phenyls, and 5-6 membered heteroaryls, R g Each occurrence of -C(O)OR g1 Selected independently from, R g1 It is hydrogen, L1 is a bond, -C(R L1 )2-, -O-, and -C(R L1 ) Independently selected from the group consisting of 2O-, R L1 C is optionally substituted with hydrogen, deuterium, and one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, and cyano. 1-6 Independently selected from the group consisting of alkyls, L2 is a bond, -C(R L2 )2-, -O-, and -C(R L1 ) Independently selected from the group consisting of 2O-, R L2 This includes hydrogen, deuterium, as well as deuterium, halogens, hydroxyl, amino, nitro, mercapto, cyano, and C 1-6 C is optionally substituted with one or more alkyl groups. 1-6 Independently selected from the group consisting of alkyls, L3 is a bond, -C(R L3 )Independently selected from the group consisting of -2-, -O-, -S-, -C(O)-, -C(O)O-, and -OC(O)-, R L3 This includes hydrogen, deuterium, as well as deuterium, halogens, hydroxyl, amino, nitro, mercapto, cyano, and C 1-6 C is optionally substituted with one or more alkyl groups. 1-6 Independently selected from the group consisting of alkyls, L4 is a bond, and m, n, o, and p are independently 0, 1, 2, or 3. Unless otherwise specified, the heteroatoms in the heterocyclyls and heteroaryls described above are independently selected from the group consisting of O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4.

[0011] In some embodiments, ring A is independently selected from the group consisting of 3- to 6-membered heterocyclyls, phenyls, and 5- to 6-membered heteroaryls. In some embodiments, ring A is independently selected from the group consisting of phenyl, 5-membered heteroaryls, and 6-membered heteroaryls, the heteroatoms in the heteroaryl are selected from the group consisting of N and S, and the number of heteroatoms is 1 or 2. In some embodiments, ring A is independently selected from the group consisting of phenyl and pyridyl. In some embodiments, ring A is selected independently of phenyl.

[0012] In some embodiments, [ka] It is independently selected from the group consisting of [the specified elements].

[0013] In some embodiments, [ka] It is independently selected from the group consisting of [the specified elements]. In some embodiments, [ka] It is selected independently of others.

[0014] In some embodiments, R a These are halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R) a1 )(Ra2 ), -N(R a1 )C(O)(R a2 ), C 1-6 Alkyl, C 1-6 Independently selected from the group consisting of alkoxys and 3-6 member heterocyclyls, the above C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 member heterocyclyl, contains one or more R a3 The heteroatoms are optionally substituted, and in the 3-6 member heterocyclyl, the heteroatoms are O or N, and the number of heteroatoms is 1 or 2.

[0015] In some embodiments, R a These are 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 Independently selected from the group consisting of alkoxys and 3-6 member heterocyclyls, the C 1-4 Alkyl, C 1-4 Alkoxy, 3-6 member heterocyclyl, contains one or more R a3 The heteroatoms are optionally substituted, and in the 3-6 member heterocyclyl, the heteroatoms are O or N, and the number of heteroatoms is 1 or 2.

[0016] In some embodiments, R a The R is independently selected from the group consisting of halogen, hydroxy, amino, cyano, -C(O)NH2, -C(O)N(CH3)2, -C(O)NH(CH3), methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, and ethoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, or ethoxy is one or more R a3 It is optionally replaced.

[0017] In some embodiments, R a is a halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3Independently selected from the group consisting of alkoxys and 4-6 member heterocyclines, the above C 1-3 Alkyl, C 1-3 The alkoxy and 4-6 membered heterocyclils are optionally substituted with one or more substituents selected from the group consisting of halogens, wherein the heteroatoms in the 4-6 membered heterocyclil are oxygen atoms, and the number of heteroatoms is 1.

[0018] In some embodiments, R a is a halogen, cyano, -C(O)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Independently selected from the group consisting of haloalkoxys and 3- to 6-membered heterocyclines, wherein the heteroatom in the 3- to 6-membered heterocycline is O, and the number of heteroatoms is 1. In some embodiments, R a These are halogen, cyano, and C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Independently selected from the group consisting of haloalkoxys and 3- to 6-membered heterocyclines, wherein the heteroatom in the 3- to 6-membered heterocycline is O, and the number of heteroatoms is 1.

[0019] In some embodiments, R a is a halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 It is independently selected from the group consisting of haloalkoxys and oxetanyls. In some embodiments, R a These are halogen, cyano, and C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 It is independently selected from the group consisting of haloalkoxys and oxetanyls.

[0020] In some embodiments, R a These are halogen, cyano, and C 1-2 Alkyl, C 1-2 Haloalkyl (preferably, C 1-2 Fluoroalkyl), C 1-2 Alkoxy, C 1-2 Haloalkoxy (preferably, C 1-2 It is independently selected from the group consisting of fluoroalkoxys and oxetanyls. In some embodiments, R a is a halogen, cyano, -C(O)NH2, C 1-3 Haloalkyl, C 1-3 It is independently selected from the group consisting of haloalkoxys and oxetanyls.

[0021] In some embodiments, R a These include fluorine, chlorine, bromine, cyano, -C(O)NH2, -CF3, -OCHF2, -OCF3, methyl, ethyl, methoxy, ethoxy, and [ka] It is independently selected from the group consisting of [the specified elements]. In some embodiments, R a These include fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, methyl, methoxy, and [ka] It is independently selected from the group consisting of [the specified elements].

[0022] In some embodiments, R a Fluorine, chlorine, cyano, -CF3, -OCHF2, -OCF3, methyl, methoxy, and [ka] It is independently selected from the group consisting of [the specified elements]. In some embodiments, R aThese include fluorine, chlorine, bromine, cyano, -C(O)NH2, -CF3, -OCHF2, methyl, ethyl, methoxy, ethoxy, and [ka] It is independently selected from the group consisting of [the specified elements].

[0023] In some embodiments, R a The element is independently selected from the group consisting of halogens, cyanosides, and -C(O)NH2. In some embodiments, R a This is independently selected from the group consisting of fluorine, chlorine, and cyano. In some embodiments, R a1 , R a2 These are hydrogen and C, respectively. 1-6 Independently selected from the group consisting of alkyl, the above C 1-6 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogens, hydroxyls, and aminos.

[0024] In some embodiments, R a1 , R a2 Each of these is selected independently of hydrogen. In some embodiments, R a3 This is independently selected from the group consisting of halogens, and is preferably fluorine or chlorine, and more preferably fluorine. In some embodiments, m is independently selected from 1 or 2, more preferably 2.

[0025] In some embodiments, ring A is a benzene ring, m is 2, and one R is a It is located in the para position of the bonding site between ring A and L1, and the other R a It is located in the ortho position of the bonding site between ring A and L1. In some embodiments, [ka] It is independently selected from the group consisting of [the specified elements].

[0026] In some embodiments, L1 is bonded and -C(R L1 ) Independently selected from the group consisting of 2O-, R L1 This is selected from the group consisting of hydrogen and methyl and ethyl methyl molecules substituted with one or more substituents from fluorine, chlorine, bromine, hydroxyl, amino, and cyano. In some embodiments, L1 is independently selected from the group consisting of bonds and -CH2O-. In some embodiments, L1 is independently selected from the group consisting of a bond and -CH2O-, where the CH2 group is bonded to one end of ring A and the O group is bonded to one end of ring B.

[0027] In some embodiments, L1 is selected independently of the bond. In some embodiments, L1 is selected independently of the -CH2O-. In some embodiments, L1 is independently selected from -CH2O-, where the CH2 group is bonded to one end of ring A and the O group is bonded to one end of ring B. In some embodiments, L1 is independently selected from -CH2O-, where the CH2 group is bonded to one end of ring B and the O group is bonded to one end of ring A.

[0028] In some embodiments, ring B is independently selected from the group consisting of 4-6 membered heterocycloalkyls, 8-10 membered bicyclic heterocyclines, phenyls, 5-6 membered monocyclic heteroaryls, and 8-10 membered bicyclic heteroaryls. In some embodiments, ring B is independently selected from the group consisting of 9-membered bicyclic heterocyclines and 5-6 membered monocyclic heteroaryls, wherein the heteroatoms in the 9-membered bicyclic heterocyclines and 5-6 membered monocyclic heteroaryls are selected from N or O, and the number of heteroatoms is 1 or 2.

[0029] In some embodiments, ring B is independently selected from the group consisting of 5-6 membered monocyclic heteroaryl groups, 5- / 6 membered fused heterocyclic groups, and 6- / 5 membered fused heterocyclic groups, wherein the heteroatoms in the 5-6 membered monocyclic heteroaryl groups, 5- / 6 membered fused heterocyclic groups, and 6- / 5 membered fused heterocyclic groups are selected from N or O, and the number of heteroatoms is 1 or 2. In some embodiments, ring B is independently selected from the group consisting of phenyl and 6-membered heteroaryls, wherein the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1 or 2.

[0030] In some embodiments, ring B is independently selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and a 9-membered bicyclic heterocycline, wherein the heteroatom in the 9-membered bicyclic heterocycline is O, and the number of heteroatoms is 2. In some embodiments, ring B is phenyl, pyridyl, pyrimidinyl, and [ka] It is independently selected from the group consisting of [the specified elements].

[0031] In some embodiments, ring B is independently selected from the group consisting of phenyl, pyridyl, and pyrimidinyl. In some embodiments, ring B is independently selected from the group consisting of pyridyl and pyrimidinyl. In some embodiments, ring B is selected independently of pyridyl.

[0032] In some embodiments, ring B is based on the following: [ka] The terminals are independently selected from the group consisting of the following, where "*" terminals represent terminals that connect to L1 and "**" terminals represent terminals that connect to L2.

[0033] In some embodiments, ring B is based on the following: [ka] The terminals are independently selected from the group consisting of the following, where "*" terminals represent terminals that connect to L1 and "**" terminals represent terminals that connect to L2.

[0034] In some embodiments, ring B is based on the following: [ka] The terminals are independently selected from the group consisting of the following, where "*" terminals represent terminals that connect to L1 and "**" terminals represent terminals that connect to L2.

[0035] In some embodiments, ring B is based on the following: [ka] The terminals are independently selected from the group consisting of the following, where "*" terminals represent terminals that connect to L1 and "**" terminals represent terminals that connect to L2.

[0036] In some embodiments, ring B is [ka] Selected independently from L1, where the "*" end represents an end that connects to L1 and the "**" end represents an end that connects to L2.

[0037] In some embodiments, R b C is a halogen, hydroxyl, amino, cyano, or optionally substituted C 1-4 Alkyl, and C 1-4 Independently selected from the group consisting of alkoxys, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R b1 This means it has been replaced with [something]. In some embodiments, R b is halogen, C1-3 Alkyl, and C 1-3 It is independently selected from the group consisting of haloalkyls. In some embodiments, R b is halogen and C 1-3 It is independently selected from the group consisting of alkyl groups.

[0038] In some embodiments, R b C 1-3 It is selected independently of alkyl. In some embodiments, R b is independently selected from the group consisting of halogens and methyl compounds, and is preferably a halogen. In some embodiments, R b is independently selected from the group consisting of fluorine, chlorine, bromine, and methyl, more preferably fluorine, chlorine, or bromine, and more preferably fluorine.

[0039] In some embodiments, R b It is selected independently of methyl. In some embodiments, R b1 This is independently selected from the group consisting of halogens (e.g., fluorine, chlorine, bromine). In some embodiments, n is independently selected from the group consisting of 0, 1, and 2, and is preferably 0 or 1, and more preferably 0. In some embodiments, n is 1, R b is halogen and C 1-3 Selected from the group consisting of alkyl groups, or n is 1, R b n is selected from the group consisting of fluorine, chlorine, bromine, and methyl. In some embodiments, n is 1, and R b It is fluorine.

[0040] In some embodiments, [ka] A group consisting of the following is selected, where the "*" ends represent ends that connect to L1, and the "**" ends represent ends that connect to L2.

[0041] In some embodiments, [ka] Here, the "*" end represents an end that connects to L1, and the "**" end represents an end that connects to L2. In some embodiments, L2 is a connection.

[0042] In some embodiments, the ring C is C 3-10 Carbon ring group, 3-10 membered heterocyclyl, C 6-10 They are independently selected from the group consisting of aryls and 5- to 10-membered heteroaryls. In some embodiments, ring C is independently selected from the group consisting of C9 bicyclic condensed carbon ring groups. In some embodiments, ring C is independently selected from the group consisting of 8-10 membered bicyclic condensed heterocyclines.

[0043] In some embodiments, the ring C is independently selected from a 9-membered bicyclic condensed heterocycline, the heteroatoms in the 9-membered bicyclic condensed heterocycline are selected from O, and the number of heteroatoms is 1 or 2. In some embodiments, ring C is independently selected from a 9-membered bicyclic heteroaryl, where the heteroatom in the 9-membered bicyclic heteroaryl is N, and the number of heteroatoms is 1 or 2. In some embodiments, the ring C is C 8-10 The group is independently selected from the group consisting of bicyclic condensed carbon rings, 8-10 membered bicyclic condensed heterocyclines, and 8-10 membered bicyclic heteroaryls.

[0044] In some embodiments, ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, a 10-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, wherein the heteroatoms in the C9 bicyclic condensed carbon ring, the 9-membered bicyclic condensed heterocyclyl, the 10-membered bicyclic condensed heterocyclyl, and the 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0045] In some embodiments, ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, wherein the heteroatoms in the C9 bicyclic condensed carbon ring, the 9-membered bicyclic condensed heterocyclyl, and the 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2. In some embodiments, ring C is independently selected from the group consisting of a 5-membered / 6-membered fused heterocyclic group, a 6-membered / 5-membered fused heterocyclic group, a 6-membered / 6-membered fused heterocyclic group, a 5-membered / 6-membered fused carbon ring group, a 6-membered / 5-membered fused carbon ring group, a 6-membered / 6-membered fused carbon ring group, a 5-membered / 6-membered fused heteroaryl group, a 6-membered / 5-membered fused heteroaryl group, and a 6-membered / 6-membered fused heteroaryl group.

[0046] In some embodiments, ring C is independently selected from the group consisting of 5-membered / 6-membered fused heterocyclic groups and 6-membered / 5-membered fused heterocyclic groups, the heteroatoms in the 5-membered / 6-membered fused heterocyclic groups and 6-membered / 5-membered fused heterocyclic groups are selected from O, and the number of heteroatoms is 1 or 2. In some embodiments, ring C is based on the following: [ka] It is independently selected from the group consisting of [the specified elements].

[0047] In some embodiments, ring C is based on the following: [ka] The terminals are independently selected from the group consisting of the following: where the "+" terminals represent terminals that connect to L2, and the "++" terminals represent terminals that connect to L3.

[0048] In some embodiments, ring C is based on the following: [ka] The terminals are independently selected from the group consisting of the following: where the "+" terminals represent terminals that connect to L2, and the "++" terminals represent terminals that connect to L3.

[0049] In some embodiments, ring C is [ka] Selected independently from L2, where the "+" terminal represents a terminal that connects to L2 and the "++" terminal represents a terminal that connects to L3.

[0050] In some embodiments, ring C is [ka] If R c is selected from the group consisting of hydroxyl, oxo, and halogen (preferably fluorine), and o is 1. In some embodiments, ring C is [ka] If R c is methyl, o is 0 or 1, where the "+" end represents the end that binds to L2 and the "++" end represents the end that binds to L3.

[0051] In some embodiments, R c C is optionally substituted with halogen, hydroxyl, amino, cyano, oxo, and 1-6Independently selected from the group consisting of alkyl groups, and the term "optionally substituted" means that the hydrogen atoms in the substituted group are unsubstituted, or one or more substituted sites in the substituted group are independently R c1 This means that it is replaced with R c1 The element is independently selected from the group consisting of halogens, hydroxyls, aminos, and cyanos.

[0052] In some embodiments, R c These include halogens, hydroxyl, amino, cyano, oxo, and C 1-4 It is independently selected from the group consisting of alkyl groups. In some embodiments, R c These are halogens, hydroxyls, oxols, and C 1-3 It is independently selected from the group consisting of alkyl groups. In some embodiments, R c The element is independently selected from the group consisting of fluorine, chlorine, hydroxy, oxo, methyl, and ethyl.

[0053] In some embodiments, R c This is independently selected from the group consisting of fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, and n-butyl. In some embodiments, R c This is independently selected from the group consisting of fluorine, chlorine, oxo, methyl, and -OH. In some embodiments, R c This is independently selected from the group consisting of fluorine, chlorine, and methyl. In some embodiments, R c This is independently selected from the group consisting of halogens, preferably independently selected from the group consisting of fluorine and chlorine, and more preferably fluorine. In some embodiments, R c1 This is independently selected from the group consisting of halogens (e.g., fluorine, chlorine, bromine).

[0054] In some embodiments, o is independently selected from the group consisting of 0, 1, and 2, preferably 0 or 1, and more preferably 0. In some embodiments, [ka] Here, the "+" terminal represents a terminal that connects to L2, and the "++" terminal represents a terminal that connects to L3.

[0055] In some embodiments, L3 is -C(R L3 )2- and -C(O)- are independently selected from the group, R L3 The element is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and n-butyl. In some embodiments, L3 is independently selected from the group consisting of -CH2-, -C(O)-, and -CH(CH3)-, preferably -CH2- or -CH(CH3)-, and more preferably -CH2-.

[0056] In some embodiments, ring D is [ka] Here, the "#" terminal represents a terminal that connects to L3, and the "##" terminal represents a terminal that connects to L4.

[0057] In some embodiments, [ka] That is the case.

[0058] In some embodiments, [ka] That is the case.

[0059] In some embodiments, R d and R eOne of the C atoms is selected from hydrogen, and the other is optionally substituted. 3-6 Selected from the group consisting of cycloalkyls, 3-6 membered heterocyclyls, and 5-6 membered heteroaryls, the term "optionally substituted" means that the hydrogen atoms in the substituted group are unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means it has been replaced with [something].

[0060] In some embodiments, R d and R e One of the C atoms is selected from hydrogen, and the other is optionally substituted. 3-4 Selected from the group consisting of cycloalkyls, 3-4 membered heterocyclines, and 5-6 membered heteroaryls, wherein the heteroatom in the heterocycline is selected from O and the number of heteroatoms is 1, and the heteroatom in the heteroaryl is selected from N and the number of heteroatoms is 1 or 2, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means it has been replaced with [something].

[0061] In some embodiments, R d and R e These are hydrogen and optionally substituted, respectively. [ka] Independently selected from the group consisting of, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means it has been replaced with [something].

[0062] In some embodiments, R d and R e One of them is selected from hydrogen, and the other is optionally substituted. [ka] Selected from the group consisting of, and the term "arbitrarily substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means it has been replaced with [something].

[0063] In some embodiments, R d and R e These are hydrogen and optionally substituted, respectively. [ka] Independently selected from the group consisting of, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means it has been replaced with [something].

[0064] In some embodiments, R d and R e These are hydrogen and optionally substituted, respectively. [ka] Independently selected from the group consisting of, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means it has been replaced with [something].

[0065] In some embodiments, R e is hydrogen, R d It is being replaced by any choice. [ka] Selected from the group consisting of, and the term "arbitrarily substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means that it is replaced with R d1 is -N(C 1-2 Alkyl)C(O)(C 1-2 C(alkyl) and C(fluorine, chlorine, cyano) which are optionally substituted with one or more of these. 1-3 It is independently selected from the group consisting of alkyl groups.

[0066] In some embodiments, R d and R e One of them is selected from hydrogen, and the other is arbitrarily substituted. [ka] Selected from the group consisting of, and the term "arbitrarily substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means that it is replaced with R d1 is -C(O)N(R d2 )(R d3 ), -N(R d2 )C(O)(R d3 ), and independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and n-butyl which are optionally substituted with one or more of fluorine, chlorine, and cyano, R d2 and R d3 Each instance of occurrence is independently selected from the group consisting of hydrogen, methyl, and ethyl.

[0067] In some embodiments, [ka] It is independently selected from the group consisting of [the specified elements]. In some embodiments, [ka] It is independently selected from the group consisting of [the specified elements]. In some embodiments, [ka] It is independently selected from the group consisting of [the specified elements].

[0068] In some embodiments, [ka]

[0069] In some embodiments, R d1 C is optionally substituted with one or more of halogens, hydroxyls, aminos, and cyanos. 1-6 It is independently selected from the group consisting of alkyl groups. In some embodiments, R d1 C is optionally substituted with one or more of fluorine, chlorine, and cyano. 1-4 It is independently selected from the group consisting of alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl). In some embodiments, R d1 The group is independently selected from the group consisting of fluorine, chlorine, bromine, hydroxy, amino, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, -CH2CN, and -CH2CH2CN. In some embodiments, R d1 The compound is independently selected from the group consisting of monofluoromethyl, -CH2CN, methyl, and ethyl. In some embodiments, R d1 The group consisting of monofluoromethyl and -CH2CN is independently selected.

[0070] In some embodiments, Rf These are halogen, hydroxy, amino, cyano, -OR f4 ,-C(O)N(R f4 )(R f5 ), -N(R f4 )C(O)(R f5 ), C 1-6 Alkyl, and C 1-6 Independently selected from the group consisting of alkoxys, the above C 1-6 Alkyl, C 1-6 Alkoxy is one or more R f1 It is optionally replaced. In some embodiments, R f These are halogen, hydroxy, amino, cyano, -OR f4 ,-C(O)N(R f4 )(R f5 ), -N(R f4 )C(O)(R f5 ), C 1-4 Alkyl, and C 1-4 Independently selected from the group consisting of alkoxys, the above C 1-4 Alkyl, C 1-4 Alkoxy is one or more R f1 It is optionally replaced.

[0071] In some embodiments, R f is 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, and C 1-3 Independently selected from the group consisting of alkoxys, the above C 1-3 Alkyl, C 1-3 The alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and phenyl. In some embodiments, R f is halogen, and C 1-3 Independently selected from the group consisting of alkoxys, the C 1-3 The alkoxy is optionally substituted with one or more fluorine atoms.

[0072] In some embodiments, R f The following are independently selected from the group consisting of fluorine, chlorine, hydroxyl, amino, -O-cyclopropyl, -C(O)NHCH3, -NHC(O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2-phenyl, -OCH2CF3, and -OCH2CHF2. In some embodiments, R f It is independently selected from the group consisting of halogens. In some embodiments, R f It is independently selected from the group consisting of fluorine and chlorine.

[0073] In some embodiments, R f is halogen, C 1-6 Alkoxy, and C 1-6 It is independently selected from the group consisting of haloalkoxys. In some embodiments, R f fluorine, chlorine, bromine, C 1-4 Alkoxy, and C 1-3 It is independently selected from the group consisting of haloalkoxys. In some embodiments, R f The group is independently selected from fluorine, chlorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CF3, and -OCH2CHF2. In some embodiments, R f The group is independently selected from the group consisting of fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OCH2CHF2. In some embodiments, R f It is -OCH3.

[0074] In some embodiments, R f1 These include halogen, hydroxyl, amino, cyano, and -R f2Independently selected from the group consisting of R f2 and R f3 Each of these C atoms is optionally substituted with hydrogen and one or more of the following: halogen, hydroxyl, amino, and cyano. 1-4 It is independently selected from the group consisting of alkyl and phenyl. In some embodiments, R f1 This is independently selected from the group consisting of fluorine, chlorine, methyl, and phenyl. In some embodiments, R f1 The halogen is preferably fluorine. In some embodiments, p is independently selected from the group consisting of 0, 1, and 2, and is preferably 0 or 1, and preferably 1. In some embodiments, p is 0.

[0075] In some embodiments, L4 is a coupling. In some embodiments, R g It is selected independently of -COOH. In some embodiments, [ka] Independently selected from the group consisting of, L4 is a bond, and R g is -COOH, p is 0 or 1, R f is halogen or C 1-3 Selected from alkoxy, the C 1-3 The alkoxy is optionally substituted with one or more substituents selected from fluorine, or R f The group is independently selected from the group consisting of fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OCH2CHF2.

[0076] In some embodiments, m, n, and o are each independently 0, 1, or 2, and p is 1. In some embodiments, m is 1 or 2, and 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. In some embodiments, ring A is phenyl, m is 2, and there are two R a These are located at the ortho and para positions of the binding site between ring A and L1, respectively.

[0077] In some embodiments, ring A is phenyl, m is 2, and there are two R a These are located at the ortho and para positions of the binding site between ring A and L1, respectively. a is a halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 It is independently selected from the group consisting of haloalkoxys and oxetanyls. In some embodiments, ring A is phenyl, m is 2, and there are two R a These are located at the ortho and para positions of the binding site between ring A and L1, respectively. a These include fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, methyl, methoxy, and [ka] It is independently selected from the group consisting of [the specified elements].

[0078] In some embodiments, ring A is phenyl, ring B is phenyl, pyridyl, or pyrimidinyl, and ring C is [ka] Here, the "+" terminal represents a terminal that connects to L2, and the "++" terminal represents a terminal that connects to L3, R a is a halogen (preferably fluorine, chlorine), cyano, C 1-2Alkyl, C 1-2 Haloalkyl (preferably, C 1-2 Fluoroalkyl), C 1-2 Alkoxy, C 1-2 Haloalkoxy (preferably, C 1-2 Fluoroalkoxy), or oxetanyl, R b is a halogen (preferably fluorine), and R c It is fluorine, [ka] R f is hydrogen, halogen (preferably fluorine), C 1-3 Alkoxy (preferably -OCH3), or C 1-3 The compound is a haloalkoxy (preferably -OCH2CHF2), where m is 2, n is 0 or 1, o is 1, p is 0 or 1, L1 is -CH2O-, where the CH2 group is bonded to one end of ring A, the O group is bonded to one end of ring B, L2 is a bond, and L3 is -CH2-.

[0079] In some embodiments, [ka] R f -OCH3, -OCH2CH3, -OCH(CH3)2, or -OCH2CHF2(R f Preferably, it is -OCH3), p is 1, L1 is -CH2O-, where the CH2 group is bonded to one end of ring A, the O group is bonded to one end of ring B, L2 is a bond, and L3 is -CH2-.

[0080] In some embodiments, ring A is independently selected from the group consisting of phenyl and pyridyl; ring B is independently selected from the group consisting of 9-membered bicyclic condensed heterocyclyls and 5-6 membered monocyclic heteroaryls; and ring C is independently selected from the group consisting of C9 bicyclic condensed carbon rings, 9-membered bicyclic condensed heterocyclyls, 10-membered bicyclic condensed heterocyclyls, 9-membered bicyclic heteroaryls, piperidinyl, and piperazinyl. [ka] Selected independently from, X1 is CH or N, R a These are 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 Independently selected from the group consisting of alkoxys and 4-6 member heterocyclines, the above C 1-4 Alkyl, C 1-4 An alkoxy or a 4-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halogens, hydroxyls, and aminos, wherein the heteroatoms in the 4-6 membered heterocyclyl are oxygen atoms, and the number of heteroatoms is 1. R b C 1-4 Selected independently of alkyl, R c These are halogen, hydroxy, amino, cyano, oxo, and C. 1-4 Alkyl, and C 1-4 Independently selected from the group consisting of haloalkyls, R f is 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, and C 1-3 Independently selected from the group consisting of alkoxys, the above C 1-3 Alkyl or C 1-3 The alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and phenyl. L1 is independently selected from the group consisting of a bond and -CH2O-, L2 is independently selected from the group consisting of a bond and -CH2-, and L3 is -CH2-, -C(O)-, and -CH(C 1-4L4 is independently selected from the group consisting of alkyl)-, and L4 is independently selected from the bond. m, n, o, and p are independently 0, 1, 2, or 3, The aforementioned compound, [ka] isn't it.

[0081] In some embodiments, ring A is independently selected from the group consisting of phenyl and 5-6 membered heteroaryls. Ring B is independently selected from the group consisting of 9-membered bicyclic heterocyclines and 5-6 membered monocyclic heteroaryls, wherein the heteroatoms in the 9-membered bicyclic heterocyclines and 5-6 membered monocyclic heteroaryls are selected from N or O, and the number of heteroatoms is 1 or 2. Ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, and the heteroatoms in the C9 bicyclic condensed carbon ring, the 9-membered bicyclic condensed heterocyclyl, and the 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2. Ring D is, [ka] Independently selected from the group consisting of, where "#" ends represent ends that connect to L3, and "##" ends represent ends that connect to L4, R a These are independently selected from the group consisting of fluorine, chlorine, cyano, -C(O)NH2, -C(O)N(CH3)2, -C(O)NH(CH3), methyl, ethyl, methoxy, and ethoxy. R b It is selected independently of methyl, R c This is independently selected from the group consisting of fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, and n-butyl. R d and R eOne of the C atoms is selected from hydrogen, and the other is optionally substituted. 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines, the term "optionally substituted" means that the hydrogen atoms in the substituted group are unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means that it is replaced with R d1 C is optionally substituted with one or more of fluorine, chlorine, hydroxyl, amino, or cyano. 1-4 Independently selected from the group consisting of alkyls, R f R is independently selected from the group consisting of fluorine and chlorine. g It is selected independently of -COOH, L1 is independently selected from the group consisting of bonds and -CH2O-, L2 is independently selected from bonds, L3 is independently selected from the group consisting of -CH2-, -C(O)-, and -CH(CH3)-, and L4 is independently selected from bonds. m, n, o, and p are each independently 0, 1, or 2.

[0082] In some embodiments, ring A is independently selected from the group consisting of phenyl and pyridyl, ring B is independently selected from pyridyl, ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, the heteroatoms in the C9 bicyclic condensed carbon ring, the 9-membered bicyclic condensed heterocyclyl, and the 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2. Ring D is, [ka] Independently selected from the group consisting of, where "#" ends represent ends that connect to L3, and "##" ends represent ends that connect to L4, R aare each independently selected from the group consisting of fluorine, chlorine, cyano, -C(O)NH2, -C(O)N(CH3)2, -C(O)NH(CH3), methyl, ethyl, methoxy, and ethoxy, R b are each independently selected from methyl, R c are each independently selected from the group consisting of fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, and n-butyl, R d and R e one of which is selected from hydrogen, and the other is optionally substituted C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl; the said "optionally substituted" means that hydrogens on the substituted group are unsubstituted, or one or more substitutable sites on the substituted group are independently substituted by R d1 ; R d1 is each independently selected from the group consisting of C alkyl optionally substituted with one or more of fluorine, chlorine, hydroxy, amino, and cyano 1-4 alkyl, R f are each independently selected from the group consisting of fluorine and chlorine, R g is each independently selected from -COOH, L1 is each independently selected from the group consisting of a bond and -CH2O-, L2 is each independently selected from a bond, L3 is each independently selected from the group consisting of -CH2-, -C(O)-, and -CH(CH3)-, L4 is each independently selected from a bond, m, n, o, and p are each independently 0, 1, or 2.

[0083] In some embodiments, Ring A is each independently selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, Ring B is each independently selected from the group consisting of 9-membered bicyclic fused heterocyclyl and 5- to 6-membered monocyclic heteroaryl, Ring C is 9-membered bicyclic fused heterocyclyl, Ring D is [Chem] each is independently selected from the group consisting of, wherein the "# end represents the end binding to L3, the "##" end represents the end binding to L4, R a is independently selected from the group consisting of 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, and C 1-4 alkoxy, wherein said C 1-4 alkyl and C 1-4 alkoxy are optionally substituted with one or more substituents selected from halogen, hydroxy, and amino, R b is independently selected from the group consisting of C 1-6 alkyl, R c is independently selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C 1-4 alkyl, and C 1-4 haloalkyl, R d and R e one of is selected from hydrogen, and the other is selected from the group consisting of optionally substituted C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl, said "optionally substituted" means that hydrogen on the substituted group is unsubstituted, or one or more substitutable sites on the substituted group are independently substituted with R d1 which means that it is substituted with , R d1 is independently selected from the group consisting of C 1-6 alkyl optionally substituted with one or more of halogen, hydroxy, amino, and cyano, R f is independently selected from the group consisting of halogen and R g s, L1 is independently selected from the group consisting of a bond and -CH2O-, L2 is independently selected from the group consisting of a bond and -CH2-, and L3 is -CH2-, -C(O)-, and -CH(C 1-4 L4 is independently selected from the group consisting of alkyl)-, and L4 is independently selected from the bond. m, n, o, and p are each independently 0, 1, or 2.

[0084] In some embodiments, ring A is independently selected from the group consisting of phenyl and 5-6 membered heteroaryls; ring B is independently selected from the group consisting of 9 membered bicyclic condensed heterocyclyls and 5-6 membered monocyclic heteroaryls; and ring C is independently selected from the group consisting of C9 bicyclic condensed carbon rings, 9 membered bicyclic condensed heterocyclyls, 10 membered bicyclic condensed heterocyclyls, 9 membered bicyclic heteroaryls, piperidinyl, and piperazinyl. [ka] Selected independently from, X1 is CH or N, R a These are 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 Independently selected from the group consisting of alkoxys and 4-6 member heterocyclines, the above C 1-4 Alkyl, C 1-4 The alkoxy, 4-6 membered heterocyclil is optionally substituted with one or more substituents selected from halogens, hydroxyls, and aminos, wherein the heteroatoms in the 4-6 membered heterocyclil are oxygen atoms, and the number of heteroatoms is 1. R b C 1-4 Independently selected from the group consisting of alkyls, R c These are halogen, hydroxy, amino, cyano, oxo, and C. 1-4 Alkyl, and C 1-4Independently selected from the group consisting of haloalkyls, R f 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, and C 1-3 Independently selected from the group consisting of alkoxys, the above C 1-3 Alkyl, C 1-3 The alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and phenyl. L1 is independently selected from the group consisting of a bond and -CH2O-, L2 is independently selected from the group consisting of a bond and -CH2-, and L3 is -CH2-, -C(O)-, and -CH(C 1-4 L4 is independently selected from the group consisting of alkyl)-, and L4 is independently selected from the bond. m, n, and o are independently 0, 1, or 2, and p is 1. The aforementioned compound, [ka] isn't it.

[0085] In another embodiment, the present invention relates to the following formula (II) or formula (III): [ka] [In the formula, 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 similarly to the compounds represented by formula (I') according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0086] In some embodiments, ring A is independently selected from the group consisting of phenyl and pyridyl. Ring B is independently selected from the group consisting of a 9-membered bicyclic condensed heterocyclyl, pyridyl, phenyl, and pyrimidinyl, wherein the heteroatom of the 9-membered bicyclic condensed heterocyclyl is O, and the number of heteroatoms is 1 or 2. Ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, a 10-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, and the heteroatoms in the C9 bicyclic condensed carbon ring, 9-membered bicyclic condensed heterocyclyl, 10-membered bicyclic condensed heterocyclyl, and 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0087] In some embodiments, ring A is independently selected from the group consisting of phenyl and pyridyl. Ring B is independently selected from the group consisting of a 9-membered bicyclic condensed heterocyclyl, a 10-membered bicyclic condensed heterocyclyl, and pyridyl, wherein the heteroatoms of the 9-membered bicyclic condensed heterocyclyl and the 10-membered bicyclic condensed heterocyclyl are O, and the number of heteroatoms is 1 or 2. Ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, a 10-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, and the heteroatoms in the C9 bicyclic condensed carbon ring, 9-membered bicyclic condensed heterocyclyl, 10-membered bicyclic condensed heterocyclyl, and 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0088] In some embodiments, ring C is [ka] The terminals are independently selected from the group consisting of the following: where the "+" terminals represent terminals that connect to L2, and the "++" terminals represent terminals that connect to L3.

[0089] In some embodiments, ring A is independently selected from the group consisting of phenyl and pyridyl. Ring B is, [ka] The terminals are independently selected from the group consisting of the following, where "*" terminals represent terminals that connect to L1 and "**" terminals represent terminals that connect to L2.

[0090] In some embodiments, ring A is selected independently of phenyl. In yet another embodiment, the present invention relates to the following formula (II-1) or formula (III-1): [ka] [In the formula, 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 in the same way as in the compounds represented by formula (I'), formula (II), or formula (III) according to the present invention. The present invention provides compounds represented by ], or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof.

[0091] In yet another embodiment, the present invention relates to the following formulas (II-2), (II-3), (III-2), or (III-3): [ka] [In the formula, ring C, L1, L3, R a , R b , R c , R d , R e , R f m, n, o, and p are defined in the same way as in the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), or formula (III-1) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0092] In some embodiments, Ring C is independently selected from the group consisting of a C9 bicyclic fused carbocyclic group, 9-membered bicyclic fused heterocyclyl, 10-membered bicyclic fused heterocyclyl, and 9-membered bicyclic heteroaryl; the heteroatoms in said C9 bicyclic fused carbocyclic group, 9-membered bicyclic fused heterocyclyl, 10-membered bicyclic fused heterocyclyl, and 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0093] In some embodiments, Ring C is the following group: [Chemical Formula] wherein the "+" terminus represents the end binding to L2, and the "++" terminus represents the end binding to L3.

[0094] In some embodiments, [Chemical Formula] wherein the "+" terminus represents the end binding to L2, and the "++" terminus represents the end binding to L3.

[0095] According to still another aspect, the present invention provides a compound represented by the following formula (IV): [Chemical Formula] [wherein X1 is CH or N, 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 for the compound 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) according to the present invention.], or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0096] In some embodiments, ring A is phenyl or pyridyl. In some embodiments, ring B is independently selected from the group consisting of a 9-membered bicyclic condensed heterocyclyl, pyridyl, phenyl, and pyrimidinyl, wherein the heteroatom in the 9-membered bicyclic condensed heterocyclyl is O, and the number of heteroatoms is 2. In some embodiments, ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, a 10-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, wherein the heteroatoms in the 9-membered bicyclic condensed heterocyclyl, the 10-membered bicyclic condensed heterocyclyl, and the 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0097] In some embodiments, ring C is [ka] Here, the "+" terminal represents a terminal that connects to L2, and the "++" terminal represents a terminal that connects to L3. In some embodiments, R f This is independently selected from the group consisting of halogens (more preferably fluorine and chlorine). In some embodiments, R f is halogen, C 1-6 Alkoxy, and C 1-6 It is independently selected from the group consisting of haloalkoxys. In some embodiments, R f fluorine, chlorine, bromine, C 1-4 Alkoxy, and C 1-3 It is independently selected from the group consisting of haloalkoxys. In some embodiments, R f The group is independently selected from fluorine, chlorine, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CF3, and -OCH2CHF2.

[0098] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, X1 is CH. In some embodiments, p is 0 or 1, and ring C is [ka] The terminals are independently selected from the group consisting of the following: where the "+" terminals represent terminals that connect to L2, and the "++" terminals represent terminals that connect to L3.

[0099] In some embodiments, p is 1, and the ring C is independently selected from the group consisting of a C9 bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, a 10-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl, wherein the heteroatoms in the 9-membered bicyclic condensed heterocyclyl, the 10-membered bicyclic condensed heterocyclyl, and the 9-membered bicyclic heteroaryl are selected from N or O, and the number of heteroatoms is 1 or 2.

[0100] In some embodiments, p is 0, [ka] Here, the "*" ends represent ends that connect to L1, the "**" ends represent ends that connect to L2, and the ring C is, [ka] A group consisting of the following is selected, where the "+" terminal represents a terminal that connects to L2, and the "++" terminal represents a terminal that connects to L3.

[0101] In yet another embodiment, the present invention is given by the following formula (IV-1): [ka] [In the formula, X1 is CH or N, X2 is CH or N, and ring B, ring C, L1, L3, R a , R b , R c , Rd , R e , R f m, n, o, and p are defined in the same way as in 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) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0102] In some embodiments, X1 is CH. In some embodiments, X2 is CH. In some embodiments, p is 0. In some embodiments, p is 1.

[0103] In yet another form, the present invention is given by the following formula (IV-3): [ka] [In the formula, X1 is CH or N, X2 is CH or N, and rings B, L1, L3, R a , R b , R c , R d , R e , R f m, n, o, and p are defined in the same way as the compounds represented by formulas (I'), (II), (III), (II-1), (II-2), (II-3), (III-1), (III-2), (III-3), (IV), and (IV-1) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0104] In yet another embodiment, the present invention relates to the following formulas (IV-4) and (IV-6): [ka] [In the formula, X1 is CH or N, X2 is CH or N, and the rings C, L3, R a , R b , R c, R d , R e , R f m, n, o, and p are defined in the same way as in 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-3) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0105] In some embodiments, p is 0. In some embodiments, p is 1.

[0106] In some embodiments of formula (IV-4), p is 0, and ring C is [ka] A group consisting of the following is selected, where the "+" terminal represents a terminal that connects to L2, and the "++" terminal represents a terminal that connects to L3. In some embodiments, X1 is CH. In some embodiments, X2 is CH. In some embodiments, X2 is CH and m is 2.

[0107] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, o is 0. In some embodiments, o is 1.

[0108] In yet another embodiment, the present invention relates to the following formulas (IV-10), (IV-11), (IV-12), (IV-13), (IV-14), (IV-15), (IV-16), and (IV-17): [ka] [In the formula, X1 is CH or N, X2 is CH or N, X3 is CH or N, X4 is N, L3, R a , Rb , R c , R d , R e , R f m, n, o, and p are defined in the same way as 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-3), formula (IV-4), or formula (IV-6) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0109] In yet another form, the present invention is given by the following formula (V): [ka] [In the formula, X1 is CH or N, and ring B, ring C, L1, L3, R a , R b , R c , R d , R f m, n, o, and p are defined in the same way as in the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), or formula (IV-1) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0110] In yet another form, the present invention is given by the following formula (V-1): [ka] The present invention provides a compound represented by, or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof. [In the formula, X1 is CH or N, and ring A, ring B, L1, L3, R a , R b , R c , R d , R fm, n, o, and p are defined in the same way as in the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), or formula (IV-1) according to the present invention.

[0111] In some embodiments, ring A is independently selected from the group consisting of phenyl and 5-6 membered heteroaryls, the heteroatoms in the heteroaryl are selected from N, and the number of heteroatoms is 1 or 2. In some embodiments, ring A is independently selected from the group consisting of phenyl and pyridyl, and is preferably phenyl. In some embodiments, ring B is independently selected from the group consisting of phenyl and 6-membered heteroaryls, wherein the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1 or 2.

[0112] In some embodiments, ring B is independently selected from the group consisting of phenyl, pyridyl, and pyrimidinyl, and is preferably pyridyl or pyrimidinyl. In some embodiments, ring B is based on the following: [ka] Here, the "*" end represents an end that connects to L1, and the "**" end represents an end that connects to L2.

[0113] In some embodiments, R a is a halogen, cyano, -C(O)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Independently selected from the group consisting of haloalkoxys and 3- to 6-membered heterocyclines, wherein the heteroatom in the 3- to 6-membered heterocycline is O, and the number of heteroatoms is 1. In some embodiments, R a These are halogen, cyano, and C 1-3 Alkyl, C 1-3 Haloalkyl, C1-3 Alkoxy, C 1-3 It is independently selected from the group consisting of haloalkoxys and oxetanyls. In some embodiments, R a Fluorine, chlorine, cyano, -CF3, -OCHF2, -OCF3, methyl, methoxy, and [ka] It is independently selected from the group consisting of [the specified elements].

[0114] In some embodiments, R b This is independently selected from the group consisting of halogens, and is preferably fluorine, chlorine, or bromine, and is preferably fluorine. In some embodiments, R c This is independently selected from the group consisting of halogens, and is preferably fluorine, chlorine, or bromine, and is preferably fluorine. In some embodiments, R d It is being replaced by an optional substitution. [ka] Selected from the group consisting of, and the term "arbitrarily substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R d1 This means that it is replaced with R d1 C is optionally substituted with one or more of fluorine, chlorine, and cyano. 1-3 It is selected independently of alkyl.

[0115] In some embodiments, [ka] That is the case. In some embodiments, R f is halogen, C 1-6 Alkoxy, and C 1-6It is independently selected from the group consisting of haloalkoxys.

[0116] In some embodiments, R f fluorine, chlorine, bromine, C 1-4 Alkoxy, and C 1-3 It is independently selected from the group consisting of haloalkoxys. In some embodiments, R f The group is independently selected from the group consisting of fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OCH2CHF2. In some embodiments, L1 is independently selected from the group consisting of a bond and -CH2O-, preferably -CH2O-, more preferably -CH2O-, where the CH2 group is bonded to one end of ring A and the O group is bonded to one end of ring B.

[0117] In some embodiments, L3 is independently selected from the group consisting of -CH2-, -C(O)-, and -CH(CH3)-, preferably -CH2- or -CH(CH3)-, and more preferably -CH2-. In some embodiments, m is 2. In some embodiments, n is independently selected from the group consisting of 0 and 1, and is preferably 0. In some embodiments, o is independently selected from the group consisting of 0 and 1, and is preferably 0. In some embodiments, p is independently selected from the group consisting of 0 and 1, and is preferably 1. In some embodiments, X1 is CH.

[0118] In yet another form, the present invention is given by the following formula (V-2): [ka] [In the formula, X1 is CH or N, and rings B, L1, L3, R a , R b , R c , R d, R f m, n, o, and p are defined in the same way as in the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), or formula (V-1) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0119] In yet another form, the present invention is given by the following formula (V-3): [ka] [In the formula, ring B, L1, L3, R a , R b , R c , R f m, n, o, and p are defined in the same way as in the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), or formula (V-1) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0120] In yet another embodiment, the present invention relates to the following formulas (V-4), (V-5), (V-6), (V-7), and (V-8): [ka] [In the formula, X1 is CH or N, and the ring C, R a , R b , R c , R d , R f m, n, o, and p are defined in the same way as in the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), or formula (V-1) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0121] In yet another embodiment, the present invention relates to the following formulas (V-9), (V-10), (V-11), (V-12), (V-13), (V-14), (V-15), (V-16), and (V-17): [ka] [In the formula, X1 is CH or N, R a , R b , R c , R d , R f m, n, o, and p are defined in the same way as in the compounds represented by formula (I'), formula (II), formula (III), formula (II-1), formula (III-1), formula (IV), formula (IV-1), formula (V), or formula (V-1) according to the present invention. The present invention provides compounds represented by ], or tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0122] In some embodiments, m is 2 and there are two R a These are located at the ortho and para positions of the binding site between ring A and L1, respectively. a is a halogen, cyano, -C(O)NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Independently selected from the group consisting of alkoxys and oxetanyls, or R a These include fluorine, chlorine, cyano, -C(O)NH2, -CF3, -OCHF2, methyl, methoxy, and [ka] It is independently selected from the group consisting of [the specified elements].

[0123] In some embodiments, n is 0. In some embodiments, n is 1, R b It is independently selected from the group consisting of halogens, or R b is independently selected from the group consisting of fluorine, chlorine, and bromine, or R b It is fluorine. In some embodiments, o is 0. In some embodiments, o is 1, R c is a halogen, or independently selected from the group consisting of fluorine and chlorine. In some embodiments, L3 is independently selected from the group consisting of -CH2-, -C(O)-, and -CH(CH3)-, or L3 is -CH2-. In some embodiments, [ka] It is independently selected from the group consisting of [the specified elements].

[0124] In some embodiments, [ka] In some embodiments, X1 is CH. In some embodiments, X1 is N. In some embodiments, p is 0.

[0125] In some embodiments, p is 1, R f is halogen and C 1-3 Independently selected from the group consisting of alkoxys, the C 1-3 The alkoxy is optionally substituted with one or more fluorines, or R f C 1-3 Selected independently of alkoxy, or R f The group is independently selected from the group consisting of fluorine, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OCH2CHF2. Based on satisfying common sense in this field, preferred embodiments of the present invention can be obtained by arbitrarily combining the above preferred conditions. Preferably, the present invention provides a compound, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure.

[0126] [Table 1] JPEG2026529536000083.jpg243166JPEG2026529536000084.jpg242170JPEG2026529536000085.jpg238167JPEG2026529536000086.jpg148168

[0127] The present invention further aims to provide a method for producing a compound represented by formula (I') above, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The above method can be manufactured, for example, using the method shown in the following scheme. [ka]

[0128] The carboxyl group of intermediate 1.1 reacts with the two amino groups of compound 1.2 to obtain intermediate 1.3. There are two ways to convert intermediate 1.3 into the target product. Method 1: The halogen in intermediate 1.1 is converted to boric acid or a boric acid ester, then undergoes a Suzuki coupling reaction with compound 1.5 to obtain intermediate 1.6, and finally the target compound is obtained via an esterification reaction. Method 2: The halogen in compound 1.5 is converted to the substituted tin fragment 1.7, then undergoes a Stille coupling reaction with intermediate 1.3 to obtain intermediate 1.6, and finally converts to the target compound. Method 3: Intermediate 1.8 and intermediate 1.9 are reacted to form intermediate 1.10, and then the ester group is hydrolyzed under basic conditions to obtain target compound 1.11. [ka] Note: The partial protection and partial deprotection reaction steps included in this step have been omitted. However, ring F is a monocyclic aryl or monocyclic heteroaryl, preferably phenyl or a 5-6 member heteroaryl, more preferably phenyl or pyridyl, and rings A, B, C, D, L1, L2, L3, L4, R a , R b , R c , R d , R e , R f , R g m, n, o, and p are defined in the same way as in the compounds according to the present invention.

[0129] In another aspect, the present invention further provides pharmaceutical compositions comprising a compound according to the present invention, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Furthermore, the pharmaceutical composition according to the present invention comprises the compound according to the present invention, its tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (auxiliary material).

[0130] The compounds according to the present invention, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, may be administered in pure form or in the form of a suitable pharmaceutical composition, by any mode of administration acceptable to the agent providing similar use. Pharmaceutical compositions according to the present invention can be prepared by combining the compounds according to the present invention with a suitable pharmaceutically acceptable excipient. Pharmaceutical compositions according to the present invention can be prepared as solid, semi-solid, liquid, or gaseous formulations. Generally, the pharmaceutical compositions can be prepared by conventional methods using excipients commonly used in the pharmaceutical field.

[0131] In another aspect, the present invention further provides the use of compounds according to the present invention, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions according to the present invention, in the manufacture of pharmaceuticals for the prevention and / or treatment of diseases, symptoms, or conditions by activation of GLP-1R-mediated cascade signals.

[0132] Furthermore, the use of the present invention is limited to GLP-1R-related diseases, symptoms, and conditions, including diabetes, obesity, overweight, metabolic fatty liver disease, and Alzheimer's disease. In another aspect, the present invention further provides the use of compounds according to the present invention, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions according to the present invention, in the manufacture of pharmaceuticals for use in the treatment of diabetes, weight loss, metabolic fatty liver disease, and Alzheimer's disease.

[0133] In yet another form, the present invention provides a method for preventing and / or treating diseases, conditions, or pathologies mediated by activation of GLP-1R-mediated cascade signaling, comprising administering a compound according to the present invention, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, to an individual in need thereof. The aforementioned diseases, conditions, or pathologies are GLP-1R-related, including diabetes mellitus, obesity, overweight, metabolic fatty liver disease, and Alzheimer's disease.

[0134] In yet another form, the present invention provides compounds, tautomers, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in preventing and / or treating diseases, conditions, or pathologies mediated by activation of GLP-1R-mediated cascade signals. The aforementioned diseases, conditions, or pathologies are GLP-1R-related, including diabetes mellitus, obesity, overweight, metabolic fatty liver disease, and Alzheimer's disease.

[0135] In yet another form, the present invention provides the use of a compound according to the present invention, or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to the present invention, for the prevention and / or treatment of diseases, conditions, or pathologies mediated by the activation of GLP-1R-mediated cascade signals. The aforementioned diseases, conditions, or pathologies are GLP-1R-related, including diabetes mellitus, obesity, overweight, metabolic fatty liver disease, and Alzheimer's disease.

[0136] Furthermore, the use or method of the present invention involves using the compound according to the present invention, or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to the present invention, in combination with one or more other compounds useful for the same or similar indications. The present invention further provides pharmaceutical compositions comprising a compound according to the present invention, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, and one or more other compounds useful for the same or similar indications.

[0137] [Definition] C as described in this specification m-n This means that this part has an integer number of carbon atoms within a predetermined range. For example, "C 1-6 " means that the group may have one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms.

[0138] Any variable (for example, R a When a compound appears once or more in its composition or structure, the definition of each is independent. Therefore, for example, a single group, a single site, or a single atom has two R groups. a If replaced by each R a Each of these has its own independent options. The term "plural" means 2 to 10 (items), for example 2, 3, 4, 5, 6, 7, 8, 9, or 10 (items), preferably 2, 3, 4, 5, 6, 7, or 8 (items), preferably 2, 3, 4, 5, or 6 (items), and more preferably 2 or 3 (items).

[0139] "R b C is a hydrogen atom, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenil, C2-6 Alkinyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 "Independently selected from the group consisting of aryls and 5-12 member heteroaryls" means "R b C is optionally substituted with hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, etc. 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 Alkinyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 member heterocyclyl, optionally substituted C 6-14 This should be understood as "independently selected from the group consisting of aryls and substituted 5- to 12-membered heteroaryls." The present invention should also be understood by referring to the above understanding for other similar expressions.

[0140] The terms "optional," "optional," "optionally," or "at will" mean that the event or situation described thereafter may occur, but is not necessarily to occur, and the description includes both cases in which the event or situation occurs and cases in which it does not. The term "oxo" refers to the formation of a double bond (i.e., =O) when two hydrogen atoms at the same substitution position are replaced by the same oxygen atom.

[0141] Unless otherwise specified, the term "alkyl" means a monovalent saturated aliphatic hydrocarbon group comprising a linear or branched chain containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., C 1-10 It contains alkyl, and more preferably 1 to 8 carbon atoms (C 1-8 Alkyl) and more preferably 1 to 6 carbon atoms (i.e., C 1-6Includes alkyl, for example, "C 1-6 "Alkyl" means that the group is an alkyl group whose carbon chain contains 1 to 6 carbon atoms (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, and n-octyl.

[0142] Unless otherwise specified, the term "alkenyl" means an unsaturated aliphatic hydrocarbon group having at least one double bond in a straight or branched chain consisting of carbon atoms and hydrogen atoms. Alkenyls may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 It contains an alkenyl, and more preferably 2 to 8 carbon atoms (C 2-8 It contains an alkenyl, more preferably 2 to 6 carbon atoms (i.e., C 2-6 It contains alkenyls and has 2 to 5 carbon atoms (i.e., C 2-5 Alkenyl), 2-4 carbon atoms (i.e., C 2-4 Alkenyl), 2-3 carbon atoms (i.e., C 2-3 Alkenyls) contain two carbon atoms (i.e., C2 alkenyls), for example, "C 2-6 The term "alkenyl" means that the group contains 2 to 6 carbon atoms (specifically 2, 3, 4, 5, or 6) in its carbon chain. Non-exclusive examples of alkenyls include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0143] Unless otherwise specified, the term "alkynyl" means an unsaturated aliphatic hydrocarbon group having at least one triple bond in a straight or branched chain consisting of carbon atoms and hydrogen atoms. Alkynnyl may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 It contains an alkynyl, and more preferably 2 to 8 carbon atoms (C 2-8 It contains an alkynyl, more preferably 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl), 2-5 carbon atoms (i.e., C 2-5 Alkynyl), 2-4 carbon atoms (i.e., C 2-4 Alkynyl), 2-3 carbon atoms (i.e., C 2-3 Alkynyl) contains two carbon atoms (i.e., C2 alkynyl), for example, "C 2-6 The term "alkynyl" means that the group contains 2 to 6 carbon atoms (specifically 2, 3, 4, 5, or 6) in its carbon chain. Non-exclusive examples of alkynyls include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0144] Unless otherwise specified, the term "alkoxy" means "-O-alkyl," where alkyl is defined as above, i.e., it contains 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Typical examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, t-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, and 1-ethylpropoxy.

[0145] Unless otherwise specified, the term "alkylamino" means -NR'R'', where R' and R'' may be the same or different, and may be H or the alkyl defined above, the alkyl being defined in the same way as above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Typical examples include, but are not limited to, -NH(CH3), -N(CH3)(CH3), -N(CH2CH3)(CH3), and -N(CH2CH3)[CH(CH3)2].

[0146] Unless otherwise specified, the terms "halogen" or "halogenated" / "halo" refer to F, Cl, Br, or I. The term "haloalkyl" refers to an alkyl group in which one, two, or more hydrogen atoms, or all of the hydrogen atoms, are substituted with a halogen. Typical examples of haloalkyls include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0147] Unless otherwise specified, the term "carbocyclyl group" or "carbocyclyl" refers to a non-aromatic hydrocarbon group having 3 to 14 ring carbon atoms ("C"). 3-14 The term "carbon ring group" means a non-aromatic ring system that does not contain heteroatoms. In some examples, the carbon ring group has 3 to 12 ring carbon atoms ("C"). 3-12 A "carbocyclic group"), or a ring of 4 to 12 carbon atoms ("C"). 4-12 A "carbocyclic group"), or a ring of 3 to 10 carbon atoms ("C"). 3-10 It has a "carbon ring group". In some examples, the carbon ring group has 3 to 8 ring carbon atoms ("C"). 3-8 It has a "carbon ring group". In some examples, the carbon ring group has 3 to 7 ring carbon atoms ("C 3-7 It has a "carbon ring group". In some examples, the carbon ring group has 4 to 6 ring carbon atoms ("C 4-6It has a "carbon ring group". In some examples, the carbon ring group has 5 to 10 ring carbon atoms ("C 5-10 A "carbocyclic group"), or a ring of 5-7 carbon atoms ("C"). 5-7 It has a "carbon ring group". An example C 3-6 Examples of carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-8 The carbon ring group is the C mentioned above. 3-6 Examples include, but are not limited to, carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieenyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), and bicyclo[2.2.2]octyl (C8). 3-10 The carbon ring group is the C mentioned above. 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl(C9), decahydronaphthyl(C9) 10 ), spiro[4.5]decyl(C 10Examples include, but are not limited to, the above. As shown in the above examples, in some embodiments, the carbocyclic group is a monocyclic ("monocyclic carbocyclic group"), a condensed ("condensed carbocyclic group"), a bridged ("bridged ring group"), or a spiro-condensed ("spiro-ring group"), such as a bicyclic ("bicyclic carbocyclic group"), and may be saturated or partially unsaturated. The "carbocyclic group" further includes a ring system in which the ring of the carbocyclic group is condensed with one or more aryls, as defined above, where the bond site is on the carbocyclic group or aryl ring, and in such cases the number of members of the ring system of the carbocyclic group is the number of carbons in the carbocyclic system after condensation. In some embodiments, each example of a carbocyclic group may be independently and optionally substituted, for example, an unsubstituted group ("unsubstituted carbocyclic group") or a group substituted with one or more substituents ("substituted carbocyclic group"). In some embodiments, the carbocyclic group is an unsubstituted C 3-10 It is a carbon ring group. In some examples, the carbon ring group is a substituted C 3-10 It is a carbon ring group.

[0148] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably 3 to 12 carbon atoms (i.e., C 3-12 It contains a cycloalkyl group, and more preferably 3 to 10 carbon atoms (C 3-10 It contains a cycloalkyl group, and more preferably 3 to 7 carbon atoms (C 3-7 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 This includes cycloalkyl compounds. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, and dimethylcyclobutyl.

[0149] Unless otherwise specified, the terms “heterocyclyl” or “heterocycle” / “heterocycle” mean saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituents having a carbon atom and 1 to 4 ring heteroatoms, comprising 3 to 20 ring atoms, where 1, 2, 3 or more ring atoms are selected from the group consisting of N, O, and S, and the remaining ring atoms are C. Preferably, comprising 3 to 12 ring atoms (3 to 12-membered heterocyclyls), more preferably 3 to 10 ring atoms (3 to 10-membered heterocyclyls), or 3 to 8 ring atoms (3 to 8-membered heterocyclyls), or 3 to 6 ring atoms (3 to 6-membered heterocyclyls), or 4 to 6 ring atoms (4 to 6-membered heterocyclyls), or 5 to 6 ring atoms (5 to 6-membered heterocyclyls). The heteroatoms are 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, and pyranyl. Polycyclic heterocyclic groups include fused rings, spiro rings, and bridging ring heterocyclic groups (heterocyclyls). A "heterocyclyl" can be a monocyclic ("monocyclic heterocyclyl"), fused ("fused heterocyclyl"), bridging ("heterobridging heterocyclyl"), or spiro ("heterospirocyclic", "spiroheterocyclyl"), or "spirocyclic heterocyclyl," for example, a bicyclic ("bicyclic heterocyclyl") which may be saturated or partially unsaturated. A bicyclic heterocyclyl may contain one or more heteroatoms in one or both rings."Heterocyclyl" further includes a ring system in which the heterocyclyl ring defined above is fused with one or more carbocyclic groups, where the bond site is on the carbocyclic group or the heterocyclyl ring, or "heterocyclyl" further includes a ring system in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which the cycloalkyl ring defined above is fused with one or more heteroaryl groups, where the bond site is on the heterocyclyl ring, cycloalkyl ring, aryl ring, or heteroaryl ring, in which case the number of members of the heterocyclyl ring system is the number of atoms in the fused ring system. In some examples, each example of the heterocyclic group (heterocyclyl) may be independently and optionally substituted, for example, an unsubstituted group ("unsubstituted heterocyclic group (unsubstituted heterocyclyl)") or a group substituted with one or more substituents ("substituted heterocyclic group (substituted heterocyclyl)"). Examples of three-membered heterocyclyls containing one heteroatom include, but are not limited to, azilidinyl, oxiranyl, and thiiranyl. Examples of four-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidine-2-one. Examples of five-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyls containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl.Exemplary six-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary six-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazinanyl, oxadiazinanyl, thiadiazinanyl, oxathiazinanyl, and dioxazinanyl. Exemplary seven-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyls containing one heteroatom include, but are not limited to, azocanyl, oxocanyl, and thiocanyl. Examples of five-membered heterocyclines condensed to a C6 aryl ring (also referred herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclines condensed to an aryl ring (also referred herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0150] Unless otherwise specified, the term "condensed ring" refers to a non-aromatic, saturated or partially unsaturated ring system formed by two or more cyclic structures sharing two adjacent atoms, and includes condensed carbocyclyls and condensed heterocyclyls. The term "non-aromatic" means that the entire ring system is non-aromatic.

[0151] A fused carbocyclyl may contain 5 to 14 ring atoms, preferably 6 to 12 ring atoms, and more preferably 7 to 10 ring atoms. Examples of fused carbocyclyls include bicyclic, tricyclic, tetracyclic, or polycyclic fused carbocyclyls, preferably bicyclic, tricyclic, or tetracyclic fused carbocyclyls, and more preferably bicyclic or tricyclic fused carbocyclyls. Exemplary examples of fused carbocyclyls include: [ka] These are some examples, but they are not limited to these.

[0152] The fused heterocyclic group may contain 5 to 14 ring atoms, preferably 6 to 12 ring atoms, more preferably 7 to 10 ring atoms, of which 1 to 4 ring heteroatoms, preferably 1 to 3 (i.e., 1, 2, or 3) ring heteroatoms, and the heteroatoms are independently selected from the group consisting of N, O, and S. The fused heterocyclic group may include bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic fused heterocyclic groups, more preferably bicyclic or tricyclic fused heterocyclic groups. Exemplary examples of fused heterocyclic groups include: [ka] Examples include, but are not limited to, bicyclic heterocyclines or bicyclic condensed heterocyclines. [ka] These are some examples, but they are not limited to these.

[0153] Unless otherwise specified, the terms "aryl" or "aromatic cyclyl" refer to monocyclic, bicyclic, and tricyclic aromatic carbocyclic systems containing 6 to 16 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably containing 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryls include, but are not limited to, phenyl, naphthyl, anthracenyl, phenantrenyl, or pyrenyl.

[0154] Unless otherwise specified, the terms "heteroaryl" or "heteroaromatic ring group" mean aromatic monocyclic or polycyclic ring systems comprising a 5-14 member structure, preferably a 5-18 member structure, preferably a 5-12 member structure, preferably a 5-10 member structure, preferably a 5-8 member structure, and more preferably a 5-6 member structure, where one, two, three, or more ring atoms are heteroatoms, the remaining atoms are carbon, the heteroatoms are independently selected from the group consisting of O, N, and S, and the number of heteroatoms is preferably one, two, or three. Polycyclic heteroaryls are condensed heteroaryls. Examples of heteroaryls include furanil, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranil, benzothienyl, benzo Examples include, but are not limited to, pyridyl, benzopyrimidinil, benzopyradinil, benzimidazolyl, benzophthalazinil, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinil, imidazo[1,2-b]pyridazinil, [1,2,4]triazolo[4,3-b]pyridazinil, [1,2,4]triazolo[1,5-a]pyrimidinil, and [1,2,4]triazolo[1,5-a]pyridyl.

[0155] Unless otherwise specified, the term "condensed heteroaryl" refers to an aromatic ring system formed by two or more cyclic structures sharing two adjacent atoms with each other, where each ring in the condensed heteroaryl is an unsaturated aromatic ring, which may contain 5 to 20 ring atoms, preferably 6 to 14 ring atoms, more preferably 7 to 10 ring atoms, of which 1 to 4 ring heteroatoms, preferably 1 to 3 (i.e., 1, 2, or 3) ring heteroatoms, and the heteroatoms are independently selected from the group consisting of N, O, and S. Examples of condensed heteroaryls include bicyclic, tricyclic, tetracyclic, or polycyclic condensed heteroaryls, preferably bicyclic, tricyclic, or tetracyclic condensed heteroaryls, and more preferably bicyclic or tricyclic condensed heteroaryls. Exemplary examples of condensed heteroaryls include: [ka] These are some examples, but they are not limited to these.

[0156] Unless otherwise specified, the term “pharmaceutically acceptable salt” or “medicinal salt” means a salt that, within the bounds of sound medical judgment, is suitable for contact with mammalian tissues, particularly human tissues, without causing excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. Such salts may be prepared in situ during the final isolation and purification of the compounds of the present invention, or they may be prepared separately by reacting a free base or free acid with a suitable reagent.

[0157] Unless otherwise specified, the compounds according to the present invention further include their "isotope derivatives." Unless otherwise specified, the term "isotope derivative" means that the compounds according to the present invention may exist in an isotopic or enriched form containing one or more atoms with atomic weights or mass numbers different from those of the most abundant atoms in nature. The isotopes may be radioactive or non-radioactive. 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 isotope ( 15 O, 17 O, and 18 O), as well as sulfur isotopes ( 35 S) These isotope-labeled compounds can be used to study the distribution of drug molecules within tissues. In particular, 3 H and 13 C is more widely used because it is easy to label and detect. For example, deuterium ( 2 Substitution with certain heavy isotopes, such as H), enhances metabolic stability, extends the half-life, thereby achieving the objective of reducing the dosage and providing therapeutic efficacy benefits. Isotope-labeled compounds are generally synthesized from labeled starting materials, similar to how unisotopically labeled compounds are synthesized using known synthetic techniques.

[0158] Unless otherwise specified, the compounds according to the present invention also include their “solvates” or “solvated compounds.” The terms “solvate” and “solvated compound” mean the physical association of a compound according to the present invention with one or more solvent molecules (whether organic or inorganic). Such physical associations include 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 can be isolated. The solvent molecules in the solvate can exist in regular and / or disordered arrangements. The solvate can contain stoichiometric or non-stoichiometric amounts of solvent molecules. “Solvate” includes the solvate that can be isolated from the solution phase. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art. The term "hydrate" refers to a substance formed when water molecules are bonded to cations or anions in a compound via coordinate bonds or covalent bonds, or when water ions do not directly bond to cations or anions but exist in a certain proportion at specific positions within the crystal lattice of a solid.

[0159] Unless otherwise specified, the term "stereoisomer" refers to a compound that has the same chemical structure but differs in the spatial arrangement of its atoms or groups. Stereoiomers include enantiomers (mirror-image isomers), diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atrop isomers, and others. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, or diastereomers, for example, by chromatography and / or fractional crystallization, based on the differences in the physicochemical properties of the components. Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may include carbon-carbon double bonds or carbon-nitrogen double bonds having an E or Z configuration, where the term "E" represents a higher-order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents a higher-order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond (as determined by the Cahn-Ingold-Prelog priority rule). The compounds according to the present invention may also exist in the form of a mixture of "E" and "Z" isomers.

[0160] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert across low energy barriers. When tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via rearrangement of some bonding electrons.

[0161] Unless otherwise specified, the structural formulas described in this invention include all isomer forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformosomers)), such as the R, S configuration including a chiral center, the (Z), (E) isomers of a double bond, and the (Z), (E) conformosomers. Therefore, individual stereochemical isomers of the compounds according to the present invention, or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformosomers), are included within the scope of this invention.

[0162] Unless otherwise specified, the compounds according to the present invention further include their “prodrugs.” The term “prodrug” means a drug that is converted to a parent drug in vivo. Prodrugs are usually useful and may improve several identified, undesirable physical or biological properties. Physical properties are generally related to solubility (excess or insufficient solubility in lipids or water) or stability, while biological properties of concern may include excessively rapid metabolism or insufficient bioavailability, which may be related to physicochemical properties. For example, they may be bioavailable by oral administration, while the parent drug cannot. The solubility of prodrugs in pharmaceutical compositions is also improved to some extent compared to their parent drugs. An example of a prodrug may be any of the compounds according to the present invention administered as an ester ("prodrug") to facilitate delivery across cell membranes, whose water solubility is detrimental to mobility, but which is beneficial once the prodrug enters the cell, after which it is metabolized and hydrolyzed to a carboxylic acid, i.e., the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active site.

[0163] Unless otherwise specified, the term “treatment / to treat” means all treatment of diseases, disorders (diseases), and conditions in a patient, including (a) suppressing the symptoms of a disease, disorder, or condition, i.e., preventing its progression or onset; (b) reducing the symptoms of a disease, disorder, or condition, i.e., causing regression of the disease or symptoms; or (c) improving or eliminating a disease, disorder, condition, or one or more symptoms associated with the disease.

[0164] The abbreviations used in the manufacturing examples, examples, and other parts of this specification are as follows: AIBN: Azobisisobutyronitrile, DCM: Dichloromethane, DIAD: Diisopropyl azodicarboxylate, DIPEA: N,N-diisopropylethylamine, DMF: N,N-dimethylformamide, EA: ethyl acetate, HATU:2-(7-azabenzotriazole)-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(diphenylphosphin)ferrocenedichloropalladium(II), TCFH: N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate THF: Tetrahydrofuran, BINAP: 1,1'-Binaphthyl-2,2'-Bisdiphenylphosphine DMA: N,N-dimethylacetamide, DMSO: dimethyl sulfoxide, XantPhos: 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene.

[0165] [Effects of the invention] This invention designs a group of compounds with novel structures. Enzymatic studies have shown that the compounds according to the present invention have a strong agonist effect on GLP-1R, offering new directions for the treatment of diseases such as diabetes, metabolic fatty liver disease, and Alzheimer's disease, as well as for weight loss. In vivo studies have shown that the compounds according to the present invention have excellent pharmacokinetic properties. hERG studies have confirmed that the compounds according to the present invention have a low risk of cardiotoxicity and excellent safety. In terms of appetite suppression rates, the compounds according to the present invention have shown a good appetite suppression effect, and studies on weight loss efficacy in mice have shown that the compounds according to the present invention have a weight loss effect. Furthermore, this invention is studying a specific synthesis method that is simple and easy to operate, and is advantageous for large-scale industrial production and application. [Modes for carrying out the invention]

[0166] The present invention will be further described below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and do not limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not explicitly stated are usually carried out under general conditions or conditions suggested by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those well known to those skilled in the art. Furthermore, any similar or equivalent methods and materials described herein can be applied to the methods of the present invention. Preferred methods and materials shown herein are illustrative only.

[0167] The following are examples of the production of exemplary compounds of the present invention. Synthesis of 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetic acid (intermediate 1.1-A) [ka]

[0168] Step 1: Synthesis of 7-bromobenzo[d][1,3]dioxolane-4-carboxylate ethyl ester 4-bromo-2,3-dihydroxybenzoate ethyl ester (2 g, 7.66 mmol) was dissolved in DMF (20 mL), then cesium carbonate (5.5 g, 16.86 mmol) was added, and the mixture was reacted at 20°C with stirring for 1 hour. Subsequently, CH2I2 (328.45 mg, 1.24 mmol) was added, and the mixture was reacted at 70°C with stirring for 12 hours. After the reaction was complete, water was added to quench the reaction mixture, it 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 = 1:1) to obtain 7-bromobenzo[d][1,3]dioxolane-4-carboxylate ethyl ester (1.05 g). ESI-MS (m / z): 273.2 [M+H] + .

[0169] Step 2: Synthesis of (7-bromobenzo[d][1,3]dioxolan-4-yl)methanol The product obtained in 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 in batches. The mixture was reacted at 0°C with continued stirring for 1 hour. After the reaction was complete, water was added to quench the reaction mixture, it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (7-bromobenzo[d][1,3]dioxolan-4-yl)methanol (1.05 g). ESI-MS (m / z): 231.2 [M+H] + .

[0170] Step 3: Synthesis of 4-bromo-7-(chloromethyl)benzo[d][1,3]dioxolane The product obtained in the previous step (1.05 g, 4.54 mmol) was dissolved in DCM (10 mL), SOCl2 (2.70 g, 22.72 mmol) was added, and the mixture was reacted at 20°C with stirring for 2 hours. After detecting the completion of the reaction by TLC, the mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain 4-bromo-7-(chloromethyl)benzo[d][1,3]dioxolane (830 mg). ESI-MS (m / z): 249.0 [M+H] + .

[0171] Step 4: Synthesis of 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetonitrile The product obtained in 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 reacted at 90°C with stirring for 5 hours. After the reaction was complete, water was added to quench the reaction mixture, which was then 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 = 1:2) to obtain 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetonitrile (570 mg). ESI-MS (m / z): 240.1 [M+H] + .

[0172] Step 5: Synthesis of 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetic acid The product obtained in the previous step (570 mg, 2.37 mmol) was added to EtOH (5.7 mL), then KOH (483.6 mg, 8.62 mmol) was dissolved in H2O (5.7 mL), and the mixture was reacted at 80°C with stirring for 5 hours. After the reaction was complete, water was added to the reaction solution, and then extracted with trichloromethane. The aqueous phase was adjusted to pH=5 with 1 M hydrochloric acid, then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 2-(7-bromobenzo[d][1,3]dioxolan-4-yl)acetic acid (500 mg). ESI-MS (m / z): 257.0 [MH] - .

[0173] Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetic acid (intermediate 1.1-B) [ka]

[0174] Step 1: Synthesis of methyl 3-(allyloxy)-4-bromobenzoate 30 g, 129.84 mmol of 4-bromo-3-hydroxybenzoate methyl ester was dissolved in 300 mL of DMF, then 26.93 g, 194.81 mmol of K2CO3 was added, and the mixture was reacted at 60°C with stirring for 3 hours. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 31 g of 3-(allyloxy)-4-bromobenzoate methyl ester. ESI-MS (m / z): 271.1 [M+H] + .

[0175] Step 2: Synthesis of methyl 2-allyl-4-bromo-3-hydroxybenzoate The product obtained in the previous step (10 g, 7.37 mmol) was added to NMP (58 mL). The mixture was reacted at 200 °C under microwave conditions with stirring for 5 hours. After the reaction was complete, 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 the 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] + .

[0176] Step 3: Synthesis of 2-hydroxy-7-bromo-2,3-dihydrobenzofuran-4-carboxylate methyl ester The product obtained in 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 NaI / O4 (7.89 g, 36.89 mmol) were added. The mixture was reacted at 20°C with stirring for 6 hours. After the reaction was complete, 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 the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain 2-hydroxy-7-bromo-2,3-dihydrobenzofuran-4-carboxylate methyl ester (4.2 g). ESI-MS (m / z): 273.1 [M+H] + .

[0177] Step 4: Synthesis of 4-bromo-3-hydroxy-2-(2-hydroxyethyl)methyl benzoate The product obtained in the previous step (4.2 g, 14.65 mmol) was added to THF (56 mL) and MeOH (56 mL), then NaBH4 (554.16 mg, 14.65 mmol) was added, and the mixture was reacted at 0°C with stirring for 1 hour. After the reaction was complete, water was added to the reaction solution, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 4-bromo-3-hydroxy-2-(2-hydroxyethyl)methyl benzoate (3.5 g). ESI-MS (m / z): 275.0 [M+H] + .

[0178] Step 5: Synthesis of 7-bromo-2,3-dihydrobenzofuran-4-carboxylate methyl ester The product obtained in the previous step (3.5 g, 12.00 mmol) was dissolved in THF (103 mL), then PPh3 (3.78 g, 14.41 mmol) and DIAD (2.91 g, 14.40 mmol) were added, and the mixture was reacted at 50°C with stirring for 5 hours. After detecting complete reaction of the starting materials by TLC, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain 7-bromo-2,3-dihydrobenzofuran-4-carboxylate methyl ester (2.5 g). ESI-MS (m / z): 257.2 [M+H] + .

[0179] Step 6: Synthesis of (7-bromo-2,3-dihydrobenzofuran-4-yl)methanol The product obtained in 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 in batches. The mixture was reacted at 0°C with continuous stirring for 1 hour. After the reaction was complete, water was added to quench the reaction mixture, it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (7-bromo-2,3-dihydrobenzofuran-4-yl)methanol (1.9 g). ESI-MS (m / z): 229.0 [M+H] + .

[0180] Step 7: Synthesis of 7-bromo-4-(chloromethyl)-2,3-dihydrobenzofuran The product obtained in the previous step (1.9 g, 8.16 mmol) was dissolved in dichloromethane (18.7 mL), SOCl2 (4.86 g, 40.82 mmol) was added, and the mixture was reacted at 20°C with stirring for 2 hours. After detecting the completion of the reaction by TLC, water was added to quench the reaction mixture, it 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 obtain 7-bromo-4-(chloromethyl)-2,3-dihydrobenzofuran (1.6 g). ESI-MS (m / z): 247.1 [M+H] + .

[0181] Step 8: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile The product obtained in 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 reacted at 90°C with stirring for 4 hours. After the reaction was complete, water was added to the reaction solution, followed by extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the crude product. The crude product was then analyzed by column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile (1 g). ESI-MS (m / z): 238.1 [M+H] + .

[0182] Step 9: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetic acid The product obtained in the previous step (1 g, 4.20 mmol) was dissolved in EtOH (10 mL) and H2O (10 mL), then KOH (855 mg, 15.25 mmol) was added, and the mixture was reacted at 80°C with stirring for 3 hours. After the reaction was complete, water was added to quench the reaction mixture, and it was extracted with trichloromethane. The pH was adjusted to 5 with 1 M HCl, and then extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetic acid (900 mg). ESI-MS (m / z): 255.1 [MH] - .

[0183] Synthesis of 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetic acid (intermediate 1,1-C) [ka]

[0184] Step 1: Synthesis of 4-bromo-2,3-dihydrobenzofuran-7-carboxylate tert-butyl ester 4-bromo-2-fluorobenzoic acid tert-butyroester (20 g, 72.7 mmol) was added to THF (400 mL) and purged with nitrogen gas. The temperature in the bottle was cooled to -78°C using a dry ice acetone bath. LDA (1.5 M, 48.46 mL) was gradually added dropwise to the mixture using a constant-pressure dropping funnel. After 60 minutes of dropwise addition, the reaction mixture was stirred at -78°C for 4 hours. When the solution turned yellow, ethylene oxide was added to the reaction mixture, and the reaction mixture was stirred at -78°C for 6 hours. After the reaction was complete, the mixture was quenched with aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, washed with brine to recover the organic phase, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-bromo-2,3-dihydrobenzofuran-7-carboxylic acid tert-butyl ester (3 g). ESI-MS (m / z): 299.2 [M + H] + .

[0185] Step 2: Synthesis of methyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate The product obtained in the previous step (2.3 g, 7.69 mmol) was dissolved in a methanol solution of hydrochloric acid (46 mL), and the mixture was reacted at 20°C with stirring for 3 hours. After the reaction was complete, 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 4-bromo-2,3-dihydrobenzofuran-7-carboxylate methyl ester (1.7 g). ESI-MS (m / z): 257.2 [M+H] + .

[0186] Step 3: Synthesis of (4-bromo-2,3-dihydrobenzofuran-7-yl)methanol The product obtained in the previous step (1.7 g, 6.61 mmol) was added to THF (17 mL), then lithium tetrahydroaluminum (301 mg, 7.94 mmol) was added at 0°C, and the mixture was reacted at 0°C with stirring for 2 hours. After the reaction was complete, water was added to quench the reaction mixture, then it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (4-bromo-2,3-dihydrobenzofuran-7-yl)methanol (1.4 g). ESI-MS (m / z): 229.1 [M+H] + .

[0187] Step 4: Synthesis of 4-bromo-7-(chloromethyl)-2,3-dihydrobenzofuran The product obtained in the previous step (1.4 g, 6.11 mmol) was added to DCM (14 mL), cooled to 0°C, then SOCl2 (3.64 g, 30.56 mmol) was added, and the mixture was reacted at 0°C with stirring for 2 hours. Complete completion of the reaction of the starting materials was detected by TLC. The reaction mixture was quenched with water, then 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 obtain 4-bromo-7-(chloromethyl)-2,3-dihydrobenzofuran (1.3 g). ESI-MS (m / z): 247.2 [M+H] + .

[0188] Step 5: Synthesis of 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetonitrile The product obtained in 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 reacted at 90°C with stirring for 4 hours. After the reaction was complete, water was added to quench the reaction mixture, then it 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 then subjected to 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] + .

[0189] Step 6: Synthesis of 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetic acid The product obtained in the previous step (800 mg, 3.36 mmol) was dissolved in EtOH (8 mL), then KOH (684 mg, 12.20 mmol) was added, and the mixture was reacted at 80°C with stirring for 3 hours. After detecting the completion of the reaction by TLC, water was added to the reaction solution, extracted with trichloromethane, adjusted to pH=5 with 1 M HCl, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 2-(4-bromo-2,3-dihydrobenzofuran-7-yl)acetic acid (760 mg). ESI-MS (m / z): 255.1 [MH] - .

[0190] Synthesis of 2-(7-bromo-1H-indole-4-yl)acetic acid (intermediate 1,1-D) [ka] Step 1: Synthesis of 7-bromo-4-methyl-1-p-toluenesulfonyl-1H-indole 7-Bromo-4-methyl-1H-indole (1.4 g, 6.7 mmol) and N,N-dimethylformamide (20 mL) were placed in a 100 mL flask. Sodium hydride (536 mg, 13.4 mmol) was added in batches at 0°C, and the mixture was stirred for 10 minutes. p-methylbenzenesulfonyl chloride (1.91 g, 10 mmol) was added, and the mixture was gradually heated to room temperature while stirring was continued. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate, 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] + .

[0191] Step 2: Synthesis of 7-bromo-4-(bromomethyl)-1-p-toluenesulfonyl-1H-indole 7-Bromo-4-methyl-1-p-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 placed in a 100 mL flask and heated to 80°C, reacting with stirring. After the reaction was complete, 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-p-toluenesulfonyl-1H-indole (1.6 g). ESI-MS (m / z): 441.9 [M+H] + .

[0192] Step 3: Synthesis of 2-(7-bromo-1-p-toluenesulfonyl-1H-indole-4-yl)acetonitrile 7-Bromo-4-(bromomethyl)-1-p-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 placed in a 100 mL flask and heated to 80°C, reacting with stirring. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate, dried, and concentrated. The crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 2-(7-bromo-1-p-toluenesulfonyl-1H-indole-4-yl)acetonitrile (1.2 g). ESI-MS (m / z): 389.0 [M+H] + .

[0193] Step 4: Synthesis of 2-(7-bromo-1H-indole-4-yl)acetonitrile 1.4 g (3.61 mmol) of 2-(7-bromo-1-p-toluenesulfonyl-1H-indole-4-yl)acetonitrile and 40 mL of methanol were placed in a 100 mL flask. 1.44 g (36.1 mmol) of sodium hydroxide was added, and the mixture was heated to 65°C with continued stirring to allow the reaction to proceed. After the reaction was complete, the mixture was concentrated, and the crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain 500 mg of 2-(7-bromo-1H-indole-4-yl)acetonitrile. ESI-MS (m / z): 235.0 [M+H] + .

[0194] Step 5: Synthesis of 2-(7-bromo-1H-indole-4-yl)acetic acid: 200 mg (0.85 mmol) of 2-(7-bromo-1H-indole-4-yl)acetonitrile, 476 mg (8.5 mmol) of potassium hydroxide, 5 mL of ethanol, and 10 mL of water were placed in a 25 mL round-bottom flask and heated to 100 °C, reacting with stirring. After the reaction was complete, the reaction mixture was concentrated, the pH was adjusted to 3 with acetic acid, and the mixture was further concentrated. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to obtain 2-(7-bromo-1H-indole-4-yl)acetic acid (180 mg). ESI-MS (m / z): 254.0 [M+H] + .

[0195] Synthesis of 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid (intermediate 1.1-E) [ka] Step 1: 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetonitrile 500 mg (2.11 mmol) of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile and 10 mL of N,N-dimethylformamide were placed in a 100 mL flask, and then 337 mg (2.5 mmol) of N-chlorosuccinimide was added. The mixture was reacted at 60°C with stirring. After the reaction was complete, the mixture was cooled, added to ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated, and the crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 480 mg of 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetonitrile.

[0196] Step 2: 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid 480 mg (1.77 mmol) of 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetonitrile and 20 mL of ethanol were placed in a 100 mL flask. Potassium hydroxide (992 mg, 17.7 mmol) and water (25 mL) were then added, and the mixture was reacted at 100°C with stirring. After the reaction was complete, the mixture was cooled, the solution was acidified with 1 N hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated, and the crude product was separated and purified by thin-layer chromatography (methanol:dichloromethane = 1:15) to obtain 480 mg of 2-(7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)acetic acid. ESI-MS (m / z): 289.0 [MH] - .

[0197] Synthesis of 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid (intermediate 1.1-F) [ka] Step 1: 2-(4-bromo-2-fluoro-5-methoxyphenyl)acetic acid 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 mixture was carried out at 20°C with stirring. After the reaction was complete, water was added to the reaction mixture, and acetic acid was added to adjust the pH to approximately 5. The mixture 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] - .

[0198] Step 2: 2-(4-bromo-2-fluoro-5-methoxyphenyl)methyl acetate The product obtained in 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 was carried out at 20°C with stirring. After the reaction was complete, water was added to the reaction mixture, and after extraction with ethyl acetate, the organic phase was washed with a semi-saturated NaCl solution, dried over anhydrous sodium sulfate, and the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain 2-(4-bromo-2-fluoro-5-methoxyphenyl)methyl acetate (4.2 g). ESI-MS (m / z): 277.0 [M+H] + .

[0199] Step 3: 2-(4-bromo-2-fluoro-5-hydroxyphenyl)acetic acid methyl ester The product obtained in the previous step (4.2 g, 15.16 mmol) was dissolved in dichloromethane (72 mL), then BBr3 (11.39 g, 45.47 mmol) was added, and the reaction was carried out at 0°C with stirring. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 (20 mL) solution, extracted with ethyl acetate, washed the organic phase with saturated NaCl solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 2-(4-bromo-2-fluoro-5-hydroxyphenyl)acetic acid methyl ester (4 g). ESI-MS (m / z): 263.0 [M+H] + .

[0200] Step 4: 2-(5-allyloxy-4-bromo-2-fluorophenyl)methyl acetate The product obtained in the previous step (4 g, 15.21 mmol) and allyl bromide (2.76 g, 22.81 mmol) were dissolved in DMF (40 mL), then potassium carbonate (3.15 g, 22.81 mmol) was added, and the reaction was carried out at 60°C with stirring. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was washed with a semi-saturated NaCl solution, dried over anhydrous sodium sulfate, and the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain methyl 2-(5-allyloxy-4-bromo-2-fluorophenyl)acetate (3.7 g). ESI-MS (m / z): 303.1 [M+H] + .

[0201] Step 5: 2-(2-allyl-4-bromo-6-fluoro-3-hydroxyphenyl) acetate methyl ester The product obtained in the previous step (3.7 g, 12.21 mmol) was dissolved in NMP (15 mL), and the microwave reaction was maintained at 200 °C for 4 hours. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was washed with a semi-saturated NaCl solution, dried over anhydrous sodium sulfate, and the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain 2-(2-allyl-4-bromo-6-fluoro-3-hydroxyphenyl)methyl acetate (2.45 g). ESI-MS (m / z): 303.1 [M+H] + .

[0202] Step 6: 2-(7-bromo-5-fluoro-2-hydroxy-2,3-dihydrobenzofuran-4-yl)methyl acetate The product obtained in the previous step (2.35 g, 7.75 mmol) was dissolved in THF (40 mL) and H2O (40 mL), and NaI / O4 (3.32 g, 15.51 mmol) and OsO4 (1.41 g, 5.53 mmol) were added. The reaction was carried out at 20°C with stirring. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was washed with NaCl solution, dried over anhydrous sodium sulfate, and the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain 2-(7-bromo-5-fluoro-2-hydroxy-2,3-dihydrobenzofuran-4-yl)methyl acetate (1.3 g). ESI-MS (m / z): 305.1 [M+H] + .

[0203] Step 7: 2-(4-bromo-6-fluoro-3-hydroxy-2-(2-hydroxyethyl)phenyl)methyl acetate The product obtained in the previous step (1.2 g, 3.93 mmol) was dissolved in THF (15 mL) and MeOH (15 mL), NaBH4 (148.80 mg, 3.93 mmol) was added, and the reaction was carried out at 0°C with stirring. After the reaction was complete, the reaction mixture was quenched with NH4Cl solution, extracted with ethyl acetate, washed the organic phase with semi-saturated NaCl, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product 2-(4-bromo-6-fluoro-3-hydroxy-2-(2-hydroxyethyl)phenyl)methyl acetate (1.1 g). ESI-MS (m / z): 307.1 [M+H] + .

[0204] Step 8: 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl acetate The product obtained in the previous step (1.1 g, 3.58 mmol) was dissolved in THF (22 mL), and PPh3 (1.13 g, 4.3 mmol) and DIAD (1.9 M, 2.26 mL) were added at 20 °C. The reaction mixture was then stirred and allowed to proceed at 50 °C. If the presence of the target product was confirmed by LC-MS detection, the reaction mixture was quenched with H2O, extracted with ethyl acetate, washed with semi-saturated NaCl (20 mL), dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product. This crude product was then purified by column chromatography (PE:EA = 2:1) to obtain 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid methyl ester (834 mg). ESI-MS (m / z): 289.1 [M + H] + .

[0205] Step 9: 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid The product obtained in 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 reacted with stirring at 20°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, the reaction mixture was made acidic 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 obtain 2-(7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)acetic acid (120 mg). ESI-MS (m / z): 273.1 [MH] - .

[0206] Synthesis of 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)acetic acid (intermediate 1.1-G) [ka] Referring to the synthesis method of intermediate 1.1-A, the target compound 2-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)acetic acid was obtained using ethyl 4-bromo-2,3-dihydroxybenzoate and 1,2-dibromoethane as starting materials. ESI-MS (m / z): 271.0 [MH] - .

[0207] Synthesis of 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetic acid (intermediate 1,1-H) [ka]

[0208] Step 1: (E)-4-(2-ethoxyvinyl)-7-methoxy-2,3-dihydro-1H-inden-1-one 4-bromo-7-methoxy-1-indanone (5g, 20.74 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (4.5g, 22.85 mmol), dichloro[1,1'-di(diphenylphosphino)ferrocene]palladium (1.5g, 2.05 mmol), and cesium carbonate (20g, 60.79 mmol) were added to dioxane (50 mL) and water (10 mL), and the mixture was heated to 100°C under an argon atmosphere and reacted with stirring. After the reaction was complete, 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 the 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] + .

[0209] Step 2: 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetaldehyde The product obtained in the previous step (4.6 g, 19.82 mmol) was dissolved in formic anhydride (40 mL) and reacted at room temperature with stirring. After the reaction was complete, the crude product 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetaldehyde was obtained by vacuum distillation.

[0210] Step 3: 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid The product obtained in the previous step was dissolved in a mixed solution of dimethyl sulfoxide (25 mL) and tetrahydrofuran (25 mL). 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 reaction mixture under ice bath conditions. The reaction mixture was allowed to react under ice bath conditions with stirring for 30 minutes, then allowed to rise to room temperature and stirring was continued. After the reaction was complete, saturated brine was added, 1N hydrochloric acid was added dropwise to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid.

[0211] Step 4: 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)ethyl acetate The product obtained in the previous step was dissolved in anhydrous N,N-dimethylformamide (30 mL), then potassium carbonate (5.5 g, 39.57 mmol) was added, followed by ethyl iodide (3.7 g, 23.72 mmol). The reaction was carried out at room temperature with stirring. After the reaction was complete, 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 the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain ethyl 2-(7-methoxy-1-oxo-2,3-dihydro-1H-inden-4-yl)ethyl acetate (4.1 g). ESI-MS (m / z): 249.1 [M+H] + .

[0212] Step 5: 2-(7-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl)ethyl acetate The product obtained in the previous step was dissolved in dichloromethane (10 mL), and then boron tribromide (1 g, 3.99 mmol) was added dropwise under an ice bath. The reaction was carried out while stirring the mixture under an ice bath. After the reaction was complete, anhydrous ethanol was added to quench the reaction, saturated sodium bicarbonate solution was added, and the reaction 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 acetate 2-(7-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl).

[0213] Step 6: 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)ethyl acetate The product obtained in the previous step was dissolved in dichloromethane (20 mL), then diisopropylethylamine (331 mg, 2.57 mmol) was added, followed by the dropwise addition of trifluoromethanesulfonic anhydride (360 mg, 1.28 mmol), and the reaction was carried out at room temperature with stirring. After the reaction was complete, 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 the crude product was obtained by vacuum distillation. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:8) to obtain 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)ethyl acetate (190 mg). ESI-MS (m / z): 367.0 [M+H] + .

[0214] Step 7: 2-(1-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetic acid The product obtained in the previous step (110 mg, 0.31 mmol) was dissolved in dioxane (8 mL), then water (1.5 mL) and lithium hydroxide (24 mg, 1.00 mmol) were added, and the reaction was carried out at room temperature with stirring. After the reaction was complete, the pH of the reaction solution was adjusted to approximately 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 obtain 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] - .

[0215] Synthesis of (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate (intermediate 1.2-A) [ka] Step 1: Synthesis of (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)methyl benzoate 3-Fluoro-4-nitrobenzoate methyl ester (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 placed in a 200 mL round-bottom flask and heated to 70°C, reacting with stirring for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, extracted with water and ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target product (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate methyl ester (13.1 g). ESI-MS (m / z): 267.1 [M+H] + .

[0216] Step 2: Synthesis of (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate The product obtained in the previous step, (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)methyl 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 placed in a 100 mL round-bottom flask and reacted at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, the ethanol was removed using a rotary evaporator, extracted with water and ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the target product, (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate (3.6 g). ESI-MS (m / z): 237.1 [M+H] + .

[0217] Synthesis of (S)-4-amino-5-fluoro-3-((oxetane-2-ylmethyl)amino)methyl benzoate (intermediate 1.2-B) [ka] Referring to the synthesis method of intermediate 1.1-A, compound (S)-4-amino-5-fluoro-3-((oxetane-2-ylmethyl)amino)methyl benzoate (3.8g) was synthesized using methyl 3,5-difluoro-4-nitrobenzoate as a starting material. ESI-MS (m / z): 255.1 [M+H] + .

[0218] Synthesis of 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)methyl benzoate (intermediate 1,2-C) [ka] Referring to the synthesis method of intermediate 1.2-A, 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)methyl benzoate (520 mg) was synthesized using 2-(1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate as a starting material. ESI-MS (m / z): 260.2 [M+H] + .

[0219] Synthesis of 4-amino-3-(((1-((fluoromethyl))cyclopropyl)methyl)amino)benzoate methyl ester (intermediate 1,2-D) [ka] Referring to the synthesis method of intermediate 1.2-C, (1-((fluoromethyl))cyclopropyl)methylamine was used as a starting material to synthesize 4-amino-3-(((1-((fluoromethyl))cyclopropyl)methyl)amino)methyl benzoate (1543 mg). ESI-MS (m / z): 253.1 [M+H] + .

[0220] Here, the synthesis of (1-((fluoromethyl))cyclopropyl)methylamine is as follows: [ka] Step 1: 1-((fluoromethyl))cyclopropane-1-carboxylate ethyl ester 1-(hydroxymethyl)cyclopropane-1-carboxylate ethyl ester (3 g, 26.3 mmol) and dichloromethane (50 mL) were placed in a 100 mL flask and cooled to -78°C. Then diethylaminotrifluoride sulfur (5.1 g, 31.1 mmol) was added, and the reaction was carried out at room temperature with stirring. After the reaction was complete, the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1-((fluoromethyl))cyclopropane-1-carboxylate ethyl ester (4.7 g, crude product).

[0221] Step 2: (1-((fluoromethyl))cyclopropyl)methanol The product obtained in the previous step (4.7 g, crude product) and tetrahydrofuran (30 mL) were placed in a 250 mL flask, and lithium aluminum hydride (1.5 g, 39.45 mmol) was added in batches under ice bath. The reaction was carried out at room temperature with stirring. After the reaction was complete, the reaction mixture was gradually added dropwise to water, extracted with dichloromethane, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain (1-((fluoromethyl))cyclopropyl)methanol (4.0 g, crude product).

[0222] Step 3: (1-((fluoromethyl))cyclopropyl)methylmethanesulfonate (1-((fluoromethyl))cyclopropyl)methanol (4.0 g, crude product) and dichloromethane (50 mL) were placed in a 250 mL flask, and then triethylamine (11.6 g, 0.11 mol) and methanesulfonyl chloride (5.3 g, 46.1 mmol) were added and the mixture was reacted at room temperature with stirring. After the reaction was complete, the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain (1-((fluoromethyl))cyclopropyl)methylmethanesulfonate (6 g, crude product).

[0223] Step 4: (1-((fluoromethyl))cyclopropyl)methylamine (1-((fluoromethyl))cyclopropyl)methylmethanesulfonate (6 g, crude product) and methanol (50 mL) were placed in a 250 mL flask, and ammonia / methanol solution (7 M, 10 mL) was added. The mixture was reacted at room temperature with stirring. After the reaction was complete, the mixture was concentrated to obtain (1-((fluoromethyl))cyclopropyl)methylamine (4 g). ESI-MS (m / z): 104.1 [M+H] + .

[0224] Synthesis of 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate methyl ester (intermediate 1,2-E) [ka] Referring to the synthesis method of intermediate 1.2-C, 6-chloro-5-nitropicolinate methyl ester was used as a starting material to obtain 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate methyl ester (640 mg). ESI-MS (m / z): 261.1 [M+H] + .

[0225] (S)-4-amino-3-methoxy-5-((oxetan-2-yl-methyl)amino)methyl benzoate (intermediate 1,2-F) [ka] Step 1: (S)-3-fluoro-4-nitro-5-((oxetan-2-yl-methyl)amino)methyl benzoate 3,5-Difluoro-4-nitro-methyl benzoate (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 sequentially added to the reaction mixture. The reaction mixture was allowed to proceed at 20°C for 2 hours with stirring. After the reaction was complete, the reaction mixture was extracted with water and ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-3-fluoro-4-nitro-5-((Oxetane-2-yl-methyl)amino)methyl benzoate (2.8 g). ESI-MS (m / z): 285.1 [M+H] + .

[0226] Step 2: (S)-3-Methoxy-4-nitro-5-((Oxetan-2-yl-methyl)amino)methyl benzoate The product obtained in 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 reacted at 20°C with stirring for 36 hours. After the reaction was complete, saturated ammonium chloride solution was added to the reaction mixture, 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 (S)-3-methoxy-4-nitro-5-((oxetan-2-yl-methyl)amino)methyl benzoate (850 mg). ESI-MS (m / z): 297.1 [M+H] + .

[0227] Step 3: (S)-4-amino-3-methoxy-5-((oxetane-2-yl-methyl)amino)methyl benzoate The product obtained in the previous step (650 mg, 2.19 mmol) was dissolved in EtOH (13 mL) and H2O (2.6 mL). Then, NH4Cl (587 mg, 10.97 mmol) and iron powder (368 mg, 6.59 mmol) were added to the reaction mixture, and the mixture was reacted at 80°C with stirring for 1 hour. After the reaction was complete, the iron powder was filtered off, the filtrate was concentrated under reduced pressure, and after dissolving in dichloromethane and filtering, the filtrate was concentrated under reduced pressure to obtain (S)-4-amino-3-methoxy-5-((oxetan-2-yl-methyl)amino)methyl benzoate (650 mg). ESI-MS (m / z): 267.0 [M+H] + . Intermediate 1.2-G~1.2-O was synthesized by referring to the synthesis methods of other intermediates.

[0228] [Table 2] JPEG2026529536000109.jpg209153

[0229] Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane (intermediate 1.5-A) [ka] 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 reacted at 140°C with stirring for 60 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane (600 mg). ESI-MS (m / z): 343.1 [M+H] + .

[0230] Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (intermediate 1.5-B) [ka] 3.2 g, 20 mmol of 2-fluoro-4-chlorobenzyl alcohol and 50 mL of N,N-dimethylformamide were placed in a 100 mL round-bottom flask. Sodium hydride (1.2 g, 30 mmol) was added in batches under ice bath conditions, and the reaction mixture was stirred under ice bath conditions for 20 minutes. Then, 3.5 g, 20 mmol of 2-bromo-6-fluoropyridine was added, followed by heating to room temperature and stirring. After the reaction was complete, the reaction mixture was added to 250 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography (ethyl acetate:n-hexane = 1:100) to obtain 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (5 g, yield 79%). ESI-MS (m / z): 316.0 [M+H] + .

[0231] The intermediate 1.5-C~1.5-AH was synthesized by referring to the synthesis method of the intermediate described above. [Table 3] JPEG2026529536000113.jpg246158JPEG2026529536000114.jpg240156JPEG2026529536000115.jpg244164JPEG2026529536000116.jpg138153

[0232] Synthesis of 3-fluoro-4-(((6-(tri-n-butyltin)pyridine-2-yl)oxy)methyl)benzonitrile (intermediate 1.7-A) [ka] 4-(((6-chloropyridine-2-yl)oxy)methyl)-3-fluorobenzonitrile (1 g, 3.81 mmol) was added to 1,4-dioxane (10 mL), followed by hexa-n-butyldisin (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 reacted with stirring for 12 hours. After the reaction was complete, water was added to quench the reaction mixture, then it 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 obtain 3-fluoro-4-(((6-(tri-n-butyltin)pyridine-2-yl)oxy)methyl)benzonitrile (700 mg). ESI-MS (m / z): 519.2 [M+H] + .

[0233] Synthesis of tri-n-butyl(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)tin (intermediate 1.7-B) [ka] Referring to the synthesis method of intermediate 1.7-A, tri-n-butyl(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane (1.5-A) was used as a starting material to obtain tri-n-butyl(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)tin (320 mg). ESI-MS (m / z): 555.1 [M+H] + .

[0234] (S)-2-(chloromethyl)-4-methoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (intermediate 1.9-A) [ka] Intermediate 1.2-F (850 mg, 3.19 mmol) and 2-chloro-1,1,1-trimethoxyethane (592 mg, 3.83 mmol) were dissolved in MeCN (17 mL) and stirred at room temperature for 20 minutes. Then, p-toluenesulfonic acid monohydrate (61 mg, 319.20 μmol) was added to the reaction mixture, and the mixture was reacted at 50°C with stirring for 2 hours. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (601 mg). ESI-MS (m / z): 325.0 [M+H] + , 1 H NMR (400 MHz, CDCl3) δ7.76 (s, 1H), 7.42 (s, 1H), 5.22 (td, J = 4.9, 7.2 Hz, 1H), 5.10 - 4.99 (m, 2H), 4.65 - 4.50 (m, 3H), 4.31 (td, J = 6.0, 9.2 Hz, 1H), 4.09 (s, 3H), 3.96 (s, 3H), 2.80 - 2.69 (m, 1H), 2.45 - 2.36 (m, 1H).

[0235] Synthesis of (S)-2-(chloromethyl)-4-isopropoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate isopropyl ester (intermediate 1.9-B) [ka] Step 1: (S)-3-fluoro-4-nitro-5-(oxetane-2-ylmethyl)amino)methyl benzoate 3,5-Difluoro-4-nitrobenzoate methyl ester (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 placed in a reaction flask and reacted at 60°C for 2 hours. After the reaction was complete, the mixture was cooled and concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain (S)-3-fluoro-4-nitro-5-(oxetane-2-ylmethyl)amino)benzoate methyl ester (770 mg). ESI-MS (m / z): 285.18 [M+H] + .

[0236] Step 2: (S)-3-Isopropoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)isopropyl benzoate The product obtained in the previous step (700 mg, 2.46 mmol), cesium carbonate (1.6 g, 4.92 mmol), and isopropanol (15 mL) were placed in a reaction flask and reacted at room temperature for 20 hours. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain (S)-3-isopropoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)isopropyl benzoate (400 mg). ESI-MS (m / z): 353.27 [M+H] + .

[0237] Step 3: (S)-4-amino-3-isopropoxy-5-((oxetane-2-ylmethyl)amino)isopropyl benzoate The product obtained in 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 placed in a reaction flask and reacted at 80°C for 1 hour. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain (S)-4-amino-3-isopropoxy-5-((oxetane-2-ylmethyl)amino)isopropyl benzoate (320 mg). ESI-MS (m / z): 323.31 [M+H] + .

[0238] Step 4: (S)-2-(chloromethyl)-4-isopropoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid isopropyl ester The product obtained in 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 placed in a reaction flask and reacted at 50°C for 2 hours. After the reaction was complete, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain (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] + .

[0239] (S)-2-(chloromethyl)-4-difluoromethoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (intermediate 1.9-C) [ka]

[0240] Step 1: Methyl 3-fluoro-5-methoxy-4-nitrobenzoate 3,5-Difluoro-4-nitrobenzoate methyl ester (4.5 g, 20.73 mmol) was dissolved in methanol (90 mL). A methanol solution containing sodium methoxide (3.92 g, 21.76 mmol) was added dropwise to the reaction mixture, and the reaction was carried out at 65°C for 2.5 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain 3-fluoro-5-methoxy-4-nitrobenzoate methyl ester (4.5 g). ESI-MS (m / z): 230.0 [M+H] + .

[0241] Step 2: Methyl 3-fluoro-5-hydroxy-4-nitrobenzoate The product obtained in the previous step (4.9 g, 21.30 mmol) was taken and dissolved in dichloromethane (50 mL). Boron tribromide (5.33 g, 21.30 mmol) was added dropwise to the reaction mixture under an ice bath, and the mixture was stirred overnight at room temperature. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Separation by column chromatography (ethyl acetate:petroleum ether = 1:3) yielded methyl 3-fluoro-5-hydroxy-4-nitrobenzoate (2.5 g). ESI-MS (m / z): 216.0 [M+H] + .

[0242] Step 3: 3-Difluoromethoxy-5-fluoro-4-nitrobenzoate methyl ester The product obtained in the previous step (2.0 g, 9.3 mmol) and sodium difluorochloroacetate were taken and dissolved in DMF (70 mL) and water (70 mL). Then cesium carbonate (6.06 g, 18.59 mmol) was added, and the reaction was carried out at 100°C for 4 hours with stirring. After the reaction was complete, the reaction mixture was filtered and freeze-dried to obtain methyl 3-difluoromethoxy-5-fluoro-4-nitrobenzoate (2.0 g). ESI-MS (m / z): 252.0 [M+H] + .

[0243] Step 4: (S)-3-difluoromethoxy-4-nitro-5-(oxetane-2-ylmethyl)amino)methyl benzoate The product obtained in the previous step (1.5 g, 5.66 mmol) was taken and dissolved in DMF (20 mL), then potassium carbonate (2.35 g, 16.97 mmol) and (S)-oxetane-2-ylmethylamine (0.74 g, 8.49 mmol) were added, and the mixture was reacted overnight at room temperature with stirring. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Separation by column chromatography (ethyl acetate:petroleum ether = 1:3) yielded (S)-3-difluoromethoxy-4-nitro-5-(oxetane-2-ylmethyl)amino)methyl benzoate (1.6 g). ESI-MS (m / z): 333.1 [M+H] + .

[0244] Step 5: (S)-4-amino-3-difluoromethoxy-5-(oxetane-2-ylmethyl)amino)methyl benzoate The product obtained in the previous step (1.6 g, 4.82 mmol) was taken and dissolved in ethanol (16 mL) and water (4 mL). Then, ammonium chloride (1.29 g, 24.08 mmol) and iron powder (0.87 g, 14.45 mmol) were added, and the mixture was reacted at 100°C with stirring for 2 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Separation by column chromatography (ethyl acetate:petroleum ether = 1:3) yielded (S)-4-amino-3-difluoromethoxy-5-(oxetan-2-ylmethyl)amino)methyl benzoate (1.4 g). ESI-MS (m / z): 303.1 [M+H] + .

[0245] Step 6: (S)-2-(chloromethyl)-4-difluoromethoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester The product obtained in the previous step (500 mg, 1.65 mmol) was taken and dissolved in acetonitrile (20 mL), then 2-chloro-1,1,1-trimethoxyethane (640 mg, 4.13 mmol) and a catalytic amount of p-toluenesulfonic acid were added, and the mixture was reacted at 60°C with stirring for 4 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Separation by thin-layer chromatography (ethyl acetate:petroleum ether = 1:3) yielded (S)-2-(chloromethyl)-4-difluoromethoxy-1-((oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (460 mg). ESI-MS (m / z): 361.1 [M+H] + , 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 1.4 Hz, 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).

[0246] (S)-2-(chloromethyl)-7-methoxy-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester (intermediate 1.9-D) [ka]

[0247] Step 1: 2-Chloro-4-methoxy-6-methyl-3-nitropyridine 2,4-Dichloro-6-methyl-3-nitropyridine (3 g, 14.5 mmol) and anhydrous methanol (25 mL) were placed in a 100 mL round-bottom flask, and then sodium methoxide (1.17 g, 21.7 mmol) was added. The mixture was reacted at 60°C with stirring for 1.5 hours. After the reaction was complete, the mixture was concentrated to obtain 2-chloro-4-methoxy-6-methyl-3-nitropyridine (2.7 g). ESI-MS (m / z): 203.1 [M+H] + .

[0248] Step 2: 6-Chloro-4-methoxy-5-nitropicolinic acid The product obtained in the previous step (2.7 g, 13.4 mmol) and concentrated sulfuric acid (25 mL) were placed in a 100 mL round-bottom flask, chromium oxide (2.67 g, 26.7 mmol) was added, and the mixture was reacted at 60°C with stirring for 3 hours. After the reaction was complete, the reaction mixture was poured into ice water, extracted with ethyl acetate, and concentrated to obtain 6-chloro-4-methoxy-5-nitropicolinic acid (ESI-MS(m / z):233.3[M+H]). + ) was obtained. This was used directly in the next reaction.

[0249] Step 3: 6-Chloro-4-methoxy-5-nitropicolinate methyl ester The product obtained in the previous step (2.6 g, 11.2 mmol) and anhydrous methanol (25 mL) were placed in a 100 mL round-bottom flask, thionyl chloride (2 g, 16.8 mmol) was added, and the reaction mixture was heated to 60°C and stirred for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, the residue was extracted with ethyl acetate, and saturated sodium bicarbonate aqueous solution was added to concentrate the organic phase. The crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:20) to obtain methyl 6-chloro-4-methoxy-5-nitropicolinate (2.5 g). ESI-MS (m / z): 247.3 [M+H] + .

[0250] Step 4: (S)-4-methoxy-5-nitro-6-((oxetane-2-ylmethyl)amino) methyl picolinate The product obtained in the previous step (2.5 g, 10.1 mmol), (S)-oxetane-2-ylmethylamine (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 placed in a 100 mL round-bottom flask and reacted under a nitrogen atmosphere at 90 °C with stirring for 5 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain (S)-4-methoxy-5-nitro-6-((oxetane-2-ylmethyl)amino) methyl picolinate (1.3 g). ESI-MS (m / z): 298.3 [M+H] + .

[0251] Step 5: (S)-5-amino-4-methoxy-6-((oxetane-2-ylmethyl)amino) methyl picolinate The product obtained in 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 placed in a 100 mL round-bottom flask and reacted at 80°C with stirring for 3 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was separated and purified by column chromatography (methanol:dichloromethane = 1:20) to obtain (S)-5-amino-4-methoxy-6-((oxetane-2-ylmethyl)amino) methyl picolinate (800 mg). ESI-MS (m / z): 268.3 [M+H] + .

[0252] Step 6: (S)-5-(2-chloroacetylamino)-4-methoxy-6-((oxetane-2-ylmethyl)amino) methyl picolinate The product obtained in the previous step (800 mg, 3.0 mmol), triethylamine (605 mg, 6.0 mmol), and dichloromethane (20 mL) were taken and placed in a 50 mL round-bottom flask. Chloroacetyl chloride (504 mg, 4.5 mmol) was added dropwise at 0°C, and the mixture was reacted at room temperature with stirring for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was separated and purified by column chromatography (methanol:dichloromethane = 1:30) to obtain (S)-5-(2-chloroacetylamino)-4-methoxy-6-((oxetane-2-ylmethyl)amino) methyl picolinate (800 mg). ESI-MS (m / z): 344.3 [M+H] + .

[0253] Step 7: (S)-2-(chloromethyl)-7-methoxy-3-((oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester The product obtained in the previous step (800 mg, 2.33 mmol), acetic acid (0.5 mL), and tetrahydrofuran (20 mL) were placed in a 50 mL round-bottom flask and reacted at 80°C with stirring for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was separated 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-carboxylate methyl ester (600 mg). ESI-MS (m / z): 326.3 [M+H] + .

[0254] The intermediate 1.9-I~1.9-O was synthesized by referring to the synthesis method of the intermediate described above. [Table 4]

[0255] Example 1: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 1) [ka]

[0256] Step 1: Synthesis of (S)-2-((7-bromobenzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 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), and then TCFH (649 mg, 2.31 mmol) and NMI (554 mg, 6.75 mmol, 485 μL) were added to the reaction mixture. The reaction mixture was allowed to proceed at 25°C with stirring for 16 hours. After the reaction was complete, water was added to quench the reaction mixture, and then it 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). Next, the purified intermediate was added to glacial acetic acid (10 mL), heated to 50°C, and reacted with stirring for 3 hours. After the reaction was complete, water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with NaHCO3 solution and saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the crude product (S)-2-((7-bromobenzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (430 mg). ESI-MS (m / z): 459.1 [M+H] + .

[0257] Step 2: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester The product obtained in 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 allowed to proceed at 100°C with stirring for 16 hours. The reaction mixture was quenched with water, then 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 (methanol:dichloromethane = 1:15) to obtain (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (90 mg). ESI-MS (m / z): 607.2 [M+H] + .

[0258] Step 3: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)benzo[d][1,3]dioxolan-4-yl)methyl)-1-(oxetane-2-methyl)-1H-benzo[d]imidazole-6-carboxylic acid The product obtained in 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 mixture at 0°C, and the mixture was reacted for 4 hours while stirring and gradually increasing the temperature to room temperature. After the reaction was complete, water was added to the reaction mixture, followed by extraction with trichloromethane. The aqueous phase was adjusted to pH=5 with 1M acetic acid, then extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to obtain (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-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 (400 MHz, CDCl3) δ8.25 - 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, 7.8 Hz, 1H), 7.38 (dd, J = 1.2, 9.3 Hz, 1H), 7.02 - 6.91 (m, 1H), 6.77 (dd, J = 2.0, 6.9 Hz, 1H), 6.11 (s, 2H), 5.59 (s, 2H), 5.11 (dq, J = 3.0, 6.9 Hz, 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).

[0259] Example 2: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 2) [ka]

[0260] Step 1: Synthesis of (S)-2-((7-bromo-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 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 allowed to react at 20°C with stirring for 2.5 hours. After the reaction was complete, 20 mL of water was added to quench the reaction mixture, and it was filtered. The filtered cake was dissolved in acetic acid (17 mL), and the mixture was allowed to react at 50°C with stirring for 3 hours. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (S)-2-((7-bromo-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (760 mg). ESI-MS (m / z): 457.1 [M+H] + .

[0261] Step 2: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester The product obtained in the previous step (118.5 mg, 0.26 mmol) was added to 1,4-dioxane (4 mL), and then 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) were added. The mixture was heated to 100°C and reacted with stirring for 16 hours. After the reaction was complete, water was added to quench the reaction mixture, then it 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 = 1:10) to obtain (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (54 mg). ESI-MS (m / z): 605.1 [M+H] + .

[0262] Step 3: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 2) The product obtained in the previous step (54 mg, 0.09 mmol) was dissolved in isopropanol (0.5 mL), THF (0.5 mL), and H2O (0.5 mL), LiOH (8.6 mg, 0.36 mmol) was added, and the reaction mixture was allowed to react for 12 hours with stirring at 20°C. After the reaction was complete, water was added to the reaction mixture, 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 obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain two components, one of which is (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (6.4 mg). ESI-MS (m / z): 589.1 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ8.22 (s, 1H), 7.92 - 7.88 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.82 - 7.76 (m, 3H), 7.76 - 7.68 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 6.85 - 6.77 (m, 2H), 5.57 (s, 2H), 4.98 (dq, J = 2.3, 7.1 Hz, 1H), 4.70 - 4.59 (m, 3H), 4.54 (d, J = 2.5 Hz, 1H), 4.50 - 4.45 (m, 1H), 4.41 - 4.31 (m, 3H), 3.16 (dt, J = 3.4, 8.6 Hz, 2H), 2.68 - 2.65 (m, 1H), 2.35 - 2.30 (m, 1H).

[0263] Example 3: Synthesis of (S)-2-((7-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 3) [ka] The synthesis method was the same as for compound 2, and finally, one other component was recovered to obtain (S)-2-((7-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridine-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 (400 MHz, DMSO-d6) δ8.22 (s, 1H), 8.02 (br s, 1H), 7.92 (d, J = 8.1 Hz, 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 = 2.5 Hz, 1H), 4.51 - 4.47 (m, 1H), 4.41 - 4.37 (m, 2H), 4.35 (dd, J = 3.0, 5.9 Hz, 1H), 3.16 (dt, J = 3.2, 8.7 Hz, 3H), 2.69 - 2.64 (m, 1H), 2.33 (br dd, J = 1.9, 3.6 Hz, 1H).

[0264] Example 4: Synthesis of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 4) [ka]

[0265] Step 1: Synthesis of (S)-2-((4-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester Intermediate 1.1-C (760 mg, 2.96 mmol) was added to acetonitrile (15.2 mL), followed by intermediate 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 allowed to react at 20°C with stirring for 2.5 hours. After the reaction was complete, 20 mL of water was added to quench the reaction mixture, which was then filtered. The filtered cake was dissolved in acetic acid (20 mL), and the mixture was allowed to react at 50°C with stirring for 3 hours. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (S)-2-((4-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (880 mg). ESI-MS (m / z): 457.1 [M+H] + .

[0266] Step 2: Synthesis of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester The product obtained in the previous step (119 mg, 0.26 mmol) was added to 1,4-dioxane (4 mL), and then 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) were added. The mixture was reacted at 100°C with stirring for 16 hours. After the reaction was complete, water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (90 mg). ESI-MS (m / z): 605.1 [M+H] + .

[0267] Step 3: Synthesis of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 4) The product obtained in 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 mixture was stirred at 20°C for 12 hours. After the reaction was complete, 5 mL of water was added to the reaction mixture and 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 obtain the crude product. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to obtain two components, one of which is (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (24.5 mg). ESI-MS (m / z): 589.1 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ8.21 (s, 1H), 7.91 (d, J = 10.3 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 3.9 Hz, 2H), 7.59 (br d, J = 8.4 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 5.55 (s, 2H), 4.95 (dq, J = 2.8, 7.2 Hz, 1H), 4.70 - 4.61 (m, 1H), 4.59 - 4.52 (m, 3H), 4.52 - 4.42 (m, 2H), 4.39 - 4.32 (m, 2H), 4.28 - 4.22 (m, 1H), 3.49 (t, J = 8.7 Hz, 2H), 2.66 - 2.60 (m, 1H), 2.38 - 2.33 (m, 1H).

[0268] Example 5: Synthesis of (S)-2-((4-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 5) [ka] The synthesis method was the same as for compound 4, and finally, another component was recovered to obtain (S)-2-((4-(6-((4-aminocarbonyl-2-fluorobenzyl)oxy)pyridine-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 (400 MHz, DMSO-d6) δ8.19 (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 = 7.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.1 Hz, 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 = 8.6 Hz, 2H), 2.69 - 2.64 (m, 1H), 2.34 - 2.31 (m, 1H).

[0269] Example 6: Synthesis of 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 6) [ka]

[0270] Step 1: Synthesis of 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (34 mg, 0.058 mmol), methyl iodide (17 mg, 0.12 mmol), potassium carbonate (17 mg, 0.12 mmol), and DMF (1 mL) were taken and stirred at room temperature for 30 minutes. Then, methyl iodide (17 mg, 0.12 mmol) and sodium hydride (5 mg, 0.12 mmol) were added, and the mixture was continued to react at room temperature with stirring. After the reaction was complete, water was added to the reaction mixture, extracted with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (methanol:dichloromethane = 1:30) to obtain 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (23 mg). ESI-MS (m / z): 619.5 [M+H] + .

[0271] Step 2: Synthesis of 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (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 placed in a 25 mL round-bottom flask and reacted with stirring at 50°C. After the reaction was complete, the pH was adjusted to 6 with acetic acid, the mixture was concentrated, and separated by thin-layer chromatography (methanol:dichloromethane = 1:15) to obtain 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (13 mg). ESI-MS (m / z): 605.2 [M+H] + , 1 H NMR (600 MHz, CDCl3) δ 8.15 - 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), 4.20 - 4.08 (m, 2H), 3.06 - 2.85 (m, 2H), 2.72 - 2.51 (m, 2H), 1.91 - 1.84 (m, 3H).

[0272] Example 7: Synthesis of (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 7) [ka]

[0273] Step 1: Synthesis of (S)-2-((7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (S)-2-((7-bromo-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate 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 reacted at 60°C with stirring for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (methanol:dichloromethane = 1:50) to obtain (S)-2-((7-bromo-5-chloro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (138 mg). ESI-MS (m / z): 491.1 [M+H] + .

[0274] Step 2: Synthesis of (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester The product obtained in the previous step (100 mg, 0.20 mmol) was added to 1,4-dioxane (2 mL), and then intermediates 1.7-A (105 mg, 0.20 mmol), Pd(PPh3)4 (7.0 mg, 0.06 mmol), and LiCl (46 mg, 1.08 mmol) were added sequentially. The reaction mixture was heated to 100 °C and reacted with stirring for 48 hours. After the reaction was complete, water was added to the reaction mixture, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridyl-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (150 mg). ESI-MS (m / z): 639.2 [M+H] + .

[0275] Step 3: Synthesis of (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid The product obtained in 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 mixture was stirred at 20°C for 12 hours. After the reaction was complete, water was added to the reaction mixture, and it was extracted with the organic solvent 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 obtain the crude product. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to obtain (S)-2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridyl-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (5.34 mg). ESI-MS (m / z): 623.1 [MH] - , 1 H NMR (400 MHz, DMSO-d6) δ=12.75 (br s, 1H), 8.24 (d, J = 1.0 Hz, 1H), 7.92 (d, J = 10.4 Hz, 1H), 7.86 - 7.81 (m, 2H), 7.81 - 7.70 (m, 4H), 7.55 (d, J = 8.4 Hz, 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 = 8.7 Hz, 2H), 4.52 - 4.45 (m, 2H), 4.37 (td. 1H).

[0276] 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)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 8) [ka]

[0277] Step 1: 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-carboxylate methyl ester 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-carboxylate 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, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction mixture 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 obtain 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 methyl ester (140 mg). ESI-MS (m / z): 641.1 [M+H] + .

[0278] 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 The product obtained in 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 mixture was stirred at 20°C for 16 hours. After the reaction was complete, the reaction solution was diluted with water, then extracted with methyl (tert-butyl) ether, the pH was adjusted to 5 with acetic acid, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to obtain 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 (36.3 mg). ESI-MS (m / z): 625.1 [MH] - , 1H NMR (400 MHz, DMSO-d6) δ=12.76 (br s, 1H), 8.24 (s, 1H), 7.83 - 7.77 (m, 1H), 7.69 (t, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.56 (br d, J = 12.2 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.07 (dd, J = 2.0, 7.1 Hz, 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 = 8.6 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.02 (s, 3H).

[0279] Example 9: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1H-indole-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 9) [ka]

[0280] Step 1: Synthesis of (S)-2-((7-bromo-1H-indole-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 250 mg, 1 mmol of 2-(7-bromo-1H-indole-4-yl)acetic acid (1,1-D) and 25 mL of N,N-dimethylformamide were placed in a 100 mL flask, 57 mg, 1.5 mmol of HATU and 305 mg, 3 mmol of triethylamine were added, and then (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate (305 mg, 1.3 mmol) was added while stirring, and the mixture was reacted at room temperature with stirring. After the reaction was complete, the reaction mixture was added to water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and 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 placed in a 100 mL flask, heated to 120 °C, and reacted with stirring. After the reaction was complete, the reaction mixture was added to water, extracted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, concentrated, and the crude product was separated and purified by column chromatography (methanol:dichloromethane = 1:50) to obtain (S)-2-((7-bromo-1H-indole-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (220 mg). ESI-MS (m / z): 454.1 [M+H] + .

[0281] Step 2: Synthesis of (S)-1-(oxetan-2-ylmethyl)-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (S)-2-((7-bromo-1H-indole-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (220 mg, 0.49 mmol), bis(pinacolato)diborone (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 placed in a 50 mL round-bottom flask. The mixture was then subjected to a nitrogen atmosphere. The reaction was carried out under controlled conditions at 100°C with stirring. After the reaction was complete, the mixture was concentrated, and the crude product was purified by column chromatography (methanol:dichloromethane = 1:30) to obtain (S)-1-(oxetan-2-ylmethyl)-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (180 mg). ESI-MS (m / z): 502.2 [M+H] + .

[0282] Step 3: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (S)-1-(oxetan-2-ylmethyl)-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-4-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (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 placed in a 100 mL flask. The mixture was reacted under a nitrogen atmosphere at 80°C with stirring. After the reaction was complete, the reaction mixture was added to water, then extracted with ethyl acetate, dried, concentrated, and the crude product was purified by thin-layer chromatography (methanol:dichloromethane = 1:30) to obtain (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (20 mg). ESI-MS (m / z): 611.2 [M+H] + .

[0283] Step 4: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1H-indole-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (50 mg, 0.082 mmol), sodium hydroxide (33 mg, 0.82 mmol), methanol (4 mL), tetrahydrofuran (4 mL), and water (2 mL) were placed in a 25 mL flask. The mixture was reacted at room temperature with stirring. After the reaction was complete, the mixture was concentrated to remove the organic solvent, glacial acetic acid was added to adjust the pH to 3, and the mixture was concentrated again. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to obtain (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1H-indole-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 (600 MHz, CDCl3) δ 10.46 (s, 1H), 8.12 (s, 1H), 8.05 (d, J = 6.5 Hz, 1H), 7.86 (d, J = 7.1 Hz, 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 = 6.6 Hz, 1H), 6.80 (d, J = 7.2 Hz, 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).

[0284] Example 10: Synthesis of 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1H-indole-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 10) [ka] Referring to the synthesis method of compound 8, 2-((7-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1H-indole-4-yl)methyl)-1-(((S)-oxetan-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 (600 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.86 (s, 1H), 8.20 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.31-7.30 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 7.06-7.05 (m, 1H), 7.02-6.99 (m, 2H), 6.93 (d, J = 7.4 Hz, 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).

[0285] Example 11: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-methyl-1H-indole-4-yl)methyl-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 11) [ka]

[0286] Step 1: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-methyl-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (70 mg, 0.11 mmol) and N,N-dimethylformamide (5 mL) were placed in a 100 mL flask, and then cesium carbonate (375 mg, 1.15 mmol) and methyl iodide (163 mg, 1.15 mmol) were added. The mixture was stirred at room temperature. After the reaction was complete, the mixture was added to water, extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography (methanol:dichloromethane = 1:30) to obtain (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-methyl-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (60 mg). ESI-MS (m / z): 625.2 [M+H] + .

[0287] Step 2: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-methyl-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-methyl-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (60 mg, 0.096 mmol), sodium hydroxide (40 mg, 1 mmol), methanol (4 mL), tetrahydrofuran (4 mL), and water (2 mL) were placed in a 100 mL flask. The mixture was heated to 50°C and reacted with stirring. After the reaction was complete, the organic solvent was removed under reduced pressure, the pH was adjusted to 3 with acetic acid, and the mixture was further concentrated. The crude product was purified by column chromatography (methanol:dichloromethane = 1:15) to obtain (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-methyl-1H-indole-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg). ESI-MS (m / z): 611.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.20 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 9.7 Hz, 1H), 7.34-7.25 (m, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 6.2 Hz, 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).

[0288] Example 12: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 12) [ka] Referring to the synthesis of compound 7, (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg) was obtained using 1.1-F and 1.2-A as starting materials. ESI-MS (m / z): 618.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.83-7.79 (m, 2H), 7.78-7.73 (m, 2H), 7.60-7.58 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 9.9, 1.7 Hz, 1H), 7.31 (dd, J = 8.2, 1.5 Hz, 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 = 8.8 Hz, 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).

[0289] Example 13: Synthesis of (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 13) [ka] Referring to the synthesis method of compound 12, (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg) was obtained using 1.1-F and intermediate 1.2-B as starting materials. ESI-MS (m / z): 627.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.12 (s, 1H), 7.91 (d, J = 9.9 Hz, 1H), 7.84-7.81 (m, 2H), 7.76-7.70 (m, 2H), 7.68 (d, J = 11.6 Hz, 1H), 7.49 (d, J = 11.3 Hz, 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 = 9.0 Hz, 2H), 4.65-4.62 (m, 1H), 4.51-4.47 (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).

[0290] Example 14: Synthesis of 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 14) [ka] Referring to the synthesis method of compound 12, 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (32 mg) was obtained using 1.1-F and intermediate 1.2-D as starting materials. ESI-MS (m / z): 634.2 [M+H] + , 1 H NMR (600 MHz, CDCl3) δ 8.20 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 11.4 Hz, 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 = 8.1 Hz, 1H), 5.50 (s, 2H), 4.67 (t, J = 8.4 Hz, 2H), 4.47-4.35 (m, 4H), 4.18-4.13 (m, 1H), 4.10-4.05 (m, 1H), 3.20 (t, J = 8.5 Hz, 2H), 0.83-0.77 (m, 4H).

[0291] Example 15: Synthesis of 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 15) [ka]

[0292] Step 1: Synthesis of 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (intermediate of compound 14, synthesized referring to the method of compounds 12 and 14, 60 mg, 0.093 mmol) and N,N-dimethylformamide (5 mL) were placed in a 100 mL flask, methyl iodide (66 mg, 0.46 mmol) and cesium carbonate (91 mg, 0.28 mmol) were added, and the mixture was reacted at room temperature with stirring. After the reaction was complete, the reaction 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 (methanol:dichloromethane = 1:50) to obtain 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (30 mg). ESI-MS (m / z): 662.2 [M+H] + .

[0293] Step 2: Synthesis of 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 30 mg, 0.045 mmol of 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-carbonyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester and 4 mL of tetrahydrofuran were placed in a 25 mL flask, then methanol (4 mL), sodium hydroxide (18 mg, 0.45 mmol), and water (4 mL) were added, and the mixture was reacted with stirring at 50°C. After the reaction was complete, the mixture was cooled, 0.1 mL of glacial acetic acid was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was then concentrated, and the crude product was separated and purified by thin-layer chromatography (methanol:dichloromethane = 1:30) to obtain 2-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-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 (600 MHz, CDCl3) δ 8.45 (s, 1H), 8.11 (d, J = 6.0 Hz, 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 = 8.1 Hz, 1H), 5.50 (s, 2H), 4.90 (br, 2H), 4.79-4.76 (m, 2H), 4.09 (d, J = 47.8 Hz, 2H), 3.46-3.43 (m, 2H), 0.88-0.84 (m, 2H), 0.70 (br, 2H).

[0294] Example 16: Synthesis of 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 16) [ka]

[0295] Step 1: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propionitrile 300 mg (1.27 mmol) of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)acetonitrile and 10 mL of tetrahydrofuran were placed in a 100 mL flask, and 899 mg (6.33 mmol) of methyl iodide and 2.1 g (6.33 mmol) of cesium carbonate were added. The mixture was reacted at room temperature with stirring. After the reaction was complete, 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).

[0296] Step 2: Synthesis of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propionic acid 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propionitrile (200 mg, 0.8 mmol) and ethanol (5 mL) were placed in a 100 mL flask, potassium hydroxide (446 mg, 8 mmol) and water (10 mL) were added, and the mixture was reacted at 100°C with stirring. After the reaction was complete, the mixture was cooled, the solution was made acidic with 1 N hydrochloric acid solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by thin-layer chromatography (ethyl acetate:petroleum ether = 1:10) to obtain 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propionic acid (180 mg).

[0297] Step 3: Synthesis of 2-(1-(7-bromo-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 180 mg, 0.67 mmol of 2-(7-bromo-2,3-dihydrobenzofuran-4-yl)propionic acid and 10 mL of N,N-dimethylformamide were placed in a 100 mL flask, and 382 mg, 1 mmol of HATU and 202 mg, 2 mmol of triethylamine were added. The mixture was stirred at room temperature for 10 minutes, and 4-amino-3-(((1-((fluoromethyl))cyclopropyl)methyl)amino)methyl benzoate (1.2-D, 203 mg, 0.8 mmol) was added and the mixture was reacted at room temperature with stirring. After the reaction was complete, the mixture was added to water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then filtered to concentrate. The crude product and 10 mL of glacial acetic acid were placed in a 100 mL flask and heated to 120°C, reacting with stirring. After the reaction was complete, the mixture was cooled, added to ethyl acetate, and washed with water and saturated sodium bicarbonate aqueous solution. 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 = 1:50) to obtain 2-(1-(7-bromo-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (240 mg). ESI-MS (m / z): 487.1 [M+H] + .

[0298] Step 4: Synthesis of 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 methyl ester 2-(1-(7-bromo-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (240 mg, 0.49 mmol), bis(pinacolato)diborone (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 placed in a 100 mL flask and the mixture was stirred under a nitrogen atmosphere at 100 °C. After the reaction was complete, the mixture was cooled and concentrated, and the crude product was separated and purified by column chromatography (methanol:dichloromethane = 1:30) to obtain 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 methyl ester (170 mg). ESI-MS (m / z): 535.3 [M+H] + .

[0299] Step 5: Synthesis of 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 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 methyl ester (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 taken and placed in a 100 mL flask, and the mixture was stirred under a nitrogen atmosphere at 80°C. After the reaction was complete, the mixture was cooled, added to water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated, and the crude product was separated and purified by thin-layer chromatography (methanol:dichloromethane = 1:50) to obtain 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (65 mg). ESI-MS (m / z): 644.2 [M+H] + .

[0300] Step 6: Synthesis of 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (65 mg, 0.1 mmol) and tetrahydrofuran (4 mL) were placed in a 100 mL flask, methanol (4 mL), sodium hydroxide (40 mg, 1 mmol), and water (4 mL) were added, and the mixture was heated to 50°C and reacted with stirring. After the reaction was complete, the mixture was cooled, glacial acetic acid (0.1 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was then concentrated, and the crude product was separated and purified by thin-layer chromatography (methanol:dichloromethane = 1:30) to obtain 2-(1-(7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-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 (600 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.19 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77-7.73 (m, 3H), 7.57-7.54 (m, 1H), 7.46 (d, J = 9.9 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 5.43 (s, 2H), 4.71-4.67 (m, 2H), 4.57-4.53 (m, 1H), 4.30 (d, J = 15.4 Hz, 1H), 4.22 (d, J = 15.4 Hz, 1H), 4.18-4.03 (m, 2H), 3.29-3.25 (m, 1H), 3.20-3.16 (m, 1H), 1.73 (d, J = 6.6 Hz, 3H), 0.69-0.59 (m, 4H).

[0301] Example 17: Synthesis of 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 17) [ka] Referring to the synthesis method of compound 16, 4-(((6-bromopyridine-2-yl)oxy)methyl)-3-fluorobenzonitrile was used as a starting material to synthesize 2-(1-(7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)ethyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (21 mg). ESI-MS (m / z): 621.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 9.0 Hz, 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, 0.7 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 5.53 (s, 2H), 4.70-4.67 (m, 2H), 4.55 (q, J = 6.9 Hz, 1H), 4.30 (d, J = 15.4 Hz, 1H), 4.22 (d, J = 15.4 Hz, 1H), 4.18 (d, J = 10.2 Hz, 0.5H), 4.12-4.08 (m, 1H), 4.04 (d, J = 10.2 Hz, 0.5H), 3.28-3.24 (m, 1H), 3.19-3.15 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H), 0.69-0.59 (m, 4H).

[0302] Example 18: Synthesis of 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 18) [ka] Referring to the synthesis method of compound 14, 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg) was obtained using 1.1-E and 1.2-C as starting materials. ESI-MS (m / z): 648.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.26 (d, J = 1.2 Hz, 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, 1.5 Hz, 1H), 7.72-7.70 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 6.90 (dd, J = 8.1 Hz, 0.6 Hz, 1H), 5.59 (s, 2H), 4.73 (t, J = 8.8 Hz, 2H), 4.59 (s, 2H), 4.43 (s, 2H), 3.22 (t, J = 8.8 Hz, 2H), 2.69 (s, 2H), 0.78-0.77 (m, 2H), 0.75-0.73 (m, 2H).

[0303] Example 19: Synthesis of 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 19) [ka] Referring to the synthesis method of compound 14, 2-((5-chloro-7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (42 mg) was obtained using 1.1-E and 1.2-E as starting materials. ESI-MS (m / z): 649.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.85-7.83 (m, 2H), 7.80 (d, J = 7.1 Hz, 1H), 7.74-7.70 (m, 2H), 6.92-6.89 (m, 1H), 5.59 (s, 2H), 4.74 (t, J = 8.8 Hz, 2H), 4.55 (s, 2H), 4.50 (s, 2H), 3.24 (t, J = 8.8 Hz, 2H), 2.80 (s, 2H), 1.10 (t, J = 5.3 Hz, 2H), 0.72 (t, J = 5.4 Hz, 2H).

[0304] Example 20: Synthesis of (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-oxo-2,3-dihydro-1H-inden-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 20) [ka] Referring to the synthesis method of compound 14, (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-oxo-2,3-dihydro-1H-inden-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (42 mg) was obtained using 2-(7-bromo-1-oxo-2,3-dihydro-1H-inden-4-yl)acetic acid and intermediate 1.2-A as starting materials. ESI-MS (m / z): 610.2 [MH] - , 1 H NMR (600 MHz, CDCl3) δ 8.11 - 8.05 (m, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.19 (d, J = 7.4 Hz, 1H), 7.11 (dd, J = 8.2, 2.3 Hz, 1H), 7.09 - 7.05 (m, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.35 (s, 2H), 5.21 - 5.14 (m, 1H), 4.74 - 4.60 (m, 3H), 4.43 - 4.35 (m, 2H), 4.31 (d, J = 15.3 Hz, 1H), 3.14 - 3.09 (m, 2H), 2.74 - 2.72 (m, 2H), 2.44 - 2.34 (m, 2H).

[0305] Example 21: (S)-4-Methoxy-2-((7-(6-((2-Methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)benzo[d][1,3]dioxysan-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 42) [ka] Referring to the synthesis method of compound 1, compound (S)-4-methoxy-2-((7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)benzo[d][1,3]dioxysan-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (15 mg) was obtained using intermediates 1.1-A and 1.2-F as starting materials. ESI-MS (m / z): 678.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.79 (s, 1H), 7.86 (s, 1H), 7.84-7.81 (m, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.61-7.58 (m, 2H), 7.33-7.30 (m, 2H), 7.25 (s, 1H), 6.85 (dd, J = 15.6, 7.1 Hz, 1H), 6.17-6.16 (m, 2H), 5.50 (s, 2H), 4.99-4.95 (m, 1H), 4.63 (dd, J = 19.6, 8.3 Hz 1H), 4.51-4.48 (m, 1H), 4.46-4.44 (m, 1H), 4.38 (d, J = 16.3 Hz, 1H), 4.34-4.32 (m, 1H), 4.30 (d, J = 16.5 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 2.66-2.63 (m, 1H), 2.35-2.31 (m, 1H).

[0306] Example 22: (S)-4-Methoxy-2-((8-(6-((2-Methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzo[b][1,4]dioxysan-5-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 62) [ka] Referring to the synthesis method of compound 1, compound (S)-4-methoxy-2-((8-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzo[b][1,4]dioxysan-5-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (18 mg) was obtained using intermediates 1.1-G and 1.2-F as starting materials. ESI-MS (m / z): 692.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.86 (s, 1H), 7.77-7.75 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.32-7.30 (m, 2H), 7.26-7.24 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 4.99-4.95 (m, 1H), 4.60 (dd, J = 15.4, 7.0 Hz, 1H), 4.49-4.45 (m, 2H), 4.36-4.31 (m, 6H), 4.22 (d, J = 16.2 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.69-2.65 (m, 1H), 2.38-2.33 (m, 1H).

[0307] Example 23: 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 63) [ka] Referring to steps 2, 3, and 4 of Example 9, intermediate 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-oxo-2,3-dihydro-1H-inden-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained using intermediate 1.1-H as a starting material. Then, the product obtained in the previous step (13 mg, 0.02 mmol), methanol (10 mL), and sodium borohydride (3 mg, 0.08 mmol) were taken and placed in a 50 mL round-bottom flask and stirred at room temperature for 1 hour. After confirmation of the completion of the reaction by LC-MS detection, ethyl acetate was added and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol 15:1) to obtain 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (9 mg). ESI-MS (m / z): 614. 1 [M+H] + ; 1 H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 6.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.41 (q, J = 8.1 Hz, 2H), 7.27 (s, 1H), 7.19 - 7.07 (m, 3H), 6.81 (d, J = 8.3 Hz, 1H), 5.39 - 5.36 (m, 2H), 5.30 (s, 1H), 5.15 - 5.06 (m, 1H), 4.70 - 4.54 (m, 3H), 4.42 - 4.33 (m, 2H), 4.30 - 4.24 (m, 1H), 3.25 - 3.13 (m, 1H), 3.08 - 2.94 (m, 1H), 2.73 - 2.66 (m, 1H), 2.41 - 2.31 (m, 2H), 2.29 - 2.23 (m, 1H).

[0308] Example 24: 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 65) [ka]

[0309] Step 1: Synthesis of 2-((7-((6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonylfluoride 2-((7-((6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (2 mg, 3.25 μmol) was taken and dissolved in anhydrous dichloromethane (1.5 mL), placed in a 10 mL two-necked flask, and cooled to -78 °C under a nitrogen atmosphere. Diethylaminotrifluoride (100 μL) was added dropwise, the mixture was stirred at -78°C for 1 hour, then gradually increased to room temperature and stirred for another 1 hour. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The mixture was washed with aqueous sodium bicarbonate solution, then with water, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the target product 2-((7-((6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonylfluoride (2.0 mg). ESI-MS (m / z): 618.2 [M+H] + .

[0310] Step 2: Synthesis of 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl ester)-1H-benzo[d]imidazole-6-carboxylic acid Take 2-((7-((6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonylfluoride (2.01 mg, 3.25 μmol), tetrahydrofuran (2 mL), and methanol (2 mL), place them in a 25 mL round-bottom flask, add sodium hydroxide (65 mg, 1.63 mmol) dissolved in water (2 mL), and allow to react at room temperature for 1 hour. After the reaction was complete, water was added, the pH was adjusted to 1-2 with dilute hydrochloric acid under an ice bath, extracted with ethyl acetate, washed with saturated sodium chloride, and the solvent was removed under reduced pressure. The crude product was then separated into thin layers using a preparative plate (dichloromethane:methanol = 15:1) to obtain the target product 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-1-fluoro-2,3-dihydro-1H-inden-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl ester)-1H-benzo[d]imidazole-6-carboxylic acid (1.5 mg). ESI-MS (m / z): 616.2[M+H] + .

[0311] Example 25: (S)-2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 71) [ka]

[0312] Referring to Step 1 of Example 1, intermediate (S)-2-((7-bromo-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester was synthesized using intermediate 1.1-B as a starting material. Then, referring to Steps 2, 3, and 4 of Example 9, (S)-2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (32 mg). ESI-MS (m / z): 664.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.23 ​​(d, J = 0.9 Hz, 1H), 7.83-7.79 (m, 2H), 7.77 (dd, J = 8.4, 1.5 Hz, 1H), 7.63 (d, J = 11.6 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.33-7.30 (m, 2H), 6.87 (dd, J = 7.2, 1.8 Hz, 1H), 5.52 (s, 2H), 5.08-5.04 (m, 1H), 4.76-4.72 (m, 1H), 4.67 (t, J = 8.8 Hz, 2H), 4.61 (dd, J = 15.5, 2.3 Hz, 1H), 4.52-4.45 (m, 2H), 4.39-4.33 (m, 2H), 3.94 (s, 3H), 3.15-3.08 (m, 2H), 2.74-2.68 (m, 1H), 2.41-2.35 (m, 1H).

[0313] Example 26: 4-(2,2-difluoroethoxy)-2-((5-fluoro-7-(6-(2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 79) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-D, and 1.2-O were used as starting materials to obtain 4-(2,2-difluoroethoxy)-2-((5-fluoro-7-(6-(2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg). ESI-MS (m / z): 760.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.89 (brs, 1H), 7.99 (s, 1H), 7.84 - 7.78 (m, 2H), 7.65 (d, J = 11.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.35 - 7.28 (m, 3H), 6.87 (d, J = 4.2 Hz, 1H), 6.41 (t, J = 54.9 Hz, 1H), 5.52 (s, 2H), 4.83 (d, J = 24.1 Hz, 2H), 4.67 (t, J = 8.6 Hz, 2H), 4.53 (t, J = 13.3 Hz, 2H), 4.34 (s, 2H), 3.94 (s, 3H), 3.09 (t, J = 8.4 Hz, 2H), 2.29 - 2.19 (m, 4H), 1.93 - 1.83 (m, 2H).

[0314] Example 27: (S)-2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 80) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-D, and 1.2-F were used as starting materials to obtain (S)-2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg). ESI-MS (m / z): 694.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.86 (s, 1H), 7.83-7.81 (m, 2H), 7.64 (d, J = 11.7 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.32-7.31 (m, 2H), 7.24 (s, 1H), 6.87 (dd, J = 6.6, 1.8 Hz, 1H), 5.53 (s, 2H), 5.06-5.02 (m, 1H), 4.71-4.66 (m, 3H), 4.58-4.55 (m, 1H), 4.51-4.47 (m, 1H), 4.43 (d, J = 17.0 Hz, 1H), 4.35-4.31 (m, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.11-3.07 (m, 2H), 2.72-2.66 (m, 1H), 2.38-2.33 (m, 1H).

[0315] Example 28: (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 81) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (68 mg) was obtained using intermediates 1.1-B, 1.5-B, and 1.2-F as starting materials. ESI-MS (m / z): 648.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 7.87 (s, 1H), 7.83-7.79 (m, 2H), 7.75 (d, J = 11.5 Hz, 1H), 7.62-7.59 (m, 1H), 7.49 (d, J = 9.9 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.24 (s, 1H), 6.83 (dd, J = 6.2, 2.6 Hz, 1H), 5.51 (s, 2H), 5.07-5.04 (m, 1H), 4.72-4.67 (m, 3H), 4.59-4.56 (m, 1H), 4.51-4.48 (m, 1H), 4.45 (d, J = 16.9 Hz, 1H), 4.37-4.32 (m, 2H), 3.88 (s, 3H), 3.13-3.08 (m, 2H), 2.72-2.67 (m, 1H), 2.38-2.35 (m, 1H).

[0316] Example 29: 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-(2,2-difluoroethoxy)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 82) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-E, and 1.2-O were used as starting materials to obtain 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-(2,2-difluoroethoxy)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (26 mg). ESI-MS (m / z): 762.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.88 (brs, 1H), 7.99 (s, 1H), 7.83 - 7.80 (m, 2H), 7.72 (d, J = 11.6 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.39 (s, 1H), 7.36 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 6.84 (dd, J = 6.3, 2.5 Hz, 1H), 6.42 (t, J = 54.6 Hz, 1H), 5.48 (s, 2H), 4.86 (s, 1H), 4.861(s, 1H), 4.68 (t, J = 8.8 Hz, 2H), 4.54 (td, J = 14.5, 3.4 Hz, 2H), 4.35 (s, 2H), 3.11 (t, J = 8.7 Hz, 2H), 2.29 - 2.19 (m, 4H), 1.92 - 1.83 (m, 2H).

[0317] Example 30: 2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 83) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-D, and 1.2-D were used as starting materials to obtain 2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (32 mg). ESI-MS (m / z): 680.2[M+H]+, 1 H NMR (600 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.28 (s, 1H), 7.82-7.75 (m, 3H), 7.63 (d, J = 11.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.33-7.29 (m, 2H), 6.87 (d, J = 6.8 Hz, 1H), 5.52 (s, 2H), 5.21-5.19 (m, 2H), 4.88-4.84 (m, 2H), 4.68 (t, J = 8.6 Hz, 2H), 4.34 (s, 2H), 3.94 (s, 3H), 3.12 (t, J = 8.6 Hz, 2H), 2.02-1.93 (m, 2H), 1.92-1.84 (m, 2H).

[0318] Example 31: (S)-2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 84) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-E, and 1.2-F were used as starting materials to obtain (S)-2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (24 mg). ESI-MS (m / z): 696.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 7.83-7.80 (m, 3H), 7.72 (d, J = 11.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.39 (br, 1H), 7.36 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (t, J = 73.4 Hz, 1H), 7.25 (s, 1H), 6.86-6.82 (m, 1H), 5.49 (s, 2H), 5.07-5.03 (m, 1H), 4.68 (t, J = 8.9 Hz, 3H), 4.57-4.55 (m, 1H), 4.51-4.47 (m, 1H), 4.44 (d, J = 16.7 Hz, 1H), 4.35-4.31 (m, 2H), 3.87 (s, 3H), 3.15-3.07 (m, 2H), 2.72-2.67 (m, 1H), 2.39-2.35 (m, 1H).

[0319] Example 32: 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-benzo[d][1,3]dioxolan-4-yl)methyl)-4-(2,2-difluoroethoxy)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 86) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-G, 1.5-E, and 1.2-O were used as starting materials to obtain 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluorobenzo[d][1,3]dioxolan-4-yl)methyl)-4-(2,2-difluoroethoxy)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (19 mg). ESI-MS (m / z): 764.1 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.90 (brs, 1H), 7.99 (s, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 11.9 Hz, 1H), 7.39 (s, 1H), 7.36 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (t,J=73 Hz, 1H), 7.30 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.42 (tt, J = 54.6, 3.5 Hz, 1H), 6.20 (s, 2H), 5.49 (s, 2H), 4.85 (d, J = 24.3 Hz, 2H), 4.52 (td, J = 14.5, 3.5 Hz, 2H), 4.32 (s, 2H), 2.28-2.16 (m , 4H), 1.92 - 1.83 (m, 2H).

[0320] Example 33: 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 87) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-E, and 1.2-J were used as starting materials to obtain 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (42 mg). ESI-MS (m / z): 712.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.92 (s, 1H), 7.82-7.80 (m, 2H), 7.71 (d, J = 11.7 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.39-7.35 (m, 2H), 7.34 (t, J = 73.5 Hz, 1H), 7.24 (s, 1H), 6.86-6.83 (m, 1H), 5.49 (s, 2H), 4.82 (d, J = 24.2 Hz, 2H), 4.69 (t, J = 8.8Hz, 2H), 4.31 (s, 2H), 3.87 (s, 3H), 3.80-3.70 (m, 1H), 3.60-3.56 (m, 1H), 3.10 (t, J = 8.7 Hz, 2H), 2.26-2.21 (m, 4H).

[0321] Example 34: 2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 89) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-D, and 1.2-J were used as starting materials to obtain 2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (33 mg). ESI-MS (m / z): 710.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.92 (s, 1H), 7.83-7.80 (m, 2H), 7.63 (d, J = 11.6 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.32-7.30 (m, 2H), 7.24 (s, 1H), 6.87 (dd, J = 6.7, 2.1 Hz, 1H), 5.52 (s, 2H), 4.82 (d, J = 24.2 Hz, 2H), 4.68 (t, J = 8.8 Hz, 2H), 4.31 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.780-3.72(m, 1H), 3.65-3.56 (m, 1H), 3.09 (t, J = 8.7 Hz, 2H), 2.26-2.21 (m, 4H).

[0322] Example 35: 2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-((fluoromethyl))cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 90) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-D, and 1.2-K were used as starting materials to obtain 2-((5-fluoro-7-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-((fluoromethyl))cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (22 mg). ESI-MS (m / z): 681.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.85-7.78 (m, 2H), 7.64-7.59 (m, 2H), 7.33-7.31 (m, 2H), 6.88 (dd, J = 7.4, 1.3 Hz, 1H), 5.52 (s, 2H), 4.85 (d, J = 23.2 Hz, 2H), 4.68 (t, J = 8.8 Hz, 2H), 4.39 (s, 2H), 3.94 (s, 3H), 3.79-3.71 (m, 1H), 3.61-3.56 (m, 1H), 3.11 (t, J = 8.7 Hz, 2H), 2.45-2.39 (m, 2H), 2.28-2.19 (m, 2H).

[0323] Example 36: 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-((fluoromethyl))cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 91) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-E, and 1.2-J were used as starting materials to obtain 2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-3-((1-((fluoromethyl))cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (28 mg). ESI-MS (m / z): 683.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 4.2 Hz, 2H), 7.71 (d, J = 11.6 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.37-7.35 (m, 1H), 7.34 (t, J = 73.5 Hz,1H), 6.86-6.83 (m, 1H), 5.49 (s, 2H), 4.85 (d, J = 23.2 Hz, 2H), 4.69 (t, J = 8.8 Hz, 2H), 4.39 (s, 2H), 3.79-3.71 (m, 1H), 3.61-3.56 (m, 1H), 3.12 (t, J = 8.7 Hz, 2H), 2.45-2.38 (m, 2H), 2.28-2.19 (m, 2H).

[0324] Example 37: 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 92) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-B, and 1.2-J were used as starting materials to obtain 2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (40 mg). ESI-MS (m / z): 664.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.82 (q, J = 4.6, 4.0 Hz, 2H), 7.74 (d, J = 11.5 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.48 (dd, J = 10.0, 2.1 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.24 (s, 1H), 6.83 (dd, J = 6.4, 2.5 Hz, 1H), 5.51 (s, 2H), 4.82 (d, J = 24.1 Hz, 2H), 4.69 (t, J = 8.7 Hz, 2H), 4.32 (s, 2H), 3.87 (s, 3H), 3.10 (t, J = 8.8 Hz, 2H), 2.30 - 2.21 (m, 4H), 1.93 - 1.78 (m, 2H).

[0325] Example 38: 2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 93) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-C, and 1.2-J were used as starting materials to obtain 2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (15 mg). ESI-MS (m / z): 655.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.96 - 7.88 (m, 2H), 7.82 (q, J = 4.2, 3.3 Hz, 2H), 7.76 - 7.70 (m, 2H), 7.66 (d, J = 11.6 Hz, 1H), 7.24 (d, J = 1.3 Hz, 1H), 6.87 (dt, J = 7.6, 3.8 Hz, 1H), 5.60 (s, 2H), 4.82 (d, J = 24.2 Hz, 2H), 4.68 (t, J = 8.8 Hz, 2H), 4.31 (s, 2H), 3.87 (s, 3H), 3.10 (t, J = 8.8 Hz, 2H), 2.31 - 2.15 (m, 4H), 2.03 - 1.75 (m, 2H).

[0326] Example 39: (S)-2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid (compound 95) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid (7 mg) was obtained using intermediates 1.1-B, 1.5-E, and 1.2-A as starting materials. ESI-MS (m / z) 666.2 [M+H] + .

[0327] Example 40: (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-(2,2-difluoroethoxy)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 96) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-(2,2-difluoroethoxy)-1-((1-((fluoromethyl))cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg) was obtained using intermediates 1.8-I and 1.9-O as starting materials. ESI-MS (m / z): 714.2 [M+H] + .

[0328] Example 41: (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 100) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg) was obtained using intermediates 1.1-B, 1.5-C, and 1.2-F as starting materials. ESI-MS (m / z): 639.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 7.91 (d, J = 9.7 Hz, 1H), 7.87 (s, 1H), 7.83-7.82 (m, 2H), 7.76-7.71 (m, 2H), 7.67 (d, J = 11.6 Hz, 1H), 7.24 (s, 1H), 6.89-6.87 (m, 1H), 5.61 (s, 2H), 5.07-5.03 (m, 1H), 4.72-4.66 (m, 3H), 4.59-4.57 (m, 1H), 4.51-4.47 (m, 1H), 4.44 (d, J = 16.8 Hz, 1H), 4.36-4.31 (m, 2H), 3.88 (s, 3H), 3.13-3.07 (m, 2H), 2.72-2.67 (m, 1H), 2.39-2.33 (m, 1H).

[0329] Example 42: [ka] (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 101) Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (16 mg) was obtained using intermediates 1.1-B, 1.5-F, and 1.2-F as starting materials. ESI-MS (m / z): 666.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.79 (s, 1H), 7.87 (s, 1H), 7.83-7.81 (m, 1H), 7.80-7.76 (m, 1H), 7.69 (d, J = 11.5 Hz, 1H), 7.64-7.61 (m, 1H), 7.51 (dd, J = 10.0, 1.9 Hz, 1H), 7.34 (dd, J = 8.2, 1.7 Hz, 1H), 7.24 (s, 1H), 5.60 (s, 2H), 5.08-5.04 (m, 1H), 4.72-4.67 (m, 3H), 4.59-4.56 (m, 1H), 4.51-4.46 (m, 1H), 4.44 (d, J = 16.7 Hz, 1H), 4.36-4.31 (m, 2H), 3.88 (s, 3H), 3.14-3.08 (m, 2H), 2.73-2.67 (m, 1H), 2.39-2.34 (m, 1H).

[0330] Example 43: (S)-2-((7-(6-((4-chloro-2-fluorophenoxy)methyl)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 103) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-chloro-2-fluorophenoxy)methyl)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (37 mg) was obtained using intermediates 1.1-B, 1.5-H, and 1.2-F as starting materials. ESI-MS (m / z): 648.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.94 (dd, J = 7.8, 7.8 Hz, 1H), 7.88 (s, 1H), 7.71 (d, J = 12 Hz, 1H), 7.49-7.45 (m, 2H), 7.33 (dd, J = 9, 9 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.37 (s, 2H), 5.07-5.06 (m, 1H), 4.71-4.69 (m, 3H), 4.60-4.57 (m, 1H), 4.51-4.44 (m, 2H), 4.38-4.33 (m, 2H),3.89 (s, 3H), 3.13-3.12 (m, 2H), 2.73-2.69 (m, 1H), 2.38-2.35 (m, 1H).

[0331] Example 44: (S)-2-((7-(3-((4-trifluoromethyl-2-methoxybenzyl)oxy)-4-fluorophenyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 104) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(3-((4-trifluoromethyl-2-methoxybenzyl)oxy)-4-fluorophenyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (9 mg) was obtained using intermediates 1.1-B, 1.5-I, and 1.2-F as starting materials. ESI-MS (m / z): 711.2[M+H] + .

[0332] Example 45: (S)-2-((7-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 105) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (55 mg) was obtained using intermediates 1.1-B, 1.5-K, and 1.2-F as starting materials. ESI-MS (m / z): 665.2[M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 7.87 (s, 1H), 7.63-7.60 (m, 2H), 7.52 (dd, J = 9.9, 2.0 Hz, 1H), 7.38-7.36 (m, 2H), 7.30-7.26 (m, 2H), 7.24 (s, 1H), 5.29 (s, 2H), 5.07-5.04 (m, 1H), 4.72-4.68 (m, 1H), 4.60-4.57 (m, 3H), 4.51-4.48 (m, 1H), 4.42 (d, J = 16.6 Hz, 1H), 4.34-4.31 (m, 2H), 3.89 (s, 3H), 3.11-3.07 (m, 2H), 2.71-2.69 (m, 1H), 2.39-2.35 (m, 1H).

[0333] Example 46: (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 106) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-J, and 1.2-F were used as starting materials to obtain (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (35 mg). ESI-MS (m / z): 649.2[M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.68 (d, J = 4.8 Hz, 1H), 7.87-7.85 (m, 2H), 7.82 (d, J = 11.4 Hz, 1H), 7.62 (dd, J =8.4, 7.8 Hz, 1H), 7.50 (dd, J =10.2, 2.4 Hz, 1H), 7.33 (dd, J = 8.4, 1.8 Hz, 1H), 7.23 (d, J = 0.6Hz, 1H), 5.52 (s, 2H), 5.08-5.04 (m, 1H), 4.75-4.69 (m, 3H), 4.60-4.57 (m, 1H), 4.51-4.45 (m, 2H), 4.39-4.31 (m, 2H),3.87 (s, 3H), 3.18-3.08 (m, 2H), 2.73-2.67 (m, 1H), 2.38-2.33 (m, 1H).

[0334] Example 47: (S)-2-((7-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 107) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg) was obtained using intermediates 1.1-B, 1.5-AC, and 1.2-F as starting materials. ESI-MS (m / z): 647.2[M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.79 (s, 1H), 7.87 (s, 1H), 7.63-7.61 (m, 1H), 7.51 (dd, J = 9.9, 1.9 Hz, 1H), 7.39-7.34 (m, 4H), 7.25-7.23 (m, 2H), 7.02-7.00 (m, 1H), 5.19 (s, 2H), 5.08-5.04 (m, 1H), 4.72-4.68 (m, 1H), 4.59-4.56 (m, 3H), 4.51-4.47 (m, 1H), 4.42 (d, J = 16.7 Hz, 1H), 4.34-4.31 (m, 2H), 3.89 (s, 3H), 3.79-3.72 (m, 1H), 3.62-3.51 (m, 1H), 3.12-3.06 (m, 2H), 2.73-2.67 (m, 1H), 2.39-2.33 (m, 1H).

[0335] Example 48: (S)-2-((7-(5-chloro-6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 108) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(5-chloro-6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (15 mg) was obtained using intermediates 1.1-B, 1.5-L, and 1.2-F as starting materials. ESI-MS (m / z): 682.1 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.80 (brs, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 11.3 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 9.5 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 5.61 (s, 2H), 5.06 (d, J = 5.2 Hz, 1H), 4.73 - 4.67 (m, 3H), 4.58 (d, J = 14.8 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.45 (d, J = 16.8 Hz, 1H), 4.38 - 4.31 (m, 2H), 3.88 (s, 3H), 3.14 - 3.07 (m, 2H), 2.73 - 2.66 (m, 1H), 2.39 - 2.32 (m, 1H).

[0336] Example 49: (S)-2-((7-(5-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 109) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(5-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid (13 mg) was obtained using intermediates 1.1-B, 1.5-AD, and 1.2-F as starting materials. ESI-MS (m / z) 726.1 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ12.79 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.50 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 5.60 (s, 2H), 5.10-5.01 (m, 1H), 4.76-4.65 (m, 3H), 4.61-4.54 (m, 1H), 4.53-4.41 (m, 2H), 4.39-4.30 (m, 2H), 3.88 (s, 3H), 3.16-3.06 (m, 2H), 2.73-2.66 (m, 1H), 2.41-2.34 (m, 1H).

[0337] Example 50: (S)-2-((7-(2-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 110) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(2-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (29 mg) was obtained using intermediates 1.5-M, 1.5-E, and 1.2-F as starting materials. ESI-MS (m / z): 695.1[M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.68 (d, J = 5.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.77 (d, J = 11.4 Hz, 1H), 7.62 (d, J =8.4 Hz, 1H), 7.34-7.33(m, 2H), 7.24 (s, 1H), 5.53 (s, 2H), 5.08-5.04 (m, 1H), 4.75-4.69 (m, 3H), 4.60-4.57 (m, 1H), 4.51-4.45 (m, 2H), 4.39-4.31 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.18-3.08 (m, 2H), 2.73-2.67 (m, 1H), 2.38-2.32 (m, 1H).

[0338] Example 51: 2-((7-((6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(1-ethyl-1H-imidazole-5-ylmethyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 111) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-B, and 1.2-L were used as starting materials to obtain 2-((7-((6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(1-ethyl-1H-imidazole-5-ylmethyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (11 mg). ESI-MS (m / z): 686.1 [M+H] + .

[0339] Example 52: 2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 112) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-J, and 1.2-J were used as starting materials to obtain 2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-((1-((fluoromethyl))cyclopropyl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid (31 mg). ESI-MS (m / z): 665.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.69 (d, J = 5.4 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J = 5.4 Hz, 1H), 7.82 (d, J = 11.4 Hz, 1H), 7.62 (dd, J = 7.8, 7.8 Hz, 1H), 7.50 (dd, J = 10.2, 1.8 Hz, 1H), 7.34 (dd, J = 7.8, 1.2 Hz, 1H), 7.24 (s, 1H), 5.52 (s, 2H), 4.83 (d, J = 24 Hz, 2H), 4.74 (t, J = 9 Hz, 2H), 4.34 (s, 2H), 3.87 (s, 3H), 3.13 (t, J = 9 Hz, 2H), 2.26-2.21 (m, 4H), 1.90-1.87 (m, 2H).

[0340] Example 53: (S)-2-((7-(2-((2-difluoromethoxy-4-chlorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 113) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(2-((2-difluoromethoxy-4-chlorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (22 mg) was obtained using intermediates 1.1-B, 1.5-N, and 1.2-F as starting materials. ESI-MS (m / z): 697.1[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 7.87-7.85 (m, 2H), 7.80 (d, J = 11.4 Hz, 1H), 7.62 (d, J =8.4 Hz, 1H), 7.41-7.37 (m, 2H), 7.36 (t, J = 73.4 Hz, 1H), 7.24 (s, 1H), 5.50 (s, 2H), 5.08-5.04 (m, 1H), 4.75-4.69 (m, 3H), 4.59-4.57 (m, 1H), 4.51-4.45 (m, 2H), 4.39-4.31 (m, 2H), 3.87 (s, 3H), 3.15-3.11 (m, 2H), 2.74-2.67 (m, 1H), 2.38-2.33 (m, 1H).

[0341] Example 54: (S)-2-((7-((6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 114) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-((6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (6 mg) was obtained using intermediates 1.1-B, 1.5-O, and 1.2-F as starting materials. ESI-MS (m / z): 714.2 [M+H] + .

[0342] Example 55: (S)-2-((7-((6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 115) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-((6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (13 mg) was obtained using intermediates 1.1-B, 1.5-P, and 1.2-F as starting materials. ESI-MS (m / z): 657.1 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.7 (brs, 1H) 7.91 (d, J = 9.6 Hz, 1H), 7.85 (s, 1H), 7.83 - 7.75 (m, 3H), 7.73 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 11.4 Hz, 1H), 7.23 (s, 1H), 5.69 (s, 2H), 5.07 - 5.02 (m, 1H), 4.71 - 4.64 (m, 3H), 4.56 (d, J = 14.4 Hz, 1H), 4.50 - 4.46 (m, 1H), 4.43 (d, J = 16.8 Hz, 1H), 4.36 - 4.30 (m, 2H), 3.87 (s, 3H), 3.11 - 3.07 (m, 2H), 2.70 - 2.67 (m, 1H), 2.37 - 2.34 (m, 1H)h

[0343] Example 56: (S)-2-((7-(5-fluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 116) [ka] Referring to the synthesis method of compound 71, intermediates 1.1-B, 1.5-G, and 1.2-F were used as starting materials to obtain (S)-2-((7-(5-fluoro-6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (17 mg). ESI-MS (m / z): 712.2 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 7.87-7.75 (m, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 11.5 Hz, 1H), 7.34 (d, J = 9.0 Hz, 2H), 7.27 (s, 1H), 5.62 (s, 2H), 5.09-5.02 (m, 1H), 4.71-4.63 (m, 3H), 4.56-4.47 (m, 2H), 4.42 (d, J = 16.7 Hz, 1H), 4.36-4.31 (m, 2H), 3.96 (s, 3H), 3.86 (s, 3H), 3.12-3.06 (m, 2H), 2.72-2.65 (m, 1H), 2.41-2.33 (m, 1H).

[0344] Example 57: (S)-2-((7-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 117) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (6 mg) was obtained using intermediates 1.1-B, 1.5-Q, and 1.2-F as starting materials. ESI-MS (m / z): 649.1[M+H] + .

[0345] Example 58: (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 118) [ka] Referring to the synthesis method of compound 128, (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (36 mg) was obtained using 4-chloro-2-fluorobenzyl alcohol as a starting material. ESI-MS (m / z): 667.1[M+H] + , 1 H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.86 (s, 1H), 7.50-7.48 (m, 2H), 7.24 (d, J = 10.6 Hz, 1H), 7.15-7.11 (m, 2H), 5.46 (s, 2H), 5.07-5.03 (m, 1H), 4.65-4.60 (m, 5H), 4.51-4.47 (m, 1H), 4.45-4.41 (m, 1H), 4.35 (d, J = 13.9 Hz, 1H), 4.08 (s, 3H), 3.34 (br, 1H), 3.23-3.17 (m, 1H), 2.74-2.68 (m, 1H), 2.41-2.35 (m, 1H).

[0346] Example 59: (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)-pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-isopropoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 119) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)-pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-isopropoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (28 mg) was obtained using intermediates 1.1-B, 1.5-J, and 1.2-M as starting materials. ESI-MS (m / z): 677.1[M+H] + .

[0347] Example 60: (S)-2-((7-(2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 120) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (27 mg) was obtained using intermediates 1.1-B, 1.5-S, and 1.2-F as starting materials. ESI-MS (m / z): 671.1[M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.68 (d, J =4.8 Hz, 1H), 7.89-7.81 (m, 3H), 7.58 (t, J = 7.8 Hz, 1H), 7.32 (d, J =11.4 Hz, 1H), 7.26 (dd, J =7.8, 1.1 Hz, 1H), 7.24 (s, 1H), 5.53 (s, 2H), 5.09-5.03 (m, 1H), 4.95-4.90 (m, 2H), 4.76-4.69 (m, 3H), 4.64-4.55 (m, 3H), 4.52-4.44 (m, 2H), 4.41-4.24 (m, 3H), 3.87 (s, 3H), 3.16-3.08 (m, 2H), 2.73-2.67 (m, 1H), 2.38-2.33 (m, 1H).

[0348] Example 61: (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 121) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (32 mg) was obtained using intermediates 1.1-B, 1.5-J, and 1.2-N as starting materials. ESI-MS (m / z): 663.1[M+H] + .

[0349] Example 62: (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 122) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine 2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (24 mg) was obtained using intermediates 1.1-B, 1.5-F, and 1.2-N as starting materials. ESI-MS (m / z): 680.1[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.87 (s, 1H), 7.84-7.82 (m, 1H), 7.80-7.77 (m, 1H), 7.70 (d, J =11.4 Hz, 1H), 7.62 (dd, J =8.4, 7.8 Hz, 1H), 7.51 (dd, J =10.2, 1.8 Hz, 1H), 7.34 (dd, J =8.4, 1.8 Hz, 1H), 7.25 (s, 1H), 5.61 (s, 2H), 5.07-5.03 (m, 1H), 4.73-4.69 (m, 3H), 4.60-4.57 (m, 1H), 4.51-4.45 (m, 2H), 4.39-4.31 (m, 2H), 4.22 (q, J =6.6 Hz, 2H), 3.14-3.08 (m, 2H), 2.71-2.67 (m, 1H), 2.39-2.33 (m, 1H), 1.37 (t, J =7.2 Hz, 3H).

[0350] Example 63: (S)-2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 123) [ka] Referring to the synthesis method of compound 71, (S)2-((7-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (21 mg) was obtained using intermediates 1.1-B, 1.5-F, and 1.2-A as starting materials. ESI-MS (m / z): 636.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.23 ​​(s, 1H), 7.84-7.75 (m, 3H), 7.69 (d, J = 11.5 Hz, 1H), 7.65-7.60 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 9.9, 1.6 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 5.60 (s, 2H), 5.10-5.05 (m, 1H), 4.77-4.72 (m, 1H), 4.69 (t, J = 8.8 Hz, 2H), 4.64-4.60 (m, 1H), 4.52-4.45 (m, 2H), 4.40-4.33 (m, 2H), 3.15-3.10 (m, 2H), 2.75-2.68 (m, 1H), 2.40-2.35 (m, 1H).

[0351] Example 64: (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 124) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (33 mg) was obtained using intermediates 1.1-B, 1.5-J, and 1.2-A as starting materials. ESI-MS (m / z): 619.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.23 ​​(s, 1H), 7.90-7.74 (m, 3H), 7.66-7.49 (m, 3H), 7.41-7.29 (m, 1H), 5.52 (s, 2H), 5.15-5.03 (m, 1H), 4.80-4.70 (m, 3H), 4.65-4.58 (m, 1H), 4.54-4.48 (m, 2H), 4.43-4.33 (m, 2H), 3.20-3.10 (m, 2H), 2.74-2.66 (m, 1H), 2.40-2.35 (m, 1H).

[0352] Example 65: (S)-2-((7-(4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 125) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(4-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (37 mg) was obtained using intermediates 1.1-B, 1.5-AH, and 1.2-F as starting materials. ESI-MS (m / z): 695.2[M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.64 (d, J = 5.7 Hz, 1H), 7.87 (s, 1H), 7.66-7.64 (m, 2H), 7.34-7.32 (m, 2H), 7.24 (s, 1H), 6.92 (d, J = 5.7 Hz, 1H), 5.59 (s, 2H), 5.08-5.04 (m, 1H), 4.72-4.68 (m, 1H), 4.62-4.56 (m, 3H), 4.51-4.44 (m, 2H), 4.37-4.31 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.12-3.05 (m, 2H), 2.73-2.67 (m, 1H), 2.39-2.33 (m, 1H).

[0353] Example 66: (S)-2-((7-(5-fluoro-6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 126) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(5-fluoro-6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (18 mg) was obtained using intermediates 1.1-B, 1.5-T, and 1.2-F as starting materials. ESI-MS (m / z): 688.1 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.80 (brs, 1H), 7.87 (s, 1H), 7.83 - 7.80 (m, 1H), 7.79 - 7.75 (m, 1H), 7.71 (d, J = 11.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 11.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 5.61 (s, 2H), 5.09 - 5.02 (m, 1H), 4.91 (dd, J = 8.1, 6.1Hz, 2H), 4.73 - 4.67 (m, 3H), 4.63 - 4.56 (m, 3H), 4.49 (dd, J = 13.7, 7.7 Hz, 1H), 4.45 (d, J = 16.8 Hz, 1H), 4.38 - 4.31 (m, 2H), 4.30 - 4.25 (m, 1H), 3.88 (s, 3H), 3.11 (dd, J = 14.6, 8.0 Hz, 2H), 2.74 - 2.67 (m, 1H), 2.39 - 2.34 (m, J = 9.3 Hz, 1H).

[0354] Example 67: (S)-2-((7-(4-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 127) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(4-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (22 mg) was obtained using intermediates 1.1-B, 1.5-U, and 1.2-F as starting materials. ESI-MS (m / z): 671.2 [M+H] + , 1 H NMR (600 MHz, DMSO-d6) δ 12.79 (brs, 1H), 8.63 (d, J = 5.7 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J = 11.2 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 11.1 Hz, 1H), 7.27 - 7.22 (m, 2H), 6.88 (d, J = 5.7 Hz, 1H), 5.59 (s, 2H), 5.06 (d, J = 5.0 Hz, 1H), 4.91 (dd, J = 8.3, 6.1 Hz, 2H), 4.71 (dd, J = 15.6, 6.8 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 4.62 - 4.57 (m, 3H), 4.51 - 4.44 (m, 2H), 4.39 - 4.32 (m, 2H), 4.27 (dt, J = 15.0, 7.6 Hz, 1H), 3.88 (s, 3H), 3.13 - 3.07 (m, 2H), 2.74 - 2.68 (m, 1H), 2.40 - 2.33 (m, 1H).

[0355] Example 68: (S)-2-((7-(5-fluoro-2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 128) [ka]

[0356] Step 1: (S)-2-((7-(2-chloro-5-fluoropyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 4-bromo-2-chloro-5-fluoropyrimidine (23 mg, 0.11 mmol), (S)-2-((5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (prepared according to the method of Example 2, 55 mg, 0.1 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol), potassium carbonate (27 mg, 0.2 mmol), 1,4-dioxane (3 mL), and water (1 mL) were placed in a 100 mL round-bottom flask and the mixture was stirred under a nitrogen atmosphere at 80°C. After the reaction was complete, the mixture was cooled, added to water (100 mL), extracted with ethyl acetate, and 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 thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain (S)-2-((7-(2-chloro-5-fluoropyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (49 mg). ESI-MS (m / z): 557.1 [M+H]+ .

[0357] Step 2: (S)-2-((7-(5-fluoro-2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 2-Fluoro-4-(oxetan-3-yl)benzyl alcohol (44 mg, 0.24 mmol), (S)-2-((7-(2-chloro-5-fluoropyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (55 mg, 0.1 mmol), potassium t-butoxide (44 mg, 0.4 mmol), and tert-butanol (3 mL) were placed in a 100 mL round-bottom flask and reacted with stirring at 50°C. After the reaction was complete, the mixture was cooled, and water (50 mL) and glacial acetic acid (0.5 mL) were added to the mixture. The mixture was stirred at room temperature for 20 minutes, then extracted with dichloromethane (3 × 50 mL), and the organic phases were combined and concentrated. The crude product was separated and purified by medium-pressure preparative liquid chromatography (mobile phase: acetonitrile / water (0.1% formic acid), changing from 1 / 20 to 20 / 1) to obtain (S)-2-((7-(5-fluoro-2-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (15 mg). ESI-MS (m / z): 689.2 [M+H] + , 1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 7.90 (s, 1H), 7.54-7.51 (m, 2H), 7.27 (s, 1H), 7.17-7.14 (m, 2H), 5.49 (s, 2H), 5.19-5.07 (m, 2H), 5.04-4.97 (m, 3H), 4.73 (t, J = 6.3 Hz, 2H), 4.66-4.62 (m, 3H), 4.56-4.52 (m, 1H), 4.49-4.45 (m, 1H), 4.39-4.37 (m, 1H), 4.23-4.18 (m, 1H), 4.09 (s, 3H), 3.53-3.49 (m, 1H), 3.26-3.22 (m, 1H), 2.77-2.73 (m, 1H), 2.44-2.37 (m, 1H).

[0358] Example 69: (S)-2-((7-(5-fluoro-4-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 129) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(5-fluoro-4-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyrimidine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (26 mg) was obtained using intermediates 1.1-B, 1.5-W, and 1.2-F as starting materials. ESI-MS (m / z): 689.2[M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.87 (br s, 1H), 8.72 (d, J = 2.8 Hz, 1H), 7.83 (s, 1H), 7.68-7.65 (m, 2H), 7.34 (dd, J = 10.8, 1.2 Hz, 1H), 7.28 (dd, J = 7.9, 1.4 Hz, 1H), 7.25 (s, 1H), 5.68 (s, 2H), 5.08-5.04 (m, 1H), 4.93-4.90 (m, 2H), 4.70-4.68 (m, 1H), 4.66-4.63 (m, 2H), 4.61 (t, J = 6.4 Hz, 2H), 4.58-4.55 (m, 1H), 4.51-4.49 (m, 1H), 4.45 (d, J = 16.7 Hz, 1H), 4.37-4.34 (m, 1H), 4.33-4.31 (m, 1H), 4.39-4.27 (m, 1H), 3.87 (s, 3H), 3.13-3.07 (m, 2H), 2.73-2.67 (m, 1H), 2.40-2.34 (m, 1H).

[0359] Example 70: (S)-2-((7-(5-fluoro-2-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 130) [ka] Referring to the synthesis method of compound 128, (S)-2-((7-(5-fluoro-2-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (14 mg) was obtained using 2-methoxy-4-(trifluoromethyl)benzyl alcohol as a starting material. ESI-MS (m / z): 713.2 [M+H]+ , 1 H NMR (600 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.76 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 9.7 Hz, 2H), 7.26-7.19 (m, 2H), 5.47 (s, 2H), 5.11-5.04 (m, 1H), 4.73-4.68 (m, 1H), 4.63-4.56 (m, 3H), 4.51-4.45 (m, 2H), 4.40-4.36 (m, 1H), 4.35-4.30 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.16-3.09 (m, 2H), 2.74-2.66 (m, 1H), 2.39-2.36 (m, 1H).

[0360] Example 71: (S)-2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-5-fluoropyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 131) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(6-((4-chloro-2-(difluoromethoxy)benzyl)oxy)-5-fluoropyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (6 mg) was obtained using intermediates 1.1-B, 1.5-Y, and 1.2-F as starting materials. ESI-MS (m / z): 715.2 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.77 (d, J = 1.8 Hz, 1H), 7.94 - 7.85 (m, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.35 (t, J = 73.4 Hz, 1H), 7.27 - 7.22 (m, 1H), 5.44 (s, 2H), 5.11 - 5.04 (m, 1H), 4.72 (dd, J = 15.7, 6.9 Hz, 1H), 4.65 - 4.56 (m, 3H), 4.49 (dd, J = 15.6, 8.4 Hz, 2H), 4.39 (d, J = 16.8 Hz, 1H), 4.33 (dt, J = 9.1, 5.9 Hz, 1H), 3.89 (s, 3H), 3.13 (p, J = 7.6 Hz, 2H), 2.71 (dd, J = 10.6, 7.5 Hz, 1H), 2.42 - 2.33 (m, 1H).

[0361] Example 72: (S)-2-((7-(5-fluoro-6-((2-fluoro-4-methylbenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 132) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(5-fluoro-6-((2-fluoro-4-methylbenzyl)oxy)pyridine-2-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (23 mg) was obtained using intermediates 1.1-B, 1.5-Z, and 1.2-F as starting materials. ESI-MS (m / z): 646.1 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.73 (br s, 1H), 7.87 (s, 1H), 7.82 - 7.79 (m, 1H), 7.76 (d, J = 9.7 Hz, 1H), 7.72 (d, J = 11.6 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.09 (d, J = 11.2 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 5.56 (s, 2H), 5.06 (d, J = 5.2 Hz, 1H), 4.69 (dd, J = 18.9, 10.5 Hz, 3H), 4.58 (d, J = 14.5 Hz, 1H), 4.49 (d, J = 6.4 Hz, 1H), 4.44 (d, J = 16.8 Hz, 1H), 4.38 - 4.31 (m, 2H), 3.88 (s, 3H), 3.15 - 3.08 (m, 2H), 2.73 - 2.67 (m, 1H), 2.39 - 2.35 (m, 1H), 2.32 (s, 3H).

[0362] Example 73: (S)-2-((7-(2-((2-fluoro-4-methylbenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 133) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(2-((2-fluoro-4-methylbenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (36 mg) was obtained using intermediates 1.1-B, 1.5-AA, and 1.2-F as starting materials. ESI-MS (m / z): 629.2 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.79 (br s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.88 - 7.83 (m, 3H), 7.46 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 0.9 Hz, 1H), 7.09 (d, J = 11.2 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 5.48 (s, 2H), 5.08 - 5.04 (m, 1H), 4.74 (t, J = 8.9 Hz, 2H), 4.72 - 4.68 (m, 1H), 4.59 (dd, J = 15.6, 2.5 Hz, 1H), 4.51 - 4.45 (m, 2H), 4.38 (d, J = 16.8 Hz, 1H), 4.33 (dt, J = 9.0, 5.9 Hz, 1H), 3.88 (s, 3H), 3.13 (dd, J = 14.3, 8.3 Hz, 2H), 2.72 - 2.68 (m, 1H), 2.39 - 2.36 (m, 1H), 2.32 (s, 3H).

[0363] Example 74: (S)-2-((7-(5-fluoro-2-((2-fluoro-4-methylbenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 134) [ka] Referring to the synthesis method of compound 71, (S)-2-((7-(5-fluoro-2-((2-fluoro-4-methylbenzyl)oxy)pyrimidine-4-yl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-4-methoxy-1-(oxetan-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid (16 mg) was obtained using intermediates 1.1-B, 1.5-AB, and 1.2-F as starting materials. ESI-MS (m / z): 647.2 [M+H] + , 1H NMR (600 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.76 (d, J = 1.4 Hz, 1H), 7.87 (s, 1H), 7.47 - 7.43 (m, 1H), 7.27 - 7.23 (m, 2H), 7.09 (d, J = 11.2 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 5.42 (s, 2H), 5.10 - 5.04 (m, 1H), 4.74 - 4.68 (m, 1H), 4.64 - 4.57 (m, 3H), 4.53 - 4.45 (m, 2H), 4.40 - 4.36 (m, 1H), 4.34-4.31 (m, 1H), 3.89 (s, 3H), 3.21 - 3.07 (m, 2H), 2.75 - 2.67 (m, 1H), 2.38 - 2.30 (m, 4H).

[0364] The following are the efficacy tests and data for the compound of the present invention. [Test Example 1] Enzymatic test of the compound according to the present invention The agonist activity of the test compound against GLP-1R will be measured using GLP1R-cAmp-Luc cells. 1) Dissolve the test compound in DMSO and mix thoroughly until completely dissolved. After preparing the compound in a 10 mM mother liquor with DMSO, transfer all compounds to DMEM medium (high glucose, puromycin + Hygromycin B + Dilute to an initial concentration of 1250 nM with ) and generate a total of 7 concentration gradients through 5-step dilutions. Place 1 × 10⁶ GLP1R-cAmp-Luc cells in a white-walled 96-well cell culture plate. 5 Seeds were seeded at a density of / mL, and 90 μL of cell suspension was added to each well. Then, 10 μL of the test compound was added to each well according to a 7-step concentration gradient, bringing the actual working concentration to 125 nM, and the cells were cultured in an incubator at 37°C and 5% CO2 for 4 hours. 2) Add 100 μL of luciferin potassium salt solution diluted to 300 μg / mL with PBS (final working concentration 150 μg / mL) to each well and incubate at room temperature for 30 minutes. 3) The fluorescence signal of firefly luciferin was measured using a multifunctional enzyme immunoassay analyzer (PerkinElmer, Nivo), and the fluorescence values ​​were analyzed using GraphPad Prism software. 50 Calculate the value.

[0365] As shown by the test results, the compounds according to the present invention have a stronger GLP-1R agonist activation effect, and preferably, the GLP-1R agonist activation effect of the compounds is superior to that of the control compounds (i.e., positive control EC 50 / Compound EC according to the present invention 50 >1) more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧2, more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧3, more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧4, more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧5, more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧6, more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧7, more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧10, more preferably (positive control EC 50 / Compound EC according to the present invention 50 )≧15, more preferably (positive control EC 50 / Compound EC according to the present invention 50 ) ≥ 20. For example, 1 < positive control EC 50 / Compound EC according to the present invention 50 <2, or 2 ≤ positive control EC 50 / Compound EC according to the present invention 50 <3, or 3 ≤ positive control EC 50 / Compound EC according to the present invention 50 <4, or 4 ≤ positive control EC 50 / Compound EC according to the present invention50 <5, or 5 ≤ positive control EC 50 / Compound EC according to the present invention 50 <6, or 6 ≤ positive control EC 50 / Compound EC according to the present invention 50 <7, or 7 ≤ positive control EC 50 / Compound EC according to the present invention 50 <10, or 10 ≤ positive control EC 50 / Compound EC according to the present invention 50 <20, or positive control EC 50 / Compound EC according to the present invention 50 The value is ≥20. Examples of compounds are shown in the table below.

[0366] [Table 5]

[0367] [Test Example 2] Mouse in vivo pharmacokinetic study Experimental animals: ICR mice (female, 22-25g) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Test procedure: The test compound was administered intragastricly to ICR mice. Whole blood samples were collected from the mice at 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. Plasma was separated by centrifugation, and the compound concentration was detected by LC-MS / MS. Pharmacokinetic parameters such as the area under the drug-time curve (AUC) were calculated using Winnolin software.

[0368] Oral intragastric dose: 10 mg / kg. Measurement method: After pretreatment by protein precipitation, quantitative analysis is performed using an LC / MS / MS system. The compounds according to the present invention exhibit good in v...

Claims

1. A compound represented by formula (I') having the following structure, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, Ring A is independently selected from the group consisting of phenyl and 5-6 membered heteroaryls. Ring B is independently selected from the group consisting of 8-10 membered bicyclic heterocyclyls, phenyls, 5-6 membered monocyclic heteroaryls, and 8-10 membered bicyclic heteroaryls. Ring C is C ８－１０ Independently selected from the group consisting of bicyclic condensed carbon rings, 8-10 membered bicyclic condensed heterocyclyls, and 8-10 membered bicyclic heteroaryls, 【Chemistry 2】 Independently selected from the group consisting of, R ａ at each occurrence is independently selected from the group consisting of 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, and 3- to 6-membered heterocyclyl, wherein said C １－６ alkyl, C １－６ alkoxy, C １－６ alkylamino, C ３－６ cycloalkyl, or 3- to 6-membered heterocyclyl is optionally substituted with one or more R ａ３ , R ａ１ and R ａ２ Each instance of appearance is hydrogen, deuterium, and C, respectively. １－６ Alkyl, C １－６ Alkoxy, C ３－６ A C is independently selected from the group consisting of cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl. １－６ Alkyl, C １－６ Alkoxy, C ３－６ Cycloalkyls, 3-6 membered heterocyclyls, phenyls, or 5-6 membered heteroaryls are halogens, hydroxy, amino, nitro, mercapto, cyano, oxo, and C. １－６ Alkyl, C １－６ Alkoxy, C ３－６ It is optionally substituted with one or more substituents selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines. R ａ３ Each instance of appearance contains deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -R. ａ４ Independently selected from the group consisting of, R ａ４ is hydrogen, deuterium, C １－６ Alkyl and C １－６ Independently selected from the group consisting of alkoxys, the above C １－６ Alkyl, C １－６ The alkoxy is optionally substituted with one or more substituents selected from the group consisting of halogens, hydroxyl, amino, nitro, mercapto, and cyano. R ｂ Each instance of C is substituted with deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and optionally substituted C. １－６ Alkyl or C １－６ Independently selected from the group consisting of alkoxys, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R ｂ１ This means that it has been replaced by R ｂ１ Each instance of appearance contains deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -R. ｂ２ Independently selected from the group consisting of, R ｂ２ These include hydrogen, deuterium, as well as halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. １－６ Alkyl, C １－６ C is optionally substituted with one or more alkoxys. １－６ Alkyl and C １－６ Independently selected from the group consisting of alkoxys, R ｃ Each instance of C is substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, and optionally substituted C. １－６ Alkyl or C １－６ Independently selected from the group consisting of alkoxys, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R ｃ１ This means that it has been replaced by Alternatively, two R's ｃ These, together with the atoms to which they are bonded, form a 3- to 6-membered heterocycline or a 5- to 6-membered heteroaryl, which is optionally substituted with one or more of the following: deuterium, halogen, hydroxyl, amino, cyano, oxo, methyl, ethyl, methoxy, or ethoxy. R ｃ１ C is optionally substituted with one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and halogen, hydroxyl, amino, and cyano at each occurrence. １－４ Independently selected from the group consisting of alkyls, R ｄ and R ｅ One of the atoms is selected from hydrogen or deuterium, and the other is optionally substituted with C ３－６ Selected from the group consisting of cycloalkyl groups, 3-6 membered heterocyclyl groups, and 5-6 membered heteroaryl groups, the term "optionally substituted" means that the hydrogen atoms in the substituted group are unsubstituted, or one or more substituted sites in the substituted group are independently R ｄ１ This means that it has been replaced by R ｄ１ Each instance of appearance is associated with deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and -C(O)N(R). ｄ２ ) (Caution ｄ３ ), -N(R ｄ２ )C(O)(R ｄ３ ), C １－６ Alkyl and C １－６ Independently selected from the group consisting of alkoxys, the above C １－６ Alkyl, C １－６ Alkoxy compounds include deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. １－６ Alkyl, C １－６ Haloalkyl and C １－６ It is optionally substituted with one or more substituents selected from the group consisting of alkoxys. R ｄ２ and R ｄ３ Each instance of appearance is hydrogen, deuterium, and C, respectively. １－６ Alkyl and C １－６ Independently selected from the group consisting of alkoxys, the above C １－６ Alkyl, C １－６ Alkoxy compounds include halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, and C. １－６ Alkyl and C １－６ It is optionally substituted with one or more substituents selected from the group consisting of alkoxys. R ｆ , at each occurrence, is independently selected from the group consisting of 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- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C １－６ alkyl, C １－６ alkoxy, C １－６ alkylamino, C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with one or more R ｆ１ , R ｆ１ Each instance of this occurs contains deuterium, halogen, hydroxyl, amino, cyano, and -R. ｆ２ Independently selected from the group consisting of, R ｆ２ is independently selected from the group consisting of hydrogen, deuterium, and C １－６ alkyl, C １－６ alkoxy, C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C １－６ alkyl, C １－６ alkoxy, C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with one or more of halogen, hydroxy, amino, nitro, mercapto, cyano, and oxo, R ｆ４ and R ｆ５ Each instance of appearance is hydrogen, deuterium, and C, respectively. １－６ Alkyl, C ３－６ Independently selected from the group consisting of cycloalkyls, 3-6 membered heterocyclines, phenyls, and 5-6 membered heteroaryls, R ｇ Each occurrence is -C(O)OR ｇ１ Selected independently from, R ｇ１ It is hydrogen, L １ is a bond, -C(R Ｌ１ ) ２ -, -O-, and -C(R Ｌ１ ) ２ Independently selected from the group consisting of O-, R Ｌ１ C is optionally substituted with hydrogen, deuterium, and one or more of deuterium, halogen, hydroxyl, amino, nitro, mercapto, and cyano. １－６ Independently selected from the group consisting of alkyls, L ２ is a bond, -C(R Ｌ２ ) ２ -, -O-, and -C(R Ｌ１ ) ２ Independently selected from the group consisting of O-, R Ｌ２ These include hydrogen, deuterium, as well as deuterium, halogens, hydroxyl, amino, nitro, mercapto, cyano, and C １－６ C is optionally substituted with one or more alkyl groups. １－６ Independently selected from the group consisting of alkyls, L ３ is a bond, -C(R Ｌ３ ) ２ Independently selected from the group consisting of -, -O-, -S-, -C(O)-, -C(O)O-, and -OC(O)-, R Ｌ３ These include hydrogen, deuterium, as well as deuterium, halogens, hydroxyl, amino, nitro, mercapto, cyano, and C １－６ C is optionally substituted with one or more alkyl groups. １－６ Independently selected from the group consisting of alkyls, L ４ is a bond, and m, n, o, and p are independently 0, 1, 2, or 3, Unless otherwise specified, the heteroatoms in the heterocyclyl and heteroaryl compounds are independently selected from the group consisting of O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4.

2. Ring A was independently selected from the group consisting of phenyl and pyridyl. Alternatively, ring A may be independently selected from phenyl. or 【Transformation 3】 Selected independently from, Furthermore / or R ａ is halogen, hydroxy, amino, cyano, -C(O)N(C １－４ Alkyl) ２ , -C(O)NH(C １－４ Alkyl), -C(O)NH ２ , C １－４ Alkyl, C １－４ Independently selected from the group consisting of alkoxys and 3-6 membered heterocyclines, the above C １－４ Alkyl, C １－４ Alkoxy, 3-6 membered heterocyclyl, one or more R ａ３ The heteroatoms in the 3-6 member heterocyclyl are either O or N, and the number of heteroatoms is 1 or 2. Alternatively, R ａ These are halogen, cyano, and C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Independently selected from the group consisting of haloalkoxys and 3- to 6-membered heterocyclines, wherein the heteroatom in the 3- to 6-membered heterocycline is O, and the number of heteroatoms is 1. Alternatively, R ａ is halogen, cyano, -C(O)NH ２ , C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Independently selected from the group consisting of haloalkoxys and oxetanyls, Alternatively, R ａ These are halogen, cyano, and C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Independently selected from the group consisting of haloalkoxys and oxetanyls, Alternatively, R ａ Fluorine, chlorine, cyano, -C(O)NH ２ , -CF ３ , -OCHF ２ methyl, methoxy, and 【Chemistry 4】 Independently selected from the group consisting of, Alternatively, R ａ It is independently selected from the group consisting of fluorine, chlorine, and cyano, Alternatively, R ａ１ , R ａ２ Each is selected independently of hydrogen, Alternatively, R ａ３ It is independently selected from the group consisting of halogens, Alternatively, R ａ３ It is independently selected from the group consisting of fluorine and chlorine, Alternatively, m is 2, or, 【Transformation 5】 Independently selected from the group consisting of, The compound described in claim 1, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

3. L １ The bond and -CH ２ Independently selected from the group consisting of O-, Or, L １ is, -CH ２ Selected independently from O-, here CH ２ The O group is bonded to one end of ring A, and the O group is bonded to one end of ring B. A compound according to any one of claims 1 or 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. Ring B is independently selected from the group consisting of phenyl and six-membered heteroaryls, wherein the heteroatom in the heteroaryl is N, and the number of heteroatoms is 1 or 2. Alternatively, ring B is independently selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and a 9-membered bicyclic heterocycline, wherein the heteroatom in the 9-membered bicyclic heterocycline is O, and the number of heteroatoms is 2. Alternatively, ring B may be phenyl, pyridyl, pyrimidinyl, and 【Transformation 6】 Independently selected from the group consisting of, Alternatively, ring B is the following base: 【Transformation 7】 It is independently selected from the group consisting of, where the "*" end is L １ The ends that connect are represented by "**" and the ends are L ２ It represents the end that connects, Alternatively, ring B is the following base: 【Transformation 8】 It is independently selected from the group consisting of, where the "*" end is L １ The ends that connect are represented by "**" and the ends are L ２ It represents the end that connects, Alternatively, ring B is the following base: 【Chemistry 9】 It is independently selected from the group consisting of, where the "*" end is L １ The ends that connect are represented by "**" and the ends are L ２ The end that connects, A compound according to any one of claims 1 to 3, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. R ｂ It is independently selected from the group consisting of halogens and methyl compounds. Alternatively, R ｂ It is independently selected from the group consisting of halogens, Alternatively, R ｂ It is independently selected from the group consisting of fluorine, chlorine, and bromine, Alternatively, R ｂ It is selected independently of fluorine, Alternatively, n is independently selected from the group consisting of 0 and 1. Alternatively, n is 0, or, 【Chemistry 10】 A group consisting of is selected, where the "*" end is L １ The ends that connect are represented by "**" and the ends are L ２ The end that connects, A compound according to any one of claims 1 to 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. Ring C is C ９ A C is independently selected from the group consisting of a bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, a 10-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl. ９ In bicyclic condensed carbocyclic groups, 9-membered bicyclic condensed heterocyclines, 10-membered bicyclic condensed heterocyclines, and 9-membered bicyclic heteroaryls, the heteroatoms are selected from N or O, and the number of heteroatoms is 1 or 2. Ring C is C ９ A C is independently selected from the group consisting of a bicyclic condensed carbon ring, a 9-membered bicyclic condensed heterocyclyl, and a 9-membered bicyclic heteroaryl. ９ In bicyclic condensed carbocyclic groups, nine-membered bicyclic condensed heterocyclyls, and nine-membered bicyclic heteroaryls, the heteroatoms are selected from N or O, and the number of heteroatoms is one or two. Alternatively, ring C is independently selected from a 9-membered bicyclic condensed heterocycline, the heteroatoms in the 9-membered bicyclic condensed heterocycline are selected from O, and the number of heteroatoms is 1 or 2. Alternatively, ring C is independently selected from the group consisting of 5-membered / 6-membered fused heterocyclic groups and 6-membered / 5-membered fused heterocyclic groups, the heteroatoms in the aforementioned 5-membered / 6-membered or 6-membered / 5-membered fused heterocyclic groups are selected from O, and the number of heteroatoms is 1 or 2. Alternatively, ring C is, 【Chemistry 11】 Furthermore / or, R ｃ C is optionally substituted with halogen, hydroxyl, amino, cyano, oxo, and １－６ Independently selected from the group consisting of alkyl groups, and the term "optionally substituted" means that the hydrogen atoms in the substituted group are unsubstituted, or one or more substituted sites in the substituted group are independently R ｃ１ This means that it is replaced by R ｃ１ These are independently selected from the group consisting of halogens, hydroxyls, aminos, and cyanos. Alternatively, R ｃ These are halogens, hydroxyls, oxols, and C １－３ Independently selected from the group consisting of alkyls, Alternatively, R ｃ It is independently selected from the group consisting of fluorine, chlorine, and methyl, Alternatively, R ｃ It is independently selected from the group consisting of halogens, Alternatively, R ｃ It is independently selected from the group consisting of fluorine and chlorine, Alternatively, R ｃ It is selected independently of fluorine, Alternatively, R ｃ１ It is independently selected from the group consisting of halogens (e.g., fluorine, chlorine, bromine), Alternatively, o is independently selected from the group consisting of 0 and 1. Alternatively, o is 0, or, 【Chemistry 12】 A compound according to any one of claims 1 to 5, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. L ２ It is selected independently of the combination, Furthermore / or, L ３ is, -CH ２ -, -C(O)-, and -CH(CH ３ ) - independently selected from the group consisting of, Or, L ３ is, -CH ２ - Selected independently of A compound according to any one of claims 1 to 6, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 8】 【Chemistry 13】 Furthermore / or, R ｄ and R ｅ One of the C atoms is selected from hydrogen, and the other is optionally substituted. ３－６ Selected from the group consisting of cycloalkyl groups, 3-6 membered heterocyclyl groups, and 5-6 membered heteroaryl groups, the term "optionally substituted" means that the hydrogen atoms in the substituted group are unsubstituted, or one or more substituted sites in the substituted group are independently R ｄ１ This means that it has been replaced by Alternatively, R ｄ and R ｅ These are hydrogen and optionally substituted, respectively. 【Chemistry 14】 Independently selected from the group consisting of, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R ｄ１ This means that it has been replaced by Alternatively, R ｄ and R ｅ These are hydrogen and optionally substituted, respectively. 【Chemistry 15】 Independently selected from the group consisting of, and the term "optionally substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R ｄ１ This means that it has been replaced by Alternatively, R ｅ is hydrogen, R ｄ It is being replaced by an optional substitution. 【Chemistry 16】 Selected from the group consisting of, and the term "arbitrarily substituted" means that the hydrogen in the substituted group is unsubstituted, or one or more substituted sites in the substituted group are independently R ｄ１ This means that it is replaced by R ｄ１ is -N(C １－２ Alkyl)C(O)(C １－２ C(alkyl) and C(fluorine), which is optionally substituted with one or more of fluorine, chlorine, and cyano(alkyl) compounds. １－３ Independently selected from the group consisting of alkyls, 【Chemistry 17】 Alternatively, R ｄ１ C is optionally substituted with one or more of fluorine, chlorine, and cyano compounds. １－４ Independently selected from the group consisting of alkyls, Alternatively, R ｄ１ Fluorine, chlorine, bromine, hydroxy, amino, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, -CH ２ CN, and -CH ２ CH ２ Independently selected from the group consisting of CN, Alternatively, R ｄ１ It is monofluoromethyl, -CH ２ It is independently selected from the group consisting of CN, methyl, and ethyl. Furthermore / or, R ｆ are halogen, hydroxy, amino, cyano, -OR ｆ４ , -C(O)N(R ｆ４ ) (Caution ｆ５ ), -N(R ｆ４ )C(O)(R ｆ５ ), C １－６ Alkyl and C １－６ Independently selected from the group consisting of alkoxys, the above C １－６ Alkyl, C １－６ Alkoxy is one or more R ｆ１ It is optionally replaced by, Alternatively, R ｆ is 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 and C １－３ Independently selected from the group consisting of alkoxys, the above C １－３ Alkyl or C １－３ The alkoxy is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and phenyl. Alternatively, R ｆ It is fluorine, chlorine, hydroxy, amino, -O-cyclopropyl, -C(O)NHCH ３ , -NHC(O)CH ３ ien-CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCHF ２ , -OCF ３ , -OCH ２ -phenyl, -OCH ２ CF ３ , and -OCH ２ CHF ２ Independently selected from the group consisting of, Alternatively, R ｆ It is independently selected from the group consisting of halogens, Alternatively, R ｆ It is independently selected from the group consisting of fluorine and chlorine, Alternatively, R ｆ fluorine, chlorine, bromine, C １－４ Alkoxy, and C １－３ Independently selected from the group consisting of haloalkoxys, Alternatively, R ｆ Fluorine, chlorine, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCHF ２ , -OCF ３ , -OCH ２ CF ３ , and -OCH ２ CHF ２ Independently selected from the group consisting of, Alternatively, R ｆ Fluorine, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , and -OCH ２ CHF ２ Independently selected from the group consisting of, Alternatively, R ｆ１ It is independently selected from the group consisting of halogens, Alternatively, R ｆ is halogen and C １－３ Independently selected from the group consisting of alkoxys, the C １－３ The alkoxy is optionally substituted with one or more fluorines. Alternatively, p is independently selected from the group consisting of 0 and 1. Alternatively, p is 1, Alternatively, p is 0, or, [Chemistry 18] Independently selected from the group consisting of, A compound according to any one of claims 1 to 7, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. 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-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 (IV-12), Formula (IV-13) Structures represented by formulas (IV-14), (IV-15), (IV-16), (IV-17), (V), (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), (V-7), (V-8), (V-9), (V-10), (V-11), (V-12), (V-13), (V-14), (V-15), (V-16), and (V-17): 【Chemistry 19】 【change】 【change】 Having, A compound according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. The aforementioned compound is the following compound: Table 1 Selected from the group consisting of, The compound described in claim 1, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further comprising, optionally, one, two, or more compounds useful for the same or similar indications.

12. Use of a compound according to any one of claims 1 to 10, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the manufacture of a pharmaceutical for preventing and / or treating a disease, symptom, or condition by activation of a cascade signal mediated by GLP-1R. Preferably, the diseases, symptoms, and conditions are GLP-1R-related, including diabetes mellitus, obesity, overweight, metabolic fatty liver disease, and Alzheimer's disease.

Images