Cycloalkene derivative regulator, its manufacturing method and application

Abstract

Provided are polycyclic derivative regulators, their preparation methods and applications. In particular, provided are compounds as shown in general formula (I'), their preparation methods and pharmaceutical compositions containing the compounds, and their application as regulators in the manufacture of medicines for treating metabolic and related diseases, wherein each substituent in general formula (I') is as defined in the specification. [Case 1] TIFF2024529527000157.tif40170

Description

[Technical field]

[0001] The present invention belongs to the field of biopharmaceuticals, specifically relates to a cycloalkene derivative regulator, its preparation method and application. [Background technology]

[0002] Diabetes mellitus is a common endocrine and metabolic disease that causes multiple system and multiple organ disorders due to metabolic disorders caused by various causes. It has a high prevalence, with about 425 million diabetic patients in the world, and the prevalence of diabetes in China is about 10%, of which type II diabetes accounts for 90%, and the incidence rate is still increasing and the age of onset is becoming younger.

[0003] Currently, many drugs are available on the market for the treatment of type II diabetes, including insulin, biguanides, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase IV (DPP-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, α-glycosidase, etc., among which GLP-1 receptor agonists have attracted the most attention.

[0004] GLP-1 is a peptide hormone secreted by human intestinal L cells, and its receptors are distributed in pancreatic islet cells, multiple types of gastrointestinal cells, and neurons in the central and peripheral nervous systems. When GLP-1 receptors are activated, they have physiological effects such as promoting insulin secretion, inhibiting glucagon secretion, suppressing appetite, and delaying gastric emptying. Clinical evidence has shown that compared with other hypoglycemic drugs, GLP-1 receptor agonists have better hypoglycemic effects and are less likely to cause side effects such as hypoglycemia. In addition, they also have additional cardiovascular benefits, can reduce food intake, and delay gastric emptying, which is favorable for weight control.

[0005] Currently, all commercially available GLP-1 receptor agonists are polypeptide-based drugs, which often require subcutaneous administration, leading to poor patient compliance and very poor oral polypeptide bioavailability. Therefore, there is a great clinical need for the development of oral small molecule GLP-1 receptor agonists.

[0006] At present, no small molecule GLP-1 receptor agonists have been approved, and three small molecule GLP-1 receptor agonists have entered the clinical research stage, such as PF-06882961 and PF-07081532 developed by Pifzer, and TTP273 developed by vTv, all of which are currently in phase I / II research. Here, PF-06882961 has shown significant blood glucose lowering and weight loss effects in early clinical trials, and its safety is similar to that of polypeptide GLP-1 receptor agonists, and it is expected to provide more treatment options for diabetes, obesity, and NASH patients in the future.

[0007] There is a huge clinical need for GLP-1 receptor agonists. Oral small molecule GLP-1 receptor agonists with lower cost and better compliance have the potential to treat various metabolic diseases and have broad market prospects. Summary of the Invention

[0008] The object of the present invention is to provide a compound represented by the general formula (IA), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, [ka] Where: L 1 represents a bond, an alkenylene group, an alkynylene group, -(CH 2 ) n1 -, -(CH 2 ) n1 (CR aa R bb ) n2 -, -(CR aa R bb ) n1 O(CH 2) n2 -, -(CH 2 ) n1 O(CR aa R bb ) n2 -, -(CR aa R bb ) n1 S(CH 2 ) n2 -, -(CH 2 ) n1 S(CR aa R bb ) n2 -, -(CR aa R bb ) n1 (CH 2 ) n2 NR cc -, -(CH 2 ) n1 NR aa (CR bb R cc ) n2 -, -(CH 2 ) n1 C(O)(CR aa R bb ) n2 -, -(CH 2 ) n1 NR aa C(O)(CR aa R bb ) n2 -, -(CH 2 ) n1 P(O)R aa -, -(CH 2 ) n1 S(O) m1 -, -(CH 2 ) n1 S(O) m1 NR aa -, -(CH 2 ) n1 NR aa S(O) m1 -or-(CH 2 ) n1 C(O)NR aa - selected from R aa , R bb and R ccare each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, deuterated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or R aa , R bb and R cc any two of may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group may be optionally further substituted; L 2 represents a bond, an alkenylene group, an alkynylene group, -(CH 2 ) n3 -, -(CH 2 ) n3 (CR a1 R b1 ) n4 -, -(CR a1 R b1 ) n3 O(CH 2 ) n4 -, -(CH 2 ) n3 O(CR a1 R b1 ) n4 -, -(CR a1 R b1 ) n3 S(CH 2 ) n4 -, -(CH 2 ) n3 S(CR a1 R b1 ) n4 -, -(CR a1R b1 ) n3 (CH 2 ) n4 NR c1 -, -(CH 2 ) n3 NR a1 (CR b1 R c1 ) n4 -, -(CH 2 ) n3 C(O)(CR a1 R b1 ) n4 -, -(CH 2 ) n3 NR a1 C(O)(CR a1 R b1 ) n4 -, -(CH 2 ) n3 P(O)R a1 -, -(CH 2 ) n3 S(O) m2 -, -(CH 2 ) n3 S(O) m2 NR a1 -, -(CH 2 ) n3 NR a1 S(O) m2 -or-(CH 2 ) n3 C(O)NR a1 - selected from R a1 , R b1 and R c1are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or R a1 does not exist, Or R a1 , R b1 and R c1 any two of may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group may be optionally further substituted; L 3 represents a bond, an alkenylene group, an alkynylene group, -(CH 2 ) n5 -, -(CH 2 ) n5 (CR a2 R b2 ) n6 -, -(CR a2 R b2 ) n5 O(CH 2 ) n6 -, -(CH 2 ) n5 O(CR a2 R b2 ) n6 -, -(CR a2 R b2 ) n5 S(CH 2 ) n6 -, -(CH 2 ) n5 S(CR a2 R b2 )n6 -, -(CR a2 R b2 ) n5 (CH 2 ) n6 NR c2 -, -(CH 2 ) n5 NR a2 (CR b2 R c2 ) n6 -, -(CH 2 ) n5 C(O)(CR a2 R b2 ) n6 -, -(CH 2 ) n5 NR a2 C(O)(CR a2 R b2 ) n6 -, -(CH 2 ) n5 P(O)R a2 -, -(CH) n (CH 2 ) n5 S(O) m3 -, -(CH 2 ) n5 S(O) m3 NR a2 -, -(CH 2 ) n5 NR a2 S(O) m3 -or-(CH 2 ) n5 C(O)NR a2 - selected from R a2 , R b2 and R c2are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or R a2 does not exist, Or R a2 , R b2 and R c2 any two of may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group may be optionally further substituted; Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted; Or, ring A is absent, Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted; Or, ring B is absent, Ring C is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted; Or, ring C is absent, Ring D is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted; or ring D is absent, R 1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, deuterated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or any two R 1 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 1 and L 1 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R 2are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or any two R 2 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 2 and L 1 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 2 and L 2 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 2 and R 3 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R 3are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or any two R 3 can be linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups can be optionally further substituted; Or R 3 and L 2 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 3 and L 3 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, which may optionally be further substituted; [ka] represents a single bond or a double bond, x is an integer from 0 to 12; y is an integer from 0 to 12; z is an integer from 0 to 12, m1 to m3 are integers from 0 to 2, and n1 to n6 are integers from 0 to 3.

[0009] In some further preferred embodiments of the present invention, the compound is further as shown in general formula (I') or (I"): [ka] R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , x, y, z, and ring B are defined as above; W is for CR m or N, W 3 CR m1 R m2 or NR m3 is selected from Ring C is selected from an aryl group or a heteroaryl group, preferably a phenyl group or a pyridyl group; L 4 is a bond, -(CH 2 ) n7 -, -(CH 2 ) n7 (CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 O(CH 2 ) n8 -, -(CH 2 ) n7 O(CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 S(CH 2 ) n8 -, -(CH 2 ) n7 S(CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 (CH 2 ) n8 NR c3 -, -(CH 2 ) n7 NR a3 (CR b3 R c3 ) n8 -, -(CH 2 ) n7 C(O)(CR a3 R b3 ) n8 -, -(CH 2 ) n7 NR a3 C(O)(CR a3 R b3 ) n8 -, -(CH 2 ) n7 P(O)R a3 -, -(CH 2 ) n7 S(O) m4 -, -(CH 2 ) n7 S(O)m4 NR a3 -, -(CH 2 ) n7 NR a3 S(O) m4 -or-(CH 2 ) n7 C(O)NR a3 - selected from R a3 , R b3 and R c3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, optionally further substituted; Or R a3 , R b3 and R c3 any two of may be joined to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be further substituted; R 4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, optionally further substituted; R 5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, optionally further substituted; R m , R m1 , R m2 and R m3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, optionally further substituted; M 1 are O, S, N, C, (CH) n9 , (CH 2 ) n9 O, (CH 2 ) n9 S, (CH 2 ) n9 NH or (CH 2 ) n9 and M 2 are O, S, N, C, (CH) n10 , (CH 2 ) n10 O, (CH 2 ) n10 S, (CH 2 ) n10 NH or (CH 2 ) n10 and p is an integer from 0 to 4; n7 to n10 are integers from 0 to 3, m4 is an integer from 0 to 2.

[0010] In some further preferred embodiments of the present invention, the compound is further represented by general formula (I'): [ka] [ka] is a single bond or a double bond, Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which may optionally be further substituted; or Ring B is absent; Ring C is selected from an aryl group or a heteroaryl group, preferably a phenyl group or a pyridyl group; L 1 represents a bond, an alkenylene group, an alkynylene group, -(CH 2 ) n1 -, -(CH 2 ) n1 (CR aa R bb ) n2 -, -(CR aa R bb ) n1 O(CH 2 ) n2 -, -(CH 2 ) n1 O(CR aa R bb ) n2 -, -(CR aa R bb ) n1 S(CH 2 ) n2 -, -(CH 2 ) n1 S(CR aa R bb ) n2 -, -(CR aa R bb ) n1 (CH 2 ) n2 NR cc -, -(CH 2 ) n1 NR aa (CR bb R cc ) n2 -, -(CH 2 ) n1 C(O)(CR aa R bb ) n2 -, -(CH 2 ) n1 NR aa C(O)(CR aa R bb ) n2-, -(CH 2 ) n1 P(O)R aa -, -(CH 2 ) n1 S(O) m1 -, -(CH 2 ) n1 S(O) m1 NR aa -, -(CH 2 ) n1 NR aa S(O) m1 -or-(CH 2 ) n1 C(O)NR aa - selected from R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, deuterated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or R aa , R bb and R cc any two of may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group may be optionally further substituted; L 2 represents a bond, an alkenylene group, an alkynylene group, -(CH 2 ) n3 -, -(CH 2 ) n3 (CR a1 Rb1 ) n4 -、-(CR a1 R b1 ) n3 AND 2 ) n4 -、-(CH 2 ) n3 O(CR a1 R b1 ) n4 -、-(CR a1 R b1 ) n3 S(CH 2 ) n4 -、-(CH 2 ) n3 S(CR a1 R b1 ) n4 -、-(CR a1 R b1 ) n3 (CH 2 ) n4 NR c1 -、-(CH 2 ) n3 NR a1 (CR b1 R c1 ) n4 -、-(CH 2 ) n3 C(O)(CR) a1 R b1 ) n4 -、-(CH 2 ) n3 NR a1 C(O)(CR) a1 R b1 ) n4 -、-(CH 2 ) n3 PORE a1 -、-(CH 2 ) n3 S(O) m2 -、-(CH 2 ) n3 S(O) m2 NR a1 -、-(CH 2 ) n3 NR a1 S(O) m2 -なり-(CH 2 ) n3 C(O)NR a1 - from selected R a1 , R b1 and R c1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or R a1 does not exist, Or R a1 , R b1 and R c1 any two of may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group may be optionally further substituted; L 3 represents a bond, an alkenylene group, an alkynylene group, -(CH 2 ) n5 -, -(CH 2 ) n5 (CR a2 R b2 ) n6 -, -(CR a2 R b2 ) n5 O(CH 2 ) n6 -, -(CH 2 ) n5 O(CR a2 R b2 ) n6 -, -(CR a2 R b2 ) n5 S(CH 2 ) n6 -, -(CH 2 )n5 S(CR a2 R b2 ) n6 -, -(CR a2 R b2 ) n5 (CH 2 ) n6 NR c2 -, -(CH 2 ) n5 NR a2 (CR b2 R c2 ) n6 -, -(CH 2 ) n5 C(O)(CR a2 R b2 ) n6 -, -(CH 2 ) n5 NR a2 C(O)(CR a2 R b2 ) n6 -, -(CH 2 ) n5 P(O)R a2 -, -(CH) n (CH 2 ) n5 S(O) m3 -, -(CH 2 ) n5 S(O) m3 NR a2 -, -(CH 2 ) n5 NR a2 S(O) m3 -or-(CH 2 ) n5 C(O)NR a2 - selected from R a2 , R b2 and R c2are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or R a2 does not exist, W is for CR m or N, R m is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, optionally further substituted; L 4 is a bond, -(CH 2 ) n7 -, -(CH 2 ) n7 (CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 O(CH 2 ) n8 -, -(CH 2 ) n7 O(CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 S(CH 2 ) n8 -, -(CH2 ) n7 S(CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 (CH 2 ) n8 NR c3 -, -(CH 2 ) n7 NR a3 (CR b3 R c3 ) n8 -, -(CH 2 ) n7 C(O)(CR a3 R b3 ) n8 -, -(CH 2 ) n7 NR a3 C(O)(CR a3 R b3 ) n8 -, -(CH 2 ) n7 P(O)R a3 -, -(CH 2 ) n7 S(O) m4 -, -(CH 2 ) n7 S(O) m4 NR a3 -, -(CH 2 ) n7 NR a3 S(O) m4 -or-(CH 2 ) n7 C(O)NR a3 - selected from R a3 , R b3 and R c3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, optionally further substituted; Or R a3 , R b3 and R c3 any two of may be joined to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be further substituted; R 1 each independently represents hydrogen, deuterium, halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a heterocycloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) n1 C(O)NR aa R bb wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or any two R 1 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 1 and L 1 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R 2are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or any two R 2 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 2 and L 1 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 2 and L 2 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 2 and R 3 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R 3are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, mercapto, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted; Or any two R 3 can be linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups can be optionally further substituted; Or R 3 and L 2 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R 3 and L 3 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R 4 are each independently selected from hydrogen, deuterium, halogen, oxo, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, optionally further substituted; R 5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, optionally further substituted; M 1 are O, S, N, C, (CH) n9 , (CH 2 ) n9 O, (CH 2 ) n9 S, (CH 2 ) n9 NH or (CH 2 ) n9 and M 2 are O, S, N, C, (CH) n10 , (CH 2 ) n10 O, (CH 2 ) n10 S, (CH 2 ) n10 NH or (CH 2 ) n10 and x is an integer from 0 to 12; y is an integer from 0 to 12; z is an integer from 0 to 12, p is an integer from 0 to 4; n1 to n6 are integers from 0 to 3, and n7 to n10 are integers from 0 to 3, m1 to m3 are integers from 0 to 2, m4 is an integer from 0 to 2.

[0011] In some further preferred embodiments of the present invention, the compound is further as shown in general formula (I): [ka] R 1 , R 2 , R3 , L 1 , L 2 , L 3 , x, y, z, and ring B are defined as above; L 4 is a bond, -(CH 2 ) n7 -, -(CH 2 ) n7 (CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 O(CH 2 ) n8 -, -(CH 2 ) n7 O(CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 S(CH 2 ) n8 -, -(CH 2 ) n7 S(CR a3 R b3 ) n8 -, -(CR a3 R b3 ) n7 (CH 2 ) n8 NR c3 -, -(CH 2 ) n7 NR a3 (CR b3 R c3 ) n8 -, -(CH 2 ) n7 C(O)(CR a3 R b3 ) n8 -, -(CH 2 ) n7 NR a3 C(O)(CR a3 R b3 ) n8 -, -(CH 2 ) n7 P(O)R a3 -, -(CH 2 ) n7 S(O) m4-, -(CH 2 ) n7 S(O) m4 NR a3 -, -(CH 2 ) n7 NR a3 S(O) m4 -or-(CH 2 ) n7 C(O)NR a3 - selected from R a3 , R b3 and R c3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, optionally further substituted; Or R a3 , R b3 and R c3 any two of may be joined to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be further substituted; R 4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, optionally further substituted; R 5is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, optionally further substituted; M 1 are O, S, N, C, (CH) n9 , (CH 2 ) n9 O, (CH 2 ) n9 S, (CH 2 ) n9 NH or (CH 2 ) n9 and M 2 are O, S, N, C, (CH) n10 , (CH 2 ) n10 O, (CH 2 ) n10 S, (CH 2 ) n10 NH or (CH 2 ) n10 and p is an integer from 0 to 4; n7 to n10 are integers from 0 to 3, m4 is an integer from 0 to 2.

[0012] In some further preferred embodiments of the present invention, in the compounds of the above general formulas (IA), (I′), (I″) and (I), Ring B is C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, C 3-8 Cycloalkyl groups, 4-12 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, More preferably, C 5-8Cycloalkyl groups, 5-10 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-8 It is preferably an aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 N, O or S atoms, more preferably a 5- to 10-membered nitrogen-containing heterocyclyl group, and most preferably a piperidinyl group or a piperazinyl group.

[0013] In a further preferred embodiment of the present invention, in the compounds of the above general formulae (IA), (I′), (I″) and (I), Ring B is C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, C 3-8 Cycloalkyl groups, 4-12 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, More preferably, C 5-8 Cycloalkyl groups, 5-10 membered heterocyclyl groups containing 1-3 N, O or S atoms, C 6-8 It is preferably an aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 N, O or S atoms, more preferably a 5- to 10-membered nitrogen-containing heterocyclyl group, and most preferably a piperidinyl group.

[0014] In some further preferred embodiments of the present invention, the compound is further represented by general formula (II') or (IV): [ka] W is for CR m or N, W 1 is selected from CH or N; W 2 CR m5 or N, W 3 CR m1 R m2 or NR m3 is selected from R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, cyano groups, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 A halogenated alkoxy group, more preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, -OCD 3 or a methoxy group, R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group or C 1-6 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, cyano groups, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group or C 1-3 a halogenated alkoxy group, more preferably a hydrogen, deuterium, fluorine, chlorine or methyl group; R 3 are each independently selected from hydrogen, deuterium, fluorine, a methyl group, a deuterated methyl group, or a halogenated methyl group, and are preferably hydrogen or a methyl group; R m5 is hydrogen, deuterium, fluorine, chlorine, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, cyano groups, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 is a halogenated alkoxy group, more preferably hydrogen or deuterium; R 4 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl group or C 1-6 is selected from halogenated alkyl groups, preferably carboxyl groups; R 5 is C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or a 5-10 membered heteroaryl group, optionally selected from halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 Further substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3-8 membered heterocyclyl groups, preferably C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclyl group, optionally including halogen, C1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 3-8 It is further substituted with one or more substituents selected from a cycloalkyl group and a 3- to 8-membered heterocyclyl group, more preferably [ka] and L 1 , L 2 each independently represents a bond or -(CH 2 ) n1 -, preferably a bond; L 3 is a bond or -(CH 2 ) n1 -, preferably -CH 2 - and L 4 is a bond or -(CH 2 ) n7 -, preferably a bond or -CH 2 - and M 1 is N, C or (CH) n9 and M 2 is N, C or (CH) n10 and n9 and n10 each independently represent an integer of 0 to 2; The definitions of x, y, and z are as described above.

[0015] In some further preferred embodiments of the present invention, the compound is further represented by general formula (II') or (IV): [ka] W 1 is selected from CH or N; W 2 CR m5 or N, R 1are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups; R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group or C 1-6 halogenated alkoxy groups; R 3 are each independently selected from hydrogen, deuterium, fluorine, a methyl group, a deuterated methyl group, or a halogenated methyl group; R m5 is hydrogen, deuterium, fluorine, chlorine, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, cyano groups, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 is a halogenated alkoxy group, more preferably hydrogen or deuterium; R 4 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, an oxo group, or C 1-6 Carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6or a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S, 1-6 A carboxyl group or a 5- to 6-membered heteroaryl group containing 1 to 4 atoms selected from N, O, or S is preferably an oxo, halogen, a cyano group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 and is further substituted with one or more substituents selected from halogenated alkoxy groups, preferably carboxyl groups or -C(O)OCH 3 and R 5 is C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or a 5-10 membered heteroaryl group, optionally selected from halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Cyanoalkyl group, C 3-8 Further substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3-8 membered heterocyclyl groups, preferably C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclyl group, optionally including halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6Halogenated alkyl groups, C 1-6 Cyanoalkyl group, C 3-8 further substituted with one or more substituents selected from the group consisting of a cycloalkyl group and a 3- to 8-membered heterocyclyl group; L 1 , L 2 each independently represents a bond or -(CH 2 ) n1 -, preferably a bond; L 3 is a bond or -(CH 2 ) n1 -, preferably -CH 2 - and L 4 is a bond or -(CH 2 ) n7 -, preferably a bond or -CH 2 - and M 1 is N, NH, O, S, C or (CH) n9 and M 2 is N, NH, O, S, C or (CH) n10 and n9 and n10 each independently represent an integer of 0 to 2; The definitions of x, y, and z are as described above.

[0016] In some further preferred embodiments of the present invention, the compound is further represented by the general formula (II'): [ka] W 1 is selected from CH or N; W 2 CR m5 or N, R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy group, -C(O)R aa or -C(O)NR aa R bb is selected from R aa and R bb are independently hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group or C 1-6 halogenated alkoxy groups; R 3 are each independently selected from hydrogen, deuterium, fluorine, a methyl group, a deuterated methyl group, or a halogenated methyl group; R m5 is hydrogen, deuterium, fluorine, chlorine, cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, cyano groups, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3is a halogenated alkoxy group, more preferably hydrogen or deuterium; R 4 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, an oxo group, or C 1-6 Carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 A halogenated alkyl group or a substituted or unsubstituted 5- to 6-membered heteroaryl group, and optionally 1-6 The carboxyl group is free of halogens and C 1-6 It is further substituted with one or more substituents selected from alkyl groups, preferably carboxyl groups or -C(O)OCH 3 and R 5 is C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or a 5-10 membered heteroaryl group, optionally selected from halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Cyanoalkyl group, C 3-8 Further substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3-8 membered heterocyclyl groups, preferably C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclyl group, optionally including halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C1-6 Halogenated alkyl groups, C 1-6 Cyanoalkyl group, C 3-8 further substituted with one or more substituents selected from the group consisting of a cycloalkyl group and a 3- to 8-membered heterocyclyl group; L 1 , L 2 each independently represents a bond or -(CH 2 ) n1 -, preferably a bond; L 3 is a bond or -(CH 2 ) n1 -, preferably -CH 2 - and L 4 is a bond or -(CH 2 ) n7 -, preferably a bond or -CH 2 - and M 1 is N, NH, O, S, C or (CH) n9 and M 2 is N, NH, O, S, C or (CH) n10 and n9 and n10 each independently represent an integer of 0 to 2.

[0017] In some further preferred embodiments of the present invention, R aa and R bb are independently hydrogen, deuterium, and C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclyl groups, C 6-10 It is selected from an aryl group or a 5- to 6-membered heteroaryl group.

[0018] In some further preferred embodiments of the present invention, the compound further comprises the following general formula: [ka] As shown in the figure.

[0019] In some further preferred embodiments of the present invention, the compound is further as shown in general formula (II): [ka] R 1 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or any two R 1 is combined with C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10An aryl group or a 5- to 10-membered heteroaryl group is formed, 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or R 2 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or any two R 2 is combined with C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group is formed, and optionally, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or R 3 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or R 4 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or any two R 4 is combined with C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group is formed, 3-8Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or R 5 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or M 1 is O, S, N, C, CH or (CH) 2 and Or M 2 is O, S, N, C, CH or (CH) 2 and or x is 0, 1, 2, 3, 4 or 5; Or, y is 0, 1, 2, 3 or 4; Or, z is 0, 1, 2, 3 or 4; Or, p is 0, 1, 2 or 3.

[0020] In some further preferred embodiments of the present invention, the compound is further as shown in general formula (II): [ka] R 1 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or any two R 1 is combined with C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group is formed, 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; R 2 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or any two R 2 is combined with C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group is formed, and optionally, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; R 3 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; R 4 are each independently hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; Or any two R 4 is combined with C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group is formed, 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, a C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; R 5 is hydrogen, deuterium, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, oxo group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or 5-10 membered heteroaryl group, and optionally halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Cyanoalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 further substituted with one or more substituents selected from the group consisting of aryl and 5-10 membered heteroaryl groups; M 1 is O, S, N, NH, C, CH or (CH) 2 and M 2 is O, S, N, NH, C, CH or (CH) 2 and x is 0, 1, 2, 3, 4 or 5; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3.

[0021] In some further preferred embodiments of the present invention, in each of the above general formulas, R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, cyano groups, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3A halogenated alkoxy group, more preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, -OCD 3 Or a methoxy group.

[0022] In some further preferred embodiments of the present invention, in each of the above general formulas, R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, cyano groups, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 It is a halogenated alkoxy group, more preferably a hydrogen, deuterium, fluorine, chlorine or methyl group.

[0023] In some further preferred embodiments of the present invention, in each of the above general formulas, R 3 are each independently selected from hydrogen, deuterium, fluorine, a methyl group, a deuterated methyl group, or a halogenated methyl group, and are preferably hydrogen or a methyl group.

[0024] In some further preferred embodiments of the present invention, in each of the above general formulas, R 4 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl group or C 1-6 It is selected from halogenated alkyl groups, preferably carboxyl groups.

[0025] In some further preferred embodiments of the present invention, in each of the above general formulas, R 4are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, an oxo group, or C 1-6 Carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 or a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S, 1-6 A carboxyl group or a 5- to 6-membered heteroaryl group containing 1 to 4 atoms selected from N, O, or S is preferably an oxo, halogen, a cyano group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 and is further substituted with one or more substituents selected from halogenated alkoxy groups, preferably carboxyl groups or -C(O)OCH 3 It is.

[0026] In some further preferred embodiments of the present invention, in each of the above general formulas, R 5 is C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or a 5-10 membered heteroaryl group, optionally selected from halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Cyanoalkyl group, C 3-8 Further substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3-8 membered heterocyclyl groups, preferably C1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 3-6 a cycloalkyl group, a 3- to 6-membered heterocyclyl group, optionally including halogen, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Cyanoalkyl group, C 3-6 Further substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3- to 6-membered heterocyclyl groups, more preferably C 3-6 A cycloalkyl group or a 3-6 membered heterocyclyl group containing 1-2 atoms selected from N, O or S, optionally including halogen, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Cyanoalkyl group or C 1-3 Further substituted with one or more substituents of halogenated alkyl groups, even more preferably [ka] It is.

[0027] In some further preferred embodiments of the present invention, in each of the above general formulas, R 5 is C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 aryl group or a 5-10 membered heteroaryl group, optionally selected from halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6Halogenated alkoxy groups, C 3-8 Further substituted with one or more substituents selected from the group consisting of cycloalkyl groups and 3-8 membered heterocyclyl groups, preferably C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 3-6 a cycloalkyl group, a 3- to 6-membered heterocyclyl group, optionally including halogen, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 3-6 It is further substituted with one or more substituents selected from the group consisting of a cycloalkyl group and a 3- to 6-membered heterocyclyl group, and more preferably [ka] It is.

[0028] In some further preferred embodiments of the present invention, in each of the above general formulas, M 1 is N, C or (CH) n9 It is.

[0029] In some further preferred embodiments of the present invention, in each of the above general formulas, M 2 is N, C or (CH) n10 It is.

[0030] In some further preferred embodiments of the present invention, in each of the above general formulae, n9 and n10 are each independently an integer of 0 to 2.

[0031] In some further preferred embodiments of the present invention, in each of the above general formulas, L 1 , L 2 each independently represents a bond or -(CH 2 ) n1 -, preferably a bond.

[0032] L 3 is a bond or -(CH 2 ) n1-, preferably -CH 2 -It is.

[0033] L 4 is a bond or -(CH 2 ) n7 -, preferably a bond or -CH 2 -It is.

[0034] In a further preferred embodiment of the present invention, in each of the above general formulas, R 1 each independently represents hydrogen, deuterium, fluorine, chlorine, a cyano group, a methoxy group, or -OCD 3 is selected from.

[0035] R 2 are each independently selected from hydrogen, deuterium, fluorine, or a methyl group.

[0036] R 3 are each independently selected from hydrogen or a methyl group.

[0037] R 4 are each independently selected from hydrogen or a carboxyl group.

[0038] R 5 teeth, [ka] is selected from.

[0039] R 5 teeth, [ka] is selected from.

[0040] L 1 , L 2 are each independently a bond; L 3 is -CH 2 - and L 4 is a bond.

[0041] In a further preferred embodiment of the present invention, R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, a cyano group, or a methoxy group.

[0042] R 2 are each independently selected from hydrogen, deuterium, fluorine, or a methyl group.

[0043] R 3 are each independently selected from hydrogen.

[0044] R 4 are each independently selected from hydrogen or a carboxyl group.

[0045] R 5 teeth, [ka] is selected from.

[0046] R 5 teeth, [ka] is selected from.

[0047] L 1 , L 2 are each independently a bond; L 3 is -CH 2 - and L 4 is a bond.

[0048] In a further preferred embodiment of the present invention, the compound is further represented by general formula (III) to (III-3): [ka] R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups; R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 halogenated alkoxy groups; R 3 are each independently selected from hydrogen, deuterium, fluorine, a methyl group, a deuterated methyl group, or a halogenated methyl group; R 4 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl group or C 1-6 selected from halogenated alkyl groups, R 5 is C 3-8 cycloalkyl group or a 3- to 8-membered heterocyclyl group, optionally selected from halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl group or C 1-6 further substituted with one or more substituents of halogenated alkyl groups; M 1 is O, S, N, C, CH or (CH) 2 and M 2 is O, S, N, C, CH or (CH) 2 and n7 is 0, 1, 2 or 3; x is 0, 1, 2, 3, 4 or 5; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3.

[0049] In a further preferred embodiment of the present invention, the compound is further represented by general formula (III) to (III-7), wherein: R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 halogenated alkoxy groups; R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 halogenated alkoxy groups; R 3 are each independently selected from hydrogen, deuterium, or fluorine; R 4 are each independently selected from a 5- to 6-membered heteroaryl group containing 1 to 4 atoms selected from N, O, or S, and are selected from oxo, halogen, cyano, C 1-3 Alkyl group and C 1-3 is further substituted with one or more substituents selected from halogenated alkyl groups, -(CH 2 ) n COOH or -(CH 2 ) n C(O)OCH 3 and R 5 is C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group containing 1-2 atoms selected from N, O or S, and optionally halogen, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Cyanoalkyl group or C 1-3further substituted with one or more substituents of halogenated alkyl groups; M 1 and M 2 are each independently N, CH or (CH) 2 is selected from n is 0, 1, 2 or 3.

[0050] In some further preferred embodiments of the present invention, the compound is further as shown in general formula (III): [ka] R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group or C 1-6 halogenated alkoxy groups; R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 halogenated alkoxy groups; R 3 are each independently selected from hydrogen, deuterium, and fluorine; R 4 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl group or C 1-6 selected from halogenated alkyl groups, R 5 is C 3-8 cycloalkyl group or a 3- to 8-membered heterocyclyl group, optionally selected from halogen, C 1-6 Alkyl group, C 1-6Deuterated alkyl group or C 1-6 further substituted with one or more substituents of halogenated alkyl groups; M 1 is O, S, N, C, CH or (CH) 2 and M 2 is O, S, N, C or CH, n7 is 0, 1, 2 or 3; x is 0, 1, 2, 3, 4 or 5; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3.

[0051] In some further preferred embodiments of the present invention, the compounds represented by the general formulas (III) to (III-7), their stereoisomers, or pharma- ceutically acceptable salts thereof are represented by the following formulas: In some embodiments, R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 A halogenated alkoxy group is preferably selected from hydrogen, deuterium, fluorine, chlorine, a cyano group, a methoxy group, or -OCD. 3 and In some embodiments, R 2 are each independently preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group or C 1-3 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine or methyl groups; In some embodiments, R 3are each independently selected from hydrogen, deuterium, fluorine or a methyl group, preferably hydrogen or a methyl group; In some embodiments, R 4 are each independently a carboxyl group; In some embodiments, R 5 are each independently [ka] is selected from In some embodiments, x is 0, in some embodiments, x is 1, in some embodiments, x is 2, in some embodiments, x is 3, in some embodiments, x is 4, and in some embodiments, x is 5. In some embodiments, y is 0, in some embodiments, y is 1, in some embodiments, y is 2, and in some embodiments, y is 3; In some embodiments, z is 0, in some embodiments, z is 1, in some embodiments, z is 2, and in some embodiments, z is 3; In some embodiments, n7 is 0; in some embodiments, n7 is 1; in some embodiments, n7 is 2; In some embodiments, p is 0; in some embodiments, p is 1; in some embodiments, p is 2; and in some embodiments, p is 3.

[0052] In a further preferred embodiment of the present invention, the compound represented by the general formula (III), its stereoisomer or its pharma- ceutically acceptable salt is represented by the following formula (III): R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 halogenated alkoxy groups; R 2 are each independently preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group or C 1-3 halogenated alkoxy groups; R 3 are each independently selected from hydrogen, deuterium, or fluorine; R 4 is a carboxyl group.

[0053] In a further preferred embodiment of the present invention, the compound is further as shown in general formula (III'): [ka] R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, methoxy group or -OCD 3 and R 2 are each independently preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine or methyl groups; R 3 are each independently selected from hydrogen, deuterium or fluorine, preferably hydrogen; M 1 is N or CH, preferably N; W 2 is N or CH, preferably CH; x, y, and z are each independently 0, 1, or 2; R 5 teeth, [ka] is selected from, preferably [ka] It is.

[0054] In a further preferred embodiment of the present invention, the compound is further represented by general formula (V-1) or general formula (V-2): [ka] R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, methoxy group or -OCD 3 and R 2 are each independently preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C1-3 Deuterated alkoxy group or C 1-3 halogenated alkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine or methyl groups; R 3 are each independently selected from hydrogen, deuterium or fluorine, preferably hydrogen; M 1 is N or CH, preferably N; W 2 is N or CH, preferably CH; x, y, and z are each independently 0, 1, or 2; R 5 teeth, [ka] is selected from, preferably [ka] and more preferably, [ka] It is.

[0055] In a further preferred embodiment of the present invention, the compound further comprises a compound represented by the general formula (V-3) or the general formula (V-4): [ka] As shown in the figure.

[0056] In a further preferred embodiment of the present invention, the compound further comprises a compound represented by the general formula (V-5) or the general formula (V-6): [ka] As shown in the figure.

[0057] The present invention further relates to pharmaceutical compositions, which comprise a therapeutically effective amount of any of the compounds of the general formulas shown, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0058] The present invention further relates to the application of any of the compounds of the general formula shown, their stereoisomers or pharma- ceutically acceptable salts thereof, or said pharmaceutical compositions in the manufacture of GLP-1 receptor agonist medicaments.

[0059] The present invention further relates to the application of the compound as shown in the general formula, its stereoisomer or its pharma- ceutically acceptable salt, or its pharmaceutical composition in the manufacture of a medicament for treating a metabolic-related disease, wherein said metabolic-related disease is selected from diabetes, obesity or non-alcoholic steatohepatitis-related disease or other related disease caused by diabetes, obesity or non-alcoholic steatohepatitis.

[0060] The present invention further relates to a process for the preparation of a medicament for treating metabolic and related disorders using a compound of the general formula, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0061] The present invention further relates to a method for preventing and / or treating a metabolic-related disease, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula, its stereoisomer, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0062] The present invention further provides methods of treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including, but not limited to, conditions associated with GLP-1 receptor modulators.

[0063] The present invention further relates to a method for treating a disease associated with a metabolic disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0064] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0065] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl. , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms, and non-limiting examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, and a 2,3-dimethylbutyl group. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available binding site, and said substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, and in the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, halogenated alkyl, deuterated alkyl, alkyl substituted with alkoxy and alkyl substituted with hydroxy.

[0066] The term "alkylene group" refers to an alkyl group in which one hydrogen atom is further substituted; for example, a "methylene group" is -CH 2 -, and "ethylene group" is -(CH 2 ) 2 -, and "propylene group" refers to -(CH 2 ) 3 -, and "butylene group" is -(CH 2 ) 4 -, etc.

[0067] The term "alkenylene group" refers to an alkenyl group in which one hydrogen atom is further substituted; for example, a "vinylene group" is -CH 2 =CH 2 -, and "propenylene group" refers to -CH 2 -=CH 2 -CH 2 - and the like. The alkenylene group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups. The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the ring of the cycloalkyl group containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 8 carbon atoms, and even more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused ring, and bridged ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0068] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the ring of the cycloalkyl group containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., and polycyclic cycloalkyl groups include spiro, fused and bridged cyclic cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0069] The term "spirocycloalkyl group" refers to a 5-20 membered polycyclic group in which the monocyclic rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of shared spiro atoms between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups, bisspirocycloalkyl groups or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Including, Also included are spirocycloalkyl groups in which the monospirocycloalkyl group and the heterocycloalkyl group share a spiro atom, non-limiting examples of which are: [ka] Includes.

[0070] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that it comprises, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes.

[0071] "Bridged cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly bonded, and it may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of rings that it comprises, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, and is preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following: [ka]

[0072] The ring of the cycloalkyl group can be fused onto the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group can be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0073] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, in which one or more of the ring atoms is nitrogen, oxygen or S(O). m (wherein m is an integer of 0 to 2), but does not include the ring moiety -OO-, -OS-, or -SS-, and the other ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 10 ring atoms, even more preferably 3 to 8 ring atoms, and even more preferably 3 to 6 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen, oxygen, or sulfur. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl groups, and preferably pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrazolidinyl, morpholinyl, [ka] piperazinyl group and pyranyl group, and more preferably pyrrolidinyl group, azetidinyl group, oxetanyl group, oxanyl group, piperidinyl group, [ka] Polycyclic heterocyclyl groups include spirocyclic, fused-ring and bridged-ring heterocyclyl groups, where such spirocyclic, fused-ring and bridged-ring heterocyclyl groups are optionally linked to other groups via single bonds or further tandemly linked to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups via any two or more atoms on the ring.

[0074] The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiro atom), where one or more of the ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2), and the other ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group or a polyspiroheterocyclyl group, preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0075] The term "fused heterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more of the rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and wherein one or more of the ring atoms is nitrogen, oxygen or S(O). m (wherein m is an integer of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0076] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, which may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more ring atoms is not nitrogen, oxygen or S(O). m (wherein m is an integer of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0077] The ring of the heterocyclyl group may be fused onto the ring of an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring connected to the base skeleton is a heterocyclyl group, non-limiting examples of which are: [ka] Includes.

[0078] Heterocyclyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0079] The term "aryl group" refers to a 6-14 membered all carbon monocyclic or fused polycyclic (i.e. rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6-10 membered, more preferably 6-8 membered, such as phenyl and naphthyl groups. More preferably, phenyl group. The ring of the aryl group can be fused onto the ring of a heteroaryl group, heterocyclyl group or cycloalkyl group, where the ring connected to the base skeleton is the ring of the aryl group, non-limiting examples of which are: [ka] Includes.

[0080] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0081] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5 to 8-membered, and most preferably 5 or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyridinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl, more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The ring of the heteroaryl group may be condensed onto the ring of an aryl group, a heterocyclyl group, or a cycloalkyl group, where the ring connected to the base skeleton is the ring of the heteroaryl group, non-limiting examples of which are: [ka] Includes.

[0082] Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0083] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definition of alkyl group is as described above, and preferably is an alkyl group containing 1 to 8 carbon atoms, more preferably is an alkyl group containing 1 to 6 carbon atoms, and more preferably is an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0084] "Alkenyl group" refers to alkenyl, also called olefin group, and is preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, etc., wherein the alkenyl group may be further substituted with other related groups, such as an alkyl group, an alkenyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

[0085] "Alkynyl group" refers to (CH≡C-), preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group containing 2 to 6 carbon atoms, and most preferably an alkynyl group containing 2 to 3 carbon atoms, wherein the alkynyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0086] The term "alkynylene group" refers to an alkynyl group in which one hydrogen atom is further replaced, for example, an "ethynylene group" is [ka] "Provinylene group" refers to [ka] Alkynylene groups (containing three or more carbon atoms) may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0087] "Halogenated alkyl group" refers to an alkyl group that is substituted with one or more halogens, where the alkyl group is as defined above.

[0088] A "halogenated alkoxy group" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0089] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

[0090] "C 1-6 "Cyanoalkyl group" is -C 1-6 Refers to the alkyl group CN, e.g., -CH 2 CN, -CH 2 CH 2 CN, etc.

[0091] "C 1-6 Carboxyl group: -C 1-5 Refers to the alkyl group COOH.

[0092] "Hydroxy" refers to an -OH group.

[0093] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0094] "Amino group" is -NH 2Refers to...

[0095] A "cyano group" refers to -CN.

[0096] "Nitro group" is -NO 2 Refers to...

[0097] A "carboxyl group" refers to -C(O)OH.

[0098] "THF" refers to tetrahydrofuran.

[0099] "EtOAc" refers to ethyl acetate.

[0100] "MeOH" refers to methanol.

[0101] "DMF" refers to N,N-dimethylformamide.

[0102] "DIPEA" refers to diisopropylethylamine.

[0103] "TFA" refers to trifluoroacetic acid.

[0104] "MeCN" refers to acetonitrile.

[0105] "DMA" refers to N,N-dimethylacetamide;

[0106] "Et 2 "O" refers to ether.

[0107] "DCE" refers to 1,2 dichloroethane.

[0108] "DIPEA" refers to N,N-diisopropylethylamine.

[0109] "NBS" refers to N-bromosuccinimide.

[0110] "NIS" refers to N-iodosuccinimide.

[0111] "Cbz-Cl" refers to benzyl chloroformate;

[0112] "Pd 2 (dba) 3 " refers to tri(dibenzylideneacetone)dipalladium.

[0113] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0114] "HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0115] "KHMDS" refers to potassium hexamethyldisilazane.

[0116] "LiHMDS" refers to lithium bistrimethylsilylamide;

[0117] "MeLi" refers to methyllithium.

[0118] "n-BuLi" refers to n-butyllithium.

[0119] "NaBH(OAc) 3 " refers to sodium triacetoxyborohydride.

[0120] [ka] represents a single bond or a double bond.

[0121] The various terms "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all mean the same thing, i.e., X can be one or more of A, B, C.

[0122] Any hydrogen atom described in the present invention may be replaced with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be replaced with a deuterium atom.

[0123] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0124] "Substituted" refers to the substitution of one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group, with the corresponding number of substituents, independently of each other. Needless to say, the substituents are only present in their possible chemical positions, and the skilled person can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, amino or hydroxy groups with free hydrogen may be unstable if they are attached to carbon atoms with unsaturated (e.g., olefinic) bonds.

[0125] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein or physiologically / pharmaceutical acceptable salts or prodrugs thereof with other chemical components, as well as other components such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and facilitate absorption of the active ingredient, thereby exerting a biological activity.

[0126] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0127] Intermediate Im-1 Synthesis of ((S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester [ka] Step 1 (S)-4-Nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester In a 50 mL reaction flask, 3-fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxo)cyclopropyl)benzonitrile (2 g, 10.04 mmol), K 2 CO 3 (2.78 g, 20.08 mmol) was dissolved in tetrahydrofuran (30 mL) and (S)-oxetan-2-ylmethylamine (874 mg, 10.04 mmol) was added, and the reaction was stirred at room temperature for 12. The reaction was stopped, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL x 2), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2.0 g, yellow solid) in 74.8% yield. MS m / z(ESI): 267.0[M+1]. Step 2 (S)-4-Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (3 g, 11.27 mmol) was dissolved in methanol (30 mL) and 10% Pd / C (300 mg) was added. Hydrogen gas was replaced three times and the mixture was reacted for 3 hours with stirring. The reaction solution was filtered and the organic phase was dried and then spin-dried to obtain the title product (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2.6 g, yellow solid), with a yield of 97.7%. MS m / z(ESI): 237.1[M+1]. Step 3 (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester In a 50 mL reaction flask, (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2 g, 8.46 mmol), p-toluenesulfonic acid (86 mg, 499.41 μmol) were dissolved in tetrahydrofuran (100 mL) and 2-chloro-1,1,1-trimethoxyethane (1.3 g, 8.41 mmol) was added and the reaction was stirred at 60° C. for 1 h. The reaction was quenched, cooled to room temperature, concentrated under reduced pressure and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Im-1) (1.3 g, yellow solid) in 52.0% yield. MS m / z(ESI): 295.0[M+1].

[0128] Intermediate Im-2 Synthesis of ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester) [ka] Step 1 (S)-5-Nitro-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester Starting from 6-chloro-5-nitro-2-pyridinecarboxylic acid methyl ester, the title product (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester was obtained by referring to step 1 of intermediate Im-1. MS m / z(ESI): 268.1[M+1]. Step 2 (S)-5-Amino-6-((oxetan-2-ylmethyl)amino)2-pyridinecarboxylic acid methyl ester. Starting from (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester, the title product (S)-5-amino-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester was obtained by referring to step 2 of intermediate Im-1. MS m / z(ESI): 238.1[M+1]. Step 3 ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester At room temperature, (S)-5-amino-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester (340 mg, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL) and a solution of chloroacetic anhydride (257.27 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise, stirred at room temperature for 30 minutes, and heated to 60° C., reacted for 2 hours, cooled to room temperature, and LCMS showed the completion of the reaction. The reaction was diluted with ethyl acetate (30 mL) and washed with saturated sodium bicarbonate solution (15 mL×3), saturated sodium chloride solution (15 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and spun dry to give the title product ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester (Im-2) (yellow oil, 0.4 g), 94.4% yield, the crude was used directly in the next step. MS m / z(ESI): 296.1[M+1].

[0129] Intermediate Im-3 (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester [ka] Using 5-fluoro-6-nitronicotinic acid methyl ester as raw material, the product (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester was obtained by referring to the synthesis of intermediate Im-2. MS m / z(ESI): 296.1[M+1].

[0130] Intermediate Im-4 Synthesis of 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester [ka] Step 1 1-(Fluoromethyl)cyclopropane-1-carboxylic acid ethyl ester 1-(Hydroxymethyl)cyclopropyl carboxylic acid ethyl ester (7 g, 48.55 mmol) was dissolved in DCM (100 mL) and DAST (8.61 g, 53.41 mmol) was added thereto at -78 ° C. The reaction system was allowed to warm to room temperature naturally and stirred for 16 hours. After the reaction was completed, 50 mL of water was added thereto, extracted with dichloromethane (50 mL x 2), washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and then concentrated to obtain the title product 1-(fluoromethyl)cyclopropane-1-carboxylic acid ethyl ester (6.5 g, yellow oil), with a yield of 91.6%. 1 H NMR (400 MHz, CDCl 3 ):δ4.52(dd,1.5Hz,2H),4.17(q,2H),1.41-1.33(m,2H),1.26(t,3H),1.05-0.95(m,2H). Step 2 1-(Fluoromethyl)cyclopropylmethanol 1-(Fluoromethyl)cyclopropane-1-carboxylic acid ethyl ester (6.5 g, 44.47 mmol) was dissolved in THF (60 mL), and LiAlH4 (2.53 g, 66.71 mmol) was added thereto under ice-water bath. The reaction system was allowed to warm to room temperature naturally and stirred for 16 hours. After the reaction was completed, 15 g of sodium sulfate decahydrate was added thereto to quench the reaction, and the mixture was filtered and concentrated to obtain the title product 1-(fluoromethyl)cyclopropylmethanol (3.5 g, yellow oil), with a yield of 75.6%. 1 H NMR (400 MHz, CDCl 3 ):δ4.36(d,2H),3.58(s,2H),0.60(m,4H). Step 3 (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate 1-(Fluoromethyl)cyclopropylmethanol (1.3 g, 12.49 mmol) was dissolved in DCM (30 mL), and methylsulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) and triethylamine (2.53 g, 24.97 mmol, 3.48 mL) were added dropwise thereto under ice-water bath. The reaction system was stirred at 20 °C. After the reaction was completed, saturated NaHCO 3 (10 mL) was added dropwise to quench the reaction, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to give crude (1-(fluoromethyl)cyclopropyl)methyl methanesulfonate (2.0 g, light yellow oil), with a yield of 87.0%. 1 H NMR (400 MHz, CDCl 3 )δ4.32(d,2H),4.19(s,2H),3.05(s,3H),0.81-0.72(m,4H). Step 4 (1-(Fluoromethyl)cyclopropyl)methylamine (1-(fluoromethyl)cyclopropyl)methyl methanesulfonate (1.0 g, 5.49 mmol) was dissolved in NH3 / i-PrOH (10 mL) and the reaction was heated in a microwave at 60° C. for 6 h. After the reaction was complete, it was concentrated to give the title product (1-(fluoromethyl)cyclopropyl)methylamine (600 mg, yellow oil). The crude was used directly in the next step reaction. Step 5 Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate Ethyl 3-fluoro-4-nitrobenzoate (1.24 g, 5.82 mmol) was dissolved in DMF (30 mL), and (1-(fluoromethyl)cyclopropyl)methylamine (600 mg, 5.82 mmol) and K 2 CO 3(1.61 g, 11.64 mmol) was added. The reaction was stirred at 20° C. for 4 hours. After the reaction was completed, it was diluted by adding water (10 mL) therein, extracted with ethyl acetate (20 mL×2), washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The obtained residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, pale yellow solid) in 69.6% yield. MS m / z(ESI): 297.1[M+1]. 1 H NMR (400 MHz, CDCl 3 ):δ8.22(d,1H),7.56(s,1H),7.25(d,1H),4.41(q,2H),4.30(d,2H),3.42(d,2H),1.41(t,3H),0.76(m,4H). Step 6 Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, 4.05 mmol) was dissolved in MeOH (30 mL), and Pd / C (200 mg, 10% purity) was added thereto. Hydrogen gas was removed from the reaction system three times, and the mixture was stirred at 20°C for 2 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the title product ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, yellow solid), with a yield of 92.7%. MS m / z(ESI): 267.1[M+1]. Step 7 2-(Chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, 3.76 mmol) was dissolved in MeCN (30 mL) and p-toluenesulfonic acid (193.99 mg, 1.13 mmol) and 2-chloro-1,1,1-trimethoxyethane (1.16 g, 7.51 mmol) were added thereto. The reaction system was stirred in an oil bath at 60° C. for 4 hours. After completion of the reaction, it was concentrated to obtain the crude product. The obtained residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (700 mg, yellow solid) in a yield of 57.4%. MS m / z(ESI): 325.1[M+1]. 1 H NMR (400 MHz, CDCl 3 ): δ8.21(s,1H),8.04(d,1H),7.81(d,1H),4.97(s,2H),4.47(s,2H),4.44(q,2H),4.03(d,2H),1.43(t,3H),0.92-0.82(m,4H).

[0131] Intermediate Im-5 Synthesis of 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid ethyl ester [ka] Starting from 6-chloro-5-nitropyridine carboxylic acid ethyl ester, the title product 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid ethyl ester was obtained by referring to the synthesis of intermediate Im-4. MS m / z(ESI):326.10[M+1].

[0132] Intermediate Im-6 Methyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate [ka] Starting from methyl 5-fluoro-6-nitronicotinate, the product methyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate was obtained by referring to the synthesis of intermediate Im-4.

[0133] MS m / z(ESI): 312.1[M+1].

[0134] Intermediate Im-7 tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate [ka] Step 1 tert-Butyl 4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate 1-(3-bromo-2-hydroxyphenyl)ethan-1-one Im-7a (20 g, 0.09 mol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (32 g, 0.10 mol), Pd(dppf)Cl 2 ·CH 2 Cl 2(7.6 g, 9.40 mmol) and anhydrous potassium carbonate (39 g, 0.28 mol) were dissolved in 250 mL of a mixture of dioxane and water (4:1). The reaction was heated to 100° C. and stirred for 8 hours. The reaction was stopped, the reaction was cooled to ambient temperature, the reaction was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with eluent petroleum ether and ethyl acetate to give the title product tert-butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate Im-7b (26 g, colorless oil) in 88.1% yield. MS m / z(ESI): 318.1[M+1]. Step 2 tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate Im-7b (26 g, 0.08 mol) and Pd / C (2.6 g, 10% wt.) were dispersed in methanol (300 mL), hydrogen gas was introduced three times, and air was discharged. The reaction solution was reacted for 12 hours while stirring. The reaction was stopped, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography with eluent petroleum ether and ethyl acetate to obtain the title product tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (25 g, white solid), with a yield of 95.6%. MS m / z(ESI): 320.1[M+1].

[0135] Example 1 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one Sodium tetraborate decahydrate (45.97 g, 66.50 mmol) was added to a solution of 1-(3-bromo-2-hydroxy-phenyl)ethanone (13 g, 60.45 mmol) and 4-chloro-2-fluoro-benzene(form)aldehyde (10.06 g, 63.48 mmol) in ethanol (125 mL) and water (200 mL), and the mixture was cooled to 90°C. o C for 12 hours, cooled, filtered, washed the filter cake with water, and dried the filter cake to obtain the title product (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one (20 g, yellow solid), yield 93.0%. MS m / z(ESI):354.9[M+1] Step 2 8-Bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one A solution of (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one (2 g, 5.62 mmol), concentrated hydrochloric acid (4 mL) in ethanol (10 mL) was stirred at 110° C. for 20 hours under microwave conditions, cooled, spun to dryness, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 8-bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one (1.8 g, yellow solid), with a yield of 90.0%. MS m / z(ESI):355.0[M+1] Step 3 8-Bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman To a solution of 8-bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one (1.8 g, 5.06 mmol) in tetrahydrofuran (10 mL) was added dropwise 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-sulfanyl)ethylamine (10 mL), and the mixture was cooled to 70°C. o C for 12 hours, cooled, added water to quench the reaction, extracted with dichloromethane (50mL x 3), washed the organic phase with saturated sodium bicarbonate solution (50mL x 2) and saturated sodium chloride solution (50mL x 2), dried over anhydrous sodium sulfate, filtered, spin-dried, and purified the resulting residue using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 8-bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman (400mg, yellow solid), with a yield of 20.9%. MS m / z(ESI):377.0[M+1] Step 4 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-formic acid tert-butyl ester A mixture of 8-bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman (400 mg, 1.06 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (360.32 mg, 1.17 mmol), sodium carbonate (280.71 mg, 2.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (77.44 mg, 105.94 μmol), 1,4-dioxane (10 mL), and water (2 mL) was heated under nitrogen gas protection for 100 minutes. oC for 2 hours, cooled, added water, extracted with dichloromethane (10 mL x 2), washed the organic phase with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, spin-dried, and purified the resulting residue using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-formic acid tert-butyl ester (450 mg, yellow oil), yield 88.5%. MS m / z(ESI):480.1[M+1] Step 5 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-formic acid tert-butyl ester A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-formic acid tert-butyl ester (450 mg, 937.66 μmol), palladium carbon (80 mg, 10%), and ethyl acetate (30 mL) was replaced with hydrogen gas three times and reacted for 5 hours with stirring. After filtration and spin drying, the title product 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-formic acid tert-butyl ester (380 mg, pale yellow oil) was obtained in 84.1% yield. MS m / z(ESI):482.2[M+1] Step 6 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-formic acid tert-butyl ester (340 mg, 705.49 μmol) and hexafluoroisopropanol (10 mL) was heated for 80 min under microwave conditions. oC for 4 hours, cooled, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with an eluent system petroleum ether and ethyl acetate to give the title product 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine (40 mg, colorless oil) in 15.7% yield. MS m / z(ESI):362.1[M+1] Step 7 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylic acid methyl ester A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine (40 mg, 110.55 μmol), Im-1 (46.68 mg, 143.72 μmol), potassium carbonate (61.03 mg, 442.22 μmol), and acetonitrile (5 mL) was added to 50 mL of water. o C for 3 hours, cooled, added 5mL of water, extracted with dichloromethane (20mL x 3), washed the organic phase with saturated sodium chloride solution (20mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the resulting residue using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylic acid ethyl ester (30mg, colorless oil), yield 43.7%. MS m / z(ESI):620.2[M+1] Step 8 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylic acid methyl ester (30 mg, 48.38 μmol), lithium hydroxide monohydrate (20 mg, 476.62 μmol), methanol (2 mL), water (2 mL), and tetrahydrofuran (3 mL) was stirred at room temperature for 12 hours, and formic acid was added. The mixture was then adjusted to pH=6, spin-dried, and the resulting residue was purified using silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg, white solid), yield 68.2%. MS m / z(ESI): 606.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (1-A) MS m / z(ESI): 606.2[M+1]. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (1-B) MS m / z(ESI): 606.2[M+1].

[0136] Example 2 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid By replacing Im-1 with Im-2 and referring to Example 1, 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained. MS m / z(ESI): 607.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 2-A) MS m / z(ESI): 607.2[M+1]. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 2-B) MS m / z(ESI): 607.2[M+1].

[0137] Example 3 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid By substituting Im-1 with Im-4 and referring to Example 1, 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained. MS m / z(ESI): 622.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 3-A) MS m / z(ESI): 622.2[M+1]. (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 3-B) MS m / z(ESI): 622.2[M+1].

[0138] Example 4 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid By substituting Im-5 for Im-1, 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained with reference to Example 1. MS m / z(ESI): 623.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 4-A) MS m / z(ESI): 623.2[M+1]. (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 4-B) MS m / z(ESI): 623.2[M+1].

[0139] Example 5 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 (E)-1-(3-bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one Using 2,4-dichlorobenzene(form)aldehyde as a raw material, (E)-1-(3-bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one was obtained by referring to Step 1 of Example 1. MS m / z(ESI): 371.0[M+1]. Step 2 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine Using (E)-1-(3-bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one as a raw material, 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine was obtained by following steps 2 to 6 of Example 1. MS m / z(ESI): 378.1[M+1]. Step 3 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-5 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 7 and 8 of Example 1. MS m / z(ESI): 639.2[M+1]. Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] (R)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 5-A) MS m / z(ESI): 639.2[M+1]. (S)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 5-B) MS m / z(ESI): 639.2[M+1].

[0140] Example 6 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid By substituting Im-1 with Im-6 and referring to Example 1, 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was obtained. MS m / z(ESI): 623.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid gave [ka] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 6-A) MS m / z(ESI): 623.2[M+1]. (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 6-B) MS m / z(ESI): 623.2[M+1].

[0141] Example 7 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 (E)-4-(3-(3-bromo-2-hydroxyphenyl)-3-carbonylprop-1-en-1-yl)-3-fluorobenzonitrile Using 3-fluoro-4-formylbenzonitrile as a raw material, (E)-4-(3-(3-bromo-2-hydroxyphenyl)-3-carbonylprop-1-en-1-yl)-3-fluorobenzonitrile was obtained by referring to Step 1 of Example 1. MS m / z(ESI): 346.0[M+1]. Step 2 3-Fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile Using (E)-1-(3-bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one as a raw material, 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile was obtained by referring to steps 2 to 6 of Example 1. MS m / z(ESI): 353.1[M+1]. Step 3 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-4 as raw materials, 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to steps 7 and 8 of Example 1. MS m / z(ESI): 613.2[M+1]. Chiral separation of 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] (R)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 7-A) MS m / z(ESI): 613.2[M+1]. (S)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 7-B) MS m / z(ESI): 613.2[M+1].

[0142] Example 8 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-1 as raw materials, 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI): 597.2[M+1]. Chiral separation of 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 8-A) MS m / z(ESI): 597.2[M+1]. 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 8-B) MS m / z(ESI): 597.2[M+1].

[0143] Example 9 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-6 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was obtained with reference to Example 1. MS m / z(ESI): 639.2[M+1]. Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid gave [ka] (R)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 9-A) MS m / z(ESI): 639.2[M+1]. (S)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 9-B) MS m / z(ESI): 639.2[M+1].

[0144] Example 10 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 (E)-4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-formic acid tert-butyl ester Using (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one as a raw material, (E)-4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-formic acid tert-butyl ester was obtained by referring to steps 4 and 5 of Example 1. MS m / z(ESI): 460.2[M+1]. Step 2 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-formic acid tert-butyl ester Sodium borohydride (248 mg, 6.54 mmol) was added to a solution of (E)-4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.18 mmol) in isopropanol (25 mL) at 50° C., and stirred at room temperature for 16 hours. The reaction was quenched by adding 10 mL of water, extracted with dichloromethane (50 mL×3), the organic phase was washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography with eluent petroleum ether and ethyl acetate to obtain 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-formic acid tert-butyl ester (260 mg, pale yellow oil), with a yield of 26.9%. MS m / z(ESI): 444.2[M+1]. Step 3 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-formic acid tert-butyl ester and Im-5 as raw materials, 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 6 to 8 of Example 1. MS m / z(ESI): 605.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 10-A) MS m / z(ESI): 605.2[M+1]. (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 10-B) MS m / z(ESI): 605.2[M+1].

[0145] Example 11 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid Using 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine and Im-3 as raw materials, 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI): 607.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid gave [ka] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 11-A) MS m / z(ESI): 607.2[M+1]. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 11-B) MS m / z(ESI): 607.2[M+1].

[0146] Example 12 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-4 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained with reference to Example 1. MS m / z(ESI): 638.2[M+1]. Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] (R)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 12-A) MS m / z(ESI): 638.2[M+1]. (S)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 12-B) MS m / z(ESI): 638.2[M+1].

[0147] Example 13 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-2 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI): 623.2[M+1]. Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 13-A) MS m / z(ESI): 623.2[M+1]. 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 13-B) MS m / z(ESI): 623.2[M+1].

[0148] Example 14 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-1 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI): 622.2[M+1]. Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 14-A) MS m / z(ESI): 622.2[M+1]. 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 14-B) MS m / z(ESI): 622.2[M+1].

[0149] Example 15 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-3 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI): 623.2[M+1]. Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid gave [ka] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 15-A) MS m / z(ESI): 623.2[M+1]. 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 15-B) MS m / z(ESI): 623.2[M+1].

[0150] Example 16 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate Starting from 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one, the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate was obtained by following steps 4 and 5 of Example 1. MS m / z(ESI): 460.1[M+1]. Step 2 tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxo)-2H-chromen-8-yl)piperidine-1-carboxylate tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate (1g, 2.17mmol) was dissolved in 20mL of THF, and lithium bistrimethylsilylamide (2.4mL, 2.40mmol) was added at -78°C, and the mixture was allowed to react for 1 hour. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (0.94g, 2.4mmol) in THF (20mL) was added at -78°C, and the mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction was quenched by adding sodium bicarbonate (10mL) and extracted with ethyl acetate (20mL x 3). The organic phases were combined and then washed with saturated sodium chloride solution (20mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The resulting residue was purified using silica gel column chromatography with an eluent system petroleum ether and ethyl acetate to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxo)-2H-chromen-8-yl)piperidine-1-carboxylate (456 mg, yield: 35.5%). MS m / z(ESI): 592.1[M+1]. Step 3 tert-Butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxo)-2H-chromen-8-yl)piperidine-1-carboxylate (0.5 g, 0.84 mmol) was dissolved in 10 mL of DMA / THF (v:v=1:3), nickel acetate tetrahydrate (24.8 mg, 0.1 mmol), Zn powder (10 mg, 0.16 mmol), 1,5-cyclooctadiene (11 mg, 0.1 mmol) and lithium chloride (53 mg, 1.3 mmol) were added, and the mixture was reacted at room temperature for 16 hours under nitrogen gas protection. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and then washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The resulting residue was purified using silica gel column chromatography with an eluent system petroleum ether and ethyl acetate to give tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate (241 mg, yield: 60.0%). MS m / z(ESI): 478.1[M+1]. Step 4 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-1 as raw materials, the product 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to steps 6 to 8 of Example 1. MS m / z(ESI): 622.1[M+1]. 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to give the following products: [ka] 2-((4-((R)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 16-A) MS m / z(ESI): 622.1[M+1]. 2-((4-((S)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 16-B). MS m / z(ESI): 622.1[M+1].

[0151] Example 17 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-2 as raw materials, the product 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 6 to 8 of Example 1. MS m / z(ESI): 623.1[M+1]. 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was resolved to give the following products: [ka] 2-((4-((R)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 17-A) MS m / z(ESI): 623.1[M+1]. 2-((4-((S)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 17-B). MS m / z(ESI): 623.1[M+1].

[0152] Example 18 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 (E)-2-Bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (E)-1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one (1 g, 2.81 mmol) was dissolved in 30 mL of THF, and methylmagnesium bromide (7 mL, 7 mmol) was added at 0° C., and the mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction was quenched by adding ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The obtained residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain (E)-2-bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (831 mg, yield: 79.6%). MS m / z(ESI): 370.9[M+1]. Step 2 8-Bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene (E)-2-Bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (0.5 g, 1.34 mmol) was dissolved in 15 mL of nitromethane, (2,3,4,5-tetrafluorophenyl)boronic acid (52 mg, 0.26 mmol) was added, and the mixture was stirred at 60° C. for 16 hours. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL×3). The crude product was obtained by washing with saturated sodium chloride solution (20 mL×2), drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The obtained residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene (326 mg, yield: 68.0%). MS m / z(ESI): 356.9[M+1]. Step 3 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene as the raw material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to steps 4, 5, 7 and 8 of Example 1. MS m / z(ESI): 602.2[M+1]. 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to give the following products: [ka] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 18-A) MS m / z(ESI): 602.2[M+1]. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 18-B). MS m / z(ESI): 602.2[M+1].

[0153] Example 19 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 4-chloro-2-methoxybenzene(form)aldehyde as the raw material, the product 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 3. MS m / z(ESI): 634.2[M+1]. 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to give the following products: [ka] (R)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 19-A) MS m / z(ESI): 634.2[M+1]. (S)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 19-B). MS m / z(ESI): 634.2[M+1].

[0154] Example 20 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-chloro-2-methoxybenzene(form)aldehyde as the raw material, the product 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Example 4. MS m / z(ESI): 635.2[M+1]. 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was resolved to give the following products: [ka] (R)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 20-A) MS m / z(ESI): 635.2[M+1]. (S)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 20-B).

[0155] MS m / z(ESI): 635.2[M+1].

[0156] Example 21 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid Using 4-chloro-2-methoxybenzene(form)aldehyde as a raw material, the product 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was obtained by referring to Example 6. MS m / z(ESI): 635.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid gave [ka] (R)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 21-A) MS m / z(ESI): 635.2[M+1]. (S)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 21-B) MS m / z(ESI): 635.2[M+1].

[0157] Example 22 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-2 as raw materials, the product 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 7 and 8 of Example 1. MS m / z(ESI): 598.2[M+1]. Chiral separation of 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 22-A) MS m / z(ESI): 598.2[M+1]. 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 22-B) MS m / z(ESI): 598.2[M+1].

[0158] Example 23 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-chloro-2-(methoxy-d3)benzene(form)aldehyde as a raw material, the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Example 2. MS m / z(ESI): 622.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 23-A) MS m / z(ESI): 622.2[M+1]. 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 23-B) MS m / z(ESI): 622.2[M+1].

[0159] Example 24 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 4-chloro-2-(methoxy-d3)benzene(form)aldehyde as the raw material, the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI): 621.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 24-A) MS m / z(ESI): 621.2[M+1]. 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 24-B) MS m / z(ESI): 621.2[M+1].

[0160] Example 25 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperazine-1-carboxylate A mixture of 8-bromo-2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman (1 g, 2.65 mmol), tert-butyl piperazine-1-carboxylate (740 mg, 3.97 mmol), cesium carbonate (2.59 g, 7.95 mmol) and toluene (30 mL) was dissolved in tri(dibenzylideneacetone)dipalladium (238 mg, 0.26 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (300 mL). g, 0.52 mmol), and then purged with nitrogen gas, and stirred at 80°C for 12 hours. After the reaction was completed, the mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure and dried. The resulting residue was purified using silica gel column chromatography with an eluent of petroleum ether and ethyl acetate to obtain tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperazine-1-carboxylate (750 mg), with a yield of 58.6%. MS m / z(ESI): 483.1[M+1]. Step 2 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperazine-1-carboxylate as the raw material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to steps 6 to 8 of Example 1. MS m / z(ESI): 607.1[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 25-A) MS m / z(ESI): 607.1[M+1]. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 25-B) MS m / z(ESI): 607.1[M+1].

[0161] Example 26 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazine 2-Chloro-1-(4-chloro-2-fluorophenyl)ethan-1-one (1g, 4.83mmol) and 2-amino-6-bromophenol (908mg, 4.83mmol) were dissolved in THF (30mL), and after nitrogen gas replacement, the mixture was stirred in a microwave at 60°C for 2 hours. After the reaction was completed, the mixture was cooled, and the filtrate was concentrated under reduced pressure and dried. The resulting residue was purified using silica gel column chromatography with an eluent petroleum ether and ethyl acetate system to obtain 8-bromo-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazine (810mg), with a yield of 49.2%. MS m / z(ESI): 340.1 [M+1]. Step 2 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 8-bromo-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxane as the raw material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to steps 4 to 8 of Example 1. MS m / z(ESI): 589.2[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 26-A) MS m / z(ESI): 589.2[M+1]. 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 26-B) MS m / z(ESI): 589.2[M+1].

[0162] Example 27 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 8-bromo-2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester as raw materials, the product 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 25. MS m / z(ESI):621.2[M+1] Chiral separation of 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-(((S)-4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 27-A) MS m / z(ESI): 621.2[M+1]. 2-(((S)-4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 27-B) MS m / z(ESI): 621.2[M+1].

[0163] Example 28 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-5 as raw materials, 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 7 and 8 of Example 1. MS m / z(ESI): 614.2[M+1]. Chiral separation of 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] (S)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 28-A) MS m / z(ESI): 614.2[M+1]. (R)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 28-B) MS m / z(ESI): 614.2[M+1].

[0164] Example 29 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 (E)-4-Chloro-2-fluoro-1-(2-nitrovinyl)benzene 4-Chloro-2-fluorobenzene(form)aldehyde (4 g, 25.23 mmol) and nitromethane (14 mL) were dissolved in glacial acetic acid (50 mL), ammonium acetate (5.83 g, 75.68 mmol) was added, and the mixture was stirred at 110° C. for 3 hours, cooled, and the reaction solution was added to ice water to precipitate a solid. The solid was filtered, and the residue obtained from the filter cake was purified by silica gel column chromatography using an eluent of petroleum ether and ethyl acetate to obtain (E)-4-chloro-2-fluoro-1-(2-nitrovinyl)benzene (2.50 g, yield: 49.2%). MS m / z(ESI):202.0[M+1]. Step 2 5-Bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one To a solution of (E)-4-chloro-2-fluoro-1-(2-nitrovinyl)benzene (451.26 mg, 2.24 mmol), 2-bromo-6-hydroxybenzene(form)aldehyde (300 mg, 1.49 mmol), and 4A molecular sieves (400 mg) in dichloromethane (10 mL) was added 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (37.63 mg, 149.24 μmol), and the mixture was stirred at room temperature for 0.5 hours. The mixture was stirred for 1 hour, and then 1,4-diazabicyclo[2.2.2]octane (33.48 mg, 298.48 μmol) was added dropwise, and stirred at room temperature under nitrogen gas protection for 12 hours. The silica gel was stirred, concentrated under reduced pressure and dried, and the obtained residue was purified using silica gel column chromatography with an eluent petroleum ether and ethyl acetate system to obtain 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one (90 mg, yield: 16.9%). MS m / z(ESI): 355.0[M+1]. Step 3 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one as the raw material, the product 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 3 to 8 of Example 1. MS m / z(ESI): 627.2[M+1]. Chiral separation of 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 29-A) MS m / z(ESI): 627.2[M+1]. 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 29-B) MS m / z(ESI): 627.2[M+1].

[0165] Example 30 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 5-Bromo-3-(4-chloro-fluorophenyl)chroman Triethylsilane (655 mg, 0.9 mL, 5.65 mmol) was added dropwise to 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one (500 mg, 1.41 mmol) in trifluoroacetic acid (5 mL), and stirred at 60° C. for 8 hours, cooled, added water to quench the reaction, extracted with dichloromethane (30 mL×3), washed the organic phase with saturated sodium bicarbonate solution (50 mL×2) and sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the obtained residue by silica gel column chromatography with eluent petroleum ether and ethyl acetate system to obtain pale yellow solid 5-bromo-3-(4-chloro-2-fluorophenyl)chroman (230 mg, yield: 47.8%). MS m / z(ESI): 340.9[M+1]. Step 2 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 5-bromo-3-(4-chloro-2-fluorophenyl)chroman as a raw material, 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 4 to 8 of Example 1. MS m / z(ESI): 591.2[M+1]. Chiral separation of 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 30-A) MS m / z(ESI): 591.2[M+1]. 2-((4-((R)-3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 30-B) MS m / z(ESI): 591.2[M+1].

[0166] Example 31 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 4-(3-Hydroxy-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 3-Bromo-2-nitrophenol (2 g, 9.17 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-formic acid tert-butyl ester (2.84 g, 9.17 mmol), sodium carbonate (1.94 g, 18.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (335.48 mg, 458.5 μmol) were dissolved in 1,4-dioxane (20 mL), water (3 mL) and the reaction was stirred at 80 °C for 6 h. 20mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (5mL×2), saturated ammonium chloride solution (5mL×2), and saturated saline solution (5mL×2), successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified using silica gel column chromatography with an eluent of petroleum ether and ethyl acetate to obtain the title product 4-(3-hydroxy-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.3g, yellow solid), with a yield of 78.3%. MS m / z(ESI):321.1[M+1] Step 2 4-(3-(2-(4-chloro-2-fluorophenyl)-2-carbonylethoxy)-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl ester 4-(3-Hydroxy-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.30 g, 7.18 mmol), 2-chloro-1-(4-chloro-2-fluorophenyl)ethan-1-one (1.49 g, 7.18 mmol), potassium carbonate (1.98 g, 14.36 mmol) were dissolved in toluene (20 mL) and the reaction was stirred at 80 °C for 2 h. 20mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (5mL×2), saturated ammonium chloride solution (5mL×2), and saturated saline solution (5mL×2), successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified using silica gel column chromatography with an eluent petroleum ether and ethyl acetate system to obtain the title product 4-(3-(2-(4-chloro-2-fluorophenyl)-2-carbonylethoxy)-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl ester (3.1g, yellow solid), with a yield of 87.9%. MS m / z(ESI):491.1[M+1] Step 3 4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl ester 4-(3-(2-(4-chloro-2-fluorophenyl)-2-carbonylethoxy)-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl ester (3.10 g, 6.31 mmol), paraformaldehyde (1.13 g, 12.62 mmol) were dissolved in 30 mL of methanol and 10 mL of water, palladium / carbon (310 mg, 10%) was added, hydrogen gas was replaced three times, and the reaction was carried out with stirring for 12 hours. Filtration, concentration of the filtrate under reduced pressure, and purification of the resulting residue using silica gel column chromatography with an eluent petroleum ether and ethyl acetate system afforded the title product 4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl ester (1.30 g, yellow oil), yield 44.9%. MS m / z(ESI):459.1[M+1] Step 4 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl ester as raw material, the product 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by following steps 5 to 8 of Example 1. MS m / z(ESI):606.2[M+1] Chiral separation of 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid afforded [ka] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 31-A) MS m / z(ESI):606.2[M+1] 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 31-B) MS m / z(ESI):606.2[M+1]

[0167] Example 32 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 2-(Chloromethyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Using 6-fluoro-5-nitromethylpicolinic acid methyl ester and 2-(1-(aminomethyl)cyclopropyl)acetonitrile as raw materials, the final product 2-(chloromethyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester was obtained by referring to the synthesis of Im-2. MS m / z(ESI):319.0[M+1] Step 2: 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 2-(chloromethyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester and 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine as raw materials, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to the synthesis of steps 7 to 8 in Example 1. MS m / z(ESI):630.2[M+1] Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave [ka] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 32-A) MS m / z(ESI):630.2[M+1] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 32-B) MS m / z(ESI):630.2[M+1]

[0168] Example 33 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (E)-1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one (500 mg, 1.41 mmol) was dissolved in methanol (15 mL), sodium borohydride (64 mg, 1.69 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water, extracted with dichloromethane (30 mL x 3), washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified using silica gel column chromatography with an eluent petroleum ether and ethyl acetate system to obtain (E)-2-bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (454 mg, yield: 90.0%). MS m / z(ESI): 356.9[M+1]. Step 2 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (300 mg, 0.84 mmol) was dissolved in dichloromethane (10 mL), p-toluenesulfonic acid (29 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water, extracted with dichloromethane (30 mL x 3), washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography using an eluent petroleum ether and ethyl acetate system to obtain (8-bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (200 mg, yield: 70.1%). MS m / z(ESI): 338.9[M+1]. Step 3 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol (8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (200 mg, 0.59 mmol) was dissolved in THF (10 mL), and a THF solution of borane (0.71 mL, 0.71 mmol) was added. o C for 1 h, 2 mL of water was added, followed by NaOH (71 mg, 1.77 mmol) and 0.1 mL of hydrogen peroxide solution, and the mixture was cooled to 40°C for 1 h. o The mixture was stirred at C for 2 h. The reaction was quenched by adding 10 mL of water, extracted with dichloromethane (30 mL x 3), washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with an eluent petroleum ether and ethyl acetate system to give 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol (63 mg, yield: 29.8%). MS m / z(ESI): 356.9[M+1]. Step 4 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol (500 mg, 1.40 mmol) was dissolved in DCM (20 mL), Dess-Martin oxidant (0.71 mL, 1.67 mmol) was added, and the resulting mixture was cooled to room temperature for 0.5 min. o The mixture was stirred at C for 1 hour. The reaction was quenched by adding 10 mL of water, extracted with dichloromethane (30 mL x 3), washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with an eluent petroleum ether and ethyl acetate system to give 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one (448 mg, yield: 89.9%). MS m / z(ESI): 354.9[M+1]. Step 5 tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate Using 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one as the raw material, the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate was obtained by following steps 3 to 5 of Example 1. MS m / z(ESI): 482.2[M+1]. Step 6 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine Starting from tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate, the product 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine was obtained by following step 6 of Example 1. MS m / z(ESI): 362.1[M+1]. Step 7 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine as raw material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to steps 7 and 8 of Example 1. MS m / z(ESI): 607.1[M+1]. Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 33-A) MS m / z(ESI): 607.1[M+1]. 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 33-B) MS m / z(ESI): 607.1[M+1].

[0169] Example 34 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 4-formyl-3-hydroxybenzonitrile as the raw material, the product 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 24. MS m / z(ESI): 612.2[M+1]. Chiral separation of 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave [ka] 2-((4-((R)-2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 34-A) MS m / z(ESI): 612.2[M+1]. 2-((4-((S)-2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 34-B) MS m / z(ESI): 612.2[M+1].

[0170] Example 35 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-formyl-3-hydroxybenzonitrile as the raw material, the product 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Example 20. MS m / z(ESI):629.2[M+1]. Chiral separation of 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid afforded [ka] (R)-2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 35-A) MS m / z(ESI):629.2[M+1]. (S)-2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 35-B) MS m / z(ESI):629.2[M+1].

[0171] Example 36 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 1-(4-chloro-2-hydroxyphenyl)ethan-1-one 36a (15 g, 87.93 mmol), deuterated iodomethane (16.57 g, 114.31 mmol), and anhydrous potassium carbonate (36.46 g, 0.26 mol) were dispersed in DMF (150 mL). The reaction mixture was heated to 50° C. and reacted for 12 hours with vigorous stirring. The reaction mixture was stopped, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with eluent petroleum ether and ethyl acetate to obtain the title product 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 36b (15 g), with a yield of 90.9%. MS m / z(ESI): 188.1[M+1]. Step 2 tert-Butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (25 g, 79.94 mmol) was dissolved in tetrahydrofuran (300 mL). The solution was cooled in a dry ice / ethanol bath, and LiHMDS (18.4 mL, 0.184 mol, 1 M THF solution) was slowly added thereto, and after completion, the reaction was carried out for 30 minutes with stirring. 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 36b (15 g, 79.94 mmol) was dissolved in THF (30 mL), and the solution was slowly added dropwise to the reaction solution described above, and the temperature of the dry ice / ethanol bath was maintained, and the reaction was carried out for 40 minutes with stirring. The reaction was stopped, the dry ice / ethanol bath was removed, and the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate (300 mL x 2), the organic phases were combined, washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with an eluent system petroleum ether and ethyl acetate to obtain the title product tert-butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 36c (31 g), with a yield of 76.5%. MS m / z(ESI): 507.2[M+1]. Step 3 tert-Butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate tert-Butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 36c (2.00 g, 4.07 mmol) and BAST (10 mL) were dissolved in DMF (10 mL), and then ethanol (20 μL) was added to the reaction solution and reacted for 4 hours with stirring. The reaction was stopped, and the reaction solution was quenched by slowly adding the reaction solution dropwise to ice water, extracted with ethyl acetate (50 mL×2), and the organic phase was combined and washed with water. (100 mL), washed with saturated sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with an eluent system petroleum ether and ethyl acetate to obtain the title product tert-butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate 36d (750 mg), with a yield of 38.7%. MS m / z(ESI): 491.2[M+1]. Step 4 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine tert-Butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate 36d (750 mg, 1.53 mmol), boron trifluoride diethyl etherate (543 mg, 3.83 mmol), and powdered 4 Å molecular sieves (750 mg) were dispersed in dichloromethane (10 mL), and the mixture was reacted for 3 hours while stirring at 0° C. The reaction was stopped and a saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The mixture was filtered through diatomaceous earth, the filtrate was settled, the organic layer was separated, the aqueous layer was extracted with dichloromethane (20mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with an eluent system of dichloromethane and methanol to give the title product 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine 36e (490mg), with a yield of 82.1%. MS m / z(ESI): 391.2[M+1]. Step 5 Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine 36e (490 mg, 1.25 mmol), methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (371 mg, 1.25 mmol), anhydrous potassium carbonate (518 mg, 3.75 mmol) were dispersed in acetonitrile (8 mL). The reaction solution was heated to 50° C. and reacted for 3 hours with vigorous stirring. The reaction was stopped, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with ethyl acetate as an eluent, and the purified sample was then separated by chiral HPLC to obtain the title product methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 36f (210 mg), with a yield of 26.5%. MS m / z(ESI): 632.2[M+1]. Step 6 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 36f (210 mg, 332.19 μmol) and lithium hydroxide (133 mg, 3.32 mmol) were dissolved in 9 mL of a mixture of THF, water and methanol (4:4:1) and reacted for 3 hours with stirring. The reaction was quenched and adjusted to pH=6 by adding formic acid, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 36 (170 mg), 82.8% yield. MS m / z(ESI):618.2[M+1]. 1 H NMR(400MHz,MeOD)δ8.16-7.97(m,2H),7.29(d,J=8.2Hz,1H),7.08-6.98(m,2H),6.94-6.85(m,2H),6.81(t,J=7.5Hz,1H),6.57(d ,J=9.8Hz,1H),5.78(d,J=9.8Hz,1H),5.25(dd,J=7.5,3.0Hz,1H),4.96(dd,J=14.9,6.7Hz,1H),4.83(dd,J=14.9,3.1Hz,1H),4.66 -4.53(m,1H),4.48-4.35(m,1H),4.25(d,J=14.2Hz,1H),4.16(d,J=14.2Hz,1H),3.25(d,J=11.5Hz,1H),3.12(d,J=11.5Hz,1H),2. 91(s,1H),2.83-2.70(m,1H),2.61-2.41(m,3H),1.85(q,J=3.9Hz,2H),1.78(s,3H),1.68(d,J=3.7Hz,1H),1.59(d,J=14.9Hz,1H).

[0172] Example 37 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Using 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im-7 and 1-(4-chloro-2-fluorophenyl)ethan-1-one as raw materials, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 37 was obtained by referring to steps 2 to 6 of Example 36. MS m / z(ESI): 621.2[M+1].

[0173] Example 38 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 tert-Butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate Referring to the synthesis method of Example 37, 1-(4-chloro-2-fluorophenyl)ethan-1-one 38a (5 g, 28.97 mmol), Im-7 (9.25 g, 28.97 mmol), LiHMDS (66.6 mL, 66.63 mmol), THF (100 mL) were added to obtain the title product tert-butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 41b (7.60 g), with a yield of 53.3%. MS m / z(ESI): 492.2[M+1]. Step 2 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one tert-Butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 38b (5 g, 10.16 mmol) and p-toluenesulfonic acid (5.25 g, 30.48 mmol) were dissolved in toluene (50 mL). The reaction solution was heated to 100° C. and reacted for 5 hours with stirring. The reaction was stopped, the reaction solution was cooled to room temperature, and 2M sodium hydroxide solution was added thereto to quench the reaction, the organic layer was separated, the aqueous layer was extracted with dichloromethane (50mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography with dichloromethane and methanol as eluents to obtain the title product 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one 38c (2.36g), with a yield of 62.1%. MS m / z(ESI): 374.1[M+1]. Step 3 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one 38c (2 g, 5.35 mmol) was dissolved in methanol (30 mL). Sodium borohydride (396 mg, 10.70 mmol) was slowly added to the solution in an ice bath in small portions. After completion, the ice bath was removed and the reaction solution was allowed to warm to ambient temperature and react for 2 hours. The reaction was stopped, and the reaction liquid was added with saturated ammonium chloride solution to quench the reaction, and the reaction liquid was adjusted to pH=10 with 1M sodium hydroxide solution, and extracted with dichloromethane (50mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol 38d (1.88g), the yield was 93.5%, and the compound was used directly in the next step reaction without purification. MS m / z(ESI): 376.1[M+1]. Step 4 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol 38d (1.50 g, 3.99 mmol) and p-toluenesulfonic acid (2.06 g, 11.97 mmol) were dissolved in toluene (20 mL). The reaction solution was heated to 100° C. and reacted for 30 minutes while stirring. The reaction was stopped, the reaction solution was cooled to room temperature, and 2M sodium hydroxide solution was added thereto to quench the reaction, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL×3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 38e (1.02 g), the yield was 71.4%, and the compound was used directly in the next step reaction without purification. MS m / z(ESI): 358.1[M+1]. Step 5 Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Referring to the synthesis method of Step 5 of Example 37, 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 38e (500 mg, 1.40 mmol), methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (413 mg, 1.40 mmol), anhydrous potassium carbonate (58 0 mg, 4.20 mmol) and acetonitrile (10 mL) were added to give the title product methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 41f (263 mg), yield 30.5%. MS m / z(ESI):617.2[M+1]. Step 6 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Referring to the synthesis method of Step 6 of Example 37, methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 38f (100 mg, 162 μmol), lithium hydroxide C. to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 38 (76 mg), yield 77.8%. MS m / z(ESI):603.2[M+1].

[0174] Example 39 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Referring to the synthesis method of Example 36, the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained using Im-1 as the starting material. MS m / z(ESI): 617.3[M+1].

[0175] Example 40 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 4-Chloro-2-fluoro<α-2H>benzene(formaldehyde)aldehyde 4-Chloro-2-fluoro-1-iodo-benzene (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask, and isopropanol sodium chloride (12.9 mL, 3 M, 38.99 mmol) was added at -30° C., and the reaction was allowed to react for 2 h at -20° C. Then N,N-dimethylformamide-D7 (3.12 g, 38.99 mmol) was added to the reaction, and the reaction was allowed to continue for 1 h at 0° C. The reaction was stopped, the reaction solution was quenched with saturated aqueous ammonium chloride solution, water (50 mL) was added, extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with an eluent system petroleum ether and ethyl acetate to obtain the title product 4-chloro-2-fluoro<α-2H>benzene(form)aldehyde 40b (2.7 g), with a yield of 86.79%. MS m / z(ESI): 160.0[M+1]. Step 2 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-Chloro-2-fluoro<α-2H>benzene(form)aldehyde 40b (1.5 g, 9.40 mmol), 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im-7 (3.00 g, 9.40 mmol) and tetrahydrofuran (40 mL) were added to a 100 mL flask, sodium hydride (1.13 g, 28.20 mmol, 60% purity) was added at 0° C., and the reaction solution was reacted at 25° C. for 3 h. The reaction was stopped, the reaction was quenched with saturated aqueous ammonium chloride solution, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 40c (3 g), with a yield of 69.23%. MS m / z(ESI): 461.1[M+1]. Step 3 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 40c as a raw material, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 40 was obtained by referring to the synthesis method of steps 3 to 6 of Example 36. MS m / z(ESI): 608.1[M+1]. 1H NMR(400MHz,DMSO-d6)δ8.10(d,1H),7.97(d,1H),7.54(dd,1H),7.41(t,1H),7.29(dd,1H),7.24-7.15 (m,2H),6.96(t,1H),5.67(d,1H),5.20-5.11(m,1H),4.88-4.79(m,1H),4.74-4.65(m,1H),4.53-4.43 (m,1H),4.41-4.31(m,1H),3.97(d,1H),3.88(d,1H),2.98-2.91(m,1H),2.87-2.79(m,1H),2.75-2.62 (m,2H),2.49-2.41(m,1H),2.25-2.07(m,2H),1.73-1.59(m,2H),1.54-1.41(m,1H),1.37-1.29(m,1H).

[0176] Example 41 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 1-Bromo-4-chloro-2-(methoxy-d3)benzene Using 2-bromo-5-chlorophenol 41a as a raw material, 1-bromo-4-chloro-2-(methoxy-d3)benzene 41b was obtained according to the synthesis method of Step 1 of Example 36. MS m / z(ESI): 223.9[M+1]. Step 2 4-Chloro-2-(methoxy-d3)<α-2H>benzene(formaldehyde) Using 1-bromo-4-chloro-2-(methoxy-d3)benzene 41b as a raw material, 4-chloro-2-(methoxy-d3)<α-2H>benzene(form)aldehyde 41c was obtained by referring to the synthesis method in Step 1 of Example 40. MS m / z(ESI): 175.0[M+1]. Step 3 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Using 4-chloro-2-(methoxy-d3)<α-2H>benzene(form)aldehyde 41c as a raw material, 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 41d was obtained by referring to the synthesis method of step 2 of Example 40. MS m / z(ESI): 476.2[M+1]. Step 4 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 41d as a raw material, 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 41 was obtained by referring to the synthesis method of steps 3 to 6 of Example 36. MS m / z(ESI): 623.2[M+1]. 1H NMR(400MHz,Methanol-d4)δ8.14-8.04(m,2H),7.31(d,1H),7.20-7.13(m,2H),7.05(d,1H),6.96- 6.87(m,2H),5.36(d,1H),5.29-5.24(m,1H),5.03-4.93(m,1H),4.82-4.75(m,1H),4.65-4.55(m,1H) ),4.45-4.36(m,1H),4.20(d,1H),4.10(d,1H),3.23-3.15(m,1H),3.09-3.02(m,1H),2.91-2.86(m, 1H),2.81-2.72(m,1H),2.57-2.37(m,3H),1.88-1.78(m,2H),1.71-1.63(m,1H),1.59-1.52(m,1H).

[0177] Example 42 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 4-Chloro-2-fluoro<α-2H>benzene(formaldehyde)aldehyde 4-Chloro-2-fluoro-1-iodo-benzene 42a (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask, and isopropanol sodium chloride (12.9 mL, 3 M, 38.99 mmol) was added at -30 °C, and the reaction was allowed to react for 2 h at -20 °C. Then N,N-dimethylformamide-D7 (3.12 g, 38.99 mmol) was added to the reaction, and the reaction was allowed to continue for 1 h at 0 °C. The reaction was stopped, the reaction liquid was quenched with saturated aqueous ammonium chloride solution, water (50 mL) was added, extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the obtained residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 4-chloro-2-fluoro<α-2H>benzene(form)aldehyde 42b (2.7 g), with a yield of 86.79%. MS m / z(ESI): 160.0[M+1]. Step 2 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-Chloro-2-fluoro<α-2H>benzene(form)aldehyde 42b (1.5 g, 9.40 mmol), 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im-7 (3.00 g, 9.40 mmol) and tetrahydrofuran (40 mL) were added to a 100 mL flask, sodium hydride (1.13 g, 28.20 mmol, 60% purity) was added at 0° C., and the reaction mixture was reacted at 25° C. for 3 h. The reaction was stopped, the reaction was quenched with saturated aqueous ammonium chloride solution, water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 42c (3 g), with a yield of 69.23%. MS m / z(ESI): 461.1[M+1]. Step 3 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 42c (3 g, 6.51 mmol) and isopropanol (50 mL) were added to a 250 mL flask, and sodium borohydride (369.33 mg, 9.76 mmol) was added at 0° C. The reaction solution was then reacted at 20° C. for 3 hours. The reaction was stopped and quenched with water (10 mL), extracted with ethyl acetate (20 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spun dry to give the title product 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 42d (3 g), 99.56% yield. MS m / z(ESI): 463.1[M+1]. Step 4 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 42d (3 g, 6.48 mmol) and N,N-dimethylformamide (30 mL) were added to a 100 mL flask, and p-toluenesulfonic acid (1.67 g, 9.72 mmol) was added at 25° C. The reaction solution was then reacted at 50° C. for 4 hours. The reaction was stopped, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylic acid tert-butyl ester 42e (1.7 g,) in a yield of 58.96%. MS m / z(ESI): 445.1[M+1]. Step 5 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylic acid tert-butyl ester 42e (1.7 g, 3.82 mmol) and dichloromethane (25 mL) were added to a 100 mL flask, and 4A molecular sieves (1.7 g) and boron trifluoride diethyl etherate (1.36 g, 9.55 mmol) were added at 0° C., and the reaction was allowed to react at 0° C. for 2 hours. The reaction was stopped and the reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL), water (10 mL) was added, extracted with dichloromethane (20 mL×3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and spun to dryness to give the title product 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 42f (1.3 g), 98.67% yield. MS m / z(ESI):345.1[M+1] Step 6 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 42f (1.3 g, 3.77 mmol) and acetonitrile (15 mL) were added to a 100 mL flask, and potassium carbonate (1.04 g, 7.54 mmol) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Im2 (1.11 g, 3.77 mmol) were added at 25° C. The reaction solution was then reacted at 25° C. for 10 hours. The reaction was stopped, the reaction solution was quenched with aqueous solution (10 mL), extracted with dichloromethane (10 mL x 3), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 42g (1.7 g,), yield 74.65%. MS m / z(ESI):604.2[M+1] Step 7 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 42g was subjected to chiral separation to obtain 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 42h. Division conditions: D-H4.6*250 Hexane:EtOH:MeOH:DEA=70:15:15:0.1% F = 1mL T = 35°C Step 8 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 42h (100 mg, 165.54 μmol) and methanol (2 mL) were added to a 25 mL flask, and lithium hydroxide (39.64 mg, 1.66 mmol) was dissolved in water (1 mL) and added dropwise to the reaction solution at 25° C. The reaction solution was then reacted at 25° C. for 1 hour. The reaction was stopped, the reaction was quenched with formic acid (0.1 mL), water (2 mL) was added, extracted with dichloromethane (2 mL x 3), the organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, spun dry, and the resulting residue was purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 42 (70 mg) in 71.66% yield. MS m / z(ESI):590.2[M+1] 1 H NMR(400MHz,DMSO)δ8.08(d,1H),7.96(d,1H),7.52(dd,1H),7.34(t,1H),7.27(dd,1H),7.05(dd,1H),6.98 (dd,1H),6.85(t,1H),6.75(d,1H),5.91(d,1H),5.18-5.11(m,1H),4.87-4.80(m,1H),4.72-4.65(m,1H),4 .53-4.43(m,1H),4.39-4.31(m,1H),3.96(d,1H),3.87(d,1H),3.01-2.90(m,1H),2.89-2.79(m,1H),2.77- 2.61(m,2H),2.48-2.45(m,1H),2.27-2.08(m,2H),1.73-1.61(m,2H),1.54-1.42(m,1H),1.42-1.34(m,1H).

[0178] Example 43 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 1-Bromo-4-chloro-2-(methoxy-d3)benzene 2-Bromo-5-chlorophenol 43a (10 g, 48.20 mmol), deuterated iodomethane (10.48 g, 72.30 mmol), and anhydrous potassium carbonate (13.33 g, 96.41 mol) were dispersed in DMF (100 mL). The reaction mixture was heated to 50° C. and reacted for 12 hours with vigorous stirring. The reaction mixture was stopped, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with eluent petroleum ether and ethyl acetate to obtain the title product 1-bromo-4-chloro-2-(methoxy-d3)benzene 43b (10 g), yield: 92.5%. MS m / z(ESI): 223.9[M+1]. Step 2 4-Chloro-2-(methoxy-d3)benzaldehyde-d 1-Bromo-4-chloro-2-(methoxy-d3)benzene 43b (1.6 g, 7.13 mmol) was dissolved in tetrahydrofuran (30 mL), and after removing nitrogen gas, n-BuLi (2.5 M, 3.42 mL) was slowly added dropwise thereto at -78°C. After the addition was completed, the mixture was stirred at -78°C for 1 hour, and N,N-dimethylformamide-D7 (856.71 mg, 10.69 mmol) was added thereto. The reaction system was stirred for 3 hours and allowed to warm to room temperature naturally. Saturated ammonium chloride solution (20 mL) was slowly added dropwise thereto to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL×3), washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid 4-chloro-2-(methoxy-d3)-benzaldehyde-d43c (1.2 g, 6.87 mmol), with a yield of 96.42%. MS m / z(ESI): 175.0[M+1]. Step 3 tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 4-Chloro-2-(methoxy-d3)-benzaldehyde-d43c (700 mg, 4.01 mmol) and tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (1.28 g, 4.01 mmol) were dissolved in tetrahydrofuran (40 mL), and sodium hydride (481.05 mg, 12.03 mmol, 60% purity) was added little by little in an ice-water bath. The reaction system was stirred in an ice-water bath for 0.5 hours, and then the mixture was stirred for 20 minutes. oC at room temperature and stirred for 2.5 hours. After the reaction was completed, water (20 mL) was added dropwise to quench the reaction, extracted with ethyl acetate (30 mLX3), washed with saturated brine (30 mLX2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product tert-butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43d (1.5 g). Yield: 78.6% MS m / z(ESI): 476.2[M+1]. Step 4 tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43d (1.4 g, 2.94 mmol) was dissolved in tetrahydrofuran (30 mL) and sodium borohydride (333.82 mg, 8.82 mmol) was added thereto in small portions at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added dropwise to quench the reaction, extracted with ethyl acetate (30 mLX3), washed with saturated brine (30 mLX2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title product tert-butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43e (1.4 g). MS m / z(ESI): 478.2[M+1]. Step 5 tert-Butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43e (1.40 g, 2.93 mmol,) was dissolved in dichloromethane (20 mL) and p-toluenesulfonic acid (151.62 mg, 880.49 μmol) was added thereto. The reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was directly concentrated to obtain the crude product. The crude product was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product tert-butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 43f (600 mg, 1.30 mmol), with a yield of 44.4%. MS m / z(ESI): 460.2[M+1]. Step 6 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine tert-Butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 43f (260 mg, 565.22 μmol) was dissolved in dichloromethane (10 mL), and 4A was added thereto under ice-water bath. o Molecular sieves (260 mg) and boron trifluoride diethyl etherate (240.66 mg, 1.70 mmol) were added. The reaction was kept stirring under ice-water bath for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added dropwise to quench the reaction, extracted with dichloromethane (20 mLX3), washed with saturated saline (20 mLX2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine 43 g (200 mg). MS m / z(ESI): 360.2[M+1]. Step 7 Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine 43g (200mg, 555.74μmol, crude), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Im-2 (180.17mg, 611.31μmol) and potassium carbonate (230.42mg, 1.67mmol) were dissolved in acetonitrile (10mL). The reaction system was placed in an oil bath for 60 o C for 4 hours. After the reaction was completed, water (10 mL) was added to dilute the reaction solution, extracted with ethyl acetate (20 mLX3), washed with saturated saline (20 mLX2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified using silica gel column chromatography with eluent petroleum ether and ethyl acetate, and then the purified sample was separated by chiral HPLC to obtain the title product methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 43h (100 mg, 161.5 μmol,) in 29.1% yield. MS m / z(ESI):619.2[M+1]. Step 8 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 43h (100 mg, 161.5 μmol) and lithium hydroxide (38.8 mg, 1.62 mmol) were dissolved in 9 mL of a mixed solvent of THF, water and methanol (4:4:1) and reacted for 3 hours with stirring. The reaction was quenched and adjusted to pH=6 by the addition of formic acid, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 43 (60 mg), 61.5% yield. MS m / z(ESI): 605.2[M+1]. 1 H NMR(400MHz,DMSO)δ8.08(d,1H),7.96(d,1H),7.22(d,1H),7.14(d,1H),7.02(d,1H),6.99-6.91( m,2H),6.82(t,1H),6.66(d,1H),5.86(d,1H),5.17-5.11(m,1H),4.86-4.77(m,1H),4.73-4.65(m ,1H),4.51-4.45(m,1H),4.38-4.30(m,1H),3.97-3.84(m,2H),2.98-2.91(m,1H),2.87-2.81(m,1 H),2.76-2.64(m,2H),2.47-2.45(m,1H),2.24-2.09(m,2H),1.70-1.64(m,2H),1.50-1.38(m,2H).

[0179] Example 44 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d Using 4-chloro-2-fluoro<α-2H>benzene(form)aldehyde 44a and 1-(3-bromo-2-hydroxyphenyl)ethan-1-one as raw materials, 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 44b was obtained by referring to the synthesis method of step 1 of Example 1. MS m / z(ESI): 355.9[M+1]. Step 2 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 44b as the raw material, 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 44 was obtained by referring to the synthesis method of Example 33. MS m / z(ESI): 608.1[M+1].

[0180] Example 45 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Step 1 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d Using 4-chloro-2-(methoxy-d3)<α-2H>benzene(form)aldehyde 45a and 1-(3-bromo-2-hydroxyphenyl)ethan-1-one as raw materials, 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 45b was obtained by referring to the synthesis method of step 1 of Example 1. MS m / z(ESI): 371.0[M+1]. Step 2 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 45b as a raw material, 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 45 was obtained by referring to the synthesis method of Example 33. MS m / z(ESI): 623.2[M+1].

[0181] Example 46 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Using intermediate Im1 as a raw material, product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained with reference to Example 40. MS m / z(ESI): 607.2[M+1].

[0182] Example 47 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Using intermediate Im1 as a raw material, product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 42. MS m / z(ESI): 589.2[M+1].

[0183] Example 48 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Method 1 Referring to Example 42, the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained. Method 2 [ka] Step 1 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im7 (20.3 g, 63.56 mmol) and tetrahydrofuran (300 mL) were added to a 1000 mL flask, cooled at 0° C. for 10 minutes, and sodium hydride (7.63 g, 190.67 mmol, 60% purity) was added. Then, 4-chloro-2-fluorobenzaldehyde 48a (10.08 g, 63.56 mmol) was dissolved in THF (100 mL) and slowly added dropwise to the reaction solution over 20 minutes from a constant pressure dropping funnel. After completion, the temperature was raised to 25° C. and the reaction was carried out for 2 hours. The reaction was stopped and the reaction was quenched with saturated aqueous ammonium chloride solution (200 mL), water (50 mL) was added, extracted with ethyl acetate (200 mL x 3), the organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, ethyl acetate (60 mL) was added, triturated (stirred for 15 min), filtered, the filter cake was washed with petroleum ether (30 mL) and dried to give the title product 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 48b (15.2 g), the yield was 52.00%. MS m / z(ESI): 460.1[M+1]. Step 2 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 48b (25 g, 54.36 mmol) and isopropanol (500 mL) were added to a 1000 mL flask, and sodium borohydride (3.08 g, 81.53 mmol) was added at 0° C. Then the reaction was allowed to react at 20° C. for 3 hours. The reaction was stopped, the reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL×3), the organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and spun dry to give the title product 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 48c (25 g), with a yield of 99.56%. MS m / z(ESI): 462.1[M+1]. Step 3 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 48c (25 g, 54.12 mmol) and N,N-dimethylformamide (300 mL) were added to a 500 mL flask, and p-toluenesulfonic acid (13.98 g, 81.18 mmol) was added at 25° C. The reaction solution was then reacted at 50° C. for 4 hours. The reaction was stopped, the reaction solution was quenched with water (200 mL), extracted with ethyl acetate (200 mL x 3), the organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 48d (13 g), with a yield of 54.11%. MS m / z(ESI): 444.1[M+1]. Step 4 (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester Chiral separation of 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 48d gave (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 48e. Split condition OD-H4.6*150 Hexane:IPA:DEA=90:10:0.1% F = 1mL T = 35°C MS m / z(ESI): 444.1[M+1]. Step 5 (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 48e (2.55 g, 5.74 mmol) and dichloromethane (50 mL) were added to a 100 mL flask, and 4A molecular sieves (2.55 g) and boron trifluoride diethyl etherate (2.04 g, 14.36 mmol) were added at 0° C. The reaction was then allowed to react at 0° C. for 2 hours. The reaction was stopped and the reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL), water (10 mL) was added, extracted with dichloromethane (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and spun to dryness to give the title product (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine 48f (1.97 g,) in 100% yield. MS m / z(ESI):344.1[M+1] Step 6 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine 48f (1.97 g, 5.73 mmol) and acetonitrile (50 mL) were added to a 100 mL flask, and potassium carbonate (1.58 g, 11.46 mmol) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Im2 (1.69 g, 5.73 mmol) were added at 25° C. The reaction solution was then reacted at 25° C. for 10 hours. The reaction was stopped, the reaction solution was quenched with aqueous solution (20 mL), extracted with dichloromethane (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 48g (3.1 g,), yield 89.71%. MS m / z(ESI):603.2[M+1] Step 7 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 48g (3.1g, 5.14mmol) and methanol (25mL) were added to a 100mL flask, and lithium hydroxide (1.23g, 51.40mmol) was dissolved in water (10mL) and added dropwise to the reaction solution at 25°C. The reaction solution was then reacted at 25°C for 1 hour. The reaction was stopped, the reaction solution was quenched with formic acid (1 mL), water (20 mL) was added, extracted with dichloromethane (20 mL x 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spun dry, and the resulting residue was separated and purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 48 (2.1 g,) in 69.35% yield. MS m / z(ESI):589.1[M+1] 1 H NMR(400MHz,MeOD)δ8.14-8.03(m,2H),7.40(t,1H),7.25(dd,1H),7.15(dd,1H),7.05(dd,1H),6.92(dd,1H), 6.84(t,1H),6.68(dd,1H),6.21(dd,1H),5.82(dd,1H),5.30-5.24(m,1H),5.03-4.93(m,1H),4.85-4.81(m,1 H),4.64-4.54(m,1H),4.45-4.35(m,1H),4.23(d,1H),4.13(d,1H),3.25-3.18(m,1H),3.12-3.05(m,1H),2.9 5-2.85(m,1H),2.83-2.70(m,1H),2.57-2.38(m,3H),1.88-1.78(m,2H),1.78-1.63(m,1H),1.59-1.51(m,1H).

[0184] Example 49 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] The product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 41. MS m / z(ESI): 622.2[M+1].

[0185] Example 50 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] The product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 43. MS m / z(ESI): 604.2[M+1].

[0186] Example 51 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] Using 4-cyano-2-fluorobenzaldehyde and intermediate Im-2 as raw materials, product 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Example 42. MS m / z(ESI): 580.2[M+1]. 1 H NMR(400MHz,MeOD)δ8.13-8.02(m,2H),7.71-7.57(m,2H),7.55-7.49(m,1H),7.15-7.02(m,1H),6.97-6.91(m ,1H),6.92-6.83(m,1H),6.73-6.64(m,1H),6.33-6.25(m,1H),5.89-5.80(m,1H),5.37-5.18(m,1H),5.05-4. 92(m,1H),4.84-4.79(m,1H),4.72-4.58(m,1H),4.52-4.39(m,1H),4.35-4.19(m,2H),3.29-3.25(m,1H),3.2 1-3.12(m,1H),3.02-2.86(m,1H),2.82-2.69(m,1H),2.65-2.42(m,3H),1.98-1.72(m,3H),1.68-1.59(m,1H).

[0187] Example 52 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Using 4-cyano-2-fluorobenzaldehyde and intermediate Im-1 as raw materials, product 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 42. MS m / z(ESI): 579.2[M+1]. 1 H NMR(400MHz,DMSO)δ8.25(d,1H),7.95(dd,1H),7.79(dd,1H),7.70(dd,1H),7.62(d,1H),7.52(t,1H),7. 07(dd,1H),6.99(dd,1H),6.87(t,1H),6.75(dd,1H),6.33(dd,1H),5.93(dd,1H),5.11-5.00(m,1H),4.85 -4.71(m,1H),4.67-4.58(m,1H),4.52-4.44(m,1H),4.42-4.31(m,1H),3.92(d,1H),3.75(d,1H),3.04-2. 92(m,1H),2.83-2.62(m,3H),2.46-2.38(m,1H),2.23-2.02(m,2H),1.73-1.56(m,2H),1.48-1.34(m,2H).

[0188] Example 53 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Using Im-1 as a raw material, the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 48. MS m / z(ESI): 588.2[M+1]. 1 H NMR(400MHz,MeOD)δ8.30(s,1H),7.96(dd,1H),7.66(d,1H),7.40(t,1H),7.25(s,1H),7.16(d,1H),7 .04(dd,1H),6.92(dd,1H),6.83(d,1H),6.68(dd,1H),6.23-6.19(m,1H),5.83(dd,1H),5.27-5.20(m ,1H),4.85-4.80(m,1H),4.74-4.62(m,2H),4.48-4.41(m,1H),4.05(d,1H),3.95(d,1H),3.12-3.05( m,1H),2.94-2.77(m,3H),2.55-2.46(m,1H),2.39-2.25(m,2H),1.82-1.73(m,2H),1.66-1.50(m,2H).

[0189] Example 54 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester [ka] The product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester was obtained by referring to Example 48. MS m / z(ESI):603.2[M+1].

[0190] Example 55 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile [ka] Step 1 (S)-2-Bromo-4-nitro-5-((oxetan-2-ylmethyl)amino)pyridine 1-oxide Starting from 2-bromo-5-fluoro-4-nitropyridine N-oxide, the product (S)-2-bromo-4-nitro-5-((oxetan-2-ylmethyl)amino)pyridine 1-oxide was obtained by referring to step 1 of intermediate Im-1. MS m / z(ESI): 303.9[M+1]. Step 2 (S)-6-Bromo-N3-(oxetan-2-ylmethyl)pyridine-3,4-diamine At room temperature, ((S)-2-bromo-4-nitro-5-((oxetan-2-ylmethyl)amino)pyridine 1-oxide (1 g, 3.28 mmol) and Zn powder (2.1 g, 32.8 mmol) were dissolved in methanol (25 mL), and acetic acid (985 mg, 16.4 mmol) was added dropwise. o The mixture was heated to C and stirred for 2 hours. It was cooled to room temperature, filtered, the filtrate was adjusted to pH=7 with saturated sodium bicarbonate, extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and spun to dryness to give the title product (S)-6-bromo-N3-(oxetan-2-ylmethyl)pyridine-3,4-diamine (804 mg) in 95% yield. MS m / z(ESI): 258.0[M+1]. Step 3 (S)-4-Amino-5-((oxetan-2-ylmethyl)amino)pyridinecarbonitrile (S)-6-bromo-N3-(oxetan-2-ylmethyl)pyridine-3,4-diamine (500 mg, 1.94 mmol), RuPhos-Pd-G3 (324.5 mg, 0.39 mmol), X-Phos (186 mg, 0.39 mmol) and Zn(CN) were added at room temperature. 2 (458 mg, 3.9 mmol) was dissolved in NMP (15 mL), and the nitrogen gas was replaced three times. oThe mixture was heated to C and stirred for 0.5 hours. It was cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product (S)-4-amino-5-((oxetan-2-ylmethyl)amino)pyridinecarbonitrile (345 mg), with a yield of 87.1%. MS m / z(ESI): 205.1[M+1]. Step 4 (S)-2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile Starting from (S)-4-amino-5-((oxetan-2-ylmethyl)amino)pyridinecarbonitrile, the product (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile was obtained by referring to step 3 of intermediate Im-2. MS m / z(ESI):263.0[M+1]. Step 5 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile Using (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine as raw materials, product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile was obtained by referring to step 6 of Example 48. MS m / z(ESI): 570.2[M+1]. Step 6 Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate At room temperature, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (500 mg, 0.88 mmol) was dissolved in methanol (15 mL), sodium methoxide (95 mg, 1.76 mmol) was added, and the mixture was stirred at room temperature for 24 hours. 20 mL of water was added, extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun dry to give the title product methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate (450 mg), 85% yield. MS m / z(ESI): 602.2[M+1]. Step 7 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate (100 mg, 0.17 mmol) and 2-hydrazino-2-oxoacetamide (35 mg, 0.34 mmol) were dissolved in n-butanol (5 mL), DIEA (66 mg, 0.51 mmol) was added, and the mixture was purged with nitrogen gas three times. The mixture was then stirred at 120° C. for 30 minutes under nitrogen gas protection. oC for 16 hours. Cool to room temperature, add 20 mL of water, extract with ethyl acetate (30 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, spin dry, and purify the resulting residue using silica gel column chromatography with eluent system dichloromethane and methanol to obtain the title product 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (67 mg), yield 60%. MS m / z(ESI): 655.2[M+1]. Step 8 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (50 mg, 0.076 mmol) and DIEA (30 mg, 0.23 mmol) were dissolved in DCM, TFAA (24 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. 50 mL of water was added, extracted with ethyl acetate (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was separated and purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile (12 mg), yield 25%. MS m / z(ESI): 637.2[M+1].

[0191] Example 56 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine [ka] Step 1 (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-formamidine 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (50 mg, 0.088 mmol), DIEA (57 mg, 0.44 mmol) and hydroxylamine hydrochloride (12 mg, 0.18 mmol) were dissolved in ethanol (5 mL) and diluted with 90 mL of ethanol. o C for 2 h. Filtration and spin drying of the solid afforded the title product (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-formamidine (21.2 mg) in 40% yield. MS m / z(ESI):603.2[M+1]. Step 2 3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl-3H-imidazo[4,5-c]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-formamidine (50 mg, 0.083 mmol) and trifluoroacetic anhydride TFAA (87 mg, 0.42 mmol) were dissolved in THF (5 mL) and 60 o C for 2 hours. 10 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system dichloromethane and methanol to obtain the title product (3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl-3H-imidazo[4,5-c]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (41.3 mg), yield 73%. MS m / z(ESI): 681.2[M+1]. Step 3 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl-3H-imidazo[4,5-c]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (50 mg, 0.073 mmol) and 2 drops of hydrazine hydrate were dissolved in DMF (2 mL) and stirred at room temperature for 2 hours. Filtered and spun. Upon drying, the resulting residue was separated and purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (21 mg), yield 42%. MS m / z(ESI):680.2[M+1].

[0192] Example 57 3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one [ka] (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-formamidine (50 mg, 0.083 mmol) and CDI (27 mg, 0.166 mmol) were dissolved in DMF (2 mL) and 80 oC for 2 h. Filtration, spin drying, and the resulting residue were separated and purified by prep-HPLC to give the title product 3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (20.9 mg) in 40% yield. MS m / z(ESI):629.2[M+1].

[0193] Example 58 2-((4-((R)-2-(4-aminoformyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg, 172.52 μmol) and ethanol (5 mL) were added to a 25 mL flask, and potassium hydroxide (96.79 mg, 1.73 mmol) was dissolved in water (1 mL) and added dropwise to the reaction solution at 25° C. The reaction solution was then reacted at 80° C. for 2 hours. The reaction was stopped and cooled to 25° C., the reaction was quenched with formic acid (0.1 mL), water (2 mL) was added, extracted with dichloromethane (2 mL×3), the organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, spun dry, and the resulting residue was separated and purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-aminoformyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (40 mg), yield 38.79%. MS m / z(ESI):598.2[M+1]

[0194] Example 59 2-((4-((R)-2-(4-aminoformyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (100 mg, 172.82 μmol) and ethanol (5 mL) were added to a 25 mL flask, potassium hydroxide (96.96 mg, 1.73 mmol) was dissolved in water (1 mL) and added dropwise to the reaction solution at 25° C. Then the reaction solution was reacted at 80° C. for 2 hours. The reaction was stopped and cooled to 25° C., the reaction was quenched with formic acid (0.1 mL), water (2 mL) was added, extracted with dichloromethane (2 mL×3), the organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, spun dry, and the resulting residue was separated and purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-aminoformyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (35 mg), yield 33.94%. MS m / z(ESI):597.2[M+1]

[0195] Example 60 2-((4-((R)-2-(4-(dimethylaminoformyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 3-Fluoro-4-formyl-N,N-dimethylbenzamide 3-Fluoro-4-formylbenzoic acid (5g, 29.74mmol) was dissolved in N,N-dimethylformamide (50mL) and dimethylamine (1.34g, 29.74mmol), HATU (11.30g, 29.74mmol), DIEA (3.84g, 29.74mmol) were added to the reaction. The reaction was allowed to react for 8 hours under stirring at 25°C. The reaction was stopped, water (50mL) was added, extracted with dichloromethane (30mL x 3), the organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product 3-fluoro-4-formyl-N,N-dimethylbenzamide (4.5g) with a yield of 77.52%. MS m / z(ESI): 196.0[M+1]. Step 2 2-((4-((R)-2-(4-(dimethylaminoformyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 3-fluoro-4-formyl-N,N-dimethylbenzamide as a raw material, the target product 2-((4-((R)-2-(4-(dimethylaminoformyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 48. MS m / z(ESI): 625.2[M+1].

[0196] Example 61 2-((4-((R)-2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] Step 1 (R)-4-(2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester (R)-4-(2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.30 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL flask, and cyclopropylmagnesium bromide (2.3 mL, 1 M, 2.30 mmol) was added at 0° C., and the reaction was allowed to react at 80° C. for 12 h. The reaction was cooled to 0° C., and 2N hydrochloric acid (2 mL) was added to the reaction, and the reaction was allowed to continue for 2 h at 0° C., and then neutralized with a saturated solution of sodium bicarbonate. Extraction with ethyl acetate (20 mL×3) and washing the organic phase with saturated sodium chloride solution (20 mL), drying over anhydrous sodium sulfate, filtering, spin drying and purifying the resulting residue using silica gel column chromatography with eluent system petroleum ether and ethyl acetate to obtain the title product (R)-4-(2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester (0.6 g) in a yield of 54.59%. MS m / z(ESI):478.2[M+1] Step 2 2-((4-((R)-2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using (R)-4-(2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester as a raw material, the target product 2-((4-((R)-2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to steps 5 to 7 of Example 48. MS m / z(ESI): 622.2[M+1]. Biological Test Evaluation The present invention will be further described below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0197] 1. Measurement of the ability of the compounds of the present invention to stimulate cAMP production by human GLP1 receptor-stabilized transgenic cell lines 1. Purpose of the experiment: The purpose of this experimental example is to test the ability of compounds to activate human GLP-1 receptors on the cell surface. EC2 activation stimulates AMP production after agonism. 50 characterize the activation ability of compounds towards the human GLP-1 receptor. 2. Experimental Reagents and Equipment: 2.1 Experimental equipment: Microplate reader (BioTek Synergy H1), Pipettes (Eppendorf & Rainin). 2.2 Experimental Reagents: DMEM / F12 medium, purchased from Gibco, catalog number 11330032; Casein, purchased from Sigma, catalog number C3400; 384-well plates purchased from Sigma, catalog number CLS4514; IBMX, purchased from Sigma and with catalog number I7018; Cisbio cAMP-Gs Dynamic kit was purchased from Cisbio and has the catalog number 62AM4PEC. 3. Experimental Method: The frozen human GLP1 receptor stabilized transgenic cell line CHO-K1 / GLP-1R / CRE-luc was taken out of the liquid nitrogen tank, and quickly thawed in a water bath at 37℃, resuspended in DMEM / F12 medium, centrifuged, washed once, and resuspended in experimental buffer, i.e., DMEM / F12 medium containing 0.1% casein, and adjusted cell density with experimental buffer, seeded in a 384-well plate at a density of 2500 cells / 5μL / well, and added 2.5μL of IBMX working solution prepared with buffer and with a final IBMX concentration of 0.5mM, and 2.5μL of gradient diluted compound sample (starting from 1000nM, diluted 3-fold, 11 concentrations), centrifuged at 1000rpm for 1min, shaken for 30 seconds to mix evenly, and incubated at room temperature for 30 minutes. Detected using Cisbio cAMP-Gs Dynamic kit, and cAMP-d2 and Anti-cAMP-Eu 3+ -Cryptate was diluted 20-fold with cAMP Lysis & Detection Buffer and mixed uniformly. 5 μL of diluted cAMP-d2 solution was added to each well, followed by diluted Anti-cAMP-Eu3 + 5 μL of -Cryptate solution was added, and the mixture was mixed uniformly by shaking for 30 seconds, and incubated at room temperature for 1 hour in the dark. HTRF signal reading was performed using a Biotek Synergy H1 microplate reader, with an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm. 4. How to process the experimental data: The signal ratio (665 nm / 620 nm*10,000) was calculated, and nonlinear fitting was performed on the signal ratio and sample concentration using a four-parameter equation in GraphPad Prism 6 to obtain the EC 50 Got the value. 5. Experimental Results:

[0198] [Table 1] 6. Experimental Conclusion From the above scheme, it has become clear that the compounds of the examples of the present invention exhibit good biological activity in the experiment of stimulating cAMP production by a human GLP1 receptor-stabilized transgenic cell line.

[0199] 2. The effect of a single dose of the compound of the present invention on intraperitoneal glucose tolerance in GLP-1R humanized mice 1. Purpose of the test: The effect of a single dose of a compound of the invention on glycemic changes in an intraperitoneal glucose tolerance (ipGTT) experiment in GLP-1R humanized C57BL / 6 mice is evaluated. 2. Materials: C57BL / 6_hGLP-1R, male, 5-8 weeks old, clean bench, electronic balance, active blood glucose meter, glucose. 3. Experimental Procedures and Data Processing: 3.1. On the day before the experiment, the animals were randomly divided into groups of 5 animals each according to their weight. All animals were fasted overnight after food was removed, and were fasted for at least 16 hours until the time of administration. 3.2. Prepare a 0.2 g / mL glucose solution in pure water, filter it through a 0.22 μm filter membrane, and then wait. 3.3. On the day of the test, measure the blood glucose level of each animal by tail cut method before administration and record it as the baseline value. Blood glucose test method: Place the mouse in a restrainer, disinfect the tip of the tail with an alcohol cotton ball, and then cut off a small part of the tip of the tail with scissors. After discarding the first drop of blood, drop the second drop of blood onto the blood glucose test paper to measure the blood glucose level. 3.4. The animals were administered according to their body weight, and the administration time for each animal was recorded. One hour after administration, the blood glucose level of each animal was measured sequentially and recorded as the 0 min blood glucose level. 3.5, then immediately intraperitoneally injected pure water or glucose solution according to the body weight of that day, the volume is 10mL / kg, and the glucose dose is 2g / kg; 3.6. Measure the blood glucose level of each mouse at 15, 30, 60, 90 and 120 min after injection of pure or glucose solution, respectively, and record the time and data; 3.7 After the study was completed, all animals were re-fed. 3.8. Data Processing: A blood glucose (BG)-time curve was created and the area under the blood glucose-time curve was calculated using the following formula:

number

number

[0200] [Table 2] 5. Experimental Conclusion The above experimental results demonstrate that the compounds of the examples of the present invention can effectively lower blood glucose in mice.

[0201] 3. Effects of long-term administration of the compound of the present invention on body weight and food intake in GLP-1R humanized mice fed a high-fat diet 1. Purpose of the experiment: The aim of the study is to evaluate the effect of chronic administration of the compound on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high fat diet. 2. Experimental Reagents and Equipment C57BL / 6_hGLP-1R, male, 5-8 weeks old, 60% high fat diet (HFD), clean bench, electronic balance. 3. Experimental Method 3.1 On the day when the high-fat diet was started, C57BL / 6 mice were randomly divided into two groups according to their body weight. The first group was the blank group, which consisted of 7 animals, and was fed with normal control diet; the remaining animals were the model group, which was fed with high-fat diet until the end of the experiment. 3.2 On the 8th week of HFD feeding, the animals in the modeling group were randomly divided into groups of 7 animals each according to body weight, the first group was the vehicle group (Vehicle: 0.5% CMC-Na + 1% Tween 80) and was given the solvent, the remaining groups were the treatment groups, and the administration scheme was: the corresponding compound was orally administered once a day for a 14-day administration period, the dose was 10 mg / kg, and the administration volume was 10 mL / kg. The blank group continued to be given normal chow without any administration manipulation. 3.3 The day of administration was defined as Day 0. 3.4 Every time the animals were administered, they were weighed and the data were recorded, and the animals were orally administered according to their body weight, with the administration volume being 10 mL / kg. 3.5 From day 0 of the experiment, the food intake of the mice in each group was measured once every three days. Specifically, the mice were weighed and the food was replaced every time they were administered, and the added and surplus amounts were recorded. 3.6 On the final day of Day 14, all mice were euthanized sequentially according to grouping order, dissected, and the livers were removed and weighed. 4. Experimental data processing and statistical analysis The body weight and body weight change rate of the mice after administration were collected and analyzed. Body weight change rate calculation: (BWt-BW0) / BW0×100%. BWt represents the body weight of the mice on day t of the experiment, and BW0 represents the body weight of the mice on day 0 of the experiment. Food intake calculation is (additional amount (g) - residual amount (g)) / number of animals per cage, and cumulative food intake is the sum of each animal's daily food intake during the treatment period. The experimental data were analyzed with GraphPad Prism software. Comparisons between two groups were tested by the t-test method. Comparisons between three or more groups were tested by the one-way ANOVA method. 5. Experimental Results

[0202] [Table 3]

[0203] [Table 4] 6. Experimental Conclusion The above experimental results show that long-term administration of the compounds according to the examples of the present invention has a good weight loss effect on GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[0204] 4. Pharmacokinetics in SD rats 1. Research purpose: SD rats were used as test animals, and the pharmacokinetic behavior of the following compound examples in rat plasma when orally administered at a dose of 50 mg / kg was examined. 2. Test Scheme 2.1 Test Drugs: Solvent formulation: 0.5% CMC-Na (1% Tween 80), Example of the present invention, homemade. 2.2 Test animals: SD rats, 3 per group, male. 2.3 Administration: Three male SD rats per group were each administered PO after overnight fasting, with a dose of 50 mg / kg and an administration volume of 10 mL / kg. 2.4 Sampling: Before administration and at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, 0.2 mL of blood was collected from the jugular vein of each rat. 2 The mixture was placed in a test tube and centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, which was then stored at -80°C and fed to the subjects 4 h after administration. 2.5 Sample processing: 1) 40uL of plasma sample was added to 160uL of acetonitrile to precipitate, mixed, and then centrifuged at 3500xg for 5-20 minutes. 2) 100 uL of the treated supernatant solution was taken and the concentration of the test compound was analyzed by LC / MS / MS. 2.6 Liquid phase analysis Liquid phase conditions: Shimadzu LC-20AD pump · Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer Chromatography column: phenomenex Gemiu 5um C18 50×4.6mm Mobile phase: Solution A is 0.1% formic acid in water, and solution B is methanol. · Flow rate: 1.0mL / min The elution time was 0 to 4.0 minutes, and the eluent was as follows:

[0205] [Table 5] 3. Test results and analysis The main pharmacokinetic parameters were calculated with WinNonlin 8.2. 4. Test Results

[0206] [Table 6] 5. Test conclusion: From the results of the pharmacokinetic experiments in rats in the table, the compounds of the examples of the present invention showed good metabolic properties at a dose of 50 mg / kg, and the exposure amount AUC and maximum blood concentration C max Both were shown to be good.

Claims

1. A compound represented by the general formula (I'), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 [Chemical 2] is a single bond or a double bond, ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may optionally be further substituted, or ring B is absent, ring C is selected from an aryl group or a heteroaryl group, preferably a phenyl group or a pyridyl group, L １ is a combination, an alkenylene group, an alkynylene group, -(CH ２ ) ｎ１ -, -(CH ２ ) ｎ１ (CR ａａ R ｂｂ ) ｎ２ -, -(CR ａａ R ｂｂ ) ｎ１ O(CH ２ ) ｎ２ -, -(CH ２ ) ｎ１ O(CR ａａ R ｂｂ ) ｎ２ -, -(CR ａａ R ｂｂ ) ｎ１ S(CH ２ ) ｎ２ -, -(CH ２ ) ｎ１ S(CR ａａ R ｂｂ ) ｎ２ -, -(CR ａａ R ｂｂ ) ｎ１ (CH ２ ) ｎ２ NR ｃｃ -, -(CH ２ ) ｎ１ NR ａａ (CR ｂｂ R ｃｃ ) ｎ２ -, -(CH ２ ) ｎ１ C(O)(CR ａａ R ｂｂ ) ｎ２ -, -(CH ２ ) ｎ１ NR ａａ C(O)(CR ａａ R ｂｂ ) ｎ２ -, -(CH ２ ) ｎ１ P(O)R ａａ -, -(CH ２ ) ｎ１ S(O) ｍ１ -, -(CH ２ ) ｎ１ S(O) ｍ１ NR ａａ -, -(CH ２ ) ｎ１ NR ａａ S(O) ｍ１ - or -(CH ２ ) ｎ１ C(O)NR ａａ selected from, R ａａ , R ｂｂ and R ｃｃ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, carboxyl group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, deuterated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, Or, R ａａ , R ｂｂ and R ｃｃ Any two of which may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group may optionally be further substituted, L ２ is a bond, an alkenylene group, an alkynylene group, -(CH ２ ) ｎ３ -, -(CH ２ ) ｎ３ (CR ａ１ R ｂ１ ) ｎ４ -, -(CR ａ１ R ｂ１ ) ｎ３ O(CH ２ ) ｎ４ -, -(CH ２ ) ｎ３ O(CR ａ１ R ｂ１ ) ｎ４ -, -(CR ａ１ R ｂ１ ) ｎ３ S(CH ２ ) ｎ４ -, -(CH ２ ) ｎ３ S(CR ａ１ R ｂ１ ) ｎ４ -, -(CR ａ１ R ｂ１ ) ｎ３ (CH ２ ) ｎ４ NR ｃ１ -, -(CH ２ ) ｎ３ NR ａ１ (CR ｂ１ R ｃ１ ) ｎ４ -, -(CH ２ ) ｎ３ C(O)(CR ａ１ R ｂ１ ) ｎ４ -, -(CH ２ ) ｎ３ NR ａ１ C(O)(CR ａ１ R ｂ１ ) ｎ４ -, -(CH ２ ) ｎ３ P(O)R ａ１ -, -(CH ２ ) ｎ３ S(O) ｍ２ -, -(CH ２ ) ｎ３ S(O) ｍ２ NR ａ１ -, -(CH ２ ) ｎ３ NR ａ１ S(O) ｍ２ - or -(CH ２ ) ｎ３ C(O)NR ａ１ selected from, R ａ１ , R ｂ１ and R ｃ１ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, carboxyl group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. or, R ａ１ does not exist, or R ａ１ 、R ｂ１ and R ｃ１ any two of which may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group may optionally be further substituted, L ３ represents a bond, an alkenylene group, an alkynylene group, -(CH ２ ) ｎ５ -, -(CH ２ ) ｎ５ (CR ａ２ R ｂ２ ) ｎ６ -, - (CR ａ２ R ｂ２ ) ｎ５ O (CH ２ ) ｎ６ -, -(CH ２ ) ｎ５ O (CR ａ２ R ｂ２ ) ｎ６ -, - (CR ａ２ R ｂ２ ) ｎ５ S (CH ２ ) ｎ６ -, -(CH ２ ) ｎ５ S (CR ａ２ R ｂ２ ) ｎ６ -, - (CR ａ２ R ｂ２ ) ｎ５ (CH ２ ) ｎ６ NR ｃ２ -, -(CH ２ ) ｎ５ NR ａ２ (CR ｂ２ R ｃ２ ) ｎ６ -, -(CH ２ ) ｎ５ C(O)(CR ａ２ R ｂ２ ) ｎ６ -, -(CH ２ ) ｎ５ NR ａ２ C(O)(CR ａ２ R ｂ２ ) ｎ６ -, -(CH ２ ) ｎ５ P(O)R ａ２ -, -(CH) ｎ (CH ２ ) ｎ５ S (O) ｍ３ -, -(CH ２ ) ｎ５ S (O) ｍ３ NR ａ２ -, -(CH ２ ) ｎ５ NR ａ２ S(O) ｍ３ - or -(CH ２ ) ｎ５ C(O)NR ａ２ selected from, R ａ２ , R ｂ２ and R ｃ２ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, carboxyl group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. Or, R ａ２ does not exist, W is selected from CR ｍ or N, R ｍ is selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and optionally may be further substituted; L ４ is a bond, -(CH ２ ) ｎ７ -, -(CH ２ ) ｎ７ (CR ａ３ R ｂ３ ) ｎ８ -, -(CR ａ３ R ｂ３ ) ｎ７ O(CH ２ ) ｎ８ -, -(CH ２ ) ｎ７ O(CR ａ３ R ｂ３ ) ｎ８ -, -(CR ａ３ R ｂ３ ) ｎ７ S(CH ２ ) ｎ８ -, -(CH ２ ) ｎ７ S(CR ａ３ R ｂ３ ) ｎ８ -, -(CR ａ３ R ｂ３ ) ｎ７ (CH ２ ) ｎ８ NR ｃ３ -, -(CH ２ ) ｎ７ NR ａ３ (CR ｂ３ R ｃ３ ) ｎ８ -, -(CH ２ ) ｎ７ C(O)(CR ａ３ R ｂ３ ) ｎ８ -, -(CH ２ ) ｎ７ NR ａ３ C(O)(CR ａ３ R ｂ３ ) ｎ８ -, -(CH ２ ) ｎ７ P(O)R ａ３ -, -(CH ２ ) ｎ７ S(O) ｍ４ -, -(CH ２ ) ｎ７ S(O) ｍ４ NR ａ３ -, -(CH ２ ) ｎ７ NR ａ３ S(O) ｍ４ - or -(CH ２ ) ｎ７ C(O)NR ａ３ selected from - R ａ３ , R ｂ３ and R ｃ３ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, carboxyl group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and optionally may be further substituted, or, R ａ３ , R ｂ３ and R ｃ３ any two of which may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and optionally may be further substituted, R １ is, independently of each other, hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, deuterated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｎ１ C(O)R ａａ or -(CH ２ ) ｎ１ C(O)NR ａａ R ｂｂ and is selected from, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. Or, any two Rs １ combine to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, Or, R １ and L １ are combined to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. R ２ is independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, Or, any two Rs ２ combine to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. Or, R ２ and L １ are combined to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group may optionally be further substituted. or, R ２ and L ２ are combined to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. or R ２ and R ３ are combined to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group may optionally be further substituted. R ３ is, independently of one another, selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, mercapto group, oxo group, thio group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the amino group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, Or, any two Rs ３ may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted, or, R ３ and L ２ are combined to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. Or, R ３ and L ３ are combined to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may optionally be further substituted. R ４ is, independently of one another, hydrogen, deuterium, halogen, oxo group, amino group, nitro group, hydroxy group, C １－６ carboxyl group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and optionally may be further substituted, R ５ is selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and optionally may be further substituted, M １ is O, S, N, C, (CH) ｎ９ , (CH ２ ), ｎ９ (CH ２ ), ｎ９ (CH ２ ), ｎ９ NH or (CH ２ ), ｎ９ and M ２ is O, S, N, C, (CH) ｎ１０ , (CH ２ ) ｎ１０ O, (CH ２ ) ｎ１０ S, (CH ２ ) ｎ１０ NH or (CH ２ ) ｎ１０ and x is an integer from 0 to 12, y is an integer from 0 to 12, z is an integer from 0 to 12, p is an integer from 0 to 4, n1 to n6 are each independently an integer from 0 to 3, n7 to n10 are each independently an integer from 0 to 3, m1 to m3 are each independently an integer from 0 to 2, and m4 is an integer from 0 to 2, the compound, its stereoisomer, or its pharmaceutically acceptable salt.

2. The compound is further as shown in the general formula (I), 【Chemical 3】 L ４ is a bond, -(CH ２ ) ｎ７ -, -(CH ２ ) ｎ７ (CR ａ３ R ｂ３ ) ｎ８ -, -(CR ａ３ R ｂ３ ) ｎ７ O(CH ２ ) ｎ８ -, -(CH ２ ) ｎ７ O(CR ａ３ R ｂ３ ) ｎ８ -, -(CR ａ３ R ｂ３ ) ｎ７ S(CH ２ ) ｎ８ -, -(CH ２ ) ｎ７ S(CR ａ３ R ｂ３ ) ｎ８ -, -(CR ａ３ R ｂ３ ) ｎ７ (CH ２ ) ｎ８ NR ｃ３ -, -(CH ２ ) ｎ７ NR ａ３ (CR ｂ３ R ｃ３ ) ｎ８ -, -(CH ２ ) ｎ７ C(O)(CR ａ３ R ｂ３ ) ｎ８ -, -(CH ２ ) ｎ７ NR ａ３ C(O)(CR ａ３ R ｂ３ ) ｎ８ -, -(CH ２ ) ｎ７ P(O)R ａ３ -, -(CH ２ ) ｎ７ S(O) ｍ４ -, -(CH ２ ) ｎ７ S(O) ｍ４ NR ａ３ -, -(CH ２ ) ｎ７ NR ａ３ S(O) ｍ４ - or -(CH ２ ) ｎ７ C(O)NR ａ３ selected from, R ａ３ 、 R ｂ３ and R ｃ３ are each independently selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, carboxyl group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and optionally may be further substituted, or R ａ３ 、R ｂ３ and R ｃ３ any two of which may combine to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, and optionally may be further substituted, R ４ is independently selected from hydrogen, deuterium, halogen, oxo group, amino group, nitro group, hydroxy group, carboxyl group, cyano group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and optionally may be further substituted. R ５ is selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, thio group, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, alkoxy group, halogenated alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and optionally may be further substituted, M １ is O, S, N, C, (CH) ｎ９ , (CH ２ ), ｎ９ (CH ２ ), ｎ９ (CH ２ ), ｎ９ NH or (CH ２ ), ｎ９ and M ２ is O, S, N, C, (CH) ｎ１０ , (CH ２ ), ｎ１０ , (CH ２ ), ｎ１０ , (CH ２ ), ｎ１０ , NH or (CH ２ ), ｎ１０ and p is an integer from 0 to 4, n7 to n10 are each independently an integer from 0 to 3, m4 is an integer from 0 to 2, the compound, its stereoisomer, or its pharmaceutically acceptable salt according to Claim 1, characterized in that.

3. Ring B is C ３－１２ a cycloalkyl group, a 3- to 12-membered heterocyclyl group, C ６－１４ selected from an aryl group or a 5- to 14-membered heteroaryl group, Preferably, C ３－８ is a cycloalkyl group, a 4- to 12-membered heterocyclyl group, a C ６－１０ aryl group or a 5- to 10-membered heteroaryl group, More preferably, C ５－８ a cycloalkyl group, a 5- to 10-membered heterocyclyl group containing 1 to 3 N, O or S atoms, C ６－８ an aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 N, O or S atoms, More preferably, it is a piperidinyl group or a piperazinyl group, and even more preferably, it is a piperidinyl group, the compound, its stereoisomer, or its pharmaceutically acceptable salt according to Claim 1, characterized in that.

4. The compound is further as shown in the general formula (II'), 【Chemical Formula 4】 W １ is selected from CH or N, W ２ is selected from CR ｍ５ or N, and R １ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ alkoxy group, C １－６ deuterated alkoxy group, C １－６ halogenated alkoxy group, -C(O)R ａａ or -C(O)NR ａａ R ｂｂ and is selected from R ａａ and R ｂｂ each independently represents hydrogen, deuterium, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and is selected from R ２ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ alkoxy group or C １－６ halogenated alkoxy group, and is selected from the group consisting of: R ３ each independently selected from hydrogen, deuterium, fluorine, a methyl group, a deuterated methyl group or a halogenated methyl group, R ｍ５ is selected from hydrogen, deuterium, fluorine, chlorine, cyano group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ alkoxy group, C １－６ deuterated alkoxy group or C １－６ halogenated alkoxy group, preferably hydrogen, deuterium, fluorine, chlorine, cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, more preferably hydrogen or deuterium, R ４ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, cyano group, oxo group, C １－６ carboxyl group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group or a substituted or unsubstituted 5- to 6-membered heteroaryl group, and optionally, the C １－６ carboxyl group is further substituted with one or more substituents selected from halogen and C １－６ alkyl group, preferably a carboxyl group or -C(O)OCH ３ and is R ５ is a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C １－６ hydroxyalkyl group, a C １－６ alkoxy group, a C １－６ halogenated alkoxy group, a C ３－８ cycloalkyl group, a 3- to 8-membered heterocyclyl group, a C ６－１０ aryl group or a 5- to 10-membered heteroaryl group, optionally substituted with a halogen, a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C １－６ hydroxyalkyl group, a C １－６ alkoxy group, a C １－６ halogenated alkoxy group, a C １－６ cyanoalkyl group, a C ３－８ substituted further with one or more substituents of a cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C ３－８ cycloalkyl group, a 3- to 8-membered heterocyclyl group, optionally substituted with a halogen, a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C １－６ cyanoalkyl group, a C ３－８ substituted further with one or more substituents of a cycloalkyl group or a 3- to 8-membered heterocyclyl group, L １ and L ２ are each independently selected from a bond or -(CH ２ ) ｎ１ -, preferably a bond L ３ is selected from a bond or -(CH ２ ) ｎ１ -, preferably -CH ２ -, and L ４ is selected from a bond or -(CH ２ ) ｎ７ -, preferably a bond or -CH ２ -, and M １ is N, NH, O, S, C or (CH) ｎ９ and M ２ is N, NH, O, S, C or (CH) ｎ１０ and n9 or n10 is each independently an integer from 0 to 2, the compound, its stereoisomer, or its pharmaceutically acceptable salt according to Claim 1, characterized in that.

5. The compound is further as shown in the general formula (II'-a) or (II'-b) 【Chemical Formula 5】 as shown, the compound, its stereoisomer, or its pharmaceutically acceptable salt according to Claim 1, characterized in that.

6. The compound is further as shown in the general formula (II), 【Chemical Formula 6】 R １ is, independently of one another, hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ deuterated alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, optionally further substituted with one or more substituents selected from halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, and is further substituted with one or more of the substituents thereof, Or, any two Rs １ are combined to form C ３－８ a cycloalkyl group, a 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, and the C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group are optionally further substituted with one or more substituents selected from halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, R ２ is, independently of one another, hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and is optionally further substituted with one or more substituents selected from halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, Or, any two Rs ２ combine to form C ３－８ a cycloalkyl group, a 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, and optionally, halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an oxo group, C １－６ an alkyl group, C １－６ a deuterated alkyl group, C １－６ a halogenated alkyl group, C １－６ a hydroxyalkyl group, C １－６ an alkoxy group, C １－６ a halogenated alkoxy group, C ２－６ an alkenyl group, C ２－６ an alkynyl group, C ３－８ a cycloalkyl group, a 3- to 8-membered heterocyclyl group, C ６－１０ is further substituted with one or more substituents selected from an aryl group and a 5- to 10-membered heteroaryl group, R ３ is, independently of one another, hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, carboxyl group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and is optionally further substituted with one or more substituents selected from halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, R ４ is, independently of one another, hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, carboxyl group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and is optionally further substituted with one or more substituents selected from halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, Or, any two Rs ４ combine to form C ３－８ a cycloalkyl group, a 3- to 8-membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, and the C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group are optionally further substituted with one or more substituents selected from halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, R ５ is selected from hydrogen, deuterium, halogen, amino group, nitro group, hydroxy group, cyano group, carboxyl group, oxo group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group or 5- to 10-membered heteroaryl group, and optionally further substituted with one or more substituents selected from halogen, amino group, nitro group, hydroxy group, cyano group, oxo group, carboxyl group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ hydroxyalkyl group, C １－６ alkoxy group, C １－６ halogenated alkoxy group, C １－６ cyanoalkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－８ cycloalkyl group, 3- to 8-membered heterocyclyl group, C ６－１０ aryl group and 5- to 10-membered heteroaryl group, and is further substituted with one or more of these substituents, M １ is O, S, N, NH, C, CH or (CH) ２ and M ２ is O, S, N, NH, C, CH or (CH) ２ and x is 0, 1, 2, 3, 4, or 5, y is 0, 1, 2, 3, or 4, z is 0, 1, 2, 3, or 4, p is 0, 1, 2, or 3, the compound, its stereoisomer, or its pharmaceutically acceptable salt according to Claim 3, characterized in that.

7. R １ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ alkoxy group or C １－６ halogenated alkoxy group, and is preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group or C １－３ halogenated alkoxy group, and more preferably hydrogen, deuterium, fluorine, chlorine, a cyano group or a methoxy group, R ２ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ alkoxy group or C １－６ halogenated alkoxy group, and is preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group or C １－３ halogenated alkoxy group, and more preferably is hydrogen, deuterium, fluorine, chlorine or a methyl group, R ３ is each independently selected from hydrogen, deuterium or fluorine, preferably hydrogen, R ４ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, a carboxyl group, C １－６ alkyl group, C １－６ deuterated alkyl group or C １－６ halogenated alkyl group, preferably a carboxyl group, R ５ is a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C １－６ hydroxyalkyl group, a C １－６ alkoxy group, a C １－６ halogenated alkoxy group, a C ３－８ cycloalkyl group, a 3- to 8-membered heterocyclyl group, a C ６－１０ aryl group or a 5- to 10-membered heteroaryl group, optionally substituted with one or more substituents selected from halogen, a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C １－６ hydroxyalkyl group, a C １－６ alkoxy group, a C １－６ halogenated alkoxy group, a C ３－８ cycloalkyl group or a 3- to 8-membered heterocyclyl group, and is preferably further substituted with one or more substituents selected from a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C ３－８ cycloalkyl group, a 3- to 8-membered heterocyclyl group, and is optionally further substituted with one or more substituents selected from halogen, a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C ３－８ cycloalkyl group or a 3- to 8-membered heterocyclyl group, and more preferably 【Chemical Formula 7】 wherein L １ 、 L ２ each independently represents a bond or - (CH ２ ), ｎ１ is selected from the group consisting of, preferably a bond L ３ is selected from a bond or -(CH ２ ) ｎ１ - and preferably is -CH ２ -. L ４ is selected from a bond or -(CH ２ ) ｎ７ -, preferably a bond or -CH ２ -, a compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that.

8. R １ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ alkoxy group, C １－６ deuterated alkoxy group or C １－６ halogenated alkoxy group, and is preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, and more preferably hydrogen, deuterium, fluorine, chlorine, a cyano group, -OCD ３ or a methoxy group, R ２ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, cyano group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group, C １－６ alkoxy group, C １－６ deuterated alkoxy group or C １－６ halogenated alkoxy group, preferably hydrogen, deuterium, fluorine, chlorine, cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, more preferably hydrogen, deuterium, fluorine, chlorine or methyl group, R ３ is independently selected from hydrogen, deuterium or fluorine, preferably hydrogen, R ４ is, independently of each other, hydrogen, deuterium, fluorine, chlorine, a cyano group, an oxo group, C １－６ carboxyl group, C １－６ alkyl group, C １－６ deuterated alkyl group, C １－６ halogenated alkyl group or a 5- to 6-membered heteroaryl group containing 1 to 4 atoms selected from N, O or S, and optionally, the C １－６ carboxyl group or a 5- to 6-membered heteroaryl group containing 1 to 4 atoms selected from N, O or S is further substituted with one or more substituents selected from oxo, halogen, cyano group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, and is preferably a carboxyl group or -C(O)OCH ３ and R ５ is selected from a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C １－６ hydroxyalkyl group, a C １－６ alkoxy group, a C １－６ halogenated alkoxy group, a C ３－８ cycloalkyl group, a 3- to 8-membered heterocyclyl group, a C ６－１０ aryl group or a 5- to 10-membered heteroaryl group, and optionally is further substituted with one or more substituents selected from halogen, a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ halogenated alkyl group, a C １－６ hydroxyalkyl group, a C １－６ alkoxy group, a C １－６ halogenated alkoxy group, a C １－６ cyanoalkyl group, a C ３－８ cycloalkyl group or one or more substituents of a 3- to 8-membered heterocyclyl group, and preferably is a C １－３ alkyl group, a C １－３ deuterated alkyl group, a C １－３ halogenated alkyl group, a C ３－６ cycloalkyl group, a 3- to 6-membered heterocyclyl group, and optionally is further substituted with one or more substituents selected from halogen, a C １－３ alkyl group, a C １－３ deuterated alkyl group, a C １－３ halogenated alkyl group, a C １－３ cyanoalkyl group, a C ３－６ cycloalkyl group or one or more substituents of a 3- to 6-membered heterocyclyl group, and more preferably is a C ３－６ cycloalkyl group or a 3- to 6-membered heterocyclyl group containing 1 to 2 atoms selected from N, O or S, and optionally is further substituted with one or more substituents selected from halogen, a C １－３ alkyl group, a C １－３ deuterated alkyl group, a C １－３ cyanoalkyl group or a C １－３ halogenated alkyl group, and even more preferably, 【Chemical 8】 wherein L １ 、L ２ each independently represents a bond or -(CH ２ ) ｎ１ - and is preferably a bond L ３ is selected from a bond or -(CH ２ ) ｎ１ -, preferably -CH ２ - and L ４ is selected from a bond or -(CH ２ ) ｎ７ -, preferably a bond or -CH ２ -, a compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that.

9. The compound is further as shown in general formula (III)-(III-1), 【Chemical Formula 9】 wherein, R ５ is selected from a C ３－８ cycloalkyl group or a 3- to 8-membered heterocyclyl group and is optionally further substituted with one or more substituents selected from halogen, a C １－６ alkyl group, a C １－６ deuterated alkyl group, a C １－６ cyanoalkyl group or a C １－６ halogenated alkyl group, M １ is O, S, N, C, CH or (CH) ２ and M ２ is O, S, N, C, CH or (CH) ２ and n7 is 0, 1, 2 or 3, x is 0, 1, 2, 3, 4 or 5, y is 0, 1, 2, 3 or 4, z is 0, 1, 2, 3 or 4, p is 0, 1, 2 or 3, and the compound according to claim 4, its stereoisomers or its pharmaceutically acceptable salts are characterized thereby.

10. R １ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, and is selected from the group consisting of: R ２ is, independently of one another, hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, and is selected from R ３ each independently selected from hydrogen, deuterium or fluorine, R ４ is independently selected from 5- to 6-membered heteroaryl groups containing 1 to 4 atoms selected from N, O or S, and is further substituted with one or more substituents selected from oxo, halogen, cyano group, C １－３ alkyl group and C １－３ halogenated alkyl group, and is —(CH ２ ) ｎ COOH or —(CH ２ ) ｎ C(O)OCH ３ wherein R ５ is selected from a C ３－６ cycloalkyl group or a 3- to 6-membered heterocyclyl group containing one or two atoms selected from N, O or S, and optionally further substituted with one or more substituents selected from halogen, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ cyanoalkyl group or C １－３ halogenated alkyl group, M １ and M ２ are each independently selected from N, CH or (CH) ２ and n is 0, 1, 2 or 3, and the compound according to claim 4, its stereoisomers or its pharmaceutically acceptable salts are characterized thereby.

11. The compound is further as shown in general formula (V-1) or general formula (V-2), 【Chemical Formula 10】 wherein, R １ is each independently selected from hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, and is preferably hydrogen, deuterium, fluorine, chlorine, a methoxy group or -OCD ３ and R ２ is, independently of one another, preferably hydrogen, deuterium, fluorine, chlorine, cyano group, C １－３ alkyl group, C １－３ deuterated alkyl group, C １－３ halogenated alkyl group, C １－３ alkoxy group, C １－３ deuterated alkoxy group or C １－３ halogenated alkoxy group, and is preferably hydrogen, deuterium, fluorine, chlorine or methyl group, R ３ is independently selected from hydrogen, deuterium or fluorine, preferably hydrogen, M １ is N or CH, preferably N, W ２ is N or CH, preferably CH, x, y and z are each independently 0, 1 or 2, R ５ is 【Chemical 11】 selected from, preferably, 【Chemical 12】 and the compound according to claim 4, its stereoisomers or its pharmaceutically acceptable salts are characterized thereby.

12. The following compound, its stereoisomers or its pharmaceutically acceptable salts, wherein the structure of the compound is as follows, 【Chemical Formula 13】 【Chemical 14】 【Chemical Formula 15】 【Chemical Formula 16】 【Chemical 17】 【Chemical 18】 【Chemical 19】 the compound, its stereoisomers or its pharmaceutically acceptable salts.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1 to 12, and one or more pharmaceutically acceptable carriers or excipients.

14. Use of the compound, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1 to 12 in the manufacture of a GLP-1 receptor agonist pharmaceutical.

15. Use of the compound, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1 to 12 in the manufacture of a pharmaceutical for treating a metabolic-related disease, preferably, the metabolic-related disease is selected from diabetes, obesity or non-alcoholic fatty liver disease-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic fatty liver.

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